Anti-Selective Organocatalytic Michael Addition between Phenylacetaldehyde and Nitrostyrene

Article abstract of DOI:10.1021/acs.joc.6b01061

Using the reaction between phenylacetaldehyde and nitrostyrene catalyzed by pyrrolidine as a simple model, we have studied the diastereochemical outcome of the organocatalytic Michael reactions between benzylic aldehydes and nitrostyrenes. We found that t

Full text of DOI:10.1021/acs.joc.6b01061

Note
pubs.acs.org/joc
Anti-Selective Organocatalytic Michael Addition between
Phenylacetaldehyde and Nitrostyrene
†
†
‡
§,⊥
Lucía Gandolfi Donadío, Mariana A. Galetti, Gianluca Giorgi, Marcello Rasparini,
,
†
and Maria J. Comin*
†Laboratory of Organic Synthesis, Center of Research and Development in Chemistry, National Institute of Industrial Technology,
Buenos Aires, Argentina
‡
Department of Biotechnologies, Chemistry & Pharmacy, University of Siena, 53100 Siena, Italy
§Chemessentia SRL, 28100 Novara, Italy
*
S Supporting Information
ABSTRACT: Using the reaction between phenylacetaldehyde
and nitrostyrene catalyzed by pyrrolidine as a simple model, we
have studied the diastereochemical outcome of the organo-
catalytic Michael reactions between benzylic aldehydes and
nitrostyrenes. We found that the anti adduct was obtained in
high yield and diastereoselection as was demonstrated by the X-
ray structure of the product. In situ NMR studies showed a
different reaction pathway when compared to aliphatic
aldehydes that yield the syn adduct as major isomer.
he stereoselective conjugate addition of chiral enamines to
Scheme 1. Organocatalyzed Conjugate Addition of
T
prochiral nitro alkenes to provide γ-nitro carbonyl
derivatives is widely recognized as a powerful tool to install
two adjacent stereogenic centers with high enantio- and
diastereoselectivity using a wide range of substrates. In fact,
the organocatalytic version has become a benchmark reaction
Aldehydes to Nitro Olefins
1
,2
for assessing new catalysts performance as well as for the
development of cascade reaction sequences.
3
−5
Accordingly,
many new organocatalysts displaying high syn diastereo- and
6
−8
enantioselectivity were developed.
Among them, the
silylated diphenylprolinol 1 proved to be particularly efficient
(Scheme 1).
The diastereochemical outcome of the reaction has been
generally rationalized assuming Seebach model that postulates
the attack of an enamine nucleophile to a Michael acceptor.
The syn selectivity is explained according to a preferential
acyclic synclinal transition state, where there are favorable
electrostatic interactions between the enamine nitrogen atom
9
and the nitro group in the transition state. Recent studies have
shed light on the mechanism of the catalytic process, but some
The simplicity and mildness of reaction protocol and the
opportunity for further elaboration of γ-nitro carbonyl
derivatives into valuable building blocks represents an
important synthetic transformation that allows for the
preparation of many products in a diastereo- and enantiose-
lective manner. A remarkable example is the synthesis of anti-
10−13
controversy regarding the reaction route still remains.
For
the case of monosubstituted nitro olefins, in situ NMR
spectroscopy, reaction calorimetry, and crystallographic studies
showed that cyclobutane species 4 are formed rapidly at the
onset of the reaction most likely through a zwitterionic
intermediate 3. At higher conversions, product enamine 6
becomes prevalent and thus, erosion of the diastereoselectivity
is observed (Scheme 1).
Received: May 6, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b01061
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
4,15
influenza drug (−)-Oseltamivir,
developed by Hayashi and
We first optimized reaction conditions. As the starting point,
we employed toluene as solvent, 0.5-fold excess of aldehyde,
24
co-workers. In addition to cascade reaction, its synthetic
versatility has been applied for the synthesis of γ-butyrolactones
and 3,4-disubstituted pyrrolidines that are common structural
units of natural products and pharmaceutically relevant
compounds, such as the histone deacethylase inhibitor 7
and a quantitative clean reaction occurred in the presence of 20
mol% of pyrrolidine as organocatalyst. There was no need to
use a large excess of aldehyde as no competing aldol pathways
6
1
,6,19,25
were observed.
Then, the effect of solvent nature on
16
developed by Roche, the bacterial peptide deformylase
inhibitor 8, and the NK2 receptor antagonist 9 (Scheme 2).
reaction performance was established. A high diastereoselection
was observed in most cases with only a small variation on the
product diasteriomeric ratio. In contrast, reaction rate was
strongly modulated by the solvent. Overall, toluene gave the
best results, smooth reaction occurred to generate the Michael
adduct in high conversions (≥99%) and excellent diaster-
eoselectivities (dr = 98:2) (Table S1). We then explored the
influence of catalyst’s nature on diastereoselection and reaction
rate (Table S2). So, we tested different secondary amines as
organocatalysts. Pyrrolidine and 3-pyrrolidinol gave the best
results in terms of both diastereoselection and conversion.
Consequently, pyrrolidine was selected for further studies due
to its wider availability. When the catalyst loading was reduced,
the diastereoselection was affected and low conversion was
observed within the same reaction period (Table S3).
1
7
18
Scheme 2. Pharmaceutically Relevant Compounds with trans
,4-Disubstituted Pyrrolidine Moiety
3
When designing an original synthetic route toward
antipsychotic drug (±)-Asenapine (10), we envisioned that
an organocatalyzed Michael addition between known aldehyde
Once the best reaction conditions were established, the
reaction was scaled up and the products were characterized in
detail. No variations in conversion and in diastereoselection
were observed during this process and we were able to perform
the reaction in a 36 mmol scale with excellent results. The
NMR spectroscopic data of the major diastereomer obtained
was in accordance with that already described for the syn
(
11) and nitrostyrene (12) could be used as key step for the
installation of the required substitution pattern at its central
disubstituted trans-pyrrolidine ring in a diastereoselective
fashion through the cis hemiacetal 13b (Scheme 3).
Scheme 3. Retrosynthetic Strategy Toward (± )-Asenapine
19−23
(10)
diastereomer
but, surprisingly, when the absolute relative
configuration was established through X-ray diffraction the
major product was identified as the anti isomer 17a (Figure
S2).
This result unequivocally shows that, in contrast to the
generally observed trend, the major diastereomer obtained by
the Michael reaction between 15 and 16 under our optimized
experimental conditions was anti. So, in this case, the course of
the reaction does not follow the stereochemical pathway
predicted by Seebach model. At least two possible explanations
could be given both related to the more acidic nature of
phenylacetaldehyde’s α protons. First, an alternative mecha-
nism involving deprotonation by pyrrolidine to give an enolate
favoring the anti product could be postulated. Second, the
higher thermodynamic stability of the conjugated product
enamine 18 could favor its formation over the hydrolysis of the
corresponding iminion ion of type 5 again favoring the
formation of the anti adduct. In this regard, we observed that
anti 17a is favored at higher conversions (Tables S3, entries 2,
Surprisingly, under all conditions assayed, we obtained
diastereomeric mixtures favoring the trans isomer 13a, derived
from the anti Michael adduct after spontaneous hemiacetal
formation.
The stereochemical outcome was different than that
observed for aliphatic aldehydes during this type of cascade
4
reactions. The desired hemiacetal product was isolated as a 5:1
diastereomeric mixture favoring the trans isomer 13a as
deduced from its crystal structure (Figure S1). This result
showed that in this case, the Michael addition preferentially
yielded the anti adduct.
3
, and 4) while syn 17b is formed preferentially at lower
Despite extensive studies on aliphatic aldehydes, very few
reports have addressed α-unsubstituted benzylic aldehydes as
conversions (Table S3, entry 1) suggesting that the anti nitro
aldehyde 17a might be the thermodynamic product.
1
9−23
substrates.
So, in order to understand this result, we
Therefore, in order to see if the enolate mechanism was
active, we tried the same reaction but using triethylamine
instead of pyrrolidine as catalyst. In this case, in spite of the
usually observed difficulty of generating enols or enolates from
studied the reaction between commercially available phenyl-
acetaldehyde (15) and nitrostyrene (16) as a simple model in
more detail (Scheme 4). In the case of 15, reported results
showed low syn diastereo- and enantioselectivity when
compared to the aliphatic counterparts.
26
naked aldehydes, a clean reaction took place and the desired
Michael adduct 17 was obtained as a 94:6 diastereomeric
mixture favoring the anti isomer 17a in quantitative yield.
For the sake of comparison, we tested our experimental set of
conditions on n-hexanal (19) as a model of aliphatic aldehydes.
Scheme 4. Organocatalytic Reaction between
Phenylacetaldehyde (15) and Nitrostyrene (16)
1
,27,28
In accordance with published data,
the reaction proceeded
cleanly favoring the syn adduct 20b (dr 62:38). In this case,
when pyrrolidine was replaced by triethylamine no reaction was
observed, indicating that the enolate pathway was not relevant.
B
DOI: 10.1021/acs.joc.6b01061
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The Journal of Organic Chemistry
Note
Figure 1. (A) Michael addition between 15 and 16 in the presence of an equimolar amount of pyrrolidine (ratio 1:1:1). The reaction was carried out
in an NMR tube: an equimolar amount of 16 was added to a suspension of preformed enamine 21 in the presence of 4 Å molecular sieves in toluene-
d8. (B) Idem A but without 4 Å molecular sieves. (C) Michael addition between 19 and 16 in the presence of equimolar amount of pyrrolidine (ratio
1
:1:1). The reaction was carried out in an NMR tube: an equimolar amount of 16 was added to a suspension of preformed enamine 23, in the
presence of 4 Å molecular sieves in toluene-d . (D) Idem C but without 4 Å molecular sieves.
8
With the aim of gaining understating on the reaction pathway
when pyrrolidine was used as organocatalyst, several H NMR
The same NMR experiment was made without molecular
1
sieves in order to study the formation of cyclobutane versus
Michael adducts (Figure 1B). In this case, an initial low
concentration of cyclobutane 22 (ca. 20%) was observed while
the emergence of product enamine 18 was predominant. The
amount of Michael adducts 17a and 17b was low, indicating
that deprotonation of the corresponding iminium ion
intermediate to give conjugated enamine 18 was much more
rapid than the nucleophilic attack on the iminiun C atom to
give 17.
experiments were performed. Recent mechanistic studies on
reactions between aliphatic aldehydes and nitrostyrenes
12,24,29
catalyzed by diaryl prolinol ethers
have identified four
(
cyclobutane, CB) and six (oxazine N-oxides)-membered cyclic
intermediates that play a central role in the reaction cycle.
These species are formed via [2+2] or [4+2] cycloadditions
between the enamine and the nitroalkene, respectively.
Therefore, we hypothesized that if we were able to detect the
presence of one of these intermediates for the model in study,
we could show that this mechanism was active. Consequently,
NMR experiments in stoichiometric conditions that would give
us evidence about possible intermediates of the organocatalytic
process were designed. In fact, the use of stoichiometric model
reactions proved to be a useful tool for the recognition of key
steps and for the understanding of the stereochemical courses
Again, we performed the same sequence of NMR experi-
ments on an aliphatic aldehyde (n-hexanal, 19). In the presence
of molecular sieves, we observed the spontaneous, fast, and
almost quantitative formation of cyclobutane intermediate 24
that then gradually converts into product enamine 25 (Figure
1C). Similar profiles have been reported for others aliphatic
12,24,29,30
aldehydes.
The structure of cyclobutane 24 was
11
of the catalytic process. First, we examined the formation of
enamine 21 from equimolar amounts of phenylacetaldehyde
and pyrrolidine in the presence of molecular sieves that
prevents enamine hydrolysis. Indeed, 21 was formed
quantitatively in less than 20 min. So, an equimolar amount
of nitrostyrene was then added and the formation of the
products and the intermediates were monitored (Figure 1A).
After 10 min, only a maximum ca. 15% of cyclobutane 22 was
detected that then decayed while product enamine 18 grew. We
were not able to isolate the cyclobutane intermediate because of
confirmed by 2D NMR experiments (Supporting Information).
Lastly, in the absence of molecular sieves, the Michael addition
between n-hexanal and nitrostyrene yielded cyclobutane 24
almost quantitatively (95% maximum) at the beginning of the
reaction and it then gradually decreased while Michael adducts
20a,b and product enamine 25 increased. In contrast to what
we have observed for phenylacetaldehyde, in the case of n-
hexanal, the rate of formation was higher for the syn Michael
adduct 20b than for product enamine 25 (Figure 1D). So,
NMR data confirms the typical reaction behavior for these kind
of aldehydes and suggests that the different results obtained
were only inherent to aldehydes nature. Indeed, a remarkable
difference in the rate of product enamine formation was
observed between both cases. As already mentioned, enamine
18 grows fast during the first hours of the reaction and is
1
its low concentration and stability. Nonetheless, H NMR
spectra of the stoichiometric reaction showed signals that share
24
the same pattern with those previously described. Moreover,
as previously observed for the case of monosubstituted nitro
olefins, no oxazine N-oxides were detected.
C
DOI: 10.1021/acs.joc.6b01061
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The Journal of Organic Chemistry
Note
indeed the major product over Michael adducts 17a and 17b at
any time. On the contrary, in case of n-hexanal, the major
product observed since the beginning of the reaction is the syn-
Michael adduct 20b and only at higher conversions values,
product enamine 25 concentration increases. Other important
difference observed is that for the benzylic aldehyde, the anti
adduct 17a is always formed preferentially over the syn isomer
thereof) were used to explain the multiplicities: s = singlet, d =
doublet, t = triplet, m = multiplet, br = broad. Chemical shifts of
carbon are referenced to the carbon resonances of the solvent.
General Procedure for the Organocatalytic Michael Addi-
tion between Aldehydes and Nitrostyrenes. To a stirred solution
of aldehyde (0.45 mmol) and nitrostyrene (0.30 mmol) in solvent (0.3
mL), catalytic amine (x mol%) was added. The reaction mixture was
stirred at room temperature. After complete consumption of the
nitrostyrene (as monitored by TLC), aq. 1 M HCl (1 mL) was added.
The mixture was stirred for 10 min at room temperature and extracted
with ethyl acetate (3 × 3 mL). The combined organic phases were
dried (Na SO ) and the solvent was removed in vacuo.
1
7b, whereas for n-hexanal, the syn isomer 20b is prevalent at
all conversion values.
It is well documented that acid additives play an important
role in accelerating the enamine-mediated Michael reac-
2
4
2
4,31,32
6-Chloro-3-(2-chlorophenyl)-4-(nitromethyl)chroman-2-ol (13).
Prepared from 5-chlorophenylacethaldehyde (11) and nitrostyrene
derivative (12), catalytic pyrrolidine (20 mol%), and toluene as solvent
tions.
So, we also studied its influence on our simple
model. When phenylacetaldehyde was used as substrate, no rate
acceleration (in fact the reaction was slower) and no changes in
the diastereochemical outcome were observed. In contrast, in
the case of n-hexanal, the reaction was complete within 50 min,
more than three times faster than without the additive. These
results add further evidence that for phenylacetadehyde both
mechanisms are active (Table S4).
33
34
according to general procedure. Starting materials 11 and 12 were
synthesized from commercially available compounds following
1
published procedures. H NMR of the crude showed a mixture of
two diastereomers (83:17) each one as a mixture of anomers. The two
diastereomers could be separated by column chromatography and
analyzed by NMR. After flash column chromatography purification
(hexane to 10% EtOAc in hexanes), the major product 13a was
In conclusion, we have shown that the Michael reaction
between benzylic aldehydes and nitrostyrenes derivatives afford
the anti-product with high diastereoselection as demonstrated
by its X-ray structures. From the NMR experiments, we can
conclude that in the case of phenylacetaldehyde the organo-
catalytic reaction does not show the typical profile. Under
stoichiometric conditions, the cyclobutane intermediate is
formed in a relative low ratio during the initial phase of the
reaction. The major product is the conjugated enamine 18 that
isolated in 79.5% yield (558 mg) as pale yellow crystals: mp 114−115
1
°
(
C; H NMR (400 MHz, CDCl ) δ (ppm) 7.60−6.85 (m, 7 H), 5.71
3
s, 0.2 H, minor anomer), 5.59 (s, 0.8 H, major anomer), 5.13 (dd, 0.2
H, J = 13.1, 7.8 Hz), 4.81 (dd, 0.2 H, J = 13.1, 6.3 Hz), 4.57 (m, 1.6
H), 4.31 (m, 0.8 H), 4.04 (d, 0.8 H, J = 12.1 Hz), 3.92 (s, 0.2 H), 3.87
(
2
t, 0.2 H, J = 7.1 Hz), 3.30 (d, 0.2 H, J = 3.3 Hz), 3.08 (d, 0.8 H, J =
13
.8 Hz); C NMR (100 MHz, CDCl ) δ (ppm) 149.6, 149.5, 136.0,
3
1
35.5, 134.0, 133.5, 130.1, 130.0, 129.7, 129.6, 129.4, 128.6, 127.8,
127.6, 127.5, 127.1, 126.9, 126.4, 123.3, 121.0, 119.4, 119.3, 93.4, 91.8,
11,30
facilitates, as it is well documented,
the erosion of the
80.5, 77.2, 41.2, 40.3, 36.5, 33.8; MS (EI) m/z (relative intensity)
+
diastereomeric ratio yielding the thermodynamic anti adduct
353.05 (M , 17.37), 306.05 (11.49), 291.05(10.79), 195.00 (12.62),
1
65.05 (13.07), 154.00 (100), 125.00 (83.66), 91.10 (53.01), 89.05
1
2
7a. On the contrary, in the case of n-hexanal, the cyclobutane
4 is formed quantitatively and the syn-Michael adduct 20b is
(
51.58); Anal. Calcd for C H Cl NO : C, 54.26; H, 3.70; N, 3.95.
16 13
2
4
Found: C, 53.93; H, 3.80, N, 3.77.
formed preferentially over the corresponding product enamine
5. These results evidence the different reaction pathways that
Anti-4-nitro-2,3-diphenylbutanal (17a) and syn-4-Nitro-2,3-
diphenylbutanal (17b). Compounds 17a and 17b were prepared
from phenylacethaldehyde (15) and nitrostyrene (16) and catalytic
pyrrolidine (20 mol%) and toluene as solvent according to general
2
are prevalent in each case. For benzylic aldehydes two
mechanisms are likely to be coexisting. The occurrence of the
enolate mechanism was demonstrated by the experiment where
triethylamine was used as catalyst and by the different reaction
profiles observed in the NMR experiments. On the other hand,
the presence of cyclobutane 22 evidenced the enamine-
mediated reaction route. Moreover, the effect of an acid
additive further proves the differences in reaction pathways in
agreement with the idea that probably not a single catalytic
1
procedure. H NMR of the crude mixture showed a dr (anti:syn) =
96:4. After flash chromatography (hexanes to 5% EtOAc in hexanes),
the diastereomeric mixture (anti:syn, 96:4) was isolated as a white solid
(80.5%, 7.60 g). Pure translucent white crystals corresponding to the
major isomer could be selectively isolated from a chloroform solution;
1
9
mp 157−160 °C, lit. 168−171 °C. Compound 17a (anti major
1
isomer): H NMR (400 MHz, CDCl ) δ (ppm) 9.56 (d, 1 H, J = 2.2
3
Hz), 7.45−7.25 (m, 10 H), 4.49 (dd, 1 H, J = 10.3, 12.8 Hz), 4.39 (dd,
11
cycle could be postulated for different reactants. The
important factor that may be governing the diastereochemical
outcome is the major thermodynamic stability of conjugated
product enamines derived from benzylic aldehydes that yield
toward the anti Michael adducts as was exemplified by 18.
Further work could probably lead to the development of new
asymmetric versions of antiselective Michael additions.
1
=
H, J = 4.4, 12.8 Hz), 4.30 (dt, 1 H, J = 4.4, 10.3 Hz), 4.07 (dd, 1 H, J
13
2.0, 10.2 Hz); C NMR (100 MHz, CDCl ) δ (ppm) 196.8, 137.0,
3
1
32.3, 129.8, 129.4, 129.1, 128.9, 128.2, 128.1, 78.4, 61.6, 44.3.
1
Compound 17b (syn isomer): H NMR (400 MHz, CDCl ) δ (ppm)
3
9.75 (d, 1 H, J = 1.1 Hz), 7.74−6.95 (m, 10 H), 4.92 (dd, 1 H, J = 5.2,
12.6 Hz), 4.78 (dd, 1 H, J = 8.8, 12.6 Hz), 4.26 (dt, 1 H, J = 5.5, 9.3
Hz), 4.01 (dd, 1 H, J = 0.9, 9.2 Hz).
(2-Nitro-1-phenylethyl)hexanal (20). Compound 20 was prepared
from hexanal, nitrostyrene, and catalytic pyrrolidine (20 mol%) and
toluene as solvent according to general procedure. The reaction
mixture was stirred at room temperature for 20 h. Compound 20 was
EXPERIMENTAL SECTION
■
General. All reactions were carried out under an atmosphere of
argon. Solvents were purified by standard procedures and distilled
before use. Reagents and starting materials obtained from commercial
suppliers were used as received unless otherwise stated. TLC was
performed on 0.2 mm silica gel 60 F254 aluminum supported plates.
Detection was effected by exposure to UV light or by spraying with 5%
isolated as a colorless syrup (62:38 syn/anti diastereomeric mixture,
1
89%, 633 mg): H NMR (400 MHz, CDCl ) δ (ppm) 9.71 (d, 0.62 H,
3
J = 2.8 Hz, syn isomer), 9.48 (d, 0.38 H, J = 3.0 Hz, anti isomer),
7.41−7.14 (m, 5 H), 4.84−4.75 (m, 0.76 H, anti isomer), 4.73−4.61
(m, 1.24 H, syn isomer), 3.86−3.72 (m, 1 H), 2.70 (m, 0.62 H, syn
isomer), 2.61 (m, 0.38 H, anti isomer), 1.76−1.10 (m, 6 H), 0.90 (m,
(
v/v) sulfuric acid in EtOH and charring. Mass spectra were recorded
2
8
on a GCMS mass spectrometer operating at 70 eV ionizing energy.
NMR spectra were recorded on a 400 MHz instrument, and chemical
shifts of protons are reported in parts per million downfield from
tetramethylsilane and are referenced to the proton resonances of the
solvent or TMS. The following abbreviations (or combinations
1
.14 H), 0.78 (t, 1.86 H, J = 6.7 Hz).
NMR Analysis of Reaction Intermediates under Stoichio-
metric Conditions. Reaction between Phenyl Acetaldehyde (15)
and Nitrostyrene (16). A NMR tube was charged with phenyl-
acetaldehyde (15, 7 μL, 0.06 mmol), MS (4 Å), pyrrolidine (5 μL, 0.06
D
DOI: 10.1021/acs.joc.6b01061
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The Journal of Organic Chemistry
Note
mmol), and toluene-d8 (500 μL) under argon atmosphere. The
Notes
suspension was shaken and this time was taken as time zero. Enamine
The authors declare no competing financial interest.
1
formation was monitored by NMR. After 10 min, the H NMR spectra
35
1
showed total conversion to enamine 21 (lit. ): H NMR (400 MHz,
ACKNOWLEDGMENTS
toluene-d ) δ ppm 7.21−7.10 (m, 5 H), 6.84 (d, 1 H, J = 13.9 Hz),
8
■
6
.93 (m, 1 H), 5.14 (d, 1H, J = 13.9 Hz), 2.83 (m, 4 H), 1.50−1.36
The research was supported in part by The National Institute
of Industrial Technology (INTI), Consejo Nacional de
(
m, 4H). At this point, 100 μL of a 0.6 M (toluene-d ) fresh stock
8
solution of nitrostyrene (16) was added. After the mixture was shaken,
NMR recordings were run until no further changes were observed in
the reaction profile.
́
́ ́
Investigacion Cientifica y Tecnologica (CONICET), Chem-
essentia SRL, and University of Siena. Authors acknowledge
Ing. Leandro Santos for NMR support.
Cyclobutane 22, 1-(2-Nitro-3,4-diphenylcyclobutyl)-
1
pyrrolidine. H NMR (400 MHz, toluene-d ) δ (ppm) 7.17−6.76
8
(
(
(
m, 10 H), 4.85 (dd, 1 H, J = 7.2, 8.7 Hz), 3.88−3.91 (m, 1 H), 3.65
REFERENCES
■
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(
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1
4
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1
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́
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2
(
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4
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8
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́
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8
(
(
C), 132.9−126.3 (CH), 133.3 (C), 108.9 (C), 80.5 (CH ), 67.5
2
CH), 52.1 (CH ), 26.3 (CH ).
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2
2
Reaction between Hexanal (19) and Nitrostyrene (16). A NMR
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8
atmosphere. The suspension was shaken and this time was taken as
́
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1
the H NMR spectra (400 MHz, toluene-d ) δ ppm 6.11 (d, 1 H, J =
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8
́
1
2
3
3.6 Hz), 4.18 (dt, 1 H, J = 13.6, 7.0 Hz), 2.79 (t, 4 H, J = 6.4 Hz),
.05−2.15 (m, 2 H) 1.48−1.57 (m, 4 H) 1.36−1.46 (m, 4 H), 0.94 (t,
H, J = 7.1 Hz) showed total conversion to enamine 23; and 100 μL
1
(
273−1277.
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of a 0.6 M (toluene-d ) fresh stock solution of nitrostyrene was added.
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4
(
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pyrrolidine. H NMR (400 MHz, toluene-d ) δ (ppm) 7.13−7.01
8
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(
m, 5 H), 4.68 (dd, 1 H, J = 6.8, 8.6 Hz), 3.36 (t, 1 H, J = 8.9 Hz), 3.17
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jcomin@inti.gob.ar
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