Asymmetric Organocatalyzed Aza-Henry Reaction of Hydrazones: Experimental and Computational Studies

Article abstract of DOI:10.1002/chem.202000232

The first asymmetric catalyzed aza-Henry reaction of hydrazones is presented. In this process, quinine was used as the catalyst to synthesize different alkyl substituted β-nitrohydrazides with ee up to 77 %. This ee was improved up to 94 % by a further recrystallization and the opposite enantiomer can be obtained by using quinidine as the catalyst, opening exciting possibilities in fields in which the control of chirality is vital, such as the pharmaceutical industry. Additionally, experimental and ab initio studies were performed to understand the reaction mechanism. The experimental results revealed an unexpected secondary kinetic isotope effect (KIE) that is explained by the calculated reaction pathway, which shows that the protonation of the initial hydrazone and the C?C bond forming reaction occur during a concerted process. This concerted mechanism makes the catalysis conceptually different to traditional base-promoted Henry and aza-Henry reactions.

Full text of DOI:10.1002/chem.202000232

A Journal of
Accepted Article
Title: Asymmetric organocatalyzed aza-Henry reaction of hydrazones:
experimental and computational studies
Authors: Raquel Perez Herrera, Isaac G. Sonsona, Juan V. Alegre-
Requena, Eugenia Marqués-López, and M. Concepcion
Gimeno
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To be cited as: Chem. Eur. J. 10.1002/chem.202000232
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Asymmetric organocatalyzed aza-Henry reaction of hydrazones:
experimental and computational studies
Isaac G. Sonsona,[a] Juan V. Alegre-Requena,*[a] Eugenia Marqués-López,[a] M. Concepción Gimeno[b]
and Raquel P. Herrera*[a]
Dedication ((optional))
Abstract: The first asymmetric catalyzed aza-Henry reaction of
hydrazones is presented. In this process, quinine was used as the
catalyst to synthesize different alkyl substituted β-nitrohydrazides
with ee up to 77%. This ee was improved up to 94% by a further
recrystallization and the opposite enantiomer can be obtained using
quinidine as catalyst, opening exciting possibilities in fields where
the control of chirality is vital, such as the pharmaceutical industry.
Additionally, experimental and ab initio studies were performed to
understand the reaction mechanism. The experimental results
revealed an unexpected secondary kinetic isotope effect (KIE) that is
explained by the calculated reaction pathway, which shows that the
protonation of the initial hydrazone and the C-C bond forming
acylhydrazones in Mannich reactions could be valuable
medicinal targets due to the pharmacological activity that
compounds bearing a hydrazide core exhibit (Scheme 1C).[3] To
the best of our knowledge, the use of N-acylhydrazones in an
asymmetric nitro-Mannich reaction has been overlooked in the
literature so far. Instead, in catalysis, β-nitroalkylhydrazides have
been only synthesized as racemic mixtures by addition of
hydrazides to nitroalkene derivatives (aza-Michael reaction).[4]
Since it is known that different enantiomers could exhibit
different biological properties, the design of new efficient
synthetic methods for the production of enantiomerically
enriched β-nitroalkylhydrazides is highly desirable.[5] We have
pioneered the first asymmetric organocatalyzed aza-Michael
protocol to synthesize chiral β-nitroalkylhydrazides.[6] In this
reaction, a bifunctional thiourea was employed as the catalyst,
affording good stereoselectivity when aryl substituted β-
nitroalkenes are used as the initial reagents. However, this
process is not efficient to generate alkyl substituted β-
nitrohydrazides from β-nitroalkenes (Scheme 1A) and, currently,
there is not any efficient catalytic methodology to produce this
type of compounds asymmetrically.[7] This lack of precedents
motivated us to develop, for the first time, an organocatalytic
process to generate enantioenriched alkyl-substituted β-
nitrohydrazides. Hence, in this work, we did not follow the chiral
synthetic strategies based on aza-Michael transformations used
previously.[6] Instead, we have designed a conceptually different
protocol starting from N-acylhydrazones (Scheme 1B).
reaction occur during
a concerted process. This concerted
mechanism makes the catalysis conceptually different to traditional
base-promoted Henry and aza-Henry reactions.
Introduction
The nucleophilic enantioselective addition of nitroalkanes to
imines (asymmetric aza-Henry or nitro-Mannich reaction) is an
efficient C-C bond forming transformation, useful to create chiral
synthetic building blocks containing two versatile functional
groups: a nitro and an amino groups.[1] To carry out this
synthetic strategy, several N-protected imines have been
prepared and incorporated in a great number of methodologies,
including both metal-based and metal-free (organocatalysis)
catalytic approaches.[1]
N-Acylhydrazones are considered stable and storable synthetic
imine surrogates, which can be easily prepared by condensation
of N-acylhydrazines with a broad spectrum of aldehydes and
ketones.[2] In addition, the resulting products using N-
[a]
Dr. I. G. Sonsona, Dr. J. V. Alegre-Requena, Dr. E. Marqués-López,
Prof. Dr. R. P. Herrera
Laboratorio de Organocatálisis Asimétrica. Departamento de
Química Orgánica
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH)
CSIC-Universidad de Zaragoza
C/ Pedro Cerbuna, No. 12. E-50009 Zaragoza, Spain
E-mail: raquelph@unizar.es
[b]
Prof. Dr. M. Concepción Gimeno
Departamento de Química Inorgánica
Instituto de Síntesis Química y Catálisis Homogénea (ISQCH)
CSIC-Universidad de Zaragoza
C/ Pedro Cerbuna, No. 12. E-50009 Zaragoza, Spain
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Results and Discussion
Based on our own experience in the aza-Henry reaction,[8]
we envisioned that, in the presence of a chiral basic
organocatalyst, nitroalkanes and N-acylhydrazones could
react to give the desired β-nitroalkylhydrazides. Cinchona
alkaloids, which have been extensively employed in
organocatalysis,[9] are interesting candidates as catalysts in
this process.[10] These chiral natural compounds present
some advantages such as low cost and easy
functionalization through their hydroxyl substituents.[11]
Moreover, we hypothesized that their basic quinuclidine
group could contribute to activate the nucleophilic
nitroalkane molecule and, at the same time, the chiral
structure of this type of catalyst might provide an optimum
environment for stereoselective induction. Additionally, the
OH group could simultaneously contribute to activate the N-
acylhydrazone electrophile, since these substrates present
different hydrogen bond acceptor sites in their structures
that have been previously activated by Lewis acids.[2,12] This
plausible bifunctional activation mode could afford good
reactivities as well as the adequate transference of chirality
from the catalyst to the substrates.
In order to find the best organocatalytic system, the activity of
several cinchona-based catalysts (3a-d,g-i), as well as other
bifunctional basic (3e,f) and acid (3j,k) organocatalysts, was
tested in the model reaction depicted in Scheme 2.
Scheme 1. Asymmetric organocatalyzed approaches for the enantioselective
synthesis of β-nitroalkylhydrazides.
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Scheme 2. Catalysts tested in the asymmetric addition of nitromethane (2a) to N-acylhydrazone 1a. DCM = dichloromethane; n.r. = no reaction; n.d. = not
determined; rac. = racemic mixture; r.t. = room temperature.
Based on the results shown in Scheme 2, the best
enantioselectivity (52% ee) was achieved with acid catalyst
The results of this study showed better enantioselectivity and
reactivity values for hydrazones bearing electron-withdrawing
groups in their phenyl rings (1a-d, Scheme S1). With the aim of
improving the reactivity and selectivity provided by catalyst 3a,
different parameters of this reaction were studied, such as
solvent, catalyst loading and concentration (Table S2).
Remarkably, the best reaction conditions were found when using
30 mol% of 3a and CH3NO2 (1 mL) at room temperature (entry
20, Table S2), which led to final product 4aa with an
unprecedented result of selectivity for this compound (40% ee,
57% yield). To study the applicability of this process, the scope
using different N-acylhydrazones 1a,g-n and nitroalkanes 2a,b
was explored (Table 1).
3j
.
However, this improvement of selectivity was
accompanied by a very low yield (5% yield). Additionally,
cinchonine (3b) and epi-cinchonidine derived squaramide
3d achieved low enantiomeric excesses (22% and 18% ee,
respectively). To our delight, cheap quinine alkaloid (3a
)
showed a promising value of enantioselectivity (34% ee) as
well as the best reactivity among the catalysts tested (22%
yield). Therefore, catalyst 3a was further explored using
different hydrazones 1a-f under the same reaction
conditions (Scheme S1).
Table 1. Scope of the asymmetric catalyzed aza-Henry reaction of hydrazones 1.[a]
Entry
1
Alkyl N-acylhydrazone 1
1a R1: 4-NO2Ph
1g R1: 4-NO2Ph
1h R1: 4-ClPh
Nitroalkane 2
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2a R3: H
2b R3: Me
2b R3: Me
2b R3: Me
2b R3: Me
2b R3: Me
Product
4aa
4ga
4ha
4ia
Yield (%)[b]
57
d.r.[c]
ee (%)[d]
40
R2: i-Pr
˗
2
R2: Me
91
˗
42
3
R2: Me
55
˗
37
4
1i R1: 4-BrPh
R2: Me
24
˗
39
5
1j R1: 4-NO2Ph
1k R1: 4-NO2Ph
1l R1: 4-NO2Ph
1m R1: 4-NO2Ph
1n R1: 4-NO2Ph
1g R1: 4-NO2Ph
1n R1: 4-NO2Ph
1g R1: 4-NO2Ph
1n R1: 4-NO2Ph
1g R1: 4-NO2Ph
1j R1: 4-NO2Ph
1k R1: 4-NO2Ph
1l R1: 4-NO2Ph
1n R1: 4-NO2Ph
R2: Et
4ja
79
˗
39
6
R2: n-Hex
R2: i-Bu
4ka
4la
79
˗
39
7
83
˗
40
8
R2: -(CH2)-Ph
R2: -(CH2)2-Ph
R2: Me
4ma
4na
4ga
4na
4ga
4na
4gb
4jb
74
˗
43
9
80
˗
41
10[e]
11[e]
12[f]
13[f]
14[g]
15[g]
16[g]
17[g]
79
˗
45
R2: -(CH2)2-Ph
R2: Me
32
˗
51
44
˗
56 (94)[h]
56
R2: -(CH2)2-Ph
R2: Me
18
˗
65
1.4:1
1.7:1
2.2:1
2.4:1
1.7:1
54[i]
50[i]
72[i]
77[i]
73[i]
R2: Et
40
R2: n-Hex
R2: i-Bu
4kb
4lb
27
25
18[g]
R2: -(CH2)2-Ph
4nb
41
[a]
Nitroalkane 2 (1 mL) is added to a mixture of N-acylhydrazone 1 (0.1 mmol) and catalyst 3a (0.03 mmol). The reaction mixture is stirred at the indicated
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[b]
[d]
temperature during the corresponding reaction time. After isolation of product by column chromatography. [c] Determined by NMR from the reaction mixture.
Determined by chiral HPLC analysis (see experimental section). ee after recrystallization is shown between brackets. [e] Reaction carried out at 10 °C for 4 days. [f]
Reaction carried out at -20 °C for 5 days, employing a mixture of nitromethane (2a):CHCl3 8:2 as solvent. [g] Reaction carried out at -20 °C during 7 days. [h] The
reaction was carried out on higher scale (0.5 mmol of 1g) and the product isolated by column chromatography was recrystallized in a mixture of ethyl
acetate/diethyl ether 1:3, affording 4ga with 94% ee. [i] Enantiomeric excess provided for the major diastereomer.
In general, the products obtained showed similar enantiomeric
excesses for all alkyl substituted hydrazones tested at room
temperature (Table 1, entries 1-9). Moreover, we observed that
the size of substituent R2 influences the reactivity of this process
in a great extent (entries 1, 2 and 5). Electronic effects of the
substituents in the benzoyl group also play an important role in
the reaction and affect the reactivity of the process. As
envisioned, the presence of electron-withdrawing groups in the
aromatic ring of the hydrazone could accelerate the reaction,
obtaining the best yield in case of the nitro group (entries 2-4).
Carrying out the reaction at lower temperature (20 °C) affords
better results of selectivity but, as expected, lower yields are
obtained (entries 2 and 9 versus 12 and 13, respectively).
Remarkably, when employing a mixture of 2a:CHCl3 8:2 as the
solvent, 2a reacts with hydrazone 1g at 20 °C to produce 4ga
with a moderate yield (44%), showing an appreciable increase of
selectivity (entries 2 ,10, and 12). To our delight, we increased
Figure 1. X-ray crystal structure of (S)-4ga (obtained using 3a as catalyst) and
(R)-4ga (obtained using 3l instead of 3a).
the ee of 4ga to 94% by recrystallization using a mixture of ethyl
acetate:diethyl ether 8:2 as solvent (entry 12), which opens new
doors to improve the stereocontrol of this reaction in a great
extent. Finally, the use of nitroethane (2b) afforded moderate to
good results of enantioselectivity at 20 °C (entries 14-18, 50-
Mechanistic studies
77% ee). Unfortunately, aryl N-substituted hydrazones did not
react under these reaction conditions, even when very electron
withdrawing aryl groups were employed, which is most likely due
Experimental reaction orders and kinetic isotope effects
(KIE) of the reaction
to the high insolubility of these compounds in MeNO2, CH2Cl2
We studied the mechanism of this asymmetric addition of
and CHCl3 (Table S3).
nitroalkanes 2 to hydrazones 1 using kinetic experiments as well
as density functional theory (DFT) calculations. Most of the
previously reported Henry reactions of aldehydes and aldimines
In order to know the absolute configuration of our products,
single crystals were grown from adduct 4ga (94% ee) using a
mixture of ethyl acetate:toluene 1:1 as solvent. The absolute
catalyzed by chiral Brønsted bases commonly involve three
configuration of this product is S when using 3a as catalyst
reactions steps (Scheme 3).[1,14] In the first step, the catalyst
(Figure 1).[13] We assume the same absolute configuration for all
deprotonates the nitroalkane substrate, leading to the formation
final products. Following an identical procedure, a pure crystal of
of the corresponding nitronate anion (Scheme 3A). In the
adduct (R)-4ga was obtained using quinidine (3e) as catalyst,
proving that we could easily tune the absolute configuration of
the generated chiral center.
second step, the nitronate anion from substrate-catalyst complex
5 attacks to the sp2 pro-chiral center of the electrophile under
stereoselective control (Scheme 3B). This step usually
determines the reactivity and selectivity of the process. Finally,
the resulting intermediate is protonated in a subsequent step to
form the enantioenriched product and the catalyst is regenerated.
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(secondary KIE) was observed using CH3NO2 and CD3NO2
(Table 2, entries 1 and 4). This value is difficult to rationalize
based on the previous studies mentioned in Scheme 3, since the
RLS of these studies was proposed to be the nitronate attack to
the carbonyl or imine group, which would lead to an inverse
secondary 2H KIE (kH/kD
deprotonation of 2a was the RLS, a primary H KIE (kH/kD > 2)
would be expected and, therefore, we can also rule out this
possibility.[17a,b]
<
1).[17c,d] Also, if the initial
2
All the results obtained from these initial kinetic studies suggest
that (i) the order of reaction of hydrazones 1 and catalyst 3a is
one and, therefore, one molecule of both species is participating
in the RLS, (ii) the reaction follows a different reaction
mechanism compared to previous Henry and aza-Henry
reactions due to the distinct KIE value observed, and (iii) the
RLS does not correspond to the initial step of deprotonation of
nitroalkane 2a. This information is crucial to generate a reliable
computational model and will help to evaluate the theoretical
outcomes.
Scheme 3. Previously reported mechanisms of the Henry reaction with
aldehydes and imines promoted by chiral basic catalysts. (A) Formation of the
nitronate anion. (B) Attack of the nitronate anion to the electrophilic aldehyde
or aldimine with the subsequent protonation step.
Computational study of the mechanism
In a preliminary kinetic study, the concentration of hydrazone 1
over time was monitored by H-NMR spectroscopy at 22.5 ºC.
1
In order to understand which are the steps and interactions that
influence the kinetics and thermodynamic parameters of this
process, we carried out a mechanistic computational study using
the addition of 2a to hydrazone 1g as the model reaction. In the
analysis, a significant number of conformations for the catalyst
and substrates interacting through different functional groups
were considered (42 in total). From all the possible isomers, 13
possible transition states (TSs) were found for the S enantiomer
(see the ESI for more information). The structures observed in
the most favorable TS-I systems indicate that electrophile 1g
interacts with the protonated quinuclidine group of the quinine
catalyst before the nucleophilic attack of the nitronate takes
place (Figure 2A). This model has been suggested previously by
Houk and coworkers for other chemical transformations
catalyzed by cinchona alkaloids,[18b] and a mechanism with
similar interaction mode has been proposed by Paton and
coworkers in the Henry reaction of aldehydes catalyzed by chiral
phosphazenes.[18a] In contrast, all TS-I steps in which the
electrophile is interacting with the OH group of the catalyst show
considerably higher energies (Figure 2B).[19]
We studied the addition of CD3NO2 (2a) to N-acylhydrazone 1h
because this homogeneous reaction presents signals that are
1
easy to track using H-NMR techniques (Figure S71).[15] Since
the concentration of CD3NO2 barely changes during the reaction,
this is a pseudo-first order process. The concentration profile of
substrate 1h in the reaction medium (CD3NO2/CDCl3 3:2)
(Figure S69), as well as the outcomes of initial rate method
experiments (Figure S70, Table 2, entries 1 and 3), suggested
that the hydrazone has a reaction order of one. Furthermore, the
reaction order of catalyst 3a was determined to be one by the
initial rate method (Table 2, entries 1 and 2).[16] Therefore, these
results suggest that there are one molecule of catalyst and one
of hydrazone involved in the rate-limiting step/s (RLS) of the
reaction.
Table 2. Initial rates study in the asymmetric addition of deuterated
nitromethane to hydrazone 1h.
Entry
[1h]o
(mol·L-1)
0.10
0.10
0.05
[3a]o
Initial rate
Relative
initial rate
1.00
1.96
0.47
(mol·L-1)
0.03
(10-7 mol·L-1·s-1)
3.80 ± 0.06
7.46 ± 0.04
1.80 ± 0.07
4.97 ± 0.03
1
2
0.06
0.03
0.03
3
4[b]
0.10
1.31
[a]
To
a solution of hydrazone 1h, catalyst 3a, and mesitylene (internal
standard, 0.05 mmol) in 200 µL of CDCl3 at 22.5 ºC, 300 µL of deuterated
nitromethane was added. The concentration of reagent 1h vs time is
[b]
monitored by 1H-NMR spectroscopy.
The reaction is carried out using
nitromethane (2a, CH3NO2) instead of deuterated nitromethane (CD3NO2).
Figure 2. General different binding modes between quinine and the substrates
of the reaction, along with the calculated relative G (Grel, in kcal·mol1) of
individual conformers of TS-I for each type of binding mode. Ar = 4-NO2Ph.
In order to gather more valuable mechanistic information, kinetic
isotope effects (KIE) were also measured. For the model
reaction previously employed,
a
2H KIE (kH/kD) of 1.31
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The reaction pathway leading to the enantiomer obtained
entries 1 and 4). Assuming that the initial deprotonation of
CH3NO2 is a fast process and does not significantly affect the
overall 2H KIE, the calculated 2H KIE corresponds to that of TS-I
and it is 1.65 for the most stable conformer (Figure S75), which
is similar to the experimental value. This secondary KIE value
suggests that the mechanism is concerted, averaging the
mismatching KIE effects of the C-C bond formation (associated
with secondary inverse KIEs)[17c] and the protonation of the imine
group (causing a primary KIE). It is worth to mention that the
catalyst plays an important role in the kinetics of the reaction,
since it considerably stabilizes the nitronate nucleophile (2a)
compared to the uncatalyzed 2a:CH2NO2H tautomeric
equilibrium (Figure 3A, red versus black lines).
experimentally
(S)
was
studied,
including
the
substrates···catalyst (Int-I) and product···catalyst (Int-II)
complexes formed before and after the C-C bond forming
reaction (Figure 3A). Based on the calculated reaction profile,
the protonation of the C=N group and the C-C bond forming
reaction occur at the same time in a concerted TS (TS-I, Figure
3B). Intrinsic reaction coordinate (IRC)[20] calculations and
relaxed potential energy surface scans suggest that there might
be a stable intermediate between Int-I and TS-I corresponding
to the protonation of hydrazone 1g before the C-C bond is
created (Figure S73). However, this intermediate is found as a
stable intermediate only in some conformational pathways while
it represents a hidden intermediate[21] in the others. This
concerted process is analogous to the basic phosphazene-
catalyzed Henry reaction previously reported by Paton and
coworkers.[18a] Remarkably, the calculated mechanism might
2
explain the unusual secondary H KIE of 1.31 for an aza-Henry
reaction observed in the experimental initial rates study (Table 2,
Figure 3. (A) Reaction pathway and energy profile (in kcal·mol1) of the reaction between nitromethane and hydrazone 1g. Distances are indicated in Å.
Boltzmann weighted Gibbs free energies (G) were calculated using ωB97X-D/Def2-QZVPP//ωB97X-D/6–311G(d) (SMD = CH3NO2, T = 20 °C).[22] Quasi-
harmonic and concentration corrections were applied to G using GoodVibes,[23] assuming concentrations of 1.00 M for 1g, 3a, 4ga, CH2=NO2H, intermediates and
TSs, and 22.64 M for CH3NO2 (solvent). Ar1 = 4-NO2Ph, Ar2 = 6-methoxyquinoline. (B) Representation of the most stable conformer found in TS-I. Bonds involved
in the transition states are represented with yellow lines. The 4-NO2PhCO group of 1g is omitted to allow for a better visualization. (C) Concentration profiles of 1g
and (S)-4ga obtained with kinetic simulations (using Berkeley Madonna, see section Berkeley Madonna kinetic simulations in the ESI).[24] ΔG‡simul = energy of TS-I
used in the simulation in kcal·mol1. The two circles represent the experimental yields obtained at 20 and 20 °C.
As expected, the calculated reaction is exergonic by 0.9
kcal·mol-1 (Figure 3A). Experimentally, we found that this
reaction is kinetically controlled since the retro-Henry reaction
was very slow under the conditions employed (Table S4). This is
consistent with the calculated profile since the energy barrier of
the reverse reaction (from Int-II to TS-I) is 2.7 kcal·mol-1 higher
than that of the forward reaction. Therefore, in this Curtin-
Hammett scenario,[25] the reaction profile shown in Figure 3A
suggests that the rate- and stereo-determining step is TS-I,
since it is the step that contains the chiral information with
highest energy.[26] Further kinetic simulations suggest that the
calculated energy profile reproduces significantly well the
reactivity observed experimentally at different temperatures
(Table 1, entries 2 and 12), since concentration profiles identical
to the experimental results (91% yield over three days and 44%
yield over five days, at 20 °C and 20 °C, respectively,
represented with circles in Figure 3C) are obtained just by
slightly adjusting the G of TS-I from 22.6 to 23.1 and 21.0
kcal·mol-1 (Figure 3C).
Studies regarding the origin of enantioselectivity, based on the
differences between the most stable TS-I conformers leading to
each enantiomer, are very useful in the design of more efficient
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311G(d);
ωB97X-D/6–311++G(d,p);
D3(BJ)/Def2-QZVPP//B3LYP-D3(BJ)/6–311G(d).
D
=
B3LYP-D3(BJ)/Def2-QZVPP//ωB97X-D/6–311G(d);
B3LYP-D3(BJ)/6–311G(d); B3LYP-
Solvent used in
E =
catalysts. Unfortunately, in this case, such a comprehensive
study does not proceed because the computational study leads
to the opposite enantiomer (R) compared to experimental
findings.
F
=
G =
[b]
geometry optimizations and single-point corrections. [c] Calculated using the
ee obtained from Boltzmann probabilities of 14 different TS-I conformers
(seven for each enantiomer), see Tables S6 and S8 for more information.
Thus, even though the orders of reaction, KIE, thermodynamic
parameters and kinetic profile of the model reaction (using 1g)
match considerably well the experimental data, the absolute
configuration observed experimentally (S) could not be captured
when using different relatively high DFT levels of theory (Table 3,
entries 1-7, and Table S6). The calculated ΔΔG‡ values differed
depending on the level of theory employed ranging from 0.6 to
1.9 kcal·mol1 or 47% to 92% ee. It is worth to mention that (i)
we used different solvents to account for potential sources of
error from the solvation model based on density (SMD), and (ii)
changing the solvent from CH3NO2 to CH2Cl2 does not
practically influence the experimental ee (from 34% to 40% ee
when using 1a and 2a at r.t., Scheme 2 and Table 1, entry 1). A
more extreme example of misleading selectivity predictions is
observed when using 1o (hydrazone with a tBu substituent,
which has not been considered experimentally), instead of 1g.[27]
In this case, the uncertainty of DFT methods leads to the
prediction of different absolute configurations depending on the
method employed (Table 3, entries 8-11, and Table S8). In this
example, the ΔΔG‡ values also changed depending on the DFT
protocol employed (from 0.8 to 1.2 kcal·mol1). Although the
total variation range is only 0.7 kcal·mol1 broader than the
previous case (1.3 versus 2.0 kcal·mol1 of variation between
DFT methods), this time the results lead to predicted ee values
that range from 60% of the R to 77% of the S enantiomer (Table
3, entries 8 and 10, respectively). This study clearly shows that
the DFT techniques employed are not suitable to predict
enantioselectivity and absolute configuration for this substrate
even though the variation range for ΔΔG‡ calculations are inside
reasonable values for this relatively high-demanding DFT
protocols (triple-zeta and quadruple-zeta basis sets with and
without diffuse functions, as well as functionals that include
dispersion corrections).
The prediction of misleading enantioselectivity values and
absolute configurations is not surprising since (i) the ee of the
model reaction ranges from 42% (at 20 °C, r.t.) to 56% (at
20 °C), which represents ΔΔG‡ values of only 0.52 and 0.64
kcal·mol-1, respectively, and (ii) the stereo-controlling step
contains a considerable high number of possible conformers,
which adds multiple potential error sources to the results (i.e.
missing conformers after the conformational search, individual
errors of each conformer, etc.). In fact, errors ranging from two
to four kcal·mol-1 (or even larger) are not uncommon when
measuring ΔΔG‡ with DFT in other relatively complex systems.
A good example to show the limitations of enantioselectivity
calculations with DFT is the dioxirane-catalyzed epoxidations
studied by Breslow, Friesner and coworkers.[28a] In Table S1 of
their ESI, there are many examples in which the error of the
calculated ΔΔG‡ is larger than two or three kcal·mol-1, which led
to the prediction of wrong absolute configurations.[28b] Therefore,
the erroneous DFT results observed when predicting absolute
configurations in this work could serve as an example that
enantioselectivity prediction is not very precise in some complex
systems with low or moderate ee. In many cases when studying
relatively complex molecular systems, the right absolute
configuration might be obtained for the wrong reasons (i.e. since
there are only two possible outcomes, S and R, “randomly
predicted” ee values have a 50% probability to lead to the right
configuration). The results of this study strongly stress the
necessity of comparing computational predictions with
experimental data when calculating ee and absolute
configurations.
Considering all the kinetic experimental and computational
results, a plausible catalytic cycle is proposed for this reaction
(Scheme 4). Initially, catalyst 3a deprotonates the nitromethane
(2a) through its basic quinuclidine group, leading to the nitronate
anion···catalyst complex [3a-H+···2a]. Subsequently, hydrazone
1 interacts with [3a-H+···2a] to make a new complex including
the three reaction components (Int-I). Once this ternary complex
is formed, the hydrazone molecule is protonated by the N-H+
group of the catalyst at the same time as the C-C bond
formation takes place between 1 and the nitronate anion (TS-I).
As a consequence of the bifunctional activation of both
substrates by catalyst 3a,[29] the nitronate anion attacks
hydrazone 1, leading to a (S)-product···catalyst complex (Int-II).
In the last step, a molecule of nitromethane (2a) replaces
product 4 in the product···catalyst complex, which regenerates
the catalyst and starts a new catalytic cycle.
Table 3. Enantioselectivity prediction using different DFT methods, solvents
and substrates at 20 °C.
DFT
ΔΔG‡
(kcal·mol-1)[c]
1.8
1.2
1.7
0.7
1.9
1.3
0.6
0.8
0.4
1.2
1.1
Entry
Hydrazone
Solvent[b]
ee (%)[c]
Method[a]
1
2
3
4
5
6
7
8
9
10
1g
1g
1g
1g
1g
1g
1g
1o
1o
1o
1o
A
B
C
D
E
F
G
A
B
F
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH2Cl2
92 (R)
77 (R)
90 (R)
53 (R)
92 (R)
80 (R)
47 (R)
60 (R)
32 (R)
77 (S)
CH2Cl2
CH3NO2
CH3NO2
CH2Cl2
11
G
CH2Cl2
73 (S)
[a]
DFT methods:
A = ωB97X-D/6–311G(d); B = ωB97X-D/Def2-
QZVPP//ωB97X-D/6–311G(d); C = M06-2X-D3/Def2-QZVPP//ωB97X-D/6–
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10.1002/chem.202000232
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Experimental Section
General information.
All commercially available solvents and reagents were used as received
without further purification. Thin layer chromatography (TLC) analyses
were carried out using aluminum sheets recoated with silica gel (60 F254
,
Merk) and fluorescent-indicator. The spots of compounds were visualized
by UV light at 254 nm. The column chromatography purification of
products was performed using silica gel (0.06-0.2 nm, Sigma) as
stationary phase and a mixture of n-hexane/ethyl acetate as eluent. The
corresponding 1H-NMR and 13C-NMR spectra of starting materials and
products were recorded at 300 MHz (Bruker ARX-300) or 400 MHz
(Bruker AV400) using deuterated DMSO as solvent. Chemical shifts are
provided in the δ scale relative to residual DMSO (2.50 ppm) for 1H-NMR
spectra and to the central line of DMSO-d6 (39.43 ppm) for 13C-NMR
(APT) spectra. Chiral HPLC analysis was performed in a Waters 600
equipment with Daicel Chiralpak IA and IC columns, employing mixtures
of n-hexane/ethyl acetate and n-hexane/tetrahydrofuran as eluent. The
specific rotation of products was recorded in CHCl3 or acetone using a
Jasco P-1020 polarimeter. Melting point determination was carried out in
a Gallenkamp MPD 350 BM 2.5 apparatus. Infrared spectra of starting
materials and products were recorded by employment of attenuated total
reflection infrared (ATR-IR) equipment (PerkinElmer Spectrum 100 FT-
IR). The HRMS analysis was performed using a Q-TOF analyzer and ESI
as ionization method (Bruker MicroTof-Q equipment). The synthesis of N-
acylhydrazones 1a,[30,31] 1e,[30,31] 1f,[30] 1l,[30,31] and 1n,[30] as well as
catalysts 3c[32] and 3d,[33] was reached following the protocols described
in literature. The spectroscopic data obtained of alkyl substituted N-
acylhydrazones 1a,[30,31] 1e,[30,31] 1f,[30] 1l,[30,31] and 1n,[30] catalysts 3c[32]
and 3d,[34] and hydrazide derivative 4na[6] are consistent with the values
previously reported in literature. DFT calculations were performed by
using Gaussian 16;[22a] kinetic simulations to obtain concentration profiles
were carried out with Berkeley Madonna.[24]
Scheme 4. Proposed catalytic cycle for the asymmetric organocatalyzed
addition of nitromethane 2a to hydrazones 1.
Conclusions
In this work, the first asymmetric catalytic aza-Henry reaction
using hydrazones is reported. This process has proven to be an
efficient method to synthesize alkyl substituted β-nitroalkyl
hydrazide derivatives with ee up to 77%, which can increase up
to 94% after recrystallization. Considering that the maximum
value of ee achieved previously was 28%,[6] this new asymmetric
protocol might help to generalize the use of these compounds in
different fields where using chiral compounds is crucial, such as
the pharmaceutical industry. Among the different catalysts
tested, the best results were obtained with quinine, which makes
this synthetic protocol more appealing since this type of catalyst
is relatively cheap and commercially available. Moreover, the
use of quinidine let us to obtain the opposite enantiomer, which
could be interesting in order to study distinct biological activity of
each enantiomer.
Experimental and kinetic studies were carried out in order to
gain insight into the reaction mechanism. Interestingly, the
results revealed that in the transition state of the enantio-
determining and rate-limiting step of the reaction, the hydrazone
electrophile is protonated by the catalyst at the same time as the
C-C bond forms. This leads to an unexpected experimental and
computational secondary KIE. In this step, the catalyst is
activating both substrates in a bifunctional fashion, leading to the
stereo-controlled attack of nitronate anions to hydrazones 1.
This work represents an interesting example about the
difficulties of computational calculations for estimating small free
energy differences.
Synthesis of alkyl substituted N-acyl hydrazones 1.
(E)-N´-(2-Ethylidene)-4-nitrobenzohydrazide (1g)
An excess of acetaldehyde (2.0 mL, 35.8 mmol) is added to a solution of
4-nitrobenzoic acid hydrazide (2.59 g, 14.0 mmol) in dichloromethane (40
mL). The reaction mixture is stirred during one day at room temperature.
After this time, the solvent is evaporated, and the residue is recrystallized
in ethanol to afford 1.60 g of pale yellow solid (55% yield). The starting
material 1g is obtained as a mixture of isomers (E)/(Z) 90:10. M.p. 197-
199 °C. IR (cm-1) 3260 (N-H), 3080, 1651 (C=O), 1599, 1554 (N-H), 1518
(NO2), 1487, 1380, 1340 (NO2), 1302, 1281, 868, 843, 718. 1H-NMR (400
MHz, DMSO-d6) δ 1.95 (d, J = 7.2 Hz, 3H, RCH3), 7.77 (q, J = 7.2 Hz, 1H,
N=CHR), 8.08 (d, J = 11.6 Hz, 2H, Ar-H), 8.34 (d, J = 11.6 Hz, 2H, Ar-H),
11.72 (s, 1H, N-H). 13C-NMR (100.6 MHz, DMSO-d6) δ 18.4 (CH3), 123.5
(2 x CAr-H), 129.0 (2 x CAr-H), 139.3 (CAr), 149.1 (CAr), 149.8 (N=CHR),
161.0 (C=O). HRMS (ESI+) calcd for [NaC9H9N3O3]+ 230.0536; found
230.0534 [M + Na]+.
(E)-N´-(2-Ethylidene)-4-chlorobenzohydrazide (1h)
An excess of acetaldehyde (0.85 mL, 15.1 mmol) is added to a solution
of 4-chlorobenzoic acid hydrazide (0.87 g, 5.0 mmol) in dichloromethane
(5 mL). The reaction mixture is stirred during one day at room
temperature. After this time, the solvent is evaporated and the residue is
recrystallized in ethanol to afford 0.42 g of a white solid (42% yield). The
starting material 1h is obtained as a mixture of isomers (E)/(Z) 93:7. M.p.
180-182 °C. IR (cm-1) 3204 (N-H), 3061, 2914, 1647 (C=O), 1621, 1594,
1
1546 (N-H), 1485, 1400, 1352, 1297, 1275, 868, 842, 528. H-NMR (400
MHz, DMSO-d6) δ 1.93 (d, J = 5.6 Hz, 3H, RCH3), 7.57 (d, J = 8.4 Hz, 2H,
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10.1002/chem.202000232
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Ar-H), 7.74 (q, J = 5.2 Hz, 1H, N=CHR), 7.86 (d, J = 8.4 Hz, 2H, Ar-H),
11.50 (s, 1H, N-H). 13C-NMR (100.6 MHz, DMSO-d6) δ 18.4 (CH3), 128.5
(2 x CAr-H), 129.4 (2 x CAr-H), 132.3 (CAr), 136.3 (CAr), 148.9 (N=CHR),
161.6 (C=O). HRMS (ESI+) calcd for [NaC9H9ClN2O]+ 219.0296; found
219.0306 [M + Na]+.
NMR (300 MHz, DMSO-d6) δ 3.65 (d, J = 6.0 Hz, 2H, RCH2R’), 7.23-7.38
(m, 5H, Ar-H), 7.87 (t, J = 6.0 Hz, 1H, N=CHR), 8.09 (d, J = 8.9 Hz, 2H,
Ar-H), 8.34 (d, J = 8.8 Hz, 2H, Ar-H), 11.81 (s, 1H, N-H). 13C-NMR (75
MHz, DMSO-d6) δ 38.4 (CH2), 123.6 (2 x CAr-H), 126.7 (CAr-H), 128.7 (2
x CAr-H), 128.9 (2 x CAr-H), 129.1 (2 x CAr-H), 136.7 (CAr), 139.1 (CAr),
149.2 (CAr), 152.0 (N=CHR), 161.3 (C=O). HRMS (ESI+) calcd for
[NaC15H13N3O3]+ 306.0849; found 306.0870 [M + Na]+.
(E)-N´-(2-Ethylidene)-4-bromobenzohydrazide (1i)
An excess of acetaldehyde (0.85 mL, 15.1 mmol) is added to a solution
of 4-bromobenzoic acid hydrazide (1.10 g, 5.0 mmol) in dichloromethane
(5 mL). The reaction mixture is stirred during one day at room
temperature. After this time, the solvent is evaporated, and the residue is
recrystallized in ethanol to afford 0.68 g of white solid (56% yield). The
starting material 1i is obtained as a mixture of isomers (E)/(Z) 93:7. M.p.
189-191 °C. IR (cm-1) 3187 (N-H), 3060, 2833, 1650 (C=O), 1621, 1591,
1552 (N-H), 1484, 1395, 1354, 1300, 1283, 1269, 868, 837, 504. 1H-
NMR (400 MHz, DMSO-d6) δ 1.93 (d, J = 5.2 Hz, 3H, -CH3), 7.70-7.80 (m,
5H, Ar-H + N=CHR), 11.50 (s, 1H, N-H). 13C-NMR (100.6 MHz, DMSO-
d6) δ 18.4 (CH3), 125.2 (CAr), 129.6 (2 x CAr-H), 131.4 (2 x CAr-H), 132.6
(CAr), 148.9 (N=CHR), 161.8 (C=O). HRMS (ESI+) calcd for
[NaC9H9BrN2O]+ 262.9790; found 262.9805 [M + Na]+.
General procedure for the enantioselective synthesis of hydrazide
derivatives 4.
The corresponding nitroalkane 2 (1 mL) is added to a mixture of N-
acylhydrazone 1 (0.1 mmol) and catalyst 3a (0.03 mmol, 9.73 mg) in a
test tube. The reaction mixture is stirred at the indicated temperature and
the formation of corresponding products is followed by TLC. After the
time described below, the residue is purified by column chromatography
using a mixture of n-hexane/ethyl acetate to afford the pure adducts 4.
Diastereomeric ratio (dr) is determined by 1H-NMR spectroscopy analysis
from an aliquot of the reaction mixture after the time described, using
DMSO-d6 as solvent. Enantiomeric excesses (ee) of isolated products
are obtained via chiral HPLC analysis using mixtures of n-hexane/ethyl
acetate and n-hexane/tetrahydrofuran as eluent. The reaction conditions
as well as yield and selectivity of distinct products are collected in Table
1.
(E)-N´-(2-Propylidene)-4-nitrobenzohydrazide (1j)
An excess of propionaldehyde (0.44 mL, 6.0 mmol) is added to a solution
of 4-nitrobenzoic acid hydrazide (0.92 g, 5.0 mmol) in dichloromethane
(10 mL). The reaction mixture is stirred during one day at room
temperature. After this time, the solvent is evaporated, and the residue is
recrystallized in ethanol to afford 0.52 g of a pale yellow solid (47% yield.
The starting material 1j is obtained as a mixture of isomers (E)/(Z) 91:9.
M.p. 160-162 °C. IR (cm-1) 3212 (N-H), 3055, 2973, 1651 (C=O), 1600,
1557 (N-H), 1516 (NO2), 1489, 1341 (NO2), 1325, 1302, 1279, 868, 847,
707. 1H-NMR (300 MHz, DMSO-d6) δ 1.06 (t, J = 7.5 Hz, 3H, RCH3), 2.30
(dq, J1 = 5.1 Hz, J2 = 7.5 Hz, 2H, RCH2R’), 7.78 (t, J = 5.1 Hz, 1H,
N=CHR), 8.06-8.09 (m, 2H, Ar-H), 8.32-8.35 (m, 2H, Ar-H), 11.70 (s, 1H,
N-H). 13C-NMR (75 MHz, DMSO-d6) δ 10.5 (CH3), 25.5 (CH2) 123.6 (2 x
CAr-H), 129.1 (2 x CAr-H), 139.3 (CAr), 149.1 (CAr), 154.5 (N=CHR), 161.2
(C=O). HRMS (ESI+) calcd for [NaC10H11N3O3]+ 244.0693; found
244.0712 [M + Na]+.
(S)-N'-(3-Methyl-1-nitrobutan-2-yl)-4-nitrobenzohydrazide (4aa)
From hydrazone 1a (23.52 mg, 0.1 mmol) and nitromethane (2a) (1 mL,
18.3 mmol), after three days at room temperature, compound 4aa was
purified by column chromatography in n-hexane-ethyl acetate 8:2 to
afford 16.89 mg of yellow oil (57% yield). The corresponding ee (40%)
was determined by HPLC using a Daicel Chiralpak IC column (n-
hexane/ethyl acetate 85:15, flow rate 1 mL·min-1, λ = 347.9 nm): τmajor =
19.7 min; τminor = 22.7 min. [α]D24.2 = -1.82 (c 1.17, acetone, 40% ee). IR
(cm-1) 3285 (N-H), 3106, 2958, 1648 (C=O), 1599, 1550 (N-H), 1523
(NO2), 1461, 1376, 1344 (NO2), 867, 849, 714. 1H-NMR (300 MHz,
DMSO-d6) δ 0.97 (dd, J1 = 7.1 Hz, J2 = 0.8 Hz, 6H, RCH3), 1.87-1.98 (m,
1H, R’CHR2), 3.54 (dq, J1 = 4.0 Hz, J2 = 1.2 Hz, 1H, NCHRR’), 4.54 (dd,
J1 = 13.6 Hz, J2 = 7.9 Hz, 1H, RCH2NO2), 4.72 (dd, J1 = 13.6 Hz, J2 = 3.9
Hz, 1H, RCH2NO2), 5.48 (t, J = 5.9 Hz, 1H, N-NH-C), 7.97-8.01 (m, 2H,
Ar-H), 8.29-8.31 (m, 2H, Ar-H), 10.32 (d, J = 6.2 Hz, 1H, (RC=O)NHR).
13C-NMR (75 MHz, DMSO-d6) δ 18.1 (CH3), 19.0 (CH3), 28.8 (CH), 63.2
(NCHRR’), 76.9 (RCH2NO2), 124.0 (2 x CAr-H), 129.1 (2 x CAr-H), 139.0
(CAr), 149.6 (CAr), 164.7 (C=O). HRMS (ESI+) calcd for [NaC12H16N4O5]+
319.1013; found 319.1017 [M + Na]+.
(E)-N´-(2-Heptylidene)-4-nitrobenzohydrazide (1k)
An excess of heptaldehyde (0.86 mL, 6.0 mmol) is added to a solution of
4-nitrobenzoic acid hydrazide (0.92 g, 5.0 mmol) in dichloromethane (10
mL). The reaction mixture is stirred during one day at room temperature.
After this time, the solvent is evaporated and the residue is recrystallized
in ethanol to afford 1.02 g of a pale yellow solid (74% yield). The starting
material 1k is obtained as a mixture of isomers (E)/(Z) 90:10. M.p. 106-
108 °C. IR (cm-1) 3244 (N-H), 3073, 2938, 1660 (C=O), 1599, 1552 (N-H),
(S)-4-Nitro-N'-(1-nitropropan-2-yl)benzohydrazide (4ga)
From hydrazone 1g (20.72 mg, 0.1 mmol) and nitromethane (2a) (1 mL,
18.3 mmol), after three days at room temperature, compound 4ga was
purified by column chromatography in n-hexane-ethyl acetate 6:4 to
afford 24.50 mg of yellow solid (91% yield). The corresponding ee (42%)
was determined by HPLC using a Daicel Chiralpak IC column (n-
1
1513 (NO2), 1348 (NO2), 1318, 1288, 867, 845, 693. H-NMR (400 MHz,
DMSO-d6) δ 0.85-0.89 (m, 3H, RCH3), 1.23-1.36 (m, 6H, RCH2R’), 1.46-
1.53 (m, 2H, RCH2R’), 2.25-2.30 (m, 2H, RCH2R’), 7.76 (t, J = 5.2 Hz, 1H,
N=CHR), 8.07-8.09 (m, 2H, Ar-H), 8.33-8.35 (m, 2H, Ar-H), 11.70 (s, 1H,
N-H). 13C-NMR (100.6 MHz, DMSO-d6) δ 13.9 (CH3), 22.0 (CH2), 25.9
(CH2), 28.3 (CH2), 31.1 (CH2), 32.0 (CH2), 123.6 (2 x CAr-H), 129.0 (2 x
CAr-H), 139.3 (CAr), 149.1 (CAr), 153.7 (N=CHR), 161.1 (C=O). HRMS
(ESI+) calcd for [NaC14H19N3O3]+ 300.1319; found 300.1309 [M + Na]+.
hexane/ethyl acetate 85:15, flow rate 1 mL·min-1, λ = 325.2 nm): τmajor =
28.5
19.4 min; τminor = 20.8 min. [α]D
= -1.91 (c 1.23, acetone, 45% ee).
M.p. 112-114 °C. IR (cm-1) 3352 (N-H), 3313 (N-H), 3110, 2977, 1665
(C=O), 1597, 1555 (N-H), 1516 (NO2), 1409, 1379, 1343 (NO2), 1324,
1305, 866, 844, 712. 1H-NMR (300 MHz, DMSO-d6) δ 1.12 (d, J = 6.6 Hz,
3H, RCH3), 3.81-3.85 (m, 1H, NCHRR’), 4.56 (dd, J1 = 13.0 Hz, J2 = 5.4
Hz, 1H, RCH2NO2), 4.65 (dd, J1 = 13.0 Hz, J2 = 7.2 Hz, 1H, RCH2NO2),
5.49-5.61 (m, 1H, N-NH-C), 8.04 (d, J = 9.0 Hz, 2H, Ar-H), 8.32 (d, J =
9.0 Hz, 2H, Ar-H), 10.32 (d, J = 6.4 Hz, 1H, (RC=O)NHR). 13C-NMR (75
MHz, DMSO-d6) δ 15.9 (CH3), 53.4 (NCHRR’), 79.0 (RCH2NO2), 123.5 (2
x CAr-H), 128.7 (2 x CAr-H), 138.6 (CAr), 149.1 (CAr), 164.3 (C=O). HRMS
(ESI+) calcd for [NaC10H12N4O5]+ 291.0700; found 291.0709 [M + Na]+.
(E)-N´-(2-Benzylmethylidene)-4-nitrobenzohydrazide (1m)
An excess of phenylacetaldehyde (0.59 mL, 4.8 mmol) is added to a
solution of 4-nitrobenzoic acid hydrazide (0.74 g, 4.0 mmol) in
dichloromethane (15 mL). The reaction mixture is stirred during one day
at room temperature. After this time, the solvent is evaporated and the
residue is recrystallized in ethanol to afford 0.78 g of a yellow solid (68%
yield). The starting material 1m is obtained as a mixture of isomers
(E)/(Z) 90:10. M.p. 158-160 °C. IR (cm-1) 3179 (N-H), 3046, 1654 (C=O),
1599, 1542 (N-H), 1513 (NO2), 1347 (NO2), 1284, 860, 845, 695. 1H-
(S)-4-Chloro-N'-(1-nitropropan-2-yl)benzohydrazide (4ha)
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From hydrazone 1h (19.63 mg, 0.1 mmol) and nitromethane (2a) (1 mL,
18.3 mmol), after three days at room temperature, compound 4ha was
purified by column chromatography in n-hexane/ethyl acetate 7:3 to
afford 14.17 mg of pale yellow solid (55% yield). The corresponding ee
(37%) was determined by HPLC using a Daicel Chiralpak IA column (n-
hexane/ethyl acetate 70:30, flow rate 1 mL·min-1, λ = 247.2 nm): τmajor =
19.5 min; τminor = 18.0 min. [α]D27.8 = -3.68 (c 0.72, acetone, 37% ee).
M.p. 114-116 °C. IR (cm-1) 3277 (N-H), 2982, 1623 (C=O), 1596, 1542
(N-H), 1459, 1444, 1389, 1306, 1092, 839, 802, 527. 1H-NMR (300 MHz,
DMSO-d6) δ 1.11 (d, J = 6.6 Hz, 3H, RCH3), 3.63-3.76 (m, 1H, NCHRR’),
4.53 (dd, J1 = 13.2 Hz, J2 = 5.4 Hz, 1H, RCH2NO2), 4.62 (dd, J1 = 13.2
Hz, J2 = 7.2 Hz, 1H, RCH2NO2), 5.43 (t, J = 6.3 Hz, 1H, N-NH-C), 7.52-
7.56 (m, 2H, Ar-H), 7.80-7.85 (m, 2H, Ar-H), 10.06 (d, J = 6.3 Hz, 1H,
M.p. 96-98 °C. IR (cm-1) 3391 (N-H), 3311 (N-H), 3108, 2952, 1661
(C=O), 1598, 1549 (N-H), 1517 (NO2), 1462, 1383, 1339 (NO2), 1327,
872, 846, 713. 1H-NMR (300 MHz, DMSO-d6) δ 0.80-0.91 (m, 3H, RCH3),
1.17-1.36 (m, 6H, Alk-H), 1.35-1.49 (m, 3H, Alk-H), 1.49-1.60 (m, 1H,
Alk-H), 3.56-3.63 (m, 1H, NCHRR’), 4.61 (d, J = 6.0 Hz, 2H, RCH2NO2),
5.51 (t, J = 5.9 Hz, 1H, N-NH-C), 8.00-8.04 (m, 2H, Ar-H), 8.29-8.34 (m,
2H, Ar-H), 10.30 (d, J = 6.5 Hz, 1H, (RC=O)NHR). 13C-NMR (75 MHz,
DMSO-d6) δ 14.0 (CH3), 22.0 (CH2), 25.1 (CH2), 28.6 (CH2), 29.8 (CH2),
31.1 (CH2), 57.8 (NCHRR’), 78.0 (RCH2NO2), 123.5 (2 x CAr-H), 128.7 (2
x CAr-H), 138.6 (CAr), 149.1 (CAr), 164.2 (C=O). HRMS (ESI+) calcd for
[NaC15H22N4O5]+ 361.1482; found 361.1479 [M + Na]+.
(S)-N'-(3-Methyl-1-nitropentan-2-yl)-4-nitrobenzohydrazide (4la)
(RC=O)NHR). 13C-NMR (75 MHz, DMSO-d6)
δ 15.9 (CH3), 53.5
From hydrazone 1l (24.93 mg, 0.1 mmol) and nitromethane (2a) (1 mL,
18.3 mmol), after three days at room temperature, compound 4la was
purified by column chromatography in n-hexane/ethyl acetate 8:2 to
afford 25.87 mg of yellow solid (83% yield). The corresponding ee (40%)
was determined by HPLC using a Daicel Chiralpak IC column (n-
hexane/ethyl acetate 85:15, flow rate 1 mL·min-1, λ = 255.5 nm): τmajor =
12.4 min; τminor = 17.7 min. [α]D29.1 = -8.20 (c 1.29, acetone, 40% ee).
M.p. 118-120 °C. IR (cm-1) 3379 (N-H), 3301 (N-H), 3108, 2953, 1657
(C=O), 1596, 1550 (N-H), 1513 (NO2), 1467, 1383, 1345 (NO2), 1320,
867, 845, 714. 1H-NMR (300 MHz, DMSO-d6) δ 0.90 (t, J = 6.6 Hz, 6H,
RCH3), 1.20 (ddd, J1 = 13.8 Hz, J2 = 7.7 Hz, J3 = 5.1 Hz, 1H, RCH2R’),
1.46 (ddd, J1 = 14.0 Hz, J2 = 7.7 Hz, J3 = 6.5 Hz, 1H, RCH2R’), 1.74-1.90
(m, 1H, R2CHR’), 3.61-3.71 (m, 1H, NCHRR’), 4.54-4.66 (m, 2H,
RCH2NO2), 5.50 (t, J = 6.0 Hz, 1H, N-NH-C), 8.00-8.04 (m, 2H, Ar-H),
8.30-8.34 (m, 2H, Ar-H), 10.31 (d, J = 6.5 Hz, 1H, (RC=O)NHR). 13C-
NMR (75 MHz, DMSO-d6) δ 22.2 (CH3), 22.8 (CH3), 24.0 (CH), 39.0
(CH2), 56.1 (NCHRR’), 78.3 (RCH2NO2), 123.6 (2 x CAr-H), 128.7 (2 x
CAr-H), 138.6 (CAr), 149.1 (CAr), 164.3 (C=O). HRMS (ESI+) calcd for
[NaC13H18N4O5]+ 333.1169; found 333.1167 [M + Na]+.
(NCHRR’), 79.1 (RCH2NO2), 128.4 (2 x CAr-H), 129.1 (2 x CAr-H), 131.6
(CAr), 136.2 (CAr), 165.1 (C=O). HRMS (ESI+) calcd for
[NaC10H12ClN3O3]+ 280.0459; found 280.0433 [M + Na]+.
(S)-4-Bromo-N'-(1-nitropropan-2-yl)benzohydrazide (4ia)
From hydrazone 1i (24.11 mg, 0.1 mmol) and nitromethane (2a) (1 mL,
18.3 mmol), after three days at room temperature, compound 4ia was
purified by column chromatography in n-hexane/ethyl acetate 7:3 to
afford 7.25 mg of white solid (24% yield). The corresponding ee (39%)
was determined by HPLC using a Daicel Chiralpak IA column (n-
hexane/ethyl acetate 70:30, flow rate 1 mL·min-1, λ = 246.0 nm): τmajor =
27.9
23.5 min; τminor = 20.0 min. [α]D
= -5.07 (c 0.36, acetone, 39% ee).
M.p. 121-123 °C. IR (cm-1) 3275 (N-H), 3095, 2975, 1623 (C=O), 1591,
1544 (N-H), 1459, 1444, 1389, 1302, 1071, 837, 801, 503. H-NMR (300
1
MHz, DMSO-d6) δ 1.11 (d, J = 6.6 Hz, 3H, RCH3), 3.63-3.76 (m, 1H,
NCHRR’), 4.53 (dd, J1 = 12.9 Hz, J2 = 5.1 Hz, 1H, RCH2NO2), 4.62 (dd,
J1 = 12.9 Hz, J2 = 6.9 Hz, 1H, RCH2NO2), 5.40-5.45 (m, 1H, N-NH-C),
7.66-7.70 (m, 2H, Ar-H), 7.73-7.77 (m, 2H, Ar-H), 10.06 (d, J = 6.3 Hz,
1H, (RC=O)NHR). 13C-NMR (75 MHz, DMSO-d6) δ 15.9 (CH3), 53.5
(NCHRR’), 79.1 (RCH2NO2), 125.1 (CAr), 129.3 (2 x CAr-H), 131.3 (2 x
CAr-H), 132.0 (CAr), 165.2 (C=O). HRMS (ESI+) calcd for
[NaC10H12BrN3O3]+ 323.9954; found 323.9943 [M + Na]+.
(S)-4-Nitro-N'-(1-nitro-3-phenylpropan-2-yl)benzohydrazide (4ma)
From hydrazone 1m (28.33 mg, 0.1 mmol) and nitromethane (2a) (1 mL,
18.3 mmol), after three days at room temperature, compound 4ma was
purified by column chromatography in n-hexane/ethyl acetate 7:3 to
afford 25.47 mg of yellow solid (74% yield). The corresponding ee (43%)
was determined by HPLC using a Daicel Chiralpak IC column (n-
hexane/ethyl acetate 85:15, flow rate 1 mL·min-1, λ = 256.7 nm): τmajor =
16.1 min; τminor = 18.2 min. [α]D24.5 = -5.73 (c 1.27, acetone, 43% ee).
M.p. 153-155 °C. IR (cm-1) 3281 (N-H), 3200 (N-H), 3106, 2926, 1670
(C=O), 1649, 1597, 1548 (N-H), 1528 (NO2), 1448, 1388, 1346 (NO2),
1319, 864, 849, 707. 1H-NMR (75 MHz, DMSO-d6) δ 2.74 (dd, J1 = 14.0
Hz, J2 = 7.4 Hz, 1H, RCH2Ph), 2.95 (dd, J1 = 13.9 Hz, J2 = 6.3 Hz, 1H,
RCH2Ph), 3.85-3.96 (m, 1H, NCHRR’), 4.51 (dd, J1 = 13.4 Hz, J2 = 4.5
Hz, 1H, RCH2NO2), 4.64 (dd, J1 = 13.4 Hz, J2 = 7.7 Hz, 1H, RCH2NO2),
5.67 (t, J = 6.4 Hz, 1H, N-NH-C), 7.19-7.36 (m, 5H, Ar-H), 7.99-8.03 (m,
(S)-4-Nitro-N'-(1-nitrobutan-2-yl)benzohydrazide (4ja)
From hydrazone 1j (24.11 mg, 0.1 mmol) and nitromethane (2a) (1 mL,
18.3 mmol), after three days at room temperature, compound 4ja was
isolate by column chromatography in n-hexane/ethyl acetate 7:3 to afford
22.3 mg of yellow solid (79% yield). The corresponding ee (39%) was
determined by HPLC using a Daicel Chiralpak IC column (n-hexane/ethyl
acetate 85:15, flow rate 1 mL·min-1, λ = 255.5 nm): τmajor = 17.4 min;
τminor = 19.2 min. [α]D29.5 = -6.91 (c 1.11, acetone, 39% ee). M.p. 135-
137 °C. IR (cm-1) 3271 (N-H), 3107, 2934, 1625 (C=O), 1595, 1551 (N-H),
1511 (NO2), 1424, 1395, 1346 (NO2), 1326, 1315, 868, 849, 714. 1H-
NMR (300 MHz, DMSO-d6) δ 0.97 (t, J = 7.5 Hz, 3H, RCH3), 1.39-166 (m,
2H, RCH2R’), 3.48-3.59 (m, 1H, NCHRR’), 4.59-4.66 (m, 2H, RCH2NO2),
5.52 (t, J = 6.0 Hz, 1H, N-NH-C), 8.00-8.05 (m, 2H, Ar-H), 8.29-8.33 (m,
2H, Ar-H), 10.30 (d, J = 6.3 Hz, 1H, (RC=O)NHR). 13C-NMR (75 MHz,
DMSO-d6) δ 10.1 (CH3), 22.9 (CH2), 59.2 (NCHRR’), 77.6 (RCH2NO2),
123.5 (2 x CAr-H), 128.7 (2 x CAr-H), 138.6 (CAr), 149.1 (CAr), 164.3 (C=O).
HRMS (ESI+) calcd for [NaC11H14N4O5]+ 305.0856; found 305.0850 [M +
Na]+.
2H, Ar-H), 8.28-8.33 (m, 2H, Ar-H), 10.39 (d,
(RC=O)NHR). 13C-NMR (75 MHz, DMSO-d6)
J
=
6.5 Hz, 1H,
δ
36.2 (CH2), 59.4
(NCHRR’), 77.2 (RCH2NO2), 123.5 (2 x CAr-H), 126.5 (CAr-H), 128.4 (2 x
CAr-H), 128.7 (2 x CAr-H), 129.3 (2 x CAr-H), 137.6 (CAr), 138.5 (CAr),
149.1 (CAr), 164.2 (C=O). HRMS (ESI+) calcd for [NaC16H16N4O5]+
367.1013; found 367.1020 [M + Na]+.
(S)-4-Nitro-N'-(1-nitro-4-phenylbutan-2-yl)benzohydrazide (4na)[6]
(S)-4-Nitro-N'-(1-nitrooctan-2-yl)benzohydrazide (4ka)
From hydrazone 1n (29.73 mg, 0.1 mmol) and nitromethane (2a) (1 mL,
18.3 mmol), after three days at room temperature, compound 4na was
purified by column chromatography in n-hexane/ethyl acetate 8:2 to
afford 28.67 mg of yellow solid (80% yield). The corresponding ee (41%)
was determined by HPLC using a Daicel Chiralpak IC column (n-
hexane/ethyl acetate 85:15, flow rate 1 mL·min-1, λ = 256.7 nm): τmajor =
From hydrazone 1k (27.73 mg, 0.1 mmol) and nitromethane (2a) (1 mL,
18.3 mmol), after three days at room temperature, compound 4ka was
purified by column chromatography in n-hexane/ethyl acetate 8:2 to
afford 26.73 mg of yellow solid (79% yield). The corresponding ee (39%)
was determined by HPLC using a Daicel Chiralpak IC column (n-
hexane/ethyl acetate 85:15, flow rate 1 mL·min-1, λ = 255.5 nm): τmajor =
12.5 min; τminor = 14.2 min. [α]D29.6 = -4.92 (c 1.34, acetone, 39% ee).
This article is protected by copyright. All rights reserved.

10.1002/chem.202000232
Chemistry - A European Journal
FULL PAPER
15.5 min; τminor = 17.8 min. [α]D27.7 = -7.29 (c 1.43, acetone, 41% ee).
8.29-8.35 (m, 2Ha + 2 Hb, Ar-H), 10.14 (d, J = 5.6 Hz, 1Hb, (RC=O)NHR),
10.37 (d, J = 6.3 Hz, 1Ha, (RC=O)NHR). 13C-NMR (75 MHz, DMSO-d6) δ
12.7 (CH3), 13.3 (CH3), 14.0 (CH3), 22.1 (CH2), 25.2 (CH2), 25.7 (CH2),
27.3 (CH2), 28.6 (CH2), 28.6 (CH2), 29.4 (CH2), 31.1 (CH2), 31.1 (CH2),
61.6 (NCHRR’), 62.2 (NCHRR’), 83.9 (RCHR’NO2), 84.3 (RCHR’NO2),
123.5 (2 x CAr-H), 123.6 (2 x CAr-H), 128.7 (2 x CAr-H), 128.7 (2 x CAr-H),
138.6 (CAr), 138.7 (CAr), 149.1 (CAr(a) + CAr(b)), 163.9 (C=O), 164.4
(C=O). HRMS (ESI+) calcd for [NaC16H24N4O5]+ 375.1639; found
375.1645 [M + Na]+.
{lit.[6] [α]D25 = -10.5 (c 0.31, acetone) for (S)-4na, 26% ee}.
4-Nitro-N'-(3-nitrobutan-2-yl)benzohydrazide (4gb)
From hydrazone 1g (20.72 mg, 0.1 mmol) and nitroethane (2b) (1 mL
12.6 mmol), after seven days at -20 °C, compound 4gb was purified by
column chromatography in n-hexane/ethyl acetate 7:3 to afford 18.46 mg
of a mixture of diastereomers (1.4:1 d.r.) as a yellow solid (65% yield).
The corresponding ee (54%) was determined respect to the major
diastereomer by HPLC using
a Daicel Chiralpak IC column (n-
N'-(4-Methyl-2-nitrohexan-3-yl)-4-nitrobenzohydrazide (4lb)
hexane/tetrahydrofuran 90:10, flow rate 1 mL·min-1, λ = 241.7 nm):
τmajor = 27.0 min; τminor = 36.5 min. M.p. 111-113 °C. IR (cm-1) 3242
(N-H), 3092, 2988, 1640 (C=O), 1598, 1541 (N-H), 1522 (NO2), 1451,
1392, 1344 (NO2), 1321, 1307, 871, 849, 690. 1H-NMR (300 MHz,
DMSO-d6) δ 1.04 (d, J = 6.6 Hz, 3Ha, RCH3), 1.09 (d, J = 6.7 Hz, 3Hb,
RCH3), 1.46 (d, J = 6.7 Hz, 3Ha, RCH3), 1.51 (d, J = 6.7 Hz, 3Hb, RCH3),
3.51-3.66 (m, 1Ha + 1Hb, NCHRR’), 4.73-4.86 (m, 1Ha + 1Hb, RCHR’NO2),
5.39 (dd, J1 = 5.5 Hz, J2 = 4.5 Hz, 1Hb, N-NH-C), 5.49 (t, J = 6.0 Hz, 1Ha,
N-NH-C), 7.98-8.07 (m, 2Ha+2Hb, Ar-H), 8.29-8.34 (m, 2Ha+2Hb, Ar-H),
10.20 (d, J = 5.6 Hz, 1Hb, (RC=O)NHR), 10.33 (d, J = 6.3 Hz, 1Ha,
(RC=O)NHR). 13C-NMR (75 MHz, DMSO-d6) δ 13.5 (CH3), 13.9 (CH3),
14.1 (CH3), 14.8 (CH3), 57.3 (NCHRR’), 57.8 (NCHRR’), 85.0
(RCHR’NO2), 85.1 (RCHR’NO2), 123.6 (2 x CAr-H), 123.6 (2 x CAr-H),
128.7 (2 x CAr-H(a) + 2 x CAr-H(b)), 138.6 (CAr), 138.7 (CAr), 149.1 (CAr(a)
From hydrazone 1l (0.1 mmol, 24.93 mg, 0.1 mmol) and nitroethane (2b)
(1 mL, 12.6 mmol), after seven days at -20 °C, compound 4lb was
purified by column chromatography in n-hexane/ethyl acetate 8:2 to
afford 8.16 mg of a mixture of diastereomers (2.4:1 d.r.) as a pale yellow
solid (25% yield). The corresponding ee (77%) was determined by HPLC
using a Daicel Chiralpak IC column (n-hexane/tetrahydrofuran 90:10,
flow rate 1 mL·min-1, λ = 255.5 nm): τmajor = 27.8 min; τminor = 24.7 min.
M.p. 132-134 °C. IR (cm-1) 3263 (N-H), 2953, 2867, 1644 (C=O), 1599,
1548 (N-H), 1517 (NO2), 1468, 1387, 1343 (NO2), 1302, 870, 851, 718.
1H-NMR (300 MHz, DMSO-d6) δ 0.85-1.23 (m, 6Ha + 6Hb, RCH3), 1.31-
1.43 (m, 4H, RCH2R’), 1.46-1.51 (m, 3Ha + 3Hb, RCH3), 1.79-1-94 (m,
1Ha + 1Hb, R2CHR’), 3.48-3.56 (m, 1H, NCHRR’), 3.65-3.72 (m, 1H,
NCHRR’), 4.69-4.77 (m, 1H, RCHR’NO2), 4.81-4.89 (m, 1H, RCHR’NO2),
5.28-5.31 (m, 1H, N-NH-C), 5.40-5.44 (m, 1H, N-NH-C), 7.93-7.97 (m,
2H, Ar-H), 8.04-8.08 (m, 2H, Ar-H), 8.29-8.35 (m, 2Ha + 2Hb, Ar-H), 10.13
(d, J = 5.4 Hz, 1H, (RC=O)NHR), 10.37 (d, J = 6.3 Hz, 1H, (RC=O)NHR).
13C-NMR (300 MHz, DMSO-d6) δ 12.7 (CAlk), 12.7 (CAlk), 21.7 (CAlk), 22.1
(CAlk), 23.0 (CAlk), 23.6 (CAlk), 24.3 (CAlk), 24.4 (CAlk), 36.5 (CH2), 38.6
(CH2), 59.8 (NCHRR’), 60.5 (NCHRR’), 84.0 (RCHR’NO2), 84.5
(RCHR’NO2), 123.6 (2 x CAr-H), 123.7 (2 x CAr-H), 128.8 (2 x CAr-H),
128.8 (2 x CAr-H), 138.6 (CAr), 138.8 (CAr), 149.2 (CAr), 149.2 (CAr), 164.2
(C=O), 164.5 (C=O). Exact mass calculated for [NaC14H20N4O5]+ [M +
Na]+ 347.1326; found 347.1321.
+
CAr(b)), 164.1 (C=O), 164.6 (C=O). HRMS (ESI+) calcd for
[NaC11H14N4O5]+ 305.0856; found 305.0869 [M + Na]+.
4-Nitro-N'-(2-nitropentan-3-yl)benzohydrazide (4jb)
From hydrazone 1j (24.11 mg, 0.1 mmol) and nitroethane (2b) (1 mL,
12.6 mmol), after seven days at -20 °C, compound 4jb was purified by
column chromatography in n-hexane/ethyl acetate 7:3 to afford 11.72 mg
of a mixture of diastereomers (1.7:1 dr) as a yellow solid (40% yield). The
corresponding ee (50%) was determined by HPLC using a Daicel
Chiralpak IC column (n-hexane/tetrahydrofuran 90:10, flow rate
1
mL·min-1, λ = 256.7 nm): τmajor = 32.2 min; τminor = 25.5 min. M.p. 81-
4-Nitro-N'-(4-nitro-1-phenylpentan-3-yl)benzohydrazide (4nb)
83 °C. IR (cm-1) 3251 (N-H), 3082, 2968, 1627 (C=O), 1596, 1546 (N-H),
1
1519 (NO2), 1448, 1390, 1338 (NO2), 1318, 1302, 861, 847, 697. H-
From hydrazone 1n (29.73 mg, 0.1 mmol) and nitroethane (2b) (1 mL,
12.6 mmol), after seven days at -20 °C, compound 4nb was purified by
column chromatography in n-hexane/ethyl acetate 8:2 to afford 9.36 mg
of a mixture of diastereomers (1.7:1 d.r.) as a yellow oil a yield of 41%
(yellow oil). The corresponding ee (73%) was determined by HPLC using
a Daicel Chiralpak IC column (n-hexane/ethyl acetate 85:15, flow rate 1
mL·min-1, λ = 247.1 nm): τmajor = 14.1 min; τminor = 15.6 min. IR (cm-1)
3284 (N-H), 2923, 1656 (C=O), 1600, 1544 (N-H), 1522 (NO2), 1453,
1391, 1344 (NO2), 1298, 866, 849, 699. 1H-NMR (300 MHz, DMSO-d6) δ
1.49-1.52 (m, 3Ha + 3Hb, RCH3), 1.59-1.79 (m, 2Ha + 2Hb, RCH2R’), 2.66-
2.93 (m, 2Ha + 2Hb, RCH2R’), 3.42-3.50 (m, 1H, NCHRR’), 3.62-3.64 (m,
1H, NCHRR’), 4.79-4.93 (m, 1Ha + 1Hb, RCHR’NO2), 5.50-5.53 (m, 1H,
N-NH-C), 5.67 (t, J = 6.0 Hz, 1H, N-NH-C), 7.16-7.31 (m, 5Ha + 5Hb, Ar-
H), 7.94-7.99 (m, 2H, Ar-H), 8.04-8.08 (m, 2H, Ar-H), 8.30-8.35 (m, 2Ha +
2 Hb, Ar-H), 10.18 (d, J = 5.6 Hz, 1H, (RC=O)NHR), 10.41 (d, J = 6.3 Hz,
1H, (RC=O)NHR). 13C-NMR (75 MHz, DMSO-d6) δ 12.9 (CH3), 13.7
(CH3), 29.0 (CH2), 29.6 (CH2), 31.3 (CH2), 31.5 (CH2), 61.4 (NCHRR’),
62.0 (NCHRR’), 83.9 (RCHR’NO2), 84.2 (RCHR’NO2), 123.5 (2 x CAr-H),
123.6 (2 x CAr-H), 125.8 (CAr-H), 125.9 (CAr-H), 128.3 (2 x CAr-H(a) + 2 x
CAr-H(b)), 128.4 (2 x CAr-H(a) + 2 x CAr-H(b)), 128.7 (2 x CAr-H), 128,8 (2
x CAr-H), 138.6 (CAr), 138.7 (CAr), 141.6 (CAr), 141.7 (CAr), 149.1 (CAr),
149.1 (CAr), 164.1 (C=O), 164.5 (C=O). HRMS (ESI+) calcd for
[NaC18H20N4O5]+ 395.1326; found 395.1329 [M + Na]+.
NMR (300 MHz, DMSO-d6) δ 0.96-1.04 (m, 3Ha + 3Hb, RCH3), 1.40-1.53
(m, 5Ha + 5Hb, Alk-H), 3.56-3.37 (m, 1Ha + 1Hb, NCHRR’), 4.72-4.88 (m,
1Ha + 1Hb, RCHR’NO2), 5.34 (dd, J1 = 5.4 Hz, J2 = 4.6 Hz, 1Hb, N-NH-C),
5.47 (t, J = 6.0 Hz, 1Ha, N-NH-C), 7.94-7.98 (m, 2Hb, Ar-H) 8.04-8.07 (m,
2Ha, Ar-H), 8.29-8.35 (m, 2Ha + 2 Hb, Ar-H), 10.13 (d, J = 5.6 Hz, 1Hb,
(RC=O)NHR), 10.36 (d, J = 6.3 Hz, 1Ha, (RC=O)NHR). 13C-NMR (75
MHz, DMSO-d6) δ 10.2 (CH3), 10.8 (CH3), 12.7 (CH3), 13.7 (CH3), 20.4
(CH2), 22.5 (CH2), 63.3 (NCHRR’), 63.7 (NCHRR’), 83.9 (RCHR’NO2),
84.0 (RCHR’NO2), 123.5 (2 x CAr-H), 123.6 (2 x CAr-H), 128.7 (2 x CAr-H),
128.7 (2 x CAr-H), 138.5 (CAr), 138.7 (CAr), 149.1 (CAr(a) + CAr(b)), 163.9
(C=O), 164.4 (C=O). HRMS (ESI+) calcd for [NaC12H16N4O5]+ 319.1013;
found 319.1020 [M + Na]+.
4-Nitro-N'-(2-nitrononan-3-yl)benzohydrazide (4kb)
From hydrazone 1k (27.73 mg, 0.1 mmol) and nitroethane (2b) (1 mL,
12.6 mmol), after seven days at -20 °C, compound 4kb was purified by
column chromatography in n-hexane/ethyl acetate 8:2 to afford 9.34 mg
of a mixture of diastereomers (2.2:1 d.r.) as a yellow oil (27% yield). The
corresponding ee (72%) was determined by HPLC using a Daicel
Chiralpak IC column (n-hexane/tetrahydrofuran 90:10, flow rate
1
mL·min-1, λ = 255.5 nm): τmajor = 24.7 min; τminor = 16.0 min. IR (cm-1)
3282 (N-H), 2950, 2917, 1651 (C=O), 1600, 1547 (N-H), 1525 (NO2),
1456, 1376, 1345 (NO2), 1300, 867, 849, 718. 1H-NMR (300 MHz,
DMSO-d6) δ 0.78-0.90 (m, 3Ha + 3Hb, RCH3), 0.97-1.60 (m, 13Ha + 13Hb,
Alk-H), 3.38-3.49 (m, 1H, NCHRR’), 3.54-3.65 (m, 1H, NCHRR’), 4.71-
4.87 (m, 1Ha + 1Hb, RCHR’NO2), 5.30-5.34 (m, 1Hb, N-NH-C), 5.45 (t, J =
5.9 Hz, 1Ha, N-NH-C), 7.93-7.97 (m, 2Hb, Ar-H), 8.03-8.07 (m, 2Ha, Ar-H),
General procedure for the calculation of initial rates.
A solution of mesitylene (0.25 M), as internal standard, in CDCl3 (200 µl)
is added to a mixture of hydrazone (1h, 0.05 or 0.025 mmol) and quinine
(3a, 0.015 or 0.03 mmol) in a vial. The resulting mixture is stirred to form
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10.1002/chem.202000232
Chemistry - A European Journal
FULL PAPER
a transparent colorless solution. The corresponding nitroalkane (5.5
mmol) is subsequently added and the new solution is transferred to an
NMR tube after stirring. The concentration of hydrazone 1h over reaction
time is monitored by 1H-NMR spectroscopy at 22.5 °C. Corresponding
spectra are collected in a 300 MHz NMR spectrometer (Bruker, ARX-
300), using the signal of mesitylene to calculate the concentration of
reagent 1h in the reaction medium. Initial rates are obtained from the
slope of the straight lines resulting from interpolation of concentration vs
time at the first moments of the reactions (Figure S70). A minimum of two
replicas by experiment was performed, being the corresponding error the
standard devia4agtion between distinct samples.
[8]
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P. Herrera, A. Ricci, V. Sgarzani, Tetrahedron 2006, 62, 375-380.
a) K. Kacprzak, J. Gawroński, Synthesis 2001, 961-998; b) S.-K. Tian,
Y. Chen, J. Hang, L. Tang, P. McDaid, L. Deng, Acc. Chem. Res. 2004,
37, 621-631; c) C. E. Song (Ed) Cinchona Alkaloids in Synthesis and
Catalysis; Wiley‐VCH Verlag GmbH & Co. KGaA, 2009; d) T. Marcelli,
H. Hiemstra, Synthesis 2010, 1229-279; e) Q.-F. Wang, Synlett 2010,
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This work was supported by a 2018 Leonardo Grant for
Researchers and Cultural Creators, BBVA Foundation. Authors
thank Ministerio de Economía, Industria
y Competitividad
(MINECO/FEDER CTQ2016-75816-C2-1-P and CTQ2017-
88091-P), Universidad de Zaragoza (JIUZ-2017-CIE-05) and
Gobierno de Aragón-Fondo Social Europeo (E07_17R) for
financial support of their research. All the calculations were
performed in the Trueno cluster facility of SGAI-CSIC and the
Extreme Science and Engineering Discovery Environment
(XSEDE) through allocation TG-CHE190111. J.V.A.-R. thanks
Dr. R. S. Paton for his help with the script to generate the PyMol
style and GoodVibes.
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Keywords: aza-Henry
•
hydrazone
•
nitroalkane
•
β-
nitroalkylhydrazide • computational calculations
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Entry for the Table of Contents (Please choose one layout)
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Isaac G. Sonsona,[a] Juan V. Alegre-
Requena,*[a] Eugenia Marqués-López,[a]
M. Concepción Gimeno[b] and Raquel P.
Herrera*[a]
Page No. – Page No.
Asymmetric organocatalyzed aza-
Henry reaction of hydrazones:
experimental and computational
studies
The first asymmetric catalyzed aza-Henry reaction of hydrazones is presented. In
this process, quinine was used as catalyst to synthesize a variety of alkyl
substituted β-nitrohydrazides with up to 94% ee. Additionally, experimental and ab
initio studies were performed to understand the reaction mechanism. The results
revealed a concerted mode of activation in which a C-C bond forming reaction and
a protonation occur simultaneously.
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