Sage Journals: Discover world-class research

Abstract

An efficient, one-pot synthesis of 3-substituted-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-ones is developed via sequential esterification, substitution, and 1,3-dipolar cycloaddition processes of various propargyl alcohols, chloroacetyl chloride, and sodium azide. This method provides a variety of novel 1,2,3-triazole-fused oxazinones and has several advantages including simple operation, high efficiency, and good-to-excellent product yields (80%–95%) without the need to isolate the ester and azide intermediates.

Keywords

chloroacetyl chloride one-pot procedure propargyl alcohols sodium azide

Introduction

1,2,3-Triazoles are a very important class of heterocyclic compounds, which are widely applied in pharmaceuticals, agrochemicals, dyes, corrosion inhibitors, biochemicals, polymers, and functional materials.^1–5 Up to now, many methods based on the azide–alkyne cycloaddition have been developed to prepare 1,2,3-triazole derivatives.^6–11 Among them, one-pot multicomponent reactions in which azides are prepared in situ prior to the cycloaddition are an attractive approach, as time-consuming work-up and purification protocols are minimized and they avoid the handling of potentially explosive azides. Poly-heterocyclic compounds may be used as potential drug candidates because they might exhibit different modes of biological activities compared with their parent ring systems.¹² 1,2,3-Triazoles fused with other heterocyclic moieties have also gained significant importance due to their diverse array of pharmaceutically active functionalities, exhibiting antitumor, antiproliferative, antivirus, and glycosidase inhibitory activities.¹³

The 1,4-oxazinone framework is a well-known heterocyclic moiety, which is widely present in numerous biologically active compounds with potential applications in pharmaceuticals and agrochemicals.^14,15 Thus, it is not surprising that the incorporation of an oxazinone ring into poly-heterocyclic structures might result in novel and potentially biologically active compounds. To our knowledge, several heterocyclic ring-fused oxazinones such as pyrido[3,2-d][1,2]oxazinones,¹⁶ [3,4-d][1,2] oxazin-4-ones, thieno[3,4-d][1,2]oxazin-4-ones, and pyrido [3,2-d][1,2]oxazin-5-ones¹⁷ have been documented. However, little work relating to the synthesis or bioactivities of the triazolo-fused oxazinones has been reported.^18–20 Thus, the development of simple and efficient methods for the construction of the triazolo-fused oxazinones that avoid the isolation of organic azide intermediates are highly desirable. Herein, we report a facile, one-pot, three-step protocol for the synthesis of 3-substituted-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-ones involving in situ generation and intramolecular 1,3-dipolar cycloaddition of propargylic azidoacetates. The latter were obtained sequential esterification of propargylic alcohols with chloroacetyl chloride followed by nucleophilic displacement with sodium azide.

Results and discussion

As outlined in Scheme 1, our initial exploratory efforts were devoted to the synthesis of 3-phenyl-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3a) from 3-phenyl-2-propyn-1-ol (1a), which was treated with chloroacetyl chloride (1.2 equiv.) in the presence of triethylamine to give 3-phenyl-propargyl chloroacetate (2a) in 95% yield. Next, the reaction of 2a with an excess amount of sodium azide (2 equiv.) in N,N-dimethylformamide (DMF) at 100 °C for 1 h formed the intermediate (2a’). Without isolation of the azide 2a’, the reaction mixture was further heated for 4 h, where upon the latter underwent a constrained intramolecular 1,3-dipolar cycloaddition with the alkyne moiety to furnish regioselectively the desired bicyclic compound 3a in 95% yield as the only product. The formation of compound 3a was confirmed by nuclear magnetic resonance (NMR) spectroscopy. The ¹H NMR spectrum of 3a has two characteristic singlets corresponding to the methylene protons at 3.90 (–OCH₂–) and 4.99 (–COCH₂–) ppm, respectively. In the ¹³C NMR spectrum, the ester carbonyl carbon appeared at 167.8 ppm, and the aromatic carbon signals appeared in the range of 131.9–121.9 ppm.

Scheme 1.

Synthesis of bicyclic triazole 3a from 3-phenyl-2-propyn-1-ol (1a).

Not surprisingly, when 1a was reacted with chloroacetyl chloride, other solvents such as toluene, dichloromethane, tetrahydrofuran (THF), DMF, dimethyl sulfoxide (DMSO), or 1,4-dioxane were also applicable for this transformation, and all gave excellent results. However, among the various solvents screened, non-polar or weak polar solvents were not suitable for the subsequent substitution and 1,3-dipolar cycloaddition reactions, while the aprotic, highly polar solvent DMF provided the best results.

Second, encouraged by the above results, we attempted the preparation of 3a through a one-pot, three-step procedure starting from 1a. To our delight, the one-pot synthesis of 3a could be also realized by treating 1a with chloroacetyl chloride in DMF at room temperature using triethylamine as the base for 1 h, followed by the addition of sodium azide. After stirring for 5 h at 100 °C, the desired triazolo-fused oxazinone 3a was isolated in 91% yield (Table 1, entry 1) as the exclusive product in three-steps.

Table 1.

Preparation of compounds 3a–l via one-pot three-step reactions.^a

Entry	R	Product (3)	Yield (%)^b
1	C₆H₅ (1a)	3a	91
2	4-MeOC₆H₄ (1b)	3b	93
3	2-MeOC₆H₄ (1c)	3c	88
4	4-MeC₆H₄ (1d)	3d	91
5	2-MeC₆H₄ (1e)	3e	86
6	3-MeC₆H₄ (1f)	3f	90
7	4-BrC₆H₄ (1g)	3g	86
8	2-BrC₆H₄ (1h)	3h	82
9	3-BrC₆H₄ (1i)	3i	84
10	4-ClC₆H₄ (1j)	3j	85
11	2-ClC₆H₄ (1k)	3k	83
12	Me (1l)	3l	95

Reaction conditions: 1 (1.0 mmol), chloroacetyl chloride (1.2 mmol), Et₃N (3.0 mmol), NaN₃ (2.0 mmol), and solvent (10 mL).

Isolated yield.

Finally, to explore the generality and scope of the reaction (Scheme 2), the reaction was carried out with various propargyl alcohols under the optimized reaction conditions and the results are summarized in Table 1.

Scheme 2.

One-pot, three-step synthesis of triazolo-fused oxazinone derivatives 3.

As observed in Table 1, for all substrates, the reaction proceeded smoothly and the corresponding products 3a–l were obtained in good-to-excellent yields. In addition, no significant difference in the reactivity was found for the examined aromatic propargyl alcohols, including those containing chloro, bromo, methyl, or methoxy substituents on the phenyl ring (Table 1, entries 2–11). It is noteworthy that a higher yield was obtained when R was a methyl group rather than an aryl group (Table 1, entry 12).

In summary, an efficient, one-pot, three-step protocol has been developed for the preparation of 3-substituted-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-ones with good-to-excellent yields via sequential esterification, substitution and 1,3-dipolar cycloaddition reactions. This procedure should make it possible to rapidly prepare compound libraries for drug discovery programs as it avoids time-consuming and costly isolation and purification protocols involving synthetic intermediates.

Experimental

Propargyl alcohols 1a–k were prepared in good yields by the reactions of aryl bromides with propargyl alcohol in the presence of dichlorobis(triphenylphosphine)palladium according to a reported method.²¹ Other reagents and solvents were purchased from commercial suppliers and were used without further purification. The reaction progress was monitored by thin-layer chromatography (TLC) on GF254 silica gel analytical aluminum plates, and the products were visualized under UV spectrophotometer. Column chromatography was performed using silica gel 60 (250–004 mesh) with petroleum ether (bp. 60–90 °C)/ethyl acetate as eluent. Melting points were measured using a Beijing-Taike X-4 apparatus without correction. ¹H NMR and ¹³C NMR spectra were recorded in deuterated CDCl₃ on a Bruker Avance 400 MHz NMR spectrometer, operating at 400 and 100 MHz, respectively. Fourier-transform infrared spectroscopy (FTIR) analyses were performed with a Perkin-Elmer SP One FTIR spectrophotometer. Microanalyses were performed with a Carlo Erba 1106 Elemental Analyzer.

General procedure for the preparation of 3-substituted-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-ones

Propargyl alcohol 1a–l (1.0 mmol) was dissolved in dry DMF (10 mL) and then cooled to 0 °C. Anhydrous Et₃N (0.3 g, 3 equiv.) and chloroacetyl chloride (0.14 g; 1.2 mmol) were added, and the reaction mixture was allowed to stir at room temperature. After the disappearance of the starting materials (monitored by TLC), sodium azide (0.13 g, 2.0 mmol) was added to the reaction mixture. The reaction was heated to 100 °C, stirred for 5 h and then cooled to room temperature. The reaction mixture was treated with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was subjected to flash column chromatography with petroleum ether/ethyl acetate (5/1) as eluent to afford the desired product 3a–l.

3-Phenyl-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3a):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.46–7.44 (m, 2 H), 7.34–7.27 (m, 3 H), 4.99 (s, 2 H), 3.90 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.8, 131.9, 129.0, 128.4, 121.9, 87.3, 82.1, 53.9, 50.1; IR (film): 3025, 2965, 1727, 1607, 1466, 1368, 1269, 1136, 1065, 742 cm⁻¹. Anal. calcd for C₁₁H₉N₃O₂: C, 61.39; H, 4.22; N, 19.53; found: C, 61.50; H, 4.35; N, 19.42%.

3-(4-Methoxyphenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3b):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.38 (d, J = 8.4 Hz, 2 H), 6.82 (d, J = 8.4 Hz, 2 H), 4.98 (s, 2 H), 3.91 (s, 2 H), 3.75 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.9, 160.1, 133.5, 114.0, 113.7, 87.2, 80.9, 55.2, 54.0, 50.0; IR (film): 3053, 2944, 2543, 2113, 1749, 1608, 1505, 1160, 1038, 832 cm⁻¹; Anal. calcd for C₁₂H₁₁N₃O₃: C, 58.77; H, 4.52; N, 17.13; found: C, 58.94; H, 4.63; N, 17.20%.

3-(2-Methoxyphenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3c):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.42 (dd, J = 7.5, 1.4 Hz, 1 H), 7.34–7.30 (m, 1 H), 6.93–6.87 (m, 2 H), 5.08 (s, 2 H), 3.95 (s, 2 H), 3.87 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ 1678, 160.3, 134.0, 130.6, 128.9, 120.5, 110.7, 85.8, 83.8, 55.8, 54.3, 50.2; IR (film): 3042, 2970, 1730, 1605, 1463, 1370, 1262, 1130, 1068, 755 cm⁻¹; Anal. calcd for C₁₂H₁₁N₃O₃: C, 58.77; H, 4.52; N, 17.13; found: C, 58.96; H, 4.71; N, 17.23%.

3-(4-Methylphenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3d):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.33 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 7.8 Hz, 2 H), 4.98 (s, 2 H), 3.89 (s, 2 H), 2.30 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.8, 139.3, 131.9, 129.2, 118.8, 87.5, 81.5, 54.0, 50.1, 21.4; IR (film): 3035, 2978, 1741, 1610, 1508, 1375, 1164, 1041, 828 cm⁻¹; Anal. calcd for C₁₂H₁₁N₃O₂: C, 62.87; H, 4.84; N, 18.33; found: C, 62.99; H, 4.98; N, 18.47%.

3-(2-Methylphenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3e):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.41 (d, J = 7.6 Hz, 1 H), 7.23–7.17 (m, 2 H), 7.11 (t, J = 7.4 Hz, 1 H), 5.02 (s, 2 H), 3.89 (s, 2 H), 2.41 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.8, 140.7, 132.3, 129.6, 129.1, 125.6, 121.7, 86.3, 85.9, 54.1, 50.2, 20.6; IR (film): 3037, 2984, 1740, 1612, 1510, 1165, 1042, 742 cm⁻¹; Anal. calcd for C₁₂H₁₁N₃O₂: C, 62.87; H, 4.84; N, 18.33; found: C, 62.94; H, 4.96; N, 18.45%.

3-(3-Methylphenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3f):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.31 (s, 1 H), 7.24 (d, J = 7.2 Hz, 1 H), 7.17 (t, J = 8.0 Hz, 1 H), 7.11 (d, J = 7.6 Hz, 1 H), 4.97 (s, 2 H), 3.88 (s, 2 H), 2.28 (s, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.8, 138.1, 132.5, 129.9, 129.0, 128.3, 121.7, 87.5, 81.8, 53.9, 50.1, 21.1; IR (film): 3033, 2987, 1737, 1610, 1508, 1168, 1040, 865, 780, 728 cm⁻¹. Anal. calcd for C₁₂H₁₁N₃O₂: C, 62.87; H, 4.84; N, 18.33; found: C, 62.96; H, 4.97; N, 18.48%.

3-(4-Bromophenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3g):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.45 (d, J = 8.4 Hz, 2 H), 7.30 (d, J = 8.4 Hz, 2 H), 5.00 (s, 2 H), 3.95 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.7, 133.4, 131.7, 123.4, 120.8, 86.2, 83.2, 53.8, 50.2; IR (film): 3068, 2968, 1760, 1568, 1285, 1173, 1035, 820, 690, 558 cm⁻¹; Anal. calcd for C₁₁H₈N₃O₂Br: C, 44.92; H, 2.74; N, 14.29; found: C, 45.13; H, 2.92; N, 14.48%.

3-(2-Bromophenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3h):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.48 (dd, J = 8.0, 0.8 Hz, 1 H), 7.38 (dd, J = 7.6, 1.6 Hz, 1 H), 7.17 (dd, J = 7.4, 1.0 Hz, 1 H), 7.10 (dd, J = 7.8, 1.8 Hz, 1 H), 4.97 (s, 2 H), 3.87 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.7, 133.8, 132.5, 130.2, 127.1, 125.7, 124.0, 86.5, 85.7, 53.9, 50.2; IR (film): 3066, 2965, 1756, 1565, 1284, 1175, 1032, 780, 675, 555 cm⁻¹; Anal. calcd for C₁₁H₈N₃O₂Br: C, 44.92; H, 2.74; N, 14.29; found: C, 45.19; H, 2.90; N, 14.45%.

3-(3-Bromophenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3i):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.58 (s, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.37–7.35 (m, 1 H), 7.16 (t, J = 8.0 Hz, 1 H), 5.00 (s, 2 H), 3.95 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.7, 134.6, 132.2, 130.5, 129.9, 123.8, 122.1, 85.6, 83.5, 53.7, 50.1; IR (film): 3065, 2963, 1758, 1562, 1281, 1178, 1029, 786, 674, 553 cm⁻¹; Anal. calcd for C₁₁H₈N₃O₂Br: C, 44.92; H, 2.74; N, 14.29; found: C, 45.14; H, 2.92; N, 14.41%.

3-(4-Chlorophenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3j):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.36 (dd, J = 6.8, 2.0 Hz, 2 H), 7.28 (dd, J = 6.8, 2.0 Hz, 2 H), 5.00 (s, 2 H), 3.94 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.8, 135.1, 133.2, 128.7, 120.3, 86.1, 83.1, 53.8, 50.1; IR (film): 3056, 2975, 1760, 1568, 1170, 1042, 825, 780, 674 cm⁻¹; Anal. calcd for C₁₁H₈N₃O₂Cl: C, 52.92; H, 3.23; N, 16.83; found: C, 53.12; H, 3.52; N, 16.94%.

3-(2-Chlorophenyl)-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3k):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 7.47 (dd, J = 7.6, 1.6 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.28–7.20 (m, 2 H), 5.06 (s, 2 H), 3.95 (s, 2 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.7, 136.1, 133.7, 130.1, 129.3, 126.5, 121.8, 87.2, 83.9, 53.8, 50.2; IR (film): 3061, 2982, 1755, 1600, 1558, 1165, 1040, 739 cm⁻¹; Anal. calcd for C₁₁H₈N₃O₂Cl: C, 52.92; H, 3.23; N, 16.83; found: C, 53.18; H, 3.54; N, 16.92%.

3-Methyl-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6(7H)-one (3l):

Yellow liquid; ¹H NMR (400 MHz, CDCl₃): δ 4.98 (s, 2 H), 3.87 (s, 2 H), 2.38 (3 H); ¹³C NMR (100 MHz, CDCl₃): δ 167.5, 85.7, 83.0, 53.9, 49.9, 12.2; IR (film): 3035, 2968, 1742, 1602, 1550, 1385, 1166, 1042 cm⁻¹; Anal. calcd for C₆H₇N₃O₂: C, 47.06; H, 4.61; N, 27.44; found: C, 47.28; H, 4.85; N, 27.62%.

Supplemental Material

sj-pdf-1-chl-10.1177_1747519820948355 – Supplemental material for One-pot synthesis of 3-substituted-4H-[1,2,3] triazolo[5,1-c][1,4]oxazin-6(7H)-ones from propargyl alcohols, chloroacetyl chloride, and sodium azide

Supplemental material, sj-pdf-1-chl-10.1177_1747519820948355 for One-pot synthesis of 3-substituted-4H-[1,2,3] triazolo[5,1-c][1,4]oxazin-6(7H)-ones from propargyl alcohols, chloroacetyl chloride, and sodium azide by Xiao-Lan Zhang, Mei-Hong Wei, Jun-Min Chen, Shou-Ri Sheng and Xiao-Ling Liu in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (No. 21762022), the Research Program of Jiangxi Province Department of Education (Nos GJJ160289 and GJJ11380), the Opening Foundation of Key Laboratory of Functional Small Organic Molecules of Ministry of Education (Nos KLFS-KF-201912 and KLFS-KF-201928), and the Opening Foundation of National Research Center for Carbohydrate Synthesis (No. GJDTZX-KF-201414).

ORCID iD

Xiao-Ling Liu

Supplemental material

Supplemental material for this article is available online.

References

Moses

Moorhouse

AD.

Chem Soc Rev 2007; 36: 1249.

Mamidyala

Finn

MG.

Chem Soc Rev 2010; 39: 1252.

Thirumurugan

Matosiuk

Jozwiak

Chem Rev 2013; 113: 4905.

Schulze

Schubert

US.

Chem Soc Rev 2014; 43: 2522.

Kantheti

Narayan

Raju

KVSN

. RSC Adv 2015; 5: 3687.

Meldal

Tomøe

CW.

Chem Rev 2008; 108: 2952.

Meldal

Tomøe

CW.

Chem Soc Rev 2010; 39: 1280.

Hein

Fokin

VV.

Chem Soc Rev 2010; 39: 1302.

Sokolova

Nenajdenko

VG.

RSC Adv 2013; 3: 16212.

10.

Hassan

Müller

TJJ

. Adv Synth Catal 2015; 357: 617.

11.

Chen

Cao

Song

, et al. Chin J Chem 2017; 35: 1797.

12.

Horton

Bourne

Smythe

ML.

Chem Rev 2003; 103: 893.

13.

Tron

Pirali

Billington

, et al. Med Res Rev 2008; 28: 278.

14.

Shukla

Nycholat

Subramanian

, et al. J Agric Food Chem 2004; 52: 5144.

15.

Isshiki

Kohchi

Iikura

, et al. Bioorg Med Chem Lett 2011; 21: 1795.

16.

Frackenpohl

Adelt

Antonicek

, et al. Bioorg Med Chem 2009; 17: 4160.

17.

Cheng

Tetrahedron 2013; 69: 888.

18.

Balducci

Bellucci

Petricci

, et al. J Org Chem 2009; 74: 1314.

19.

Moliner

Crosignani

Galatini

, et al. ACS Comb Sci 2011; 13: 453.

20.

Tong

Liang

, et al. RSC Adv 2016; 6: 63855.

21.

Guan

Weng

G-A

, et al. Tetrahedron Lett 2007; 48: 7129.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.80 MB

One-pot synthesis of 3-substituted-4 H -[1,2,3] triazolo[5,1- c ][1,4]oxazin-6(7 H )-ones from propargyl alcohols,chloroacetyl chloride,and sodium azide