Ultrasound-Promoted One-Pot Synthesis of Mono - ACS Publications

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Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

Ultrasound-Promoted One-Pot Synthesis of Mono- or BisSubstituted Organylselanyl Pyrroles Thiago J. Peglow,† Gabriel P. da Costa,† Luis Fernando B. Duarte,† Maŕ cio S. Silva,† Thiago Barcellos,‡ Gelson Perin,*,† and Diego Alves*,† †

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Laboratório de Síntese Orgânica LimpaLASOL, CCQFA, Universidade Federal de PelotasUFPel, P.O. Box 354, 96010-900 Pelotas, RS, Brazil ‡ Laboratório de Biotecnologia de Produtos Naturais e Sintéticos, Universidade de Caxias do SulUCS, 95070-560 Caxias do Sul, RS, Brazil S Supporting Information *

ABSTRACT: A simple method for the direct mono- and bisorganylselenylation of N-substituted pyrroles through a multicomponent reaction promoted by ultrasonic radiation was described. These sonochemical promoted reactions were performed between different primary amines, 2,5-hexanedione and dialkyl, diheteroaryl, or diaryl diselenides, using catalytic amounts of copper iodide. Depending on the amount of copper iodide and diorganyl diselenide used in the reactions, mono- or bis-organylselenylation products were efficiently synthesized in high yields.

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INTRODUCTION Nitrogen-containing heterocycles represent important structural units1 that display a large spectrum of biological activities,2 drugs under development,3 pharmaceuticals,2,3 agrochemicals,4 and functional materials.5 In this sense, we can highlight pyrroles as versatile heteroaromatic compounds, which serve a range of applications in different fields of chemical/pharmaceutical sciences.6 Research works on the synthesis of pyrrole scaffolds are being performed because their derivatives show several pharmacological activities, including antibiotics, cholesterol-reducing drugs, anti-inflammatory drugs, fungicides, and antitumor agents.7 Also, it is well known that pyrrole derivatives inhibit reverse transcriptase (HIV-1), as well as are present in dyes, fluorescent compounds, and conductive materials, among others.7a,8 For example, atorvastatin, nonsteroidal anti-inflammatory drug tolmetin (marketed as Tolectin), and the anticancer agent tallimustine contain pyrrole in their structure (Figure 1).6 Although a variety of methods were described to synthesize pyrroles, Paal−Knorr reaction9 has received considerable attention due to the applicability of simple starting materials, efficiency, and greener characteristics, and it is one of the most classical approaches.10 Some synthetic methods to functionalize pyrroles have some disadvantages, such as high temperature and requirement of excess reagents.11 On the other hand, N-heterocycles containing selanyl moieties have attracted interest in different areas of research, including the design of new drug candidates.12 Selenium is © XXXX American Chemical Society

considered as an essential nutrient for all mammals and it plays important roles in metabolic pathways.13 Additionally, the interest in the “selenium” pharmacology14 and chemistry15 has increased in this century, and the development of new and efficient methods to synthesize these scaffolds is a growing area in organic synthesis.16 Numerous methodologies have been reported for the selective C−Se bond formation.17 Direct organylselenylation of N-heterocycles is an economic, practical, and useful method to introduce different substituted organylselanyl units to these scaffolds.17a−l For the C−Se bond formation starting from diaryl diselenides,18 our research group has recently described the copper(I)-catalyzed synthesis of selanyl pyrazoles starting from hydrazines, 1,3-diketones, and diorganyl diselenides by a multicomponent reaction (Scheme 1, eq 1).18 In addition, Zhu and co-workers described a method for C5-selanylation of 8amidoquinoline scaffolds using copper(II) bromide in stoichiometric amounts (Scheme 1, eq 2).18b In another study, Cera and Ackermann developed an effective method in which copper(I) acetate promoted the C−H selenylation of the 1H-1,2,3-triazole-4-carboxamides with diaryl diselenides (Scheme 1, eq 3).18c Thus, in view of the above explanation and combining the versatility of multicomponent reactions19 with the sonochemistry,20 we describe our results on the synthesis of a range of Received: February 14, 2019

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DOI: 10.1021/acs.joc.9b00405 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

Figure 1. Examples of drugs containing pyrrole in their structure.

4a, and a set of optimization reactions were performed (Table 1). Thus, we carried out the one-pot reaction of aniline 1a (0.5 mmol), 2,5-hexanedione 2a (0.5 mmol), and diphenyl diselenide 3a (0.25 mmol) under identical reaction conditions shown in Scheme 2, and 2,5-dimethyl-1-phenyl-3-(phenylselanyl)-1H-pyrrole 4a was obtained in 55% yield after 1.0 h (Table 1, entry 1). A small increase in the yield of product 3a occurs in the reaction carried out under microwave irradiation; however, 2.0 h of reaction is needed (Table 1, entry 2). The effect of different temperatures was studied, and decreasing the temperature to 80 °C yielded the product 4a in a similar yield (Table 1, entries 1 vs 3). In another experiment, a slight increase in the yield of the product 4a was observed on gentle heating (50 °C) (Table 1, entry 4). Reaction conducted at room temperature gave only traces of the product 4a, even after 24.0 h (Table 1, entry 5). These results led us to explore an alternative procedure to obtain selectively the product 4a in higher yield. In this sense, we choose ultrasound (US)21 as an alternative energy source to provide the selective reactions. Thus, the same reaction conditions were applied for the reaction under US irradiation (40% of amplitude); however, product 4a was not obtained (Table 1, entry 6). A notable enhancement in yield was observed in the reaction carried out using US irradiation with 60% of amplitude, and the mono-arylselenylated pyrrole 4a was obtained in 70% yield after 0.5 h (Table 1, entry 7). When the reaction was performed under US irradiation with an amplitude of 80%, the starting materials were consumed in only 0.25 h (Table 1, entry 8). Nevertheless, the reaction was not selective because in this case, both mono- and bisarylselenylation products 4a and 5a were obtained in 52 and 24% yields, respectively (Table 1, entry 8). Inspired by the result described in entry 7, we followed the additional experiments using US irradiation (60% of amplitude). We also studied the effects of few copper salts, solvents, and stoichiometry of the starting materials. Different solvents such as dimethylformamide (DMF), N-methyl pyrrolidone (NMP), N,N-dimethylacetamide (DMA), CH3CN, PEG-400, and EtOH were evaluated and very poor

Scheme 1. Examples of Direct Arylselenylation of NHeterocycles by C−H Bond Cleavage

mono- and bis-substituted organylselanyl pyrroles by one-pot copper-catalyzed Paal−Knorr condensation and C−H bond selenylation reactions.

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RESULTS AND DISCUSSION Based on a study conducted in 2012 by our research group,17i in which we performed sulfenylation of pyrroles with disulfides or thiols, we start our studies by reacting 2,5-dimethyl-1phenyl-1H-pyrrole A (0.5 mmol) with diphenyl diselenide 3a (0.25 mmol), using CuI (10 mol %) as a catalyst in dimethyl sulfoxide (DMSO) at 110 °C (Scheme 2). Under these reaction conditions, after 1.0 h, both products mono-phenylselenylation 4a and bis-phenylselenylation 5a were obtained in 80 and 10% yield, respectively. With this result, we turn our efforts to a one-pot Paal−Knorr condensation and successive C−H bond selenylation reaction for the selective formation of mono-substituted selanyl pyrrole Scheme 2

B


Article

The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditions for the One-Pot Synthesis of Compound 4aa

entry

CuX (mol %)

solvent

temp. (°C)

time (h)

yield of 4a (%)

yield of 5a (%)

1 2b 3 4 5 6c 7d 8e 9d 10d 11d 12d 13d 14d 15d 16d 17d 18d 19d 20d 21d 22d,f 23d,g 24d,g,h

CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuI (10) CuBr (10) CuBr2 (10) Cu2O (10) Cu(OAc)2 (10) CuCl (10) CuI (15) CuI (5) CuI (10) CuI (10) CuI (10)

DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMF NMP DMA CH3CN PEG-400 EtOH DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO DMSO

110 110 80 50 rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt

1.0 2.0 2.0 3.0 24.0 0.5 0.5 0.25 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5

55 67 50 69 traces traces 70 52 9 63 traces traces traces

9 8 11 4

52 62 22 40 62 31 63 80 15

5 24 4

8 7

11 4 8 5

a Reactions were carried out with aniline 1a (0.5 mmol), 2,5-hexanedione 2a (0.5 mmol), and diphenyl diselenide 3a (0.25 mmol) in solvent (2.0 mL). The reaction progress was followed by thin layer chromatography (TLC) until the total consumption of the starting materials. bReaction performed under microwave irradiation. Temperature was measured with an IR sensor on the outer surface of the reaction vial. cReaction performed under ultrasound (US) irradiation (40% of amplitude). dReaction performed under ultrasound irradiation (60% of ampitude). eReaction performed under ultrasound irradiation (80% of amplitude). fReaction was performed with 0.3 mmol of diphenyl diselenide 3a. gReaction performed with 0.6 mmol of the aniline 1a and 0.6 mmol of the 2,5-hexanedione 2a. hReaction performed under argon atmosphere.

results were obtained (Table 1, entries 9−14). When the reaction was carried out using both copper(I) and copper(II) species such as CuBr, CuBr2, Cu2O, Cu(OAc)2, and CuCl as catalyst, product 4a was obtained in lower yields (Table 1, compare entries 15−19 and 7). Furthermore, on increasing the catalyst charge from 10 to 15 mol %, a slight decrease in the yield of compound 4a was observed (Table 1, entry 20). On reducing the catalyst charge from 10 to 5 mol %, no gain in the yield of 4a was obtained, and in this case, there was incomplete consumption of starting materials (Table 1, entry 21). We verified the use of an excess of diphenyl diselenide 3a (0.3 mmol) in this reaction, and it did not seem to significantly influence the yield (Table 1, entry 22). Instead, when we use 0.6 mmol of both starting materials 1a and 2a, the monoarylselenylated pyrrole 4a was obtained in 80% yield, showing that a little excess of these starting materials is required to obtain better results (Table 1, entry 23). To check the influence of inert atmosphere, we performed a reaction under argon atmosphere, which generated only 15% of the desired product 4a, proving the importance of the atmosphere of air for this reaction (Table 1, entry 24). Analyzing Table 1, we judge that the optimal reaction condition to obtain the mono-arylselenylated pyrrole 4a is the

use of aniline 1a (0.6 mmol), 2,5-hexanedione 2a (0.6 mmol), diphenyl diselenide 3a (0.25 mmol), CuI as a catalyst (10 mol %), and 2.0 mL of DMSO as solvent under US irradiation (60% of amplitude). After reaction optimization, to demonstrate the generality of this method, we synthesized a series of mono-arylselenylated pyrroles 4a−p using different amines and diorganyl diselenides substituted with aryl, heteroaryl, benzyl, or alkyl groups. The presence of electron-donating methyl or methoxy group in para position of the phenyl ring of the diaryl diselenides, as in 3b and 3c, affords products 4b and 4c in 57 and 64% yields after 1.5 and 1.0 h, respectively (Table 2, compounds 4b and 4c). On the other hand, the electron-withdrawing effect exerted by fluoro or chloro in the ring of the diaryl diselenides 4d and 4e was considerable. In these cases, the reaction required more time (3.0 h) to obtain even slightly lower yields than the electron-donating groups (Table 2, compounds 4b-c vs 4d-e). To extend the scope, the di(thiophen-2-yl)diselenide 3f was reacted giving the desired compound 4f in 36% after 1.5 h (Table 2, compound 4f). When we used dibutyl diselenide 3g to give the desired product 4g, an unsatisfactory result was obtained. The reaction was maintained for 2.0 h and furnished C


Article

The Journal of Organic Chemistry Table 2. Reaction Scope for Synthesis of Mono-Organylselenylated Pyrroles 4a−pa

a

Reaction conditions: amine 1a−j (0.6 mmol), 2,5-hexanedione 2a (0.6 mmol), diorganyl diselenide 3a−g (0.25 mmol), CuI (10 mol %) as catalyst, in DMSO (2.0 mL) as solvent under US irradiation (60% of amplitude). The reaction progress was followed by TLC. bThe yield was determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as internal standard.

Scheme 3

D


Article

The Journal of Organic Chemistry Table 3. Optimization of the Reaction Conditions for the One-Pot Synthesis of Compound 5aa

entry

CuI (mol %)

time (h)

3a (mmol)

yield 4a (%)

yield 5a (%)

1b 2 3 4 5 6b 7c

10 10 15 20 15 15 15

1.0 1.0 1.0 1.0 1.0 1.0 0.5

0.50 0.50 0.50 0.50 0.60 0.50 0.50

12 7 traces traces traces 6 8

79 79 91 89 86 84 83

a

Reactions were carried out with aniline 1a (0.5 mmol) and 2,5-hexanedione 2a (0.5 mmol), using DMSO (2.0 mL) as solvent under US irradiation (60% of amplitude). The reaction progress was followed by TLC until the total consumption of the starting materials. bReaction performed with 0.6 mmol of the aniline 1a and 0.6 mmol of the 2,5-hexanedione 2a. cReaction performed under ultrasound irradiation (80% of amplitude).

diselenide 3a (0.5 mmol). Gratifyingly, after 1.0 h, the bisarylselenated product was obtained in 79% yield, however together with the mono-arylselenylation product 4a (Table 3, entry 1). A similar result was obtained when the amount of aniline 1a and 2,5-hexanedione 2a was decreased to 0.5 mmol (Table 3, entry 2). To our satisfaction, excellent results for the selective synthesis of bis-selenylated pyrrole 5a were obtained in reactions using 15 and 20 mol % of CuI, giving the product 5a in 91 and 89% yields, respectively (Table 3, entries 3 and 4). In these reactions, only traces of mono-selenylated pyrrole 4a were observed. Additional tests were performed in reactions using 15 mol % of catalyst, with different amounts of diphenyl diselenide 3a and also of the starting materials 1a and 2a, however without a substantial increment in the reaction yield (Table 3, entries 5 and 6 vs 3). Identical result was observed when the reaction was realized under US irradiation with an amplitude of 80% (Table 3, entry 7 vs 3). Hence, the suitable conditions for the selective synthesis of bis-selenylated pyrroles 5 were defined was follows: aniline 1a (0.5 mmol), 2,5-hexanedione 2a (0.5 mmol), diphenyl diselenide 3a (0.5 mmol), CuI as a catalyst (15 mol %), and 2.0 mL of DMSO as solvent under US irradiation (60% of amplitude), which could afford 5a in 91% yield. The generality of this protocol was expanded for the synthesis of different bis-selenylated pyrrole 5a−p. First, the scope was extended to diorganyl diselenides containing different electronic demands (3b−e), and according to our results, reactions were not sensitive to electron-donating and -withdrawing groups at the phenyl ring on the diselenide 3 (Table 4, compounds 5b−e). Additionally, when the di(thiophen-2-yl)diselenide 3f was reacted under optimized conditions, the product 5f was obtained in 31% yield after 3.5 h (Table 4, compound 5f). We also used dibutyl diselenide 3g, and in this case, the reaction did not occur satisfactorily. In the same way as the reaction for the synthesis of mono-butylselenylated pyrrole 4g, we maintained the reaction time of 2.0 h and obtained a mixture of compounds A, 4g, and 5g. Analysis of 1H NMR showed the formation of the bis-selenylation product 5g in 9% yield and the mono-selenylated compound 4g in 19% yield. We

an inseparable mixture of the 2,5-dimethyl-1-phenyl-1Hpyrrole A and mono-selenylation product (Table 2, compound 4g). This reaction was not maintained for a long time because we noted a significant increase in byproduct formation. In the next series of experiments, we extend the applicability of the optimized reaction conditions to other substituted anilines, benzylamine and butylamine. Thus, different substituted anilines were screened, and the electronic effects presented an influence on the yield of mono-arylselenylated pyrroles. For instance, substituted anilines having a 4-methoxy (1b) or a 4-methyl group (1c) provided better yields than para-substituted anilines bearing clorine (1e) and fluorine (1g) (Table 2, compounds 4h-i vs 4k and 4m). In addition, it is interesting to note that when substituents at the ortho-position are evaluated in the substituted anilines 1d and 1f, moderated yields of mono-arylselenylated pyrroles 4j and 4l were obtained and when nitro substituent is used in the metaposition of the aniline, the desired product 4n was obtained in moderate yield (50%). We also examined the reactivity of the butyl and benzylamine 1i and 1j, respectively, in this reaction, and under the same reaction conditions, the desired products 4o and 4p were obtained in satisfactory yields (56 and 79%, respectively). We try to extend the reaction scope to other dicarbonyl compounds such as 1-(4-chlorophenyl)-4-phenylbutane-1,4dione 2b. Thus, a mixture of aniline 1a (0.5 mmol), dicarbonyl compound 2b (0.5 mmol), diphenyl diselenide 3a (0.5 mmol), CuI as a catalyst (15 mol %), and 2.0 mL of DMSO as solvent was sonicated for 2.0 h under US irradiation (60% of amplitude) (Scheme 3). In this reaction, we neither observed the formation of desired selanylation products 4q or 4q′ nor the formation of the Paal−Knorr condensation product. In this reaction, all of the starting materials were recovered. In all reactions performed, small amounts of bis-substituted organylselanyl pyrroles were obtained. Thus, with the aim of direct reaction for the selective formation of bis-selenylated pyrroles 5, we turned our attention to optimize the reaction conditions to these products (Table 3). In this sense, under the optimal conditions (Table 1, entry 23), we performed the reaction of aniline 1a (0.6 mmol) and 2,5-hexanedione 2 (0.6 mmol) with an excess of diphenyl E


Article

The Journal of Organic Chemistry Table 4. Reaction Scope for Synthesis of Bis-Organylselenylated Pyrroles 5a−pa

a

Reaction conditions: amine 1a−j (0.5 mmol), 2,5-hexanedione 2a (0.5 mmol), diorganyl diselenide 3a−g (0.5 mmol), CuI (15 mol %) as catalyst, and DMSO (2.0 mL) as solvent under US irradiation (60% of amplitude). The reaction progress was followed by TLC. bThe yield was determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as internal standard.

pyrroles were obtained in 68 and 75% yields, respectively (Table 4, compounds 5o and 5p). In addition, we also try to obtain nonsymmetric bissubstituted products by the reaction of 2,5-dimethyl-1-phenyl3-(phenylselanyl)-1H-pyrrole 4a with 1,2-di-p-tolyldiselenide 3b or 1,2-bis(4-chlorophenyl)diselenide 3e under the previous optimized conditions (Scheme 4). Thus, after 1.5 h of the reaction between pyrrole 4a with diselenide 3b, an inseparable mixture of compounds was obtained. The components of this mixture and their ratio were identified by gas chromatography−mass spectrometry (GC−MS) analyses, and the desired nonsymmetric compound 5q was obtained in a ratio of 52%. Surprisingly, the symmetric pyrroles 5a and 5b were also obtained in ratios of 17 and 31%, respectively (Scheme 4). A similar result was obtained in the reaction between pyrrole 4a with diselenide 3e, giving the nonsymmetric bis-substituted product 5r preferably (59%), however with the formation of

attributed these poor results to the low reactivity of the dibutyl diselenide 3g relative to the aryl analogues. Good results were obtained using substituted anilines, and this approach tolerates different electronic demands on the aniline. When we used 4-anisidine 1b, the product 5h in was obtained in 85% yield (Table 4, compound 5h). A similar result was observed when para-toluidine 1c or ortho-toluidine 1d were used, yielding products 5i and 5j in 90 and 95% yields, respectively (Table 4, compounds 5i and 5j). Reactions performed with 4-chloroaniline 1e and 4fluoroaniline 1g provided the respective products 5k and 5m in 80 and 86% yields, whereas 2-chloroaniline 1f and 3nitroaniline 1h gave the products in moderated yields (50 and 55%, respectively) (Table 4, compounds 5l and 5n). Inspired by the positive result of mono-arylselenylation using butylamine 1i and benzylamine 1j, the reactions were performed with these substrates and the bis-selenylated F


Article

The Journal of Organic Chemistry Scheme 4

Figure 2. Plausible mechanism of the reaction from synthesis of compounds 4 and 5.

substituted organylselanyl pyrroles 4 instead of pyrrole A (cycle II).

the other symmetrical products 5a and 5e (ratios of 16 and 25%, respectively) (Scheme 4). Based on these results and previous reported studies,17f,g we believe that, first, the reaction between amine 1 and the 2,5hexanedione 2a generates the Paal−Knorr condensation product (pyrrole A). In parallel, the interaction of CuI with diorganyl diselenide 3 could occur, leading to the intermediate B (Figure 2). After that, the nucleophilic attack of the pyrrole A in the intermediate B delivers the intermediates C and D. Subsequently, intermediate C loses a proton to form product 4, releases the CuI to the catalytic cycle, giving the organylselenol E, which was oxidized to diorganyl diselenide 3 (cycle I). For the synthesis of bis-substituted organylselanyl pyrroles 5, the catalytic cycle is almost the same, however starting from mono-

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CONCLUSIONS

Summarizing, we developed a simple method for the direct mono- and bis-organylselenylation of N-substituted pyrroles through a multicomponent reaction promoted by ultrasonic radiation. In this new copper(I)-catalyzed multicomponent methodology, mono- or bis-substituted organylselanyl pyrroles could be obtained in moderate to excellent yields starting from primary amines, 2,5-hexanedione and diorganyl diselenides. The selectivity of the products depends of the amount of copper catalyst and diorganyl diselenide employed in the reactions. G


Article

The Journal of Organic Chemistry

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2,5-Dimethyl-1-phenyl-3-(phenylselanyl)-1H-pyrrole 4a. Yield: 0.131 g (80%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.50−7.40 (m, 3H); 7.29−7.17 (m, 6H); 7.13−7.09 (m, 1H); 6.102−6.10 (m, 1H); 2.09 (s, 3H); 2.04 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 138.9, 135.0, 134.1, 130.0, 129.2, 128.9, 128.3, 128.1, 128.07, 125.2, 113.0, 100.6, 12.9, 12.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 238.1. MS (rel. int., %) m/z: 327 (34.7), 247 (100.0), 170 (16.1), 77 (28.9). HRMS (APCI-QTOF) calculated mass for C18H17NSe [M + H]+: 328.0604, found: 328.0614. 2,5-Dimethyl-1-phenyl-3-(4-tolylselanyl)-1H-pyrrole 4b. Yield: 0.097 g (57%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.43−7.32 (m, 3H); 7.16−7.11 (m, 4H); 6.95 (d, J = 7.9 Hz, 2H); 6.02−6.01 (m, 1H); 2.20 (s, 3H); 2.01 (s, 3H); 1.95 (s, 3H). 13 C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 138.9, 135.0, 133.8, 131.0, 129.7, 129.4, 129.2, 128.8, 128.1, 128.0, 112.9, 101.1, 20.9, 12.9, 12.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 232.1. MS (rel. int., %) m/z: 341 (24.2), 261 (100.0), 170 (12.3), 77 (22.8). HRMS (APCI-QTOF) calculated mass for C19H19NSe [M + H]+: 342.0761, found: 342.0759. 3-[(4-Methoxyphenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyrrole 4c. Yield: 0.114 g (64%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.41−7.32 (m, 3H); 7.20 (d, J = 8.6 Hz, 2H); 7.13 (d, J = 7.4 Hz, 2H); 6.71 (d, J = 8.6 Hz, 2H); 6.00 (s, 1H); 3.68 (s, 3H); 2.02 (s, 3H); 1.94 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 158.1, 138.8, 133.4, 130.9, 129.3, 129.2, 128.1, 128.0, 124.6, 114.7, 112.7, 102.0, 55.3, 12.9, 12.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 228.2. MS (rel. int., %) m/z: 357 (24.5), 277 (100.0), 170 (9.9), 77 (21.0). HRMS (APCI-QTOF) calculated mass for C19H19NOSe [M + H]+: 358.0710, found: 358.0708. 3-[(4-Fluorophenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyrrole 4d. Yield: 0.095 g (55%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.42−7.32 (m, 3H); 7.19−7.12 (m, 4H); 6.82 (t, J = 8.7 Hz, 2H); 6.00 (s, 1H); 2.00 (s, 3H); 1.95 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 161.4 (d, J = 242.4 Hz), 138.7, 134.8 (d, J = 8.0 Hz), 133.8, 130.3 (d, J = 7.4 Hz), 129.6, 129.2, 128.11, 128.07, 115.9 (d, J = 21.4 Hz), 112.8, 101.1, 12.8, 12.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 236.6. MS (rel. int., %) m/z: 345 (31.5), 265 (100.0), 170 (15.7), 77 (30.9). HRMS (APCI-QTOF) calculated mass for C18H16FNSe [M + H]+: 346.0510, found: 346.0511. 3-[(4-Chlorophenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyrrole 4e. Yield: 0.088 g (49%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.44−7.33 (m, 3H); 7.16−7.06 (m, 6H); 6.01−6.0 (m, 1H); 2.00 (s, 3H); 1.96 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 138.7, 134.1, 133.4, 131.1, 129.7, 129.6, 129.3, 128.9, 128.2, 128.1, 112.8, 100.4, 12.9, 12.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 241.0. MS (rel. int., %) m/z: 361 (46.9), 281 (100.0), 170 (25.5), 77 (44.9). HRMS (APCI-QTOF) calculated mass for C18H16ClNSe [M + H]+: 362.0215, found: 362.0208. 2,5-Dimethyl-1-phenyl-3-(thiophen-2-ylselanyl)-1H-pyrrole 4f. Yield: 0.060 g (36%); yellow solid, mp: 69−70 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.47−7.38 (m, 3H); 7.27−7.26 (m, 1H); 7.18−7.16 (m, 2H); 7.14−7.13 (m, 1H); 6.92−6.90 (m, 1H); 6.11 (s, 1H); 2.16 (s, 3H); 1.98 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 138.7, 132.8, 131.7, 129.2, 129.11, 129.08, 128.7, 128.1, 128.0, 127.7, 112.0, 103.8, 12.8, 12.3. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 179.2. MS (rel. int., %) m/z: 333 (10.1), 253 (68.1), 170 (11.5), 77 (100.0), 51 (54.7). HRMS (APCI-QTOF) calculated mass for C16H15NSSe [M + H]+: 334.0169, found: 334.0173. 3-(Butylselanyl)-2,5-dimethyl-1-phenyl-1H-pyrrole 4g. Yield by 1 H NMR (14%); yellowish oil. Mixture of compounds 4g and pyrrole A (ratio 1:3). Asterisk denotes the chemical shifts of the pyrrole A. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.46−7.35 (m, 3H); 7.21−7.16 (m, 2H); 6.04 (s, 1H); 5.90* (s, 2H); 2.65 (t, J = 7.4 Hz, 2H); 2.11 (s, 3H); 2.02* (s, 6H); 2.0 (s, 3H); 1.65 (quint, J = 7.4 Hz, 2H); 1.42 (sext, J = 7.4 Hz, 2H); 0.90 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 139.0, 138.9*, 132.3, 129.0, 128.9*, 128.71, 128.65*, 128.2*, 128.1, 127.8, 127.5*, 112.5, 105.6*, 101.8,

EXPERIMENTAL SECTION

General Information. The reactions were monitored by TLC carried out on Merck silica gel (60 F254) by using UV light as visualization agent and the mixture of 5% vanillin and 10% H2SO4 under heating conditions as developing agents. Merck silica gel (particle size 0.040−0.063 mm) was used for flash chromatography. Hydrogen nuclear magnetic resonance (1H NMR) spectra were obtained on a Bruker Avance III HD 400 spectrometer at 400 MHz. The spectra were recorded in CDCl3 solutions. The chemical shifts are reported in ppm, referenced to tetramethylsilane as the internal reference. Coupling constants (J) are reported in hertz. Abbreviations to denote the multiplicity of a particular signal are s (singlet), d (doublet), ddd (doublet of doublet of doublets), t (triplet), quint (quintet), sext (sextet), and m (multiplet). 13C NMR spectra were obtained on a Bruker Avance III HD 400 spectrometer at 100 MHz. The chemical shifts are reported in ppm, referenced to the solvent peak of CDCl3. 77Se NMR spectra were obtained on a Bruker Avance III HD 400 spectrometer at 76 MHz using CDCl3 as the solvent and diphenyl diselenide as an internal standard. High-resolution electrospray ionization mass spectrometry analysis was performed on a Bruker Daltonics micrOTOF-Q II instrument in positive mode. The samples were solubilized in high-performance liquid chromatographygrade acetonitrile and injected into the APCI source by means of a syringe pump at a flow rate of 5.0 μL min−1. The following instrument parameters were applied: capillary and cone voltages, +3500 and −500 V, respectively; desolvation temperature, 180 °C. For data acquisition and processing, Compass 1.3 for micrOTOF-Q II software (Bruker Daltonics) was used. The data were collected in the m/z range of 50−1200 at the speed of two scans per second. Lowresolution mass spectra were obtained with a Shimadzu GC-MSQP2010 mass spectrometer. Melting point (mp) values were measured in a Marte PFD III instrument with a 0.1 °C precision. The ultrasound-promoted reactions were performed using a Cole Parmer-ultrasonic processor Model CPX 130, with a maximum power of 130 W, operating at an amplitude of 60% and a frequency of 20 kHz. The temperature of the reaction under US was monitored using a Incoterm digital infrared thermometer Model Infraterm (Brazil). General Procedure for Synthesis 2,5-Dimethyl-1-phenyl1H-pyrrole A. Aniline 1a (0.093 g; 1.0 mmol), 2,5-hexanedione 2a (0.114 g; 1.0 mmol), and DMSO (2.0 mL) were added to a 10.0 mL glass tube. An ultrasound probe was placed in the glass tube containing the reaction mixture. The amplitude of the ultrasound waves was fixed at 60%. Then, the reaction mixture was sonicated for 10 min. The crude product obtained was subsequently purified by column chromatography using hexane as eluent. General Procedure for Synthesis of Mono-Organylselenylated Pyrroles 4a−p. Amines 1a−j (0.6 mmol), 2,5-hexanedione 2a (0.068 g; 0.6 mmol), diselenides 3a−g (0.25 mmol), CuI (10 mol %, 0.0095 g), and DMSO (2.0 mL) were added to a 10.0 mL glass tube. An ultrasound probe was placed in the glass tube containing the reaction mixture. The amplitude of the ultrasound waves was fixed at 60%. Then, the reaction mixture was sonicated for 0.5−3.0 h. The crude product obtained was subsequently purified by column chromatography using hexane as eluent. General Procedure for Synthesis of Bis-Organylselenylated Pyrroles 5a−p. Amines 1a−j (0.5 mmol), 2,5-hexanedione 2 (0.057 g; 0.5 mmol), diselenides 3a−g (0.5 mmol), CuI (15 mol %, 0.0142 g), and DMSO (2.0 mL) were added to a 10.0 mL glass tube. An ultrasound probe was placed in the glass tube containing the reaction mixture. The amplitude of the ultrasound waves was fixed at 60%. Then, the reaction mixture was sonicated for 1.0−4.0 h. The crude product obtained was subsequently purified by column chromatography using hexane/ethyl acetate (99/1%) as eluent. Spectral Data of the Compounds. 2,5-Dimethyl-1-phenyl-1Hpyrrole A.22 Yield: 0.164 g (96%); white solid, mp: 49−51 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.46−7.35 (m, 3H); 7.21−7.18 (m, 2H); 5.90 (s, 2H); 2.03 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 139.0, 129.0, 128.7, 128.2, 127.6, 105.6, 12.9. MS (rel. int., %) m/z: 171 (86.2), 170 (100.0), 154 (15.6), 128 (11.8), 77 (27.8), 51 (17.3). H


Article

The Journal of Organic Chemistry 32.4, 28.8, 22.8, 13.6, 12.9*, 12.7, 12.3. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 119.4. MS (rel. int., %) m/z: 307 (37.0), 250 (27.2), 171 (100.0), 170 (83.2), 77 (25.9). HRMS (APCI-QTOF) calculated mass for C16H21NSe [M + H]+: 308.0917, found: 308.0906. 1-(4-Methoxyphenyl)-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole 4h. Yield: 0.164 g (92%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.20−7.17 (m, 2H); 7.13−7.00 (m, 5H); 6.92−6.88 (m, 2H); 6.003−6.001 (m, 1H); 3.78 (s, 3H); 2.00 (s, 3H); 1.95 (s, 3H). 13 C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 159.1, 135.1, 134.3, 131.6, 129.8, 129.1, 128.8, 128.3, 125.1, 114.3, 112.7, 100.2, 55.5, 12.8, 12.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 238.3. MS (rel. int., %) m/z: 357 (36.9), 277 (100.0), 200 (11.1), 107 (2.9), 77 (12.7). HRMS (APCI-QTOF) calculated mass for C19H19NOSe [M + H]+: 358.0710, found: 358.0706. 2,5-Dimethyl-3-(phenylselanyl)-1-(4-tolyl)-1H-pyrrole 4i. Yield: 0.142 g (83%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.20−7.18 (m, 4H); 7.12−7.09 (m, 2H); 7.04−7.00 (m, 3H); 6.01 (s, 1H); 2.34 (s, 3H); 2.00 (s, 3H); 1.95 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 137.9, 136.2, 135.1, 134.1, 129.8, 129.5, 128.8, 128.3, 127.8, 125.1, 112.8, 100.3, 21.1, 12.9, 12.2. 77 Se NMR (CDCl3, 76 MHz) δ (ppm) = 238.3. MS (rel. int., %) m/z: 341 (29.3), 261 (100.0), 184 (13.2), 91 (17.1), 77 (3.9). HRMS (APCI-QTOF) calculated mass for C19H19NSe [M + H]+: 342.0761, found: 342.0758. 2,5-Dimethyl-3-(phenylselanyl)-1-(2-tolyl)-1H-pyrrole 4j. Yield: 0.107 g (63%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.28−7.20 (m, 3H); 7.17−7.15 (m, 2H); 7.12−7.08 (m, 3H); 7.04−6.99 (m, 1H); 6.044−6.042 (m, 1H); 1.90 (s, 3H); 1.89 (s, 3H); 1.86 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 137.9, 136.7, 135.4, 133.7, 130.9, 129.0, 128.8, 128.7, 128.6, 127.9, 126.8, 125.0, 112.8, 100.1, 17.0, 12.4, 11.7. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 236.0. MS (rel. int., %) m/z: 341 (41.1), 261 (100.0), 184 (15.2), 91 (20.3), 77 (5.9). HRMS (APCI-QTOF) calculated mass for C19H19NSe [M + H]+: 342.0761, found: 342.0762. 1-(4-Chlorophenyl)-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole 4k. Yield: 0.108 g (60%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.37−7.34 (m, 2H); 7.19−7.17 (m, 2H); 7.11−7.05 (m, 4H); 7.03−6.99 (m, 1H); 6.01 (s, 1H); 1.99 (s, 3H); 1.94 (s, 3H). 13 C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 137.3, 134.8, 134.0, 133.8, 129.4, 129.3, 128.8, 128.4, 125.2, 113.4, 101.1, 12.8, 12.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 239.3. MS (rel. int., %) m/z: 361 (43.1), 281 (100.0), 204 (10.0), 111 (21.0), 77 (8.7). HRMS (APCIQTOF) calculated mass for C18H16ClNSe [M + H]+: 362.0215, found: 362.0208. 1-(2-Chlorophenyl)-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole 4l. Yield: 0.090 g (50%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.51−7.47 (m, 1H); 7.37−7.30 (m, 2H); 7.28−7.23 (m, 1H); 7.18−7.15 (m, 2H); 7.12−7.09 (m, 2H); 7.04−7.00 (m, 1H); 6.052−6.051 (m, 1H); 1.94 (s, 3H); 1.91 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 136.6, 135.1, 134.3, 133.7, 130.4, 130.0, 129.4, 128.9, 127.9, 127.7, 125.0, 113.1, 100.6, 12.4, 11.7. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 236.7. MS (rel. int., %) m/z: 361 (59.0), 281 (100.0), 204 (17.9), 111 (24.1), 77 (18.3). HRMS (APCI-QTOF) calculated mass for C18H16ClNSe [M + H]+: 362.0215, found: 362.0205. 1-(4-Fluorophenyl)-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole 4m. Yield: 0.114 g (66%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.19−7.17 (m, 2H); 7.12−6.98 (m, 7H); 6.005−6.003 (m, 1H); 1.98 (s, 3H); 1.93 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 162.0 (d, J = 246.6 Hz), 134.9, 134.8 (d, J = 3.2 Hz), 134.0, 129.7 (d, J = 8.6 Hz), 129.5, 128.8, 128.3, 125.2, 116.1 (d, J = 22.6 Hz), 113.1, 100.8, 12.8, 12.1. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 239.0. MS (rel. int., %) m/z: 345 (35.0), 265 (100.0), 188 (17.6), 95 (25.4), 77 (3.6). HRMS (APCI-QTOF) calculated mass for C18H16FNSe [M + H]+: 346.0510, found: 346.0508. 2,5-Dimethyl-1-(3-nitrophenyl)-3-(phenylselanyl)-1H-pyrrole 4n. Yield: 0.093 g (50%); yellow oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.24 (ddd, J = 8.1, 2.1 and 1.1 Hz, 1H); 8.07 (t, J = 2.1 Hz, 1H); 7.63 (t, J = 8.1 Hz, 1H); 7.52 (ddd, J = 8.1, 2.1 and 1.1 Hz, 1H);

7.22−7.19 (m, 2H); 7.16−7.11 (m, 2H); 7.08−7.04 (m, 1H); 6.077− 6.075 (m, 1H); 2.05 (s, 3H); 1.99 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 148.7, 139.9, 134.4, 134.2, 133.7, 130.2, 129.3, 129.0, 128.6, 125.5, 123.2, 123.0, 114.2, 102.4, 12.9, 12.3. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 240.9. MS (rel. int., %) m/z: 372 (32.8), 292 (100.0), 215 (4.8), 122 (1.6), 77 (8.6). HRMS (APCIQTOF) calculated mass for C18H16N2O2Se [M + H]+: 373.0455, found: 373.0437. 1-Butyl-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole 4o. Yield: 0.086 g (56%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.18−7.12 (m, 4H); 7.09−7.04 (m, 1H); 5.97 (s, 1H); 3.79 (t, J = 7.3 Hz, 2H); 2.28 (s, 3H); 2.23 (s, 3H); 1.62 (quint, J = 7.3 Hz, 2H); 1.37 (sext, J = 7.3 Hz, 2H); 0.96 (t, J = 7.3 Hz, 3H). 13 C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 135.5, 132.8, 128.8, 128.1, 127.9, 124.9, 112.7, 99.4, 44.5, 32.9, 20.1, 13.8, 12.3, 11.4. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 235.1. MS (rel. int., %) m/z: 307 (67.9), 227 (79.4), 185 (63.8), 150 (10.0), 108 (100.0), 77 (13.4). HRMS (APCI-QTOF) calculated mass for C16H21NSe [M + H]+: 308.0917, found: 308.0920. 1-Benzyl-2,5-dimethyl-3-(phenylselanyl)-1H-pyrrole 4p. Yield: 0.135 g (79%); colorless oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.33−7.14 (m, 7H); 7.10−7.06 (m, 1H); 6.90 (d, J = 7.4 Hz, 2H); 6.08 (s, 1H); 5.08 (s, 2H); 2.20 (s, 3H); 2.16 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 137.8, 135.4, 133.6, 128.8, 128.0, 127.2, 125.5, 125.0, 113.2, 100.1, 47.7, 12.3, 11.4. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 236.4. MS (rel. int., %) m/z: 341 (10.7), 261 (19.8), 170 (5.7), 91 (100.0), 77 (10.7). HRMS (APCIQTOF) calculated mass for C19H19NSe [M + H]+: 342.0761, found: 342.0755. 2,5-Dimethyl-1-phenyl-3,4-bis(phenylselanyl)-1H-pyrrole 5a. Yield: 0.220 g (91%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.52−7.42 (m, 3H); 7.26−7.24 (m, 2H); 7.19−7.16 (m, 4H); 7.11−7.02 (m, 6H); 2.17 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 138.8, 135.4, 134.4, 129.4, 128.7, 128.67, 128.5, 127.9, 125.2, 109.3, 13.3. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 234.8. MS (rel. int., %) m/z: 483 (56.8), 326 (84.8), 246 (43.6), 170 (14.2), 77 (100.0). HRMS (APCI-QTOF) calculated mass for C24H21NSe2 [M]+: 483.0004, found: 483.0010. 2,5-Dimethyl-1-phenyl-3,4-bis(4-tolylselanyl)-1H-pyrrole 5b. Yield: 0.141 g (55%); yellow solid, mp: 86−88 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.41−7.31 (m, 3H); 7.14−7.12 (m, 2H); 7.50 (d, J = 8.0 Hz, 4H); 6.81 (d, J = 8.0 Hz, 4H); 2.14 (s, 6H); 2.08 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 138.8, 135.0, 134.9, 130.5, 129.4, 129.3, 129.2, 128.4, 127.9, 109.7, 20.9, 13.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 228.3. MS (rel. int., %) m/z: 511 (57.6), 340 (100.0), 260 (38.1), 170 (12.2), 77 (67.0). HRMS (APCI-QTOF) calculated mass for C26H25NSe2 [M]+: 511.0317, found: 511.0343. 3,4-Bis[(4-methoxyphenyl)selanyl]-2,5-dimethyl-1-phenyl-1Hpyrrole 5c. Yield: 0.160 g (59%); yellowish solid, mp: 104−106 °C. 1 H NMR (CDCl3, 400 MHz) δ (ppm) = 7.41−7.32 (m, 3H); 7.18− 7.12 (m, 2H); 7.07 (d, J = 8.5 Hz, 4H); 6.56 (d, J = 8.5 Hz, 4H); 3.63 (s, 6H); 2.09 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 158.0, 138.8, 134.7, 131.4, 129.3, 128.4, 127.9, 124.2, 114.4, 110.4, 55.1, 13.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 222.7. MS (rel. int., %) m/z: 543 (49.7), 356 (100.0), 276 (28.9), 170 (8.2), 77 (63.6). HRMS (APCI-QTOF) calculated mass for C26H25NO2Se2 [M]+: 543.0216, found: 543.0217. 3,4-Bis[(4-fluorophenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyrrole 5d. Yield: 0.117 g (45%); yellowish solid, mp: 118−120 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.43−4.34 (m, 3H); 7.16−7.14 (m, 2H); 7.06−7.03 (m, 4H); 6.70 (t, J = 8.8 Hz, 4H); 2.09 (s, 6H). 13 C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 161.4 (d, J = 243.0 Hz), 138.6, 135.4, 130.9 (d, J = 7.6 Hz), 129.5, 128.6, 128.5 (d, J = 2.3 Hz), 127.9, 115.7 (d, J = 21.5 Hz), 109.7, 13.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 232.2. MS (rel. int., %) m/z: 519 (67.4), 344 (95.0), 264 (47.8), 170 (14.4), 77 (100.0). HRMS (APCI-QTOF) calculated mass for C24H19F2NSe2 [M]+: 518.9816, found: 518.9814. I


Article

The Journal of Organic Chemistry 3,4-Bis[(4-chlorophenyl)selanyl]-2,5-dimethyl-1-phenyl-1H-pyrrole 5e. Yield: 0.138 g (50%); yellowish solid, mp: 135−137 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.47−7.37 (m, 3H); 7.19−7.16 (m, 2H); 7.00−6.95 (m, 8H); 2.10 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 138.6, 135.7, 132.5, 131.4, 130.2, 129.5, 128.75, 128.69, 127.9, 109.1, 13.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 237.5. MS (rel. int., %) m/z: 551 (52.1), 360 (46.2), 325 (100.0), 280 (15.9), 170 (10.5), 77 (80.0). HRMS (APCI-QTOF) calculated mass for C24H19Cl2NSe2 [M]+: 550.9225, found: 550.9216. 2,5-Dimethyl-1-phenyl-3,4-bis(thiophen-2-ylselanyl)-1H-pyrrole 5f. Yield: 0.077 g (31%); yellow oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.48−7.39 (m, 3H); 7.21 (dd, J = 5.2 and 1.1 Hz, 2H); 7.17−7.14 (m, 2H); 7.12 (dd, J = 3.5 and 1.1 Hz, 2H); 6.86 (dd, J = 5.2 and 3.5 Hz, 2H); 2.20 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 138.6, 134.4, 132.0, 129.34, 129.30, 128.5, 128.4, 128.0, 127.5, 111.1, 13.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 169.1. MS (rel. int., %) m/z: 495 (5.6), 332 (17.8), 252 (28.8), 77 (100.0). HRMS (APCI-QTOF) calculated mass for C20H17NS2Se2 [M + H]+: 495.9211, found: 495.9201. 3,4-Bis(butylselanyl)-2,5-dimethyl-1-phenyl-1H-pyrrole 5g. Yield by 1H NMR (9%); yellowish oil. Mixture of compounds 4g, 5g, and pyrrole A (ratio 5:2:2). Asterisk denotes the chemical shifts of the pyrrole A. Double asterisk denotes the chemical shifts of the compound 4g. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.48−7.37 (m, 3H); 7.21−7.18 (m, 2H); 6.03** (s, 1H); 5.90* (s, 2H); 2.70 (t, J = 7.4 Hz, 4H); 2.65** (t, J = 7.4 Hz, 2H); 2.16 (s, 6H); 2.10** (s, 3H); 2.03* (s, 6H); 2.0** (s, 3H); 1.68−1.57 (m, 2H); 1.47−1.37 (m, 2H); 0.92−0.88 (m, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 139.2, 139.0**, 138.9*, 133.5, 132.3**, 129.2, 129.1**, 129.0*, 128.73**, 128.68*, 128.2*, 128.1**, 128.0, 127.8**, 127.5*, 112.5**, 109.2, 105.6*, 101.8**, 32.5**, 32.2, 29.1, 28.9**, 22.9, 22.8**, 13.64, 13.61**, 13.2, 12.9*, 12.8**, 12.3**. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 119.3**, 110.7. MS (rel. int., %) m/z: 443 (49.2), 305 (26.0), 250 (70.2), 171 (100.0), 170 (56.4), 77 (37.5). HRMS (APCI-QTOF) calculated mass for C20H29NSe2 [M]+: 443.0630, found: 443.0650. 1-(4-Methoxyphenyl)-2,5-dimethyl-3,4-bis(phenylselanyl)-1Hpyrrole 5h. Yield: 0.218 g (85%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.08−7.05 (m, 4H); 7.05−7.01 (m, 2H); 6.98−6.89 (m, 6H); 6.88−6.84 (m, 2H); 3.70 (s, 3H); 2.06 (s, 6H). 13 C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 159.3, 135.6, 134.4, 131.3, 128.8, 128.6, 128.58, 125.1, 114.4, 108.8, 55.4, 13.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 234.8. MS (rel. int., %) m/z: 513 (63.7), 356 (100.0), 276 (28.5), 200 (11.1), 107 (12.1), 77 (40.8). HRMS (APCI-QTOF) calculated mass for C25H23NOSe2 [M]+: 513.0110, found: 513.0125. 2,5-Dimethyl-3,4-bis(phenylselanyl)-1-(4-tolyl)-1H-pyrrole 5i. Yield: 0.224 g (90%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.22−7.18 (m, 2H); 7.10−6.94 (m, 12H); 2.35 (s, 3H); 2.09 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 138.5, 136.2, 135.5, 134.5, 130.0, 128.7, 128.66, 127.6, 125.2, 109.0, 21.2, 13.3. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 234.5. MS (rel. int., %) m/z: 497 (64.1), 340 (100.0), 260 (39.2), 184 (12.5), 91 (57.4), 77 (12.4). HRMS (APCI-QTOF) calculated mass for C25H23NSe2 [M]+: 497.0161, found: 497.0176. 2,5-Dimethyl-3,4-bis(phenylselanyl)-1-(2-tolyl)-1H-pyrrole 5j. Yield: 0.236 g (95%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.28−7.18 (m, 3H); 7.10−7.05 (m, 5H); 7.00−6.91 (m, 6H); 1.97 (s, 6H); 1.90 (s, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 137.8, 136.1, 134.9, 134.6, 131.0, 129.0, 128.6, 128.3, 128.2, 127.0, 125.1, 108.9, 17.0, 12.7. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 233.1. MS (rel. int., %) m/z: 497 (69.4), 340 (100.0), 260 (35.7), 184 (13.9), 91 (57.7), 77 (16.4). HRMS (APCI-QTOF) calculated mass for C25H23NSe2 [M]+: 497.0161, found: 497.0171. 1-(4-Chlorophenyl)-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyrrole 5k. Yield: 0.207 g (80%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.42−7.38 (m, 2H); 7.14−7.08 (m, 6H); 7.03−6.95 (m, 6H); 2.09 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 137.2, 135.2, 134.5, 134.2, 129.7, 129.2, 128.8, 128.7, 125.3, 109.8, 13.3. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 236.0. MS (rel. int., %)

m/z: 517 (70.8), 360 (100.0), 280 (29.2), 204 (13.2), 111 (49.5), 77 (16.7). HRMS (APCI-QTOF) calculated mass for C24H20ClNSe2 [M]+: 516.9615, found: 516.9626. 1-(2-Chlorophenyl)-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyrrole 5l. Yield: 0.129 g (50%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.54−7.49 (m, 1H); 7.40−7.28 (m, 3H); 7.10−7.05 (m, 4H); 7.03−6.95 (m, 6H); 2.04 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 136.6, 135.5, 134.4, 133.5, 130.5, 130.4, 130.1, 128.7, 128.4, 127.9, 125.1, 109.3, 12.8. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 233.8. MS (rel. int., %) m/z: 517 (73.3), 360 (100.0), 280 (32.7), 204 (13.9), 111 (40.0), 77 (23.4). HRMS (APCI-QTOF) calculated mass for C24H20ClNSe2 [M]+: 516.9615, found: 516.9617. 1-(4-Fluorophenyl)-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyrrole 5m. Yield: 0.215 g (86%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.10−7.02 (m, 8H); 6.98−6.90 (m, 6H); 2.05 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 162.1 (d, J = 247.3 Hz), 135.3, 134.6 (d, J = 3.2 Hz), 134.2, 129.6 (d, J = 8.6 Hz), 128.7, 128.6, 125.2, 116.3 (d, J = 22.5 Hz), 109.5, 13.2. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 235.8. MS (rel. int., %) m/z: 501 (70.3), 344 (100.0), 264 (45.6), 188 (16.8), 95 (69.7), 77 (14.3). HRMS (APCI-QTOF) calculated mass for C24H20FNSe2 [M]+: 500.9910, found: 500.9924. 2,5-Dimethyl-1-(3-nitrophenyl)-3,4-bis(phenylselanyl)-1H-pyrrole 5n. Yield: 0.145 g (55%); yellow solid, mp: 93−95 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 8.21 (ddd, J = 8.1, 2.1 and 1.1 Hz, 1H); 8.07 (t, J = 2.1 Hz, 1H); 7.60 (t, J = 8.1 Hz, 1H); 7.51 (ddd, J = 8.1, 2.1 and 1.1 Hz, 1H); 7.10−7.07 (m, 4H); 7.02−6.94 (m, 6H); 2.11 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 148.6, 139.7, 135.0, 134.0, 133.8, 130.4, 128.9, 128.7, 125.5, 123.4, 123.0, 110.8, 13.3. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 238.1. MS (rel. int., %) m/z: 528 (70.4), 371 (100.0), 291 (18.8), 215 (10.0), 122 (0.9), 77 (32.4). HRMS (APCI-QTOF) calculated mass for C24H20N2O2Se2 [M]+: 527.9855, found: 527.9861. 1-Butyl-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyrrole 5o. Yield: 0.157 g (68%); yellowish oil. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.09−6.98 (m, 10H); 3.87 (t, J = 7.4 Hz, 2H); 2.37 (s, 6H); 1.65 (quint, J = 7.4 Hz, 2H); 1.38 (sext, J = 7.4 Hz, 2H); 0.97 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 134.8, 134.1, 128.5, 128.3, 125.0, 108.5, 45.6, 32.7, 20.0, 13.8, 12.5. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 231.8. MS (rel. int., %) m/z: 463 (70.4), 306 (100.0), 226 (19.2), 150 (8.7), 108 (10.2), 77 (22.7). HRMS (APCI-QTOF) calculated mass for C22H25NSe2 [M]+: 463.0317, found: 463.0333. 1-Benzyl-2,5-dimethyl-3,4-bis(phenylselanyl)-1H-pyrrole 5p. Yield: 0.186 g (75%); white solid, mp: 114−115 °C. 1H NMR (CDCl3, 400 MHz) δ (ppm) = 7.35−7.25 (m, 3H); 7.13−7.01 (m, 10H); 6.91 (d, J = 7.3 Hz, 2H); 5.18 (s, 2H); 2.31 (s, 6H). 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) = 137.1, 135.0, 134.7, 128.9, 128.6, 128.4, 127.5, 125.5, 125.1, 109.3, 48.9, 12.5. 77Se NMR (CDCl3, 76 MHz) δ (ppm) = 233.4. MS (rel. int., %) m/z: 497 (9.5), 340 (10.1), 260 (1.4), 91 (100.0), 77 (4.9). HRMS (APCI-QTOF) calculated mass for C25H23NSe2 [M + H]+: 498.0239, found: 498.0238.

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ASSOCIATED CONTENT

S Supporting Information *

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H, 13C{1H}, and (PDF)

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77

Se NMR spectra of all compounds

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (G.P.). *E-mail: [email protected]. Tel/Fax: +55 5332757533 (D.A.). J


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Thiago Barcellos: 0000-0001-9872-4602 Diego Alves: 0000-0002-1074-0294 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are grateful for the financial support and scholarships from the Brazilian agencies CNPq and FAPERGS (PRONEM 16/2551-0000240-1). CNPq is also acknowledged for the fellowship for G.P. and D.A. This study was partially financed by the Coordenaçaõ de Aperfeiçoamento de Pessoal de Nivel SuperiorBrasil (CAPES)Finance Code 001.

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