Regioselective Synthesis of N2-Alkylated-1,2,3 ... - ACS Publications

Sonu Gupta , Nisha Chandna , Ajai K. Singh , and Nidhi Jain*. Department of Chemistry, Indian Institute of Technology , New Delhi , India 110016. J. O...
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Article Cite This: J. Org. Chem. 2018, 83, 3226−3235

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Regioselective Synthesis of N2‑Alkylated-1,2,3 Triazoles and N1‑Alkylated Benzotriazoles: Cu2S as a Recyclable Nanocatalyst for Oxidative Amination of N,N‑Dimethylbenzylamines Sonu Gupta, Nisha Chandna, Ajai K. Singh, and Nidhi Jain* Department of Chemistry, Indian Institute of Technology, New Delhi, India 110016 S Supporting Information *

ABSTRACT: Copper chalcogenide nanoparticles (Cu2S) synthesized for the first time from a single-source precursor, CuSPh, act as highly efficient and reusable heterogeneous catalyst for regioselective amination of N,N-dimethylbenzylamines with various azoles. The reaction involves N−H/C−H crossdehydrogenative coupling (CDC) and demonstrates wide functional group tolerance. It provides highly selective access to N1-alkylated benzotriazoles, N2-alkylated 1,2,3-triazoles and 4-phenyl-1,2,3-triazoles, and N-alkylated carbazoles in 70−89% yields under solvent-free conditions. The Cu2S nanocatalyst has been characterized by PXRD, XPS, SEM−EDX, and HR−TEM analysis. Mechanistic studies suggest that the reaction follows a radical pathway and involves an iminium ion intermediate.

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INTRODUCTION Selective conversion of C−H bonds to C−N bonds has gained tremendous importance as it streamlines the synthesis of important N-heterocycles with potential pharmaceutical and material applications. Aliphatic C−H amination reactions are particularly sought after as they provide an atom-efficient route to N-alkylamine derivatives by avoiding the typical functional group interconversions requiring prefunctionalized starting materials. Azoles are important N-heterocycles and form an integral part of many natural products, biologically active molecules, and scaffolds for new pharmaceuticals.1 N-Substituted 1,2,3-triazoles are particularly important and find widespread applications in material science and medicinal chemistry.2 The general route to accessing 1,2,3-triazoles involves the reaction of organic azides with activated alkenes,3 alkynes,4 and carbonyl compounds.5 While these methods are useful for preparing N1- or N1′-alkylated-1,2, 3-triazoles, they deny access to the N2-substituted derivatives. For this, a post-N-functionalization is required, which can be accomplished with the help of alkyl halides,6 alcohols,7 alkynes,8 and alkenes.9 In this context, methods that allow an N2-alkylation of NH-1,2,3-triazoles directly with alkanes can be highly useful. The oxidative functionalization of tertiary amines to corresponding α-substituted tertiary amines with good nucleophiles such as malonates, nitroalkanes, cyanide anion, silyl enolates, ketene acetals, and amides is reported.10 Most of these functionalizations involve either cyclic tertiary amines such as 1,2,3,4-tetrahydroisoquinoline, pyrrolidine, and piperidine or an acyclic tertiary amine such as N,N-dimethylaniline as a substrate. However, intermolecular functionalization of an sp3 C−H bond adjacent to © 2018 American Chemical Society

a nitrogen atom in N,N-dimethylbenzylamine has very few reports. α-Cyanation of N,N-dimethylbenzylamines has been achieved oxidatively with the help of iron chloride/TBHP catalysis or mediated by tropylium ion.11 In 2004, Li et al. reported a coppercatalyzed alkynylation of N,N-dimethylbenzylamine using TBHP, albeit in low yield (36%).12 In 2008, Fu and co-workers were successful in obtaining moderate yields (≤65%) of the coupled products by replacing TBHP with NBS.13 Recently, we demonstrated that with the help of a copper selenide nanocatalyst, a notable improvement in reaction efficiency could be achieved.14 Another report on oxidative carbon−carbon cross-coupling of N,N-dimethylbenzylamines came from Itami and co-workers in an iron-catalyzed reaction with electron-rich heteroarenes (Scheme 1).15 Later, a metal-free cross-dehydrogenative coupling between tertiary aliphatic amines and 1,3-dicarbonyl compounds was shown by Wang et al. using Bu4NI, but N,N-dimethylbenzylamines were found to be inert in this reaction.16 Apparently, the studies with N,N-dimethylbenzylamines are limited to C−C bondforming reactions only, with no literature precedence on a direct α-amination at the sp3 carbon. In continuation of our interest in direct C−N bond formations,17 we explored a N−H/C−H crossdehydrogenative coupling between azoles and N,N-dimethylbenzylamines using a nanocatalytic system comprising Cu2S NPs. The methodology was explored for triazoles (NH-1,2,3-triazoles, 4-phenyl-NH-1,2,3-triazoles, 1H-benzotriazoles, and 5,6-dimethyl-1H-benzotriazoles) and carbazoles as coupling partners (Scheme 1). Received: January 13, 2018 Published: February 21, 2018 3226

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235

Article

The Journal of Organic Chemistry Scheme 1. Cross-Dehydrogenative Coupling Reactions of N,N-Dimethylbenzylamines

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RESULTS AND DISCUSSION In light of the significant advantages offered by a heterogeneous nanocatalyst in a reaction, we initiated this work with the preparation of copper sulfide nanoparticles. The NPs (Scheme 2)

The oxidation states of both Cu and S in Cu2S NPs were assigned with the help of XPS analysis. As shown in Figure 1, the material was found to comprise copper and sulfur only. The Cu 2p spectrum (Figure 1a) illustrated that the peaks for the binding energies for Cu 2p3/2 and 2p1/2 appearing at 932.9 and 952.7 eV, respectively, were symmetric, narrow, and devoid of satellites.19 These values of binding energies indicated the oxidation state of Cu in Cu2S NPs to be (+1). In the S 2p XPS spectrum (Figure 1b), the binding energy peaks corresponding to S 2p3/2 and S 2p1/2 appeared at 161.7 and 162.8 eV, respectively, and were characteristic of S2−.20 Using the prepared Cu2S nanocatalyst, we investigated the reaction of N,N-dimethylbenzylamine (1a) (2 equiv) with NH-1,2,3-triazole (2a) (1 equiv) in the presence of TBHP and DMSO under nitrogen at 110 °C. After 3 h of reaction time, complete conversion of the starting materials was observed, and N-((2H-1,2,3-triazol-2-yl)methyl)-N-methyl-1-phenylmethanamine (3a) was isolated in 58% yield. It was interesting to notice that the triazole witnessed an exclusive N2 alkylation with 1a. While methods to prepare N2-aryl-6a,21 and N2-allyl1,2,3-triazoles22 have been reported recently, there is no literature on the alkylation of 4,5-unsubstituted-1,2,3-triazoles exclusively at N2 through CDC. In previous studies, N2-selective amidoalkylation has been achieved by controlling the steric requirements of the substrate and tuning the substituents at the 4 and 5 position on NH-1,2,3-triazoles.23 Alternately, NIS-mediated

Scheme 2. Synthesis of Cu2S NPs

were prepared by thermolysis of a CuSPh complex synthesized by modifying the reported procedure.18 They were authenticated by HRTEM (Figure S1 in the SI), SEM-EDX (Figure S2 in the SI), and PXRD (Figure S3 in the SI) data. TEM images revealed the particles to have hexagonal morphology with a size of ∼28−36 nm (see size distribution curve in SI Figure S4). The PXRD pattern exhibited diffraction lines (hkl) at 3.73 (242), 3.59 (302), 3.27 (420), 3.18 (262), 3.05 (243), 2.94 (091), 2.72 (044), 2.52 (423), 2.47 (433), 2.40 (1111), 2.32 (174), 2.24 (205), 2.21 (225), 1.97 (2131), 1.87 (2140), and 1.70 (406). These diffraction peaks were indexed to the hexagonal phase of Cu2S NPs, as they showed good agreement with the literature data (JCPDS 23−0961). SEMenergy-dispersive X-ray spectral data confirmed the presence of Cu and S in these NPs in the ratio 2:1.

Figure 1. High-resolution XPS of Cu2S NPs (a) Cu 2p and (b) S 2p. 3227

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235

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The Journal of Organic Chemistry

1 and reacting them with 2. As shown in Scheme 3, all of the substrates provided moderate to good yields of products 3a−g. However, 1 bearing electron-donating groups such as p-CH3 and p-OCH3 afforded corresponding products 3b and 3c in slightly higher yields (80−82%) than those (3d−3g, 70−78%) with moderately electron-withdrawing groups (Cl, Br). Furthermore, with very strong electron-withdrawing groups such as NO2 and CN, no product formation was seen. The position of a chloro substituent at the ortho, meta, or para position of 1 had little effect, and corresponding products 3d−3f were formed in similar yields. The reaction also worked with N-methyl-N-ethyl-benzylamine, and N2-methylated-1,2,3-triazole (3h) was obtained in 68% yield. Next, we tried the reaction with 4-phenyl-substituted 1,2,3-triazole (2b). 4-Aryl-NH-1,2,3-triazoles have recently been identified as potent inhibitors of cobalt-activated human methionine amino peptidase type 2 (hMetAP2)24 and indole amine 2,3-dioxygenase (IDO),25 showing promise as anticancer drugs. Gratifyingly, the coupling reaction between 1 and 2b was equally facile and furnished expected N2-alkylated products 3i−3n in good yields (77−84%). The structure of N-(4-bromobenzyl)-N-methyl1-(4-phenyl-2H-1,2,3-triazol-2-yl)methanamine (3n) was also confirmed by X-ray crystallography (see Supporting Information). The scope of the strategy was further extended to benzotriazoles (4) as they constitute an essential structural motif in medicinal chemistry, corrosion inhibitors, and supramolecular ligands.26 N1-Substituted benzotriazoles (Bt-1) are usually prepared as a mixture with their N2-substituted isomers (Bt-2) by reaction of benzotriazole with the corresponding alkylating reagents or halogen derivatives in the presence of a base. In these methods, the regioselectivity of 1-alkylated benzotriazoles is poor, and the ratio of N1/N2 varies from 1/1 to 3/1.27 Thus, advances in the synthesis of diverse N1-alkylated benzotriazoles are desirable. A CDC of unsubstituted benzotriazole 4a with 1a was carried out under the optimized conditions (Scheme 4). The reaction was completed in 1 h and afforded a single product in 81% yield. The product, characterized as N1-alkylated benzotriazole (5a), is a useful intermediate in the synthesis of kinase inhibitors.28 Other N1-alkylated benzotriazole derivatives (5b−5f) with substitutions on the phenyl ring of 1 were also obtained in good yields (77−85%). With 5,6-dimethyl substituted benzotriazoles, the corresponding N1-alkylated derivatives (5g−5h) were formed in 83−89% yields. These molecules are known to be powerful corrosion inhibitors in chemical mechanical planarization (CMP)29 and were synthesized easily by this method. N1- and N2-alkylated benzotriazoles equilibrate to different extents when dissolved in organic solvents such as DMSO, chloroform, and others.30 Thus, the observed and highlighted N1 selectivity may degrade when compounds 5 are dissolved in organic solvents. Recently, McKnight and co-workers reported aminopropyl carbazole (P7C3) to be a potent proneurogenic and neuroprotective compound.31 This prompted us to explore our N-alkylation strategy with carbazoles as substrates, since they are useful motifs in the treatment of chronic diseases such as Alzheimer’s Disease and Parkinson’s Disease.32 As shown in Scheme 5, the coupling reaction worked well and gave desired products 7a−7g in good yields (72−82%). To ascertain the synthetic utility of the developed protocol for practical purposes, this reaction was also carried out on a gram scale. One gram of carbazole 6 was treated with 11.96 mmol of 4-chloro-N,N-dimethylbenzyl amine under the standard reaction conditions, and coupled product 7f was isolated in 76% yield (1.52 g). Furthermore, the C−N bond formation was investigated with N,N-dimethylaniline (8) as the coupling partner (Scheme 6).

iodofunctionalization of olefins is reported to provide access to N2-alkylated 1,2,3-triazoles.9 Despite these advances, there still exist several constraints and challenges which tend to limit their synthetic utility. In this context, our preliminary results seemed to provide a useful solution. To improve the yield of product 3a, optimization of the reaction conditions was carried out (Table 1). Table 1. Optimization of Reaction Conditions.a

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

catalyst (mol %)

oxidant (equiv)

Cu2S NPs (5) CuBr (5) CuCl (5) Cu(OAc)2 (5) Cu2S NPs (5) Cu2S NPs (5) Cu2S NPs (5) Cu2S NPs (5) Cu2S NPs (5) Cu2S NPs (5) Cu2S NPs (1)

TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) NBS H2O2 K2S2O8 O2 balloon TBHP (3, 0.5)

Cu2S NPs (1) Cu2S NPs (1) Cu2S NPs (1) Cu2S NPs (1) Cu2S NPs (1)

solvent DMSO DMSO DMSO DMSO dioxane DCE PhCl ACN

temp (° C) 110 110 110 110 110 110 110 110 110 100, 90 90 90 90 90 90 90 90

yield (%) 58 35 45 37 35 38 20 40 65 67, 72 74, 55b, 50c, 52d 0 18

73, 54

a

Reaction conditions: 1a (2 mmol), 2a (1 mmol), copper catalyst, TBHP (5.5 M in decane, 1 equiv, 0.2 mL), N2, 90 °C. bCu2S bulk as the catalyst. cCu2O bulk as the catalyst. dCu6Se4.5 nanoparticles as catalyst.

With conventional copper salts such as CuBr, CuCl, and Cu(OAc)2, 3a was isolated in lower yields (Table 1, entries 2−4). Changing to solvents such as dioxane, DCE, chlorobenzene, and acetonitrile did not give encouraging results either (Table 1, entries 5−8). Notably, we found that under solvent-free conditions, the reaction was much cleaner, and 3a was isolated in 65% yield after 1 h (Table 1, entry 9). Lowering the reaction temperature to 90 °C increased the yield to 72% (Table 1, entry 10). Further, reducing the catalytic loading to 1 mol % did not affect the reaction, with full conversion and a similar yield obtained (Table 1, entry 11). A comparison with bulk Cu2O and Cu2S and a previously reported Cu6Se4.5 nanocatalyst14 was made, and lower yields were obtained in all of these cases (Table 1, entry 11). However, the control reaction in absence of copper catalyst did not give any product (Table 1, entry 12). Other oxidants such as NBS, H2O2, K2S2O8, and oxygen were screened, and all were found to be ineffective in enabling C−N bond formation (Table 1, entries 13−16). No improvement in the yield was observed upon increasing the amount of TBHP to 3 equiv, while it dropped to 54% on reducing TBHP to 0.5 equiv (Table 1, entry 17). The best conditions for the reaction required 1 mol % Cu2S and 1 equiv of TBHP under neat conditions at 90 °C under nitrogen (Table 1, entry 11). Furthermore, the addition of bases such as Na2CO3, K2CO3, NaOAc, and DBU to the optimized conditions did not facilitate the reaction. The scope of the reaction was examined by taking different substituents on the phenyl ring of 3228

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235

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The Journal of Organic Chemistry Scheme 3. N2-Selective Alkylation of 4,5-Unsubstituted and 4-Phenyl-Substituted 1,2,3-Triazolesa

a

Reaction conditions: 1 (2 mmol), 2 (1 mmol), Cu2S NPs (1 mol %), TBHP (5.5 M in decane, 1equiv, 0.2 mL), N2, 90 °C for 1 hour.

Scheme 4. Scope with Benzotriazolesa

a

Reaction conditions: 1 (2 mmol), 4 (1 mmol), Cu2S NPs (1 mol %), TBHP (5.5 M in decane, 1equiv, 0.2 mL), N2, 90 °C.

The reactions of 2, 4, and 6 with 8 tolerated the reaction conditions well and gave desired N-alkylated products 9a−9f in

65−88% yields. Our results are in contrast to a recent study by Li and Chen where they reported that N,N-dimethylanilines 3229

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235

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The Journal of Organic Chemistry Scheme 5. N-Alkylation of Cabazoles with N,N-Dimethylbenzylamines.a

a Reaction conditions: 1 (2 mmol), 6 (1 mmol), Cu2S NPs (1 mol %), TBHP (5.5 M in decane, 1 equiv, 0.2 mL), N2, 90 °C. bReaction was carried out on a gram scale.

Scheme 6. N-Alkylation of Aazoles (2/4/6) with N,N-Dimethylanilines (8)a

a

Reaction conditions: 8 (2 mmol), 2/4/6 (1 mmol), Cu2S NPs (1 mol %), TBHP (5.5 M in decane, 1 equiv, 0.2 mL), N2, 90 °C.

report, Wu and co-workers demonstrated the oxidative cleavage of benzylic C−N bonds through iminium ion B.33b Furthermore, changes in the oxidation state of copper during the reaction were analyzed through time-dependent EPR studies of the reaction mixture. The data indicated the generation of Cu(II) during the catalytic cycle ((Scheme 7(3) and see SI). The appearance of the peak at 134.0956 in the HRMS of the reaction mixture supported the formation of iminium ions A/B. Control experiments in the absence of either copper catalyst or TBHP did not furnish any peak at 134 in the HRMS. On the basis of the results of the control experiments and literature reports, a mechanism for the reaction has been proposed in Figure 2. It is believed that the reaction is initiated by coppercatalyzed decomposition of TBHP to generate a tert-butoxyl radical, and a single electron transfer (SET) from amine 1 generates a radical cation. This is followed by abstraction of the sp3 hydrogen of the radical cation to generate iminium-type intermediate A or B. The reaction of A with triazole/carbazole results in the formation of complex C, which furnishes the C−N coupled product via nucleophilic attack of the azole on an iminium ion with the concurrent regeneration of Cu2S for the next catalytic cycle. We believe that the amine (2 equiv)13,34 might be involved

were inert for Cu(OAc)2-catalyzed C−N bond formation with NH-1,2,3-triazoles.23 These findings are thus significant as there is no literature precedence on the synthesis of such molecules. To understand the mechanism, several control experiments were carried out as shown in Scheme 7. The involvement of freeradical species in the reaction was ascertained by performing quenching studies with a radical scavenger, (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO). It was found that the reaction of 1a with 2 in the presence of TEMPO gave corresponding products 3a and 3i in lower yields, and the yields were found to decrease in a dose-dependent manner (Scheme 7(1)). The inhibitory effect of TEMPO suggested the reaction to proceed via radical intermediates. Notably, the formation of small amounts (3%) of 4-methoxybenzaldehyde (10) was observed when the reaction of 1-(4-methoxyphenyl)-N,N-dimethylmethanamine and 2a was carried out under optimized conditions. To understand its formation, a control experiment was carried out in aqueous TBHP, wherein 3c and 10 were obtained in 65 and 15% yields, respectively (Scheme 7(2)). This is consistent with earlier observations by Smith et al., who reported the formation of 10 during the oxidation of 1 with FeIIITPPCl-PhIO and suggested its formation via a benzylic iminium ion intermediate (B).33a Similarly, in another 3230

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235

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The Journal of Organic Chemistry Scheme 7. Preliminary Mechanistic Studiesab

a

(i) EPR studies of the reaction mixture showed the formation of Cu(II) species. b(ii) HRMS of the reaction mixture showed the peak corresponding to iminium ion A/B.

is believed to follow a radical pathway involving an iminium ion intermediate.

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EXPERIMENTAL SECTION

General Remarks. All reactions were carried out in oven-dried round-bottomed flasks. Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on 0.25 mm silica gel plates (60F-254) and visualized under UV illumination at 254 nm and with an iodine chamber. Further visualization was achieved by iodine vapor adsorbed on silica gel depending on the product type. Organic extracts were dried over anhydrous sodium sulfate. Solvents were removed in a rotary evaporator under reduced pressure. Column chromatography was performed on silica gel 100−200 mesh using a mixture of hexane and ethyl acetate as the eluent, and isolated compounds were characterized by 1H NMR, 13C NMR, and HRMS data. NMR spectra for all the samples were taken in deuterochloroform (CDCl3) and dimethyl sulfoxide-d6 (DMSO-d6) as the solvents. 1 H and 13C-NMR spectra were recorded at ambient temperature on a 300 and 75 MHz spectrometers using tetramethylsilane (TMS) as an internal reference. The chemical shifts are quoted in δ units, parts per million (ppm) upfield from the signal of internal TMS. 1H NMR data is represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and dd = doublet of doublets), integration and coupling constant(s) J in Hertz (Hz). Highresolution mass spectra (HRMS) were recorded on a mass spectrometer using electrospray ionization−time-of-flight (ESI-TOF) reflectron experiments. For EDX studies, the instrument used was a model QuanTax 200, based on the SDD technology and giving an energy resolution of 127 eV at MnKα to estimate elemental compositions. The sample was mounted on a circular metallic sample holder with stick carbon tape. Powder X-ray diffraction (PXRD) studies were carried out on a Bruker D8 Advance diffractometer using Ni-filtered CuKα radiation, a scan speed of 1 s, and a scan step of 0.05°. Transmission electron microscopy (TEM) studies were carried out using a JEOL JEM200CX TEM instrument operated at 200 kV. The specimens for these studies were prepared by dispersing the powdered sample in ethanol by ultrasonic treatment. A few drops of the resulting solution were put on a porous carbon film supported on a copper grid and dried in air. X-ray photoelectron spectroscopy (XPS) measurements were carried out using an EA 125 electron spectrometer manufactured by OMICRON Nanotechnology GmbH (Germany), with Al Kα radiation (1486.7 eV). X-band EPR measurements were performed on a JEOL JES-FA 200 instrument. The electron paramagnetic resonance (EPR) spectra were measured in a frozen DMF solution at 77 K (X-band, frequency = 1.103 GHz, power = 1.15 mW).

Figure 2. Proposed mechanism.

in trapping the proton released in this step. The generation of iminium type B in the reaction mixture results in the formation of benzaldehyde as a side product of hydrolysis, as is observed with 1-(4-methoxyphenyl)-N,N-dimethylmethanamine. The formation of B might be favored with the π-Donor (+ M) substituents such as 4-OMe, which can stabilize it by direct conjugation. To check the reusability of the catalyst for the next catalytic cycle, it was recovered from the reaction mixture by centrifugation, washed with ethanol, and dried in vacuum. The activity of the recovered Cu2S catalyst was examined for up to five cycles and was found to decrease slightly after every reaction (Figure S6 of SI). After the fourth cycle, the reaction mixture containing the catalyst was centrifuged, and its surface morphology was compared to the fresh catalyst using PXRD and TEM (Figure S5 and S1 of SI, respectively), which showed agglomeration of the catalyst during the course of the reaction.

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CONCLUSIONS We demonstrated an unprecedented synthesis of Cu2S NPs via a single-source precursor route from CuSPh. The prepared NPs are highly active and catalyze an efficient and versatile C−H/N−H cross dehydrogenative coupling between the sp3 α-C−H of N,N-dimethylbenzylamines and azoles under solvent-free conditions. This method enables a highly N1- and N2-selective alkylation of benzotriazoles and 4,5-unsubstituted 1,2,3-triazoles, respectively. It also allows access to N2-alkylated 4-phenyl-1,2,3-triazoles and N-alkylated carbazoles in good yields. The catalyst is reusable for up to five reaction cycles with a slight loss in activity. The reaction 3231

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235

Article

The Journal of Organic Chemistry Reagent Information. Trioctylphosphine (TOP), CuSO4·5H2O, and thiophenol were procured from Sigma-Aldrich (USA). Hydroxylamine hydrochloride (NH2OH·HCl) and N,N-dimethylbenzylamine (Acros Organics), were used as received. All the solvents of AR grade, i.e., acetone, diethyl ether, and ethanol, were dried and distilled before use by known standard procedures. The synthesis of the CuSPh complex is detailed below. Procedure for the Synthesis of the CuSPh Complex.17 To an ice-cold mixture of conc aqueous NH3 (25 mL) and water (100 mL), was added CuSO4.·5H2O (6.26 g, 25.1 mmol), resulting in a bluecolored solution. Then, a solid form of NH2OH·HCl (3.89 g, 56.0 mmol) was added, and the contents were stirred overnight at 25 °C under a nitrogen purge to produce a colorless solution of [Cu(NH3)2]+. A solution of PhSH (2.84 g, 25.8 mmol) in 125 mL of ethanol was added dropwise, resulting in the formation of a pale-yellow solid. The solid product was collected via filtration and washed several times with water, ethanol, and ether. The solid was finally dried in vacuum. Yellowish solid; yield: 82%. Procedure for the Synthesis of Cu2S Nanoparticles. A slurry containing 0.5 mmol CuSPh in 2 mL of trioctylphosphine (TOP) in a three-necked 50 mL round-bottom flask was heated under a N2 atmosphere to 100 °C to remove water and oxygen. The resulting homogeneous solution was heated to 320 °C for 1.5 h with continuous stirring, affording a brownish-black colloidal solution. The mixture was cooled to room temperature, and 20 mL of acetone was added into the flask to obtain a brown precipitate which was separated by centrifugation. The precipitate was washed three times with acetone (20 mL) and dried in vacuum. General Procedure for the Synthesis of Compounds 3a−3n, 5a−5k, 7a−7g, and 9a−9f. To the mixture of N,N-dimethylbenzylamine/ N,N-dimethylaniline (1/8) (1.0 mmol), triazole (2)/benzotriazole (4) or carbazole (6) (0.5 mmol), tert-butyl hydroperoxide (0.1 mL, 0.6 mmol of decane solution), and Cu2S NP catalyst (1 mol %, 0.4 mg) were added under nitrogen at room temperature. The reaction temperature was raised to 90 °C, and the contents were stirred at the same temperature for 1 h. The reaction mixture was then cooled to room temperature. The resulting suspension was diluted with ethyl acetate, and the organic layer was washed off with 5% sodium bicarbonate aqueous solution (3 × 10 mL) and dried over anhydrous Na2SO4. Solvent was evaporated, and the residue was purified by column chromatography on silica gel (eluting with hexane/ethyl acetate 95:5). Characterization Data. N-[(2H-1,2,3-Triazol-2-yl)methyl]-N-methyl-1-phenylmethanamine (3a). Yellow liquid (0.15 g, 74%). 1H NMR (300 MHz, CDCl3): δ 7.66 (s, 2H), 7.39−7.26 (m, 5H), 5.30 (s, 2H), 3.71 (s, 2H), 2.34 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 138.2(C), 134.0(CH), 129.0(CH), 128.4(CH), 127.3(CH), 74.0(CH2), 58.2(CH2), 39.6(CH3). HRMS (ESI-TOF) m/z: [M]+ calcd for C11H14N4 202.1213; found 202.1214. N-[(2H-1,2,3-Triazol-2-yl)methyl]-N-methyl-1-(p-tolyl)methanamine (3b). White solid (0.173 g, 80%), mp 42−44 °C. 1H NMR (300 MHz, CDCl3): δ 7.69 (s, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 7.8 Hz, 2H), 5.32 (s, 2H), 3.70 (s, 2H), 2.36 (s, 6H). 13C{1H}NMR (75 MHz, CDCl3): δ 136.8(C), 135.2(C), 134.0(CH), 129.0(CH), 128.9(CH), 73.9(CH2), 57.9(CH2), 39.6(CH3), 21.1(CH3). HRMS (ESI-TOF) m/z: [M]+ calcd for C12H16N4 216.1369; found 216.1361. N-[(2H-1,2,3-Triazol-2-yl)methyl]-1-(4-methoxyphenyl)-N-methylmethanamine (3c). Yellow liquid (0.19 g, 82%). 1H NMR (300 MHz, CDCl3): δ 7.66 (s, 2H), 7.30 (dd, J1 = 6.6 Hz, J2 = 2.1 Hz, 2H), 6.88 (dd, J1 = 6.5 Hz, J2 = 2.1 Hz, 2H), 5.28 (s, 2H), 3.81 (s, 3H), 3.65 (s, 2H), 2.34 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 158.9(C), 134.0(CH), 130.3(C), 130.2(CH), 113.7(CH), 73.7(CH2), 57.6(CH2), 55.3(CH3), 39.6(CH3). HRMS (ESI-TOF) m/z: [M]+ calcd for C12H16N4O 232.1319; found 232.1332. N-[(2H-1,2,3-Triazol-2-yl)methyl]-1-(4-chlorophenyl)-N-methylmethanamine (3d). Yellow liquid (0.18 g, 76%). 1H NMR (300 MHz, CDCl3): δ 7.66 (s, 2H), 7.32 (m, 4H), 5.28 (s, 2H), 3.67 (s, 2H), 2.34 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 136.8(C), 134.1(CH), 133.0(C), 130.3(CH), 128.5(CH), 73.8(CH2), 57.5(CH2), 39.7(CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C11H13ClN4Na 259.0721; found 259.0722.

N-[(2H-1,2,3-Triazol-2-yl)methyl]-1-(2-chlorophenyl)-N-methylmethanamine (3e). Yellow liquid (0.165 g, 70%). 1H NMR (300 MHz, CDCl3): δ 7.68 (s, 2H), 7.52−7.49 (m, 1H), 7.39−7.36 (m, 1H), 7.26−7.22 (m, 2H), 5.34 (s, 2H), 3.82 (s, 2H), 2.40 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 135.8(C), 134.7(C), 134.1(CH), 130.9(CH), 129.7(CH), 128.6(CH), 126.6(CH), 74.3(CH2), 55.4(CH2), 39.6(CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C11H13ClN4Na 259.0721; found 259.0722. N-[(2H-1,2,3-Triazol-2-yl)methyl]-1-(3-chlorophenyl)-N-methylmethanamine (3f). Yellow liquid (0.18 g, 73%). 1H NMR (300 MHz, CDCl3): δ 7.67 (s, 2H), 7.40 (s, 1H), 7.25 (s, 3H), 5.30 (s, 2H), 3.70 (s, 2H), 2.34 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 140.5(C), 134.1(CH), 129.6(CH), 128.9(CH), 127.9(C), 127.5(CH), 127.0(CH), 74.0(CH2), 57.7(CH2), 39.6(CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C11H13ClN4Na 259.0721; found 259.0703. N-[(2H-1,2,3-Triazol-2-yl)methyl]-1-(4-bromophenyl)-N-methylmethanamine (3g). White solid (0.219 g, 78%), mp 46−48 °C. 1 H NMR (300 MHz, CDCl3): δ 7.66 (s, 2H), 7.48−7.45 (m, 2H), 7.27 (d, J = 8.4 Hz, 2H), 5.27 (s, 2H), 3.66 (s, 2H), 2.34 (s, 3H). 13 C{1H}NMR (75 MHz, CDCl3): δ 137.3(C), 134.0(CH), 131.5(CH), 130.6(CH), 121.1(C), 73.8(CH2), 57.5(CH2), 39.7(CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C11H13BrN4Na 303.0216; found 303.0187. N-[(2H-1,2,3-Triazol-2-yl)methyl]-N-benzylethanamine (3h). Colorless liquid (0.147 g, 68%). 1H NMR (300 MHz, CDCl3): δ 7.65 (s, 2H), 7.43−7.40 (m, 2H), 7.38−7.32 (m, 2H), 7.29−7.26 (m, 1H) 5.31 (s, 2H), 3.78 (s, 2H), 2.59 (q, J = 7.2 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). 13 C{1H}NMR (75 MHz, CDCl3): δ 138.8(C), 133.9(CH), 128.9(CH), 128.3(CH), 127.1(CH), 70.3(CH 2 ), 56.0(CH 2 ), 45.5(CH 2 ), 12.8(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H17N4 217.1448; found 217.1440. N-Benzyl-N-methyl-1-(4-phenyl-2H-1,2,3-triazol-2-yl)methanamine (3i). White solid (0.223 g, 80%), mp 76−78 °C. 1H NMR (300 MHz, CDCl3): δ 7.90 (s, 1H), 7.84 (d, J = 7.5 Hz, 2H), 7.47−7.27 (m, 8H), 5.31 (s, 2H), 3.77 (s, 2H), 2.40 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 147.6(C), 138.3(C), 130.9(CH), 130.6(C), 129.1(CH), 128.9(CH), 128.4(CH), 128.3(CH), 127.3(CH), 126.0(CH), 74.2(CH2), 58.3(CH2), 39.8(CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H18N4Na 301.1424; found 301.1412. N-Methyl-N-(4-methylbenzyl)-1-(4-phenyl-1H-1,2,3-triazol-1-yl)methanamine (3j). White solid (0.240 g, 82%), mp 78−80 °C. 1H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.82 (t, J = 1.2 Hz, 1H), 7.48−7.42 (m, 2H), 7.39−7.35 (m, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 5.30 (s, 2H), 3.73 (s, 2H), 2.40 (s, 3H), 2.35 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 147.5(C), 136.9(C), 135.2(C), 130.8(CH), 130.7(C), 129.1(CH), 129.0(CH), 128.9(CH), 128.4(CH), 126.0(CH), 74.1(CH 2 ), 58.0(CH 2 ), 39.7(CH3), 21.1(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H21N4 293.1761; found 293.1757. N-(2-Chlorobenzyl)-N-methyl-1-(4-phenyl-1H-1,2,3-triazol-1-yl)methanamine (3k). Colorless liquid (0.241 g, 77%). 1H NMR (300 MHz, CDCl3): δ 7.91 (s, 1H), 7.86−7.83 (m, 2H), 7.54−7.33 (m, 5H), 7.28−7.21 (m, 2H), 5.34 (s, 2H), 3.88 (s, 2H), 2.45 (s, 3H). 13 C{1H}NMR (75 MHz, CDCl3): δ 147.6(C), 135.8(C), 134.7(C), 130.9(CH), 130.5(C), 129.7(CH), 128.8(CH), 128.5(CH), 128.4(CH), 126.5(CH), 125.9(CH), 74.3(CH2), 55.4(CH2), 39.7(CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C17H17ClN4Na 335.1034; found 335.1018. N-(3-Chlorobenzyl)-N-methyl-1-(4-phenyl-1H-1,2,3-triazol-1-yl)methanamine (3l). Colorless liquid (0.247 g, 79%). 1H NMR (300 MHz, CDCl3): δ 7.90 (s, 1H), 7.85−7.82 (m, 2H), 7.49−7.43 (m, 3H), 7.39−7.33 (m, 1H), 7.29−7.26 (m, 3H), 5.30 (s, 2H), 3.74 (s, 2H), 2.40 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 147.7(C), 140.5(C), 134.3(C), 130.9(CH), 130.5(C), 129.6(CH), 129.0(CH), 128.9(CH), 128.5(CH), 127.5(CH), 127.1(CH), 126.0(CH), 74.1(CH2), 57.7(CH2), 39.8(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H18ClN4 313.1215; found 313.1187. N-(4-Chlorobenzyl)-N-methyl-1-(4-phenyl-1H-1,2,3-triazol-1-yl)methanamine (3m). White solid (0.253 g, 81%), mp 80−82 °C. 1H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H), 7.84−7.82 (m, 2H), 3232

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235

Article

The Journal of Organic Chemistry

N-Benzyl-1-[5,6-dimethyl-1H-benzo(d)(1,2,3)triazol-1-yl]-N-methylmethanamine (5g). White solid (0.236 g, 84%), mp 116−118 °C.1H NMR (300 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.67 (s, 1H), 7.35−7.30 (m, 5H), 5.55 (s, 2H), 3.66 (s, 2H), 2.38 (s, 3H), 2.37 (s, 3H), 2.20 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 144.6(C), 138.7(C), 137.7(C), 133.7(C), 133.4(C), 129.2(CH), 128.7(CH), 127.6(CH), 118.4(CH), 110.6(CH), 68.2(CH 2 ), 58.4(CH 2 ), 39.6(CH 3 ) 20.9(CH3), 20.3(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H21N4 281.1761; found 281.1761. 1-[5,6-Dimethyl-1H-benzo(d)(1,2,3)triazol-1-yl]-N-methyl-N-(4methylbenzyl)methanamine (5h). White solid (0.262 g, 89%), mp 120−122 °C. 1H NMR (300 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.65 (s, 1H), 7.25−7.13 (m, 4H), 5.53 (s, 2H), 3.60 (s, 2H), 2.38 (s, 3H), 2.37 (s, 3H), 2.29 (s, 2H), 2.18 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 144.6(C), 137.7(C), 136.7(C), 135.6(C), 133.7(C), 133.4(C), 129.3(CH), 129.2(CH), 118.4(CH), 110.7(CH), 68.1(CH2), 58.2(CH2), 39.6(CH3) 21.2(CH3), 20.9(CH3), 20.3(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H23N4 295.1917; found 295.1904. N-(2-Chlorobenzyl)-1-[5,6-dimethyl-1H-benzo(d)(1,2,3)triazol-1yl]-N-methylmethanamine (5i). Colorless liquid (0.261 g, 83%). 1H NMR (300 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.66 (s, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.45−7.42 (m, 1H), 7.38−7.29 (m, 2H), 5.58 (s, 2H), 3.77 (s, 2H), 2.37 (s, 3H), 2.36 (s, 3H), 2.23 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 144.6(C), 137.8(C), 136.0(C), 133.9(C), 133.8(C), 133.4(C), 131.3(CH), 129.9(CH), 129.4(CH), 127.5(CH), 118.4(CH), 110.6(CH), 68.4(CH2), 55.6(CH2), 39.6(CH3), 20.8(CH3), 20.3(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H20ClN4 315.1371; found 315.1367. N-(3-Chlorobenzyl)-1-(5,6-dimethyl-1H-benzo(d)(1,2,3)triazol-1yl]-N-methylmethanamine (5j). White solid (0.268 g, 85%), mp 118−120 °C. 1H NMR (300 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.66 (s, 1H), 7.39−7.30 (m, 4H), 5.54 (s, 2H), 3.67 (s, 2H), 2.39 (s, 3H), 2.37 (s, 3H), 2.22 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 144.6(C), 141.5(C), 137.8(C), 133.8(C), 133.5(C), 133.4(C), 130.6(CH), 128.8(CH), 127.7(CH), 127.6(CH), 118.4(CH), 110.6(CH), 68.1(CH2), 57.7(CH2), 39.7(CH3), 20.9(CH3), 20.3(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H20ClN4 315.1371; found 315.1375. N-(4-Chlorobenzyl)-1-[5,6-dimethyl-1H-benzo(d)(1,2,3)triazol-1yl]-N-methylmethanamine (5k). White solid (0.274 g, 87%), mp 122− 124 °C. 1H NMR (300 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.68 (s, 1H), 7.41−7.33 (m, 4H), 5.55 (s, 2H), 3.65 (s, 2H), 2.38 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 144.6(C), 137.8(C), 133.8(CH), 133.4(C), 132.1(C), 131.0(CH), 129.0(C), 128.7(CH), 118.4(CH), 110.6(CH), 68.1(CH2), 57.6(CH2), 39.6(CH3) 20.9(CH3), 20.3(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H20ClN4 315.1371; found 315.1382. N-[(9H-Carbazol-9-yl)methyl]-N-methyl-1-phenylmethanamine (7a). White solid (0.216 g, 72%), mp 58−60 °C. 1H NMR (300 MHz, CDCl3): δ 8.08 (d, J = 7.5 Hz, 2H), 7.52−7.40 (m, 5H), 7.32−7.31 (m, 3H), 7.28−7.21 (m, 3H), 4.97 (s, 2H), 3.68 (s, 2H), 2.25 (s, 3H). 13 C{1H}NMR (75 MHz, CDCl3): δ 141.2(C), 138.5(C), 128.9(CH), 128.3(CH), 127.2(CH), 125.7(CH), 123.2(C), 120.2(CH), 119.4(CH), 109.7(CH), 64.9(CH2), 59.7(CH2), 40.2(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H21N2 301.1699; found 301.1703. N-[(9H-Carbazol-9-yl)methyl]-N-methyl-1-(p-tolyl)methanamine (7b). White solid (0.252 g, 80%), mp 54−56 °C. 1H NMR (300 MHz, CDCl3): δ 8.13 (d, J = 7.8 Hz, 2H), 7.57−7.44 (m, 5H), 7.32−7.25 (m, 4H), 7.18 (d, J = 7.8 Hz, 1H), 5.0 (s, 2H), 3.70 (s, 2H), 2.39 (s, 3H) 2.28 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 141.2(C), 136.8(C), 135.3(C), 129.0(CH), 128.9(CH), 125.7(CH), 123.2(C), 120.1(CH), 119.3(CH), 109.7(CH), 64.8(CH 2 ), 59.4(CH 2 ), 40.1(CH 3 ), 21.1(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H23N2 315.1856; found 315.1865. N-[(9H-Carbazol-9-yl)methyl]-1-(4-methoxyphenyl)-N-methylmethanamine (7c). White solid (0.270 g, 82%), mp 55−57 °C. 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J = 7.8 Hz, 2H), 7.55−7.44 (m, 4H), 7.30−7.26 (m, 4H), 6.89 (d, J = 8.7 Hz, 2H), 4.99 (s, 2H), 3.83 (s, 3H), 3.66 (s, 2H), 2.28 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 158.8(C), 141.1(C), 130.1(CH), 125.7(CH), 123.1(C), 120.1(CH), 119.3(CH), 113.7(CH), 110.5(C), 109.7(CH), 64.7(CH2), 59.0(CH2),

7.48−7.43 (m, 2H), 7.39−7.30 (m, 5H), 5.28 (s, 2H), 3.72 (s, 2H), 2.39 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 147.6(C), 136.8(C), 133.0(C), 130.9(CH), 130.5(C), 130.4(CH), 128.9(CH), 128.5(CH), 128.4(CH), 125.9(CH), 73.9(CH2), 57.5(CH2), 39.8(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H18ClN4 313.1215; found 313.1210. N-(4-Bromobenzyl)-N-methyl-1-(4-phenyl-2H-1,2,3-triazol-2-yl)methanamine (3n). White solid (0.300 g, 84%), mp 84−86 °C. 1 H NMR (300 MHz, CDCl3): δ 7.89 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H) 7.48−7.36 (m, 5H), 7.28 (d, J = 8.4 Hz, 2H), 5.28 (s, 2H), 3.70 (s, 2H), 2.39 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 147.6(C), 137.3(CH), 131.5(CH), 131.0(CH), 130.8(CH), 130.5(C), 128.9(CH), 128.5(CH), 126.0(CH), 121.1(C), 73.9(CH2), 57.6(CH2), 39.8(CH3). HRMS (ESITOF) m/z: [M + Na]+ calcd for C17H17BrN4Na 379.0529; found 379.0524. N-{[1H-Benzo(d)(1,2,3)triazol-1-yl]methyl}-N-methyl-1-phenylmethanamine (5a).30 White solid (0.204 g, 81%), mp 114−116 °C. 1H NMR (300 MHz, DMSO-d6): δ 8.06 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.44−7.39 (m, 1H), 7.36−7.26 (m, 5H), 5.64 (s, 2H), 3.67 (s, 2H), 2.19 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 145.3(C), 138.6(C), 134.4(C), 129.1(CH), 128.7(CH), 127.8(CH), 127.6(CH), 124.4(CH), 119.4(CH), 111.5(CH), 68.5(CH2), 58.4(CH2), 39.5(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C15H17N4 253.1448; found 253.1448. N-{[1H-Benzo(d)(1,2,3)triazol-1-yl]methyl}-N-methyl-1-(p-tolyl)methanamine (5b). Colorless liquid (0.210 g, 79%). 1H NMR (300 MHz, DMSO-d6): δ 8.07 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 7.2 Hz, 2H), 5.64 (s, 2H), 3.64 (s, 2H), 2.29 (s, 3H), 2.19 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 145.4(C), 136.7(C), 135.5(CH), 134.4(C), 129.3(CH), 129.1(CH), 127.8(CH), 124.3(CH), 119.5(CH), 111.6(CH), 68.5(CH2), 58.2(CH2), 39.4(CH3), 21.2(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H19N4 267.1604; found 267.1595. N-{[1H-Benzo(d)(1,2,3)triazol-1-yl]methyl}-1-(4-methoxyphenyl)N-methylmethanamine (5c). Colorless liquid (0.24 g, 85%). 1H NMR (300 MHz, DMSO-d6): δ 8.07 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.60−7.55 (m, 1H), 7.44−7.39 (m, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.91−6.88 (d, J = 8.7 Hz, 2H), 5.63 (s, 2H), 3.71 (s, 3H), 3.60 (s, 2H), 2.17 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 158.9(C), 145.3(C), 134.4(C), 130.4(C), 130.4(CH), 127.8(CH), 124.4(CH), 119.5(CH), 114.1(CH), 111.6(CH), 68.3(CH2), 57.8(CH2), 55.5(CH3), 39.3((CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H18N4ONa 305.1373; found 305.1369. N-{[1H-Benzo(d)(1,2,3)triazol-1-yl]methyl}-1-(2-chlorophenyl)-Nmethylmethanamine (5d). Colorless liquid (0.221 g, 77%). 1H NMR (300 MHz, DMSO-d6): δ 8.07 (d, J = 9.0 Hz, 1H), 7.97 (d, J = 9.0 Hz, 1H), 7.60−7.50 (m, 2H), 7.46−7.40 (m, 2H), 7.37−7.31 (m, 2H), 5.69 (s, 2H), 3.80 (s, 2H), 2.24 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 145.4(C), 135.9(C), 134.4(C), 133.9(C), 131.3(CH), 129.9(CH), 129.4(CH), 127.9(CH), 127.6(CH), 124.4(CH), 119.5(CH), 111.5(CH), 68.7(CH2), 55.6(CH2), 39.5(CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H15ClN4Na 309.0877; found 309.0887. N-{[1H-Benzo(d)(1,2,3)triazol-1-yl]methyl}-1-(3-chlorophenyl)-Nmethylmethanamine (5e). Colorless liquid (0.227 g, 79%).1H NMR (300 MHz, DMSO-d6): δ 8.07 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.61−7.55 (m, 1H), 7.45−7.30 (m, 5H), 5.66 (s, 2H), 3.71 (s, 2H), 2.22 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 145.4(C), 141.5(C), 134.4(C), 133.5(C), 130.6(CH), 128.8(CH), 127.9(CH), 127.7(CH), 127.6(CH), 124.4(CH), 119.5(CH), 111.5(CH), 68.5(CH2), 57.7(CH2), 39.5(CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H15ClN4Na 309.0877; found 309.0887. N-{[1H-Benzo(d)(1,2,3)triazol-1-yl]methyl}-1-(4-chlorophenyl)-Nmethylmethanamine (5f).30 Colorless liquid (0.232 g, 81%). 1H NMR (300 MHz, DMSO-d6): δ 8.06 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.59−7.54 (m, 1H), 7.44−7.33 (m, 5H), 5.65 (s, 2H), 3.67 (s, 2H), 2.20 (s, 3H). 13C{1H}NMR (75 MHz, DMSO-d6): δ 145.4(C), 137.7(C), 134.4(C), 132.2(C), 130.9(CH), 128.7(CH), 127.9(CH), 124.4(CH), 119.5(CH), 111.5(CH), 68.4(CH2), 57.6(CH2), 39.5(CH3). HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C15H15ClN4Na 309.0877; found 309.0887. 3233

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235

Article

The Journal of Organic Chemistry

δ 8.02 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.4 Hz), 7.51 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.8 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.78 (t, J = 7.8 Hz, 1H), 6.37 (s, 2H), 3.08 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3), δ 147.8, 145.5, 133.2, 129.5, 127.9, 124.4, 119.5, 119.2, 114.7, 111.4, 65.4, 38.5. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C14H14N4Na 261.1111; found 261.1111. N-[(9H-Carbazol-9-yl)methyl]-N-methylaniline (9f). White solid (0.215 g, 75%), mp 46−48 °C. 1H NMR (300 MHz, CDCl3): δ 8.11 (d, J = 7.8 Hz, 4H), 7.46−7.44 (m, 3H), 7.42−7.36 (m, 3H), 7.28−7.24 (m, 2H), 7.05 (d, J = 8.7 Hz, 1H), 5.79 (s, 2H), 2.78 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3), δ 140.6, 139.5, 129.5, 125.8, 123.4, 120.3, 119.6, 115.5, 110.5, 109.5, 61.6, 35.7. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C20H18N2Na 309.1362; found 309.1353.

55.3(CH3), 40.1(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H23N2O 331.1805; found 331.1820. N-[(9H-Carbazol-9-yl)methyl]-1-(2-chlorophenyl)-N-methylmethanamine (7d). White solid (0.251 g, 75%), mp 52−54 °C. 1H NMR (300 MHz, CDCl3): δ 8.12 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.52−7.45 (m, 3H), 7.41−7.22 (m, 5H), 5.06 (s, 2H), 3.87 (s, 2H), 2.32 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 141.1(C), 135.9(C), 134.3(C), 130.9(CH), 129.5(CH), 128.4(CH), 126.7(CH), 125.7(CH), 123.2(C), 120.2(CH), 119.4(CH), 109.6(CH), 65.0(CH2), 56.2(CH2), 40.1(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H20ClN2 335.1310; found 335.1297. N-[(9H-Carbazol-9-yl)methyl]-1-(3-chlorophenyl)-N-methylmethanamine (7e). White solid (0.258 g, 77%), mp 53−55 °C. 1H NMR (300 MHz, CDCl3): δ 8.08 (d, J = 7.8 Hz, 2H), 7.53−7.41 (m, 5H), 7.31−7.14 (m, 5H), 4.97 (s, 2H), 3.63 (s, 2H), 2.26 (s, 3H). 13 C{1H}NMR (75 MHz, CDCl3): δ 141.1(C), 140.7(C), 134.2(C), 129.5(CH), 128.8(CH), 127.4(CH), 126.8(CH), 125.8(CH), 123.2(C), 120.2(CH), 119.4(CH), 109.6(CH), 64.9(CH2), 58.9(CH2), 40.2(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H20ClN2 335.1310; found 335.1298. N-[(9H-Carbazol-9-yl)methyl]-1-(4-chlorophenyl)-N-methylmethanamine (7f). White solid (0.264 g, 79%), mp 58−60 °C. 1H NMR (300 MHz, CDCl3): δ 8.07 (d, J = 7.8 Hz, 2H), 7.51−7.38 (m, 5H), 7.26−7.18 (m, 5H), 4.95 (s, 2H), 3.60 (s, 2H), 2.22 (s, 3H). 13 C{1H}NMR (75 MHz, CDCl3): δ 141.1(C), 137.0(C), 132.8(C), 130.1(CH), 128.4(CH), 125.7(CH), 123.2(C), 120.2(CH), 119.4(CH), 109.6(CH), 64.9(CH2), 58.7(CH2), 40.0(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H20ClN2 335.1310; found 335.1328. N-[(9H-Carbazol-9-yl)methyl]-1-(4-bromophenyl)-N-methylmethanamine (7g). White solid (0.281 g, 74%), mp 56−58 °C. 1H NMR (300 MHz, CDCl3): δ 8.07 (d, J = 8.1 Hz, 2H), 7.55−7.38 (m, 6H), 7.27−7.19 (m, 3H), 7.14 (d, J = 8.1 Hz, 1H), 4.95 (s, 2H), 3.58 (s, 2H), 2.23 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 141.1(C), 137.6(C), 131.4(CH), 130.4(CH), 125.7(CH), 123.2(C), 121.0(C), 120.2(CH), 119.4(CH), 109.6(CH), 64.9(CH2), 58.7(CH2), 40.0(CH3). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H20BrN2 379.0804; found 379.0791. N-[(2H-1,2,3-Triazol-2-yl)methyl]-N-methylaniline (9a). Colorless liquid (0.16 g, 85%).1H NMR (300 MHz, CDCl3): δ 7.61 (s, 2H), 7.31− 7.25 (m, 2H), 7.04 (d, J = 8.7 Hz, 2H), 6.84 (t, J = 7.8 Hz, 1H), 5.90 (s, 2H), 3.21 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 147.3, 134.3, 129.2, 119.0, 113.7, 70.8, 38.4. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C10H12N4Na 211.0954; found 211.0953. N-Methyl-N-[(4-phenyl-2H-1,2,3-triazol-2-yl)methyl]aniline (9b). White solid (0.196 g, 74%), mp 62−64 °C.1H NMR (300 MHz, CDCl3): δ 7.82 (s 1H), 7.78−7.75 (m, 1H), 7.44−7.39 (m, 3H), 7.35− 7.25 (m, 3H), 7.07 (d, J = 8.1 Hz, 2H), 6.84 (t, J = 7.8 Hz, 1H), 5.90 (s, 2H), 3.24 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 148.0, 147.5, 131.2, 129.2, 128.8, 128.4, 126.1, 126.0, 119.0, 113.9, 71.1, 38.5. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H16N4Na 287.1267; found 287.1261. N-4-Dimethyl-N-[(4-phenyl-2H-1,2,3-triazol-2-yl)methyl]aniline (9c). White solid (0.214 g, 77%), mp 64−66 °C.1H NMR (300 MHz, CDCl3): δ 7.82 (s, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.44−7.33 (m, 3H), 7.08 (d, J = 8.1 Hz, 2H), 6.98−6.95 (m, 2H), 5.88 (s, 2H), 3.20 (s, 3H), 2.25 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3), δ 147.7, 147.2, 131.2, 130.5, 129.7, 128.8, 128.4, 128.3, 126.0, 114.2, 71.4, 38.6, 20.3. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H19N4 279.1604; found 279.1604. 4-Chloro-N-methyl-N-[(4-phenyl-2H-1,2,3-triazol-2-yl)methyl]aniline (9d). White solid (0.194 g, 65%), mp 66−68 °C. 1H NMR (300 MHz, CDCl3): δ 7.85 (s, 1H), 7.80−7.77 (m, 2H), 7.47−7.34 (m, 3H), 7.28 (m, 2H), 7.25−7.22 (m, 1H), 7.01 (d, J = 8.7 Hz, 1H), 5.86 (s, 2H), 3.24 (s, 3H). 13C{1H}NMR (75 MHz, CDCl3): δ 147.9, 145.9, 131.3, 130.2, 129.0, 128.8, 128.5, 125.9, 124.1, 115.1, 70.9, 38.7. HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C16H15ClN4Na 321.0877; found 321.0861. N-{[1H-Benzo(d)(1,2,3)triazol-1-yl)methyl}-N-methylaniline (9e). Colorless liquid (0.209 g, 88%). 1H NMR (300 MHz, DMSO-d6):

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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.8b00107. Crystallographic data for 3n and 5a (CIF). 1 H and 13CNMR spectra for all the synthesized compounds, ORTEPs and associated X-ray crystallographic data for 3n and 5a, and nanoparticle characterization data (TEM, SEM, PXRD) (PDF).

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; fax: +91 11 26581102; tel: +91 11 26591562 ORCID

Ajai K. Singh: 0000-0003-1650-6316 Nidhi Jain: 0000-0001-8645-430X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS S.G. thanks UGC for his graduate fellowship. N.C. thanks DST for a SERB-National Post-Doctoral Fellowship. The authors thank the Council of Scientific and Industrial Research (CSIR), India (02(180)/14/EMR-II) for financially supporting this work, DST-FIST for funding the ESI-HRMS, the SCXRD facility at IIT Delhi, and MNIT Jaipur for XPS measurements. The authors thank Dr. Sayantan Paria, IITD for useful discussions on EPR and Dr. Anil Kumar, BITS Pilani for HRMS measurements.

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REFERENCES

(1) (a) Perfect, J. R. Nat. Rev. Drug Discovery 2017, 16, 603−616. (b) Rossello, A.; Bertini, S.; Lapucci, A.; Macchia, M.; Martinelli, A.; Rapposelli, S.; Herreros, E.; Macchia, B. J. Med. Chem. 2002, 45, 4903− 4912. (2) (a) Baxter, C. A.; Cleator, E.; Brands, K. M.; Edwards, J. S.; Reamer, R. A.; Sheen, F. J.; Stewart, G. W.; Strotman, N. A.; Wallace, D. J. Org. Process Res. Dev. 2011, 15, 367−375. (b) de O. Freitas, L. B.; Borgati, T. F.; de Freitas, R. P.; Ruiz, A. L.; Marchetti, G. M.; de Carvalho, J. E.; da Cunha, E. F.; Ramalho, T. C.; Alves, R. B. Eur. J. Med. Chem. 2014, 84, 595−604. (3) (a) Chen, Y.; Nie, G.; Zhang, Q.; Ma, S.; Li, H.; Hu, Q. Org. Lett. 2015, 17, 1118−1121. (b) Rohilla, S.; Patel, S. S.; Jain, N. Eur. J. Org. Chem. 2016, 2016, 847−854. (4) (a) Wang, W.; Peng, X.; Wei, F.; Tung, C. H.; Xu, Z. Angew. Chem., Int. Ed. 2016, 55, 649−653. (b) Haldón, E.; Nicasio, M. C.; Pérez, P. J. Org. Biomol. Chem. 2015, 13, 9528−9550. (5) (a) Thomas, J.; Jana, S.; Liekens, S.; Dehaen, W. Chem. Commun. 2016, 52, 9236−9239. (b) Ramasastry, S. S. Angew. Chem., Int. Ed. 2014, 3234

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235

Article

The Journal of Organic Chemistry

Parisi, O. I.; et al. Molecules 2014, 19, 9307−9317. (b) Taylor, C. J.; Jhaveri, D. J.; Bartlett, P. F. Front. Cell. Neurosci. 2013, 7. (33) (a) Smith, J. R. L.; Mortimer, D. N. J. Chem. Soc., Perkin Trans. 2 1986, 1743−1749. (b) Gong, J.-L.; Qi, X.; Wei, D.; Feng, J.-B.; Wu, X.-F. Org. Biomol. Chem. 2014, 12, 7486−7488. (34) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2007, 9, 3813− 3816.

53, 14310−14312. (c) Li, W.; Du, Z.; Huang, J.; Jia, Q.; Zhang, K.; Wang, J. Green Chem. 2014, 16, 3003−3006. (6) (a) Ueda, S.; Su, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50, 8944−8947. (b) Zhang, Y.; Li, X.; Li, J.; Chen, J.; Meng, X.; Zhao, M.; Chen, B. Org. Lett. 2012, 14, 26−29. (7) Yan, W.; Wang, Q.; Chen, Y.; Petersen, J. L.; Shi, X. Org. Lett. 2010, 12, 3308−3311. (8) Duan, H.; Yan, W.; Sengupta, S.; Shi, X. Bioorg. Med. Chem. Lett. 2009, 19, 3899−3902. (9) Zhu, L.-L.; Xu, X.-Q.; Shi, J.-W.; Chen, B.-L.; Chen, Z. J. Org. Chem. 2016, 81, 3568−3575. (10) (a) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U. S. A. 2006, 103, 8928−8933. (b) Sureshkumar, D.; Sud, A.; Klussmann, M. Synlett 2009, 2009, 1558−1561. (c) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74−100. (d) Li, C.-J. Acc. Chem. Res. 2009, 42, 335−344. (e) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U. W. Chem. - Eur. J. 2012, 18, 10092−10142. (11) (a) Allen, J. M.; Lambert, T. H. J. Am. Chem. Soc. 2011, 133, 1260−1262. (b) Wagner, A.; Han, W.; Mayer, P.; Ofial, A. R. Adv. Synth. Catal. 2013, 355, 3058−3070. (12) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810−11811. (13) Niu, M.; Yin, Z.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 3961−3963. (14) Gupta, S.; Joshi, H.; Jain, N.; Singh, A. K. J. Mol. Catal. A: Chem. 2016, 423, 135−142. (15) Ohta, M.; Quick, M. P.; Yamaguchi, J.; Wuensch, B.; Itami, K. Chem. - Asian J. 2009, 4, 1416−1419. (16) Xing, L.-J.; Wang, X.-M.; Li, H.-Y.; Zhou, W.; Kang, N.; Wang, P.; Wang, B. RSC Adv. 2014, 4, 26783−26786. (17) (a) Gupta, A.; Deshmukh, M. S.; Jain, N. J. Org. Chem. 2017, 82, 4784−4792. (b) Singh, S. K.; Chandna, N.; Jain, N. Org. Lett. 2017, 19, 1322−1325. (18) Ranjit, S.; Lee, R.; Heryadi, D.; Shen, C.; Wu, J. E.; Zhang, P.; Huang, K.-W.; Liu, X. J. Org. Chem. 2011, 76, 8999−9007. (19) Xu, W.; Zhu, S.; Liang, Y.; Li, Z.; Cui, Z.; Yang, X.; Inoue, A. Sci. Rep. 2015, 5, 1. (20) Nayak, A.; Tsuruoka, T.; Terabe, K.; Hasegawa, T.; Aono, M. Nanotechnology 2011, 22, 235201. (21) Wang, X.-j.; Zhang, L.; Lee, H.; Haddad, N.; Krishnamurthy, D.; Senanayake, C. H. Org. Lett. 2009, 11, 5026−5028. (22) (a) Xu, K.; Thieme, N.; Breit, B. Angew. Chem., Int. Ed. 2014, 53, 7268−7271. (b) Kamijo, S.; Jin, T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 7786−7787. (23) Deng, X.; Lei, X.; Nie, G.; Jia, L.; Li, Y.; Chen, Y. J. Org. Chem. 2017, 82, 6163−6171. (24) Kallander, L. S.; Lu, Q.; Chen, W.; Tomaszek, T.; Yang, G.; Tew, D.; Meek, T. D.; Hofmann, G. A.; Schulz-Pritchard, C. K.; Smith, W. W.; et al. J. Med. Chem. 2005, 48, 5644−5647. (25) Röhrig, U. F.; Majjigapu, S. R.; Grosdidier, A. l.; Bron, S.; Stroobant, V.; Pilotte, L.; Colau, D.; Vogel, P.; Van den Eynde, B. J.; Zoete, V.; et al. J. Med. Chem. 2012, 55, 5270−5290. (26) Ren, Y.; Zhang, L.; Zhou, C.-H.; Geng, R. Med. Chem. (Sharjah, United Arab Emirates) 2014, 4, 640−662. (27) Le, Z.-G.; Chen, Z.-C.; Hu, Y.; Zheng, Q.-G. Heterocycles 2004, 63, 1077−1081. (28) Fernández, J. P.; Lima, F. J. R.; Higueras, A. I. H.; González, S. M.; Hernando, J. I. M.; Saluste, C.-G. P.; Cantalapiedra, E. G.; Aparicio, C. B.; Hergueta, A. R.; Collazo, A. M. G. Tricyclic compounds for use as kinase inhibitors. WO2013004984A1, 2013. (29) Antonijevic, M.; Petrovic, M. Int. J. Electrochem. Sci. 2008, 3, 1−28. (30) Smith, J. R. L.; Sadd, J. S. J. Chem. Soc., Perkin Trans. 1 1975, 1181−1184. (31) (a) Pieper, A. A.; Xie, S.; Capota, E.; Estill, S. J.; Zhong, J.; Long, J. M.; Becker, G. L.; Huntington, P.; Goldman, S. E.; Shen, C.-H.; et al. Cell 2010, 142, 39−51. (b) Pieper, A. A.; McKnight, S. L.; Ready, J. M. Chem. Soc. Rev. 2014, 43, 6716−6726. (32) (a) Saturnino, C.; Iacopetta, D.; Sinicropi, M. S.; Rosano, C.; Caruso, A.; Caporale, A.; Marra, N.; Marengo, B.; Pronzato, M. A.; 3235

DOI: 10.1021/acs.joc.8b00107 J. Org. Chem. 2018, 83, 3226−3235