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Communication

An Efficient Synthesis of Arylated Pyridines from Conjugated Acetylenes and Substituted Benzylamines Catalyzed by Base

1
College of Chemistry and Bio-Engineering, Yichun University, Yichun 336000, Jiangxi, China
2
Engineering Center of Jiangxi University for Lithium Energy, Yichun University, Yichun 336000, Jiangxi, China
*
Author to whom correspondence should be addressed.
Molecules 2017, 22(8), 1277; https://doi.org/10.3390/molecules22081277
Submission received: 29 June 2017 / Revised: 20 July 2017 / Accepted: 29 July 2017 / Published: 31 July 2017

Abstract

:
An efficient base-catalyzed synthesis of arylated pyridines has been disclosed. This reaction involving conjugated acetylenes and substituted benzylamines proceeded smoothly, giving rise to tri-aryl substituted pyridines which are biologically relevant compounds in good to excellent yields in N,N-dimethylformamide (DMF) under air at 140 °C with K2CO3 as catalyst.

1. Introduction

The importance of pyridine motif comes from its unique biological activity in natural products [1,2,3], pharmaceutical compounds [4,5,6,7,8] and agrochemicals [9]. In addition, pyridine derivatives are widely applied in organometallic chemistry [10,11], catalysis [12], material science [13,14,15] and supramolecular chemistry [16,17,18]. Therefore, the more efficient synthesis of pyridine derivatives is still an important topic [19,20]. However, there are only very few examples reported on this topic: in 1974, Chalk [21] reported a new pyridine synthesis from conjugated acetylenes and substituted methylamines, leading to 51% of 2-p-tolyl-3,6-diphenylpyridine and 38% of 2-p-tolyl-3,6-diphenylpyridine N-oxide at 145 °C under nitrogen with dimethylsulfoxide as solvent. In 2013, Shaand coworkers [22] disclosed a facile synthetic method for the preparation of trisubstituted pyridines with high regioselectivity through a three-component assembly strategy of arynes, isocyanides, and 3-bromo- or 3-acetoxypropynes, leading to 65% of 2-(4-fluorophenyl)-3,6-diphenylpyridine. In recent years, transition-metal-catalyzed C-C cross-coupling reaction has been applied to a diverse array of fields. Peter [3] recently reported the site-selective arylation of commercially available 2,3,5,6-tetrachloropyridine using the Suzuki–Miyaura reaction, allowing the selective synthesis of mono-, di-, tri- and tetraarylated pyridines in good to quantitative yields. In this context, based on the advantages of conjugated acetylenes, which are readily prepared by the catalytic oxidative coupling of terminal alkynes [23], studying more efficient synthesis of pyridine derivatives between conjugated acetylenes and substituted methylamines is still highly desirable and challenging.

2. Resultsand Discussion

Our interest in increasing the synthetic yield of arylated pyridines from conjugated acetylenes and substituted benzylamines under optimum conditions stemmed from the fact that Chalk’s [24] work gave only a 70% yield of 2,3,6-triphenylpyridine fromsolutions of 1,4-diphenylbutadiyne in benzylamine (1:6.13 mmol) after two to three hours at 180 °C under nitrogen. Initially, we tested the reaction of 1,4-diphenylbutadiyne 1 (1 mmol) and benzylamine 2 (6 mmol) in DMSO at 140 °C in the presence of K2CO3 (0.5 mmol) under air. To our delight, 2,3,6-triphenylpyridine 3c was obtained in 85% isolated yield (Table 1, entry 3). Then, the effects of the ratio of starting materials 1:2 were examined (Table 1, entries 1–5). The yield of 3 improved to 96% with a 1:2 ratio of 1:8 or 1:10 (Table 1, entries 1–2). This result really encouraged us and extensive exploration of the conditions was further carried out. When the reaction temperature was dropped from 120 °C to 80 °C, 70% and 30% of the desired product 3 were obtained respectively (Table 1, entries 6–7). Subsequent solvent screening suggested that N,N-dimethylformamide (DMF) was the optimal one with 1,4-diphenylbutadiyne 1 (1 mmol) and benzylamine 2 (8 mmol) catalyzed by K2CO3 (0.5 mmol), and the desired product 3 was obtained in 99% isolated yield without any byproducts at 140 °C under air. It is worth noting that the reaction could proceed without a base, also as a catalyst, rendering the desired product in 38% isolated yield (Table 1, entry 11), which demonstrated that the yield of desired product 3 depends on the catalytic activity of the base. To demonstrate the catalytic value of a variety of bases, the synthetic reactions of 2,3,6-triphenylpyridine between 1,4-diphenylbutadiyne 1 (1 mmol) and benzylamine 2 (8 mmol) were carried out in DMF using different bases at 140 °C for 10 h with 0.5 mmol catalyst loading under air (Table 1, entries 12–20). The almost quantitative yield (99%) was obtained by using K2CO3 as the catalyst (Table 1, entry 8). Use of other bases, such as Na2CO3, NaOH, KOH and KHCO3 also gave good yields (Table 1, entries 13–15, 17). Under similar reaction conditions, Cs2CO3, NaF, NaH2PO4, KH2PO4 and CH3COONa afforded only moderate yield (Table 1, entries 12, 16, 18–20). These resultsindicate that K2CO3 is very effective in promoting the synthesis of arylated pyridines from conjugated acetylenes and substituted benzylamines under facile conditions.
Under the optimized reaction conditions, the scope of this synthetic protocol was evaluated to test the compatibility of varying symmetrical 1,4-diarylbuta-1,3-diynes as starting materials (Table 2). The 1,4-diarylbuta-1,3-diyne bearing two methyl groups at the 1- and 4-position was easily converted to give the desired products with excellent yield (90%) in the synthesis of arylated pyridines using benzylamine (3cbb). However, 1,4-bis(4-butylphenyl)buta-1,3-diyne was slightly less reactive, giving the desired product with 60% yield under the same conditions, and this result clearly demonstrated that steric hindrance has an effect on the yield of desired product (3cfb). The reaction using sterically hindered 1,4-di-o-tolylbuta-1,3-diyne and 1,4-di-m-tolylbuta-1,3-diyne led to 77% and 78% yields, respectively (3ccb, 3cdb).Investigations of substituted benzylamines in the synthesis of arylated pyridines using 1,4-diphenylbutadiyne were also conducted. The reaction with substituted benzylamine having an electron-donating group was carried out efficiently, affording almost quantitative yield (99%) (3cac).Various substituted benzylamines bearing electron-withdrawing groups, such as -F, -Cl, and -CF3, provided the corresponding products in moderate to good yields (3cad, 3cae, 3caf). The steric and electronic effects of the substrate bearing electron-withdrawing substituent in the 3-position of benzylamine remarkably affected the reaction yield: upon using [3-(trifluoromethyl)phenyl]methanamine, product 3,6-diphenyl-2-[3-(trifluoromethyl)phenyl]pyridine was obtained in 50% yield (3caf).

3. Materials and Methods

3.1. General Conditions

All manipulations were performed under air. All reagents employed in the synthesis were analytical grade, purchased from J&K Scientific Ltd. (Shanghai, China) and used as received without any prior purification. The products were isolated by thin layer chromatography on silica gel using petroleum ether as the eluent. 1H-NMR, 13C-NMR spectra were recorded on a Bruker Avance III (400 MHz, Bruker Corporation, Billerica, MA, USA) spectrometer using tetramethylsilane as the internal standard and CDCl3 as the solvent. Chemical shift values are expressed in ppm relative to external TMS (see Supplementary).

3.2. General Procedure for the Preparation of Arylated Pyridines

1,4-Disubstituted-1,3-diacetylene (0.25 mmol) and K2CO3 (0.5 mmol) were added, under air, to a solution of appropriate benzylamine (2.0 mmol) in DMSO (0.5 mL) previously heated at 140 °C. The resulting solution was stirred for 10 h at this temperature and washed with saturated aqNaCl, extracted with ethyl acetate (3 × 15 mL). The combined organic phase was dried with anhydrous Na2SO4, filtrated and concentrated under vacuum to yield the crude product. The crude product was purified by thin layer chromatography on silica gel with petroleum ether as eluent.

3.3. Analytical Data of Representative Products

2,3,6-Triphenylpyridine: White crystals (m.p. = 110–111 °C, lit [24] 110.5–112 °C, lit [25] 111–112 °C). 1H-NMR (400 MHz, CDCl3) δ 8.20 (d, 2H), 7.98–7.75 (m, 2H), 7.50 (dq, 5H), 7.30 (ddd, 8H).13C-NMR (101 MHz, CDCl3) δ 156.64, 155.68, 140.43, 140.01, 139.43, 139.10, 134.43, 130.23, 129.59, 129.01, 128.75, 128.37, 127.84, 127.18, 127.02, 118.59. lit [25]: 1H-NMR (400MHz, CDCl3) δ 8.16–8.14 (m, 2H), 7.78–7.77 (m, 2H), 7.51–7.42 (m, 5H), 7.30–7.21 (m, 9H); 13C-NMR (100 MHz, CDCl3) δ 156.6, 155.6, 140.4, 140.0, 139.4, 139.1, 134.4, 130.2, 129.5, 129.0, 128.7, 128.3, 127.8, 127.1, 127.0, 118.5. HRMS (EI) calcd. for C23H17N: 307.1361, found: 307.2.
2-(4-Fluorophenyl)-3,6-diphenylpyridine: White solid (m.p. = 115–117 °C, lit [22] 115–116 °C). 1H-NMR (400 MHz, CDCl3) δ 8.19 (d, 2H), 7.82 (d, 2H), 7.52 (dd, 5H), 7.32 (d, 3H), 7.27 (d, 2H), 7.01 (d, 2H). 13C-NMR (101 MHz, CDCl3) δ 162.53 (JC−F = 245.6 Hz), 155.73, 155.53, 139.81, 139.56, 138.95, 134.31 (JC−F = 4.3 Hz), 132.06, 131.97 (JC−F = 8.2 Hz), 129.55, 129.13, 128.82, 128.53, 127.34, 126.99, 118.70, 114.74(JC−F = 21.5 Hz). lit [22]: 1H-NMR (400 MHz, CDCl3): δ 8.13 (d, 2H), 7.77 (s, 2H), 7.51–7.42 (m, 5H), 7.31–7.29 (m, 3H), 7.22–7.20 (m, 2H), 6.94 (t, 2H); 13C-NMR (100 MHz, CDCl3): 162.5 (JC−F = 245.6 Hz), 155.7, 155.5, 139.8, 139.5, 138.9, 136.4 (JC−F = 4.3 Hz), 134.2, 131.9 (JC−F = 8.2 Hz), 129.5, 129.0, 128.7, 128.4, 127.2, 126.9, 118.6, 114.7 (JC−F = 21.5Hz). HRMS (EI) calcd. for C23H16FN: 325.1267, found: 325.2.

4. Conclusions

In summary, an efficient protocol for arylated pyridines from conjugated acetylenes and substituted benzylamines catalyzed by base was developed, which gives a much more convenient approach to obtain arylated pyridines with good to excellent yields. Compared to the approachreported by Chalk [21], the advantages of this protocol are inthe absence ofbyproduct detected by GC-MS even if the reaction was carried out in the air. Efforts to understand this reaction mechanism are in progress in our laboratory.

Supplementary Materials

Supplementary materials are available online.

Acknowledgments

This research was financially supported by the National Natural Science Foundation of China (No. 21363026), the Scientific and Technological Landing Project of Higher Education of Jiangxi Province (No. KJLD13091).

Author Contributions

M.G. and Q.Z. conceived and designed the experiments; B.C. performed the experiments; M.G., H.J., Q.P. and Y.K. analyzed the data and contributed with different analysis tools; finally, M.G. and B.C. wrote the paper.

Conflicts of Interest

The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds are available from the authors.
Table 1. Optimization of the reaction conditions a.
Table 1. Optimization of the reaction conditions a.
Molecules 22 01277 i001
EntryRatio of 1:2TemperatureSolventCatalystYield(%) b
11:10140 °CDMSOK2CO396
21:8140 °CDMSOK2CO396
31:6140 °CDMSOK2CO385
41:5140 °CDMSOK2CO380
51:4140 °CDMSOK2CO370
61:8120 °CDMSOK2CO370
71:880 °CDMSOK2CO330
81:8140 °CDMFK2CO399
91:8140 °CDMAcK2CO394
101:8140 °CPEG400K2CO350
111:8140 °CDMF_38
121:8140 °CDMFCs2CO365
131:8140 °CDMFNa2CO381
141:8140 °CDMFNaOH86
151:8140 °CDMFKOH88
161:8140 °CDMFNaF65
171:8140 °CDMFNaHCO387
181:8140 °CDMFNaH2PO453
191:8140 °CDMFKH2PO461
201:8140 °CDMFCH3COONa63
a The reactions were conducted with 1,4-diphenylbutadiyne and benzylamine, and base (0.5 mmol), solvent (0.5 mL), 10 h; b Isolated yield.
Table 2. Synthesis of arylated pyridines from conjugated acetylenes and substituted benzylamines under optimized conditions. a
Table 2. Synthesis of arylated pyridines from conjugated acetylenes and substituted benzylamines under optimized conditions. a
Molecules 22 01277 i044
EntryAcetyleneBenzylamineProductYield(%) b
1 Molecules 22 01277 i002 Molecules 22 01277 i003 Molecules 22 01277 i004
3cab
99
2 Molecules 22 01277 i005 Molecules 22 01277 i006 Molecules 22 01277 i007
3cac
99
3 Molecules 22 01277 i008 Molecules 22 01277 i030 Molecules 22 01277 i010
3cad
73
4 Molecules 22 01277 i011 Molecules 22 01277 i012 Molecules 22 01277 i013
3cae
62
5 Molecules 22 01277 i014 Molecules 22 01277 i015 Molecules 22 01277 i016
3caf
50
6 Molecules 22 01277 i017 Molecules 22 01277 i018 Molecules 22 01277 i019
3cbb
90
7 Molecules 22 01277 i020 Molecules 22 01277 i021 Molecules 22 01277 i022
3cbc
99
8 Molecules 22 01277 i023 Molecules 22 01277 i024 Molecules 22 01277 i025
3ccb
77
9 Molecules 22 01277 i026 Molecules 22 01277 i027 Molecules 22 01277 i028
3cdb
78
10 Molecules 22 01277 i026 Molecules 22 01277 i030 Molecules 22 01277 i031
3ccd
63
11 Molecules 22 01277 i032 Molecules 22 01277 i033 Molecules 22 01277 i034
3cec
65
12 Molecules 22 01277 i035 Molecules 22 01277 i036 Molecules 22 01277 i037
3ced
45
13 Molecules 22 01277 i038 Molecules 22 01277 i039 Molecules 22 01277 i040
3cee
48
14 Molecules 22 01277 i041 Molecules 22 01277 i042 Molecules 22 01277 i043
3cfb
60
a Reaction conditions: conjugated acetylene (1a) (0.25 mmol), substituted benzylamine (2b) (2.0 mmol), K2CO3 (0.5 mmol), DMF (0.5 mL), 140 °C, 10 h; b Isolated yield.

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MDPI and ACS Style

Guo, M.; Chen, B.; Zhu, Q.; Jin, H.; Peng, Q.; Kang, Y. An Efficient Synthesis of Arylated Pyridines from Conjugated Acetylenes and Substituted Benzylamines Catalyzed by Base. Molecules 2017, 22, 1277. https://doi.org/10.3390/molecules22081277

AMA Style

Guo M, Chen B, Zhu Q, Jin H, Peng Q, Kang Y. An Efficient Synthesis of Arylated Pyridines from Conjugated Acetylenes and Substituted Benzylamines Catalyzed by Base. Molecules. 2017; 22(8):1277. https://doi.org/10.3390/molecules22081277

Chicago/Turabian Style

Guo, Mengping, Bo Chen, Qiming Zhu, Hua Jin, Qiuling Peng, and Yanping Kang. 2017. "An Efficient Synthesis of Arylated Pyridines from Conjugated Acetylenes and Substituted Benzylamines Catalyzed by Base" Molecules 22, no. 8: 1277. https://doi.org/10.3390/molecules22081277

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