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Dec 22, 2017 - Department of Chemistry, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece. ‡. Department of Chemic...
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Cite This: J. Org. Chem. 2018, 83, 1176−1184

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 Department of Chemical Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States

‡

S Supporting Information *

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 N-alkyl/aryl substituted benzyl imines and N-methyl/phenyl substituted benzyl hydrazones were observed via a retro-azaHenry-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.

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Scheme 1. Aza-Michael Addition of N-Nucleophiles To Nitrostyrenes

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 toward N-heterocycle organic molecules synthesis.5 The Michael addition of heteroatom-centered 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 conditions or a catalyst/solvent-free procedure has been developed.9 Interestingly, during the nucleophilic addition of trimethylsilyl cyanide to the nitroalkenes, an HNO2 elimination10 toward the synthesis of 1,2-dicyanoalkanes11 has been proposed (Scheme 1). © 2017 American Chemical Society

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 Received: October 17, 2017 Published: December 22, 2017 1176

DOI: 10.1021/acs.joc.7b02637 J. Org. Chem. 2018, 83, 1176−1184

Article

The Journal of Organic Chemistry leading to the corresponding N-alkyl/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-aza-Henry-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 nitrostyrenes and the alkylamines 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 heteroMichael addition of nucleophiles into nitrostyrenes.8b In all cases, the observed N-butyl or benzyl imines were formed as side products accompanying with the desired Michael-adducts. Based on these observations and according to our general interest in 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 with hydrazines has been less reported before, i.e., the PMoA/MCM-41 heterogeneous catalyzed aza-Michael reaction of hydrazides with nitroolefins13a and the reactions of 3-β-nitrovinyl indoles with phenylhydrazine.13b,c

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 2 3d 4e 5f 6 7g 8g 9g 10g 11h 12 13 14 15

EtOH MeOH MeOH MeOH MeOH H2O THF MeCN toluene DCE acetone THF/H2O MeCN/H2O THF/MeOH MeCN/MeOH

>99 >99 >99 >99 88 98 75 78 67 72 98 96 94 88 93

87 >99 95 92 58 90

12

12

65 82 61 85

4 7 30 8 75 66 67 72 31 12 27 8

Conditions: 1 (0,2 mmol), nBuNH2 (2 equiv), solvent (1 mL), at 60 °C. Based on the consumption of 1 determined by 1H NMR. cThe 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. d1.5 equiv of nBuNH2 based on 1 amount were added for 30 min. eThe reaction performed at r.t. for 1 h. fEquimolar mixture of 1 and nBuNH2 was used and a mixture of aza-Michael adduct and 2 were observed by NMR. gA mixture of aza-Michael adduct and 1 were observed by NMR. h5-Nitro-4-(p-tolyl) pentan-2one was formed as the only product (see also Figure S1). a b

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RESULTS AND DISCUSSION 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 °C (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 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 aprotic 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, see Figure S1 in SI and Table 1, entry 11. 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 4-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 additional experiment was performed in the presence of equimolar amounts of butylamine and piperidine; however, the only observed product was the corresponding benzyl imine confirmed by 1H NMR. This result confirms that primary amines react in a faster manner than the secondary amine under the present conditions. 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 min at 60 °C, 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. In the case of substituted anilines, the reactivity of the substrates is in accordance with 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 1177

DOI: 10.1021/acs.joc.7b02637 J. Org. Chem. 2018, 83, 1176−1184

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Scheme 2. Synthesis of Various N-Substituted Phenylmethanimines and N-Substituted Hydrazones via a Retro-aza-Henry-Type Reaction

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 (1−3 h) 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 hydraza-Michael adduct 32 was observed accompanying with a mixture of unidentified products, within nonpolar or aprotic solvents, such as acetonitrile (MeCN), 1,2-dichloroethane (DCE), toluene, 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 presence

Scheme 3. Nitromethane, Nitroethane, and Nitropropane Elimination During the Reaction of α-Alkyl-Substituted Nitrostyrenes with nBuNH2

anilines bearing electron-withdrawing groups (EWG), such as COOEt and CN (results not shown). On the other hand, the reaction of aniline, 4-Cl-aniline and 2-aminopyridine leads to the formation of the corresponding Michael adducts 28−30 exclusively (see Figure S3). 1178

DOI: 10.1021/acs.joc.7b02637 J. Org. Chem. 2018, 83, 1176−1184

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(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 aminegroup to the C neighboring the nitro-group) with a free energy barrier of 28.9 kcal/mol due to a strained four-membered transition state. The formation of D requires the breaking of a strong C−C bond, 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 (TS) stabilization, or destabilization of the initial state. Specifically, including explicit methanol in our calculations (Figure 1, gray 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 TS, compared to the strained, 4-member TS 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. 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

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 2 3d 4e 5f 6f 7f 8f 9g 10g

EtOH MeOH MeOHd MeOHe MeCN DCE toluene THF THF/H2O THF/MeOH

100 100

86 >99

13

100 >99 >99 >99 >99 100 100

>99

42 64

34 27 25 37 58 36

a Conditions: 1 (0,2 mmol), MeNHNH2 (4 equiv), solvent (1 mL), measured by 1H NMR. bBased on the consumption determined by 1H NMR. cThe 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 5 h using 3 equiv of MeNHNH2. fA mixture of the corresponding Michael adduct 32 with unidentified products were observed by 1H NMR. gWater (20 μL, 0.2% V/V) or MeOH (50 μL, 0.5% V/V) was added into the solvent.

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 (4-Me- and 4-MeO-) proceeded faster than the reactions of electron deficient nitrostyrenes (4-Cl- and 4-Br-) 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. To gain an in-depth understanding of the imine formation mechanism we performed first-principles theoretical calculations

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 gray and the black pathways represent the cases where we account an explicit methanol and methylamine molecule, respectively. The free energies in the gray and black profiles have been adjusted by the adsorption energy of the explicit molecule for purposes of comparison. 1179

DOI: 10.1021/acs.joc.7b02637 J. Org. Chem. 2018, 83, 1176−1184

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(i.e., methanol) transformed into the corresponding intermediate II, as shown in Scheme 5. This transformation takes place through a six-member transition state (TS), results that supported from the theoretical calculations and clearly demonstrate the importance of 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.

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 catalyze the reaction acting as Brønsted acid catalysts. However, we calculated the proton-catalyzed 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. 2 h for reaction completion at 60 °C) compared to the reaction performed in MeOH (ca. 20 min at 60 °C). Also, the corresponding deuterium labeled aza-Michael 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 computationally identified role of the protic solvent, in which methanol acts as a proton-mediating molecule (Figure 2), via an

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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 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.

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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 Sigma-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 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 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 °C heated capillary temperature. LCMS-2010 EV Instrument (Shimadzu) under electrospray ionization (ESI) conditions and on a MS EV AutospecFissins instrument (EI at 70 eV) 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). 13 C 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,

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

energetically favorable six-member TS for the formation of the aza-Michael adduct C. To extend the applicability of our proposed reaction we attempted to synthesize a series of N-methyl pyrazoles in an onestep manner, through a plausible stepwise reaction pathway 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-Me- pyrazoles 41−44 and hetero-NMe-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-N-dimethyl-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. 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 N-substituted 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 1180

DOI: 10.1021/acs.joc.7b02637 J. Org. Chem. 2018, 83, 1176−1184

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The Journal of Organic Chemistry Scheme 4. One-Pot Synthesis of N-Methyl-Substituted Pyrazoles from Nitrostyrenes and N-Methyl Hydrazine

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. 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, 1H NMR (300 MHz, CDCl3): 8.25 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 3.78−3.69 (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, 1H NMR (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,

Scheme 5. Proposed Mechanism for the Present Retro-azaHenry-Type Process

3H). 13C 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, 1H 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), 1.41- 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, 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. 1181

DOI: 10.1021/acs.joc.7b02637 J. Org. Chem. 2018, 83, 1176−1184

Article

The Journal of Organic Chemistry

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). 13 C 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, 1H 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). 13 C 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, 1H 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 (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, 1H 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). 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. (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). 13C 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. 1,1-Dimethyl-2-(4-methylbenzylidene)hydrazine (39).32 32 mg, 99% yield, white crystals, 1H 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). 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, 1H NMR (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 13C NMR spectroscopy (Agilent AM 500). Mass spectra were determined on an LCMS-2010 EV instrument (Shimadzu) under electrospray ionization (ESI) conditions. 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.

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): 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, 1H NMR (300 MHz, CDCl3): 8.46 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.91−6.87 (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). 13C 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. 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). 13C 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). 13C 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. 4-Chloro-N-(2-nitro-1-(p-tolyl)ethyl)aniline (29). 46 mg, 93% yield, light brown solid, 1H NMR (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). Twenty-four 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). 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 N-substituted hydrazine (0.8 mmol) was added and the mixture was heated at 60 °C. After 3 h 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 13C 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). 13 C 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. 1182

DOI: 10.1021/acs.joc.7b02637 J. Org. Chem. 2018, 83, 1176−1184

Article

The Journal of Organic Chemistry 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: 303.0434/305.0400. 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). 13 C 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: 392.9391/ 390.9414/394.9366. 5-(4-Chlorophenyl)-1-methyl-3-(p-tolyl)-1H-pyrazole (45). 24 mg, 85% yield, brown solid, 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 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 C NMR (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: 283.0982/285.0952. 5-(4-Bromophenyl)-1-methyl-3-(p-tolyl)-1H-pyrazole (46). 29 mg, 88% yield, yellow solid, 1H 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: 327.0471/329.0445. 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: 343.0425/345.0399. 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). 13C 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: 346.9932/348.9906. 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, 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:277.1673. 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: 291.1839.

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ORCID

Mudit Dixit: 0000-0001-9456-7806 Giannis Mpourmpakis: 0000-0002-3063-0607 Ioannis N. Lykakis: 0000-0001-8165-5604 Author Contributions §

P.D.T. and M.D. contributed equally to this work.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS M.G.K. acknowledges the “IKY Fellowships of excellence for postgraduate studies in Greece-Siemens program” for financial support. M.G.K. and I.N.L. gratefully acknowledge the 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 cofinanced by Greece and the European Union (KA94150). P.D.T., M.D., and G.M. acknowledge start-up and Central Research Development Funds (CRDF) from the University of Pittsburgh. Computational support has been provided by the Center for Research Computing (CRC) at the University of Pittsburgh.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02637. Reaction conditions evaluation; computational methods; and optimized structures, energies, 1 H, and 13C NMR spectra of the products (PDF)

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REFERENCES

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DOI: 10.1021/acs.joc.7b02637 J. Org. Chem. 2018, 83, 1176−1184

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DOI: 10.1021/acs.joc.7b02637 J. Org. Chem. 2018, 83, 1176−1184