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N-heteroatom substitution effect in 3-aza-cope rearrangements

Chemistry Central Journal volume 7, Article number: 94 (2013) Cite this article

Abstract

Background

The nature of the heteroatom substitution in the nitrogen of a 3-aza-Cope system is explored.

Results

While N-propargyl isoxazolin-5-ones suffer 3-aza-Cope rearrangements at 60°C, the corresponding N-propargyl pyrazol-5-ones need a higher temperature of 180°C for the equivalent reaction. When the propargyl group is substituted by an allyl group, the temperature of the rearrangement for both type of compounds is less affected by the nature of the heteroatom present. Treatment with a base, such as ethoxide, facilitates the rearrangement, and in the case of isoxazol-5- ones other ring opening reactions take precedence, involving N–O ring cleavage of the 5-membered ring. However when base-catalysed decomposition is prevented by substituents, products arising from a room temperature aza-Cope rearrangement are isolated. A possible mechanistic pathway based on free energies derived from density functional calculations involving cyclic intermediates is proposed.

Conclusions

The nature of the heteroatom substitution in the nitrogen of a 3-aza-Cope system leads to a remarkable difference in the energy of activation of the reaction.

Background

Cope-type rearrangements constitute a highly efficient means for carbon–carbon bond formation, offering high regio- and stereocontrol which renders them especially useful in synthesis [1]. The Aza-Cope rearrangement in particular has some advantages over its oxo-counterpart, namely the fine tuning of the reaction temperature which can be achieved by attaching different substituents to the nitrogen of the rearranging system [2–5], by adding charges or by encapsulating it [6]. As previously reported by us appropriately substituted N-alkyl(silyl)oxy-N-allyl enamines undergo smooth 3,3-sigmatropic rearrangements to the corresponding N-alkyl(silyl)oxy imino ethers in good to excellent yields [7]. Theoretical studies also indicate that an oxyanionic substituent on the nitrogen atom reduces substantially the activation energies for these rearrangements [8]. We report in this manuscript the results obtained with the N-propargyl and N-allyl 5-membered heterocycles, pyrazolin-5-ones and isoxazolin-5-ones, either under thermolysis or in the presence of a base.

Results and discussion

The required compounds 1 for the rearrangement studies were obtained by alkylation of 3 using a Mitsunobu reaction [9] as in Scheme 1. The isolated compounds 1 and 2 were easily separated by chromatography (cf. Experimental). Heating either 1 or 2 gave rise to a 3,3-sigmatropic rearrangement [5, 10] and the same final compound 4 as in Scheme 1 (Table 1, entries 1–4).

Scheme 1
scheme 1

Synthesis and thermal rearrangement of N -propargyl pyrazolin-5-ones 1 and their isomers 2.

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Table 1 Rearrangements of pyrazolin-5-ones 1 and their isomers 2
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In the presence of EtOK and 18-crown-6 ether at r.t., it was found that the propargyl group of 1a isomerized to the corresponding allene 5a as in Scheme 2, which could in turn suffer upon heating a 3,3-sigmatropic rearrangement leading to 6a. This last compound could also be reached from 2a by treatment with base to give 7a, followed by thermolysis. Thus coupling of these two reactions opened the way to 3 isomeric compounds of 1a. It is worth noticing that, while the N-allenyl 5a (Table 1, entry 5) reacts in a similar way to the N-propargyl 1a (entry 1) in the 3-aza-Cope rearrangement, the corresponding O-allenyl 7a (entry 6) and the O-propargyl 2a (entry 3) rearrange faster and give better yields. Similar results are found for the pair 1a/2a and 1b/2b. The reason is probably related to the more facile nature of the 3-oxa-Cope (Claisen) versus the 3-aza-Cope rearrangements [3].

Scheme 2
scheme 2

Thermal and base catalyzed rearrangements of pyrazolin-5-ones and their isomers.

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Next, the N-propargyl isoxazolinones 8a,b and the N-allyl 8c,d[11] were synthesised (cf. Experimental) and heated to give the corresponding rearranged compounds, the allenes 9a,b, (Scheme 3, Table 2, entries 1,2) and the allyl 9c,d (Scheme 4, Table 2, entries 3,4). It was found that the first ones required a much lower temperature for the rearrangement.

Scheme 3
scheme 3

3-Aza-Cope rearrangement of N -propargyl isoxazolin-5-ones 8a,b.

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Scheme 4
scheme 4

3-Aza-Cope rearrangement of N -allyl isoxazolin-5-ones 8c,d.

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Table 2 Thermolysis of isoxazolin-5-ones 8 in the presence and absence of potassium ethoxide
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The synthesis of 8e is depicted in Scheme 5 as well as its product after heating (Table 2, entry 5). Desilylation [12] of compound 10 yielded the corresponding ene-hydroxylamine 11, which was found to be unstable and to lactonise spontaneously to the 2-allyl-isoxazolone 8e (Scheme 5). The latter on thermolysis (180°C) furnished 2-cyano-pent-4-enoic acid ethyl ester 12, as shown. In this case the thermodynamic gain resulting from the loss of carbon dioxide from the rearranged product 9e is also accompanied by the formation of the cyano derivative 12[13].When treated with potassium ethoxide, 8e led to the formation of N-allyl-malonamic acid ethyl ester 13 instead of the rearranged product (Scheme 6).

Scheme 5
scheme 5

Synthesis and thermal reaction of N -allyl isoxazolin-5-one 8e.

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Scheme 6
scheme 6

Base catalyzed reaction of N -allyl isoxazolinone 8e.

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Again loss of carbon dioxide, as found earlier by Woodman [14], occurred with a rearrangement possibly involving cyclic intermediates to provide the amide group of 13[15].The energetics of possible mechanistic pathways for this process were explored using a density functional approach (ωB97XD functional, 6-311G(d,p) basis set and SCRF(CPCM) continuum solvation method for ethanol as a model polar solvent). The reaction is sufficiently complex that a significant number of possible mechanistic pathways can be envisaged using the classical “arrow pushing” approach. Here we adopt the approach of incrementally locating pathways to the product and optimizing them for the lowest overall activation free energy. Such an approach of course does not guarantee finding the global energetic minimum in mechanistic pathways. Instead the objective is to find a thermally reasonable pathway that might approximately correspond to the observed rate of the reaction, and along the way eliminating pathways that have unreasonably high activation free energies.

The mechanistic exploration is set out in Scheme 6. The first route explored involved 8e and ethoxide anion acting as a nucleophile. Addition of the ethoxide gives 8e-1 as the first intermediate, followed by ring closure to 8e-2[16]. The most direct route (Occams’s razor) to 13 is by a dyotropic rearrangement of 8e-2 to 8e-3, followed by protonation and decarboxylation. The energetic high point of this pathway is the transition state for the dyotropic rearrangement of the intermediate oxaziridine (8e-TS1) which manifests as unreasonably high (Additional file 1: Table S1, entry 4) a.

The next route explored was with ethoxide acting as a base, abstracting the allylic proton to give the intermediate 8e-4. A ring closure to 8e-5, followed by 1,3 intramolecular proton transfer to give 8e-6, a second proton transfer to reform alkoxide anion and final ring opening to 8e-7 gives 8e-8, which is merely a tautomer of 8e-3 and can decarboxylate as before to give 13. The high point of this pathway is 8e-TS2, which shows as an entirely reasonable barrier for the reaction (Additional file 1: Table S1, entry 5). Whilst this does not constitute a formal mechanistic proof of the reaction, it does imply a reasonable one, and further that any alternative mechanism must have an overall lower energy barrier than this one.

Whereas it is traditional, indeed conventional, for the mechanism of a synthetic pathway to be speculated upon using mechanistic reaction arrows, we suggest here that increasingly such speculations must be supported by a computational exploration of the potential free energy surface. In this case, this has been done with a procedure which, including as it does dispersion corrections for all species, a triple-zeta quality basis with polarization functions, and a correction for continuum solvation, is suggested to be the minimum in quality appropriate for such exploration.

Exposure of 2-allyl-3,4-diphenyl-isoxazolin-5-one (8d) to similar conditions gave rise after 10 minutes to 14 in 25% yield (along with desoxybenzoin in 45%, Scheme 7) with no 3-aza-Cope rearrangement being observed. Compound 14 was found to generate desoxybenzoin (15 R = H) by quenching under aqueous acidic conditions. Quenching the reaction with deuterated acetic acid (CH3COOD) resulted in the isolation of monodeuterated benzoin (15 R = D). A possible mechanism is shown and follows along equivalent intermediates, 8d-3 or the oxaziridine derived 8d-4[17], until reaching 8d-5. A phenyl substituent on carbon 3 in the β-lactone ring of 8d-5 now leads instead to 14.

Scheme 7
scheme 7

Base catalyzed reaction of N -allyl-3,4-diphenyl-isoxalin-5-one 8d.

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Substrate 8b, where formation of the carbanion adjacent to the ring nitrogen of the oxazolidinone is blocked by substitution, was next treated with potassium ethoxide (0.1 eq), in the presence of 18-crown-6 ether, at room temperature (5 days), and gave rise to 9b in 55% yield (cf. Scheme 8). Here the opening of the five membered ring leading to 8b-1 might lower the energy of the reaction either by allowing an easier access to the conformation leading to the transition state or by anionic charge acceleration of the rearrangement. The importance of EtOK was noticed further when, after 5 days at r. t., in its absence, the rearrangement of 8b was observed to occur, but in a much lower yield (<10%). The same compound treated with LDA or tert-BuLi, in the presence of 12-crown-6 ether and in the same conditions of concentration and temperature, showed no reaction. Thus the anion derived from the possible base removal of the terminal triple bond proton does not appear to accelerate the rearrangement, but the oxyanion formed upon the isoxazolidinone ring opening did have a moderately positive effect enabling the rearrangement to occur at room temperature.

Scheme 8
scheme 8

Base catalysed rearrangement of isoxazolin-5-one 8b.

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Conclusions

In conclusion: 1) substitution of the nitrogen-1 of pyrazolin-5-ones by oxygen lowers the temperature of the 3-aza-Cope rearrangement of isoxazolin-5-ones vis-à-vis the corresponding pyrazolin-5-ones when the rearranging element includes a propargyl group attached to the heterocyclic nitrogen-2; 2) when the propargyl group is replaced by an allyl group the rearranging temperature is higher and similar in both compounds; 3) treatment with potassium ethoxide as base in the presence of 12-crown-6 ether at room temperature, while leaving the pyrazolin-5-one heterocycle untouched, leads to ring opening of isoxazolin-5-ones, followed by further reactions. The putative oxaziridine or other cyclic intermediate then suffer base catalysed ring opening reaction whenever there are protons available in the carbon α to the ring nitrogen, leading to a 6-membered aza,oxa-ring system. When such position is blocked by substituents the 3-aza-Cope rearrangement occurs at room temperature.

Experimental

General

Melting points were determined on a Reichert Thermovar apparatus and are uncorrected. Ordinary mass spectra were recorded on a Fisons TRIO 2000 or AEI MS-9 spectrometer. High-resolution MS spectra (HRMS) were obtained on a FT- ICR/ MS Finnigan FT/MS 2001-DT spectrometer at 70 eV by electron impact or on a Finnigan MAT 900 ST spectrometer by ESI. Infrared (IR) spectra were recorded on a Perkin–Elmer 1000X FT-IR spectrometer. Proton and 13C NMR spectra were recorded in CDCl3 on a Bruker ARX 400 spectrometer (400 MHz for 1H, 100.63 MHz for 13C). Chemical shifts are reported relative to tetramethylsilane as the internal reference (δH 0.00) for 1H NMR spectra and to CDCl3 (δC 77.00) for 13C NMR spectra. IR spectra were run on an FT Perkin–Elmer 1000 instrument, with absorption frequencies expressed in reciprocal centimeters. Thin-layer chromatography was performed on Merck silica gel 60 F254 0.2 mm thick plates, visualized under UV light or by exposing to iodine vapour. For preparative separations the plates were 0.5–1 mm thick. For flash chromatography silica Merck Kieselgel 60, 70–230 mesh was used. Usual work-up implies drying the water- or brine-washed organic extracts over anhydrous sodium sulfate or magnesium sulfate, followed by filtration and solvent removal under reduced pressure. Anhydrous solvents were dried and freshly distilled by standard methods [18].

Synthesis of starting materials

Ethyl 3-oxo-2-phenyl-butanoate

To a solution of ethyl acetoacetate (1.5 g, 11.5 mmol) in CH2Cl2 (45 mL), was added triphenylbismuth carbonate [19] (6.33 g, 12.6 mmol). After being stirred under argon for 24 h at 40°C, the mixture was filtered and concentrated at reduced pressure. The crude was purified by CC (silica; Et2O / n-hexane 1:3) to give the title compound as a yellow oil [20] (1.44 g, 61%): IR (NaCl) νmax (cm-1): 3063, 2983, 1745 (C = O, ester), 1721 (C = O, ketone). 1H NMR (400 MHz CDCl3) keto-enol equilibrium, enol (55%): δ 1.18 (3H, t, J = 7.2 Hz, OCH2CH3), 1.85 (3H, s, CH3CO), 4.23 (2H, m, OCH2CH3), 7.14 – 7.38 (5H, m, Ar–H), 13.13 (1H, s, OH); ketone (45%); 1.27 (3H, t, J = 7.2 Hz, OCH2CH3), 2.18 (3H, s, CH3CO), 4.23 (2H, m, OCH2CH3), 4.69 (1H, s, PhCH), 7.14 – 7.38 (5 H, m, Ar–H).

Ethyl 3-oxo-2,3-diphenyl-propanoate

To a solution of ethyl 3-oxo-3-phenyl-propionate (1.48 g, 7.7 mmol) in CH2Cl2 (25 mL), was added triphenylbismuth carbonate (4.22 g, 8.5 mmol). After being stirred under argon for 24 h at 40°C, the mixture was filtered and concentrated at reduced pressure. The crude was purified by CC (silica; Et2O / n-hexane 1:3) to give a viscous oil. Recrystallization from ethanol yielded the title compound (1.34 g, 65%): mp 88–89°C (ethanol) (lit.: [21] mp 89–90°C). IR (KBr) νmax (cm-1): 3063, 2985, 1741 (C = O, ester), 1674 (C = O, ketone).1H NMR (400 MHz CDCl3) keto-enol equilibrium, enol (12%): δ 1.25 (3H, t, J = 7.2 Hz, OCH2CH3), 4.23 (2H, m, OCH2CH3), 7.11 – 7.99 (10 H, m, Ar–H), 13.66 (1H, s, OH), and ketone (88%): δ 1.25 (3H, t, J = 7.2 Hz, OCH2CH3), 4.23 (2H, m, OCH2CH3), 5.62 (1H, s, PhCH), 7.11 – 7.99 (10 H, m, Ar–H).

Methyl-4-phenylisoxazolin-5-one

To a solution of ethyl 3-oxo-2-phenyl-butanoate (50 mg, 0.24 mmol) in EtOH (0.5 mL) and H2O (0.1 mL), was added hydroxylamine hydrochloride (32 mg, 0.46 mmol) and sodium acetate (6.4 mg, 0.078 mmol). The solution was refluxed with continuous stirring under argon for 3 h, 37% HCl (32 μL) was added and the mixture refluxed for further 30 min. The solvent was removed under reduced pressure and the crude diluted with distilled water (2 mL) and extracted with Et2O (3 × 5 mL). The organic extract was dried, filtered and concentrated under reduced pressure. Purification by CC (silica; AcOEt) yielded the title compound (32 mg, 66%): mp 138–140°C (ethyl acetate) (lit.: [22] mp 139–140°C). IR (KBr) νmax (cm-1): 3322 (NH), 1669 (C = O). 1H NMR (400 MHz CDCl3) two distinct forms, isoxazol-5(2H)-one (A) and isoxazole-5(4H)-one (B) (A:B = 90:10) A, δ 2.35 (3H, s, CH3), 6.24 (1H, sl, NH), 7.14 – 7.56 (5H, m, Ar–H); B, δ 2.04 (3H, s, CH3), 4.40 (1H, s, CH), 7.14 – 7.56 (5H, m, Ar–H).

Diphenylisoxazolin-5-one

To a solution of ethyl 3-oxo-2,3-diphenyl-propanoate (65 mg, 0.27 mmol) in EtOH (0.5 mL) and H2O (0.1 mL), was added hydroxylamine hydrochloride (32 mg, 0.46 mmol) and sodium acetate (6.4 mg, 0.078 mmol). The solution was refluxed with continuous stirring under argon for 3 h and processed as in the previous reaction to yield the title compound (40 mg, 61%) as a white powder: mp: 159°C (dec.) (benzene) (lit.: [23] mp 159°C). IR (KBr) νmax (cm-1): 3297 (NH), 1680 (C = O). 1H NMR (400 MHz CDCl3) δ 5.86 (1H, sl, NH), 7.01 – 7.79 (10H, m, Ar–H).

General procedure for the synthesis of pyrazolinones

To a stirred ethanolic solution (≈ 0.5 M) of ethyl 3-oxo-2,3-diphenylpropanoate [21] (1 eq.) in ethanol is added the desired hydrazine (1 eq.) and the reaction heated to reflux under argon. After total consumption of both starting materials (TLC control: silica, CH2Cl2:MeOH, 9:1), the solvent is evaporated under reduced pressure and the product is purified by hot recrystallization using AcOEt.

Diphenyl-1-methyl-2-pyrazolin-5-one (3a)

From methyl hydrazine, compound 3a obtained after 18 h as colourless crystals (50%): mp: 214–216°C (AcOEt). 1H NMR (400 MHz CDCl3) δ 7.72 – 7.20 (10H, m, Ar–H), 3.70 (3H, s, NCH3). 13C NMR (100.62 MHz CDCl3) δ 36.4 (NCH3), 108.4 , 124.9, 126.9, 127.2, 129.0, 131.8, 145.3, 165.8 (C = O). IR (KBr; cm-1): 3235 (N-H),1695 (C = O). EIMS (m/z, %): 250 (M+, 100), 178 (58), 77 (26). HRMS: calcd for C16H14N2O: 250.11076; found: 250.11061.

Triphenyl-2-pyrazolin-5-one (3b)

From phenylhydrazine, compound 3b obtained after 24 h as colourless crystals (71%): mp 198–199°C (AcOEt). 1H NMR (400 MHz DMSO-d6 / CDCl3, 1:2) δ 10.97 (1H, bs, OH), 7.84 – 7.25 (15H, m, Ar–H). IR (KBr, cm-1): 3236 (N-H), 1697 (C = O). EIMS (m/z, %): 312 (M+, 78), 178 (66), 77 (100). HRMS: calcd for C21H16N2O: 312.12626; found: 312.12661.

Mitsunobu propargylation of pyrazolinones 3

General procedure: To the desired pyrazolone (3a or 3b) (1.0 eq.) dissolved in dry THF (≈ 0.15 M) under argon, PPh3 (1.2 eq.) and the required propargyl alcohol (1.0 eq.) are added. The reaction is cooled to 0°C and DIAD (1.2 eq.) in dry THF (≈ 1.5 M) is added dropwise. The reaction is allowed to reach room temperature and after the reaction is finished (tlc control), the solvent is removed under vacuum. The products are purified by flash chromatography [AcOEt/n-hexane, (1:1) → AcOEt]. Following the general procedure, compounds (1a) and (2a) were obtained from 3a, and 1b and 2b from 3b.

Diphenyl-1-methyl-2-propargylpyrazolin-5-one (1a)

(65%), colourless crystals, mp 123–124°C (AcOEt). 1H NMR (400 MHz CDCl3) δ 7.47 – 7.34 (6H, m, Ar–H), 7.24 – 7.15 (4H, m, Ar–H), 4.14 (2H, d, J = 2.0 Hz, NCH2C ≡ CH), 3.49 (3H, s, NCH3), 2.21 (1H, t, J = 2.0 Hz, NCH2C ≡ CH). 13C NMR (100.62 MHz CDCl3) δ 165.5 (C = O), 152.7 [NC(Ph)], 130.4 , 130.0, 129.4, 129.0, 129.0, 128.7, 127.9, 126.7, 115.2, 75.4, 74.5, 39.0, 29.2. I.R. (NaCl; cm-1): 3279, 2109, 1651 (C = O). EIMS (m/z, %): 288 (M+, 46), 277 (100), 249 (C16H13N2O+, 25), 199 (32); 77 (45). HRMS: calcd for C19H16N2O: 288.126263; found: 288.126523.

3,4-Diphenyl-1-methyl-5-propargyloxy-pyrazole (2a)

(35%), colourless oil. 1H NMR (400 MHz CDCl3) δ 7.46 – 7.43 (2H, m, Ar–H), 7.34 – 7.22 (8H, m, Ar–H), 4.40 (2H, d, J = 2.4 Hz, OCH2C ≡ CH), 3.86 (3H, s, NCH3), 2.49 (1H, t, J = 2.4 Hz, OCH2C ≡ CH).13C NMR (100.62 MHz CDCl3) δ 149.8 [N = C(Ph)], 147.5 [N = C(Ph)C(Ph) = C], 133.7 (Ar), 132.0 (Ar), 129.6 (Ar), 128.5 (Ar), 128.1 (Ar), 127.8 (Ar), 127.4 (Ar), 126.8 (Ar), 105.6 [N = C(Ph)C(Ph) = C], 77.7 (OCH2C ≡ CH), 76.7 (OCH2C ≡ CH), 61.0 (OCH2C ≡ CH), 34.6 (NCH3). I.R. (NaCl, cm-1): 3289, 2123. EIMS (m/z, %): 288 (M+, 40), 249 (C16H13N2O+, 100), 221 (18), 178 (5), 115 (25), 91 (20). HRMS: calcd for C19H16N2O: 288.126263; found: 288.126219.

2-Propargyl-1,3,4-triphenyl-2-pyrazolin-5-one (1b)

(35%), yellowish oil. 1H NMR (400 MHz CDCl3) δ 7.65 (2H, d, J = 7.6 Hz, Ar–H), 7.52 – 7.41 (8H, m, Ar–H), 7.33 – 7.19 (5H, m, Ar–H), 4.03 (2H, d, J = 2.2 Hz, NCH2C ≡ CH), 2.16 (1H, t, J = 2.2 Hz, NCH2C ≡ CH). 13C NMR (100.62 MHz CDCl3) δ 164.6 (C = O) , 154.9 [NC(Ph) = C(Ph)] , 134.8 (Ar) , 130.2 (Ar), 130.1 (Ar), 129.5 (Ar), 129.2 (Ar), 129.0 (Ar), 129.0 (Ar), 128.0 (Ar), 127.0 (Ar), 126.6 (Ar), 123.5 (Ar), 116.6 [NC(Ph) = C(Ph)], 74.6 (NCH2C ≡ CH), 74.1 (NCH2C ≡ CH), 40.6 (NCH2C ≡ CH). IR (film, cm-1): 3298, 2116, 1667 (C = O).

5-Propargyloxy-1,3,4-triphenyl-2-pyrazole (2b)

(35%), yellowish oil. 1H NMR (400 MHz CDCl3) δ 7.91 (2H, d, J = 7.8 Hz, Ar–H), 7.58 – 7.30 (13H, m, Ar–H), 4.40 (2H, d, J = 2.3 Hz, OCH2C ≡ CH), 2.36 (1H, t, J = 2.3 Hz, OCH2C ≡ CH). 13C NMR (100.62 MHz CDCl3) δ 149.5 [N = C(Ph)C(Ph) = C], 149.0 [N = C(Ph)C(Ph) = C], 138.5 (Ar), 133.3 (Ar), 131.6 (Ar), 129.9 (Ar), 128.9 (Ar), 128.5 (Ar), 128.1 (Ar), 128.0 (Ar), 127.7 (Ar), 127.1 (Ar), 126.8 (Ar), 122.8 (Ar), 107.9 [N = C(Ph)C(Ph) = C], 77.1 (OCH2C ≡ CH), 76.8 (OCH2C ≡ CH), 61.0 (OCH2C ≡ CH). IR (film, cm-1): 3291, 2125.

General procedure for the thermal rearrangements of pyrazolinones and isomers

In a round bottom flask, the N-substituted pyrazolinone or its O-substituted isomer dissolved in o-dichlorobenzene (ca. 0.04 – 0.05 M), are heated at 180°C until total consumption of the starting material (TLC control). After solvent evaporation the products are purified by flash chromatography [Et2O/n-hexane (1:4)].

Pyrazolinone 4a from 1a

Following the general procedure, heating 1a (30 mg) for 60 min afforded 3,4-diphenyl-1-methyl-4-(prop-1′,2′-dienyl) pyrazolin-5-one (4a) (10.5 mg, 35%) as a colourless crystals: mp 146–147°C (Et2O). 1H NMR (400 MHz CDCl3) δ 7.56 (2H, d, J = 7.0 Hz, Ar–H), 7.37 – 7.26 (8H, m, Ar–H), 5.79 (1H, t, J = 6.6 Hz, (CH = C = CH2), 4.90 (1H, dd, J = 11.6, 6.6 Hz, CH = C = CH2), 4.74 (1H, dd, J = 11.6, 6.6 Hz, CH = C = CH2), 3.45 (3H, s, NCH3).13C NMR (100.62 MHz CDCl3) δ 208.9, 174.5, 158.8, 136.1, 129.9, 129.2, 128.4, 128.2, 127.0, 89.1, 79.1, 60.1, 31.8. IR (film, cm-1 ) : 3061, 2921, 1956 (C = C = C), 1714 (C = O), 1496.EIMS (m/z, %): 288 (M+, 60), 230 (40), 178 (20), 128 (65), 77 (100). HRMS: calcd for C19H16N2O: 288.126263; found: 288.126455.

Pyrazolinone 4b from 1b

Following the general procedure, heating 1b (14 mg) for 10 min afforded 4-(prop-1′,2′-dienyl)-1,3,4-triphenylpyrazolin-5-one (4b) (10.1 mg, 72%) as a colourless oil. 1H NMR (400 MHz CDCl3) δ 8.07 (2H, d, J = 7.8 Hz, Ar–H), 7.70 (2H, d, J = 7.8 Hz, Ar–H), 7.47 – 7.23 (11H, m, Ar–H), 5.90 (1H, t, J = 6.7 Hz, CH = C = CH2), 4.94 (1H, dd, J = 11.7, 6.7 Hz, CH = C = CH2), 4.77 (1H, dd, J = 11.7, 6.7 Hz, CH = C = CH2). 13C NMR (100.62 MHz CDCl3) δ 209.0 (CH = C = CH2), 172.7 (C = O), 159.1 (N = C), 138.2, 136.0, 130.2, 130.1, 129.3, 128.9, 128.4, 127.4, 127.0, 125.3, 119.1, 89.1 (CH = C = CH2), 79.5 (CH = C = CH2), 61.6 (C–CH = C = CH2). IR (film, cm-1): 3063, 2921, 1954 (C = C = C), 1721 (C = O), 1596, 1494. EIMS (m/z, %): 350 (M+, 25), 230 (12), 178 (10), 128 (21), 91 (32), 77 (100). HRMS: calcd for C24H18N2O: 350.141913; found: 350.142194.

Pyrazolinone 4a from isomer 2a

Following the general procedure, heating 2a (20 mg) for 10 min afforded 3,4-diphenyl-1-methyl-4-(prop-1′,2′-dienyl)pyrazolin-5-one (4a) (18 mg, 90%) as a white solid with data identical with 4.4.1.

Pyrazolinone 4b from isomer 2b

Following the general procedure, heating 2b (24 mg) for 10 min afforded 4-(prop-1′,2′-dienyl)-1,3,4-triphenylpyrazolin-5-one (4b) (24 mg, 99%) as a white solid with data identical with 4.4.2.

Pyrazolinone 6a from 5a

Following the general procedure, heating 5a (10 mg) for 30 min afforded the pyrazolinone 6a (3 mg, 30%) as a glassy solid. 1H NMR (400 MHz CDCl3) δ 7.52 (2H, d, J = 7.3 Hz, Ar–H), 7.38 – 7.22 (8H, m, Ar–H), 3.47 (3H, s, NCH3), 3.43 (1H, dd, J = 16.0 Hz, 2.5 Hz, CH2C ≡ CH), 3.05 (1H, dd, J = 16.0, 2.5 Hz, CH2C ≡ CH), 1.91 (1H, t, J = 2.5 Hz, CH2C ≡ CH). IR (film, cm-1): 3291 (C ≡ C-H), 2923, 1956 (C ≡ C), 1713 (C = O).

Pyrazolinone 6a from isomer 7a

Following the general procedure, heating 7a (10 mg) for 10 min afforded 6a (8 mg, 80%) with data identical with the previous reaction.

Reactions of pyrazolinones with base

In a round bottom flask, the propargylated pyrazolinone 1a or its isomer 2a is dissolved in dry THF (ca. 0.07 M) (1 eq.) under argon and 18-crown-6 ether (1 eq.) is added. After total dissolution of the reactants, EtOK (0.1 eq.) is added under anhydrous conditions. The reaction is left to react at room temperature. After consumption of the starting material (TLC control) the reaction is stopped by addition of a saturated solution of NH4Cl and extraction with Et2O (2x). The product is purified by flash chromatography [AcOEt / n-hexane (1:6)].

Pyrazolinone 6a from isomer 7a

Following the general procedure, 3,4-diphenyl-1-methyl-2-(prop-1′,2′-dienyl)pyrazolin-5-one (5a) was obtained from 1a after 16 h as a colourless oil (65%). 1H NMR (400 MHz CDCl3) δ 7.69 – 7.64 (4H, m, Ar–H), 7.56 – 7.52 (2H, m, Ar–H), 7.47 – 7.43 (4H, m, Ar–H), 6.30 (1H, t, J = 6.2 Hz, N–CH = C = CH2), 5.32 (2H, d, J = 6.2 Hz, NCH = C = CH2), 3.49 (3H, s, NCH3). IR (film, cm-1): 3055, 2925, 1962 (C = C = C), 1659 (C = O), 1483.

Isomer 7a from 2a

Following the general procedure, 1-methyl-3,4-diphenyl-5-(prop-1′,2′-dienyloxy)pyrazole (7a) was obtained from 2a after 16 h as a colourless oil (74%). 1H NMR (400 MHz CDCl3) δ 7.47 – 7.43 (2H, m, Ar–H), 7.34 – 7.24 (8H, m, Ar–H), 6.79 (1H, t, J = 5.9 Hz, OCH = C = CH2), 5.36 (2H, d, J = 5.9 Hz, OCH = C = CH2), 3.81 (3H, s, NCH3). 13C NMR (100.62 MHz CDCl3) δ 200.0 (OCH = C = CH2), 147.7, 147.5, 133.5 (Ar), 131.6, 129.6, 129.2, 128.3, 128.2, 127.9, 127.6, 126.7, 121.7 (OCH = C = CH2), 93.0 (OCH = C = CH2), 34.7 (NCH3). IR (film, cm-1): 3059, 2940, 1972 (C = C = C), 1605, 1563.

Synthesis of isoxazolinones

Diphenyl-2-(prop-2′-yn-1′-yl)isoxazolin-5-one (8a)

To a solution of 3,4-diphenylisoxazolin-5-one (Section 4.2.4) (100 mg, 0.422 mmol), triphenylphosphine (121 mg, 0.46 mmol) and propargylic alcohol (21.5 mg, 0.384 mmol) in dry THF (1.5 mL) were added, dropwise, DIAD (93 mg, 0.460 mmol). After the addition was completed, the solvent was removed under reduced pressure and the crude purified by CC (silica; Et2O / n-hexane 1:2) to yield the title compound 8a (22 mg, 21 %): mp 81–82°C (Et2O / n-hexane). IR (KBr, cm-1): 3291 (HC≡C), 2127 (C≡C), 1746 (C = O). 1H NMR (400 MHz CDCl3) δ 2.64 (1H, s, HC≡C), 5.06 (2H, d, J = 2.1 Hz, NCH2), 7.26 – 7.56 (10H, m, Ar–H). EIMS (m/z, %): 275 (M+, 23), 178 (34), 105 (100), 89 (60), 77 (50). HRMS calcd for C18H13NO2: 275.09463; found: 275.09405.

Diphenyl-2-(2′-methylbut-3′-yn-2′-yl)isoxazolin-5-one (8b)

Following Nicholas protocol [24], to a stirred solution of 2-methylbut-3-yn-2-ol (25.2 mg, 0.3 mmol) in petroleum ether (2 mL), under nitrogen at RT, was added Co2(CO)8 (102.6 mg, 0.3 mmol.) and MS 4 Å, followed by boron trifluoride diethyl etherate (42.5 mg, 0.3 mmol). After 10 min 3,4-diphenylisoxazolin-5-one (Section 4.2.4) (23.7 mg, 0.1 mmol) was added and the reaction monitored by TLC (silica; CH2Cl2 / AcOEt 4:1) until consumption of the starting isoxazolone. After 48 h water (5 mL) was added to the reaction mixture which was extracted with Et2O (2x5 mL) to yield the cobalt complex as a red oil, which was purified by PTLC (silica; n-hexane / AcOEt 4:1). To a solution of this red complex in acetone (2 mL) was added Et3N (0.1 mmol) and (NH4)2Ce(NO3)6 (55 mg, 0.1 mmol) until formation of the required isoxazolinone. Water was added (10 mL), followed by extraction of the mixture with Et2O (3x5 mL) and purification by PTLC (silica; Et2O / n-hexane 1:1) afforded the N-substituted isoxazolinone 8b (17.6 mg, 58%): mp 113–115°C (Et2O / n-hexane). IR (KBr, cm-1): 3291 (HC≡C), 2113 (C≡C), 1746 (s, C = O). 1H NMR (400 MHz CDCl3) δ 1.48 (6H, s, CH3), 2.31 (1H, s, HC≡C), 7.19 – 7.50 (10H, m, Ar–H). 13C-NMR (100.62 MHz CDCl3) δ 28.5 [NC(CH3)2], 61.3 [NC(CH3)2], 73.7 (HC≡C), 82.4 (HC≡C), 127.4, 128.2, 128.3, 128.7, 129.5, 130.6, 170.2. EIMS (m/z, %): 303 (M+, 17), 237 (C15H11NO2+, 100), 178 (35), 67 (40). HRMS: calcd for C20H17NO2: 303.12593; found: 303.12641.

Allyl-3-methyl-4-phenylisoxazolin-5-one (8c)

To 3-methyl-4-phenylisoxazolin-5-one (Section 4.2.3) (0.3 g, 1.71 mmol) was added a solution of Na (39 mg) in EtOH (1.7 mL). To this solution was added allyl bromide (0.207 mg, 1.71 mmol). The reaction mixture was magnetically stirred, under argon, while being heated under reflux (1.8 h). On completion of the reaction (TLC control: silica; 1) Et2O / n-hexane 1:1, 2) AcOEt), the solvent was removed under reduced pressure. Purification by CC (silica; Et2O / n-hexane 1:1) afforded the title compound 8c (171,6 mg, 66%) as a white solid: mp 50–51°C ( Et2O / n-hexane). IR (KBr, cm-1): To 3-methyl-4-phenylisoxazolin-5-one (Section 4.2.3) (0.3 g, 1.71 mmol) was added a solution of Na (39 mg) in EtOH (1.7 mL). To this solution was added allyl bromide (0.207 mg, 1.71 mmol). The reaction mixture was magnetically stirred, under argon, while being heated under reflux (1.8 h). On completion of the reaction (TLC control: silica; 1) Et2O / n-hexane 1:1, 2) AcOEt), the solvent was removed under reduced pressure. Purification by CC (silica; Et2O / n-hexane 1:1) afforded the title compound 8c (171,6 mg, 66%) as a white solid: mp 50–51°C ( Et2O / n-hexane). IR (KBr, cm-1): 1711 (C = O), 1604 (C = C).1H NMR (400 MHz CDCl3) δ 2.29 (3H, s, CH3), 4.27 (2H, d, J 6 Hz, NCH2), 5.30 (2H, m, CH2 = CH), 5.80 (1H, m, CH2 = CH), 7.27 (1H, t, J = 7.4 Hz, p-Ar–H), 7.38 (2H, t, J = 7.5 Hz, m-Ar–H), 7.46 (2H, d, J = 7.6 Hz, o-Ar–H). 13C-NMR (100.62 MHz CDCl3) δ 11.8 (CH3), 53.1 (N–CH2), 103.8 [N–C(Me) = C(Ph)], 120.5 (CH2 = CH), 127.2 (Ar), 128.2 (Ar), 128.5 (Ar), 129.4 (Ar), 129.6 (CH2 = CH), 159.3 [N–C(Me) = C(Ph)], 169.5 (C = O). EIMS (m/z, %): 215 (M+, 100), 130 (21), 116 (38), 115 (46), 89 (13), 77 (13). HRMS: calcd for C13H13NO2: 215.09463; found: 215.09397.

Allyl-3,4-diphenylisoxazolin-5-one (8d)

3,4-Diphenylisoxazolin-5-one (Section 4.2.4) (0.406 g, 1.71 mmol), using the previous protocol, afforded the title compound (8d) (256 mg, 85%) as a white solid: mp 105–106°C (Et2O / n-hexane). IR (KBr, cm-1): 1720 (C = O), 1615 (C = C). 1H NMR (400 MHz CDCl3) δ 4.06 (2H, d, J 6.0 Hz, NCH2), 5.16 (1H, d, J = 17.2 Hz, CH2 = CH), 5.25 (1H, d, J = 10.8 Hz, CH2 = CH), 5.78 (1H, m, CH2 = CH), 7.18 – 7.48 (10 H, m, Ar–H). 13C NMR (100.62 MHz CDCl3) δ 54.9 (N–CH2), 105.2 [N–C(Ph) = C(Ph)], 121.0 (CH2 = CH), 127.2 (Ar), 127.7 (Ar), 128.2(Ar), 128.3(Ar), 128.7(Ar), 129.0(Ar), 129.2(Ar), 129.3(Ar), 131.0 (CH2 = CH), 162.8 [N–C(Ph)], 169.9 (C = O). EIMS (m/z, %): 277 (M+, 100), 236 (12), 192 (27), 178 (76), 133 (13), 117 (51), 89 (46), 77 (22). HRMS: calcd for C18H15NO2: 277.11028; found: 277.11037.

Synthesis of isoxazolidinone 8e

Diethyl 2-[(allyl-(tert-butyldimethylsilyloxy)amino) methylene]malonate (10)

To a stirred solution of N-tert-butyldimethylsilyloxyprop-2-en-1-amine (0.5 g, 2.67 mmol) in CCl4 / CHCl3 (1:3) (20 mL) under argon was added diethyl 2-(ethoxymethylene)malonate [7] (0.58 g, 2.67 mmol, 1 eq.). On completion of the reaction (TLC control: silica, Et2O / n-hexane 1:1) (30 h), the solvent was removed under reduced pressure by CC (silica; Et2O / n-hexane 1:1) to afford the title compound 10 (50%) as an oil (50%): IR (film, cm-1) 1732 (C = O), 1707 (C = O), 1621 (C = C), 1262 (Si–O-N). 1H NMR (400 MHz CDCl3) δ 0.19 [6H, s, Si(CH3)2], 0.93 [9H, s, C(CH3)3], 1.23 (6H, m, OCH2CH3), 4.00 (2H, d, J = 6.0 Hz, NCH2), 4.12 (4H, m, OCH2CH3), 5.26 (1H, d, J = 10.4 Hz, CH2 = CH), 5.35 (1H, d, J = 17.3 Hz, CH2 = CH), 5.90 (1H, m, CH2 = CH), 7.88 (1H, s, N–CH = C). 13C NMR (100.62 MHz CDCl3) δ -5.3 [Si(CH3)2], 14.1 (OCH2CH3), 17.8 [C(CH3)3], 25.8 [C(CH3)3], 59.9 (CH2N), 60.3 (OCH2CH3), 60.6 (OCH2CH3), 61.4 (NCH = C), 119.6 (CH2 = CH), 131.1 (CH2 = CH), 149.5 (N–CH), 166.2 (C = O). EIMS (m/z, %): 357 (M+, 66), 312 ([M-C2H5O]+, 86), 300 ([M-C4H9]+, 100), 226 ([M-C6H15OSi]+, 97), 198 (20), 57 (C4H9+, 49). HRMS: calcd for C17H31NO5Si: 357.19715; found: 357.19796.

Diethyl 2-[(allyl-(tert-butyldimethylsilyloxy)amino) methylene]malonate (10)

To a magnetically stirred solution of 2-[(allyl-(tert-butyldimethylsilyloxy)amino) methylene]malonate [5] (10) (50 mg, 0.140 mmol) in CH3CN [6 mL, 0.1% H2O (m/v)], at RT under nitrogen, was added SbCl5 (359 μL, from 0.039 M solution in CH3CN, 0.1 eq.). On completion of the reaction (10 m), (TLC control: silica; Et2O / n-hexane 1:1), the solvent was removed under reduced pressure. Purification by CC (silica; Et2O / n-hexane 1:1) afforded diethyl 2-[(allyl(hydroxyl)amino) methylene]malonate (11) (23 mg, 68%), and ethyl 2-allyl-5-oxo-2,5-dihydroisoxazole-4-carboxylate (8e) (3.3 mg, 12%). Compound 11 was unstable and lactonised spontaneously on standing to the 2-allyl-isoxazolinone 8e.

Ethyl 2-allyl-5-oxo-2,5-dihydroisoxazole-4-carboxylate (8e)

Colourless crystals, mp 45–46°C (n-hexane). IR (film, cm-1): 1784 (C = O, ester), 1698 (C = O), 1578 (C = C). 1H NMR (400 MHz CDCl3) δ 1.30 (3H, t, J = 7.1 Hz, OCH2CH3), 4.26 (2H, q, J = 7.1 Hz, OCH2CH3), 4.47 (2H, d, J = 6.3 Hz, NCH2), 5.46 (2H, m, CH2 = CH), 5.89 (1H, m, CH2 = CH), 8.34 (H, s, N–CH). Elemental analysis: calcd for C9H11NO4 (%): C: 54.80, H: 5.63, N: 7.11. Found (%): C: 54.53, H: 5.66, N: 7.01.

Diethyl 2-[(N-allyl(hydroxyl)amino)methylene] malonate(11)

Oil, IR (film, cm-1): 3600 – 1800 (l, OH), 1685 (C = O), 1629 (C = C). 1H NMR (400 MHz CD3CN) δ 1.26 (3H, t, J = 7.1 Hz, OCH2CH3), 1.33 (3H, t, J = 7.1 Hz, OCH2CH3), 4.16 (2H, q, J = 7.1 Hz, OCH2CH3), 4.25 (4H, m, OCH2CH3 + NCH2), 5.39 (2H, m, CH2 = CH), 5.96 (1H, m, CH2 = CH), 7.86 (1H, s, N–CH = C), 13.11 (1H, s, OH, exchange D2O). 13C NMR (100.62 MHz CD3CN) δ 14.1 (OCH2CH3), 30.2 (CCO2Et), 60.0 (OCH2CH3), 61.5 (OCH2CH3), 61.6 (NCH2), 120.8 (CH = CH2), 129.9 (CH = CH2), 147.3 (NCH = C), 166.2 (C = O). EIMS (m/z, %) 243 (M+, 2), 197 (C9H11NO4+, 100). HRMS: calcd for C11H17NO5: 243.11067; found: 243.10985.

General procedure for the thermal rearrangements of isoxazolinones

In a round bottom flask, the isoxazolinones (8a-e) dissolved in o-dichlorobenzene (ca. 0.04 – 0.05 M) are heated until total consumption of the starting material (TLC control). After solvent evaporation the products are purified by flash chromatography.

Rearrangement of the 3,4-diphenyl-2-(prop-2′-yn-1′-yl)isoxazolin-5-one (8a)

Following the general procedure, 3,4-diphenyl-4-(prop-1′,2′-dien-1-yl)isoxazolin-5-one (9a) was obtained by heating 8a (10 mg) at 60°C for 30 m, followed by CC (silica; Et2O / n-hexane 1:1), as an oil (75%): IR (film, cm-1): 1965 (C = C = C), 1798 (C = O). 1H NMR (400 MHz CDCl3) δ 4.88 (1H, dd, J = 6.6, 12.1 Hz, CH = C = CH2), 5.04 (1H, dd, J = 6.6, 12.1 Hz, CH = C = CH2), 5.80 (1H, t, J = 6.6 Hz, HC = C = CH2), 7.30 – 7.58 (10H, m, Ar–H). 13C NMR ( 100.62 MHz CDCl3) δ 57.8 [N = C(Ph)C], 80.6 (CH = C = CH2), 88.0 (CH = C = CH2), 126.9 (Ar), 127.1 (Ar), 127.7 (Ar), 128.8 (Ar), 129.2 (Ar), 129.6 (Ar), 131.6 (Ar), 134.3 (Ar), 166.6 (N = C), 175.1 (C = O), 203.0 [CH = C = C(CH3)2]. EIMS (m/z, %): 275 (M+, 19), 231 ([M-CO2]+, 100), 172 (89), 128 (99), 102 (89), 77 (82). HRMS: calcd for C18H13NO2: 275.09463; found: 275.09556.

Rearrangement of 3,4-diphenyl-2-(2′-methylbut-3′-yn-2′-yl)isoxazolin-5-one (8b)

Following the general procedure, 3,4-diphenyl-4-(3′-methylbut-1′,2′-dien-1′-yl)isoxazolin-5-one (9b) was obtained by heating 8b at 60°C for 10 m, followed by CC (silica; Et2O / n-hexane 1:1), as a colourless solid (85%): mp 77–80 (Et2O / n-hexane). IR (KBr, cm-1): 1969 (C = C = C), 1790 (C = O). 1H NMR (400 MHz CDCl3) δ 1.37 (3H, s, CH3), 1.62 (3H, s, CH3), 5.65 (1H, t, J = 2.6 Hz, HC = C = C), 7.28 – 7.54 (10H, m, Ar–H). 13C NMR (100.62 MHz CDCl3) δ 19.3 (CH3), 19.7 (CH3), 58.5 [N = C(Ph)C], 86.6 [CH = C = C(CH3)2], 102.2 (CH = C = C(CH3)2), 127.0 (Ar), 127.7 (Ar), 128.1 (Ar), 128.5 (Ar), 128.9 (Ar), 129.4 (Ar), 129.7 (Ar), 131.2 (Ar), 132.2 (Ar), 134.7 (Ar), 167.2 (N = C), 177.5 (C = O), 203.5 (CH = C = C(CH3)2). EIMS (m/z, %) 303 (M+, 1), 288 ([M-CH3]+, 29), 259 ([M-CO2]+, 53), 244 (C18H14N+, 50), 200 (C13H12O2+, 100), 141 (C11H9+, 71), 89 (C7H5+, 20), 77 (C6H5+, 76).

Rearrangement of 2-allyl-3-methyl-4-phenylisoxazolin-5-one (8c)

Following the general procedure, 4-allyl-3-methyl-4-phenylisoxazolin-5-one (9c) was obtained by heating 8c at 180°C for 7 h, followed by CC (silica; Et2O / n-hexane 1:1), as a viscous oil (95%): IR (film, cm-1): 1791 (C = O), 1643 (C = N). 1H NMR (400 MHz CDCl3) δ 1.95 (3H, s, CH3), 2.85 (1H, dd, J = 7.8, 13.7 Hz, C–CH2), 3.10 (1H, dd, J 6.7, 13.7 Hz, C–CH2), 5.25 (1H, d, J = 10.1 Hz, CH2 = CH), 5.30 (1H, d, J = 16.9 Hz, CH2 = CH), 5.60 (1H, m, CH2 = CH), 7.20 – 7.44 (5H, m, Ar–H). 13C NMR (100.62 MHz CDCl3) δ 12.4 (CH3), 36.4 (C–CH2), 59.3 (C–CH2), 121.4 (CH2 = CH), 126.2 (Ar), 127.3, 127.8, 128.9, 129.5, 129.7, 133.3 (CH2 = CH), 168.3 (C = N), 178.7 (C = O). EIMS (m/z, %): 215 (M+, 100), 116 (15), 115 (40), 77 (30). HRMS: calcd for C13H13NO2: 215.09463; found: 215.09414.

Rearrangement of 2-allyl-3,4-diphenylisoxazolin-5-one (8d)

Following the general procedure, 4-allyl-3-methyl-3,4-phenylisoxazolin-5-one (9d) was obtained by heating 8d at 180°C for 5 h, followed by CC (silica; Et2O / n-hexane 1:1), as a pale yellow solid (97%): mp 71–72°C. IR (KBr, cm-1): 1800 (f, C = O), 1644 (C = N).1H NMR (400 MHz CDCl3) δ 3.03 (1H, dd, J = 7.2, 13.2 Hz, C–CH2), 3.32 (1H, dd, J = 7.6, 13.2 Hz, C–CH2), 5.25 (1H, d, J = 16,9 Hz, CH2 = CH), 5.14 (1H, d, J = 10.1 Hz, CH2 = CH), 5.54 (1H, m, CH2 = CH), 7.33 – 7.52 (10H, m, Ar–H). 13C NMR (100.62 MHz CDCl3) δ 37.5 (C–CH2), 58.8 (C–CH2), 121.8 (CH2 = CH), 126.3 (Ar), 127.2 (Ar), 127.4 (Ar), 128.9 (Ar), 129.0 (Ar), 129.4 (Ar), 129.7 (Ar), 131.7 (CH2 = CH), 134.4 (Ar), 167.1 (N = C), 169.9 (C = O). EIMS (m/z, %): 277 (M+, 100), 236 ([M-C3H5]+, 12), 232 (21), 178 (49), 117 (51), 103 (35), 77 (30). HRMS: calcd for C18H15NO2: 277.11028; found: 277.10956.

Rearrangement of the ethyl 2-allyl-5-oxo-2,5-dihydroisoxazole-4-carboxylate (8e)

Following the general procedure, ethyl 2-cyanopent-4-enoate (12) was obtained by heating 8e at 180°C for 5 h, followed by CC (silica; Et2O / n-hexane 1:1), as a colourless oil [13] (80%): IR (film, cm-1): 2266 (-C≡N), 1750 (C = O). 1H NMR (400 MHz CDCl3) δ 1.32 (3H, t, J = 7.1 Hz, OCH2CH3), 2.69 (2H, m, CHCH2CH), 3.56 (1H, t, J = 6.8 Hz, NC–CH), 4.27 (2H, q, J = 7.1 Hz, OCH2CH3), 5.25 (2H, m, CH2 = CH), 5.83 (1H, m, CH2 = CH).

Reaction of isoxazolinones with base

Reaction of 2-allyl-3,4-diphenylisoxazolin-5-one (8d)

To a stirred solution of compound 8d (80 mg, 0.289 mmol) in dry 1,4-dioxane (2 mL) at RT under argon, potassium ethoxide (1.5 eq., 36.5 mg, 0.434 mmol) and 18-crown-6 ether (114.7 mg, 0.434 mmol) were added. After 10 m the reaction was found complete (TLC control: silica; Et2O / n-hexane 3:1), the mixture was neutralized with aq. 0.5 N AcOH and the solvent removed under reduced pressure. The crude was diluted with Et2O (5 mL) and washed with distilled water (2 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by CC (silica; Et2O / n-hexane 3:1) afforded 2-(2′-ethoxyethyl)-4,5-diphenyl-2,3-dihydro-1,3-oxazin -6-one (14) (23.3 mg, 25%) as a yellow oil: IR (film, cm-1): 3257 (NH), 1694 (C = O), 1600, 1585, 1553. 1H NMR (400 MHz CDCl3) δ 1.05 (3H, t, J = 7.0 Hz, OCH2CH3), 2.22 (2H, m, CHCH2), 3.44 (2H, m, OCH2CH3), 3.62 (1H, m, OCH2CH2), 3.77 (1H, m, OCH2CH2), 5.47 (1H, q, J = 4.9 Hz, CHCH2), 6.46 (1H, d, J = 4.1 Hz, NH – exchange D2O), 7.02 – 7.24 (10H, m, Ar–H). 13C NMR (100.62 MHz CDCl3) δ 15.0 (OCH2CH3), 32.0 (OCH2CH2), 65.7 (OCH2CH3), 66.6 (OCH2CH2), 81.6 (N–CH–O), 103.9 (N–C = C–CO), 126.1 (Ar), 127.6 (Ar), 128.2 (Ar), 129.8 (Ar), 130.2 (Ar), 131.4 (Ar), 133.9 (Ar), 134.9 (Ar), 155.5 (N–C = C–CO), 166.3 (C = O). EIMS (m/z, %) 323 (M+, 100), 250 (C16H12NO2+, 90), 178 (C14H10+, 99), 77 (C6H5+, 43). HRMS: calcd for C20H21NO3: 323.15214; found: 323.15254; and deoxybenzoin (15, R = H) (25.5 mg, 45%) as a colourless solid: mp 55–56°C (lit.: [25] mp 55–56°C). IR (KBr, cm-1): 1686 (C = O). 1H NMR (400 MHz CDCl3) δ 4.29 (2H, s, CH2), 7.24 – 8.04 (10 H, m, Ar–H). After the reaction in a parallel run was completed, glacial CH3COOD (3.0 eq.) was added to the reaction followed by H2O (2 mL). The reaction mixture was diluted with Et2O (5 mL) and washed with an aqueous solution of 1M NaHCO3. The aqueous layer was extracted with Et2O (3 × 5 mL), the combined organic extracts were dried over anhydrous sodium sulphate, filtered and concentrated. Purification by CC (silica; Et2O / n-hexane 1:1) afforded mono-deuterated deoxybenzoin (15, R = D) (37.5 mg, 66%): 1H NMR (400 MHz CDCl3) δ 4.29 (1H, s, CHD), 7.23 – 8.06 (10 H, m, Ar–H).

Reaction of ethyl 2-allyl-5-oxo-2,5-dihydroisoxazole-4-carboxylate (8e)

To a stirred solution of compound 8e (50 mg, 0.254 mmol) in dry 1,4-dioxane (1 mL) at RT under argon, was added potassium ethoxide (32 mg, 0.38 mmol, 1.5 eq.) and 18-crown-6 ether (100 mg, 0.38 mmol). On completion of the reaction (5 h, TLC control: silica; Et2O), the solvent was removed under reduced pressure and the crude purified by cc (silica; Et2O). N-Allyl-malonamic acid ethyl ester (13) was obtained as a white solid (34.7 mg, 80%): mp 40–41°C (Et2O). IR (KBr) νmax (cm-1): 3299 (NH), 1740 (C = O ester), 1659 (C = O amide). 1H NMR (400 MHz CDCl3) δ 1.22 (3H, t, J = 7.1, OCH2CH3), 3.26 (2H, s, COCH2COOEt), 3.84 (2H, t, J = 5.6 Hz, NH-CH2), 4.13 (2H, q, J = 7.1 Hz, OCH2CH3), 5.07 (1H, dd, J = 1.1, 10.3 Hz, CH2 = CH), 5.14 (1H, dd, J = 1.3, 17.1 Hz, CH2 = CH), 5.80 (1H, m, CH2 = CH), 7.29 (1H, bs, NH exchange D2O). 13C NMR (100.62 MHz CDCl3) δ 14.0 (COOCH2CH3), 41.3 (COCH2COOEt), 41.8 (NHCH2), 61.5 (COOCH2CH3), 116.2 (CH2 = CH), 133.7 (CH2 = CH), 165.0 (NHC = O), 169.3 (COOEt). EIMS (m/z, %): 171 (M+, 10), 56 (C3H6N+, 100). HRMS: calcd for C8H13NO3: 171.08954; found: 171.08894.

Reactions of 2-(2′-methylbut-3′-yn-2′-yl)-3,4-diphenylisoxazolin-5-one (8b)

With 1.5 eq. of EtOK

To a stirred solution of compound (8b) (15 mg, 0.055 mmol) in dry 1,4-dioxane (0.25 mL), under argon, was added potassium ethoxide (1.5 eq., 7.0 mg, 0.083 mmol) and 18-crown-6 ether (21.8 mg, 0.083 mmol). On completion of the reaction (10 min) (TLC control: silica; Et2O / n-hexane 3:1), the mixture was neutralized with aq. AcOH 0.5 N and the solvent removed under reduced pressure. The crude was diluted with Et2O (5 mL) and washed with destilled H2O (2 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. Purification by CC (silica; Et2O / n-hexane 3:1) afforded 4-(3′-methylbut-1′,2′-dienyl-1′-yl)-3,4-diphenylisoxazolin-5-one (9b) (4.5 mg, 30%). After 30 min of reaction, no rearrangement product could be still detected by TLC.

With 0.1 eq. of EtOK

Using the previous conditions with potassium ethoxide (0.1 eq.) and 18-crown-6 ether (0.1 eq.), the reaction after 5 days yielded 9b (55%).

With LDA

To a stirred solution of 8b (1 eq.) in dry 14-dioxane, under argon, were added LDA (1.5 eq., from a 1.47 M solution) and 12-crown-4 ether (1.5 eq.). The reaction mixture was stirred for 48 h. TLC control (silica; Et2O / n-hexane 3:1) showed no reaction and the starting material was recovered yield (5.4 mg, 90%).

With tert-BuLi

To a stirred solution of 8b (1 eq.) in dry 1,4-dioxane, under argon, were added tert-BuLi (2 eq., from an hexane solution 0.8 M, 0.066 mmol) and 12-crown-4 ether (2 eq.). The reaction mixture was stirred for 70 h. TLC control (silica; Et2O / n-hexane 3:1) showed no reaction and the starting material was recovered (9.5 mg, 95%).

Endnote

a Web Table (which contains energy profiles, molecular coordinates of intermediates and transition states as well as normal mode animations) is available via the HTML version of the article.

References

  1. Nubbemeyer U: Recent advances in charge-accelerated Aza-Claisen rearrangements. Top Curr Chem. 2005, 244: 149-213. and references cited therein

    CAS  Google Scholar 

  2. Weston MH, Nakajima K, Back TG: Tandem conjugate additions and 3-aza-Cope rearrangements of tertiary allyl amines and cyclic alpha-vinylamines with acetylenic sulfones. Applications to simple and iterative ring expansions leading to medium and large-ring nitrogen heterocycles. J Org Chem. 2008, 73: 4630-4637. 10.1021/jo800600a. and references cited therein

    Article  CAS  Google Scholar 

  3. Nubbemeyer U: Aza-Claisen Rearrangement. The Claisen Rearrangement: Methods and Applications. Edited by: Hiersemann M, Nubbemeyer U. 2007, Weinheim: Wiley-VCH, 461-

    Chapter  Google Scholar 

  4. Glória PMC, Prabhakar S, Lobo AM: Studies in N-amino-3-aza Cope rearrangements. Tetrahedron Lett. 2008, 49: 7355-7357. 10.1016/j.tetlet.2008.10.047.

    Article  Google Scholar 

  5. Gomes MJS, Sharma L, Prabhakar S, Lobo AM, Glória PMC: Studies in 3-oxy-assisted 3-aza Cope rearrangements. Chem Commun. 2002, 746-747.

    Google Scholar 

  6. Hastings CJ, Fiedler D, Bergman RG, Raymond KN: Aza Cope Rearrangement of Propargyl Enammonium Cations Catalyzed By a Self-Assembled ‘Nanozyme’. J Am Chem Soc. 2008, 130: 10977-10983. 10.1021/ja8013055.

    Article  CAS  Google Scholar 

  7. Pinto LFV, Glória PMC, Gomes MJS, Rzepa HS, Prabhakar S, Lobo AM: A dramatic effect of double bond configuration in N-oxy-3-aza Cope rearrangements¬–a simple synthesis of functionalised allenes. Tetrahedron Lett. 2009, 50: 3446-3449. 10.1016/j.tetlet.2009.02.228.

    Article  CAS  Google Scholar 

  8. Gilbert JC, Cousins KR: Theoretical and experimental studies of the 3-aza-Claisen rearrangement. Tetrahedron. 1994, 50: 10671-10784. 10.1016/S0040-4020(01)89259-0.

    Article  CAS  Google Scholar 

  9. Mitsunobu O, Mulder JA, Xiong H, Zificsak CA, Douglas CJ, Hsung RP: Efficient preparations of novel ynamides and allenamides. Tetrahedron. 2001, 57: 459-466. 10.1016/S0040-4020(00)01014-0.

    Article  Google Scholar 

  10. Makisumi Y: A facile amino-Claisen rearrangement. Tetrahedron Lett. 1966, 7: 6413-6417. 10.1016/S0040-4039(00)76118-1.

    Article  Google Scholar 

  11. Makisumi Y, Sasatani T: Sigmatropic tautomerism between n-allyl-3-isoxazolin-5-ones and 4-allyl-2-isoxazolin-5-ones. Tetrahedron Lett. 1969, 10: 543-546. 10.1016/S0040-4039(01)87743-1.

    Article  Google Scholar 

  12. Glória PMC, Prabhakar S, Lobo AM, Gomes MJS: SbCl5-wet acetonitrile: a new system for chemoselective O-desilylation. Tetrahedron Lett. 2003, 44: 8819-8821. 10.1016/j.tetlet.2003.09.191.

    Article  Google Scholar 

  13. Roustan JLA, Houlihan F: Electrophilie du ligande η3-allylique de complexes η3-allyl-dicarbonyl-nitrosyl-fer. Can J Chem. 1979, 57: 2790-2791. 10.1139/v79-451.

    Article  CAS  Google Scholar 

  14. Woodman DJ, Stonebroker PM: Ketenimine carboxylate isomer protonation. Heterocycles. 1977, 7: 247-250. 10.3987/S-1977-01-0247. and references cited therein

    Article  CAS  Google Scholar 

  15. Khalafy J, Marjani AP, Ebrahimbo ARM: Synthesis of new N-benzoxazole and N-benzothiazole derivatives of 3-(4-substituted- phenyl)aminoisoxazol-5(2H)-ones and comparison of their base induced rearrangement. J Braz Chem Soc. 2006, 17: 570-576. 10.1590/S0103-50532006000300021. and references cited therein

    Article  CAS  Google Scholar 

  16. Emmons WD: The preparation and properties of oxaziranes. J Am Chem Soc. 1957, 79: 5739-5754. 10.1021/ja01578a043.

    Article  CAS  Google Scholar 

  17. Butler AR, Challis BC, Lobo AM: Hydrolysis of oxaziridines. Part 3. Evidence for both O- and N-conjugate acid formation with 2,3,3-triethyloxaziridine. J Chem Soc Perkin II. 1979, 1035-1038.

    Google Scholar 

  18. Perrin DD, Armarego WLF, Perrin DR: Purification of Laboratory Chemicals. 1980, London: Pergamon

    Google Scholar 

  19. Barton DHR, Blazejewski J-C, Charpiot B, Finet J-P, Motherwell WB, Papoula MTB, Stanforth SP: Pentavalent organobismuth reagents. Part 3. Phenylation of enols and of enolate and other anions. J Chem Soc Perkin Trans I. 1985, 2667-2675.

    Google Scholar 

  20. Buckle ALJ, McGookin A, Robertson A: Constituents of “Cortex Piscidiae Erythrinae.” Part II. The synthesis of O-methylpiscidic acid. J Chem Soc. 1954, 3981-3986.

    Google Scholar 

  21. Howk BW, McElvain SM: The reaction of organic halides with piperidine. II. Certain alpha-bromo-beta-ketonic esters. J Am Chem Soc. 1932, 54: 282-289. 10.1021/ja01340a042.

    Article  CAS  Google Scholar 

  22. Logemann H, Almirante L, Caprio L: Studien in der heterocyclischen reihe, II. Mitteil.: die synthese von 1.3.5-triazinen und 5-oxy-isoxazol-derivaten. Chem Ber. 1954, 87: 1175-1179. 10.1002/cber.19540870819.

    Article  CAS  Google Scholar 

  23. Kohler EPB, Blatt AHAH: Diphenyl isoxazolone: a study of the tautomerism of isoxazolones. J Am Chem Soc. 1928, 50: 504-515. 10.1021/ja01389a039.

    Article  CAS  Google Scholar 

  24. Teobald BJ: The Nicholas reaction: the use of dicobalt hexacarbonyl-stabilised propargylic cations in synthesis. Tetrahedron. 2002, 58: 4133-4170. 10.1016/S0040-4020(02)00315-0.

    Article  CAS  Google Scholar 

  25. Barton DHR, Bolton M, Magnus PD, Marath KG, Poulton GA, West PJ: Photochemical transformations. Photolysis of thiobenzoic acid O-esters. Photolysis of O-phenethyl thiobenzoates and other thiobenzoates. J Chem Soc Perkin Trans. 1973, 1: 1574-1579.

    Article  Google Scholar 

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Acknowledgements

We thank Fundação para a Ciência e a Tecnologia (FC&T, Lisbon, Portugal) for financial support from grant PEst-C/EQB/LA 0006/2011 and Project POCTI/QUI/36456. Three of us (M.J.S.G., L.F.V.P., P.M.C.G.) are grateful for the award of research fellowships from FC&T.

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    Authors and Affiliations

    1. Chemistry Department, REQUIMTE/CQFB, FCT, Universidade Nova de Lisboa, 2829-516, Caparica, Portugal

      Mário JS Gomes, Luis FV Pinto, Paulo MC Glória, Sundaresan Prabhakar & Ana M Lobo

    2. Departamento das Ciências Naturais e Exatas, Escola Superior de Tecnologia da Saúde de Lisboa, Instituto Politécnico de Lisboa, Lisboa, Portugal

      Mário JS Gomes

    3. Chemistry Department, Imperial College London, South Kensington Campus, London, UK

      Henry S Rzepa

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    Authors’ contributions

    AML, HSR and SP contributed equally to this work. LFVP, MJSG and PMCG carried out the experimental work. All authors read and approved the final manuscript.

    Henry S Rzepa, Sundaresan Prabhakar and Ana M Lobo contributed equally to this work.

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    Additional file 1: Table S1: Calculated relative energies for intermediates and transition states relating to Scheme 6. (ZIP 8 MB)

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    Gomes, M.J., Pinto, L.F., Glória, P.M. et al. N-heteroatom substitution effect in 3-aza-cope rearrangements. Chemistry Central Journal 7, 94 (2013). https://doi.org/10.1186/1752-153X-7-94

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