Mechanistic Studies on the Michael Addition of Amines and Hydrazines to Nitrostyrenes: Nitroalkane Elimination via a Retro-aza-Henry-Type Process

Article abstract of DOI:10.1021/acs.joc.7b02637

In this article we report on the mechanistic studies of the Michael addition of amines and hydrazines to nitrostyrenes. Under the present conditions, the corresponding N-alkyl/aryl substituted benzyl imines and N-methyl/phenyl substituted benzyl hydrazones were observed via a retro-aza-Henry-type process. By combining organic synthesis and characterization experiments with computational chemistry calculations, we reveal that this reaction proceeds via a protic solvent-mediated mechanism. Experiments in deuterated methanol CD₃OD reveal the synthesis and isolation of the corresponding deuterated intermediated Michael adduct, results that support the proposed slovent-mediated pathway. From the synthetic point of view, the reaction occurs under mild, noncatalytic conditions and can be used as a useful platform to yield the biologically important N-methyl pyrazoles in a one-pot manner, simple starting with the corresponding nitrostyrenes and the methylhydrazine.

Full text of DOI:10.1021/acs.joc.7b02637

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Article
Mechanistic studies on the Michael addition of amines and hydrazines to
nitrostyrenes: Nitroalkane elimination via a retro-aza-Henry type process
Michael G. Kallitsakis, Peter D. Tancini, Mudit Dixit, Giannis Mpourmpakis, and Ioannis N. Lykakis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02637 • Publication Date (Web): 22 Dec 2017
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Mechanistic studies on the Michael addition of
amines and hydrazines to nitrostyrenes: Nitroalkane
elimination via a retroꢀazaꢀHenry type process
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Michael G. Kallitsakis†, Peter D. Tancini‡,§, Mudit Dixit‡,§, Giannis Mpourmpakis‡,* and Ioannis
N. Lykakis†,*
†Department of Chemistry, Aristotle University of Thessaloniki, University Campus 54124,
Thessaloniki, Greece; Tel: +30 2310 997871, lykakis@chem.auth.gr
‡Department of Chemical Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania
15261, United States.; gmpourmp@pitt.edu
KEYWORDS: retro azaꢀHenry • pyrazoles • hydrazones • nitrostyrenes • mechanistic studies •
Michael addition
ABSTRACT: In this article we report on the mechanistic studies of the Michael addition of
amines and hydrazines to nitrostyrenes. Under the present conditions the corresponding Nꢀ
alkyl/aryl substituted benzyl imines and Nꢀmethyl/phenyl substituted benzyl hydrazones were
observed via a retroꢀazaꢀHenry type process. By combining organic synthesis and
characterization experiments with computational chemistry calculations, we reveal that this
reaction proceeds via a protic solvent mediated mechanism. Experiments in deuterated methanol
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CD3OD reveal the synthesis and isolation of the corresponding deuterated intermediated Michael
adduct, results that support the proposed solvent mediated pathway. From the synthetic point of
view, the reaction occurs under mild, non catalytic conditions and can be used as a useful
platform to yield the biologically important Nꢀmethyl pyrazoles in a oneꢀpot manner, simple
starting with the corresponding nitrostyrenes and the methylhydrazine.
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INTRODUCTION
Nitrostyrenes is a versatile class of compounds with a widespread use in organic chemistry.1,2
As a result, several synthetic routes have been developed for their preparation.3 The most
common methodology incorporates the Henry condensation reaction between aliphatic
nitroalkanes and carbonyl compounds, followed by a subsequent dehydration step, to yield
conjugated nitroalkenes, i.e. nitrostyrenes.3,4 Remarkably, the modified azaꢀHenry reaction that
yields βꢀnitroamine and/or 1,2ꢀdiamine compounds, via a nucleophilic addition of nitroalkanes to
imines, has been considered of great importance, towards Nꢀheterocycle organic molecules
synthesis.5
The Michael addition of heteroatomꢀcentred nucleophiles to nitrostyrenes is a reaction of high
interest,6 since it comprises a promising route for CꢀC/CꢀN coupling, and/or introducing two
heteroatoms in vicinal positions. In recent years, the methodologies which include the addition of
nitrogenꢀbased nucleophiles to nitrostyrenes have attracted considerable attention.7,8 For the
preparation of azaꢀHenryꢀproducts, the selective conjugate addition of arylamines to
nitrostyrenes under Brønsted acid catalysts or transition metalꢀcatalyzed conditions, has been
reported.8 Moreover, the Michael addition of arylamines to nitrostyrenes under aqueous
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conditions or a catalyst/solventꢀfree procedure has been developed.9 Interestingly, during the
nucleophilic addition of trimethylsilyl cyanide to the nitroalkenes, a HNO2 elimination10 toward
the synthesis of 1,2ꢀdicyanoalkanes11 has been proposed (Scheme 1).
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In this work, we performed experimental and theoretical studies on the Michael addition of
amines or alkyl substituted hydrazines to nitrostyrenes under non metalꢀcatalyzed conditions. A
nitroalkane elimination occurred during the present reaction leading to the corresponding Nꢀ
alkyl/aryl substituted benzyl imines and Nꢀmethyl/phenyl substituted benzyl hydrazones with
high selectivity and yields. This chemical transformation found to be dualꢀcatalyzed, by the
presence of protic solvent (e.g. MeOH, H2O) and the excess of amine, as demonstrated by both
experimental and theoretical results. This nitroalkane elimination process occurs via a retroꢀazaꢀ
Henry type transformation and its mechanism was not reported in details in the literature so far.
Sporadic examples on the formation of the Nꢀsubstituted benzyl imine derived from the reaction
between the nitrostyrene and the butylamine were reported in different studies, such as in the
pyrrole synthesis catalyzed by Sm(OiꢀPr)3 using nitroalkenes, carbonyl compounds and
butylamine as starting materials,8g in the Michael addition of amines or thiols into nitroalkenes
for the synthesis of enamines in water,8f and recently in the heteroꢀMichael addition of
nucleophiles into nitrostyrenes.8b In all cases, the observed Nꢀbutyl or benzyl benzyl imines were
formed as side products accompanying with the desired Michaelꢀadducts. Based on these
observations and according to our general interest on the mechanistic studies on the catalytic
synthetic methodologies12 in the presence or absence of metal nanoparticles, herein we present ꢀ
for the first timeꢀ a detail mechanistic study on the retroꢀazaꢀHenry type process (which is
described by a nitroalkane elimination) during the reaction of amines or alkyl substituted
hydrazines with nitrostyrenes. To the best of our knowledge, the later chemical transformation
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with hydrazines has been limited reported before, i.e. the PMoA/MCMꢀ41 heterogeneous
catalyzed azaꢀMichael reaction of hydrazides with nitroolefins13a and the reactions of 3ꢀβꢀ
nitrovinyl indoles with phenylhydrazine.13b,c
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Scheme 1. AzaꢀMichael addition of NꢀNucleophiles to nitrostyrenes.
RESULTS AND DISCUSSIONS
In this work, to optimize the reaction conditions, we initially investigated the reaction between
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4ꢀmethylꢀnitrostyrene 1 and butylamine (nBuNH2) in a variety of solvents at 60 C (Table 1).
Interestingly, instead of the expected azaꢀMichael adduct, the corresponding imine 2 was formed
as the only product, via a MeNO2 elimination within 20 min. Protic solvents, such as MeOH and
EtOH or even H2O, proved to be the most suitable for the reaction forming the corresponding
imine (2) in quantitative yields (Table 1, entries 1, 2 and 6). The reaction was also completed in
the presence of 1.5 equiv. of the amine or lower temperature, (Table 1, entries 3 and 4), requiring
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however longer reaction times. The use of an equimolar amount of 1 and butylamine yields a
mixture of 2 and an azaꢀMichael adduct (3) (Table 1, entry 5). Notably, 2 was isolated after
simple filtration over a short pad of silica, without the requirement of any chromatographic
purification, with E stereochemistry as demonstrated by 1D NOE experiment. In the case of nonꢀ
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polar or protic solvents, the azaꢀMichael adduct (3) was observed by HꢀNMR as the only or
major product (Table 1, entries 7ꢀ10). Nevertheless, addition of small amount of water (20 ꢁL,
0.2% V/V) or MeOH (50 ꢁL, 0.5% V/V) in THF and MeCN, increases the reaction conversion
and 2 is obtained as the major product (Table 1, entries 12ꢀ15). These results suggest that small
excess of the protic solvent or amine are necessary to drive the synthesis of 2 via a nitromethane
elimination (retroꢀazaꢀHenry type process). The reaction was incomplete with lower amounts of
nBuNH2 (less than 1 equiv.), while using 3 or 4 equiv. of nBuNH2 a fast reaction process was
1
observed (by H NMR) with a completion time ca. 10 min in which 2 was obtained in >99%
yield (results not shown). The use of acetone as solvent yields solely the 5ꢀnitroꢀ4ꢀ(pꢀtolyl)
pentanꢀ2ꢀone, sees Figure S1 in SI and Table 1, entry11. In all cases, the relative amounts of
1
products 2 and 3 were measured from the appropriate signals in H NMR spectra of the crude
mixtures, after simple filtration over a short pad of silica with MeOH as the eluent. In an attempt
to extend this protocol by incorporating secondary and tertiary amines, the 4ꢀ
methylbenzaldehyde was isolated as the only product from the reaction of 1 with piperidine,
through probably a hydrolysis of the corresponding in situ formed iminium, while no reaction
product was observed when pyridine or triethylamine were used (Figure S2). An addition
experiment was performed in the presence of equimolar amounts of butylamine and piperidine;
however, the only observed product was the corresponding benzyl imine by 1H NMR. This result
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confirms that primary amines react in a faster manner that the secondary amine under the present
conditions.
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Table 1. Solvent screening regarding the proposed retroꢀazaꢀHenry type reaction of 1 with
butylamine
Entry
1
Solventa
EtOH
Conversion (%)b
2 (%)c
87
>99
95
92
58
90
ꢀ
3 (%)c
>99
>99
>99
>99
88
12
2
3d
4e
5f
MeOH
MeOH
4
7
MeOH
MeOH
30
8
6
7g
8g
9g
10g
11h
12
13
14
15
H2O
98
THF
75
75
66
67
72
ꢀ
MeCN
78
12
ꢀ
Toluene
DCE
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72
ꢀ
Acetone
THF/H2O
MeCN/H2O
THF/MeOH
MeCN/MeOH
98
ꢀ
96
65
82
61
85
31
12
27
8
94
88
93
a Conditions: 1 (0,2 mmol), nBuNH2 (2 equiv.), solvent (1 mL), at 60 oC. b Based on the consumption of 1
1
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determined by H NMR. The relative amounts of 2 and 3 measured by the appropriate proton signals
1
d
from the H NMR after simple filtration of the crude mixture over a short pad of silica. 1.5 equiv. of
e
f
nBuNH2 based on 1 amount were added for 30 min. The reaction performed at r.t. for 1h. Equimolar
mixture of 1 and nBuNH2 was used and a mixture of azaꢀMichael adduct and 2 were observed by NMR. g
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h
A mixture of azaꢀMichael adduct and 1 were observed by NMR. 5ꢀnitroꢀ4ꢀ(pꢀtolyl) pentanꢀ2ꢀone was
formed as the only product (see also Figure S1).
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Based on the above results, we focused on the substrate scope of the present retroꢀazaꢀHenry
type process by examining the reaction between a series of pꢀsubstituted nitrostyrenes (1, 4ꢀ11)
with the alkyl, benzyl or substituted anilines (R4NH2). Notably, in the presence of alkyl or benzyl
amine (2 equiv., based on nitrostyrene amount), all reactions were completed within 30 minutes
at 60 oC, producing the desired imines 2, 13ꢀ22 in excellent yields (Scheme 2). Also, imine 2 was
formed even when alkyl groups Me (10) and Et (11) were incorporated to the αꢀposition (R) of
the nitroꢀgroup, through the elimination of the nitroethane and nitropropane, respectively, as
shown in Scheme 3.
Scheme 2. Synthesis of various Nꢀsubstituted phenylmethanimines and Nꢀsubstituted
hydrazones via a retroꢀazaꢀHenry type reaction
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R4
NO2
HN
R4
MeOH
+ R4-NH2
(2 eq.)
N
60 oC, 30 min
X
-RCH2NO2
NO2
X
R4= alkyl, benzyl, aryl
7
X
2, 13-27
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9
1
4
X= 4-Me( ), 4-H( ), 4-MeO
(5), 2-MeO (6), 4-NO2 (7),
4-Cl ( ), 4-Br ( )
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N
N
N
N
Me
2 (97%)
13
(99%)
OMe 15 (93%)
MeO
Br
14 (94%)
N
N
N
N
16 (97%)
O2N
17
18
(96%)
Cl
(97%)
19
(97%)
Me
Me
N
N
N
N
Me
Me
Me
20 (99%)
Me
21 (96%)
22 (96%)
23
(93%)
OMe
OMe
OMe
OMe
N
N
OMe
MeO
N
N
Me
Me
Br
24 (93%)
25 (94%)
27
(93%)
26 (95%)
H
NO2
N
MeOH
R5 NHNH2
N
R5
+
60 oC, 1-3h
X
(4 eq.)
X
-CH3NO2
31, 33-40
R5= H, Me, Ph
X= 4-Me(1), 4-H(4),
5
8
4-MeO ( ), 4-Cl ( ),
4-Br (9), 3,4-diMeO (12)
H
H
H
N
Me
N
N
N
Me
Me
N
N
Me
MeO
34 (97%, 1h)
33 (97%, 3h)
31 (95%, 2h)
H
H
H
N
N
Me
N
N
Me
Me
N
N
MeO
Cl
Br
OMe
35 (98%, 1h)
36
37
(99%, 3h)
(95%, 3h)
N
Me
N
H
N
NH2
N
Me
N
Me
Me
Me
38 (97%, 1h)
39 (99%, 2h)
40 (99%, 2h)
Scheme 3. Nitromethane, nitroethane and nitropropane elimination during the reaction of
αꢀalkyl substituted nitrostyrenes with nBuNH2.
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In the case of substituted anilines, the reactivity of the substrates is in accordance to the
electronic nature of the pꢀsubstituent. In specific, anilines substituted with electronꢀdonating
groups (EDG) accelerated the reaction process giving the imines 23ꢀ27 in high yields, whereas
no imine formation was detected using anilines bearing electronꢀwithdrawing groups (EWG)
such as COOEt and CN (results not shown). On the other hand, the reaction of aniline, 4ꢀClꢀ
aniline and 2ꢀaminopyridine leads to the formation of the corresponding Michael adducts 28ꢀ30
exclusively (see Figure S3).
To extend our work, we also study the possible nitroalkane elimination in the reaction between
hydrazine and a series of substituted nitrostyrenes under the same reaction conditions described
above. During the reaction conditions evaluation, four equivalents of the corresponding
hydrazine and prolonged reaction time (1ꢀ3h) found to be required for the reaction completion
(Table 2 and Scheme 2). Among the solvents studied, methanol provided quantitative formation
of the corresponding Nꢀmethyl benzyl hydrazone 31 (Table 2, entries 2 and 4), while in ethanol,
lower yield was observed (Table 2, entry 1). In contrast, the corresponding Nꢀmethyl hydrazaꢀ
Michael adduct 32 was observed accompanying with a mixture of unidentified products, within
non polar or aprotic solvents, such as acetonitrile (MeCN), 1,2ꢀdichloroethane (DCE), toluene
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and tetrahydrofurane (THF), as shown in Table 2, entries 5ꢀ8. Similar to amines, the presence of
small amount of water or methanol in THF accelerated the reaction process leading to the
corresponding Nꢀmethyl hydrazo compound 31 in higher yields (42 and 64%, respectively, Table
2, entries 9 and 10). These results indicate that the present of a protic solvent is necessary for the
completion of the present retroꢀaza or hydrazaꢀHenry process. In general, the reactions of
electronꢀrich substituted nitrostyrenes (4Meꢀ and 4MeOꢀ) proceeded faster than the reactions of
electron deficient nitrostyrenes (4Clꢀ and 4Brꢀ) based on the reaction time completion (see
Scheme 2). All the products were determined by 1H NMR spectroscopy (see SI). Based on these
reaction condition evaluations, a series of substituted nitrostyrenes were tested in the presence of
Nꢀmethylhydrazine, N,Nꢀdimethyl hydrazine and Nꢀphenyl hydrazine. In all reactions, the
corresponding Nꢀmethyl or Nꢀphenyl substituted benzyl hydrazones (31, 33ꢀ40) were formed in
high yields, as shown in Scheme 2.
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Table 2. Solvent screening regarding the proposed retroꢀazaꢀHenry type reaction of 1 with
Nꢀmethylꢀhydrazine.
entry
1
solventa
EtOH
Conversionb (%)
31 (%)c
32 (%)c
100
100
ꢀ
86
>99
ꢀ
13
ꢀ
2
MeOH
MeOHd
MeOHe
MeCN
DCE
3d
4e
5f
ꢀ
100
>99
>99
>99
ꢀ
ꢀ
34
27
6f
ꢀ
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7f
8f
9g
Toluene
THF
>99
>99
ꢀ
ꢀ
25
37
58
THF/H2O
100
100
42
64
8
9
10g THF/MeOH
36
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b
aConditions: 1 (0,2 mmol), MeNHNH2 (4 equiv.), solvent (1 mL), measured by H NMR. Based on the
consumption determined by HꢀNMR. cThe relative amounts of 31 and the azaꢀMichael adduct 32
1
1
measured by the appropriate proton signals from the H NMR after simple filtration of the crude mixture
d
over a short pad of silica. No conversion was observed when the reaction performed at room
e
f
temperature. The reaction was completed after 5h using 3 equiv. of MeNHNH2. A mixture of the
corresponding Michael adduct 32 with unidentified products were observed by 1H NMR. g Water (20 ꢁL,
0.2% V/V) or MeOH (50 ꢁL, 0.5% V/V) was added into the solvent.
To gain an inꢀdepth understanding of the imine formation mechanism we performed firstꢀ
principles theoretical calculations (See sections SIꢀ3, SIꢀ4 and SIꢀ5 of the SI). Specifically, we
performed Density Functional Theory (DFT) calculations using the Gaussian09 package14 to
investigate the different possible mechanistic pathways for the reaction of transꢀβꢀnitrostyrene
(4) with methylamine in methanol as the implicit solvent.
Among the various pathways studied, the most energetically preferred pathway is shown in
Figure 1 (i.e. pathway exhibited the lowest free energy barriers). Initially, the free energy profile
was calculated without accounting for any explicit solvent molecules (Figure 1, orange profile
for implicit solvent). Our reference point is transꢀβꢀnitrostyrene, A (4), interacting with
methylamine. In the first step of the reaction, A, reacts with methylamine to yield adduct B with
a low barrier of 8.8 kcal/mol, with this step being almost thermoꢀneutral. The proceeding step,
B→C, is an energetically demanding step (proton transfer from the amineꢀgroup to the C
neighbouring the nitroꢀgroup) with a free energy barrier of 28.9 kcal/mol due to a strained fourꢀ
membered transition state. The formation of D requires the breaking of a strong CꢀC bond,
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therefore, it is again a highꢀbarrier process with a free energy barrier of 27.9 kcal/mol.
Subsequently, a proton abstraction to yield E occurs via a small free energy barrier. Interestingly,
the above noted high barriers (which are unlikely to be achieved at the reaction temperatures)
were found to be lowered by the solvent and presence of excessꢀreactant methylamine by means
of transition state stabilization, or destabilization of the initial state. Specifically, including
explicit methanol in our calculations (Figure 1, grey profile) significantly lowers the free energy
barrier of proton transfer for B to C transformation, from 28.9 to 12.6 kcal/mol. This is because
the reaction now occurs via a sixꢀmember transition state, compared to the strained, 4ꢀmember
transition state in the orange path. These results clearly demonstrate the importance of protic
solvents for this reaction (e.g. presence of methanol or water), as noted experimentally (Table 1).
Methanol mediates the proton transfer from the amineꢀgroup to the carbon, decreasing the energy
barrier of this step. However, for the subsequent steps, the assistance of methanol was not found
to be significant.
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Figure 1. Free energy profiles (in kcal/mol) for the reaction of 4 (A) with methylamine to yield
Nꢀmethylꢀ1ꢀphenylmethanimine in methanol, as solvent. The orange pathway represents the free
energy profile with implicit solvent (methanol), whereas, the grey and the black pathways
represent the cases where we account an explicit methanol and methylamine molecule,
respectively. The free energies in the grey and black profiles have been adjusted by the
adsorption energy of the explicit molecule for purposes of comparison.
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Comparatively, the inclusion of an explicit methylamine molecule resulted in lowering the
free energy barrier from 28 to 24 kcal/mol for the C to D transformation and the stabilization of
the intermediate D (less endothermic formation energy from C). We also note that two explicit
methylamine molecules can further reduce this reaction barrier to 20 kcal/mol. It is noteworthy
that excess amount of methylamine was found to be important in our experiments for the
reaction to occur. It should also be noted that we have performed additional calculations to
evaluate if the protic solvents can catalyse the reaction acting as Brønsted acid catalysts.
However, we calculated the protonꢀcatalysed reaction barriers to be very high, eliminating such a
possibility and further supporting that the protic solvents act as protonꢀmediating molecules.
To further confirm this protonꢀmediating role of the solvent (methanol) that the first principles
calculations revealed, we performed isotopic labeling experiments, using CD3OD as solvent.
Interestingly, we indeed observed that the reaction rate between the aniline and nitrostyrene 4
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was dramatically decreased (ca. 2h for reaction completion at 60 C) compared to the reaction
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performed in MeOH (ca. 20 min at 60 C). Also, the corresponding deuterium labeled azaꢀ
Michael C4ꢀd intermediate was observed by 1H NMR with a deuterium labeled ratio of C4ꢀd/C4
= 85/15 (see Figure S5). This experimental finding supports the computationalꢀidentified role of
the protic solvent, in which methanol act as a protonꢀmediating molecule (Figure 2), via an
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energetically favourable sixꢀmember transition state, for the formation of the azaꢀMichael adduct
C.
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Figure 2. Isotopic labeling experiments for the azaꢀMichael addition pathway of aniline to
nitrostyrene 4.
To extend the applicability of our proposed reaction we attempted to synthesize a series of Nꢀ
methyl pyrazoles in an oneꢀstep manner, through a plausible stepwise pathway reaction between
the in situ formed Nꢀmethyl benzyl hydrazone derivatives and the nitrostyrenes (for experimental
details and pyrazoles characterization see SI).15 In general, the reactions were tolerant to a
variety of electronꢀrich or electron deficient substrates affording polysubstituted homoꢀNꢀMeꢀ
pyrazoles 41ꢀ44 and heteroꢀNꢀMeꢀpyrazoles 45ꢀ50 in regioselective manner and in high isolated
yields (Scheme 4). No pyrazole formation was observed using hydrazone 38, NꢀNꢀdimethyl
substituted hydrazone 39 and Nꢀphenyl substituted hydrazone 40, as shown in Figure S4. In
details, hydrazone 38 gave the corresponding azide16 as the only product, however, NꢀNꢀ
dimethyl substituted hydrazone 39 and Nꢀphenyl substituted hydrazone 40 leads to a mixture of
unidentified products. It is interesting that the present oneꢀpot synthetic procedure has been also
tested to a 3 mmol labꢀscale reaction, with the formation of 41 in 79% isolated yields.
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Scheme 4. Oneꢀpot synthesis of Nꢀmethyl substituted pyrazoles from nitrostyrenes and Nꢀ
5
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methyl hydrazine
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Based on these experimental and theoretical studies we propose in general that nitrostyrenes in
the presence of amines or hydrazines undergoes a retroꢀazaꢀHenry type process, in which Nꢀ
substituted benzyl imines or Nꢀsubstituted benzyl hydrazones are formed respectively, through a
nitroalkane elimination pathway. In details, at initial step an azaꢀMichael addition occurs
forming the corresponding azoꢀ or hydrazo adduct intermediate I, that in the presence of one
molecule of protic solvent (i.e. methanol) transformed into the corresponding intermediate II, as
shown in Scheme 5. This transformation take place through a sixꢀmember transition state (TS),
results that supported from the theoretical calculations and clearly demonstrate the importance of
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the protic solvents for this reaction, as also noted experimentally (Table 1). Methanol mediates
the proton transfer from the amineꢀgroup to the carbon, decreasing the energy barrier of this step.
For the subsequent step, the small excess of the amine or hydrazine (R’NH2) found to assist the
deprotonation step of the intermediate II giving the corresponding Nꢀsubstituted benzyl imine or
hydrazone and the nitroalkane (i.e. CH3NO2 for the nitrostyrene derivatives) as the reaction
products.
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Scheme 5. Proposed mechanism for the present retroꢀazaꢀHenry type process
CONCLUSIONS
Herein, detail mechanistic studies for the retroꢀazaꢀHenry type process are being presented, in
which nitrostyrenes are converted to the corresponding Nꢀalkyl/aryl substituted benzyl imines or
Nꢀalkyl/phenyl substituted benzyl hydrazones. This chemical transformation proceeds via a
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solventꢀmediated (proton transfer) nitroalkane elimination. The proposed mechanism is
supported by both experiments (synthesis and characterization) and theoretical calculations.
Interestingly, the in situ formation of Nꢀsubstituted benzyl hydrazones has been demonstrated as
a useful and facile platform for the synthesis of the biologically important pyrazoles, even at
largeꢀscale lab production.
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EXPERIMENTAL SECTION
General. The aromatic nitrostyrenes were synthesized according to literature procedure
described in the Supporting Information. All the compounds, aldehydes, nitroalkanes,
hydrazines, amines and solvents were of high purity and commercially available from Sigmaꢀ
Aldrich and used without further purification.
General procedure for the reaction between nitrostyrenes and amines. Into a sealed tube
containing the nitrostyrene (0.2 mmol) dissolved in methanol (1 ml) alkyl or aryl amine (0.4
o
mmol) was added and the mixture was heated at 60 C. After 20 min the reaction was complete
as monitored by TLC. After simple filtration of the crude mixture over a short pad of silica and the
solvent evaporation under vacuum, the corresponding Nꢀalkyl/aryl substituted benzyl imine was
observed in pure form. Product analysis was conducted by 1H NMR and 13C NMR spectroscopy
(Agilent AM 500). Mass spectra were determined on an electrospray ionization mass
spectrometry (ESIꢀMS), by using a ThermoFisher Scientific (Bremen, Germany) model LTQ
Orbitrap Discovery MS, at a flow rate of 10 ꢁL/min using syringe pump. The infusion
experiments were run using a standard ESI source operating in a positive ionization mode.
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Source operating conditions were a 3.7 kV spray voltage and a 300 C heated capillary
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temperature. LCMSꢀ2010 EV Instrument (Shimadzu) under Electrospray Ionization (ESI)
conditions and on a MS EV AutospecFissins instrument (EI at 70eV) were also used for the mass
determination.
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Nꢀ(4ꢀmethylbenzylidene)butanꢀ1ꢀamine (2).17 34 mg, 97% yield, colorless oil, HꢀNMR (300
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MHz, CDCl3): 8.23 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 3.59 (t, J = 6.6
Hz, 2H), 2.37 (s, 3H), 1.73ꢀ1.60 (m, 2H), 1.45ꢀ1.30 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13CꢀNMR
(75 MHz, CDCl3): 160.8, 140.7, 133.7, 129.3, 128.0, 61.5, 33.0, 21.5, 20.5, 13.9. MS m/z (ESI)
for C12H17N [M + H]+calcd: 176.14, found: 175.98.
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Nꢀbenzylidenebutaneꢀ1ꢀamine (13).18 32 mg, 99% yield, colorless oil, HꢀNMR (300 MHz,
CDCl3): 8.28 (s, 1H), 7.80ꢀ7.68 (m, 2H), 7.44ꢀ7.30 (m, 3H), 3.62 (t, J = 6.8 Hz, 2H), 1.77ꢀ1.65
(m, 2H), 1.48ꢀ1.33 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13CꢀNMR (75 MHz, CDCl3): 160.7, 136.5,
129.1, 128.6, 128.1, 61.5, 33.1, 20.5, 13.9. MS m/z (ESI) for C11H15N [M + H]+calcd: 162.12,
found: 161.96.
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Nꢀ(4ꢀmethοxybenzylidene)butanꢀ1ꢀamine (14).18 36 mg, 94% yield, light yellow oil, HꢀNMR
(300 MHz, CDCl3): 8.20 (s, 1H), 7.66 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H),
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3.58 (t, J = 7.0 Hz, 2H), 1.73ꢀ1.59 (m, 2H), 1.47ꢀ1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). Cꢀ
NMR (75 MHz, CDCl3): 161.6, 160.0, 129.6, 114.4, 114.1, 61.3, 55.4, 33.2, 20.5, 13.9. MS m/z
(ESI) for C12H17NO [M + H]+calcd: 192.13, found: 192.01.
Nꢀ(2ꢀmethoxybenzylidene)butanꢀ1ꢀamine (15).18 18 mg, 94% yield, yellow oil, 1H NMR
(500 MHz, CDCl3): 8.69 (s, 1H), 7.93 (dd, J = 7.7, 1.4 Hz, 1H), 7.38ꢀ7.33 (m, 1H), 6.97 (t, J =
7.7 Hz, 1H), (d, J = 8.3 Hz, 1H), 3.86 (s, 3H), 3.61 (t, J = 7.0 Hz, 2H), 1.71ꢀ1.64 (m, 2H), 1.41ꢀ
1.35 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): 158.6, 156.7, 131.6, 127.3,
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124.9, 120.8, 110.9, 61.7, 55.5, 33.1, 20.5, 13.9. MS m/z (ESI) for C12H17NO [M + H]+calcd:
192.13, found: 192.06.
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MHz, CDCl3): 8.35 (s, 1H), 8.26 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 3.68 (t, J = 6.3
Hz, 2H), 1.77ꢀ1.62 (m, 2H), 1.45ꢀ1.34 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
CDCl3): 158.4, 142.0, 128.7, 123.9, 124.1, 61.6, 32.9, 20.5, 13.8. MS m/z (ESI) for C11H14N2O2
[M + H]+calcd: 207.11, found: 206.97.
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Nꢀ(4ꢀchlorobenzylidene)butanꢀ1ꢀamine (17).18 38 mg, 97% yield, yellow oil, HꢀNMR (300
MHz, CDCl3): 8.23 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 3.60 (t, J = 6.5
Hz, 2H), 1.75ꢀ1.63 (m, 2H), 1.47ꢀ1.31 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz,
CDCl3): 159.4, 136.4, 135.0, 129.3, 128.9, 61.4, 33.0, 20.5, 13.9. MS m/z (ESI) for C11H14ClN
[M + H]+calcd: 196.08/198.08, found: 195.90/197/90.
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Nꢀ(4ꢀbromobenzylidene)butanꢀ1ꢀamine (18). 46 mg, 96% yield, yellow oil, HꢀNMR (300
MHz, CDCl3):8.21 (s, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 3.60 (t, J = 6.9 Hz,
2H), 1.78ꢀ1.60 (m, 2H), 1.46ꢀ1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3):
159.5, 135.4, 131.8, 129.5, 124.8, 61.4, 33.0, 20.5, 13.9. HRMS (ESI) for C11H14BrN [M +
H]+calcd: 240.0374/242.0353, found: 240.0370/242.0350.
Nꢀ(4ꢀmethylbenzylidene)butanꢀ2ꢀamine (19).19 34 mg, 97% yield, colorless oil, 1HꢀNMR (300
MHz, CDCl3): 8.23 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 3.23ꢀ3.11 (m, 1H),
2.37 (s, 3H), 1.66ꢀ1.54 (m, 2H), 1.24 (d, J = 6.3 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H). 13CꢀNMR (75
MHz, CDCl3): 158.9, 140.6, 133.8, 129.3, 128.1, 68.4, 30.7, 22.4, 21.5, 11.2. MS m/z (ESI) for
C12H17N [M + H]+calcd: 176.14, found: 176.02.
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Nꢀ(4ꢀmethylbenzylidene)propanꢀ2ꢀamine (20).20 32 mg, 99% yield, yellow oil, HꢀNMR (300
MHz, CDCl3): 8.27 (s, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 3.67ꢀ3.45 (m, 1H),
2.37 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H). 13CꢀNMR (75 MHz, CDCl3): 158.4, 140.6, 133.8, 129.3,
128.1, 61.7, 24.2, 21.5 (2). MS m/z (ESI) for C11H15N [M + H]+calcd: 162.12, found: 161.97.
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Nꢀ(4ꢀmethylbenzylidene)cyclopentanamine (21).21 36 mg, 96% yield, light yellow oil, Hꢀ
NMR (300 MHz, CDCl3): 8.25 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 3.78ꢀ
3.69 (m, 1H), 2.37 (s, 3H), 1.78ꢀ1.49 (m, 4H), 1.92ꢀ1.81 (m, 4H). 13CꢀNMR (75 MHz, CDCl3):
158.7, 140.5, 133.9, 129.3, 128.0, 71.9, 34.5, 24.8, 23.9, 21.5. MS m/z (ESI) for C13H17N [M +
H]+calcd: 188.14, found: 188.02.
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Nꢀ(4ꢀmethylbenzylidene)ꢀ1ꢀphenylꢀmethanamine (22).18 40 mg, 96% yield, colorless oil, Hꢀ
NMR (300 MHz, CDCl3): 8.36 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.38ꢀ7.29 (m, 6H), 7.24 (t, J=
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Hz, 1H), 4.82 (s, 2H), 2.39 (s, 3H). CꢀNMR (75 MHz, CDCl3): 161.9, 141.1, 139.6, 133.7,
129.4, 128.5, 128.3, 128.0, 127.0, 65.0, 21.5. MS m/z (ESI) for C15H15N [M + H]+calcd: 210.12,
found: 209.85.
4ꢀmethylꢀNꢀ(4ꢀmethylbenzylidene)aniline (23).22 42 mg, 93% yield, yellow solid, HꢀNMR
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(300 MHz, CDCl3): 8.43 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.20 (d, J =
8.3 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 2.42 (s, 3H), 2.37 (s, 3H). 13CꢀNMR (75 MHz, CDCl3):
159.7, 149.6, 141.7, 135.6, 133.8, 129.6, 128.7, 120.8, 21.6, 21.0. MS m/z (ESI) for C15H15N [M
+ H]+calcd: 210.12, found: 209.96.
4ꢀmethoxyꢀNꢀ(4ꢀmethylbenzylidene)aniline (24).23 42 mg, 93% yield, brown solid, HꢀNMR
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(300 MHz, CDCl3): 8.45 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.23 (d, J =
8.8 Hz, 2H), 6.93 (d, J = 8.7 Hz, 1H), 3.83 (s, 3H), 2.42 (s, 3H). 13CꢀNMR (75 MHz, CDCl3):
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158.6, 158.2, 141.6, 133.8, 129.6, 128.6, 122.2, 114.4, 55.6, 21.7. MS m/z (ESI) for C15H15NO
[M + H]+calcd: 225.12, found: 224.97.
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NMR (300 MHz, CDCl3): 8.46 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.91ꢀ
6.87 (m, 2H), 6.81 (dd, J1= 8.6, J2= 2.2 Hz, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 2.42 (s, 3H). 13Cꢀ
NMR (75 MHz, CDCl3): 158.8, 149.3, 147.5, 145.6, 141.7, 133.7, 129.6, 128.7, 55.9, 56.1, 21.7.
MS m/z (ESI) for C16H17NO2 [M + H]+calcd: 255.13, found: 254.86.
4ꢀmethoxyꢀNꢀ(4ꢀmethoxybenzylidene)aniline (26).23 46 mg, 95% yield, yellow solid, 1HꢀNMR
(300 MHz, CDCl3):8.40 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.98 (d, J =
8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H), 3.83 (s, 3H). 13CꢀNMR (75 MHz, CDCl3):
162.5, 158.3, 157.9, 130.7, 122.1, 116.5, 115.0, 114.5, 114.4, 55.6, 55.5. MS m/z (ESI) for
C15H15NO2 [M + H]+calcd: 242.11, found: 241.93.
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Nꢀ(4ꢀbromobenzylidene)ꢀ4ꢀmethoxyaniline (27).23 52 mg, 93% yield, yellow solid, HꢀNMR
(300 MHz, CDCl3):8.43 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.24 (d, J =
13
8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H). CꢀNMR (75 MHz, CDCl3): 158.7, 156.8,
135.6, 132.5, 132.1, 131.0, 130.0, 122.3, 114.6, 55.6. MS m/z (ESI) for C14H12BrNO [M +
H]+calcd: 290.01/292.01, found: 289.82/291.92.
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Nꢀ(2ꢀnitroꢀ1ꢀ(pꢀtolyl)ethyl)aniline (28).25 42 mg, 92% yield, yellow solid, HꢀNMR (300
MHz, CDCl3 7.28 (d, J = 8.0 Hz, 2H), 7.22ꢀ7.11 (m, 4H), 6.75 (t, J = 7.3 Hz, 2H), 6.63 (d, J =
7.7 Hz, 2H), 5.18ꢀ5.10 (m, 1H), 4.78ꢀ4.63 (m, 2H), 2.34 (s, 3H). 13CꢀNMR (75 MHz,
CDCl3):145.8, 138.6, 134.9, 130.0, 129.4, 126.4, 119.0, 114.1, 80.1, 56.6, 21.1. MS m/z (ESI) for
C15H16N2O2 [M + H]+calcd: 257.12, found: 257.02.
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4ꢀchloroꢀNꢀ(2ꢀnitroꢀ1ꢀ(pꢀtolyl)ethyl)aniline (29): 46 mg, 93% yield, light brown solid, Hꢀ
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2H), 6.53 (d, J = 8.8 Hz, 2H), 5.11ꢀ5.05 (m, 1H), 4.85ꢀ4.62 (m, 2H), 2.34 (s, 3H). CꢀNMR (75
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MHz, CDCl3):144.4, 138.8, 134.4, 130.1, 129.3, 126.3, 123.9, 115.2, 80.1, 56.7, 21.1. HRMS
(ESI) for C16H22N [M + H]+calcd: 291.0886/293.0857 found: 291.0879/293.0851.
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Nꢀ(2ꢀnitroꢀ1ꢀ(pꢀtolyl)ethyl)pyridinꢀ2ꢀamine (30): 24 mg, 93% yield, yellow solid, H NMR
(500 MHz, CDCl3) δ 8.09 (d, J = 5.2 Hz, 1H), 7.42 – 7.36 (m, 1H), 7.28 (d, J = 8.0 Hz, 2H),
7.17 (d, J = 8.0 Hz, 2H), 6.64 – 6.60 (m, 1H), 6.42 (d, J = 8.1 Hz, 1H), 5.67ꢀ5.63 (m, 1H), 5.17
(d, J=7.0 Hz, NH), 4.96 (dd, J = 12.4, 7.0 Hz, 1H), 4.73 (dd, J = 12.4, 6.0 Hz, 1H), 2.32 (s, 3H).
13C NMR (126 MHz, CDCl3): 156.8, 147.9, 138.4, 137.6, 134.6, 129.8, 126.5, 114.2, 108.3,
79.2, 53.8, 21.1. HRMS (ESI) for C14H15N3O2 [M + H]+calcd: 258.1237 found: 258.1228.
General procedure for the reaction between nitrostyrenes and hydrazines. Into a sealed
tube containing the nitrostyrene (0.2 mmol) dissolved in methanol (1 ml) or Nꢀsubstituted
o
hydrazine (0.8 mmol) was added and the mixture was heated at 60 C. After 3h the reaction was
complete as monitored by TLC. After simple filtration of the crude mixture over a short pad of silica
and the solvent evaporation under vacuum, the corresponding Nꢀalkyl/phenyl substituted benzyl
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hydrazone was observed in pure form. Product analysis was conducted by H NMR and 13C
NMR spectroscopy (Agilent AM 500). Mass spectra were determined on an LCMSꢀ2010 EV
Instrument (Shimadzu) under Electrospray Ionization (ESI) conditions.
1ꢀmethylꢀ2ꢀ(4ꢀmethylbenzylidene)hydrazine (31).26 28 mg, 95% yield, white crystals, 1HꢀNMR
(300 MHz, CDCl3): 7.53 (s, 1H), 7.45 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 2.96 (s, 3H),
2.34 (s, 3H). 13CꢀNMR (75 MHz, CDCl3): 137.8, 136.0, 133.4, 129.3, 125.8, 34.9, 21.3. MS m/z
(ESI) for C9H12N2 [M + H]+calcd: 149.12, found: 148.87.
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1ꢀbenzylideneꢀ2ꢀmethylhydrazine (33).27 26 mg, 97% yield, white crystals, HꢀNMR (300
MHz, CDCl3): 7.56 (d, 2H, J = 7.9 Hz), 7.53 (s, 1H), 7.39ꢀ7.31 (m, 2H), 7.26 (t, 1H, J = 7.2 Hz),
2.98 (s, 3H). 13CꢀNMR (75 MHz, CDCl3): 136.4, 135.5, 128.5, 127.8, 125.9, 34.8. MS m/z (ESI)
for C8H10N2 [M + H]+calcd: 135.08, found: 135.92.
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1ꢀ(4ꢀmethoxybenzylidene)ꢀ2ꢀmethylhydrazine (34).28 32 mg, 97% yield, white crystals, Hꢀ
NMR (300 MHz, CDCl3): 7.53 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 3.81
(s, 3H), 2.95 (s, 3H). 13C NMR (75 MHz, CDCl3: 159.7, 136.1, 129.2, 127.2, 114.1, 55.3, 35.1.
MS m/z (ESI) for C9H12N2O [M + H]+calcd: 165.09, found: 164.95.
1ꢀ(3,4ꢀdimethoxybenzylidene)ꢀ2ꢀmethylhydrazine (35):29 19 mg, 98% yield, white solid, 1HꢀNMR
(500 MHz, CDCl3): 7.07 (s, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.52 (dd, J = 8.1, 2.3 Hz, 1H), 6.39 (d,
J = 8.1 Hz, 1H), 3.48 (s, 3H), 3.44 (s, 3H), 2.52 (s, 3H). 13CꢀNMR (125 MHz, CDCl3): 149.3,
149.2, 136.1, 129.4, 119.8, 110.8, 107.2, 55.9, 55.8, 34.9. MS m/z (ESI) for C10H14N2O2 [M +
H]+calcd: 195.11, found: 195.02. MS m/z (ESI) for C10H14N2Ο2 [M + H]+calcd: 194.11, found:
194.03.
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1ꢀ(4ꢀchlorobenzylidene)ꢀ2ꢀmethylhydrazine (36).29 32 mg, 95% yield, white crystals, Hꢀ
NMR (300 MHz, CDCl3): 7.47 (d, 2H, J = 8.3 Hz), 7.45 (s, 1H), 7.29 (d, 2H, J = 8.3 Hz), 2.97
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(s, 3H). CꢀNMR (75 MHz, CDCl3): 134.0, 133.6, 133.3, 128.7, 126.9, 34.6. MS m/z (ESI) for
C8H9ClN2 [M + H]+calcd: 169.05/171.04, found: 168.91/170.92.
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1ꢀ(4ꢀbromobenzylidene)ꢀ2ꢀmethylhydrazine (37).30 42 mg, 99% yield, white crystals, Hꢀ
NMR (300 MHz, CDCl3): 7.45 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.40 (d, J = 8.8 Hz, 2H), 2.97
(s, 3H). 13CꢀNMR (75 MHz, CDCl3): 135.42, 133.5, 131.7, 127.2, 121.4, 34.6. MS m/z (ESI) for
C8H9BrN2 [M + H]+calcd: 212.99/214.99, found: 212.84/213.84.
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(4ꢀmethylbenzylidene)hydrazine (38).30 26 mg, 97% yield, white crystals, HꢀNMR (300
MHz, CDCl3): 7.73 (s, 1H), 7.43 (d, J = 7.7 Hz, 2H), 7.15 (d, J = 7.7 Hz, 2H), 2.34 (s, 3H). 13Cꢀ
NMR (75 MHz, CDCl3): 143.5, 129.6, 129.3, 128.5, 126.2, 21.4. MS m/z (ESI) for C8H10N2 [M
+ H]+calcd: 135.08, found: 134.98.
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1,1ꢀdimethylꢀ2ꢀ(4ꢀmethylbenzylidene)hydrazine (39).32 32 mg, 99% yield, white crystals, Hꢀ
NMR (300 MHz, CDCl3): 7.49 (d, J = 8.0 Hz, 2H), 7.28 (s, 1H), 7.16 (d, J = 8.0 Hz, 2H), 2.97
(s, 6H), 2.36 (s, 3H). 13CꢀNMR (75 MHz, CDCl3): 137.3, 134.0, 133.6, 129.2, 125.6, 43.0, 21.3.
MS m/z (ESI) for C10H14N2 [M + H]+calcd: 163.12, found: 163.02.
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1ꢀ(4ꢀmethylbenzylidene)ꢀ2ꢀphenylhydrazine (40).31 42 mg, 99% yield, white crystals, Hꢀ
NMR (300 MHz, CDCl3): 7.68 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.30ꢀ7.22 (m, 2H), 7.18 (d, J =
8.0 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.86 (t, J = 7.2 Hz, 1H), 2.37 (s, 3H). 13CꢀNMR (75 MHz,
CDCl3): 144.8, 138.5, 137.5, 132.6, 129.3, 126.2, 120.0, 112.7, 21.4. MS m/z (ESI) for C14H14N2
[M + H]+calcd: 211.12, found: 211.01.
General procedure for the synthesis of Nꢀmethyl substituted pyrazoles. After the first step
of the nitrostyrene transformation to the corresponding Nꢀmethyl substituted benzyl hydrazone
derivative (0.1 mmol) and solvent evaporation, a methanolic solution prior bubbled by O2 for 20
min (1 ml) containing the same or different paraꢀsubstituted nitrostyrene (0.1 mmol) was added,
and the reaction mixture was stirred at room temperature under oxygen atmosphere for
appropriate time. The solvent was evaporated under vacuum and the residue was separated by
column chromatography using silica gel and the mixture solvent hexane/EtOAc = 8/1 as eluent,to
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give the corresponding pyrazole in pure form. Product analysis was conducted by H NMR and
13C NMR spectroscopy (Agilent AM 500). Mass spectra were determined on an LCMSꢀ2010 EV
Instrument (Shimadzu) under Electrospray Ionization (ESI) conditions.
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1ꢀmethylꢀ3,5ꢀdiphenylꢀ1Hꢀpyrazole (41).33 18 mg, 77% yield, yellow solid, HꢀNMR (300
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MHz, CDCl3): 7.84 (d, J = 7.6 Hz, 2H), 7.51ꢀ7.44 (m, 5H), 7.41 (t, J = 7.2 Hz, 2H), 7.31 (t, J =
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7.2 Hz, 1H), 6.61 (s, 1H), 3.94 (s, 3H). CꢀNMR (75 MHz, CDCl3): 150.6, 145.2, 133.5, 130.8,
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129.8, 128.8, 128.7, 127.7, 125.7, 103.3, 37.6. MS m/z (ESI) for C16H14N2 [M + H]+calcd:
235.12, found: 234.97.
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1ꢀmethylꢀ3,5ꢀdiꢀpꢀtolylꢀ1Hꢀpyrazole (42).34 22 mg, 84% yield, light yellow solid, HꢀNMR
(300 MHz, CDCl3): 7.71 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H),
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7.21 (d, J = 8.1 Hz, 2H), 6.54 (s, 1H), 3.91 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H). CꢀNMR (75
MHz, CDCl3): 150.7, 145.1, 138.5, 137.3, 130.9, 129.3, 129.4, 129.3, 128.7, 125.6, 103.0, 37.5,
21.3. MS m/z (ESI) for C18H18N2 [M + H]+calcd: 263.15, found: 263.04.
3,5ꢀbis(4ꢀchlorophenyl)ꢀ1ꢀmethylꢀ1Hꢀpyrazole (43). 23 mg, 76% yield, yellow solid, 1HꢀNMR
(300 MHz, CDCl3): 7.75 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.42ꢀ7.35 (m, 4H), 6.56
13
(s, 1H), 3.90 (s, 3H). CꢀNMR (75 MHz, CDCl3): 149.6, 144.1, 135.0, 133.6, 131.9, 130.1,
129.1, 129.0, 128.9, 126.9, 103.4, 37.6. HRMS (ESI) for C16H12Cl2N2 [M + H]+calcd:
303.0450/305.0421, found: 303.0442/305.0414.
3,5ꢀbis(4ꢀbromophenyl)ꢀ1ꢀmethylꢀ1Hꢀpyrazole (44). 33 mg, 85% yield, brown solid, 1HꢀNMR
(300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3) δ 7.69 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.2 Hz,
2H), 7.52 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 6.57 (s, 1H), 3.90 (s, 3H). 13CꢀNMR (75
MHz, CDCl3): 149.7, 144.2, 132.3, 132.1, 131.8, 130.3, 129.5, 127.2, 123.1, 121.7, 103.4, 37.7.
HRMS (ESI) for C16H12Br2N2 [M + H]+calcd: 392.9420/390.9440/394.9399 found:
392.9414/390.9435/394.9394.
5ꢀ(4ꢀchlorophenyl)ꢀ1ꢀmethylꢀ3ꢀ(pꢀtolyl)ꢀ1Hꢀpyrazole (45). 24 mg, 85% yield, brown solid,
1HꢀNMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.46 (d, J
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= 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.57 (s, 1H), 3.92 (s, 3H), 2.38
(s, 3H). 13CꢀNMR (75 MHz, CDCl3): 150.8, 143.9, 137.6, 134.9, 130.4, 130.1, 129.4, 129.2,
129.1, 125.6, 103.3, 37.6, 21.3. HRMS (ESI) for C17H15ClN2 [M + H]+calcd:
283.0977/285.0967, found: 283.0965/285.0956.
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5ꢀ(4ꢀbromophenyl)ꢀ1ꢀmethylꢀ3ꢀ(pꢀtolyl)ꢀ1Hꢀpyrazole (46). 29 mg, 88% yield, yellow solid,
1HꢀNMR (300 MHz, CDCl3):7.71 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 7.9 Hz, 2H), 7.33 (d, J = 7.9
Hz, 2H), 7.21 (d, J = 7.5 Hz, 2H), 6.56 (s, 1H), 3.90 (s, 3H), 2.38 (s, 3H). 13CꢀNMR (75 MHz,
CDCl3): 150.8, 143.9, 137.6, 132.0, 130.5, 130.3, 129.8, 129.4, 125.5, 122.9, 103.3, 37.6, 21.3.
HRMS (ESI) for C17H15BrN2 [M + H]+calcd: 327.0491/329.0471, found: 327.0487/329.0468.
3ꢀ(4ꢀbromophenyl)ꢀ5ꢀ(4ꢀmethoxyphenyl)1ꢀmethylꢀ1Hꢀpyrazole (47). 29 mg, 85% yield, brown
solid, 1H NMR (300 MHz, CDCl3): 7.75 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.33 (d, J
= 8.3 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 6.52 (s, 1H), 3.90 (s, 3H), 3.84 (s, 3H). 13C NMR (75
MHz, CDCl3): 159.6, 150.6, 143.9, 132.0, 130.3, 129.7, 126.9, 126.1, 122.9, 114.2, 103.0, 55.4,
37.5. HRMS (ESI) for C17H15BrN2O [M + H]+calcd: 343.0441/345.0420, found:
343.0448/345.0425.
5ꢀ(4ꢀbromophenyl)ꢀ3ꢀ(4ꢀchlorophenyl)ꢀ1ꢀmethylꢀ1Hꢀpyrazole (48). 25 mg, 72% yield, yellow
solid, 1HꢀNMR (300 MHz, CDCl3): 7.75 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.37 (d, J
= 8.4 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 6.57 (s, 1H), 3.91 (s, 3H). 13CꢀNMR (75 MHz,
CDCl3):149.7, 144.2, 133.6, 132.1, 131.9, 130.3, 129.5, 128.9, 126.9, 123.1, 103.4, 37.7. HRMS
(ESI) for C16H12ΒrClN2 [M + H]+calcd: 346.9945/348.9925, found: 346.9932/348.9913.
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1,4ꢀdimethylꢀ3,5ꢀdiꢀpꢀtolylꢀ1Hꢀpyrazole (49). 22 mg, 79% yield, yellow solid, HꢀNMR (500
MHz, CDCl3): 7.61 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.27ꢀ7.23 (m, 4H), 3.81 (s, 3H),
2.44 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H). 13CꢀNMR (125 MHz, CDCl3): 149.1, 142.7, 138.5, 137.1,
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131.0, 129.8, 129.4, 129.2, 127.6, 127.4, 111.9, 37.2, 21.4, 21.3, 10.2. HRMS (ESI) for C19H20N2
[M + H]+calcd: 277.1699, found:277.1695.
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4ꢀethylꢀ1ꢀmethylꢀ3,5ꢀdiꢀpꢀtolylꢀ1Hꢀpyrazole (50). 21 mg, 72% yield, yellow solid, H NMR
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(500 MHz, CDCl3): 7.64 (d, J = 8.1 Hz, 2H), 7.30ꢀ7.25 (m, 4H), 7.05 (d, J = 8.8 Hz, 2H), 3.89
(s, 3H), 3.87 (s, 3H), 2.56 (q, J = 7.4 Hz, 2H), 2.40 (s, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR
(125 MHz, CDCl3): 160.8, 134.0, 131.0, 129.7, 129.4, 128.1, 127.5, 126.4, 119.7, 114.7, 114.6,
55.5, 36.4, 21.4, 16.9, 15.1. HRMS (ESI) for C20H22N2 [M + H]+calcd: 291.1856, found:
291.1851.
ASSOCIATED CONTENT
Supporting Information. Reaction conditions evaluation, Computational methods, Optimized
structures, energies, 1 H and 13C NMR spectra of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
lykakis@chem.auth.gr; gmpourmp@pitt.edu
Author Contributions
‡These authors contributed equally.
ACKNOWLEDGMENT
M.G.K. acknowledges the “IKY Fellowships of excellence for postgraduate studies in Greeceꢀ
Siemens program” for financial support. M.G.K. and I.N.L. gratefully acknowledge the
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sponsorship from COST action CM1201. I.N.L. acknowledges support of this work by the
project “OPENSCREENꢀGR” (MIS 5002691) funded by the Operational Program
"Competitiveness, Entrepreneurship and Innovation" (NSRF 2014ꢀ2020) and coꢀfinanced by
Greece and the European Union. P.D.T., M.D. and G.M. acknowledge startꢀup funds from the
University of Pittsburgh. Computational support has been provided by the Center for Simulation
and Modeling (SAM) at the University of Pittsburgh.
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REFERENCES
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Conjugated Nitro Compounds, Wiley, Chichester, 1994, p. 256.
(2) For reviews on nitroalkenes, see: (a) Halimehjania, A. Z.; Namboothiri, I. N. N.;
Hooshmand, S. E. RCS. Adv., 2014, 4, 31261ꢀ31299. (b) Halimehjania, A. Z.;
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