Carbon-nitrogen bond formation via catalytic alcohol activation
Yan, Tao
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2017
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Yan, T. (2017). Carbon-nitrogen bond formation via catalytic alcohol activation. University of Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Chapter 4
Pyrroles
via
Iron-Catalyzed
N-Heterocyclization
from
Unsaturated Diols and Primary Amines
Pyrroles are prominent scaffolds in pharmaceutically active compounds and play an important role in medicinal chemistry. Therefore, the development of novel, atom-economic and sustainable catalytic strategies to obtain these moieties is highly desired. Recently, direct catalytic pathways have been established that utilize readily available alcohol substrates. These approaches rely on the use of noble metals such as ruthenium or iridium. Here we report on the direct synthesis of pyrroles with a catalyst based on the earth-abundant and inexpensive iron. The method uses 2-butyne-1,4-diol or 2-butene-1,4-diol, which can be directly coupled with anilines, benzyl amines and aliphatic amines to obtain a variety of pyrroles in moderate to very good isolated yields.
Part of this chapter was published:
Introduction
Pyrroles are important building blocks in medicinal chemistry[1] since many pharmaceutically active compounds contain these moieties. For example, aloracetam[2] was been previously used in studies for treating Alzheimer’s disease, isamoltane[3] was shown to exhibit anxiolytic effects on rodents, elopiprazole[4] is an antipsychotic drug, and Lipitor is a drug for treating cardiovascular disease (Figure 1).
Figure 1: Bioactive compounds containing pyrrole moieties.
Owing to the importance of pyrroles, many classical synthetic pathways such as the Hantzsch[5], Knorr[6], and Paal-Knorr[7] synthesis (Scheme 1, A) as well as related multicomponent reactions[8] have already been established. These stoichiometric routes however, may suffer from poor substrate accessibility, harsh reaction conditions and multi-step syntheses that lead to the formation of waste and low atom economy[9]. Thus the development of novel catalytic methods, to create the pyrrole scaffold efficiently is subject of intensive research.[10] Several elegant approaches, broadly related to the borrowing hydrogen strategy,[11] have been recently reported that rely on the catalytic dehydrogenation of easily accessible alcohol substrates, (Scheme 1, A). In 2013, Beller[12] and coworkers reported on the ruthenium-catalyzed three-component pyrrole synthesis where secondary alcohols, diols and primary amines were coupled in analogy to the classical Hantzsch synthesis. Michlik and Kempe[13] achieved the direct iridium-catalyzed coupling of alcohols and amino alcohols to obtain pyrroles, and Milstein[14] and coworkers presented a similar, ruthenium-catalyzed method. In 2011, Crabtree et al.[15] described the formation of pyrroles from 1,4-diols and amines. In the course of these reactions, the alcohol substrates undergo dehydrogenation to the corresponding carbonyl-compounds, which further react with the amine to form the desired pyrrole product and the hydrogen equiv borrowed from the alcohol substrate are concomitantly liberated from the catalyst.[12-15]
In the studies by the groups of Watanabe[16] and Williams[17] it was shown that pyrroles can also be directly obtained from amines and unsaturated diols, such as 2-butyne-1,4-diol with an appropriate ruthenium catalyst. In this case it was proposed that the reaction likely proceeds through an internal hydrogen transfer
isomerization to the corresponding saturated dicarbonyl compounds that subsequently undergoes pyrrole formation with an amine reaction partner.
Our group has previously established the first iron-catalyzed formation of pyrrolidines[18] from amines and 1,4-butane-diol using Knölker’s complex[19,20] (Scheme 1, B), which was described in chapter 2. Based our previous results[18,21] and the reports of Watanabe and Williams, we envisioned the possibility of the iron catalyzed direct pyrrole formation starting from primary amines and unsaturated diols. A reactivity similar to the ruthenium-based system was expected, since the iron-complex is capable of alcohol dehydrogenation.
Scheme 1: A Classic and modern synthetic pathways to access pyrroles; B iron catalyzed direct synthesis of pyrrolidines and pyrroles from amines and diols.
A
Classic pyrrole synthesis
B
Catalytic pyrrole synthesis
C
Results and discussion
We started our investigation using 2-butyne-1,4-diol (2a) and 4-(N,N-dimethylamino)-aniline (1a) to establish the novel iron-catalyzed methodology towards pyrroles. Similarly to our previous work[18,21], Cat 3 was selected as the pre-catalyst, while Me3NO was used to generate the catalytically active iron complex. A variety of solvents were screened and the reaction temperature varied between 110-130 °C. The first attempts at 110 °C in solvents tetrahydrofuran (THF), dioxane, acetonitrile (CH3CN) and dimethylformamide (DMF) resulted in very similar conversion values of up to 70% and moderate product selectivities (Table 1, entry 1-4). Conversion of 1a and product selectivity slightly improved in
CPME and toluene at 110 °C (Table 1, entry 5-6). The results could be further improved to full conversion of 1a and near perfect selectivity of 3a at 130 °C in toluene and a good 83% isolated yield of 3a was achieved (Table 1, entry 7). Similarly, full conversion but slightly lower 3a yield (76%) was obtained when the reaction was conducted at 120 °C (Table 1, entry 8).
Table 1: Optimization of reaction conditions to obtain N-(4-dimethylamino-phenyl)-pyrrole (3a) from 4-(N,N-dimethylamino)-aniline (1a) and 1,4-diols (2).
Entry 2 Solvent T [oC] Conv. 1a [%]a Sele. 3a [%]a
1 2a THF 110 67 65 2 2a dioxane 110 70 68 3 2a CH3CN 110 68 67 4 2a DMF 110 67 66 5 2a CMPE 110 71 69 6 2a toluene 110 73 71 7 2a toluene 130 >99 98 (83) 8 2a toluene 120 >99 95 (76) 9 2b toluene 110 94 44 10 2b CPME 110 90 25 11 2b toluene 120 >99 63 (59)
General reaction conditions: General Procedure, 0.5 mmol 1a, 1 mmol 2, 0.02 mmol Cat 3, 0.04 mmol Me3NO, 2 ml solvent, 18 h, 110-130 °C, isolated yield in parenthesis. aValues based on GC-FID selectivity.
After having established that diol 2a can be successfully used as the substrate to form 3a, we explored the use of cis-2-butene-1,4-diol (2b) as the starting material. Catalytic runs conducted with 2b in toluene and CPME at 110 °C resulted in 94% and 90% conversion but only 44 and 25% selectivity for 3a, respectively (Table 1, entry 9-10). At 120 °C full 1a conversion and a good, 59% isolated yield of 3a was obtained (Table 1, entry 11) without significant over-reduction to pyrrolidines.[16] Therefore 2b can be regarded as alternative reaction partner to 2a, despite the slightly lower product yields obtained.
With the optimized reaction conditions in hand, a variety of anilines were tested (Table 2). Electron-rich 4-methoxy-aniline (1b) reacted smoothly with 2-butyne-1,diol (2a), leading to 80% isolated yield of 3b (Table 2, entry 1). When 4-methyl-aniline (1c) was used as substrate, much lower conversion and 36% isolated yield of 3c was obtained. Similar behavior was observed in the reaction of electron poor 4-fluoro-aniline (1d) with 2-butyne-1,4-diol (2a), that yielded 30% of 3d at 33% substrate conversion. Interestingly, in both of these cases almost full conversion and much higher product selectivity were achieved when cis-2-butene-1,4-diol was employed as coupling partner instead of 1a, providing 59%
and 47% isolated yields of 3c and 3d, respectively (Table 2, entry 2-3). According to these results, 2b was selected for further reactions with 4-chloro-aniline (1e), 4-bromo-aniline (1f) and 3,4-(methenedioxy)-aniline (1g). In all these cases excellent substrate conversions and very good product selectivity was observed and the desired products 3e, 3f and 3g were obtained in 45%, 44% and 37% isolated yields, respectively (Table 2, entry 4-6). It was also shown that product selectivity and isolated yields could be improved in the coupling of 1e with 4 equiv of diol 2b. Ortho-substituted anilines (1h–1j) could also be successfully used whereby electron-donating substituents gave better product yields (Table 2, entry 7–9).
Table 2: Direct synthesis of N-substituted pyrroles from anilines and 1,4-diols.
Entry 1 2 Product 3 Conv. 1 [%]a Sele. 3 [%]a
1 1b 2a 3b 92 90 (80) 2 1c 2a 2b 3c 42 >99 36 90 (59) 3 1d 2a 2b 3d 33 91 30 75 (47) 4 1e 2b 3e 85 63 (45) 2bb 98 72 (54) 5 1f 2b 3f 94 61 (44) 6 1g 2b 3g >99 68 (37) 7 1h 2b 3h 70 42 (36) 8 1i 2b 3i 90 52 (25) 9 1j 2b 3j 56 36 (15)
General reaction conditions: General Procedure, 0.5 mmol 1a, 1 mmol 2a, 0.02 mmol Cat 3, 0.04 mmol Me3NO, 2 ml toluene, 18 h, 130 °C, isolated yield in parenthesis, unless otherwise specified. aConversion is based on GC-FID selectivity; bThe reaction was operated
in a sealed 20 ml vial with 4 equiv 2b in 22 h.
After aniline derivatives were also converted to N-phenyl-pyrroles successfully, primary aliphatic amines were explored under standard reaction conditions using 2-butyne-1,4-diol (2a) as reaction partner. Interestingly, a series of benzyl amines with varying electron density all afforded full substrate conversions, excellent product selectivity and good isolated yields of the desired N-benzylpyrroles. The coupling of benzylamine (5a) with 2a leads to the formation of N-benzylpyrrole (6a) with 61% isolated yield (Table 3, entry 1). Similarly, good results were obtained with a variety of halogenated benzyl amines, such as 4-chloro-benzylamine (5b), 4-fluoro-4-chloro-benzylamine (5c), 3-trifluoromethyl-4-chloro-benzylamine (5d) and 3-fluoro-4-chloro-benzylamine (5e), which afforded the corresponding
N-(4-chlorobenzyl)-pyrrole (6b), N-(4-fluorobenzyl)-pyrrole (6c), N-(3-trifluoromethylbenzyl)-pyrrole (6d) and N-(3-fluoro-4-chlorobenzyl)-pyrrole (6e) products in 57%, 52%, 55% and 65% isolated yields, respectively (Table 3, entry 2-5). With electron-rich benzylamines 5f and 5g, the desired N-(4-methylbenzyl)-pyrrole (5f) and N-piperonyl-N-(4-methylbenzyl)-pyrrole (5g) were obtained in good, 65% and 60% isolated yields, respectively (Table 3, entry 6-7). Interestingly, even 3-picolylamine (5h) reacted smoothly with 2-butyne-1,4-diol (2a) forming N-(3-picolyl)pyrrole in 76% isolated yield, although pyridine is a potential ligand that may coordinate to iron[22] (Table 3, entry 8). Product N-furfuryl-pyrrole (6i), which has already been proposed as food additive[23], was obtained in 43% yield from furfurylamine (5i) (Table 3, entry 9). For other aliphatic amines such as 2-phenylethylamine (5g) and dodecylamine (5k), the corresponding pyrrole products were obtained in 41% and 42% isolated yield (Table 3, entry 10-11). Cyclohexylamine (5l) reacted with 2a providing N-cyclohexylpyrrole (6l) in 33% yield (Table 3, entry 12).
Table 3: Direct synthesis of N-substituted pyrroles from anilines and 1,4-diols.
Entry 5 Product 6 Sele. 3 [%]a
1 5a 6a 90 (61) 2 5b 6b 85 (57) 3 5c 6c 73 (52) 4 5d 6d 88 (55) 5 5e 6e 87 (65) 6 5f 6f 87 (65) 7 5g 6g 83 (55) 8 5h 6h 92 (76) 9 5i 6i 71 (43) 10 5j 6j (41) 11 5k 6k 86 (42) 12 5l 6l 85 (33)
General reaction conditions: General Procedure, 0.5 mmol 5, 1 mmol 2a, 0.02 mmol Cat 3, 0.04 mmol Me3NO, 2 ml toluene, 18 h, 130 °C. In all cases, full conversion was obtained.
aValues shown are GC-FID selectivity, numbers in brackets are isolated yields.
Scheme 2: GPC analysis of N-benzyl pyrrole formation from benzylamine and 2-butyne-1,4-diol.
Mn (number-average molar mass): 260 g/mol, Mw (mass-average molar mass): 347 g/mol, D (polydispersity): 1.336. Molecular weight of the highest intensity of fraction Mw = 100-200: 160; Mw = 200–300: 215; Mw = 300–5000: 340.
Scheme 3: GPC analysis of control experiment using 2-butyne-1,4-diol as the only substrate.
Mn (number-average molar mass): 234 g/mol, Mw (mass-average molar mass): 284 g/mol, D (polydispersity): 1.215; Molecular weight of the highest intensity of fraction. Mw = 100 - 200: 160; Mw = 200 – 300: 214; Mw = 300 – 100: 353.
To summarize the results in Table 1-3 discussed above, generally good to excellent substrate conversions were seen. Similarly, product selectivity was good to
excellent based on GC-FID and GC-MS measurements, albeit the isolated product yields were lower. This may be an indication of side reactions involving species not detectable by these GC measurements. Indeed, gel permeation chromatography (GPC) measurements of the crude product mixture confirmed the presence of oligomeric side products for a typical run with 2-butyne-1,4-diol (2a) and benzylamine (5a) (Scheme 2) in the broad molecular weight (Mw) range of 300– 5000 g/mol.
In addition, when 2a alone was subjected to standard catalytic conditions, full substrate conversion was observed alongside the formation of a dark brown unidentified precipitate and no volatiles were detected by GC measurement (Scheme 3). Furthermore, GPC measurement confirmed the formation of oligomeric side products. Thus, the most likely source of such competing side reactions is the isomerization of substrate 2a to the corresponding ,β-unsaturated aldehyde as shown in Scheme 4.
Scheme 4: Possible pathways for pyrrole formation.
Other reaction pathways such as the formation of secondary or tertiary amines that may be a result of over-alkylation and imine reduction were not observed, indicating the preference for intramolecular pyrrole formation. Also, the corresponding pyrrolidine analogues were only sparingly observed when 2b was used as substrate. More mechanistic and spectroscopic insights are required to understand the sequence of reaction steps occurring. This may lead to improvement of product yields. Future research should also address a broader substrate scope, especially different substitution patterns on the pyrrole ring.
Conclusion
In conclusion, in this chapter, the first iron-catalyzed direct method for the catalytic formation of pyrroles by coupling of unsaturated diols with primary amines has been described. Various derivatives of anilines, and benzyl amines as well as other aliphatic primary amines were successfully used in the construction of pyrrole moieties, which are important scaffolds in medicinal chemistry. The desired product yields range from high to moderate and future studies will address further mechanistic details of this interesting noble metal free transformation. The presented catalytic strategy is direct, straightforward, and allows for the use of a wide range of amines. In addition, this new catalytic method relies on the use of
inexpensive and abundant catalyst for the construction of scaffolds that are very important in the pharmaceutical industry.
Experimental section
General methodsChromatography: Merck silica gel type 9385 230-400 mesh or Merck Al2O3 90 active neutral, TLC: Merck silica gel 60, 0.25 mm or Al2O3 60 F254 neutral. Components were visualized by UV, Ninhydrin or I2 staining. Progress of the reactions was determined by GC-MS (GC: HP 6890, MS: HP 5973) with an HP012 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). Conversions were determined by GC-FID (GC: HP 6890) with an HP-5 column (Agilent Technologies, Palo Alto, CA). GC-MS and GC-FID analysis method: 60 °C 5 min, 180 °C 5 min (10 °C/min), 260 °C 5 min (10 °C/min). 1H- and 13C NMR spectra were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using CDCl3, CD3OD, or CD2Cl2 as solvent. Chemical shift values are reported in ppm with the solvent resonance as the internal standard (CDCl3: 7.26 for 1H, 77.00 for 13C; CD3OD: 3.31 for 1H, 49.00 for 13C; CD2Cl2: 5.32 for 1H, 53.84 for 13C). Data are reported as follows: chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br. = broad, m = multiplet), coupling constants (Hz), and integration. All reactions were carried out under an Argon atmosphere using oven (110oC) dried glassware and using standard Schlenk techniques. THF and toluene were collected from a MBRAUN solvent purification system (MB SPS-800). Dioxane (99.5%, extra dry), dichloroethane (DCE, 99.8%, extra dry), N,N-dimethylformamide (DMF, 99.8%, extra dry) and acetonitrile (CH3CN, 99.9%, extra dry) were purchased from Acros without further purification. Molecular sieves 4A were purchased from Acros, and heated in Schlenck under 180 °C in vacuo overnight for activation before using. All other reagents were purchased from Sigma or Acros in reagent or higher grade and were used without further purification. Complex Cat 3 was synthesized according to literature procedures[24] with slightly modification. The synthesis of Cat 3 was carried out as described in Chapter 2.
Representative procedures
General procedure: An oven-dried 20 ml Schlenk tube, equipped with stirring bar, was charged with amine (0.5 mmol, 1 equiv), alcohol (given amount), iron complex Cat 3 (4 mol%), Me3NO (8 mol%) and Toluene (solvent, 2 ml). The solid starting materials were added into the Schlenk tube under air, the Schlenk tube was subsequently connected to an argon line and a vacuum-argon exchange was performed three times. Liquid starting materials and solvent were charged under an argon stream. The Schlenk tube was capped and the mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at the appropriate temperature and stirred for a given time. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography to provide the pure amine product.
Procedure of synthetizing N-(dimethyl-phenyl)-pyrrole from 4-dimethylamino aniline and butyn-1,4-diol: An oven-dried 20 ml Schlenk tube, equipped with stirring bar, was charged with 4-dimethylamino aniline (0.5 mmol, 0.068 g), butyn-1,4-diol (0.5 mmol, 0.086 g), iron complex Cat 3 (4 mol%, 8 mg) and Me3NO (8 mol%, 3 mg) under air. The Schlenk tube was subsequently connected to a vacuum/argon Schlenk line and a vacuum-backfill cycle was performed three times. Toluene (solvent, 2 ml) were charged under an argon stream. The Schlenk tube was sealed with a screw cap and the mixture was rapidly stirred at room temperature for 1 min, then was placed into a pre-heated oil bath at 130 °C and stirred for 18 h. The reaction mixture was cooled down to room temperature and the crude mixture was filtered through celite, eluted with ethyl acetate, and concentrated in vacuum. The residue was purified by flash column chromatography (SiO2, pentane/EtOAc 100:0 to 80:20) to provide the pure product N-(4-dimethyl-phenyl)-pyrrole (0.077 g, 83% isolated yield).
Spectral data of isolated compounds
N-(4-dimethyl-phenyl)-pyrrole (3a): Synthesized according to General
procedure. 4-Dimethylamino aniline (0.068 g, 0.50 mmol) affords 3a (0.077 g, 83% yield). Brown solid was obtained after column chromatography (SiO2, pentane/EtOAc 100:0 to 80:20). 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.31 (m, 2H), 6.99 – 7.05 (m, 2H), 6.77 – 6.81 (m, 2H),
6.30 – 6.38 (m, 2H), 3.00 (s. 6H). 13C NMR (100 MHz, CDCl3) δ 148.86, 131.18, 122.12, 119.68, 113.04, 109.27, 40.78. The physical data were identical in all respects to those previously reported[25].
N-(4-Methoxy-phenyl)-pyrrole (3b): Synthesized according to General
procedure. 4-Methoxy aniline (0.062 g, 0.50 mmol) affords 3b (0.070 g, 80% yield). Light yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.37 (m, 2H), 6.99 – 7.06 (m, 2H), 6.91 – 6.99 (m, 2H), 6.30 – 6.38 (m, 2H), 3.84 (s. 3H). 13C NMR (100 MHz, CDCl
3) δ 157.60, 134.45, 122.13, 119.64, 114.57, 109.79, 55.51. The physical data were identical in all respects to those previously reported[26].
N-(4-Methyl-phenyl)-pyrrole (3c): Synthesized according to General
procedure. 4-Methyl aniline (0.054 g, 0.50 mmol) affords 3c (0.028 g, 36% yield with the use of 2a; 0.047 g, 59% yield with the use of 2b). Light yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.37 (m, 2H), 7.19 –
7.29 (m, 2H), 7.04 – 7.14 (m, 2H), 6.32 – 6.42 (m, 2H), 2.41 (s. 3H). 13C NMR (100 MHz, CDCl3) δ 138.44, 135.30, 129.98, 120.48, 119.33, 110.02, 20.80. The physical data were identical in all respects to those previously reported[27].
N-(4-Fluoro-phenyl)-pyrrole (3d): Synthesized according to General
procedure. 4-Fluoro aniline (0.056 g, 0.50 mmol) affords 3d (0.024 g, 30% yield with the use of 2a; 0.038 g, 47% yields with use of 2b). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl
3) δ 7.30 – 7.40 (m, 2H), 7.08 –
7.18 (m, 2H), 6.96 – 7.06 (m, 2H), 6.28 – 6.44 (m, 2H), 2.41 (s. 3H). 13C NMR (100 MHz, CDCl3) δ 160.61 (d, J = 244.98 Hz), 137.15 (d, J = 2.86 Hz), 122.26 (d, J = 8.39 Hz), 119.60, 116.25 (d, J = 22.77 Hz), 110.42, . The physical data were identical in all respects to those previously reported[28].
N-(4-Chloro-phenyl)-pyrrole (3e): Synthesized according to General
procedure. 4-Chloro aniline (0.064 g, 0.50 mmol) affords 3e (0.040 g, 45% yield). Light yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl3) δ 7.36 – 7.44 (m, 2H), 7.30 – 7.36 (m, 2H), 7.00 – 7.11 (m, 2H), 6.30 – 6.42 (m, 2H), 2.41 (s. 3H). 13C NMR (100 MHz, CDCl3) δ 139.28, 131.00, 129.58, 121.57, 119.23, 110.79. The physical data were identical in all respects to those previously reported[29].
N-(4-Bromo-phenyl)-pyrrole (3f): Synthesized according to General
procedure. 4-Bromo aniline (0.085 g, 0.50 mmol) affords 3f (0.048 g, 44% yield). Light yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR (400 MHz, CDCl
3) δ 7.50 – 7.60 (m, 2H), 7.22 – 7.35 (m, 2H), 7.00 – 7.12 (m, 2H), 6.30 – 6.45 (m, 2H), 2.41 (s. 3H). 13C NMR (100 MHz, CDCl3) δ 139.73, 132.54, 121.88, 119.15, 118.65, 110.86. The physical data were identical in all respects to those previously reported[30].
N-(3,4-Methylenedioxy-phenyl)-pyrrole (3g): Synthesized according
to General procedure. 3,4-(Methylenedioxy)aniline (0.069 g, 0.50 mmol) affords 3g (0.035 g, 37% yield). Light yellow solid was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10 to 70:30). 1H NMR (400 MHz, CDCl3) δ 6.95 – 7.02 (m, 2H), 6.88 – 6.94 (m, 1H), 6.80 – 6.88
(m, 2H), 6.27 – 6.38 (m, 2H), 6.01 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 148.30, 145.62, 135.68, 119.82, 114.01, 109.93, 108.42, 103.01, 101.57, 77.00. HRMS (APCI+, m/z): calculated for C11H10NO2 [M+H]+: 188.07061; found: 188.07078.
N-(2-Methoxy-phenyl)-pyrrole: Synthesized according to General
procedure. 2-Methoxy aniline (0.062 g, 0.50 mmol) affords 3c (0.031 g, 36% yield with the use of 2b). Light yellow liquid was obtained after column chromatography (SiO2, pentane/EtOAc 100:0 to 95:5). 1H NMR
(400 MHz, CDCl3) δ 7.20 – 7.38 (m, 2H), 6.95 – 7.10 (m, 4H), 6.25 – 6.40 (m, 2H), 3.85 (s. 3H). 13C NMR (100 MHz, CDCl3) δ 152.67, 130.21, 127.42, 125.72, 122.03, 120.85, 112.24, 108.72, 55.75. The physical data were identical in all respects to those previously reported[31].
N-(2-Methyl-phenyl)-pyrrole: Synthesized according to General
procedure. 2-Methyl aniline (0.054 g, 0.50 mmol) affords 3c (0.020 g, 25% yield with the use of 2b). Light yellow liquid was obtained after column chromatography (SiO2, pentane/EtOAc 100:0 to 95:5). 1H NMR
(400 MHz, CDCl3) δ 7.23 – 7.33 (m, 4H), 6.78 – 6.82 (m, 2H), 6.30 – 6.35 (m, 2H), 2.22 (s. 3H). 13C NMR (100 MHz, CDCl
3) δ 140.55, 133.79, 131.01, 127.45, 126.58, 126.49, 122.01, 108.64, 17.85. The physical data were identical in all respects to those previously reported[32].
N-(2-fluoro-phenyl)-pyrrole: Synthesized according to General
procedure. 2-fluoro aniline (0.056 g, 0.50 mmol) affords 3c (0.012 g, 15% yield with the use of 2b). Light yellow liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 95:5). 1H NMR
(400 MHz, CDCl3) δ 7.35 – 7.45 (m, 1H), 7.16 – 7.29 (m, 3H), 7.02 – 7.08 (m, 2H), 6.30 – 6.40 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 154.47 (d, J = 249.3 Hz), 129.0 (d, J = 10.5 Hz), 127.11 (d, J = 7.7 Hz), 124.93 (d, J = 1.5 Hz), 124.73 (d, J = 3.8 Hz), 121.35 (d, J = 3.6 Hz), 117.03 (d, J = 20.6 Hz), 109.92. The physical data were identical in all respects to those previously reported[33].
N-benzyl-pyrrole (6a): Synthesized according to General procedure.
Benzylamine (0.054 g, 0.50 mmol) affords 6a (0.048 g, 61% yield). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to 90:10). 1H NMR (400 MHz, CDCl
3) δ 7.27 – 7.38
(m, 3H), 7.10 – 7.17 (m, 2H), 6.66 – 6.76 (m, 2H), 6.16 – 6.26 (m, 2H), 5.09 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 138.13, 128.67, 127.58, 126.94, 121.12, 108.45, 53.28. The physical data were identical in all respects to those previously reported[34].
N-(4-Chloro-benzyl)-pyrrole (6b): Synthesized according to General
procedure. 4-Chloro benzylamine (0.044 g, 0.50 mmol) affords 6b (0.055 g, 57% yield). Light yellow oily liquid obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to 90:10). 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.40 (m, 3H), 7.10 – 7.13 (m, 2H), 6.64 – 6.78
(m, 2H), 6.16 – 6.30 (m, 2H), 5.05 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 136.65, 133.42, 128.81, 128.24, 121.02, 108.73, 52.57. The physical data were identical in all respects to those previously reported[35].
N-(4-Fluoro-benzyl)-pyrrole (6c): Synthesized according to General
procedure. 4-Fluoro benzylamine (0.063 g, 0.50 mmol) affords 6c (0.046 g, 52% yield). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to 90:10). 1H NMR (400 MHz, CDCl3) δ 7.07 – 7.15 (m, 3H), 6.96 – 7.06 (m, 2H), 6.65 – 6.75
(m, 2H), 6.17 – 6.27 (m, 2H), 5.05 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 162.22 (d, J = 245.87 Hz), 133.88 (d, J = 3.11 Hz), 128.65 (d, J = 8.11 Hz), 120.97, 115.55 (d, J = 21.74 Hz), 108.64, 52.58. The physical data were identical in all respects to those previously reported[36].
N-(3-Trifluoromethyl-benzyl)-pyrrole (6d): Synthesized according
to General procedure. 3-Trifluoromethyl benzylamine (0.088 g, 0.50 mmol) affords 6d (0.062 g, 55% yield). Light yellow oily liquid obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to 90:10). 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.62 (m, 1H), 7.43 – 7.49 (m, 1H), 7.38 – 7.43 (m, 1H), 7.23 – 7.29 (m, 1H), 6.65 – 6.75 (m, 2H), 6.20 – 6.30 (m, 2H), 5.14 (s. 2H). 13C NMR (100 MHz, CDCl 3) δ 139.28, 131.09 (d, J = 22.29 Hz), 130.19 (d, J = 1.41 Hz), 129.30, 124.54 (quat, J = 3.84 Hz), 129.95 (d, J = 272.50 Hz), 123.64 (quat, J = 3.83 Hz), 121.12, 109.04, 52.81. HRMS (APCI+, m/z): calculated for C12H11F3N [M+H]+: 226.08381; found: 226.08415.
N-(3-Fluoro-4-chloro-benzyl)-pyrrole (6e): Synthesized according
to General procedure. 3-Fluoro-4-chloro benzylamine (0.080 g, 0.50 mmol) affords 6e (0.068 g, 65% yield). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to 90:10). 1H NMR (400 MHz, CDCl3) δ 7.13 – 7.21 (m, 1H), 7.05 – 7.13
(m, 1H), 6.93 – 7.02 (m, 1H), 6.63 – 6.73 (m, 2H), 6.18 – 6.28 (m, 2H), 5.03 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 157.49 (d, J = 248.78 Hz), 135.25 (d, J = 3.85 Hz), 129.08, 126.59 (d, J = 7.30 Hz), 121.28 (d, J = 17.87 Hz), 120.96, 116.76
(d, J = 21.31 Hz), 108.99, 52.10. HRMS (APCI+, m/z): calculated for C11H10ClFN [M+H]+: 210.04803; found: 210.04824.
N-(4-Methyl-benzyl)-pyrrole (6f): Synthesized according to General
procedure. 4-Methyl benzylamine (0.061 g, 0.50 mmol) affords 6f (0.052 g, 60% yield). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 95:5 to 90:10). 1H NMR (400 MHz, CDCl3) δ 7.13 – 7.22 (m, 2H), 7.03 – 7.10 (m, 2H), 6.66 – 6.76
(m, 2H), 6.16 – 6.26 (m, 2H), 5.06 (s. 2H), 2.37 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 137.29, 135.06, 129.32, 127.02, 121.01, 108.34, 53.07, 21.04. The physical data were identical in all respects to those previously reported[35].
N-Piperonyl-pyrrole (6g): Synthesized according to General
procedure. Piperonylamine (0.076 g, 0.50 mmol) affords 6g (0.056 g, 55% yield). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 90:10 to 60:40). 1H NMR (400 MHz, CDCl3) δ 6.74 – 6.79 (m, 1H), 6.66 – 6.72 (m, 2H), 6.63 – 6.66
(m, 1H), 6.60 – 6.63 (m, 1H), 6.16 – 6.22 (m, 2H), 5.94 (s. 2H), 4.97 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 148.00, 147.09, 131.88, 120.88, 120.48, 108.46, 108.23, 107.72, 101.07, 53.12. The physical data were identical in all respects to those previously reported[35].
N-(3-Picolyl)-pyrrole (6h): Synthesized according to General
procedure. 3-Picolylamine (0.054 g, 0.50 mmol) affords 6h (0.060 g, 76% yield). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 80:20 to 40:60). 1H NMR (400
MHz, CDCl3) δ 8.40 – 8.60 (m, 2H), 7.32 – 7.40 (m, 1H), 7.20 -7.29 (m, 1H), 6.62 – 6.74 (m, 2H), 6.15 – 6.25 (m, 2H), 5.09 (s. 2H). 13C NMR (100 MHz, CDCl3) δ 149.05, 148.28, 134.66, 133.68, 123.68, 120.92, 109.02, 50.70. The physical data were identical in all respects to those previously reported[35].
N-(2-Furfuryl)-pyrrole (6i): Synthesized according to General
procedure. Furfurylamine (0.049 g, 0.50 mmol) affords 6i (0.032 g, 43% yield). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 80:20 to 40:60). 1H NMR (400 MHz, CDCl3) δ 7.32–
7.42 (m, 1H), 6.68 – 6.76 (m, 2H), 6.30 – 6.38 (m, 1H), 6.22 – 6.30 (m, 1H), 6.15 – 6.22 (m, 2H), 5.03 (s. 2H). 13C NMR (100 MHz, CDCl
3) δ 150.74, 142.65, 120.67, 110.36, 108.50, 108.09, 46.05. The physical data were identical in all respects to those previously reported[35].
N-(2-Phenylethyl)-pyrrole (6g): Synthesized according to General
procedure. 2-Phenyl ethylamine (0.061 g, 0.50 mmol) affords 6g (0.035 g, 41% yield). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 90:10). 1H NMR (400
MHz, CDCl3) δ 7.29– 7.39 (m, 2H), 7.26 – 7.29 (m, 1H), 7.10 – 7.18 (m, 2H), 6.58 – 6.68 (m, 2H), 6.12 – 6.22 (m, 2H), 4.14 (t, J = 7.65 Hz, 2H), 3.09 (t, J = 7.61 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 138.39, 128.62, 128.50, 126.55,
120.42, 107.95, 51.12, 38.35. The physical data were identical in all respects to those previously reported[37].
N-Dodecyl-pyrrole (6k): Synthesized according to General procedure.
Dodecylamine (0.093 g, 0.50 mmol) affords 6k (0.050 g, 42% yield). Light yellow oily liquid was obtained after column chromatography (SiO2,
Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl3) δ 6.62– 6.70 (m, 2H), 6.12 – 6.18 (m, 2H), 3.87 (t, J = 7.20 Hz, 2H), 1.70 – 1.83 (m, 2H), 1.18 – 1.38 (m, 18H), 0.90 (t, J = 6.63 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 120.41, 107.71, 49.62, 31.90, 31.57, 29.61, 29.60, 29.55, 29.48, 29.32, 29.20, 26.76, 22.67, 14.10. The physical data were identical in all respects to those previously reported[38].
N-Cyclohexyl-pyrrole (6l): Synthesized according to General procedure.
Cyclohexylamine (0.050 g, 0.50 mmol) affords 6l (0.025 g, 33% yield). Light yellow oily liquid was obtained after column chromatography (SiO2, Pentane/EtOAc 100:0 to 90:10). 1H NMR (400 MHz, CDCl 3) δ 6.70– 6.78 (m, 2H), 6.10 – 6.18 (m, 2H), 3.75 – 3.87 (m , 2H), 2.05 – 2.15 (m, 2H), 1.82 – 1.94 (m, 2H), 1.56 – 1.69 (m, 2H), 1.33 – 1.48 (m , 2H), 1.19 – 1.32 (m, 2H). 13C NMR (100 MHz, CDCl 3) δ 118.39, 107.31, 58.65, 34.66, 25.72, 25.49. The physical data were identical in all respects to those previously reported[39].
References
[1] V. Bhardwaj, D. Gumber, V. Abbot, S. Dhimana, P. Sharmaa, RSC Adv., 2015, 5, 15233–15266.
[2] F. Fischer, M. Matthisson, P. Herrling, Neurodegener. Dis., 2004, 1, 50–70.
[3] P. C. Waldmeier, M. Williams, P. A. Baumann, S. Bischoff, M. A. Sills, R. F. Neale,
Naunyn-Schmiedeberg’s Arch. Pharmacol., 1988, 337, 609–620.
[4] I. Van Wijngaarden, C. G. Kruse, R. Van Hes, J. A. M. Van der Heyden, M. T. M. Tulp,
J. Med. Chem., 1987, 30, 2099–2104.
[5] A. Hantzsch, Ber. Dtsch. Chem. Ges., 1890, 23, 1474–1476. [6] L. Knorr, Ber. Dtsch. Chem. Ges., 1884, 17, 1635–1642. [7] C. Paal, Ber. Dtsch. Chem. Ges., 1885, 18, 367–371.
[8] V. Estévez, M. Villacampa, J. C. Menendez, Chem. Soc. Rev., 2014, 43, 4633–4657. [9] a) B. M. Trost, Science, 1991, 254, 1471; b) P. T. Anastas, J. C. Warner, Green
Chemistry: Theory and Practice; Oxford University Press, Oxford, England, 1998.
[10] a) I. Nakamura, Y. Yamamoto, Chem. Rev., 2004, 104, 2127–2198; b) N. T. Patil, Y. Yamamoto, ARKIVOC, 2007, 121–141; c) X. Xin, D. Wang, X. Li, B. Wang, Angew.
Chem. Int. Ed., 2012, 51, 1693–1697; d) Y. Jiang, W. C. Chan, C. M. Park, J. Am. Chem. Soc., 2012, 134, 4104–4107; e) M. P. Huestis, L. Chan, D. R. Stuart, K.
Fagnou, Angew. Chem. Int. Ed., 2011, 50, 1338–1341; f) S. Rakshit, F. W. Patureau, F. Glorius, J. Am. Chem. Soc., 2010, 132, 9585–9587; g) D. R. Stuart, P. Alsaben, M. Kuhn, K. Fagnou, J. Am. Chem. Soc., 2010, 132, 18326–18339; h) E. Lourdusamy, L. Yao, C. M. Park, Angew. Chem. Int. Ed., 2010, 49, 7963–7967.
[11] a) A. J. A. Watson, J. M. J. Williams, Science, 2010, 329, 635–636; b) G. Guillena, D. J. Ramon, M. Yus, Chem. Rev., 2010, 110, 1611–1641; c) S. Bähn, S. Imm, L. Neubert, M. Zhang, H. Neumann, M. Beller, ChemCatChem, 2011, 3, 1853–1864; d) G. E. Dobereiner, R. H. Crabtree, Chem. Rev., 2010, 110, 681–703; e) C. Gunanathan, D. Milstein, Science, 2013, 341, 1229712; f) Q. Yang, Q. Wang, Z. Yu,
Chem. Soc. Rev., 2015, 44, 2305–2329; g) A. Quintard, J. Rodriguez, ChemSusChem, 2016, 9, 28–30.
[12] a) M. Zhang, H. Neumann, M. Beller, Angew. Chem. Int. Ed., 2013, 52, 597–601; b) M. Zhang, X. Fang, H. Neumann, M. Beller, J. Am. Chem. Soc., 2013, 135, 11384– 11388.
[13] S. Michlik, R. Kempe, Nat. Chem., 2013, 5, 140–144.
[14] D. Srimani, Y. Ben-David, D. Milstein, Angew. Chem. Int. Ed., 2013, 52, 4012–4015. [15] N. D. Schley, G. E. Dobereiner, R. H. Crabtree, Organometallics, 2011, 30, 4174–
4179.
[16] Y. Tsuji, Y. Yokoyama, K.-T. Huh, Y. Watanabe, Bull. Chem. Soc. Jpn., 1987, 60, 3456– 3458.
[17] a) S. J. Pridmore, P. A. Slatford, A. Daniel, M. K. Whittlesey, J. M. J. Williams,
Tetrahedron Lett., 2007, 48, 5115–5120; b) S. J. Pridmore, P. A. Slatford, J. E. Taylor,
M. K. Whittlesey, J. M. J. Williams, Tetrahedron, 2009, 65, 8981–8986. [18] T. Yan, B. L. Feringa, K. Barta, Nat. Commun., 2014, 5, 5602.
[19] H.-J. Knölker, E. Baum, H. Goesmann, R. Klauss, Angew. Chem. Int. Ed., 1999, 38, 2064–2066.
[20] a) A. Quintard, T. Constantieux, J. Rodriguez, Angew. Chem. Int. Ed., 2013, 52, 12883–12887; b) A. Quintard, J. Rodriguez, Angew. Chem. Int. Ed., 2014, 53, 4044– 4055; c) A. J. Rawlings, L. J. Diorazio, M. Wills, Org. Lett., 2015, 17, 1086–1089; d) H.-J. Pan, T. W. Ng, Y. Zhao, Chem. Commun., 2015, 51, 11907–11910; e) S. Elangovan, J.-B. Sortais, M. Beller, C. Darcel, Angew. Chem. Int. Ed., 2015, 54, 14483–14486.
[22] C. P. Casey, H. Guan, J. Am. Chem. Soc., 2009, 131, 2499–2507.
[23] P. Y. Nikolov, V. A. Yaylayan, J. Agric. Food Chem., 2012, 60, 10155–10161. [24] T. N. Plank, J. L. Drake, D. K. Kim, T. W. Funk, Adv. Synth. Catal., 2012, 354,
597-601.
[25] J. C. Antilla, Baskin, M. Jeremy, T. E. Barder, S. L. Buchwald, J. Org. Chem., 2004,
69, 5578–5587.
[26] A. K. Verma, T. Kesharwani, J. Singh, V. Tandon, R. C. Larock, Angew. Chem. Int.
Ed., 2009, 48, 1138–1143.
[27] Z.-L. Xu, H.-X. Li, Z.-G. Ren, W.-Y. Du, W.-C. Xu, J.-P. Lang, Tetrahedron, 2011, 67, 5282–5288.
[28] T. Niwa, H. Ochiai, Y. Watanabe, T. Hosoya, J. Am. Chem. Soc., 2015, 137, 14313– 14318.
[29] H.-C. Ma, X.-Z. Jiang J. Org. Chem., 2007, 72, 8943-8946. [30] W. Chen, J. Wang, Organometallics, 2013, 32, 1958–1963.
[31] G. Pai, A. P. Chattopadhyay, Tetrahedron Lett., 2014, 55, 941–944. [32] W. Chen, J. Wang, Organometallics, 2013, 32, 1958−1963.
[33] P. Wang, F.-P. Ma, Z.-H. Zhang, J. Mol. Liq., 2014, 198, 259–262.
[34] G. A. Molander, D. W. Ryu, M. Hosseini-Sarvari, R. Devulapally, D. G. Seapy, J. Org.
Chem., 2013, 78, 6648–6656.
[35] I. Deb, D. J. Coiroa, D. Seidel, Chem. Commun., 2011, 47, 6473–6475.
[36] Z. Zou, Z. Deng, X. Yu, M. Zhang, S. Zhao, T. Luo, X. Yin, H. Xu, W. Wang, Sci. China
Chem., 2012, 55, 43–49.
[37] A. R. Katritzky, H. Lang, X. Lan, Tetrahedron, 1993, 49, 2829-2838. [38] T. W. Brockmann, J. M. Tour, J. Am. Chem. Soc., 1995, 117, 4437–4447. [39] M. Abid, S. M. Landge, B. Torok, Org. Prep. Proc. Int., 2006, 38, 495-500.
