Mechanistic studies on the Michael addition of amines and hydrazines

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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 Downloaded from http://pubs.acs.org on December 22, 2017

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The Journal of Organic Chemistry

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†,* †Department of Chemistry, Aristotle University of Thessaloniki, University Campus 54124, Thessaloniki, Greece; Tel: +30 2310 997871, [email protected] ‡Department of Chemical Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.; [email protected] KEYWORDS: retro aza-Henry • 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 Nalkyl/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

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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 N-methyl pyrazoles in a one-pot manner, simple starting with the corresponding nitrostyrenes and the methylhydrazine.

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 aza-Henry reaction that yields β-nitroamine and/or 1,2-diamine compounds, via a nucleophilic addition of nitroalkanes to imines, has been considered of great importance, towards N-heterocycle organic molecules synthesis.5 The Michael addition of heteroatom-centred nucleophiles to nitrostyrenes is a reaction of high interest,6 since it comprises a promising route for C-C/C-N coupling, and/or introducing two heteroatoms in vicinal positions. In recent years, the methodologies which include the addition of nitrogen-based nucleophiles to nitrostyrenes have attracted considerable attention.7,8 For the preparation of aza-Henry-products, the selective conjugate addition of arylamines to nitrostyrenes under Brønsted acid catalysts or transition metal-catalyzed conditions, has been reported.8 Moreover, the Michael addition of arylamines to nitrostyrenes under aqueous


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conditions or a catalyst/solvent-free procedure has been developed.9 Interestingly, during the nucleophilic addition of trimethylsilyl cyanide to the nitroalkenes, a HNO2 elimination10 toward the synthesis of 1,2-dicyanoalkanes11 has been proposed (Scheme 1). In this work, we performed experimental and theoretical studies on the Michael addition of amines or alkyl substituted hydrazines to nitrostyrenes under non metal-catalyzed conditions. A nitroalkane elimination occurred during the present reaction leading to the corresponding Nalkyl/aryl substituted benzyl imines and N-methyl/phenyl substituted benzyl hydrazones with high selectivity and yields. This chemical transformation found to be dual-catalyzed, 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 retro-azaHenry type transformation and its mechanism was not reported in details in the literature so far. Sporadic examples on the formation of the N-substituted 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(Oi-Pr)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 hetero-Michael addition of nucleophiles into nitrostyrenes.8b In all cases, the observed N-butyl or benzyl benzyl imines were formed as side products accompanying with the desired Michael-adducts. 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 time- a detail mechanistic study on the retro-aza-Henry 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/MCM-41 heterogeneous catalyzed aza-Michael reaction of hydrazides with nitroolefins13a and the reactions of 3-βnitrovinyl indoles with phenylhydrazine.13b,c

Scheme 1. Aza-Michael addition of N-Nucleophiles to nitrostyrenes.

RESULTS AND DISCUSSIONS In this work, to optimize the reaction conditions, we initially investigated the reaction between 4-methyl-nitrostyrene 1 and butylamine (nBuNH2) in a variety of solvents at 60 oC (Table 1). Interestingly, instead of the expected aza-Michael 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 aza-Michael 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 nonpolar or protic solvents, the aza-Michael adduct (3) was observed by 1H-NMR as the only or major product (Table 1, entries 7-10). Nevertheless, addition of small amount of water (20 µL, 0.2% V/V) or MeOH (50 µL, 0.5% V/V) in THF and MeCN, increases the reaction conversion and 2 is obtained as the major product (Table 1, entries 12-15). These results suggest that small excess of the protic solvent or amine are necessary to drive the synthesis of 2 via a nitromethane elimination (retro-aza-Henry 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 observed (by 1H 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 5-nitro-4-(p-tolyl) pentan-2-one, sees Figure S1 in SI and Table 1, entry11. In all cases, the relative amounts of products 2 and 3 were measured from the appropriate signals in 1H 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 4methylbenzaldehyde 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.

Table 1. Solvent screening regarding the proposed retro-aza-Henry type reaction of 1 with butylamine

Entry

Solventa

Conversion (%)b

2 (%)c

3 (%)c

1

EtOH

>99

87

12

2

MeOH

>99

>99

3d

MeOH

>99

95

4

4e

MeOH

>99

92

7

f

MeOH

88

58

30

6

H2O

98

90

8

7g

THF

75

-

75

8g

MeCN

78

12

66

9g

Toluene

67

-

67

10g

DCE

72

-

72

Acetone

98

-

-

12

THF/H2O

96

65

31

13

MeCN/H2O

94

82

12

14

THF/MeOH

88

61

27

15

MeCN/MeOH

93

85

8

5

11

a

h

Conditions: 1 (0,2 mmol), nBuNH2 (2 equiv.), solvent (1 mL), at 60 oC. b Based on the consumption of 1

determined by 1H NMR. c The relative amounts of 2 and 3 measured by the appropriate proton signals from the 1H NMR after simple filtration of the crude mixture over a short pad of silica. d 1.5 equiv. of nBuNH2 based on 1 amount were added for 30 min. e The reaction performed at r.t. for 1h. f Equimolar mixture of 1 and nBuNH2 was used and a mixture of aza-Michael adduct and 2 were observed by NMR. g


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A mixture of aza-Michael adduct and 1 were observed by NMR.

h

5-nitro-4-(p-tolyl) pentan-2-one was

formed as the only product (see also Figure S1).

Based on the above results, we focused on the substrate scope of the present retro-aza-Henry type process by examining the reaction between a series of p-substituted nitrostyrenes (1, 4-11) 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, 13-22 in excellent yields (Scheme 2). Also, imine 2 was formed even when alkyl groups Me (10) and Et (11) were incorporated to the α-position (R) of the nitro-group, through the elimination of the nitroethane and nitropropane, respectively, as shown in Scheme 3.

Scheme 2. Synthesis of various N-substituted phenylmethanimines and N-substituted hydrazones via a retro-aza-Henry type reaction


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NO2

HN

R4

MeOH

+ R4-NH2 (2 eq.)

X

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N

60 oC, 30 min

-RCH2NO2

NO2

4

R = alkyl, benzyl, aryl

R4

X

X

2, 13-27

X= 4-Me(1), 4-H(4), 4-MeO (5), 2-MeO (6), 4-NO2 (7), 4-Cl (8), 4-Br (9) N Me

N

2 (97%)

13 (99%)

N O2N

20 (99%)

Me

21 (96%)

N 25 (94%)

Me

NO2 + R5 NHNH2 X (4 eq.) R5= H, Me, Ph X= 4-Me(1), 4-H(4), 4-MeO (5), 4-Cl (8), 4-Br (9), 3,4-diMeO (12) N

H N Me

Me 31 (95%, 2h)

OMe 35 (98%, 1h) N Me

N Br

26 (95%)

MeOH 60 oC, 1-3h -CH3NO2

27 (93%)

N X

H N Me N

H N

R5

31, 33-40

N

H N Me

MeO 34 (97%, 1h)

H N Me N

Cl

N

36 (95%, 3h) NH2

H N Me

Br 37 (99%, 3h)

Me N N Me

Me 38 (97%, 1h)

OMe

N

33 (97%, 3h)

H N Me N MeO

23 (93%)

OMe

MeO

Me

N

22 (96%)

OMe

Me

24 (93%)

Me

OMe

N

19 (97%)

N

OMe

Me

N

18 (96%)

Br

N Me

OMe 15 (93%)

14 (94%) N

17 (97%)

Cl

N Me

MeO

N

16 (97%)

N

N

N

H N

Me 39 (99%, 2h)

40 (99%, 2h)

Scheme 3. Nitromethane, nitroethane and nitropropane elimination during the reaction of α-alkyl 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 p-substituent. In specific, anilines substituted with electron-donating groups (EDG) accelerated the reaction process giving the imines 23-27 in high yields, whereas no imine formation was detected using anilines bearing electron-withdrawing groups (EWG) such as COOEt and CN (results not shown). On the other hand, the reaction of aniline, 4-Claniline and 2-aminopyridine leads to the formation of the corresponding Michael adducts 28-30 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 (1-3h) found to be required for the reaction completion (Table 2 and Scheme 2). Among the solvents studied, methanol provided quantitative formation of the corresponding N-methyl benzyl hydrazone 31 (Table 2, entries 2 and 4), while in ethanol, lower yield was observed (Table 2, entry 1). In contrast, the corresponding N-methyl hydrazaMichael adduct 32 was observed accompanying with a mixture of unidentified products, within non polar or aprotic solvents, such as acetonitrile (MeCN), 1,2-dichloroethane (DCE), toluene


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and tetrahydrofurane (THF), as shown in Table 2, entries 5-8. Similar to amines, the presence of small amount of water or methanol in THF accelerated the reaction process leading to the corresponding N-methyl 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 retro-aza or hydraza-Henry process. In general, the reactions of electron-rich substituted nitrostyrenes (4Me- and 4MeO-) proceeded faster than the reactions of electron deficient nitrostyrenes (4Cl- and 4Br-) 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 N-methylhydrazine, N,N-dimethyl hydrazine and N-phenyl hydrazine. In all reactions, the corresponding N-methyl or N-phenyl substituted benzyl hydrazones (31, 33-40) were formed in high yields, as shown in Scheme 2.

Table 2. Solvent screening regarding the proposed retro-aza-Henry type reaction of 1 with N-methyl-hydrazine.

entry

solventa

Conversionb (%)

31 (%)c

32 (%)c

1

EtOH

100

86

13

2

MeOH

100

>99

-

3d

MeOHd

-

-

-

4e

MeOHe

100

>99

-

f

MeCN

>99

-

34

DCE

>99

-

27

5

6f


10

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a

7f

Toluene

>99

-

25

8f

THF

>99

-

37

9g

THF/H2O

100

42

58

10g

THF/MeOH

100

64

36

Conditions: 1 (0,2 mmol), MeNHNH2 (4 equiv.), solvent (1 mL), measured by 1H NMR. bBased on the

consumption determined by 1H-NMR.

c

The relative amounts of 31 and the aza-Michael adduct 32

measured by the appropriate proton signals from the 1H NMR after simple filtration of the crude mixture over a short pad of silica. dNo conversion was observed when the reaction performed at room temperature. eThe reaction was completed after 5h using 3 equiv. of MeNHNH2. fA mixture of the corresponding Michael adduct 32 with unidentified products were observed by 1H NMR. g Water (20 µL, 0.2% V/V) or MeOH (50 µL, 0.5% V/V) was added into the solvent.

To gain an in-depth understanding of the imine formation mechanism we performed firstprinciples theoretical calculations (See sections SI-3, SI-4 and SI-5 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 trans-β-nitrostyrene (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 trans-β-nitrostyrene, 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 thermo-neutral. The proceeding step, B→C, is an energetically demanding step (proton transfer from the amine-group to the C neighbouring the nitro-group) with a free energy barrier of 28.9 kcal/mol due to a strained fourmembered transition state. The formation of D requires the breaking of a strong C-C bond,


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therefore, it is again a high-barrier 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 excess-reactant 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 six-member transition state, compared to the strained, 4-member 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 amine-group 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 N-methyl-1-phenylmethanimine 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.

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 proton-catalysed reaction barriers to be very high, eliminating such a possibility and further supporting that the protic solvents act as proton-mediating molecules. To further confirm this proton-mediating 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 was dramatically decreased (ca. 2h for reaction completion at 60 oC) compared to the reaction performed in MeOH (ca. 20 min at 60 oC). Also, the corresponding deuterium labeled azaMichael C4-d intermediate was observed by 1H NMR with a deuterium labeled ratio of C4-d/C4 = 85/15 (see Figure S5). This experimental finding supports the computational-identified role of the protic solvent, in which methanol act as a proton-mediating molecule (Figure 2), via an


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energetically favourable six-member transition state, for the formation of the aza-Michael adduct C.

Figure 2. Isotopic labeling experiments for the aza-Michael addition pathway of aniline to nitrostyrene 4.

To extend the applicability of our proposed reaction we attempted to synthesize a series of Nmethyl pyrazoles in an one-step manner, through a plausible stepwise pathway reaction between the in situ formed N-methyl 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 electron-rich or electron deficient substrates affording polysubstituted homo-N-Mepyrazoles 41-44 and hetero-N-Me-pyrazoles 45-50 in regioselective manner and in high isolated yields (Scheme 4). No pyrazole formation was observed using hydrazone 38, N-N-dimethyl substituted hydrazone 39 and N-phenyl substituted hydrazone 40, as shown in Figure S4. In details, hydrazone 38 gave the corresponding azide16 as the only product, however, N-Ndimethyl substituted hydrazone 39 and N-phenyl substituted hydrazone 40 leads to a mixture of unidentified products. It is interesting that the present one-pot synthetic procedure has been also tested to a 3 mmol lab-scale reaction, with the formation of 41 in 79% isolated yields.


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Scheme 4. One-pot synthesis of N-methyl substituted pyrazoles from nitrostyrenes and Nmethyl hydrazine

Based on these experimental and theoretical studies we propose in general that nitrostyrenes in the presence of amines or hydrazines undergoes a retro-aza-Henry type process, in which Nsubstituted benzyl imines or N-substituted benzyl hydrazones are formed respectively, through a nitroalkane elimination pathway. In details, at initial step an aza-Michael addition occurs forming the corresponding azo- 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 six-member transition state (TS), results that supported from the theoretical calculations and clearly demonstrate the importance of


15


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the protic solvents for this reaction, as also noted experimentally (Table 1). Methanol mediates the proton transfer from the amine-group 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 N-substituted benzyl imine or hydrazone and the nitroalkane (i.e. CH3NO2 for the nitrostyrene derivatives) as the reaction products.

Scheme 5. Proposed mechanism for the present retro-aza-Henry type process

CONCLUSIONS Herein, detail mechanistic studies for the retro-aza-Henry type process are being presented, in which nitrostyrenes are converted to the corresponding N-alkyl/aryl substituted benzyl imines or N-alkyl/phenyl substituted benzyl hydrazones. This chemical transformation proceeds via a


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solvent-mediated (proton transfer) nitroalkane elimination. The proposed mechanism is supported by both experiments (synthesis and characterization) and theoretical calculations. Interestingly, the in situ formation of N-substituted benzyl hydrazones has been demonstrated as a useful and facile platform for the synthesis of the biologically important pyrazoles, even at large-scale lab production.

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 SigmaAldrich 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 mmol) was added and the mixture was heated at 60 oC. 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 N-alkyl/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 (ESI-MS), by using a ThermoFisher Scientific (Bremen, Germany) model LTQ Orbitrap Discovery MS, at a flow rate of 10 µL/min using syringe pump. The infusion experiments were run using a standard ESI source operating in a positive ionization mode. Source operating conditions were a 3.7 kV spray voltage and a 300 oC heated capillary


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temperature. LCMS-2010 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. N-(4-methylbenzylidene)butan-1-amine (2).17 34 mg, 97% yield, colorless oil, 1H-NMR (300 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), 1.73-1.60 (m, 2H), 1.45-1.30 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C-NMR (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. N-benzylidenebutane-1-amine (13).18 32 mg, 99% yield, colorless oil, 1H-NMR (300 MHz, CDCl3): 8.28 (s, 1H), 7.80-7.68 (m, 2H), 7.44-7.30 (m, 3H), 3.62 (t, J = 6.8 Hz, 2H), 1.77-1.65 (m, 2H), 1.48-1.33 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H). 13C-NMR (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. N-(4-methοxybenzylidene)butan-1-amine (14).18 36 mg, 94% yield, light yellow oil, 1H-NMR (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), 3.58 (t, J = 7.0 Hz, 2H), 1.73-1.59 (m, 2H), 1.47-1.32 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H).

13

C-

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. N-(2-methoxybenzylidene)butan-1-amine (15).18 18 mg, 94% yield, yellow oil,

1

H NMR

(500 MHz, CDCl3): 8.69 (s, 1H), 7.93 (dd, J = 7.7, 1.4 Hz, 1H), 7.38-7.33 (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), 1.71-1.64 (m, 2H), 1.411.35 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3): 158.6, 156.7, 131.6, 127.3,


18

Page 19 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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. N-(4-nitrobenzylidene)butan-1-amine (16).18 40 mg, 97% yield, yellow oil, 1H-NMR (300 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), 1.77-1.62 (m, 2H), 1.45-1.34 (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. N-(4-chlorobenzylidene)butan-1-amine (17).18 38 mg, 97% yield, yellow oil, 1H-NMR (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), 1.75-1.63 (m, 2H), 1.47-1.31 (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. N-(4-bromobenzylidene)butan-1-amine (18). 46 mg, 96% yield, yellow oil, 1H-NMR (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), 1.78-1.60 (m, 2H), 1.46-1.32 (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. N-(4-methylbenzylidene)butan-2-amine (19).19 34 mg, 97% yield, colorless oil, 1H-NMR (300 MHz, CDCl3): 8.23 (s, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 3.23-3.11 (m, 1H), 2.37 (s, 3H), 1.66-1.54 (m, 2H), 1.24 (d, J = 6.3 Hz, 3H), 0.83 (t, J = 7.4 Hz, 3H). 13C-NMR (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.


19


Page 20 of 34

N-(4-methylbenzylidene)propan-2-amine (20).20 32 mg, 99% yield, yellow oil, 1H-NMR (300 MHz, CDCl3): 8.27 (s, 1H), 7.61 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H), 3.67-3.45 (m, 1H), 2.37 (s, 3H), 1.26 (s, 3H), 1.24 (s, 3H). 13C-NMR (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. N-(4-methylbenzylidene)cyclopentanamine (21).21 36 mg, 96% yield, light yellow oil, 1HNMR (300 MHz, CDCl3): 8.25 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 3.783.69 (m, 1H), 2.37 (s, 3H), 1.78-1.49 (m, 4H), 1.92-1.81 (m, 4H). 13C-NMR (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. N-(4-methylbenzylidene)-1-phenyl-methanamine (22).18 40 mg, 96% yield, colorless oil, 1HNMR (300 MHz, CDCl3): 8.36 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.38-7.29 (m, 6H), 7.24 (t, J= Hz, 1H), 4.82 (s, 2H), 2.39 (s, 3H). 13C-NMR (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. 4-methyl-N-(4-methylbenzylidene)aniline (23).22 42 mg, 93% yield, yellow solid, 1H-NMR (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). 13C-NMR (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. 4-methoxy-N-(4-methylbenzylidene)aniline (24).23 42 mg, 93% yield, brown solid, 1H-NMR (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). 13C-NMR (75 MHz, CDCl3):


20

Page 21 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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. 3,4-dimethoxy-N-(4-methylbenzylidene)aniline (25).24 48 mg, 94% yield, brown solid, 1HNMR (300 MHz, CDCl3): 8.46 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.916.87 (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). 13CNMR (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. 4-methoxy-N-(4-methoxybenzylidene)aniline (26).23 46 mg, 95% yield, yellow solid, 1H-NMR (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). 13C-NMR (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. N-(4-bromobenzylidene)-4-methoxyaniline (27).23 52 mg, 93% yield, yellow solid, 1H-NMR (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 = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H).

13

C-NMR (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. N-(2-nitro-1-(p-tolyl)ethyl)aniline (28).25 42 mg, 92% yield, yellow solid, 1H-NMR (300 MHz, CDCl3 7.28 (d, J = 8.0 Hz, 2H), 7.22-7.11 (m, 4H), 6.75 (t, J = 7.3 Hz, 2H), 6.63 (d, J = 7.7 Hz, 2H), 5.18-5.10 (m, 1H), 4.78-4.63 (m, 2H), 2.34 (s, 3H).

13

C-NMR (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.


21


Page 22 of 34

4-chloro-N-(2-nitro-1-(p-tolyl)ethyl)aniline (29): 46 mg, 93% yield, light brown solid, 1HNMR (300 MHz, CDCl3):7.25 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 8.8 Hz, 2H), 5.11-5.05 (m, 1H), 4.85-4.62 (m, 2H), 2.34 (s, 3H). 13C-NMR (75 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. N-(2-nitro-1-(p-tolyl)ethyl)pyridin-2-amine (30): 24 mg, 93% yield, yellow solid, 1H 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), 5.67-5.63 (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). 13

C 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 N-substituted hydrazine (0.8 mmol) was added and the mixture was heated at 60 oC. 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 N-alkyl/phenyl substituted benzyl hydrazone was observed in pure form. Product analysis was conducted by 1H NMR and

13

C

NMR spectroscopy (Agilent AM 500). Mass spectra were determined on an LCMS-2010 EV Instrument (Shimadzu) under Electrospray Ionization (ESI) conditions. 1-methyl-2-(4-methylbenzylidene)hydrazine (31).26 28 mg, 95% yield, white crystals, 1H-NMR (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). 13C-NMR (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.


22

Page 23 of 34 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1-benzylidene-2-methylhydrazine (33).27 26 mg, 97% yield, white crystals, 1H-NMR (300 MHz, CDCl3): 7.56 (d, 2H, J = 7.9 Hz), 7.53 (s, 1H), 7.39-7.31 (m, 2H), 7.26 (t, 1H, J = 7.2 Hz), 2.98 (s, 3H). 13C-NMR (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. 1-(4-methoxybenzylidene)-2-methylhydrazine (34).28 32 mg, 97% yield, white crystals, 1HNMR (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. 1-(3,4-dimethoxybenzylidene)-2-methylhydrazine (35):29 19 mg, 98% yield, white solid, 1H-NMR (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). 13C-NMR (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. 1-(4-chlorobenzylidene)-2-methylhydrazine (36).29 32 mg, 95% yield, white crystals, 1HNMR (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 (s, 3H). 13C-NMR (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. 1-(4-bromobenzylidene)-2-methylhydrazine (37).30 42 mg, 99% yield, white crystals, 1HNMR (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). 13C-NMR (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.


23


Page 24 of 34

(4-methylbenzylidene)hydrazine (38).30 26 mg, 97% yield, white crystals, 1H-NMR (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). 13CNMR (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. 1,1-dimethyl-2-(4-methylbenzylidene)hydrazine (39).32 32 mg, 99% yield, white crystals, 1HNMR (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). 13C-NMR (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. 1-(4-methylbenzylidene)-2-phenylhydrazine (40).31 42 mg, 99% yield, white crystals, 1HNMR (300 MHz, CDCl3): 7.68 (s, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.30-7.22 (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). 13C-NMR (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 N-methyl substituted pyrazoles. After the first step of the nitrostyrene transformation to the corresponding N-methyl 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 para-substituted 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 give the corresponding pyrazole in pure form. Product analysis was conducted by 1H NMR and 13

C NMR spectroscopy (Agilent AM 500). Mass spectra were determined on an LCMS-2010 EV

Instrument (Shimadzu) under Electrospray Ionization (ESI) conditions.


24

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1-methyl-3,5-diphenyl-1H-pyrazole (41).33 18 mg, 77% yield, yellow solid, 1H-NMR (300 MHz, CDCl3): 7.84 (d, J = 7.6 Hz, 2H), 7.51-7.44 (m, 5H), 7.41 (t, J = 7.2 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 6.61 (s, 1H), 3.94 (s, 3H). 13C-NMR (75 MHz, CDCl3): 150.6, 145.2, 133.5, 130.8, 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. 1-methyl-3,5-di-p-tolyl-1H-pyrazole (42).34 22 mg, 84% yield, light yellow solid, 1H-NMR (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), 7.21 (d, J = 8.1 Hz, 2H), 6.54 (s, 1H), 3.91 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H). 13C-NMR (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. 3,5-bis(4-chlorophenyl)-1-methyl-1H-pyrazole (43). 23 mg, 76% yield, yellow solid, 1H-NMR (300 MHz, CDCl3): 7.75 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H), 7.42-7.35 (m, 4H), 6.56 (s, 1H), 3.90 (s, 3H).

13

C-NMR (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. 3,5-bis(4-bromophenyl)-1-methyl-1H-pyrazole (44). 33 mg, 85% yield, brown solid, 1H-NMR (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). 13C-NMR (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. 5-(4-chlorophenyl)-1-methyl-3-(p-tolyl)-1H-pyrazole (45). 24 mg, 85% yield, brown solid, 1

H-NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.46 (d, J


25


Page 26 of 34

= 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).

13

129.1,

125.6, 103.3,

C-NMR (75 MHz, CDCl3): 150.8, 143.9, 137.6, 134.9, 130.4, 130.1, 129.4, 129.2, 37.6,

21.3.

HRMS

(ESI) for C17H15ClN2

[M

+ H]+calcd:

283.0977/285.0967, found: 283.0965/285.0956. 5-(4-bromophenyl)-1-methyl-3-(p-tolyl)-1H-pyrazole (46). 29 mg, 88% yield, yellow solid, 1

H-NMR (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). 13C-NMR (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. 3-(4-bromophenyl)-5-(4-methoxyphenyl)1-methyl-1H-pyrazole (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. 5-(4-bromophenyl)-3-(4-chlorophenyl)-1-methyl-1H-pyrazole (48). 25 mg, 72% yield, yellow solid, 1H-NMR (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).

13

C-NMR (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. 1,4-dimethyl-3,5-di-p-tolyl-1H-pyrazole (49). 22 mg, 79% yield, yellow solid, 1H-NMR (500 MHz, CDCl3): 7.61 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.9 Hz, 2H), 7.27-7.23 (m, 4H), 3.81 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H). 13C-NMR (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. 4-ethyl-1-methyl-3,5-di-p-tolyl-1H-pyrazole (50). 21 mg, 72% yield, yellow solid, 1H NMR (500 MHz, CDCl3): 7.64 (d, J = 8.1 Hz, 2H), 7.30-7.25 (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 [email protected]; [email protected] Author Contributions ‡These authors contributed equally. ACKNOWLEDGMENT M.G.K. acknowledges the “IKY Fellowships of excellence for postgraduate studies in GreeceSiemens 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

“OPENSCREEN-GR”

(MIS

5002691)

funded

by the

Operational

Program

"Competitiveness, Entrepreneurship and Innovation" (NSRF 2014-2020) and co-financed by Greece and the European Union. P.D.T., M.D. and G.M. acknowledge start-up funds from the University of Pittsburgh. Computational support has been provided by the Center for Simulation and Modeling (SAM) at the University of Pittsburgh. REFERENCES (1)

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Graphical Abstract


34

Mechanistic studies on the Michael addition of amines and hydrazines

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