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Joint use of microwave and glycerol-zinc (II) acetate catalytic system in the synthesis of 2-pyridyl-2-oxazolines

  • Rafaela C. Carmona

    Rafaela C. Carmona was born in 1988 in Buritama, Brazil. She graduated from the Federal University of São Carlos (UFSCar) with a bachelor degree in chemistry in 2010. From 2008 to 2010, she worked at Department of Chemistry of UFSCar as undergraduate researcher under the supervision of Professor Dr. Arlene A. Correa, on organic synthesis of bioactive alkaloids and natural products. In 2011, she joined the group of Professor Alcindo A. Dos Santos, at the University of São Paulo, as a MSc and her project is directed to asymmetric strategies on A3 multicomponent reactions.

         , Evelyn P. Schevciw

    Evelyn Pucci Schevciw was born in 1985 in São Paulo, Brazil. She graduated from the University of São Paulo with a bachelor’s degree in chemistry in 2007. She worked in an industry for a few years before returning to the same university, where she is currently working under the supervision of Professor Dr. Alcindo A. Dos Santos as a MSc. Her main research interest is focused on A3 multicomponent reactions and their applications in the synthesis of bioactive alkaloids.

         , João L. Petrarca de Albuquerque

    João L. Petrarca de Albuquerque was born in 1993 (São Paulo, Brazil). He started his undergraduate studies in 2010 in the Department of Chemistry of University of São Paulo and since August 2012, he has been working under the supervision of Professor Dr. Alcindo A. Dos Santos on the synthesis of natural bioactive alkaloids.

         , Edison P. Wendler

    Edison P. Wendler was born in 1980 (Curitiba, Brazil). From 1999 to 2004, he studied Chemistry at Federal University of Paraná (UFPR) where he obtained his BSc degree (2004) and MSc degree (2006). In 2010, he received his PhD in Organic Chemistry at Federal University of São Carlos (UFSCar), under the supervision of Professor Alcindo A. Dos Santos. From 2010 to 2012, he carried out postdoctoral studies, as a FAPESP Post-Doctoral Fellow, in the University of São Paulo (USP) under the guidance of Professor Dr. João V. Comasseto and at University of Santiago de Compostela (USC/Spain) under the supervision of Professor Dr. Ricardo Riguera Vega.

         and Alcindo A. Dos Santos

    Alcindo A. Dos Santos was born in 1971 in Siqueira Campos, Brazil. From 1993 to 1998, he studied chemistry at the Federal University of Paraná. In 1998, he started his master thesis, working under the supervision of Professor Dr. Alfredo R. M. de Oliveira, moving directly on to his PhD thesis in 2000. He spent about a year and a half working on insect pheromone synthesis under the supervision of Professor Wittko Francke at Hamburg University, Germany. After he obtained his PhD in 2003, he worked under the guidance of Professor João V. Comasseto at the University of São Paulo, Brazil, as a FAPESP postdoctoral fellow (2003–2006). Professor Dr. Dos Santos was appointed Adjunct Professor of Chemistry at the Federal University of São Carlos in 2006. In 2009, he accepted a position as Professor at the University of São Paulo. His research interest is focused on the synthesis of natural bioactive compounds based on multicomponent strategies, organocatalysis and supramolecular chemistry.

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Green Processing and Synthesis
From the journal Green Processing and Synthesis Volume 2 Issue 1

Abstract

Glycerol combined with zinc (II) acetate catalyzed the reaction of 2-amino alcohols and 2-cyanopyridines under microwave irradiation, resulting in 2-pyridyl-2-oxazolines. Comparing the conversion to that obtained by conventional heating, a significant decrease in the reaction time was achieved. At the end of the reaction, the product was isolated and the glycerol-zinc (II) acetate catalytic system was recycled four times for the same transformation in reasonable to acceptable yields. The products were obtained in their pure form by simple filtration in a short pad of silica.

Keywords: 2-pyridyl-2-oxazoline; glycerol-zinc (II) acetate catalyst; microwave irradiation

1 Introduction

The 2-oxazoline unit is present in a variety of biologically active compounds [1] and has received attention because of its applications in organic synthesis as a protecting group [2], a polymerization precursor [3–7] and particularly, as a catalyst for many transformations, including chirality induction/transference [8–13]. 2-Pyridyl-2-oxazolines are interesting ligands for metal complex precursors, which makes them good candidates for metal-catalyzed transformations. A myriad of well-established procedures for the preparation of optically active 2-oxazolines is known, however, many of the procedures are unappealing with regards to energy expenditure and reaction times [2, 14–21]. In 2009, Kempe and co-workers reported a clean zinc (II) acetate-catalyzed synthesis of 2-oxazolines from nitriles and 2-aminoethanol by conventional heating (130°C), using chlorobenzene as the solvent [22]. Although several nitriles were submitted to a reaction with 2-aminoethanol in the presence of various catalysts, only a few examples resulted in the product of interest. In addition, some cases required long reaction times to achieve the desired product in reasonable yields for preparative purposes. Recently, procedures involving the preparation of 2-oxazolines under microwave irradiation have been reported [23, 24].

Recently, glycerol is being produced in large quantities as a byproduct of the biodiesel industry, and traditional consumption of this commodity is not sufficient to uptake its surplus. Glycerol can be considered a green solvent, being found in many living organisms as triglycerides [25–34]. Because of the above-mentioned reasons, attention has been directed to new applications for glycerol, one of the most promising of which is its use as a green solvent. Considering that the transformation industry is deeply dependent on organic solvents, those based on renewable sources are the most attractive so far.

In this work we present our results concerning the association of glycerol and zinc (II) acetate as a renewable green reaction media for the preparation of 2-oxazolines under microwave irradiation in good yields and with short reaction times.

2 Experimental section

2.1 General information

Microwave reactions were performed with a CEM Discover Synthesis Unit (CEM Corp., Matthews, NC, USA), with a continuous focused microwave power delivery system in a glass vessel (10 ml) sealed with a septum pierced by a needle (for the ammonia realizing), under magnetic stirring.

Nuclear magnetic resonance (NMR) spectra were recorded on a BRUKER AC 200 spectrometer operating at 200 MHz and 50 MHz for 1H NMR and 13C NMR, respectively (Bruker BioSpin GmbH, Rheinstetten, Baden-Württemberg, Germany). CDCl3 was used as the solvent and as internal references, tetramethylsilane (TMS) for 1H NMR and CDCl3, for 13C NMR, chemical shifts (δ) are given in parts per million and coupling constants (J) in hertz.

Gas chromatography analyses were performed on Shimadzu GC2014 devices (Shimadzu Corp., Nakagyo-ku, Kyoto, Japan), using a flame ionization detector (FID), N2 as carrier gas and equipped with a DB-5-HT (5% – phenyl-methylpolysiloxane) column with dimensions 30 m×0.32 mm×0.10 μm (Agilent Technologies, Inc., Santa Clara, CA, USA).

High performance liquid chromatography (HPLC) analyses were performed on a Shimadzu LC-30AD device equipped with a UV-Vis SPD-M20A detector, using a Chiralpak AD-H (Chiral Technologies Europe, Illkirch Graffenstaden, Bas Rhin, France) column with dimensions 4.6 mm×250 mm and hexane:isopropanol (9:1) as a mobile phase, with 1.0 ml/min flow.

Optical rotation analyses were performed on a Perkin-Elmer 241 polarimeter (PerkinElmer, Inc., Waltham, MA, USA) with a D ray sodium lamp.

All reagents are commercial grade and were pretreated before use, when needed (All reagents were purchased from Sigma-Aldrich Corporation, St. Louis, MO, USA).

2.2 Microwave-promoted synthesis of 2-pyridyl-2-oxazolines

2.2.1 General procedure

Appropriate amino alcohol (2 mmol), 2-cyanopyridine (1, 0.104 g, 0.096 ml, 1 mmol), zinc acetate dihydrate (0.004 g, 0.02 mmol, 2 mol%) and glycerol (1 ml) were mixed into a glass vessel sealed with a septum pierced by a needle. This reaction vessel was placed into the microwave reactor and heated at 110°C for 17 min under stirring. After cooling to room temperature, the product was extracted from the reaction mixture by washing with ethyl acetate (5×2 ml). The ethyl acetate phases were combined and washed with water (2×5 ml), then dried with Na2SO4. After filtration, the solvent was removed under reduced pressure. The crude product was filtered though a plug of silica gel, and the filter cake was washed with ethyl acetate (5×2 ml). After evaporation of the solvent, pure 2-pyridyl-2-oxazolines were obtained.

4,4-dimethyl-2-(pyridin-2-yl)-2-oxazoline (3)

CAS 109660-12-0

86% yield.

NMR 1H (400 MHz, CDCl3): δ 1.42 (s, 6H), 4.21 (s, 2H), 7.39 (ddd J1=7.7 Hz, J2=4.8 Hz, J3=1.2 Hz, 1H), 7.77 (td, J1=7.7 Hz, J2=1.8 Hz, 1H), 8.03 (dt, J1=7.7 Hz, J2=1.1 Hz, 1H), 8.71 (ddd, J1=4.8 Hz, J2=1.8 Hz, J3=1.0 Hz, 1H).

NMR 13C (100 MHz, CDCl3): δ 28.3, 67.7, 79.5, 123.7, 125.3, 136.4, 146.9, 149.6, 161.1.

4,4-dimethyl-2-(pyridin-2-ylmethyl)-2-oxazoline (5) CAS 194096-82-7

63% yield.

NMR 1H (200 MHz, CDCl3): δ 1.30 (s, 6H), 3.82 (s, 2H), 3.95 (s, 2H), 7.19 (dddd, J1=7.7 Hz, J2=4.9 Hz, J3=1.0, J4=0.5 Hz, 1H), 7.29–7.35 (m, 1H), 7.66 (td, J1=7.7 Hz, J2=1.9 Hz, 1H), 8.56 (ddd, J1=4.9 Hz, J2=1.9 Hz, J3=1.0 Hz, 1H).

NMR 13C (50 MHz, CDCl3): δ 28.3 (2C), 37.6, 67.1, 79.3, 122.0, 123.0, 136.7, 149.4, 163.3.

(S)-4-isobutyl-2-(pyridin-2-yl)-2-oxazoline (6) CAS 108915-07-7

78% yield.

NMR 1H (400 MHz, CDCl3): δ 0.97 (d, J1=6.6 Hz, 3H), 0.99 (d, J1=6.6 Hz, 3H), 1.41(dt, J1=13.4 Hz, J2=7.3 Hz, 1H), 1.76 (dt, J1=13.4 Hz, J2=6.9 Hz, 1H), 1.88 (non, J1=6.7 Hz, 1H), 4.07 (t, J1=8.2 Hz, 1H), 4.35–4.45 (m, 1H), 4.60 (dd, J1=9.5 Hz, J2=8.1 Hz, 1H), 7.38 (ddd, J1=7.6 Hz, J2=4.8 Hz, J3=1.2 Hz, 1H), 7.77 (td, J1=7.8 Hz, J2=1.8 Hz, 1H), 8.04 (dt, J1=7.9 Hz, J1=1.1 Hz, 1H), 8.71 (ddd, J1=4.8 Hz, J2=1.8 Hz, J3=0.9 Hz, 1H).

NMR 13C (100 MHz, CDCl3): δ 22.6 (2C), 25.2, 45.3, 65.2, 73.5, 123.7, 125.2, 136.4, 146.7, 149.5, 162.2.

(S)-4-(2-(methylthio)ethyl)-2-(pyridin-2-yl)-2-oxazoline (7)

CAS 108915-09-9

51% yield.

NMR 1H (400 MHz, CDCl3): δ 1.83–1.97 (m, 1H), 1.99–2.11 (m, 1H), 2.14 (s, 3H), 2.70 (ddd, J1=15.0 Hz, J2=8.3 Hz, J3=6.6 Hz, 1H), 2.73 (ddd, J1=15.0 Hz, J2=8.5 Hz, J3=6.1 Hz, 1H), 4.14 (t, J1=8.2 Hz, 1H), 4.44–4.55 (m, 1H), 4.63 (dd, J1=9.6 Hz, J2=8.3 Hz, 1H), 7.40 (ddd, J1=7.7 Hz, J2=4.8 Hz, J3=1.2 Hz, 1H), 7.87 (td, J1=7.8 Hz, J2=1.8 Hz, 1H), 8.03 (d, J1=7.8 Hz, 1H), 8.72 (ddd, J1=4.8 Hz, J2=1.7 Hz, J3=0.7 Hz, 1H).

NMR 13C (100 MHz, CDCl3): δ 15.5, 30.7, 35.2, 66.0, 72.9, 123.8, 125.5, 136.6, 146.6, 149.7, 162.8.

(S)-4-phenyl-2-(pyridin-2-yl)-2-oxazoline (8)

CAS 153880-57-0

60% yield.

[α]25D = −34° (C=2.045; toluene)

NMR 1H (200 MHz, DMS): δ 4.40 (t, J=8.6 Hz, 1H), 4.91 (dd, J1=10.3 Hz, J2=8.6 Hz, 1H), 5.47 (dd, J1=10.3 Hz, J2=8.6 Hz, 1H), 7.55–7.28 (m, 6H), 7.82 (ddd, J1=7.7 Hz, J2=1.8 Hz, J3=0.9 Hz, 1H), 8.18 (dt, J1=7.7 Hz, J2=1.1 Hz, 1H), 8.75 (ddd, J1=4.8 Hz, J2=1.8 Hz, J3=0.9 Hz, 1H).

NMR 13C (50 MHz, DMSO): δ 70.3, 75.3, 124.2, 125.8, 126.8 (2C), 127.7, 128.8 (2C), 136.7, 141.8, 149.8.

(S)-4-benzyl-2-(pyridin-2-yl)-2-oxazoline (9):

CAS 108915-08-8

89% yield.

[α]25D=−52° (C=0.538; toluene)

NMR 1H (400 MHz, CDCl3): δ 2.77 (dd, J1=13.8 Hz, J2=9.0 Hz, 1H), 3.30 (dd, J1=13.8 Hz, J2=5.1 Hz, 1H), 4.23 (dd, J1=8.6 Hz, J2=7.7 Hz, 1H), 4.44 (dd, J1=9.4 Hz, J2=8.6 Hz, 1H), 4.66 (dddd, J1=9.4 Hz, J2=9.0 Hz, J3=7.7 Hz, J4=5.1 Hz, 1H), 7.20–7.33 (m, 5H), 7.39 (ddd, J1=7.6 Hz, J2=4.8 Hz, J3=1.2 Hz, 1H), 7.77 (ddd, J1=7.8 Hz, J2=7.7 Hz, J3=1.7 Hz, 1H), 8.06 (ddd, J1=7.8 Hz, J2=1.2 Hz, J3=0.9 Hz, 1H), 8.70 (ddd, J1=4.7 Hz, J2=1.7 Hz, J3=0.9 Hz, 1H).

NMR 13C (100 MHz, CDCl3): δ 41.5, 68.0, 72.3, 123.8, 125.4, 126.4, 128.4 (2C), 129.1 (2C), 136.5, 137.6, 146.6, 149.6, 163.0.

(R)-4-methyl-2-(pyridin-2-yl)-2-oxazoline (10)

CAS 242482-41-3

77% yield.

NMR 1H (200 MHz, CDCl3): δ 1.40 (d, J1=6.5 Hz, 3H), 4.05 (t, J1=7.77 Hz, 1H), 4.28–4.77 (m, 2H), 7.39 (ddd, J1=7.6 Hz, J2=4.8 Hz, J3=1.3 Hz, 1H), 7.78 (td, J1=7.8 Hz, J2=1.8 Hz, 1H), 7.96 (m, 1H), 8.71 (ddd, J1=4.9 Hz, J2=1.8 Hz, J3=1.0 Hz 1H).

NMR 13C (50 MHz, CDCl3): δ 21.1, 62.0, 74.4, 123.6, 125.3, 136.4, 146.5, 149.5, 162.4.

(S)-4-isopropyl-2-(pyridin-2-yl)-2-oxazoline (11)

CAS 108915-04-4

88% yield.

[α]25D=−98° (C=0.506; toluene)

NMR 1H (400 MHz, CDCl3): δ 0.95 (d, J1=6.8 Hz, 3H), 1.06 (d, J1=6.8 Hz, 3H), 1.90 (oct, J1=6.8 Hz, 1H), 4.18 (dd, J1=16.0 Hz, J2=8.3 Hz, J3=6.3 Hz, 1H), 4.21 (dd, J1=16.0 Hz, J2=8.3 Hz, 1H), 4.51 (dd, J1=9.0 Hz, J2=7.6 Hz, 1H), 7.38 (ddd, J1=7.6 Hz, J2=4.8 Hz, J3=1.2 Hz, 1H), 7.77 (ddd, J1=7.8 Hz, J2=7.7 Hz, J3=1.7 Hz, 1H), 8.05 (ddd, J1=7.8, J2=1.2 Hz, J1=0.9 Hz, 1H), 8.71 (ddd, J1=4.8 Hz, J2=1.7 Hz, J3=0.9 Hz, 1H).

NMR 13C (100 MHz, CDCl3): δ 18.0, 18.9, 32.6, 70.6, 72.8, 123.7, 125.2, 136.4, 146.8, 149.5, 162.4.

(S)-4-((R)-sec-butyl)-2-(pyridin-2-yl)-2-oxazoline (12)

CAS 108915-03-3

92% yield.

[α]25D=−75° (C=2.011; toluene)

NMR 1H (400 MHz, CDCl3): δ 0.89 (d, J1=6.7 Hz, 3H), 0.96 (t, J1=7.4 Hz, 3H), 1.12–1.37 (m, 1H), 1.57–1.88 (m, 2H), 4.22 (dd, J1=8.4 Hz, J2=7.7 Hz, 1H), 4,30 (ddd, J1=9,3 Hz, J2=8,4 Hz, J3=5,7 Hz, 1H), 4.50 (dd, J1=9.3 Hz, J2=7.8 Hz, 1H), 7.39 (ddd, J1=7.6 Hz, J2=4.8 Hz, J3=1.2 Hz, 1H), 7.77 (ddd, J1=9.6 Hz, J1=7.8 Hz, J2=1.8 Hz, 1H), 8.06 (dt, J1=7.9 Hz, J2=1.0 Hz, 1H), 8.71 (ddd, J1=4.8 Hz, J2=1.8 Hz, J3=1.0 Hz, 1H).

NMR 13C (100 MHz, CDCl3): δ 11.4, 14.3, 26.1, 39.0, 70.2, 71.4, 123.8, 125.3, 136.5, 146.8, 149.6, 162.4.

2-(5-bromopyridin-2-yl)-4,4-dimethyl-2-oxazoline (13) 51% yield.

NMR 1H (200 MHz, CDCl3): δ 1.41 (s, 6H), 4.21 (s, 2H), 7.91 (d, J1=1.5 Hz, 2H), 8.76 (t, J1=1.5 Hz, 1H).

NMR 13C (50 MHz, CDCl3): δ 28.3, 68.2, 79.8, 123.1, 124.9, 139.3, 145.3, 150.9.

IR (KBr): ν 3431, 3034, 2957, 2417, 2366, 2341, 1760, 1699, 1648, 1561, 1388, 1088, 991, 909, 879, 838, 680, 629.

MS (IES+): calc for C10H11BrN2O [M+H] 255.0133, found 255.0130.

MP (°C): 96.5–98.9.

(S)-2-(5-ethynylpyridin-2-yl)-4-phenyl-2-oxazoline (14)

61% yield.

[α]25D=−38° (C=1.125; chloroform)

NMR 1H (200 MHz, CDCl3): δ 3.36 (s, 1H), 4.40 (t, J1=8.6 Hz, 1H), 4.91(dd, J1=10.3 Hz, J2=8.6 Hz, 1H), 5.48 (dd, J1=10.3 Hz, J2=8.6 Hz, 1H), 7.29–7.41 (m, 5H), 7.88 (dd, J1=8.2 Hz, J2=2.0 Hz, 1H), 8.14 (dd, J1=8.2 Hz, J2=0.8 Hz, 1H), 8.82 (dd, J1=2.0 Hz, J2=0.8 Hz, 1H).

NMR 13C (50 MHz, CDCl3): δ 70.4, 75.4, 79.9, 82.9, 121.4, 123.5, 126.7 (2C), 127.8, 128.8 (2C), 139.7, 141.5, 145.6, 152.6, 163.2.

IR (KBr): ν 3391, 2924, 2855, 2367, 2333, 1652, 1514, 1384, 1068, 1026, 827, 751, 696.

MS (IES+): calc for C16H12N2O [M+H] 249.1028, found 249.1026.

MP (°C): 136.6–139.1.

2-((1H-indol-3-yl)methyl)-4-(pyridin-2-yl)-2-oxazoline (15)

61% yield.

[α]25D=+9° (C=0.320; chloroform)

NMR 1H (200 MHz, CDCl3): δ 2.92 (dd, J1=14.5 Hz, J2=9.1 Hz, 1H), 3.44 (ddd, J1=14.5 Hz, J2=4.7 Hz, J3=1.0 Hz 1H), 4.27 (dd, J1=8.6 Hz, J2=7.7 Hz, 1H), 4.45 (t, J1=9.1 Hz, 1H), 4.80 (tdd, J1=9.2 Hz, J2=7.6 Hz, J3=4.7 Hz 1H), 7.01–7.25 (m, 3H), 7.30–7.56 (m, 2H), 7.60–7.73 (m, 1H), 7.79 (td, J1=7.7 Hz, J2=1.8 Hz, 1H), 8.01–8.14 (m, 1H), 8.72 (ddd, J1=4.7 Hz, J2=1.8 Hz, J3=1.0 Hz 1H).

NMR 13C (50 MHz, CDCl3): δ 31.3, 67.2, 72.9, 111.2, 111.6, 118.7, 119.3, 122.0, 122.4, 123.9, 125.5, 127.5, 136.2, 146.7, 149.6, 163.0.

IR (KBr): ν 3201, 3184, 3105, 3043, 2983, 2900, 2883, 1647, 1384, 1361, 1323, 1274, 1249, 1101, 1085, 1037, 966, 744, 725.

MS (IES+): calc for C16H12N2O [M+H] 278.1293, found 278.1293.

MP (°C): 170.1–171.6.

4,4-dimethyl-2-phenyl-2-oxazoline (16)

CAS 19312-06-2

30% yield.

NMR 1H (200 MHz, CDCl3): δ 1.38 (s, 6H), 4.11 (s, 2H), 7.35–7.51 (m, 3H), 7.91–7.98 (m, 2H).

NMR 13C (50 MHz, CDCl3): δ 28.4 (2C), 67.5, 79.1, 128.0, 128.1 (2C), 128.2 (2C), 131.1, 162.0.

3 Results and discussion

In the course of exploring some enantioselective transformations based on chiral metal complexes, appealing and more environmentally friendly preparation procedures of 2-pyridyl-2-oxazolines were of interest in our research group. Herein, we report the associative utilization of glycerol and zinc (II) acetate as a catalyst system for the preparation of 2-pyridyl-2-oxazolines from 2-cyanopyridines and amino alcohols, under microwave irradiation. Glycerol was chosen as a solvent, because of its green aspects and also based on the premise that the product could be extracted from the reaction medium by washing with a glycerol-immiscible organic solvent. To test the feasibility of our proposition, 2-cyanopyridine (1) and 2-amino-2-methylpropanol (2, 2 eq) were subjected to a reaction in the presence of zinc (II) acetate (2 mol%) in glycerol, under conventional heating (Figure 1). Initial studies focused on the optimal temperature needed for maximum conversion into the corresponding 2-oxazoline (Table 1).

Figure 1 Oxazoline synthesis using glycerol as solvent.
Figure 1

Oxazoline synthesis using glycerol as solvent.

Table 1

2-Pyridyl-2-oxazoline synthesis under conventional heating.

EntryT (°C)t (h)Yield (%)1,2
170203lc4
29053lc4
3110288

Reactions were conducted using 1 mmol of the 2-cyanopyridine, 2 mmol of amino alcohol and 2 mol% of Zn(AcO)2 in 1 ml of glycerol.

1Analyzed by GC.

2Isolated yield.

3Starting material was not totally consumed.

4Low conversions were observed.

Even after prolonged reaction times at 70°C or 90°C, low conversions were observed. On the other hand, at 110°C, the desired oxazoline was obtained in 88% yield within 2 h. On searching for a more efficient process and tapping into the microwave irradiation absorption properties of glycerol [35], we focused our attention in the application of this energy source.

A reaction time screening for the total conversion of 2-cyanopyridine (1) into the corresponding oxazoline, was carried out at 110°C and it was observed that within 17 min, total consumption of the starting material was achieved, leading to the oxazoline (3) in 86% isolated yield, as shown in Table 2.

Table 2

Microwave screening for the oxazoline synthesis.

Entryt (min)SM:P1Yield (%)2
1273:27nd
2536:64nd
31019:81nd
4122:98nd
5151:99nd
6170:10086
720Byproducts3nd

Reactions were conducted using 1 mmol of the 2-cyanopyridine, 2 mmol of amino alcohol and 2 mol% of Zn(AcO)2 in 1 ml of glycerol at 110ºC.

nd, not determined; P, product (3, 2-oxazoline); SM, starting material (1, 2-cyanopyridine).

1Analyzed by GC.

2Isolated yield.

3Unidentified byproducts.

As can be observed, a progressively higher conversion was achieved as a function of time. Reaction times longer than 17 min resulted in the formation of unidentified byproducts (entry 7).

It is worth mentioning that the reaction was accompanied by color changes, resulting in a deep greenish-blue solution after 17 min of microwave irradiation (Figure 2). We have no explanation for this color change, since zinc glycerolate, which can be generated in situ, as well as ammonium acetate (another possible byproduct), are both white solids and their solutions are colorless [36].

Figure 2 Color changes of the reaction media through time under microwave irradiation.
Figure 2

Color changes of the reaction media through time under microwave irradiation.

As was initially hypothesized, after completion of the reaction, removal of the product from the reaction media can be easily accomplished by extraction with ethyl acetate (immiscible in glycerol), leading to the nearly pure product after solvent evaporation. Following this procedure, a purification consisting of a simple filtration through a short pad of silica was necessary for preparative purposes. According to this result, we proposed that the glycerol-zinc (II) acetate catalytic system could be recycled for new reactions. Thus, after extraction of oxazoline (3) produced in the first cycle, stoichiometric amounts of (1) and (2) were added to the reaction media and submitted to another cycle of reaction in both conditions of conventional heating and microwave irradiation. The results are shown in the bar graphic in Figure 3.

Figure 3 Recycling of the reaction media for new reactions.
Figure 3

Recycling of the reaction media for new reactions.

Five cycles were conducted by sequential reaction/extraction procedures and a decrease in yield was observed for the two new cycles, with virtually the same results for conventional heating and microwave irradiation. Interestingly, under microwave irradiation, product (3) was isolated in almost the same yield from reactions of the 4th as well as the 5th cycles. By contrast, by conventional heating, the product yield was substantially diminished in the 4th cycle, and in the 5th cycle, no product was isolated under the same reaction conditions. Despite appreciable yield reduction after the 3rd cycle, it was demonstrated that the reaction media could be reused.

2-Pyridylacetonitrile (4) was also submitted to reaction with amino alcohol (2) under several reaction conditions. No reaction was observed following the conditions reported by Kempe et al. [22], using chlorobenzene and zinc (II) acetate, or when testing different solvent-catalyst systems. However, using our reaction conditions, the expected oxazoline (5) was produced in 63% isolated yield after 40 min irradiation at 150°C (Figure 4). As presented in Table 3, progressively higher conversions were observed through time (GC analysis), but only at a higher temperature (150°C) was a nearly quantitative conversion achieved (entry 5), leading to the corresponding 2-oxazoline in 63% isolated yield.

Figure 4 Oxazoline synthesis with 2-pyridylacetonitrile.
Figure 4

Oxazoline synthesis with 2-pyridylacetonitrile.

Table 3

Microwave screening for the reaction of 2-pyridylacetonitrile (4) with amino alcohol (2).

EntryT (°C)t (min)SM:P1Yield (%)
11101772:28nd
21103451:49nd
31105149:51nd
41403026:74nd
5150401:99632

Reactions were conducted using 1 mmol of the 2-pyridylacetonitrile, 2 mmol of amino alcohol and 2 mol% of Zn(AcO)2 in 1 ml of glycerol.

nd, not determined; P, product (5, 2-oxazoline); SM, starting material (4, 2-pyridylacetonitrile).

1Analyzed by GC.

2Isolated yield.

In order to verify the scope and limitations of the protocol, other amino alcohols were submitted to a reaction with 2-cyanopyridine (1) under microwave irradiation.

In Table 4, the structure and isolated yields of the reaction of 2-cyanopyridine or benzonitrile and other amino alcohols are presented.

Table 4

2-Pyridyl-2-oxazolines synthesized under microwave irradiation.

Table 4 2-Pyridyl-2-oxazolines synthesized under microwave irradiation.

Reactions were conducted using 1 mmol of the 2-cyanopyridine, 2 mmol of amino alcohol and 2 mol% of Zn(AcO)2 in 1 ml of glycerol at 110°C.

1Isolated yield.

2Non-optimized conditions. It was not possible to obtain this oxazoline using the procedure reported in reference 22.

With the exception of 2-oxazoline (16) (entry 12), all other products were obtained in good to excellent yields, which suggests that benzonitrile is less reactive than the other nitriles used.

As enantiopure amino alcohols were used, the optical purity of the corresponding oxazolines was determined by chiral liquid chromatography. An artificially enantioenriched mixture of (R)- and (S)-2-oxazoline (8) was prepared by mixing enantiopure (R)- and (S)-phenylglycinol and reacting this mixture with the corresponding nitrile. This oxazoline was chosen because the stereogenic center is a benzylic carbon, thus if some epimerization could occur during the synthesis, an enantiomeric mixture of oxazoline (8) would be produced. The artificial enantiomeric mixture and the enantiopure oxazolines were analyzed by chiral HPLC, confirming that no epimerization occurred during the reaction. The optical rotation of other oxazolines was measured and the results are in agreement with literature reported values [37].

In conclusion, we have developed a fast and green reaction procedure to prepare 2-pyridyl-2-oxazolines under microwave irradiation. Use of the glycerol-zinc (II) acetate system has proven to be very practical, considering that at the end of the reaction, the desired product can be easily extracted from the reaction media by washing with ethyl acetate, allowing reuse of the reaction media. Modest to good yields were achieved by recycling the solvent-catalyst system. As a rule, product purification required solely filtration in a short silica pad-column. No exogenous byproducts were observed under the optimal reaction conditions.

Corresponding author: Alcindo A. Dos Santos, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Cx. P. 26077, CEP 05508–000 São Paulo, Brazil

About the authors

Rafaela C. Carmona

Rafaela C. Carmona was born in 1988 in Buritama, Brazil. She graduated from the Federal University of São Carlos (UFSCar) with a bachelor degree in chemistry in 2010. From 2008 to 2010, she worked at Department of Chemistry of UFSCar as undergraduate researcher under the supervision of Professor Dr. Arlene A. Correa, on organic synthesis of bioactive alkaloids and natural products. In 2011, she joined the group of Professor Alcindo A. Dos Santos, at the University of São Paulo, as a MSc and her project is directed to asymmetric strategies on A3 multicomponent reactions.

Evelyn P. Schevciw

Evelyn Pucci Schevciw was born in 1985 in São Paulo, Brazil. She graduated from the University of São Paulo with a bachelor’s degree in chemistry in 2007. She worked in an industry for a few years before returning to the same university, where she is currently working under the supervision of Professor Dr. Alcindo A. Dos Santos as a MSc. Her main research interest is focused on A3 multicomponent reactions and their applications in the synthesis of bioactive alkaloids.

João L. Petrarca de Albuquerque

João L. Petrarca de Albuquerque was born in 1993 (São Paulo, Brazil). He started his undergraduate studies in 2010 in the Department of Chemistry of University of São Paulo and since August 2012, he has been working under the supervision of Professor Dr. Alcindo A. Dos Santos on the synthesis of natural bioactive alkaloids.

Edison P. Wendler

Edison P. Wendler was born in 1980 (Curitiba, Brazil). From 1999 to 2004, he studied Chemistry at Federal University of Paraná (UFPR) where he obtained his BSc degree (2004) and MSc degree (2006). In 2010, he received his PhD in Organic Chemistry at Federal University of São Carlos (UFSCar), under the supervision of Professor Alcindo A. Dos Santos. From 2010 to 2012, he carried out postdoctoral studies, as a FAPESP Post-Doctoral Fellow, in the University of São Paulo (USP) under the guidance of Professor Dr. João V. Comasseto and at University of Santiago de Compostela (USC/Spain) under the supervision of Professor Dr. Ricardo Riguera Vega.

Alcindo A. Dos Santos

Alcindo A. Dos Santos was born in 1971 in Siqueira Campos, Brazil. From 1993 to 1998, he studied chemistry at the Federal University of Paraná. In 1998, he started his master thesis, working under the supervision of Professor Dr. Alfredo R. M. de Oliveira, moving directly on to his PhD thesis in 2000. He spent about a year and a half working on insect pheromone synthesis under the supervision of Professor Wittko Francke at Hamburg University, Germany. After he obtained his PhD in 2003, he worked under the guidance of Professor João V. Comasseto at the University of São Paulo, Brazil, as a FAPESP postdoctoral fellow (2003–2006). Professor Dr. Dos Santos was appointed Adjunct Professor of Chemistry at the Federal University of São Carlos in 2006. In 2009, he accepted a position as Professor at the University of São Paulo. His research interest is focused on the synthesis of natural bioactive compounds based on multicomponent strategies, organocatalysis and supramolecular chemistry.

The authors thank FAPESP (2005/59572–7, 2008/55401–1, 2010/17228–6, 2011/03244–2, 2011/11613–8 and 2012/17093–9), CNPq and CAPES for financial support and scholarships. The authors are also grateful for the financial and structural support offered by University of São Paulo through the NAP-CatSinQ (Research Core in Catalysis and Chemical Synthesis).

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Received: 2012-11-15
Accepted: 2012-12-20
Published Online: 2013-02-02
Published in Print: 2013-02-01

©2013 by Walter de Gruyter Berlin Boston

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https://doi.org/10.1515/gps-2012-0085
Keywords for this article
2-pyridyl-2-oxazoline; glycerol-zinc (II) acetate catalyst; microwave irradiation

Articles in the same Issue

  1. Masthead
  2. Masthead
  3. Graphical abstracts
  4. In this Issue
  5. Publisher’s note
  6. Green Processing and Synthesis
  7. Editorial
  8. Scattering of disciplines towards new “composites” and “personalized education”
  9. Guest editorial
  10. 4th International IUPAC Conference on Green Chemistry
  11. Original articles
  12. Chemicals from agricultural biomass: chemoenzymatic approach for production of vinylphenols and polyvinylphenols from phenolic acids
  13. Microwave assisted synthesis of 4-quinolones and N,N′-diarylureas
  14. D-glucose catalytic oxidation over palladium nanoparticles introduced in the hypercrosslinked polystyrene matrix
  15. Joint use of microwave and glycerol-zinc (II) acetate catalytic system in the synthesis of 2-pyridyl-2-oxazolines
  16. Proline derivatives as organocatalysts for the aldol reaction in conventional and non-conventional reaction media
  17. Microwave assisted green synthesis of aryl methoxylated benzamides and 2-oxazolines from biomass
  18. University profile
  19. Tver Technical University
  20. Organization profile
  21. Fraunhofer Institute for Chemical Technology
  22. Network profile
  23. The Eurokin consortium: origin, topics and aims
  24. Conference announcements
  25. 9th European Congress of Chemical Engineering – 2nd European Congress of Applied Biotechnology (World Forum, The Hague, Netherlands, April 21–25, 2013)
  26. 2nd International Symposium on Green Chemistry (ISGC-2): Renewable Carbon and Eco-efficient Processes (May 21–24, 2013, La Rochelle, France)
  27. Green Polymer Chemistry 2013: Farm wars – how sustainable is renewable? (19–21 March 2013, Cologne, Germany)
  28. 2nd Annual International Conference on Sustainable Energy and Environmental Sciences (SEES 2013), 25–26 February 2013, Singapore
  29. 8th Conference on Sustainable Development of Energy, Water and Environment Systems, September 22–27, 2013, Dubrovnik, Croatia
  30. Conferences 2013/2014
  31. Book review
  32. Biorefinery: from biomass to chemicals and fuels
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