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The Elusive Paal−Knorr Intermediates in the Trofimov Synthesis of Pyrroles: Experimental and Theoretical Studies Jarosław Sączewski,*,† Joanna Fedorowicz,† Maria Gdaniec,‡ Paulina Wiśniewska,† Emilia Sieniawska,† Zuzanna Drazḃ a,† Justyna Rzewnicka,† and Łukasz Balewski§ †

Department of Organic Chemistry, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland Faculty of Chemistry, Adam Mickiewicz University, 61-614 Poznań, Poland § Department of Chemical Technology of Drugs, Medical University of Gdańsk, Al. Gen. J. Hallera 107, 80-416 Gdańsk, Poland ‡

S Supporting Information *

ABSTRACT: We have used isoxazolo[3,4-b]pyridin-3(1H)one and isoxazolo[3,4-b]quinolin-3(1H)-one as “masked” heterocyclic hydroxylamines to generate Paal−Knorr intermediates of the Trofimov pyrrole synthesis. The previously inaccessible intermediates, trapped by ethyl propiolate, were obtained by reacting corresponding isoxazolones with 4-fold excess of ethyl propiolate under basic conditions at ambient temperature, and characterized by means of IR and NMR spectroscopic data as well as by single crystal X-ray analysis. Quantum chemical calculations of a [3,3]sigmatropic rearrangement of the N,O-divinyl hydroxylamines to corresponding imino-aldehydes (Paal−Knorr intermediates) revealed that this reaction proceeds via chairlike transition state and is exothermic.

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isolated in pure form are the hemiaminals of type G,11 while the structures of the reactive intermediates, especially those underlying the key [3,3] sigmatropic rearrangement, still elude clear characterization and remain uncertain. Thus far, several attempts have been made to confirm the presence of unstable intermediates B−F. For example, Camp and co-workers observed by 1H and 13C NMR buildup of the O-divinyl hydroxylamine B and imino-aldehyde of type C (R1 = Ph, R2 = H, R3 = H or COOMe, R4 = COOMe),8 while Anderson’s research group identified either the imino-aldehyde of type C (R1 = Ph, R2 = H, R3 = H, R4 = Me)12 or cyclic hemiacetal G (R1 = Ph, R2 = COOEt, R3 = H, R4 = Me)13 after heating the corresponding O-propenyl oxime A and DBU in THF-d8 solution at 75 °C for 2−6 h. However, in no case was the intermediate B, C, D, E or F separated from crude reaction mixture. Trofimov pyrrole synthesis remains a popular research topic and attracts the attention of organic chemists. Therefore, we wish to report here the isolation of elusive enamino-enol intermediates of type D, the formation of which can be rationalized only on the basis of 1-aza-1′-oxa Cope rearrangement of unstable N,O-divinyl hydroxylamines (B). In addition, in this article we report the results of theoretical investigations on the mechanism of this multistep reaction.

INTRODUCTION In 1970 Sheradsky demonstrated that the O-vinyl oxime derived from the addition of acetophenone oxime to dimethylacetylene dicarboxylate can be thermally rearranged to the corresponding pyrrole.1,2 This synthetic approach was further developed by Trofimov who showed that variously substituted pyrroles could be obtained from ketoximes and unactivated alkynes under superbasic conditions.3 Although the Trofimov reaction is limited by the harsh reaction conditions, the lack of regioselectivity and poor performance observed for substituted alkynes, it has been successfully applied in a number of pyrrole syntheses.4,5 Recently, Camp and co-workers have developed procedures that provide access to pyrroles with EWG-groups, that are not accessible under classical Trofimov reaction conditions, via nucleophilic catalysis6 and goldmultifaceted catalysis approach.7−9 As shown in Scheme 1, the Trofimov route features several key steps, including: (i) a base(nucleophile)-assisted addition of ketoxime to acetylene derivative with the formation of O-vinyl oxime A, (ii) tautomerization of A to corresponding N,Odivinyl hydroxylamine B, (iii) 1-aza-1′-oxa hetero-Cope rearrangement to imino-ketone C (Paal−Knorr intermediate) that may exist in the enamino-enol D, imino-enol E and enamino-ketone F tautomeric forms, (iv) cyclization of the latter intermediate to hemiacetal G that gives the final pyrrole compound upon loss of water molecule.10 However, despite the widespread application of this transformation in synthetic organic chemistry, the only intermediates that have been © 2017 American Chemical Society

Received: July 24, 2017 Published: August 17, 2017 9737

DOI: 10.1021/acs.joc.7b01851 J. Org. Chem. 2017, 82, 9737−9743

Article

The Journal of Organic Chemistry Scheme 1. Synthesis of Pyrroles from Ketoximes and Acetylenesa

a

Sheradsky1: R3,R4 = COOR; Trofimov3: R3,R4 = H, alkyl, aryl.

Scheme 2. Proposed Access to Paal−Knorr Intermediates in the Trofimov Synthesis of Pyrroles

Scheme 3. Reaction of Isoxazolones 1a and 1b with Activated Acetylenes in the Presence of Et3N (1.2 mol equiv)

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RESULTS AND DISCUSSION

followed by bimolecular base-catalyzed acyl-oxygen cleavage (BAC2) and O-alkylation to yield N,O-dialkyl hydroxylamines (Scheme 2). These results prompted us to examine the compounds 1a and 1b as potential donors in aza-Michael addition reactions with α,β-acetylenic carbonyl compounds. We reasoned that the resulting N-vinyl isoxazolone would undergo

In recent years, we have been exploring reactivity of isoxazolo[3,4-b]pyridin-3(1H)-one (1a) and its benzo analogue, isoxazolo[3,4-b]quinolin-3(1H)-one (1b)14 and found that under basic conditions 1b undergoes N1-alkylation 9738

DOI: 10.1021/acs.joc.7b01851 J. Org. Chem. 2017, 82, 9737−9743

Article

The Journal of Organic Chemistry Scheme 4. Preparation of Paal−Knorr Intermediates Trapped by Ethyl Propiolate

Scheme 5. Ability of N-Vinyl Compound 2a To Serve as a Precursor of Paal−Knorr Intermediate 5a and Amide 6

the reaction mixture (Scheme 1). Presumably, in the aminoaldehyde F (Figure 2) the pyridine substituent diminishes nucleophilicity of the amino-group while conjugation with COOEt moiety reduces electrophilicity of aldehyde functionality and, in consequence, pyrrole ring-closure is decelerated. Subsequently, nucleophilic addition of the enol D (Figure 2) to methyl propiolate occurs faster. In this context, it is important to note that according to Hwu and cooworkers17 the reaction of ArNHOH with two molar equivalents of methyl propiolate gives rise to the formation of N-aryl-N-vinyl-O-vinyl hydroxylamine, which, in turn, rearranges to corresponding indole products via 1-aza-1′-oxa hetero-Cope rearrangement. Therefore, the alternative reaction depicted in Scheme 2 results from the presence of the EWG ethoxycarbonyl substituent in position 3 of the pyridine ring. We further obtained experimental evidence that N-vinyl compound 2a may serve as a substrate for preparation of products 5a and 6. As illustrated in Scheme 5, treatment of 2a with 3 equvalents of ethyl propiolate and 2 equvalents of Et3N in ethanol solution affords the product 5a, while application of a 3-fold excess of Et3N induces isoxazolone ring opening with the formation of N-vinyl hydroxylamine (H) that subsequently tautomerizes to the nitrone I. The latter compound, analogously to other aldonitrones treated with solution of base in ethanol,18 rearranges to the isomeric amide 6. It should be noted, however, that compound 3a (isomer Z) could not serve as precursor to 5a. Structures of the products 5a,b, and 6 were determined by elemental analysis, IR and NMR spectroscopic data as well as

bimolecular base-catalyzed acyl-oxygen cleavage (BAC2) to yield N-vinyl hydroxylamine that subsequently should react with a second molecule of activated alkyne to give the corresponding N,O-divinyl hydroxylamine of type B, i.e., an unstable 1-aza1′oxa Cope system (Scheme 2). In the initial experiments, the reactions of 1a with ethyl propiolate, ethyl but-2-ynoate and but-3-yn-2-one carried out in ethanol in the presence of triethylamine (1.2 mol equiv) at 20 °C furnished the corresponding Michael addition products 2a− c (isomer E), 3a,b (isomer Z). Analogous reaction of lesssoluble 1b with ethyl propiolate and but-3-yn-2-one performed in dimethylformamide furnished products 4a,b (isomer E). In either case no isoxazolone ring opening was seen (Scheme 3). The olefin geometry of the N-vinyl isoxazolones 2, 3 and 4 were confirmed unambiguously by 1H NMR coupling constants15 and single crystal X-ray analysis of 2a−c, 3a and 4b (see the Supporting Information). It is well-known that alcohols in the presence of tertiary amines may undergo a Michael addition to alkyl propiolates giving rise to the formation of corresponding vinyl ethers.16 After extensive investigations with different acetylenic compounds (ethyl propiolate, ethyl but-2-ynoate and but-3-yn-2one), amines (triethylamine and pyridine) and solvents (ethanol and DMF), we found that ethyl propiolate and Et3N used in excess (4 and 2 equiv, respectively) deliver the desired Paal−Knorr intermediates in good yields. The optimal conditions described in Scheme 4 provide the intermediates trapped by ethyl propiolate (5a and 5b). It should be emphasized that for the reaction performed at room temperature neither pyrrole nor hemiacetal G have been isolated from 9739

DOI: 10.1021/acs.joc.7b01851 J. Org. Chem. 2017, 82, 9737−9743

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The Journal of Organic Chemistry

Figure 1. Molecular structure of 5a (left) and 5b (right).

Figure 2. Thermal-corrected energy profile calculated at PCM/B3LYP/6-31G(d) level of theory for transformation of N,O-divinyl hydroxylamine B to the enamino-enol D.

by single crystal X-ray analysis (see the Supporting Information and Figure 1). To the best of our knowledge, only one computational study of the transition state and activation energy of 1-aza-1′-oxa hetero-Cope rearrangement have been reported to date.19 Therefore, to gain insight into a cascade transformation of the N,O-divinyl hydroxylamine B to the intermediate D (Figure 2), we performed theoretical studies with use of DFT (B3LYP, O3LYP, M06, ωB97X-D, EDF2) and MP2 methods implemented in Spartan 08 and Gaussian 09 software packages.20,21

Calculations performed at the restricted DFT and MP2 levels located only a single transition structure (TS) on the potential energy surface (PES), for the concerted transformation of B. The transition structures obtained by each of the various methods are quite similar (see the Supporting Information) and the representative chairlike transition structure obtained with use of B3LYP/6-31G(d) calculations is shown in Figure 3. The data obtained with use of DFT and MP2 methods indicate a significant asynchronicity of the N1−O1′ bondbraking and C3−C3′ bond-forming processes (bond-breaking is more advanced than bond-forming), i.e., the 1-aza-1′-oxa 9740

DOI: 10.1021/acs.joc.7b01851 J. Org. Chem. 2017, 82, 9737−9743

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shorter N1−O1′ bond length which may be explained by the fact that MP2 method overestimates the correlation energies and thus the stabilities of transition states.30,31 The reaction leading from the N,O-divinyl hydroxylamine B to the 1,4-imino carbonyl (Paal−Knorr) intermediate C was calculated to be exothermic by 43.39 kcal/mol (Figure 2). The subsequent 1,3 H-shift provides the enamino-aldehyde F that is more stable than C by 8.71 kcal/mol (see the Supporting Information). Then, tautomeric transformation of F may give rise to the formation of the enamino-enol D at a small energy expense (ΔEtherm = 1.44 kcal/mol). The latter tautomer can be trapped and isolated in form of the vinyl ether 5a in a one-pot cascade reaction.32 It is also worth noting that the intermediates D and F of high dipole moments were calculated to be more stable in ethanol than the imino-aldehyde C and the imino-enol E (see the Supporting Information). These results indicate that propiolate used for the reaction with “masked” hydroxyloamines 1a and 1b favor the enamine and enol forms of the alkyne addition products due to the electron-withdrawing group at the β-position, while other alkynes without this substituent may favor the imine form of the addition product and an alternative mechanism.

Figure 3. Structure and labeling of transition state TS.

hetero-Cope rearrangement has an early dissociative transition state. The calculated lengths of the breaking N1−O1′ bonds range from 1.700 to 1.867 Å and the lengths of the forming C3−C3′ bond range from 2.621 to 3.092 Å, respectively (see the Supporting Information). Furthermore, the calculations revealed the allyl C2C3 and C2′C3′ bond lengths in the range of 1.354−1.374 Å and the N1−C2 and O1′−C2′ bond lengths in the range of 1.359−1.371 Å and 1.298−1.305 Å, respectively. Hence, they were only marginally longer than the bond lengths determined for the initial (B) and final (C) states of the hetero-Cope rearrangement. Then, unrestricted calculations were carried out to check for intermediacy of diradicals and diradical character in the transition states leading to them. In fact, the unrestricted TS was proved to be identical in terms of energy and geometry to the concerted one calculated with restricted method. Thus, the transition state can be described with a closed-shell wave function. According to a previous report, the DFT B3LYP calculations provide accurate results in the study of Cope rearrangements.22 Nevertheless, to explore the energetics of the observed 1-aza-1′oxa hetero-Cope rearrangement we performed DFT calculations using various functionals and basis sets (see the Supporting Information). The solvent effect was computed by using the polarizable continuum model (PCM), considering ethanol as solvent. First, we found that the predictions were not very sensitive to variation of the functional since the calculated energy barriers (ΔEtherm) were in narrow ranges of 20.23−24.89 kcal/mol and 19.08−23.66 kcal/mol for gas-phase and solution-phase reactions, respectively. The lowest activation barriers of ca. 20 kcal/mol were estimated with use of B3LYP/6-31G(d) and O3LYP/6-31G(d) methods. The use of a larger basis set [6311G(d)] or a diffuse function in basis set [6-31+G(d)] did not appear to be necessary, as neither the geometries nor the relative energies changed significantly. Moreover, the value of ΔEtherm‡ = 19.83 kcal/mol, calculated at the B3LYP/6-31G(d) level, is consistent with the energy barrier reported previously for other 1-aza-1′oxa hetero-Cope rearrangement19 and the empirical observation that this type of rearrangement usually occurs at significantly lower temperatures than do analogous Claisen (27.4 kcal/mol),23−25 Cope (34.2 kcal/mol)26,24 and 3aza-Cope (35.5 kcal/mol)27−29 reactions. Compared to DFT calculations, the MP2/6-31G(d) method predicted lower activation energy barrier of 14.42 kcal/mol and significantly

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CONCLUSION We have developed a method to access Paal−Knorr intermediates of the Trofimov pyrrole synthesis by reacting isoxazolo[3,4-b]pyridin-3(1H)-one (1a) and isoxazolo[3,4-b]quinolin-3(1H)-one (1b), that behave as “masked” heteroaromatic hydroxylamines, with four molar equivalents of ethyl propiolate in the presence of Et3N at room temperature. These results provide emerging evidence supporting an essential role of 1-aza-1′-oxa Cope rearrangement in a transformation of N,O-divinyl hydroxylamines (B) to enamino-enols (D) that, in turn, can be trapped by an excess acetylenic reagent to give vinyl ethers 5a and 5b. Investigation of the mechanism of this [3,3] sigmatropic reaction with use of quantum chemical methods revealed that the reaction proceeds exothermically via chairlike transition state.

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EXPERIMENTAL SECTION

General Information. 1H and 13C NMR spectra were obtained using Varian Mercury-VX 300 MHz or Varian Unity Plus 500 MHz spectrometers. 1H NMR data were internally referenced to TMS (0.0 ppm), DMSO-d6 (2.5 ppm) or CDCl3 (7.26 ppm); 13C NMR spectra were referenced to DMSO-d6 (39.50 ppm) or CD3OD (49.00 ppm). The IR (KBr) spectra were recorded on Thermo Scientific Nicolet 380 FT-IR spectrometer. The mass spectra were recorded on Shimadzu single quadrupole LCMS 2010 eV mass spectrometer. Melting points were determined on a X-4 melting point apparatus with microscope and were uncorrected. General Procedure. Isoxazolone 1a or 1b (1.22 mmol), the corresponding acetylenic compound (2.44 mmol) and triethylamine (0.20 mL, 1.46 mmol) were added to anhydrous ethanol (for 2a−c, 3a,b, 5a,b, 6) or dimethylformamide (for 4a,b) (10 mL) at room temperature. In the case of compounds 5a,b and 6 other quantities of acetylenic compounds (4.88 mmol) and triethylamine (0.34 mL, 2.44 mmol) were applied. The progress of the reaction was monitored by TLC (eluent: chloroform). After 12 h the reaction mixture was evaporated under reduced pressure. The crude mixture was purified by use of chromatotron and the obtained products were recrystallized from ethanol prior to characterization. (E)-Ethyl 3-(4,6-dimethyl-3-oxoisoxazolo[3,4-b]pyridin-1(3H)-yl)acrylate (2a). Rf = 0.30 (dichloromethane); yield 0.157 g (49%); mp 103−104 °C; 1H NMR (300 MHz, CDCl3) δ = 1.32 (t, J = 7.0 Hz, 3H, CH3), 2.59 (s, 3H, CH3), 2.62 (s, 3H, CH3), 4.24 (q, J = 7.0 Hz, 9741

DOI: 10.1021/acs.joc.7b01851 J. Org. Chem. 2017, 82, 9737−9743

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The Journal of Organic Chemistry

(d, J = 8.2 Hz, 1H, CH), 8.39 (d, J = 13.5 Hz, 1H, CH), 8.81 (s, 1H, CH); 13C NMR (75 MHz, CDCl3) δ = 28.9, 105.0, 107.2, 125.6, 126.3, 128.4, 130.4, 131.1, 134.8, 139.1, 151.8, 153.48, 161.3, 196.2; IR (KBr) 3072, 3051, 3018, 3003, 2990, 2954, 2924, 2852, 1785, 1620, 1273, 1261, 1217, 1143, 1075, 957, 933, 728, 749 cm−1; MS (ESI) m/z 255 [M + 1]+. Anal. Calcd for C14H10N2O3: C, 66.14; H, 3.96; N, 11.02. Found: C, 66.07; H, 4.04; N, 10.98. (2E,3E)-Diethyl 2-(((E)-3-ethoxy-3-oxoprop-1-enyloxy)methylene)-3-((3-(ethoxycarbonyl)-4,6-dimethylpyridin-2-ylamino)methylene)succinate (5a). Rf = 0.32 (dichloromethane/ethyl acetate, 9:1, v/v); yield 0.295 g (48%); mp 127−130 °C; 1H NMR (500 MHz, CDCl3) δ = 1.23−1.30 (m, 9H, CH3), 1.35 (t, J = 7.0 Hz, 3H, CH3), 2.46 (s, 3H, CH3), 2.48 (s, 3H, CH3), 4.16 (q, J = 7.0 Hz, 2H, CH2), 4.20−4.24 (m, 4H, CH2), 4.30 (q, J = 7.0 Hz, 2H, CH2), 5.29 (d, J = 12.2 Hz, 1H, CH), 6.60 (s, 1H, CH), 7.66 (d, J = 12.2 Hz, 1H, CH), 7.75 (s, 1H, CH), 8.93 (d, J = 12.5 Hz, 1H, CH), 10.26 (d, J = 12.5 Hz, 1H, NH); 13C NMR (75 MHz, CDCl3) δ = 14.1, 14.2, 14.2, 14.4, 23.6, 24.4, 60.1, 60.3, 60.9, 61.4, 99.3, 103.5, 106.6, 111.0, 120.1, 137.8, 151.8, 152.2, 152.8, 158.4, 161.1, 166.2, 166.4, 167.3, 168.4; IR (KBr) 3422, 3084, 2983, 2938, 1711, 1675, 1626, 1554, 1369, 1275, 1226, 1193, 1163, 1130 cm−1; MS (ESI) m/z 505 [M + 1]+. Anal. Calcd for C25H32N2O9: C, 59.51; H, 6.39; N, 5.55. Found: C, 59.50; H, 6.44; N, 5.48. Alternative method: Ethyl 3-(4,6-dimethyl-3-oxoisoxazolo[3,4-b]pyridin-1(3H)-yl)acrylate (2a) (0.100 g, 0.38 mmol), ethyl propiolate (0.11 mL, 1.14 mmol) and triethylamine (0.11 mL, 0.76 mmol) were added to anhydrous ethanol (5 mL) at room temperature. The product 5a was isolated according to the general procedure; yield 0.100 g (52%). Ethyl 2-(3-ethoxy-3-oxopropanamido)-4,6-dimethylnicotinate (6). Rf = 0.24 (dichloromethane/ethyl acetate, 9:1, v/v); yield 0.023 (6%); mp 106−108 °C; 1H NMR (300 MHz, CDCl3) δ = 1.25 (t, J = 7.4 Hz, 3H, CH3), 1.39 (t, J = 7.4 Hz, 3H, CH3), 2.43 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.71 (s, 2H, CH2), 4.20 (q, J = 7.4 Hz, 2H, CH2), 4.40 (q, J = 7.4 Hz, 2H, CH2), 6.79 (s, 1H, CH), 9.95 (bs, 1H, NH); IR (KBr) 3256, 3068, 2984, 2932, 1737, 1715, 1673, 1608, 1539, 1453, 1331, 1267, 1202, 1083 cm−1; MS (ESI) m/z 309 [M + 1]+. Anal. Calcd for C15H20N2O5: C, 58.43; H, 6.54; N, 9.09. Found: C, 58.39; H, 6.58; N, 9.03. Alternative method: Ethyl 3-(4,6-dimethyl-3-oxoisoxazolo[3,4-b]pyridin-1(3H)-yl)acrylate (2a) (0.100 g, 0.38 mmol) and triethylamine (0.26 mL, 1.90 mmol) were added to anhydrous ethanol (5 mL) at room temperature. The product 6 was isolated according to the general procedure; yield 0.056g (67%). (2E,3E)-Diethyl 2-(((E)-3-ethoxy-3-oxoprop-1-enyloxy)methylene)-3-((3-(ethoxycarbonyl)quinolin-2-ylamino)methylene)succinate (5b). The precipitated product (0.123 g, 19%) was filtered off and washed with hexanes (3 mL). The filtrate was evaporated under reduced pressure and the crude product was purified by use of chromatotron. Rf = 0.25 (dichloromethane/ethyl acetate, 9:1, v/v); combined yield 0.334 g (52%); mp 143−144 °C; 1H NMR (300 MHz, CDCl3) δ = 1.24 (t, J = 7.0 Hz, 3H, CH3), 1.28 (t, J = 7.0 Hz, 3H, CH3), 1.31 (t, J = 7.0 Hz, 3H, CH3), 1.40 (t, J = 7.0 Hz, 3H, CH3), 4.15 (q, J = 7.0 Hz, 2H, CH2), 4.20−4.28 (m, 4H, CH2), 4.37 (q, J = 7.0 Hz, 2H, CH2), 5.51 (d, J = 12.3 Hz, 1H, CH), 7.37 (t, J = 7.6 Hz, 1H, CH), 7.67 (d, J = 12.3 Hz, 1H, CH), 7.69−7.74 (m, 2H, CH), 7.80 (s, 1H, CH), 7.84 (d, J = 8.8 Hz, 1H, CH), 8.74 (s, 1H, CH), 9.07 (d, J = 12.9 Hz, 1H, CH), 10.30 (d, J = 12.9 Hz, 1H, NH); 13C NMR (75 MHz, CDCl3) δ = 14.1, 14.2 (two signals), 14.4, 60.2, 60.3, 61.0, 61.9, 100.7, 103.6, 110.5, 110.9, 123.6, 124.7, 127.4, 128.9, 133.0, 136.6, 142.6, 149.3, 149.6, 152.4, 158.4, 166.2, 166.3, 166.5, 167.1; IR (KBr) 3307, 3062, 2981, 1702, 1633, 1593, 1516, 1222, 1160, 1124, 1093, 795, 753 cm−1; MS (ESI) m/z 527 [M + 1]+. Anal. Calcd for C27H30N2O9: C, 61.59; H, 5.74; N, 5.32. Found: C, 61.53; H, 5.75; N, 5.30.

2H, CH2), 5.81 (d, J = 13.8 Hz, 1H, CH), 6.86 (s, 1H, CH), 8.25 (d, 1H, CH, J = 13.8 Hz); 13C NMR (75 MHz, CDCl3) δ= 14.4, 17.2, 25.0, 60.3, 98.6, 100.0, 121.3, 131.9, 151.1, 157.4, 162.1, 166.8, 167.8; IR (KBr) 3078, 2981, 2930, 1785, 1706, 1640, 1591, 1460, 1252, 1049, 955, 902, 845, 786 cm−1; MS (ESI) m/z 263 [M + 1]+. Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C, 59.47; H, 5.42; N, 10.65. (Z)-Ethyl 3-(4,6-dimethyl-3-oxoisoxazolo[3,4-b]pyridin-1(3H)-yl)acrylate (3a). Rf = 0.10 (dichloromethane); yield 0.058 g (18%); mp 93−94 °C; 1H NMR (500 MHz, CDCl3) δ = 1.34 (t, J = 7.3 Hz, 3H, CH3), 2.58 (s, 3H, CH3), 2.63 (s, 3H, CH3), 4.30 (q, J = 7.3 Hz, 2H, CH2), 5.33 (d, J = 10.3 Hz, 1H, CH), 6.87 (s, 1H, CH), 7.20 (d, J = 10.3 Hz, 1H, CH); 13C NMR (75 MHz, CDCl3) δ = 14.1, 17.1, 25.0, 60.7, 99.7, 101.0, 121.2, 126.4, 150.9, 158.8, 162.9, 165.0, 167.1; IR (KBr) 3430, 3068, 2990, 1789, 1767, 1720, 1663, 1601, 1543, 1377, 1270, 1219, 1188, 1106, 1026, 785 cm−1; MS (ESI) m/z 263 [M + 1]+. Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C, 59.51; H, 5.42; N, 10.66. (E)-Ethyl 3-(4,6-dimethyl-3-oxoisoxazolo[3,4-b]pyridin-1(3H)-yl)but-2-enoate (2b). Rf = 0.53 (dichloromethane); yield 0.144 g (43%); mp 123−124 °C; 1H NMR (300 MHz, CDCl3) δ = 1.29 (t, J = 7.3 Hz, 3H, CH), 2.58 (s, 3H, CH3), 2.61 (s, 3H, CH3), 2.88 (s, 3H, CH3), 4.18 (q, J = 7.3 Hz, 2H, CH2), 6.28 (s, 1H, CH), 6.83 (s, 1H, CH); 13C NMR (75 MHz, CDCl3) δ = 14.3, 15.3, 17.2, 25.3, 59.8, 99.5, 101.2, 120.7, 149.1, 150.8, 159.2, 162.3, 166.9, 167.3; IR (KBr) 2985, 1926, 1779, 1717, 1628, 1589, 1363, 1179, 1132, 1020, 834 cm−1; MS (ESI) m/z 277 [M + 1]+. Anal. Calcd for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C, 60.79; H, 5.88; N, 10.07. (Z)-Ethyl 3-(4,6-dimethyl-3-oxoisoxazolo[3,4-b]pyridin-1(3H)-yl)but-2-enoate (3b). Rf = 0.28 (dichloromethane); yield 0.127 g (38%); 1 H NMR (300 MHz, CDCl3) δ = 1.17 (t, J = 7.0 Hz, 3H, CH), 2.17 (d, 4J = 1.2 Hz, 3H, CH3), 2.50 (s, 3H, CH3), 2.60 (s, 3H, CH3), 4.10 (q, J = 7.0 Hz, 2H, CH2), 5.62 (q, 4J = 1.2 Hz, 1H, CH), 6.78 (s, 1H, CH); 13C NMR (75 MHz, CDCl3) δ = 10.2, 13.2, 16.1, 21.2, 56.4, 96.4, 105.7, 116.4, 138.2, 146.6, 155.9, 160.0, 160.9, 162.5 cm−1; IR (liquid film) 2982, 2928, 2899, 2868, 2853, 1767, 1719, 1651, 1610, 1591, 1440, 1378, 1285, 1259, 1237, 1178, 1164, 1045, 1023, 851, 791, 698; MS (ESI) m/z 277 [M + 1]+. Anal. Calcd for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C, 60.74; H, 5.91; N, 10.03. (E)-4,6-Dimethyl-1-(3-oxobut-1-enyl)isoxazolo[3,4-b]pyridin3(1H)-one (2c). The precipitated product (54 mg, 19%) was filtered off and washed with hexanes (3 mL). The filtrate was evaporated under reduced pressure and purified by use of chromatotron. Rf = 0.15 (dichloromethane/ethyl acetate, 9:1, v/v); combined yield 0.220 g (78%); mp 132−133 °C (methanol); 1H NMR (300 MHz, CDCl3) δ = 2.30 (s, 3H, CH3), 2.59 (s, 3H, CH3), 2.62 (s, 3H, CH3), 6.18 (d, J = 15.0 Hz, 1H, CH), 6.88 (s, 1H, CH), 8.20 (d, J = 15.0 Hz, 1H, CH); 13 C NMR (75 MHz, CDCl3) δ = 17.2, 25.1, 28.8, 100.2, 106.9, 121.6, 130.5, 151.1, 157.3, 161.9, 167.9, 196.1; IR (KBr) 3082, 3049, 2922, 1799, 1679, 1574, 1468, 1362, 1256, 1180, 957, 608, 570 cm−1; MS (ESI) m/z 233 [M + 1]+. Anal. Calcd for C12H12N2O3: C, 62.06; H, 5.21; N, 12.06. Found: C, 62.01; H, 5.30; N, 12.03. (E)-Ethyl 3-(3-oxoisoxazolo[3,4-b]quinolin-1(3H)-yl)acrylate (4a). Rf = 0.12 (dichloromethane/diethyl ether, 9:1, v/v); yield 0.243 g (70%); mp 162−163 °C; 1H NMR (300 MHz, CDCl3) δ = 1.33 (t, J = 7.1 Hz, 3H, CH3), 4.25 (q, J = 7.1 Hz, 2H, CH2), 5.85 (d, J = 13.8 Hz, 1H, CH), 7.55 (t, J = 8,2 Hz, 1H, CH), 7.88 (t, J = 8,2 Hz, 1H, CH), 7.95 (d, J = 8.2 Hz, 1H, CH), 8.00 (d, J = 8,2 Hz, 1H, CH), 8.48 (d, J = 13.8 Hz, 1H, CH), 8.75 (s, 1H, CH); 13C NMR (75 MHz, CDCl3) δ = 14.4, 60.4, 98.8, 104.8, 125.4, 126.2, 128.3, 130.3, 132.4, 134.6, 139.0, 151.7, 153.5, 161.4, 166.8; IR (KBr) 3096, 3062, 3005, 2981, 2959, 2924, 2854, 1785, 1708, 1625, 1370, 1317, 1292, 1265, 1200, 1176, 1165, 1145, 957, 767 cm−1; MS (ESI) m/z 285 [M + 1]+. Anal. Calcd for C15H12N2O4: C, 63.38; H, 4.25; N, 9.85. Found: C, 63.27; H, 4.41; N, 9.73. (E)-1-(3-Oxobut-1-enyl)isoxazolo[3,4-b]quinolin-3(1H)-one (4b). Rf = 0.10 (dichloromethane/diethyl ether, 9:1, v/v); yield 0.082 g (26%); mp 182−183 °C; 1H NMR (300 MHz, CDCl3) δ = 2.35 (s, 3H, CH3), 6.27 (d, J = 13.5 Hz, 1H, CH), 7.59 (t, J = 8.2 Hz, 1H, CH), 7.92 (t, J = 8.2 Hz, 1H, CH), 7.59 (d, J = 8.2 Hz, 1H, CH), 8.05

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01851. 9742

DOI: 10.1021/acs.joc.7b01851 J. Org. Chem. 2017, 82, 9737−9743

Article

The Journal of Organic Chemistry

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(21) Spartan ’08 for Windows; Wavefunction: Irvine, CA; www. wavefun.com. (22) Delso, I.; Melicchio, A.; Isasi, A.; Tejero, T.; Merino, P. Eur. J. Org. Chem. 2013, 2013, 5721−5730. (23) Blechert, S. Synthesis 1989, 1989, 71−82. (24) Wiest, O.; Black, K. A.; Houk, K. N. J. Am. Chem. Soc. 1994, 116, 10336−10337. (25) Hu, H.; Kobrak, M. N.; Xu, Ch.; Hammes-Schiffer, S. J. Phys. Chem. A 2000, 104, 8058−8066. (26) Smith, M. B. Pericyclic carbon−carbon bond forming reactions: Multiple bond disconnections. In Organic Synthesis, 3rd ed.; Wavefunction, Inc.: Irvine, 2010; pp 1116−1142. (27) Zahedi, E.; Ali-Asgari, S.; Keley, V. Cent. Eur. J. Chem. 2010, 8, 1097−1104. (28) Walters, M. A. J. Org. Chem. 1996, 61, 978−983. (29) Gilbert, J. C.; Cousins, K. R. Tetrahedron 1994, 50, 10671− 10684. (30) Arnaud, R.; Dillet, V.; Pelloux-Leon, N.; Vallee, Y. J. Chem. Soc., Perkin Trans. 2 1996, 2065−2071. (31) Wiest, O.; Montiel, D. C.; Houk, K. N. J. Phys. Chem. A 1997, 101, 8378−8388. (32) Serrano-Molina, D.; Martin-Castro, A. M. Synthesis 2016, 48, 3459−3469.

Computational methodology and data, NMR spectra and crystallographic data (PDF) Crystallographic data (CIF)

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*E-mail: [email protected]. ORCID

Jarosław Sączewski: 0000-0003-2966-7645 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by Polish Ministry of Science and Higher Education and National Science Centre, research grant IP2012 055472, KNOW programme and GUMed ST-38 subsidy.

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REFERENCES

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DOI: 10.1021/acs.joc.7b01851 J. Org. Chem. 2017, 82, 9737−9743