Substrate Controlled Regioselective Bromination of Acylated Pyrroles

6.1. Seeking higher selectivity, we investigated the mild brominating reagent pyridinium hydrobromide perbromide (PHP). Interestingly, this reagent wa...
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Cite This: J. Org. Chem. 2018, 83, 9250−9255

Substrate Controlled Regioselective Bromination of Acylated Pyrroles Using Tetrabutylammonium Tribromide (TBABr3) Shuang Gao, Travis K. Bethel, Tayeb Kakeshpour, Grace E. Hubbell, James E. Jackson, and Jetze J. Tepe* Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States

J. Org. Chem. 2018.83:9250-9255. Downloaded from pubs.acs.org by UNIV OF SUSSEX on 08/17/18. For personal use only.

S Supporting Information *

ABSTRACT: Electrophilic bromination of pyrroles bearing carbonyl substituents at C-2 typically results in a mixture of the 4- and 5-brominated species, generally favoring the 4position. Herein, we describe a substrate-controlled regioselective bromination in which tetra-butyl ammonium tribromide (TBABr3) reacts with pyrrole-2-carboxamide substrates to yield the 5-brominated species as the predominant (up to >10:1) product.

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INTRODUCTION Monobrominated pyrrole moieties occur in various marine sponge metabolites, such as hymenidin, agelastatin A, monobromophakelin, hymenialdisine, monobromoisophakelin, and bromoageliferin (Figure 1).1−6 The diverse and potent

Figure 2. Predicted regioselective bromination of 2-acyl pyrroles in current literature and regioselectivity of this work.

investigated the possibility of regioselectively monobrominating pyrroles bearing carbonyl functionalities in the C-2 position. Such methods would be useful for late stage functionalization of multiple natural products.29

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RESULTS AND DISCUSSION We initiated our investigation by screening the most common reagents for bromination of the electron poor ketone trichloroacetyl pyrrole 1, the ester methyl 1H-pyrrole-2carboxylate 2, and the amide N-methyl-1H-pyrrole-2-carboxamide 3 (Table 1) in THF at −78 °C to room temperature. Bromine (Br2), N-bromosuccinimide (NBS), and 1,3-dibromo5,5-dimethylhydantoin (DBDMH) in THF all provided a ≥ 10:1 regioselectivity favoring the C-4 position with pyrrole 1 or 2, as anticipated. However, under the same conditions, pyrrole carboxamide 3 gave roughly 1:1 ratios of C-4/C-5 monobromination. These results provided the first indications that the amide functionality could direct the electrophilic bromination away from the C-4 position. Seeking higher selectivity, we investigated the mild brominating reagent pyridinium hydrobromide perbromide (PHP). Interestingly, this reagent was not able to brominate electron-poor keto pyrrole 1 under the reaction conditions. However, the more electron-rich pyrrole 2 yielded a 2:1

Figure 1. Examples of monobrominated pyrrole natural products.

biological activity of these bromopyrrole alkaloids has drawn many researchers to pursue their total syntheses, a goal that requires control over the regioselective monobromination of 2acylated pyrroles.7−13 Typically, electrophilic substitution of pyrroles can be predictably directed by groups in the C-2 position, where electron withdrawing (EWG) groups generally favor the C-4substituted product whereas electron donating (D) groups favor reaction at C-5 to form the major products (Figure 2).14−19 However, regioselective bromination is nontrivial and presents a major challenge, especially for C-5 monobromopyrroles containing an electron withdrawing group in the C-2 position (Figure 1).20−25 A notable exception was reported by Feldman, and subsequently others, where the C-5 monobrominated pyrrole was the major product when methanol was used as an additive with electrophilic brominating reagents such as NBS.11,26−28 Intrigued by these observations, we © 2018 American Chemical Society

Received: May 15, 2018 Published: July 3, 2018 9250

DOI: 10.1021/acs.joc.8b01251 J. Org. Chem. 2018, 83, 9250−9255

Article

The Journal of Organic Chemistry

The mild brominating reagent PHP showed superior selectivity for C-5 bromination of pyrrole 3, compared to more traditional brominating reagents. Typically used to αbrominate carbonyls or alkenes,31 this reagent’s use in aromatic bromination has been mostly limited to electron rich aromatics including anilines,32 purines,33 phenol,34 aromatic ethers,35 indoles,36 thiophenes,37 and phenothiazines;38 to the best of our knowledge, no examples of pyrroles have been reported to date. To further explore the use of hydrobromide perbromide reagents, we prepared several ammonium Br3− salts and evaluated them for their regioselective bromination of 2carboxamide pyrrole 3 (Figure 3). Protonated ammonium

Table 1. Regioselectivity of Bromination of Pyrroles 1-3 Using Various Brominating Reagents in THF (Ratios by 1H NMR)

pyrrole

reagent

C-4 b

C-5 c

1 1 1 1 2 2 2 2 3 3 3 3

Br2 NBS DBDMH PHP Br2 NBS DBDMH PHP Br2 NBS DBDMH PHP

>10 >10 >10 NR >10 10 10 2 1 1 1 1

1 1 1 NR 1 1 1 1 1.4 1.3 1 6.1

mixture (C-4 vs C-5), while pyrrole 3 gave the C-5 product with 6:1 selectivity over the 4-bromopyrrole (Table 1). To gain insight into the C-4/C-5 regioselectivity differences among C-2 functionalized pyrroles 1−3, we calculated the relative stabilities of the brominated cationic intermediates A and B (see Table 2 for structures). Quantum chemical

Figure 3. Bromination of 3 by various ammonium tribromides.

hydrobromide perbromides were freshly prepared prior to use from 1:1:1 HBr, Br2, and the corresponding amines.39 Interestingly, none of the other protonated ammonium hydrobromide perbromides showed improved results over PHP; their differences in regioselectively were marginal at best (C-4/C-5 ratio of 1:∼6). These results suggest that sterics, electronics, basicity, or aromaticity of the cation partner have little to no effect on the mechanism of this tribromidemediated electrophilic bromination. In solution, PHP is in equilibrium with the pyridinium bromide and free Br2 (Scheme 1).33 This reported equilibrium

Table 2. Calculated Bromenium Affinities at C-4 and C-5 Positions for Compounds 1−3

Scheme 1. Pyridinium Hydrobromide Perbromide Equilibrium

calculations indicate that, in the gas phase, the C-5 bromination is still favored for all pyrroles, but the differences between the two cationic intermediates A and B favor C-5 bromination more for the carboxamide 3, compared to the ester 2 and ketone 1 (Table 2). This trend is consistent with our observed experimental trend of C-4/C-5 regioselectivity, where C-5 bromination is more favored for 3, compared to 2 and 1. In fact, when the solvent was modeled using SMD,30 a switch in the selectivity going from compound 1 to 3 was observed (blue numbers in Table 2).

shift is also supported by our free energy calculations (Scheme 1 and Table S1). Because the distribution of these two brominating agents depends on the polarity of the solvent, we examined the regioselectivity of bromination of pyrrole 3 as a function of solvent polarity. As anticipated, the regioselectivity of the bromination with PHP decreases in polar solvents (CH3OH/THF mixture) to match ratios seen using Br2 in THF (∼1:1.4). Due to the poor solubility of PHP,40 only THF, THF/CH3OH, and CH2Cl2 were evaluated. In dichloromethane, PHP gave the best regioselectivity (1:6.6 C-4/C-5 9251

DOI: 10.1021/acs.joc.8b01251 J. Org. Chem. 2018, 83, 9250−9255

Article

The Journal of Organic Chemistry

mild and selective reagent suitable for late stage pyrrole bromination. Only the C-2 carboxamides (3−10) provided the C-5 brominated product as the major regioisomer (3−10); significantly lower regioselectivity was observed using ester 2. The electron poor pyrrole 1 did not yield any product under these reaction conditions. It should be noted that the C-2 acylated pyrroles 1 and 2 show excellent C-4 regioselectivity under standard brominating conditions (Table 1, NBS/THF). This makes use of the mild tribromide-based brominating reagents a useful complementary method for the regioselective bromination of C-2 carboxamide substituted pyrroles.

ratio, 3b/3c), but left 18% unreacted starting material (3) and formed 10% of the 4,5-dibrominated product 3a. The more soluble tetrabutyl ammonium tribromide (TBABr3) was an improvement, showing full consumption of starting material (3) and no dibrominated pyrrole 3a. Decreasing the temperature (starting at −78 °C and warming up to room temperature) did not significantly affect the regioselectivity. Optimization with pyrrole 3 found that 1 h and 1.0 equiv TBABr3 at ambient temperature in CH2Cl2 gave the best regioselectivity (1:16, favoring C-5 bromination) and yield (78% for 3c) (Table 3).

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Table 3. Regioselective Bromination of Pyrroles 1−10 Using TBABr3a

CONCLUSION In conclusion, we report here a mild and efficient method for the regioselective bromination of pyrroles bearing carbonyl substituents at the C-2 position. Typically, electrophilic substitution of pyrroles can be predictably directed by groups in the C-2 position, where electron withdrawing (W) groups generally favor the C-4-substituted product and electron donating (D) groups favor C-5-substitution as the major products. Consequently, pyrroles substituted in the C-2 position with a trichloroacetyl or ester moiety reliably provide the C-4 brominated pyrrole using standard brominating conditions. However, we found that mild tribromide brominating agents, such as TBABr3, can provide predominantly the C-5 brominated product of pyrrole-2-carboxamides. In particular, the mono-N-substituted C-2 carboxamides provided excellent regioselective C-5 versus C-4 bromination (ratios >10:1), with C-2 N-aryl carboxamides (9 and 10) showing no benzylic or aryl bromination. Disubstituted carboxamides also rendered the C-5 brominated pyrroles as major products, albeit in lower regioselectivity (∼5:1). Due to its ease in preparation and excellent solubility characteristics, the salt TBABr3 proved to be a superior new, mild brominating reagent for pyrroles, yielding the 5-brominated species as the main product of the 2-carboxamide. This method may serve as a valuable resource for late stage bromination in natural products syntheses.

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EXPERIMENTAL SECTION

Computational Details. Calculations were performed using Gaussian 16.41 All the geometries were optimized at the ωB97X-D/ 6-31G* level of theory in the gas-phase or in solvent modeled by SMD.42 Frequency calculations confirmed that all the optimized geometries have no imaginary frequencies. Bromenium affinities were calculated based on Gibbs free energies. General Experimental. Dichloromethane (CH2Cl2) was purified through a column packed with dry alumina and was dispensed by a nitrogen pressure delivery system. THF was distilled from sodium under nitrogen. All other reagents and solvents were purchased from commercial sources and used without further purification. All flasks were oven-dried overnight and cooled under nitrogen. All reactions were monitored by TLC with 0.25 μM precoated silica gel plates and UV light was used to visualize the compounds. In some cases phosphomolybdic acid (PMA) stain or I2 was used to visualize the compounds. Column chromatography was performed using silica gel (230−400 mesh). All NMR spectra were recorded on a 500 or 300 MHz spectrometer. Mass spectrometer ionization method was ESI with a Quadrupole detector. Preparation of Pyrroles 1−3. 2,2,2-Trichloro-1-(1H-pyrrol-2yl)ethan-1-one (1). To a solution of trichloroacetyl chloride (20.0 g, 110 mmol, 1.1 equiv) in dry diethyl ether (85 mL) was added pyrrole (6.7 g, 100 mmol, 1.0 equiv) over 1.5 h. The mixture was stirred for an additional 4 h at room temperature and afterward neutralized with

a1

Total yields of monobrominated pyrroles were determined by NMR using triphenylmethane as internal control (NR = no reaction). Products 2c−10c were isolated for full characterization. 1.2 equiv TBABr3 and 1.5 h were used for full consumption of starting material.

Next, we evaluated the optimized method on various C2functionalized pyrroles (Table 3, 1−10) to examine the substrate scope of this reaction. Ratios of 1:>10 favoring bromination at C-5 of monosubstituted carboxamides 3−5 were obtained in good overall yields. This regioselectivity decreased to 1:∼5 for the N,N-dialkyl carboxamides 6−8; here, formation of dibrominated pyrroles 6a−8a was noted prior to the full consumption of starting material, indicating that the second bromination was competitive with that of the starting material. On the other hand, the C-2 N-phenyl carboxamides 9 and 10 provided the C-5 brominated product in good yields and regioselectivity (1:9). No bromination of the aryl ring (in 9 or 10) or the benzylic position (in 10) was detected in the crude mixtures. The selectivities illustrated in these two examples further highlight the potential of using TBABr3 as a 9252

DOI: 10.1021/acs.joc.8b01251 J. Org. Chem. 2018, 83, 9250−9255

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The Journal of Organic Chemistry

(500 MHz, DMSO-d6) δ 11.35 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 6.81 (td, J = 2.7, 1.4 Hz, 1H), 6.76 (ddd, J = 3.8, 2.5, 1.5 Hz, 1H), 6.05 (dt, J = 3.4, 2.4 Hz, 1H), 4.10−3.99 (m, 1H), 1.13 (d, J = 6.6 Hz, 6H). 13 C NMR (126 MHz DMSO-d6) δ 159.8, 126.5, 121.0, 109.7, 108.4, 40.2, 22.6. HRMS-ESI (m/z), calculated for C8H11N2O (M-H)− 151.0871. Found 151.0866. m.p.: 157.3−158.6 °C. 5-Bromo-N-isopropyl-1H-pyrrole-2-carboxamide (4c). Compound 4c was prepared using general procedure B, which provided 4c in 84% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.13 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 3.8 Hz, 1H), 6.11 (d, J = 3.7 Hz, 1H), 4.08−3.94 (m, 1H), 1.12 (d, J = 6.6, 6H). 13C NMR (126 MHz, DMSO-d6) δ 158.7, 128.4, 111.5, 110.7, 101.9, 40.3, 22.6. HRMS-ESI (m/z), calculated for C8H10BrN2O (M-H)− 228.9977. Found 228.9978. m.p.: 152.3−153.4 °C. N-(tert-Butyl)-1H-pyrrole-2-carboxamide (5). tButyl amine (1.2 mL, 11.4 mmol, 3.0 equiv) was added to a stirring solution of 2,2,2trichloro-1-(1H-pyrrol-2-yl)-ethanone (0.8 g, 3.8 mmol, 1.0 equiv) in 20 mL of dry CH3CN. The mixture refluxed for 72 h. After the solution was cooled to room temperature, the solvent was evaporated under reduced pressure to give a white solid (0.3 g, 47%). 1H NMR (500 MHz, DMSO-d6) δ 11.30 (s, 1H), 7.22 (s, 1H), 6.80 (td, J = 2.6, 1.5 Hz, 1H), 6.76 (ddd, J = 3.9, 2.5, 1.5 Hz, 1H), 6.03 (dt, J = 3.6, 2.4 Hz, 1H), 1.35 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 160.4, 127.2, 120.8, 110.0, 108.3, 50.4, 28.9. HRMS-ESI (m/z), calculated for C9H13N2O (M-H)− 165.1028. Found 165.1024. m.p.: decompose at 185.0 °C. 5-Bromo-N-(tert-butyl)-1H-pyrrole-2-carboxamide (5c). Compound 5c was prepared using general procedure B, which provided 5b in 77% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 7.27 (s, 1H), 6.75 (dd, J = 3.7, 2.4 Hz, 1H), 6.10 (dd, J = 3.7, 2.1 Hz, 1H), 1.34 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ 159.2, 128.9, 112.0, 110.6, 101.5, 50.5, 28.8. HRMS-ESI (m/z), calculated for C9H12BrN2O (M-H)− 243.0133. Found 243.0134. m.p.: 159.1−160.7 °C. N,N-Dimethyl-1H-pyrrole-2-carboxamide (6). Dimethyl amine· HCl salt (0.92 g, 11.4 mmol, 3.0 equiv) was added to a stirring solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone (0.8 g, 3.8 mmol, 1.0 equiv) and triethyl amine (1.57 mL, 11.4 mmol, 3.0 equiv) in 20 mL of dry CH3CN. The mixture was stirred under nitrogen, at room temperature for 24 h. 0.5 M HCl was added and the mixture extracted with CH2Cl2, dried with Mg2SO4, filtered, and the solvent removed under reduced pressure to give a white solid (0.48 g, 92%). 1 H NMR (500 MHz, DMSO-d6) δ 11.40 (s, 1H), 6.87 (td, J = 2.7, 1.4 Hz, 1H), 6.54 (ddd, J = 3.8, 2.6, 1.4 Hz, 1H), 6.11 (dt, J = 3.7, 2.5 Hz, 1H), 3.10 (s, 6H). 13C NMR (126 MHz, CDCl3) δ 162.6, 125.2, 121.0, 112.7, 109.7, 39.0 (broad, rotamer), 36.9 (broad, rotamer). HRMS-APCI (m/z), calculated for C7H11N2O (M+H)+ 139.0871. Found 139.0875 m.p.: 100.2−101.8 °C. 5-Bromo-N,N-dimethyl-1H-pyrrole-2-carboxamide (6c). Compound 6c was prepared using general procedure B, which provided 6c in 65% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.15 (s, 1H), 6.52 (dd, J = 3.8, 2.4 Hz, 1H), 6.16 (dd, J = 3.8, 2.2 Hz, 1H), 3.06 (s, 6H). 13C NMR (126 MHz, DMSO-d6) δ 161.1, 126.7, 113.9, 110.6, 102.2, methyl signals of rotameric carbons around 40 not visible, but broad singlet of 6H present in 1H and present in MS. HRMS-ESI (m/ z), calculated for C7H8BrN2O (M-H)− 214.9820. Found 214.9802. m.p: 172.0−173.5 °C. (1H-Pyrrol-2-yl)(pyrrolidin-1-yl)methanone (7). Pyrrolidine (0.58 mL, 7.0 mmol, 2.5 equiv) was added to a stirring solution of 2,2,2trichloro-1-(1H-pyrrol-2-yl)-ethanone (0.6 g, 2.8 mmol, 1.0 equiv) in 15 mL of dry CH2Cl2. The mixture was stirred under nitrogen, at room temperature for 48 h. 0.5 M HCl was added and the mixture extracted with CH2Cl2, dried with Mg2SO4, filtered, and the solvent removed under reduced pressure to give a white solid (0.45 g, 98%). 1 H NMR (500 MHz, DMSO-d6) δ 11.41 (s, 1H), 6.87 (td, J = 2.7, 1.3 Hz, 1H), 6.58 (ddd, J = 3.9, 2.5, 1.3 Hz, 1H), 6.13 (dt, J = 3.7, 2.5 Hz, 1H), 3.75−3.40 (m, 4H), 1.99−1.74 (m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 159.8, 125.8, 121.2, 111.8, 108.8, 47.6, 46.6, 26.3, 23.5. HRMS-ESI (m/z), calculated for C9H13N2O (M+H)+ 165.1028. Found 165.1011 m.p.: 118.2−119.6 °C.

an aqueous potassium carbonate solution. The organic phase was separated and dried with MgSO4. Activated charcoal was added to the solution which was then filtered through a Celite pad after stirring for 10 min. Solvent evaporation and crystallization from hexane resulted in a white solid (15.3 g, 67%). 1H NMR (500 MHz, CDCl3) δ 9.40 (s, 1H), 7.39 (ddd, J = 3.9, 2.5, 1.3 Hz, 1H), 7.17 (td, J = 2.8, 1.2 Hz, 1H), 6.39 (dt, J = 4.5, 2.5 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 173.3, 127.2, 123.1, 121.3, 112.0, 95.0. HRMS-ESI (m/z), calculated for C6H3Cl3NO (M-H)− 209.9280. Found 209.9274. m.p: 73.1−74.9 °C. Methyl 1H-Pyrrole-2-carboxylate (2). Compound 2 is commercially available. N-Methyl-1H-pyrrole-2-carboxamide (3). To a solution of 2,2,2trichloro-1-(1H-pyrrol-2-yl)-ethanone (2.0 g, 9.4 mmol, 1.0 equiv) in 40 mL of dry CH3CN, a 2 M solution of MeNH2 in THF was added (11.7 mL, 23.5 mmol, 2.5 equiv). The mixture was stirred under nitrogen, at room temperature for 24 h. The solvent was removed under reduced pressure to give a white solid (1.12 g, 96%). 1H NMR (500 MHz, DMSO-d6) δ 11.41 (s, 1H), 7.92 (q, J = 4.6 Hz, 1H), 6.81 (td, J = 2.7, 1.5 Hz, 1H), 6.69 (ddd, J = 3.8, 2.5, 1.5 Hz, 1H), 6.05 (dt, J = 3.6, 2.4 Hz, 1H), 2.72 (d, J = 4.6 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 161.2, 126.4, 121.0, 109.5, 108.5, 25.5. HRMS-ESI (m/ z), calculated for C6H9N2O (M+H)+ 125.0715. Found 125.0706. m.p: 156.1−157.4 °C. General Procedure A. General Procedure for the Brominating Reactions Listed in Table 1. To a solution of 2-substituted pyrrole (0.1 mmol, 1.0 equiv) in 3.0 mL of tetrahydrofuran (THF), brominating reagent Br2, or NBS, or DBDMH (0.1 mmol, 1.0 equiv) was added. The reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with Na2SO3 and sat. NaHCO3 solution was added. Then the crude products were extracted with CH2Cl2. The organic layer was dried over Na2SO4 and the organic solvent was evaporated under reduced pressure to provide the crude product mixture. General Procedure B. General Procedure for the Bromination Using Tetrabutylammonium Tribromide (TBABr3) Listed in Table 3. To a solution of 2-substituted pyrrole (0.1 mmol, 1.0 equiv) in 3.0 mL of CH2Cl2, TBABr3 (0.1 mmol, 1.0 equiv) was added at room temperature. The reaction was stirred at room temperature for 1 h under nitrogen. The reaction mixture was quenched with Na2SO3 and sat. NaHCO3 solution was added. Then the crude products were extracted with CH2Cl2. The organic layer was dried over Na2SO4, then filtered and the organic solvent was evaporated under reduced pressure to provide the crude product mixture. Triphenylmethane (24.4 mg, 0.1 mmol) was added to the crude product mixture followed by DMSO-d6 (1.0 mL). The yields were determined by 1H NMR using triphenylmethane as internal control. Pure products were subsequently isolated for full characterization. Methyl 5-Bromo-1H-pyrrole-2-carboxylate (2c). Procedure A did not produce 2c in significant yields. Preparation of 2c using general procedure B provided 2c in 14% yield. 1H NMR (500 MHz, DMSOd6) δ 12.71 (s, 1H), 6.77 (d, J = 3.8 Hz, 1H), 6.23 (d, J = 3.8 Hz, 1H), 3.75 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 159.8, 123.5, 116.7, 112.0, 105.4, 51.3. HRMS-ESI (m/z), calculated for C6H5BrNO2 (MH)− 201.9504. Found 201.9494. m.p.: 104.1−105.2 °C. 5-Bromo-N-methyl-1H-pyrrole-2-carboxamide (3c). Compound 3c was prepared using general procedure B which provided 3c in 78% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.19 (s, 1H), 7.97 (q, J = 4.5 Hz, 1H), 6.69 (dd, J = 3.7, 2.6 Hz, 1H), 6.11 (dd, J = 3.7, 2.4 Hz, 1H), 2.71 (d, J = 4.6 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 160.1, 128.2, 111.2, 110.8, 102.0, 25.5. HRMS-ESI (m/z), calculated for C6H8BrN2O (M+H)+ 202.9820. Found 202.9821. m.p: 172.2− 173.3 °C. N-Isopropyl-1H-pyrrole-2-carboxamide (4). Isopropyl amine (0.98 mL, 11.4 mmol, 3.0 equiv) was added to a stirring solution of 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone (0.8 g, 3.8 mmol, 1.0 equiv) in 20 mL of dry CH3CN. The mixture was stirred under nitrogen, at room temperature for 24 h. The solvents were removed under reduced pressure to give a white solid (531 mg, 92%). 1H NMR 9253

DOI: 10.1021/acs.joc.8b01251 J. Org. Chem. 2018, 83, 9250−9255

Article

The Journal of Organic Chemistry

(126 MHz, DMSO-d6) δ 159.06, 136.79, 131.88, 129.00, 126.18, 122.36, 119.99, 111.11, 108.86, 20.48. HRMS-ESI (m/z), calculated for (M+H)+ 201.1028. Found 201.1029. m.p.: 193−195 °C. 5-Bromo-N-(p-tolyl)-1H-pyrrole-2-carboxamide (10c). Compound 10c was prepared using general procedure B, which produced 10c in 72% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.40 (s, 1H), 9.73−9.69 (m, 1H), 7.58 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 3.8 Hz, 1H), 6.22 (d, J = 3.8 Hz, 1H), 2.27 (s, 3H). 13 C NMR (126 MHz, DMSO-d6) δ 158.06, 136.55, 132.26, 129.19, 129.13, 128.05, 120.11, 112.91, 111.30, 111.27, 103.53, 20.56. HRMS-ESI (m/z), calculated for (M+H)+ 279.0133. Found 279.0136. m.p.: 169−172 °C.

(5-Bromo-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone (7c). Compound 7c was prepared using general procedure B, which provided 7c in 64% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.18 (s, 1H), 6.57 (dd, J = 3.8, 2.3 Hz, 1H), 6.18 (dd, J = 3.8, 2.1 Hz, 1H), 3.68−3.41 (m, 4H), 1.96−1.74 (m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 158.9, 127.8, 113.5, 111.0, 102.7, 47.6, 46.7, 26.2, 23.5. HRMS-APCI (m/z), calculated for C9H12BrN2O (M+H)+ 243.0133. Found 243.0135. m.p.: 223.4−224.4 °C. Piperidin-1-yl(1H-pyrrol-2-yl)methanone (8). Piperidine (1.1 mL, 11.5 mmol, 3.0 equiv) was added to a stirring solution of 2,2,2trichloro-1-(1H-pyrrol-2-yl)-ethanone (0.8 g, 3.8 mmol, 1.0 equiv) in 20 mL of dry CH2Cl2. The mixture was stirred under nitrogen, at room temperature for 48 h. 0.5 M HCl was added and the solution extracted with CH2Cl2, dried with Mg2SO4, filtered, and the solvent removed under reduced pressure to give a white solid (0.57 g, 85%). 1 H NMR (500 MHz, DMSO-d6) δ 11.39 (s, 1H), 6.85 (td, J = 2.7, 1.4 Hz, 1H), 6.42 (ddd, J = 3.8, 2.5, 1.4 Hz, 1H), 6.09 (dt, J = 3.6, 2.5 Hz, 1H), 3.63 (t, J = 5.4 Hz, 4H), 1.66−1.60 (m, 2H), 1.55−1.48 (m, 4H). 13C NMR (126 MHz, CDCl3) δ 161.7, 125.1, 120.7, 111.8, 109.4, 46.1 (very broad signal of rotameric carbons), 26.2, 24.9. HRMS-ESI (m/z), calculated for C10H15N2O (M+H)+ 179.1184. Found 179.1171. m.p: 132.2−134.0 °C. (4-Bromo-1H-pyrrol-2-yl)(piperidin-1-yl)methanone (8c). Compound 8c was prepared using general procedure B, which provided 8c in 65% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.14 (s, 1H), 6.39 (dd, J = 3.7, 2.5 Hz, 1H), 6.14 (dd, J = 3.7, 2.3 Hz, 1H), 3.59 (t, J = 5.5 Hz, 4H), 1.65−1.59 (m, 2H), 1.54−1.46 (m, 4H). 13C NMR (126 MHz, DMSO-d6) δ 160.4, 126.6, 112.7, 110.3, 101.6, methyl signals of rotameric carbons around 40 not visible, 25.8, 24.2. HRMS-APCI (m/z), calculated for C10H14BrN2O (M+H)+ 257.0290. Found 257.0292. m.p: 173.1−174.0 °C. N-Phenyl-1H-pyrrole-2-carboxamide (9). 2,2,2-Trichloro-1-(1Hpyrrol-2-yl)ethan-1-one (0.88 g, 4.1 mmol, 1.0 equiv), triethylamine (0.67 mL, 5.0 mmol, 1.2 equiv), and aniline (0.46 mL, 5.0 mmol, 1.2 equiv) were combined in a round-bottom flask with a stir bar under an atmosphere of nitrogen. The mixture was heated at 60 °C for 12 h, and volatiles were then removed under vacuum to yield a brown residue. To the flask was added hexane and the mixture was triturated. The resulting brown solid was filtered and washed with hexane. The compound was purified by alumina column chromatography, yielding a white solid (0.21 g, 27%). The spectroscopic data of the product matched previous reports.43 1H NMR (500 MHz, DMSO-d6) δ 11.67 (s, 1H), 9.74 (s, 1H), 7.74 (d, J = 8.2 Hz, 2H), 7.33 (t, J = 7.9 Hz, 2H), 7.10−7.02 (m, 2H), 6.97 (td, J = 2.7, 1.4 Hz, 1H), 6.20−6.15 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 159.16, 139.34, 128.59, 126.06, 122.97, 122.53, 119.90, 111.31, 108.89. HRMS-ESI (m/z), calculated for (M+H)+ 187.0871. Found 187.0874. m.p.: 151−152 °C. 5-Bromo-N-phenyl-1H-pyrrole-2-carboxamide (9c). Compound 9c was prepared using general procedure B, which provided 9c in 69% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.76 (s, 1H), 7.72−7.70 (m, 2H), 7.33 (t, J = 7.7 Hz, 2H), 7.07−7.04 (m, 2H), 6.23 (d, J = 3.7 Hz, 1H). 13 C NMR (126 MHz, DMSO-d6) δ 158.53, 139.52, 129.10, 128.33, 123.64, 120.39, 113.47, 111.68, 104.10. HRMS-ESI (m/z), calculated for (M+H)+ 264.9977 Found 264.9981. m.p.: 166−170 °C. N-(p-Tolyl)-1H-pyrrole-2-carboxamide (10). p-Toluidine (0.52 g, 4.8 mmol, 1.2 equiv) was dissolved in triethylamine (1.0 mL, 7.5 mmol, 1.9 equiv) in a round-bottom flask with a stir bar. To this reaction mixture was added 2,2,2-trichloro-1-(1H-pyrrol-2-yl)ethan-1one (0.85 g, 4.0 mmol, 1.0 equiv). The reaction was heated at 60 °C under nitrogen atmosphere for 18 h. Volatiles were evaporated under high vacuum to yield a dark brown residue. The residue was triturated with a small amount of hexane, and the resulting solid was filtered and washed with hexane. The crude product mixture was purified using alumina chromatography to yield a white solid (0.42 g, 52%). The spectroscopic data of the product matched previous reports.44 1H NMR (500 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.66 (s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 7.05 (p, J = 1.8 Hz, 1H), 6.94 (q, J = 2.2 Hz, 1H), 6.16 (q, J = 2.7 Hz, 1H), 2.26 (s, 3H). 13C NMR

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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.8b01251. Computational details, and 1H and 13NMR spectra for all major compounds (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jetze J. Tepe: 0000-0001-5467-5589 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge financial support provided by Michigan State University, and computational resources provided by MSU’s Institute for Cyber-Enabled Research.

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REFERENCES

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