Pseudo-Four Component Synthesis of Mono- and Di-Benzylated-1,2,3-Triazoles Derived from Aniline

The pseudo-four component click synthesis of dibenzylated 1,2,3-triazoles derived from aniline is reported. The cycloaddition of sodium azide to N-(prop-2-ynyl)-benzenamine (I) in the presence of equimolar amounts of p-substituted benzyl derivatives, yields a mixture of mono- and dibenzylated 1,2,3-triazoles. When two equivalents of the benzyl derivative are added to the multicomponent reaction, the selective preparation of the dibenzylated compounds is achieved. The reactivity of the aniline N-H bond in monobenzylated 1,2,3-triazoles was tested by treatment with one equivalent of a p-substituted benzyl chloride at 40 °C, rendering the dibenzylated derivatives quantitatively.


Introduction
One-pot multicomponent reactions are increasingly important in areas such as organic chemistry and materials science because they offer several advantages over classical linear syntheses [1][2][3].

OPEN ACCESS
Multicomponent reactions are highly convergent, offering a notable increase in molecular complexity and topology in a single step [4][5][6][7][8][9]. Another important feature concerns the reduction of waste production as a result of the decrease of synthetic or isolation steps along with time savings [10][11][12][13][14].
Most click processes for triazole synthesis are usually based on three component reactions [44][45][46][47][48]. Relatively few reports on four component click reactions have been reported so far [49][50][51][52]. As part of our ongoing program in triazole chemistry, we envisioned the synthesis of 1,2,3-triazoles as potential steel corrosion inhibitors and/or transition metal ligands. In the present report, we disclose a general approach for the one-pot synthesis of a series of mono-, and dibenzylated 1,2,3-triazoles based on aniline as the parent compound. The modular synthesis described herein allows for the preparation of N-benzylated 1,2,3-triazoles under mild conditions and the functionalization of the N-H bond in the aniline moiety simultaneously through a pseudo-four component click process.

Synthesis and Characterization
The initial synthetic step involved the preparation of N-(prop-2-ynyl)benzenamine (I) by deprotonation of aniline with potassium carbonate in acetone at room temperature, followed by the addition of equimolar amounts of propargyl bromide. After work up and purification through column chromatography on silica gel, alkyne I was isolated in 79% yield according to Scheme 1 [53].

Scheme 1. Synthesis of alkyne I.
The click reaction between I and sodium azide was carried out in a 4:1 water/ethanol mixture using Cu(OAc) 2 and sodium ascorbate as the reagents to render the Cu(I) active catalyst. After addition of benzyl chloride to the reaction mixture and stirring at room temperature for 18 h we observed the complete consumption of the alkyne. At our first intention, we had targeted the preparation of the N-benzylated 1,2,3-triazole 2a, however, TLC analysis of the reaction mixture showed two main products. After separation by column chromatography using CH 2 Cl 2 and CH 2 Cl 2 -MeOH (98:2) as gradient mixtures, the two products were isolated. The 1 H-NMR spectra of the second fraction showed two single peaks corresponding to the methylene groups and a triplet signal assigned to the NH bond from the aniline moiety. All the patterns were consistent with the structure of the expected triazole 2a. On the other hand, the spectrum of the first fraction displayed three different methylene moieties and the signal for the NH group no longer appeared. Careful analysis of the 1 H and 13 C spectra and the M+H [355.1923] ion of 1a in HRMS (ESI-TOF) confirmed the dibenzylated triazole structure of this molecule. Thus, to our delight, the preparation of triazole 1a resulted from a one-pot pseudo-four component click process.
The scope of the method was extended with the use of several p-halobenzylic derivatives yielding the mono-and di-benzylated 1,2,3-triazoles 1b-e and 2b-e, respectively. Likewise the use of several benzylic derivatives allows for the preparation of 1,2,3-triazoles which feature several halogen substituents. As depicted in Table 1, the reaction proceeds smoothly under mild reaction conditions. Triazoles 1a-f and 2a-f were conveniently characterized by FT-IR, 1 H and 13 C-NMR spectroscopy, and also by High Resolution Mass Spectrometry. The formation of the 1,2,3-triazoles was apparent by the presence in the 1 H-NMR of the characteristic singlet due to the triazolyl protons in the δ = 7.99-8.02 ppm for 1a-e and δ = 7.98-8.01 ppm region for 2a-e, respectively.
For most of the series, the click reaction provides the dibenzylated products in higher yields with the exception of the reaction with 4-iodobenzyl chloride in which the monobenzylated triazole is the major product. This may be related to a deactivating effect on the N-H bond due to the presence of the large iodo atom.
As the dibenzylated products were an interesting example of a pseudo-four component process, we focused next on optimization of their preparation. Considering that the dibenzylated products were favored in the original process, we envisioned that we could facilitate their selective preparation by increasing the equivalents of p-halogenated benzyl derivatives. Thus, the original process was  Table 2, the reaction proceeds nicely providing dibenzylated products 1a-e in high yields. Once we had selectively prepared 1a-e, we targeted the synthesis of dibenzylated compounds containing mixed benzyl moieties. With this aim, the reaction was carried out in the presence of one equivalent of p-iodobenzyl chloride and one equivalent of p-bromobenzyl chloride and stirring for 24 h showing by TLC the presence of four compounds in similar ratios. Analysis by of the 1 H and 13 C suggested the presence of two mono-and two benzylated compounds, however, due to the complexity of the mixture no separation was possible.
Knowing that the N-benzylated 1,2,3-triazoles contained a N-H bond, we decided to test its reactivity towards benzyl derivatives in order to obtain bifunctionalized species. Monitoring the addition of equimolar amounts of p-iodobenzyl chloride to triazole 2e at room temperature in chloroform, it was observed that after 24 h, only 5% conversion to the desired benzylated aniline was reached. After several trials, we observed that carrying out the reaction at 40 °C and 12 h of stirring resulted in the full consumption of the starting material. After separation by column chromatography on silica gel with CH 3 Cl as eluent, compound 1e was obtained as a waxy solid in 94% yield (Scheme 2). A second example of the N-H group functionalization of compound 2e, was achieved by treatment with p-fluorobenzyl chloride under similar reaction conditions. Compounds 3 that displays different p-substituted-benzyl moieties, was obtained in 90% yield after work up and purification (Scheme 2).

General Methods
Commercially available reagents and solvents were used as received. N-(prop-2-ynyl)benzenamine (I) was synthesized as reported in the literature [53]. Flash column chromatography was performed on Kieselgel silica gel 60 (230-400 mesh). Melting points were determined on a Fisher-Johns apparatus and are uncorrected. IR spectra were recorded on a Bruker Alpha FT-IR/ATR spectrometer. NMR spectra were obtained with a JEOL ECA-500 (500 MHz) spectrometer. Chemical shifts (δ) are given in ppm downfield from Me 4 Si as an internal reference; coupling constants are given in Hertz. High-resolution mass spectra (HRMS) were recorded on a JEOL JMS-SX 102a and Agilent-MSD-TOF-1069A spectrometers 41.

Benzyl Chloride
To a 20 mL round-bottomed flask equipped with a magnetic stirrer, were charged Cu(OAc) 2 ·H 2 O (11 mg, 0.057 mmol, 5 mol%), 1,10-phenanthroline monohydrate (10 mg, 0.057 mmol, 5 mol%), and sodium L-ascorbate (224 mg, 1.14 mmol). After addition of a EtOH/H 2 O mixture (4:1 v/v, 7 mL), the resulting suspension was stirred for five minutes at room temperature. Subsequently, I (150 mg, 1.14 mmol), sodium azide (90 mg, 1.40 mmol), and benzyl chloride (0.16 mL, 1.40 mmol) were added to the reaction mixture, which was stirred during 18 h at room temperature. H 2 O (5 mL) was added to the reaction mixture and the precipitate was filtered off, washed thoroughly with H 2 O, petroleum ether, and dried under vacuum. The crude mixture containing mono-and dibenzylated products was separated by column chromatography and characterized as follows:

4-Fluorobenzyl Chloride
The general procedure was followed using 1.40 mmol 4-fluorobenzyl chloride. The mixture of products was purified by column chromatography and characterized as follows:

4-Bromobenzyl Chloride
The general procedure was followed using (1.40 mmol) of 4-bromobenzyl chloride. The mixture of products was purified by column chromatography and characterized as follows:

4-Iodobenzyl Bromide
The general procedure was followed using (1.40 mmol) of 4-iodobenzyl bromide. The mixture of products was purified by column chromatography and characterized as follows: