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. Author manuscript; available in PMC: 2013 Apr 18.
Published in final edited form as: Tetrahedron Lett. 2012 Apr 18;53(16):2096–2099. doi: 10.1016/j.tetlet.2012.02.041

Solid Phase Synthesis of Isoxazole and Isoxazoline-carboxamides via [2+3]-Dipolar Cycloaddition Using Resin-bound Alkynes or Alkenes

Sureshbabu Dadiboyena 1, Adel Nefzi 1,2,*
PMCID: PMC3376396  NIHMSID: NIHMS361984  PMID: 22715296

Abstract

An efficient approach for the parallel solid phase synthesis of isoxazole and isoxazoline derivatives has been developed. The isoxazoles and isoxazolines were constructed through a 1,3-dipolar cycloaddition reaction of nitrile oxides, with resin-bound alkynes or alkenes. The cycloaddition reaction conditions performed on solid phase supports was optimized, and an array of resin bound carboxylic acid building blocks were utilized for distinct conversions. This methodology presents a new alternative to the diversity oriented synthesis of disubstituted isoxazoles and isoxazolines different from existing routes which are limited in structural diversity

Keywords: Isoxazoles; Isoxazolines; Heterocycles; 1,3-Dipolar cycloadditions; Solid-phase synthesis; Combinatorial chemistry

Heterocycles display an array of significant bioactive properties,1–3 and heterocyclic scaffolds are present in a wide variety of drugs as well as drug like molecules of pharmaceutical relevance.4,5 Among the family of heterocyclic compounds, isoxazoles and isoxazolines are an important class of heterocycles displaying a wide variety of biological properties including antiviral,6 antitubulin,7 as well as anti-inflammatory activity.8 The synthesis of this family of heterocycles continue to attract the attention of synthetic organic and medicinal chemists.9 The isoxazoline framework is a prevalent feature of several natural products 1–6,10,11 and the isoxazole structural motif is found in the COX II inhibitors, bextra 7 and parecoxib 8 (Fig.1).9a,12 A plethora of methodologies exist toward the synthesis of isoxazoles and isoxazolines,13,14 and most of them endeavor nitrile oxide cycloaddition (NOC) as a key step.15

Figure 1.

Figure 1

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Naturally occurring isoxazolines and pharmaceutically relevant isoxazoles.

On the other hand, combinatorial chemistry and high-throughput screening have changed the scale on which drug discovery programs are carried out.4,5 The inherent potential of this technique aid to accelerate the drug discovery process through rapid synthesis and subsequent screening of much larger numbers of compounds than previously possible.16 The versatile and potential capability afforded by the tea-bag approach,17 has led to the isolation and recognition of an array of bioactive peptides, including antibacterials, antigenic peptides, opioid receptor agonists and antagonists, inhibitors and several heterocyclic compounds of biomedical importance.18 In continuation of our research investigation toward the design, and development of novel heterocycles, we developed a parallel solid-phase nitrile oxide cycloaddition (NOC) strategy to synthesize a variety of isoxazoles and isoxazolines utilizing 1,3-dipolar cycloaddition chemistry.9,15 The hydroximoyl chlorides 11 for the 1,3-dipolar cycloaddition are not commercially available and were conveniently synthesized in two steps utilizing solution phase chemistry.8,9a This methodology presents a new alternative to the diversity oriented synthesis of disubstituted isoxazoles and isoxazolines different from existing routes which, are limited in structural diversity.19,20

We envisioned the synthesis of isoxazole 9 and isoxazolines 10 via 1,3-dipolar cycloaddition of in situ generated nitrile oxides with alkyne 12 or alkenes 13. The required alkyne and alkene precursors are synthesized from the corresponding resin-bound carboxylic acid. The retrosynthetic rationale for the parallel solid-phase synthesis of isoxazoles and isoxazolines is illustrated in Scheme 1.

Scheme 1.

Scheme 1

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Retrosynthetic illustration of structurally diverse isoxazoles and isoxazolines.

The parallel solid phase synthesis of all compounds were carried out utilizing Houghten’s tea-bag approach, wherein the resin is packed within sealed polypropylene mesh packets.17 The first position of diversity was introduced by coupling several carboxylic acids to p-methylbenzhydrylamine resin. The generated secondary amide 14 was then alkylated in the presence of lithium t-butoxide and an alkylating agent (allyl bromide or propargyl bromide).21 The parallel synthesis of the resin-bound isoxazoles 9 and isoxazolines 10 was initiated by the nitrile oxide cycloaddition of the resin-bound alkynes and alkene derivatives. Structurally diverse combinations of carboxylic acids (cyclopentanecarboxylic acid, 1-cyclopenteneacetic acid, benzoic acid, 2-nitrobenzoic acid, piperonylic acid, syringyl, 4-biphenylcarboxylic acid, 1-napthalenecarboxylic, diphenylacetic acid, 1-phenyl-1-cyclopropylcarboxylic acid, and 1-phenyl-1-cyclopentanecarboxylic acid) were selected.

To investigate the feasibility of nitrile oxide cycloadditions (NOC) on solid support, three different hydroximoyl chlorides were freshly prepared and were treated with triethylamine to generate the corresponding nitrile oxides9,13c,f,14i,5a,b Treatment of resin-bound dipolarophiles 12,13 with the generated nitrile oxides proceeded in a 1,3-dipolar fashion and furnished diversified isoxazoles and isoxazolines.22 In case of resin coupled with piperonylic acid, we also observed the formation of a diol (partially cleaved protected diol) in addition to the main product. All of the cycloadditions occurred in good yields and were isolated in high purities (Table 1 and 2). The protocol for the parallel synthesis of structurally diverse isoxazoles and isoxazolines is outlined in Scheme 2.

Table 1.

Isoxazoles from resin-bound alkynes

Entry R1 R2 Mass calcd./found Yields (%)a
15a Piperonyl H 322.3/323.2 (MH+) 87
15b Cyclopentyl H 270.3/271.4 (MH+) 66
15c 1-Cyclopenteneacetyl H 282.3/283.2 (MH+) 91
15d 4-Biphenyl H 354.4/355.2 (MH+) 63
15e Syringyl H 354.4/356.0 (MH+) 54
15f 1-Phenyl-1-cyclopropyl H 318.3/319.6 (MH+) 52
15g Diphenylacetyl H 368.4/369.5 (MH+) 75
15h Phenyl 4-Ph 354.4/355.2 (MH+) 90
15i Piperonyl 4-Ph 398.4/399.3 (MH+) 83
15j Cyclopentyl 4-Ph 346.4/347.4 (MH+) 93
15k 1-Cyclopenteneacetyl 4-Ph 358.4/359.2 (MH+) 94
15l 2-Nitrophenyl 4-Ph 399.4/400.4 (MH+) 55
15m 4-Biphenyl 4-Ph 430.5/431.4 (MH+) 63
15n 1-Phenyl-1-cyclopropyl 4-Ph 394.5/395.3 (MH+) 75
15o Diphenylacetyl 4-Ph 444.5/445.3 (MH+) 62
15p Syringyl 4-Ph 430.4/453.2 (MH+) 63
15q 1-Napthyl 4-Ph 404.5/405.4 (MH+) 73
15r 2-Nitrophenyl 2,6-diCl 392.2/393.5 (MH+) 70
15s Piperonyl 2,6-diCl 391.2/392.4 (MH+) 91
15t Phenyl 2,6-diCl 347.4/349.3 (MH+) 92
15u Cyclopentyl 2,6-diCl 415.4/416.3 (MH+) 79
15v 1-Phenyl-1-cyclopentyl 2,6-diCl 415.3/438.2 (MNa+) 75
15w 4-Biphenyl 2,6-diCl 423.3/446.1 (MNa+) 86
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The products were run on a Vydac column, gradients 5 to 95% formic acid in Acetonitrile in 7 min.

a

The yields are based on the weight of purified products and are relatives to the initial loading of the resin. (The purity of the purified compounds is higher than 95% for all the compounds).

Table 2.

Isoxazolines from resin-bound alkenes

Entry R1 R2 Mass calcd./found Yields (%)a
16a Cyclopentyl H 272.3/273.1 (MH+) 96
16b 1-Cyclopenteneacetyl H 284.1/285.1 (MH+) 92
16c 4-Biphenyl H 356.4/357.3 (MH+) 67
16d 1-Phenyl-1-cyclopropyl H 320.3/321.2 (MH+) 87
16e Syringyl H 356.3/357.2 (MH+) 77
16f Piperonyl 4-Ph 400.4/423.2 (MNa+) 63
16g Cyclopentyl 4-Ph 348.4/349.3 (MH+) 93
16h 1-Cyclopenteneacetyl 4-Ph 360.4/361.3 (MH+) 88
16i 2-Nitrophenyl 4-Ph 401.5/402.4 (MH+) 84
16j Phenyl 4-Ph 356.3/357.3 (MH+) 84
16k 1-Phenyl-1-cyclopropyl 4-Ph 396.5/397.4 (MH+) 77
16l Diphenylacetyl 4-Ph 446.4/447.4 (MH+) 82
16m Syringyl 4-Ph 432.4/433.2 (MH+) 87
16n 1-Napthyl 4-Ph 406.5/429.3 (MNa+) 71
16o 4-Biphenyl 4-Ph 432.5/455.5 (MNa+) 61
16p 1-Phenyl-1-cyclopentyl 4-Ph 424.5/447.3 (MNa+) 72
16q Phenyl 2,6-diCl 349.2/372.3 (MNa+) 96
16r 2-Nitrophenyl 2,6-diCl 394.2/417.1 (MNa+) 95
16s Piperonyl 2,6-diCl 393.2/417.2 (MNa+) 96
16t Cyclopentyl 2,6-diCl 417.3/440.2 (MNa+) 87
16u 1-Phenyl-1-cyclopentyl 2,6-diCl 417.3/440.1 (MNa+) 77
16v 4-Biphenyl 2,6-diCl 425.3/447.4 (MNa+) 78
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The products were run on a Vydac column, gradients 5 to 95% formic acid in Acetonitrile in 7 min.

a

The yields are based on the weight of purified products and are relatives to the initial loading of the resin (The purity of the purified compounds is higher than 95% for all the compounds).

Scheme 2.

Scheme 2

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Solid phase synthesis of structurally diverse isoxazoles and isoxazolines

In conclusion, we have developed an efficient parallel solid-phase methodology to construct diversity oriented isoxazoles and isoxazolines via 1,3-dipolar cycloaddition reaction.22 Coupling of carboxylic acids to the resin introduced the first position of diversity which, following N-alkylation with allyl bromide or propargyl bromide furnished several resin-bound alkenes and alkynes. 1,3-Dipolar cycloaddition of the resin bound alkenes or alkynes with nitrile oxides led to the formation of the corresponding disubstituted isoxazole and isoxazolines.

Supplementary Material

01

Acknowledgments

The authors would like to thank the State of Florida Funding, NIH (1R03DA025850-01A1, Nefzi; 5P41GM081261-03, Houghten; 3P41GM079590-03S1, Houghten) for providing generous financial support.

Footnotes

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  • 22.General procedure for the 1,3-Dipolar cycloaddition: Resin-bound carboxylic acid coupling and N-alkylation using allyl bromide or propargyl bromide were performed according to the literature precedents.21 Resin-bound alkyne (alkene) and the hydroximoyl chloride (10 equiv.) in 10 mL of dry dichloromethane (DCM) was treated with triethylamine (0.16 mL, 10 equiv) and the reaction mixture was stirred overnight. The excess solution was decanted, and the resin was washed with DCM (2 x 5 mL). The resin was cleaved with anhydrous HF (10 mL) for 90 min at 0 °C, and the desired isoxazole (isoxazoline) was obtained following extraction with 95% AcOH in H2O and lyophilization as a colorless powder. The isoxazole (isoxazoline) was purified by preparative reverse-phase HPLC; Cyclopentanecarboxylic acid (3-phenyl-isoxazol-5-ylmethyl)-amide (15b): 1H NMR (500 MHz; DMSO-d6): δ 1.50–1.52 (m, 2H), 1.61–1.67 (m, 4H), 1.77–1.79 (m, 2H), 2.61–2.64 (m, 1H), 4.44 (d, J = 6.0 Hz, 2H), 6.81 (s, 1H), 7.49–7.52 (m, 3H), 7.84–7.87 (m, 2H), 8.49 (t, J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C16H18N2O2 [M+H+]: 270.3; found: 271.4; Benzo[1,3]dioxole-5-carboxylic acid (3-biphenyl-4-yl-isoxazol-5-ylmethyl)-amide (15i): 1H NMR (500 MHz; DMSO-d6): δ 1.23 (s, 2H), 4.64 (d, J = 5.5 Hz, 2H), 6.55 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.0 Hz, 1H), 7.45 (s, 1H), 7.50 (q, J = 8.0 Hz, 3H), 7.74 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H), 9.07 (t, J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C24H18N2O4 [M+H+]: 398.4; found: 399.3; Cyclopentanecarboxylic acid (3-biphenyl-4-yl-isoxazol-5-ylmethyl)-amide (15j): 1H NMR (500 MHz; DMSO-d6): δ 1.23 (s, 4H), 1.50–1.52 (m, 1H), 1.63–1.68 (m, 2H), 1.77–1.80 (m, 1H), 2.62–2.65 (m, 1H), 4.46 (t, J = 5.8 Hz, 2H), 6.88 (s, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 8.0 Hz, 2H), 7.74 (t, J = 9.5 Hz, 2H), 7.81 (t, J = 8.1 Hz, 2H), 7.95 (t, J = 10.5 Hz, 2H), 8.49–8.51 (m, 1H); MS (ESI) m/z calcd for C22H22N2O2 [M+H+]: 346.4; found: 347.4; Benzo[1,3]dioxole-5-carboxylic acid [3-(2,6-dichloro-phenyl)-isoxazol-5-ylmethyl]-amide (15s): 1H NMR (500 MHz; DMSO-d6): δ 4.69 (d, J = 5.5 Hz, 2H), 6.10 (s, 2H), 6.59 (s, 1H), 7.01 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.50 (d, J = 10.0 Hz, 1H), 7.54–7.63 (m, 1H), 7.64–7.65 (m, 2H), 9.1 (t, J = 5.5 Hz, 1H); MS (ESI) m/z calcd for C17H12Cl2N2O4 [M+H+]: 391.2; found: 393.2; Biphenyl-4-carboxylic acid [3-(2,6-dichloro-phenyl)-isoxazol-5-ylmethyl]-amide (15w): 1H NMR (500 MHz; DMSO-d6): δ 4.75 (d, J = 4.5 Hz, 2H), 6.62 (s, 1H), 7.41 (m, 1H), 7.50 (t, J = 7.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.64 (t, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 9.31 (t, J = 6.0 Hz, 2H); MS (ESI) m/z calcd for C23H16Cl2N2O2 [M+Na+]: 423.2; found: 446.1; Cyclopentanecarboxylic acid (3-phenyl-4,5-dihydro-isoxazol-5-ylmethyl)-amide (16a): 1H NMR (500 MHz; DMSO-d6): δ 1.44–168 (m, 8H), 2.54 (t, J = 7.5 Hz, 1H), 3.13 (dd, J = 7.0 Hz, 17 Hz 1H), 3.22–3.24 (m, 1H), 3.44 (dd, J = 11.0 Hz, 17 Hz 1H), 4.72–4.78 (m, 1H), 7.43–7.46 (m, 3H), 7.62–7.65 (m, 2H), 8.04 (t, J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C23H16Cl2N2O2 [M+H+]: 272.3; found: 273.1; Benzo[1,3]dioxole-5-carboxylic acid (3-biphenyl-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-amide (16f): 1H NMR (500 MHz; DMSO-d6): δ 3.40 (dd, J = 7 Hz, 17.5 Hz, 1H), 3.61–3.70 (m, 1H), 3.77–3.81 (m, 1H), 4.34 (dd, J = 5.5 Hz, 12 Hz, 1H), 4.43 (dd, J = 3.5 Hz, 12 Hz, 1H), 5.07–5.13 (m, 1H), 6.11 (s, 2H), 6.80–6.82 (m, 1H), 6.98–7.00 (m, 2H), 7.09–7.10 (m, 1H), 7.32 (s, 1H), 7.40–7.42 (m, 1H), 7.48–7.54 (m, 4H), 7.72–7.74 (m, 2H); MS (ESI) m/z calcd for C24H20N2O4 [M+Na+]: 400.4; found: 423.2; Cyclopentanecarboxylic acid (3-biphenyl-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-amide (16g): 1H NMR (500 MHz; DMSO-d6): δ 1.45–1.69 (m, 6H), 2.55–2.58 (m, 1H), 3.15–3.19 (m, 1H), 3.24–3.32 (m, 1H), 3.46–3.51 (m, 1H), 4.74–4.80 (m, 1H), 7.4 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.71–7.73 (m, 4H), 7.77–7.78 (m, 2H), 8.05 (t, J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C22H24N2O2 [M+H+]: 348.4; found: 349.3; N-[3-(2,6-Dichloro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl]-2-nitro-benzamide (16r): 1H NMR (500 MHz; DMSO-d6): δ 3.14 (dd, J = 6.5 Hz, 17.5Hz, 1H), 3.41–3.55 (m, 3H), 4.96–5.00 (m, 1H), 7.52–7.55 (m, 1H), 7.61–7.64 (m, 3H), 7.8 (t, J = 7.5 Hz, 1H), 8.05 (d, J = 10 Hz, 1H), 9.06 (t, J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C17H13Cl2N3O4 [M+Na+]: 394.20; found: 417.1; Benzo[1,3]dioxole-5-carboxylic acid [3-(2,6-dichloro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl-]-amide (16s): 1H NMR (500 MHz; DMSO-d6): δ 3.14 (dd, J = 6.5 Hz,17.5 Hz, 2H), 3.64–3.48 (m, 2H), 3.55–3.61 (m, 1H), 4.98–5.0 (m, 1H), 6.1 (s, 2H), 6.99 (d, J = 10 Hz, 2H), 7.43 (s, 1H), 7.48–7.58 (m, 2H), 7.60 (d, J = 5.0 Hz, 2H), 8.65 (t, J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C18H14Cl2N2O4 [M+Na+]: 393.22; found: 417.2

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