Regioselectivity of the Conjugate Addition of Amines to Dissymmetrical Pull-Pull Alkenes

Article abstract of DOI:10.1002/ejoc.202100325

The regioselectivity of the conjugate nucleophilic addition of amines to vicinal di-acceptor-substituted alkenes has been studied. A set of results obtained with standard primary and secondary amines gives some clues on the relative acceptor character of classical electron-withdrawing groups (EWG). We have shown in addition that computed inverse local nucleophilicity index can be used to predict the regioselectivity of the nucleophilic attack.

Full text of DOI:10.1002/ejoc.202100325

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Regioselectivity of the conjugate addition of amines to
dissymmetrical pull-pull alkenes
Authors: Alexander Rulev, Ilya N. Zubkov, Igor A. Ushakov, Valentin
A. Semenov, Alexander V. Vashchenko, and Jacques
Maddaluno
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202100325
Link to VoR: https://doi.org/10.1002/ejoc.202100325
01/2020

10.1002/ejoc.202100325
European Journal of Organic Chemistry
Regioselectivity of the conjugate addition of amines
to dissymmetrical pull-pull alkenes
Dr. Alexander Yu. Rulev,*[a] Ilya N. Zubkov, [a] Dr. Igor A. Ushakov, [a] Dr. Valentin A.
Semenov, [a] Dr. Alexander V. Vashchenko, [a] and Dr. Jacques Maddaluno[b]
[a] A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian academy of sciences,
Irkutsk 664033, Russia; e-mail: rulev@irioch.irk.ru
[b] Normandie Université, UNIROUEN, INSA de Rouen, CNRS, Laboratoire COBRA (UMR
6014 & FR 3038), 76000 – Rouen (France); e-mail: jmaddalu@crihan.fr
To the memory of Dr. Lucette Duhamel (1935 – 2020).
Two of us have had the honour and pleasure to work
with this outstanding scientist (as a CNRS Chargé de
Recherches (JM) and NATO grant scholar (AR)) in the
Laboratoire des Fonctions Azotées et Oxygénées
Complexes of the Rouen University, France.
Abstract: The regioselectivity of the conjugate nucleophilic addition of amines to vicinal di-
acceptor-substituted alkenes has been studied. A set of results obtained with standard primary
and secondary amines gives some clues on the relative acceptor character of classical electron-
withdrawing groups (EWG). We have shown in addition that computed inverse local
nucleophilicity index can be used to predict the regioselectivity of the nucleophilic attack.
Keywords: aza-Michael reaction, vicinal substituted electron-deficient alkenes, nitrogen
nucleophiles, regioselectivity
Introduction
The aza-Michael addition is one of the most powerful tools to create a new carbon – nitrogen
single bond in one step and often with high selectivity.[1] Taking into account the fact that each
seventh reaction in pharmaceutical industry involves the formation of at least one C-N bond, it is
not surprising that this reaction is especially valuable for the synthesis of bioactive compounds
and drugs.[2] In fact, it is one of the simplest and most efficient strategies to prepare β-amino
acids and their derivatives from readily available starting materials. Moreover, aza-Michael
reaction can initiate a transformation cascade to afford complex heterocyclic molecules in one
single step (the so-called aza-Michael-Initiated Ring Closure (aza-MIRC) methodology).[1b-d, 3,4]
1
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10.1002/ejoc.202100325
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In general, the conjugate addition of nitrogen nucleophiles to electron-deficient olefins
proceeds through a stepwise mechanism, including the formation of zwitterionic intermediates.
The feature of initial amine and the nature of Michael acceptor or solvent influence both kinetics
and reaction mechanism. [5]. The protic solvents such as alcohols have been reported to favour
this transformation and Lewis acids (such as dihalogens or certain transition or main-group
metals salts) proved to be one of the most efficient catalysts. [1b,6]
Traditionally, the conjugate addition of amines to olefins substituted by an electron-
deficient appendage proceeds under strongly acidic or basic conditions and generates a new C-N
bond selectively at the β-position of the Michael acceptor. If a second EWG is introduced gem to
the first one (-disubstituted olefin), the reactivity tends to increase and a similar
regioselective addition is expected at the  position.[7] In contrast, if a second group is added
onto the vicinal position of the double bond (-disubstituted olefin) the situation is not as
straightforward since the nucleophilic attack can now take place on both olefinic carbons. Thus,
the regioselectivity of the addition on olefins 1 becomes a question of interest since the
competing bond polarizations rely on an entangled combination of inductive, mesomeric,
hyperconjugative and steric effects and both isomeric adducts 2 and 3 can a priori be obtained
(Scheme 1). Obviously, the 2/3 ratio will depend on the acceptor ability of both functional
groups (kinetic control) as well as on the relative stability of the zwitterions formed during the
first step (thermodynamic control).
Scheme 1. Regioselective nucleophilic addition to vicinal disubstituted alkenes
2
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Doubly activated olefins bearing two different electron-withdrawing groups in vicinal
position (so-called pull-pull olefins)[1b,8] could a priori be regarded as highly reactive compounds
because of their global electron depletion. However, a few articles published during the last
decades on the reaction of nucleophiles on such derivatives (Scheme 2) bars generalization.[9-23]
It was nevertheless demonstrated that several nitrogen nucleophiles add to β-nitroalkenoates to
afford exclusively α-amino esters.[9-16] An analogous regioselectivity was observed when acrylic
acid derivatives bearing a carbonyl group at the β-position were treated with primary or
secondary amines.[17-19] On the contrary, only β-amino acid derivatives were formed in the
reactions of amines or N,N- and N,O-binucleophiles with β-trifluorocrotonic acid derivatives.[20-
22]
Finally, the aza-Michael addition of some primary amines and azoles to unsymmetrical
fumaric esters led to the formation of the regioisomers mixture.[23]
Scheme 2. Previous results on the regioselectivity of aza-Michael addition. The citation
references are given in square brackets.
The paucity of results in this field and the differences between the published reaction
conditions make the prediction of the regioselectivity of the addition to unsymmetrical alkenes
containing two vicinal EWG groups difficult. Relying on the chemist’s intuition being
unsatisfactory to current standards, we considered that more research in this field was needed to
3
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10.1002/ejoc.202100325
European Journal of Organic Chemistry
predict the regioselectivity of the nucleophilic attacks on these systems. We present here the
results of a series of model reactions on the nucleophilic addition of amines to Michael acceptors
bearing two electron-withdrawing groups in vicinal position, all run following similar protocols
to get fully comparable results. Two general sets of conditions were tested for the addition:
“classical” or hyperbaric (16 kbar) conditions, both at room temperature in a protic solvent
[24-28]
(methanol or ethanol). We and others
have indeed shown before that pressure exerts a
major influence on the course of aza-Michael reactions.
Results and Discussion
Benzylamine (a prototypical primary amine) and morpholine (a secondary one) were chosen as
standard models of highly nucleophilic reagents. To avoid side reactions, strong bases such as
lithium amides were excluded from the study.
We firstly examined the reaction of these nucleophiles with commercially available
disubstituted alkenes (E)-1a,b and (Z)-1c under catalyst-free conditions. As detailed underneath,
we found that the reaction of equimolar quantities of these alkenes and amines 2a,b performed
remarkably well at room temperature and atmospheric pressure in a protic solvent, here methanol
or ethanol, affording α- and/or β-amino esters 3 and 4 in good to excellent yields (Table 1).
Protic solvents are known to be more partners than just solvents in this type of addition.[4,24,25]
We began the study with trifluoromethylated acrylate (E)-1a, an olefin in which a pure -
attracting group (CF3) competes with a conjugated ester appendage. In standard conditions, 1a
undergoes a regioselective nucleophilic attack of the primary and secondary amines 2a,b and
affords, as predicted from literature,[20] β-amino esters 3aa and 3ab. Their structure was
unambiguously determined by 13C NMR: the presence of a quartet at 62.6 ppm (2JCF = 26.4 Hz
for 3aa) or at 56.4 ppm (2JCF = 28.0 Hz for 3ab) indicates that the CHNR1R2 moiety is directly
connected to the trifluoromethyl group. The yield of the reaction could be increased, even at
room temperature and both in protic and aprotic solvents, provided high pressures were applied:
4
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10.1002/ejoc.202100325
European Journal of Organic Chemistry
under 16 kbar, the reaction with morpholine led to 3aa in up to 99% yield and unaltered
regioselectivity (Table 1, entries 1-4).[26] The chiral secondary dibenzylic amine 2c was also
successfully tested in the hyperbaric version of this reaction. It afforded the corresponding target
aza-Michael adduct 3ac in high yield, a compound that, unfortunately, is not very stable and
decomposed through a rapid retro-aza-Michael reaction upon purification (Table 1, entry 5). We
did not insist on determining the diastereoselectivity of this reaction since it is expected to be
disappointing.[27]
Table 1. Reaction of β-acceptor-substituted enoates with amines.
Michael acceptor 1
#
Amine 2
Exp. conditions
Pdt (%)a
EWG1 EWG2
R
1
2
3
4
5
CF3
CF3
CF3
CF3
CF3
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
(E)-1a
(E)-1a
(E)-1a
(E)-1a
Morpholine (2a)
Morpholine (2a)
Morpholine (2a)
Benzylamine (2b)
EtOH, rt, 72 h
3aa (70)
3aa (96)
3aa (99)
3ab (90)
3ac (95)b
H
H
H
H
EtOH, rt, 16 kbar, 24 h
THF, rt, 16 kbar, 24 h
EtOH, rt, 72 h
(E)-1a PhCH(Me)NHBn (2c) EtOH, rt, 16 kbar, 24 h
6
7
8
MeC(O) CO2Me
MeC(O) CO2Me
MeC(O) CO2Me
H
H
H
(E)-1b
(E)-1b
(E)-1b
Morpholine (2a)
Morpholine (2a)
Benzylamine (2b)
EtOH, rt, 72 h
MeOH, rt, 16 kbar, 24 h 4ba (57)
EtOH, rt, 72 h
4ba (98)
4bb (57)
9
CN
CO2Et
CO2Et
CO2Et
H
H
H
(Z)-1c
(Z)-1c
(Z)-1c
Morpholine (2a)
Morpholine (2a)
Benzylamine (2b)
EtOH, rt, 72 h
EtOH, rt, 16 kbar, 24 h
EtOH, rt, 72 h
3ca (85)
3ca (91)
3cb (54) +
4cb (32)c
10 CN
11 CN
12 CN
13 CN
CO2Et
CO2Et
H
H
(Z)-1c
(Z)-1c
Benzylamine (2b)
PhNHMe (2d)
EtOH, rt, 72 h + LiClO4 3cb (28) +
4cb (43)d
EtOH, 120°C, 4 h
-
14 NO2
15 NO2
CO2Et
CO2Et
H
H
(E)-1d
(E)-1d
Morpholine (2a)
Benzylamine (2b)
DCM, rt, 1 h
DCM, 0°C, 1 h
4da (98)e
4db (81)e
16 CN
17 CN
CO2Me Ph (E)-1e
CO2Me Ph (E)-1e
Morpholine (2a)
Benzylamine (2b)
THF, 85°C, 7 h
THF, 85°C, 7 h
4ea (85)f
4eb (75)f
18 CN
CO2Et Me (E)-1f
Morpholine (2a)
EtOH, 100°C, 5 h
5 (24)
a Isolated yield.
b Compound 3ac was obtained in pure state after decompression and solvent evaporation without
further chromatographic purification.
c The ration of 3cb : 4cb is 61:39 (determined from crude 1H NMR of the reaction mixture).
d The ration of 3cb : 4cb is 43:57 (determined from crude 1H NMR of the reaction mixture).
e Data taken from literature.[13]
f The syn:anti diastereomeric ratio (dr) is ≈ 55:45.
5
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We next considered the case of methyl 4-oxopentenoate (E)-1b bearing two -conjugated
electron-withdrawing groups, namely a methoxycarbonyl and a carbonyl. This latter function is
expected to exert a superior electron-withdrawing effect, and indeed, when 1b was reacted with
benzylamine, the α-amino ester 4ba was isolated, albeit in medium yield. If the addition of
morpholine on the same enone proceeds with the same regioselectivity, the reaction is almost
quantitative this time (Table 1, entries 6 and 8). Note that the yield is not as good when the
reaction is run in methanol and under 16 kbar (entry 7) probably due to a competitive oxa-
Michael addition of the alcohol.[24˗28] The proposed structure for 4ba was unambiguously
confirmed by X-ray data (Fig. 1).
Figure 1. X-ray crystal structure of adduct 4ba.
The following doubly depleted olefin we considered was ethyl cyanoacrylate (Z)-1c in
which the two conjugated electron-withdrawing groups compete in a subtle manner, one being sp
hybridized and the other sp2. When we reacted enoate 1c with morpholine 2a, we recovered,
selectively this time, the β-amino ester 3ca in high yields, in both classical and hyperbaric
conditions (Table 1, entries 9 and 10). In contrast, this olefin reacts with benzylamine 2b leading
to a mixture of regioisomers 3cb and 4cb in a 63:37 ratio (Table 1, entry 11). Careful analysis of
1
2D NMR spectra and 1D H-coupled 13C NMR allowed us to determine unambiguously the
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European Journal of Organic Chemistry
structure of each regioisomer (See SI, S16-S19; S35-S41). If most organic chemist would
undoubtedly consider a cyano group to be more electron-withdrawing than an ester and would
therefore expect 4cb to be the predominant product, other parameters such as steric or proton
acceptor characters are evidently to be considered in this competition.[29]
Indeed, the less sterically demanding cyano group in 1c drives the exclusive attack of
morpholine at β-position. Moreover, the adduct 3ca is thermodynamically more stable than its
isomer 4ca by 4.12 (PCM) or 4.31 kcal/mol (supermolecule with two molecules of ethanol),
respectively. In contrast, the thermodynamic stability of isomeric adducts 3cb and 4cb are closer:
amino ester 3cb is more stable than 4cb by 1.4 kcal/mol only, probably due to the stabilizing and
leveling effects of hydrogen bonds.
The tangled steric and electronic variations associated to the passage from a primary to a
secondary amine prevented us from simple deciphering these results. No reaction occurred when
poorly nucleophilic amines (such as N-methylaniline) were used in the reaction even after a long
reaction time (Table 1, entry 13).
As mentioned in the Introduction, the addition of nitrogen nucleophiles to acrylates
bearing a vicinal nitro group was the object of previous works. In particular, the reaction of β-
nitroacrylate E-1d with morpholine or benzylamine was previously described by Anderson and
co-authors.[13] As expected, enoate 1d, bearing one of the strongest electron-withdrawing groups,
added both amines fast and in clear regioselectivity to give α-amino ester in high yield (Table 1,
entries 14, 15). The reaction was performed in dichloromethane to prevent the competitive
addition of alcohol to the substrate.
Recently, Mayr et al. showed that rate constants for conjugate nucleophilic addition can
be used to value the electrophilicities of Michael acceptors. Thus, the nucleophile-independent
empirical electrophilicity parameters for simple monoacceptor-substituted olefins were
determined.[30] According to this research, the electron-acceptor ability of the functional groups
(as a measure of electrophilicity of such substrates) follows the order C(O)Me > CO2Me > CN ≥
7
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CO2Et. These results are in good agreement with our experimental data. For example, the
electrophilicity parameters for cyano- and ethoxycarbonyl groups are very close (-19.05 and -
19.07 respectively),[30] that is probably why both regioisomers are obtained with benzylamine
(Table 1, entry 11).
It is interesting to note that the solvent can alter the selectivity, as demonstrated by
substituting protic solvents by aprotic ones in the reaction of cyanoacrylate 1c with benzylamine
2b. Ester 3cb becomes indeed the sole reaction product when the reaction is performed in aprotic
solvent (Table 2, entries 1-4).
Table 2. Dependence of ratio 3cb:4cb on the solvent
#
Solventa
3cb : 4cb
isomer ratiob
1
2
3
4
5
6
Benzene
DMSO
THF
100:0
100:0
100:0
92:8
neat
TFE
67:33
63:37
EtOH
a Conditions: rt, 24h.
b Estimated from 1H NMR integrations.
The data in Table 2 show that parameter solely obtained on the basis of kinetic
measurements do not always adequately describe the observed patterns of the direction of
nucleophilic attacks. Therefore, this approach based on experimentally determined
electrophilicity indices for aprotic solvents does not take into account the solvent influence
which has, here, a significant effect on the regioselectivity of the nucleophilic addition.
Theoretical considerations
Since the above experimental results do not lead to a simple rule that effectively predicts the
regioselectivity, we have performed a computational study designed to unravel the factors
controlling the regioselectivity of the nucleophilic addition of amines. Since its introduction into
8
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chemistry, the analysis of the conceptual DFT indices has become a powerful tool in the hand of
[31]
theoretical and synthetic chemists for analysis of chemical reactivity of organic compounds.
As well known, the reactivity of most organic molecules can be regarded as nucleophilic –
electrophilic interactions. All estimates of the site of electrophilic or nucleophilic attack strongly
depend on the theoretical approach. The Fukui indices provide, as a first approximation, a fair
gauge to evaluate the electrophilic sites of the molecules we have considered, in line with
previous results on structurally related electron deficient olefins. Another approach deals with
the calculation of the local electrophilicity and nucleophilicity index which is known to be able
to predict the best site for a nucleophilic or electrophilic attack.[32] We tried to compare these
approaches to theoretically explain the experimental selectivity of conjugate nucleophilic
addition of amine to pull-pull alkenes.
To quantify the relative importance of the physicochemical parameters involved and
better anticipate the reactivity of the studied substrates, first we carried out quantum-chemical
calculations of the Fukui index for all Michael acceptors 1a-f, using the Multiwfn package. [33]
The Fukui functions for olefinic centers were calculated according to the formula (1): [34]
+
fk = qk(N+1) – qk(N) (1)
+
where fk is a Fukui index for atom k, qk(N+1) and qk(N) – Hirshfeld charges for the
systems with N+1 and N electrons, respectively.
The results show that the relative electrophilicity of the carbon directly connected to the
trifluoromethyl group (for 1a) is slightly higher than that for the adjacent olefinic carbon (Table
3). In contrast, the double bond polarization in 1b and 1d is inverted by the acetyl group: in this
case the carbon attached to the ester function becomes the most electrophilic centre of the
molecule. Therefore, we have shown that, in general, Fukui parameters correlate well with the
reactivity of such systems, but not always.[35] Indeed, if Fukui indices predict correctly the site of
the nucleophilic attack,[36,37] they fail in some complex cases for which the local electrophilicity
index ωk, based on Hirshfeld charges, is generally preferred.[38,39]
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Table 3. Fukui functions for di- and tri-substituted alkenes 1a-e calculated at the
B3LYP/aug-cc-pVTZ level, e-.
+
fk


R
Entry
Michael
acceptor
EWG1 EWG2
Cβ
0.09
Cα
1
2
3
4
5
(E)-1a
(E)-1b
(Z)-1c
(E)-1d
(E)-1e
CF3 CO2Et
Ac CO2Me
CN CO2Et
NO2 CO2Et
H
0.06
0.07
0.13
0.09
0.15
H
H
H
0.03
0.11
0.03
0.11
CN CO2Me Ph
In fact, the data in Table 3 show that the Fukui functions predict correctly the best sites
for a nucleophilic attack. To confirm these results, we decided to compute the global and local
electrophilicity indices. However, the data obtained did not allow us to predict undoubtedly the
direction of nucleophilic attack due to the small range of variation (low sensitivity) of calculated
value (see SI, Tables S1, S2). To expand the range of changes we decided to estimate the local
electrophilicity index as an inverse local nucleophilicity. Previously, the similar approach was
successfully used to describe the regioselectivity of nucleophilic attack on the carbon – carbon
double bond of Michael acceptors as well as the reactivity of arenes and heteroarenes.[40]
We calculated, at the high triple-zeta level, 70 local electrophilicity indices for the α and
β centers of 5 substrates 1a-e in seven different models that account for the solvent effect
according to the standard criterion (see SI):
+
 loc= fk *2/2
We found that they assess correctly the regioselectivity of the addition, at least at a
qualitative level. However, the small differences between values of α- and β-olefinic atoms led
us to conclude that they cannot be used to unambiguously predict the direction of these
nucleophilic attacks.
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Because of electrophilicity and nucleophilicity are physically inverse of each other,[35] we
decided to calculate the inverse nucleophilicity indices for olefinic carbons of all studied
compounds as k = 1/(NNu*fk-). All 70 points showed a very good correlation with experiment
(see Table 4 and Figures 2). It was shown that the sensitivity of the proposed parameter to the
distribution of charges is significantly (more than 2 times) higher than that of the classical local
electrophilicity index.
This parameter can be expressed as the inverse of the nucleophilicity value:
(2)
The parameter Nk is itself defined by the equation:
(3)
where is a Fukui index for atom k, and NNu is a global nucleophilicity index expressed as:
(
)
(
)
(4)
where Nu represents the nucleophile, and TCE the tetracyanoethylene, whose HOMO energy is
chosen as the reference value.[41] The results of the theoretical study are presented in Table 4: the
larger the absolute value, the less electrophilic the site is.
Table 4. Inverse local nucleophilicity indices of the alkenes 1a-e calculated at the B3LYP/aug-
cc-pVTZ level, e-·eV.
Ethanol (Supermolecule) a
Atom
site
Gas
DMSO
Benzene Ethanol
Alkene
EWG1
EWG2
EWG1 + EWG2
phase (PCM)
(PCM)
(PCM)
α
β
α
β
α
β
12.64
8.84
7.30
14.03
5.73
6.72
23.31
17.02
8.01
25.83
16.04
7.75
26.36
19.21
8.54
29.01
21.96
17.47
19.34
14.45
19.31
14.43
10.66
11.24
36.85
10.78
10.039
81.46
48.50
25.13
47.02
28.31
47.89
1a
1b
1c
13.21
5.84
14.85
11.06
10.68
14.28
6.48
6.54
7.27
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α
β
α
β
5.77
5.83
13.85
5.14
5.71
15.12
7.02
5.82
13.93
5.17
7.75
31.72
6.49
7.29
10.19
48.54
40.32
83.17
1d
1e
16.41
4.86
22.35
7.07
13.56
6.98
9.34
7.04
11.35
10.60
a
Optimization of geometric parameters and calculation of the inverse local nucleophilicity indices for
intermolecular substrate-solvent complexes, in which the coordination of the proton of the ethanol hydroxyl group
was realized on EWG1, EWG2, and both EWG1 and EWG2, correspondingly.
These data show that the preferred site for the nucleophilic attack on enoate 1a is the β-
olefinic carbon: the inverse local nucleophilicity index value computed for the β-atom is >1,4
times lower than that for the α-atom. In contrast, the α-olefinic carbon of enoates 1b-e is the
most electrophilic centre of the molecule. The electron-withdrawing properties of both
substituents determine a bond polarity and, as a consequence, the regioselectivity. Note that only
for enoate 1c the inverse local nucleophilicity indices of olefinic carbons are similar. These
results suggest that the smallest changes in the reaction conditions could lead to changes in the
direction of the nucleophilic attack.
For acrylates 1a-d the inverse local nucleophilicity index of olefin atoms were calculated
in the gas phase (column 3). Solvent effects were simulated using a Tomasi IEF-PCM
[39]
polarizable continuum model
for aprotic (DMSO or benzene, column 4 and 5) or protic
solvents (ethanol, column 6) with the coordination at EWG1 (column 7) or EWG2 (column 8) or
at both functions (column 9).
These results show that, in almost all cases, the inverse local nucleophilicity index value
increases with respect to those obtained in absence of a continuum model. Therefore, the implicit
consideration of the medium polarity does not account for the solvent effect.
We thus decided to switch to supermolecules in which the solvent(s) are explicitly
incorporated. Actually, ethanol interacts with both EWGs of substrates 1, increasing their
electron-withdrawing properties. In all cases, a stable supramolecular complex is obtained with
two solvent molecules, no more. Therefore, the experimental results were best described when
both the explicit solvent molecules and the polarization IEF-PCM model were applied together.
The calculated inverse local nucleophilicity indices for 1a-e (Table 4) were used to plot
the dependence of these indices on the solvation models. We showed that the direction of the
preferable nucleophilic attack is the same for each model involving solvation effects (Figure 2).
Figure 2. The dependence of the inverse local nucleophilicity index calculated for
alkenes 1c and 1d on the type of solvation model.
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It is very interesting to note that the calculations of the inverse local nucleophilicity index
for alkene 1c bearing cyano- and alkoxycarbonyl groups allows to conclude that the nucleophilic
attack is equal on the both olefinic carbons. Only in boundary cases there is a shift towards the 
attack. This result is in excellent agreement with experimental data (Table 1, entry 12). Similar
graphs for alkenes 1a,b,e are given in SI (S52 S54). Their analysis lead to conclusion that in all
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cases the function ωk tends to converge to its limit with an increase in the number of solvated
molecules, taken into account explicitly. This is a strong evidence of the "performance" of the
proposed model and the possibility of its application in such calculations.
Another obvious factor influencing the regioisomers ratio is the selective activation or
deactivation of one of the functional groups. We thought that the interaction of 1 with a cation
exhibiting strong Lewis acid properties could lead to chelation complexes in which the olefin
would see its electron acceptor density map altered. To confirm this hypothesis, we added
lithium perchlorate (100 mol%) to the enoate 1c before reacting with benzylamine (Scheme 3). It
is well known that the lithium ion coordinates efficiently to the carbonyl oxygen.[43] This
complexation seems to decrease the π,π-conjugation between the ethoxycarbonyl group and the
carbon–carbon double bond. Nevertheless, this phenomenon is one among several factors and it
remains difficult to predict which regioisomer will benefit from the potential chelation.
Scheme 3. Lithium-mediated catalysis of nucleophilic addition
This is why the study was completed with a theoretical assessment of the possible lithium
cation effect in interaction with the enoate 1c. The results show that the unsolvated Li+ ends up
chelated by the carbonyl oxygen and the nitrogen atom of the cyano group (Fig. 3).
Topological analysis (AIM) of the electron density gives two bond critical points (3, -1) type.
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This corresponds to non-covalent interaction of lithium cation with both carbonyl oxygen and
cyano nitrogen.
Figure 3. AIM analysis of the optimized 1c-Li+ complex (MP2/aug-cc-pVTZ).
Interatomic distances are given in Å. Green dots correspond to the bond critical points (3, -1).
The obvious steric influence exerted by the double bond substituents was next evaluated
extending the reaction to the trisubstituted Michael acceptors 1e,f. We observed that if one of the
olefinic hydrogens is replaced by a phenyl (1e), the addition proceeds selectively to give the
expected α-amino esters 4ea or 4eb in high yield as the sole reaction product (Table 1, entries 16
and 17). Their structure was easily determined by NMR spectroscopy and confirmed by X-ray
data for 4ea (Fig. 4). It is worth mentioning that the inverse local nucleophilicity index computed
for the β-olefinic carbon of enoate 1e is larger than that for its α-centre (Table 4), in excellent
agreement with experimental data.
Figure 4. X-ray crystal structure of adduct 4ea.
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It should be noted that the effect of a phenyl substituent is highly dependent on its
conformation. Notably, the probability of nucleophilic attack on one of the electrophilic centres
of the acrylate 1e depends strongly on the conjugation between the double bond and the phenyl
moiety. Rising the dihedral angle  leads to the simultaneous increase of the electrophilicity of
the α-olefinic carbon atom (See, SI, Figure 3).
In contrast, when 3-cyanobut-2-enoate 1f was treated with an equimolar amount of
morpholine, the corresponding γ-morpholino ester 5 was isolated in moderate yield (Scheme 4).
If the β-olefinic carbon of 1f is probably more accessible than that of 1e, the electronic properties
of a methyl group do not favour the addition into the α-position. We suggest that the first step of
the reaction is a prototropic transformation of the initial α,β-enoate into its β,γ-isomer 6. In such
a case, a nucleophilic addition to the electron-deficient alkene bearing a terminal double bond
could afford the final adduct 5.
Scheme 4. Addition of morpholine to ethyl 3-cyanobut-2-enoate 1e.
Conclusion
In conclusion, Michael acceptors 1a-d bearing two vicinal electron-withdrawing groups behave
as electron-deficient olefins which react with nitrogen nucleophiles under mild conditions
(catalyst free, in most cases at room temperature and under atmospheric pressure). Our results
show that several parameters such as the substitution pattern of the olefin, the nature of the
solvent, or the presence of chelating cations (Li+) are likely to alter significantly the
regioselectivity of the addition. In spite of this complex dependence, the preferable direction of
the conjugate nucleophilic addition of amines to unsymmetrical alkenes bearing two vicinal
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EWG groups can be predicted on computational bases. We show in this paper that the Fukui
functions and local electrophilicity indices give good account on the reactivity of the competitive
electrophilic sites. But the best agreement was reached with inverse local nucleophilicity indices.
If these data obviously need to be further buttressed by a set of complementary experiments, they
already demonstrate that this simple chemistry opens a selective access to functionalized - or -
aminoesters from commercially available starting materials.
Experimental Section
1
13
19
15
General Remarks. H (400.1 MHz), C (100.6 MHz) F (376.5 MHz), and N (40.6 MHz)
NMR spectra were recorded on Bruker AVANCE 400 MHz spectrometer. Chemical shifts (δ)
are given in ppm; the coupling constants (J) are given in Hertz. The concerted application of 1H-
1
1H 2D homonuclear experiments NOESY and COSY as well as H-13C 2D heteronuclear
experiments HMBC and HSQC were used for the distinction of the carbon and proton
resonances. The IR spectra were recorded with a Bruker Vertex 70 FT-IR spectrometer and with
a portable Varian 3100 diamond ATR/FT-IR spectrometer. The GC/MS analyses were
performed with a Shimadzu GCMS-QP5050A instrument (EI, 70 eV). Agilent 6210 facility was
used for HRMS-ESI spectra recording. The silica gel used for column chromatography was 230-
400 Mesh. High pressure reactions were performed in a piston-cylinder type apparatus, designed
for pressures up to 20 kbar. All reagents were of reagent grade and were used as such or distilled
prior to use. All the solvents were dried according to standard procedures and freshly distilled
prior to use.
Computational details
[44]
Geometry optimization of 1a-e was performed with GAUSSIAN 09 code
at the B3LYP/cc-
pVTZ level.[45-47] Cartesian coordinates of the resulting structures are given in the Supporting
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Information. All calculated structures are minima on the potential energy surfaces as proved by
the absence of imaginary frequencies.
General procedure for the synthesis of esters 3 and 4.
A mixture of appropriate enoate 1 (1 mmol) and amine 2 (1 mmol) in ethanol (2 mL) was
maintained at room temperature for 48-72 h or heated in a sealed tube to 85°С for 7 h. The
solvent was evaporated in vacuo. The crude product was purified by column chromatography
(silica gel, eluent ether/hexane) to give target esters 3 or/and 4. The following compounds were
obtained by this procedure.
Ethyl 4,4,4-trifluoro-3-(morpholino)butanoate 3aa
Pale yellow oil, 179 mg, 70% yield; 1H NMR (CDCl3): δ 1.25 (t, J = 7.2 Hz, 3H, CH3), 2.50-2.70
(m, 4H, CH2, N(CH2)2), 2.80-2.90 (m, 2H, N(CH2)2), 3.55-3.65 (m, 5H, CH, O(CH2)2), 4.16 (q, J
= 7.2 Hz, 2H, OCH2); 13C NMR (CDCl3): δ 14.2 (CH3), 32.0 (CH2), 49.8 (N(CH2)2), 61.0
(CH2O), 62.6 (q, 2JCF = 26.4 Hz, CH), 67.6 (O(CH2)2), 126.5 (q, 1J = 290 Hz, CF3), 170.0 (C=O);
15N NMR (CDCl3): -344.4 ppm. IR (cm-1): ν 1116, 1157 (C-F), 1741 (C=O). MS (EI), m/z (%):
255 [M+, 11], 212 (31), 186 (72), 168 (100), 124 (45), 86 (46). Calculated for C10H16F3NO3: C
47.06; H 6.32; N 5.49. Found: C 47.20; H 6.25; N 5.48.
Ethyl 4,4,4-trifluoro-3-(benzylamino)butanoate 3ab
Oil, 247 mg, 90% yield; 1H NMR (CDCl3): δ 1.24 (t, J = 7.2 Hz, 3H, CH3), 1.63 (br.s., 1H, NH);
2.48 (dd, J = 15.5, 9.6 Hz, 1H, CH2), 2.68 (dd, J = 15.5, 4.0 Hz, 1H, CH2), 3.63-3.73 (m, 1H,
CHN), 3.86 (d, J = 13.0 Hz, 1H, NCH2), 4.00 (d, J = 13.0 Hz, 1H, NCH2), 4.10-4.25 (m, 2H,
13
OCH2), 7.25-7.35 (m, 5H, Ph); C NMR (CDCl3): δ 14.1 (CH3), 35.1, 52.1 (CH2N), 56.4 (q,
2JCF = 28 Hz, CH), 61.1 (OCH2), 126.5 (q, J = 284 Hz, CF3), 127.4, 128.3, 128.5, 139.6 (Ph),
169.5 (C=O); 19F NMR (CDCl3): -74.62 (d, J = 7.2 Hz) ppm. IR (cm-1): ν 1125 (C-F), 1738
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(C=O), 3356 (N-H). MS (EI), m/z (%): 275 [M+, <1], 188 (16), 106 (97), 91 (100). Calculated
for C13H16F3NO2: C 56.72; H 5.86; N 5.09. Found: C 56.74; H 6.13; N 5.12.
Ethyl 4,4,4-trifluoro-3-(N-benzyl-N-(2-methylbenzyl)amino)butanoate 3ac
Oil, 538 mg, 95% yield; 1H NMR (CDCl3): δ 1.25 (t, J = 7.1 Hz, 3H, CH3), 1.42 (d, J = 6.0 Hz,
3H, CHCH3), 2.67-2.71 (m, 2H, CH2), 3.63-3.73 (m, 1H, CHN), 3.84-3.86 (m, 1H, CHCH3),
3.87-3.97 (m, 2H, OCH2), 4.20-4.28 (m, 2H, NCH2), 7.25-7.45 (m, 10H, Ph); 13C NMR (CDCl3):
δ 14.3 (CH3), 24.5 (CHCH3), 35.3 (q, 2JCF = 1.7 Hz, CH2CO), 51.7 (CH2N), 57.6 (CHCH3), 61.3
(OCH2), 74.7 (q, 2JCF = 32 Hz, NCHCF3), 125.5 (q, J = 284 Hz, CF3), 126.9, 127.0, 127.1, 128.3,
128.5, 128.6, 140.5, 145.5 (Ph), 169.8 (C=O) ppm. IR (cm-1): ν 1129 (C-F), 1738 (C=O). MS
(EI), m/z (%): 379 [M+, <1], 364 (8), 274 (11), 196 (34), 91 (100). Calculated for C21H24F3NO2:
C 66.48; H 6.38; N 3.69. Found: C 66.69; H 6.55; N 3.64.
Methyl 2-(morpholin-4-yl)-3-oxopentanoate 4ba
1
Colourless needle crystals, 211 mg, 98% yield; mp 66ᵒC; H NMR (CDCl3): δ 2.16 (s, 3H,
CCH3), 2.35-2.50 (m, 2H, N(CH2)2), 2.55 – 2.70 (m, 3H, CH2, N(CH2)2), 3.02 (dd, J = 17.1, 9.2
13
Hz, 1H, CH2), 3.55-3.65 (m, 4H, O(CH2)2), 3.71 (s, 4H, CH, OCH3); C NMR (CDCl3): 30.3
(CH3CO), 42.9 (CH2), 50.3 (N(CH2)2), 51.6 (OCH3), 63.1 (CH), 67.4 (O(CH2)2), 171.3
15
(CO2Me), 206.2 (CH3CO); N NMR (CDCl3): -335.9 ppm. IR (cm-1): ν 1115, 1163 (C-O-C),
1724 (C=O). MS (EI), m/z (%): 215 [M+, 2], 156 (100), 114 (93) 43 (51). Calculated for
C9H15NO4: C 55.80; H 7.96; N 6.51. Found: C 55.67; H 7.77; N 6.32.
Methyl 2-(benzylamino)-4-oxopentanoate 4bb
1
Colourless oil, 135 mg, 57% yield; H NMR (CDCl3): 2.01 (s, 1H, NH), 2.09 (s, 3H, CH3CO),
2.65 – 2.90 (m, 2H, CH2CO), 3.57 – 3.75 (m, 5H, OCH3, CH, NCH2), 3.83 (d, J = 13.0 Hz, 1H,
13
NCH2), 7.13 – 7.34 (m, 5H, Ph); C NMR (CDCl3): 30.1 (CH3CO), 46.6 (CH2), 52.0 (OCH3),
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15
52.1 (CH2N), 56.4 (CH), 127.1, 128.2, 128.3, 139.6 (Ph), 174.4 (CO2Me), 205.9 (CH3CO); N
NMR (CDCl3): -336.0 ppm. IR (cm-1): ν 1730 (C=O), 3333 (NH). MS (EI), m/z (%): 235
[M+, <1], 177 (34), 176 (51), 144 (41), 134 (36), 117 (27), 106 (41), 91 (100), 65 (37), 43 (37).
Calculated for C13H17NO3: C 66.36; H 7.28; N 5.95. Found: C 66.48; H 7.10; N 5.95.
Ethyl 3-cyano-3-(morpholin-4-yl)propanoate 3ca
Pale yellow oil, 181 mg, 85% yield; 1H NMR (CDCl3): δ 1.22 (t, J = 7.1 Hz, 3H, CH3), 2.47 (m,
2H, N(CH2)2), 2.62 (m, 2H, N(CH2)2), 2.65 – 2.79 (m, 2H, CH2), 3.65 (m, 4H, O(CH2)2), 3.97 (t,
13
J = 7.7 Hz, 1H, CH), 4.14 (q, J = 7.1 Hz, 2H, OCH2); C NMR (CDCl3): δ 14.1 (CH3), 35.9
(CH2), 49.4 (N(CH2)2), 54.0 (CH), 61.3 (CH2O), 66.4 (O(CH2)2), 115.5 (C≡N), 168.7 (C=O); 15N
NMR (CDCl3): -337.5 (N(CH2)2), -125.5 (CN) ppm. IR (cm-1): ν 1119, 1195, 2230 (C≡N), 1737
(C=O). MS (EI), m/z (%): 212 [M+, 21], 156 (21), 126 (23), 125 (100), 112 (30), 109 (52), 86
(73), 54 (77), 42 (43). Calculated for C10H16N2O3: C 56.59; H 7.60; N 13.20. Found: C 56.75; H
7.60; N 12.98.
Ethyl 3-(benzylamino)-3-cyanopropanoate 3cb
1
Colourless oil, 125 mg, 54% yield; H NMR (CDCl3): δ 1.26 (t, J = 7.2 Hz, 3H, CH3), 2.11 (s,
1H, NH), 2.67 – 2.84 (m, 2H, CCH2), 3.73 – 4.11 (m, 3H, CH, NCH2), 4.18 (q, J = 7.2 Hz, 2H,
13
OCH2), 7.12 – 7.46 (m, 5H, Ph); C NMR (CDCl3): 14.1 (CH3), 38.0 (CH2), 45.6 (CH), 51.6
(CH2N), 61.2 (CH2O), 119.0 (C≡N), 127.6, 128.4, 128.6, 138.0 (Ph), 169.2 (C=O); 15N NMR
(DMSO-d6): -338.5, -130.8 ppm. IR (cm-1): ν 2230 (C≡N), 1734 (C=O). MS (EI), m/z (%): 232
[M+, 6], 175 (34), 159 (65), 104 (23), 92 (30), 91 (100), 77 (28), 65 (23). Calculated for
C13H16N2O2: C 67.22; H 6.94; N 12.06. Found: C 67.30; H 6.93; N 12.05.
Ethyl 2-(benzylamino)-3-cyanopropanoate 4cb
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1
Colourless oil, 75 mg, 32% yield; H NMR (CDCl3): 1.29 (t, J = 7.1 Hz, 3H, CH3), 2.18 (s, 1H,
NH), 2.59 – 2.76 (m, 2H, CH2), 3.53 (t, J = 6.3 Hz, 1H, NCH), 3.71 – 3.91 (dd, J = 35.1, 13.2
Hz, 2H, NCH2), 4.23 (dq, J = 7.2, 2.1 Hz, 2H, OCH2), 7.18 – 7.40 (m, 5H, Ph); 13C NMR
(CDCl3): 14.2 (CH3), 22.2 (CH2C≡N), 51.8 (CH2N), 56.5 (CHN), 61.9 (OCH2), 116.8 (C≡N),
127.5, 128.3, 128.6, 138.9 (Ph), 171.7 (C=O); 15N NMR (CDCl3): -336.8, -131.5 ppm. IR (cm-1):
ν 1193 (C-N), 1734 (C=O). MS (EI), m/z (%): 232 [M+, <1], 159 (20), 106 (19), 91 (100).
Calculated for C13H16N2O2: C 67.22; H 6.94; N 12.06. Found: C 67.26; H 6.94; N 11.69.
Methyl (2S,3S)-3-cyano-2-morpholino-3-phenylpropanoate 4ea
Colourless cubic crystals, 87 mg, 64% yield; mp 110ᵒC; 1H NMR (CDCl3): δ 2.48 – 2.60 (m, 2H,
N(CH2)2), 2.72 – 2.84 (m, 2H, N(CH2)2), 3.50 – 3.59 (m, 4H, CH3, NCH), 3.66 – 3.82 (m, 4H,
13
O(CH2)2) 4.31 (d, J = 10.9 Hz, 1H, CCH), 7.26 – 7.38 (m, 5H, Ph); C NMR (CDCl3): δ 38.6
(CCH), 50.5 (NCH), 51.7 (CH3), 67.3 (N(CH2)2), 71.3 (O(CH2)2), 119.0 (C≡N), 128.7, 128.9,
129.3, 132.6 (Ph), 168.0 (C=O). IR (cm-1): ν 1165, 1734 (C=O), 2247 (C≡N). MS (EI), m/z (%):
158 (100), 116 (27). Calculated for C15H18N2O3: C 65.68; H 6.61; N 10.21. Found: C 65.52; H
6.58; N 10.03.
Methyl 3-cyano-2-morpholino-3-phenylpropanoate 4ea (mixture of diastereomers 55:45)
1H NMR (CDCl3): δ 2.48 – 2.60 (2.29 – 2.37) (m, 2H, N(CH2)2), 2.72 – 2.84 (2.65 – 2.73) (m,
2H, N(CH2)2), 3.45-3.55 (3.67-3.75) (m, 1H, NCH), 3.55 (3.74) (s, 3H, CH3), 3.66 – 3.82 (3.44 –
3.51) (m, 4H, O(CH2)2) 4.31 (4.17) (d, J = 10.9 Hz, (J = 9.4 Hz), 1H, CCH), 7.26 – 7.38 (7.26 –
7.38) (m, 5H, Ph); 13C NMR (CDCl3): δ 38.6 (37.3) (CCH), 50.5 (50.4) (NCH), 51.7 (52.0)
(CH3), 67.3 (67.0) (N(CH2)2), 71.3 (71.3) (O(CH2)2), 119.0 (119.3) (C≡N), 128.7 (128.6), 128.9
(129.0), 129.3 (129.2), 132.6 (132.9) (Ph), 168.0 (168.8) (C=O) ppm. IR (cm-1): ν 1165, 1734
(C=O), 2247 (C≡N). MS (EI), m/z (%): 158 (100), 59 (18). Calculated for C15H18N2O3: C 65.68;
H 6.61; N 10.21. Found: C 65.53; H 6.60; N 10.03.
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Methyl 2-(benzylamino)-3-cyano-3-phenylpropanoate 4eb (55:45 mixture of diastereomers)
Pale yellow oil, 110 mg, 75% yield; 1H NMR (CDCl3): δ 2.17 (1.96) (br.s, 1H, NH), 3.56 (3.61)
(s, 3H, CH3), 3.55 – 3.71 (3.55 – 3.71) (m, 2H, NCH, NCH2), 3.74 (3.83) (d, J = 13.2 Hz, (J =
13.2 Hz), 1H, NCH2), 4.08 (4.19) (d, J = 5.1 Hz, (J = 6.5 Hz), 1H, CCH), 7.10 – 7.36 (7.10 –
7.36) (m, 10H, Ph); 13C NMR (CDCl3): δ 42.0 (41.3) (CCH), 52.2 (52.3) (NCH), 52.4 (52.5)
(CH3), 64.1 (63.1) (NCH2), 118.6 (118.8) (C≡N), 127.4, 127.5, 128.2, 128.3, 128.4, 128.5, 128.6,
128.8, 128.9, 129.0, 129.1, 131.4, 132.5, 138.8, 138.9 (Ph), 172.0 (171.4) (C=O). 15N NMR
(CDCl3): -339.3 (-340.7) (NH), -129.3 (-129.3) (C≡N) ppm. IR (cm-1): ν 1203, 1738 (C=O),
2245 (C≡N). MS (EI), m/z (%): 178 (22), 91 (100). Calculated for C18H18N2O2: C 73.45; H 6.16;
N 9.52. Found: C 73.33; H 6.12; N 9.67.
Synthesis of adduct 5.
The solution of morpholine 2a (1 mmol) in ethanol (2 mL) was added to 1 mmol of enoate 1e.
This mixture was placed in a tube and sealed. Than it was heated to 100°C for 5 h. The reaction
mixture was concentrated in vacuo and the crude product was purified by column
chromatography (silica gel, eluent ether/hexane).
Ethyl 3-cyano-4-morpholinobutanoate 5fa
Colourless oil, 54 mg, 24% yield; 1H NMR (CDCl3): δ 1.24 (t, J = 7.1 Hz, 3H, CH3), 2.40 – 2.56
(m, 5H, N(CH2)2, CCH2, NCH2), 2.56 – 2.72 (m, 3H, N(CH2)2, NCH2), 3.10-3.20 (m, 1H, CH),
3.56 – 3.70 (m, 4H, O(CH2)2), 4.15 (q, J = 7.1 Hz, 2H, CH2); 13C NMR (CDCl3): δ 14.2 (CH3),
26.0 (CH), 34.8 (CCH2), 53.7 (NCH2), 59.3 (N(CH2)2), 61.4 (OCH2CH3), 66.9 (O(CH2)2), 120.6
(C≡N), 170.0 (C=O) ppm. IR (cm-1): ν 1118, 1191, 1735 (C=O), 2244 (C≡N). MS (EI), m/z (%):
226 [M+, <1], 100 (100), 42 (16). HRMS Calculated for [C11H18N2O3+H]+: m/z = 227.139568.
Found: m/z = 227.13903.
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Acknowledgements
The spectral and analytical data were obtained using the equipment of the Baikal analytical
centre for collective use SB RAS to which authors are grateful. The high pressure experiments
have been run under the supervision of Dr Julien Legros and Prof. Isabelle Chataigner (CNRS &
University of Rouen Normandie) who are acknowledged for their advices and help.
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European Journal of Organic Chemistry
Entry for the Table of Contents
A. Rulev,* I. Zubkov, I. Ushakov,
V. Semenov, A. Vashchenko,
J. Maddaluno*
Regioselectivity of the conjugate
addition
of
amines
to
dissymmetrical pull-pull alkenes
The regioselectivity of the conjugate nucleophilic
addition of amines to vicinal di-acceptor-substituted
alkenes has been studied. The inverse local
electrophilicity indices give good account on the
reactivity of the competitive electrophilic sites.
27
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