A Lewis Acid Catalyzed annulation to 2,1-benzisoxazoles.

We report here a new, atom economical annulation to 2,1-benzisoxazole scaffolds via the BF3·Et2O-catalyzed reaction of glyoxylate esters and nitrosoarenes. The developed method represents a convergent route to this compound class from previously unexplored inputs and provides a range of 2,1-benzisoxazoles in moderate to high yields under convenient conditions. Along with exploration of substrate scope, initial mechanistic investigation through (18)O labeling and the synthesis of a reaction intermediate provides evidence for an unusual umpolung addition of glyoxylates to nitrosobenzenes with high O-selectivity, followed by a new type of Friedel-Crafts cyclization.

Introduction

In addition to their application as scaffolds in a number of biologically active compounds,[1,2] 2,1-benzisoxazoles serve as useful intermediates in organic synthesis.[2] Of particular note is the reductive cleavage of the benzisoxazole N–O bond to give 2-aminophenyl ketones, which have been widely employed in the synthesis of important pharmaceuticals and materials such as 1,4-benzodiazepines and quinolines.[2,3]

Our lab recently reported the synthesis of indazoles via the reversible Rh(III)-catalyzed addition of azobenzene C–H bonds to aldehydes, followed by intramolecular nucleophilic displacement of the hydroxyl group and aromatization (Figure 1A).[4] We reasoned that 2,1-benzisoxazoles might also be prepared by the Rh(III)-catalyzed coupling of isoelectronic nitrosobenzenes and aldehydes, two inputs that had not previously been applied to benzisoxazole synthesis (Figure 1B).[2,5,6] However, in our exploration of this approach, we uncovered an unprecedented Lewis acid catalyzed annulation that generated 2,1-benzisoxazoles from nitrosobenzenes and glyoxylate esters. The reaction can readily be performed on the benchtop under practical conditions with 10 mol % of BF3·Et2O as the Lewis acid. Subjecting 18O-labeled substrates to the reaction conditions clearly establishes that the nitrosoarene oxygen is incorporated into the isoxazole ring rather than the oxygen from the aldehyde partner. A novel reaction pathway is proposed based upon the observed oxygen incorporation, substrate scope, and product regioselectivity. The proposed mechanism is supported by the independent synthesis and transformation of a putative reaction intermediate.

Figure 1

(A) Previous indazole synthesis from azobenzenes. (B) New, Lewis acid catalyzed annulation to give benzisoxazoles from nitrosobenzenes.

Results and Discussion

In our initial efforts to couple nitrosobenzene and ethyl glyoxylate, we employed the catalyst system that we had previously successfully applied to indazole synthesis: [Cp*RhCl2]2 as a precatalyst and AgSbF6 as a chloride abstractor (entry 1, Table 1).[4] We were encouraged by the 20% yield of desired product, but before carrying out additional optimization experiments, we first performed control reactions wherein the two constituents of the catalyst system were evaluated separately (entries 2 and 3). To our surprise, AgSbF6 alone was capable of catalyzing the reaction (entry 3). We, therefore, chose to explore the competence of a series of inexpensive Lewis acids in affording the desired 2,1-benzisoxazole products (entries 4–6). Because of its low cost and the promising initial results, we focused our efforts on development of the transformation with BF3·Et2O as the Lewis acid. Examination of catalyst loading showed 10 mol % of BF3·Et2O to be ideal, with reduced yields obtained at significantly higher or lower loading (entries 6–9). Extended reaction times resulted in higher conversion (entry 10), as did an increase in the reaction temperature to a gentle reflux (entry 11). A number of aprotic and protic solvents of varying polarity were investigated, but all were inferior to dichloromethane and dichloroethane (data not shown). Inversion of the reaction stoichiometry brought the yield to 70% (entry 12). Conveniently, the reaction proved amenable to scale up (1 mmol) with setup on the benchtop giving a 79% isolated yield (entry 13).

Table 1

Optimization of Reaction Conditionsa

entry	catalyst (mol %)	time (h)	temperature (°C)	1a:2a	yield (%)c
1b	[Cp*RhCl2]2 (5)/AgSbF6 (20)	24	110	1:2	20
2b	[Cp*RhCl2]2 (5)	24	110	1:2	0
3b	AgSbF6 (20)	24	110	1:2	29
4	FeCl3 (20)	24	rt	1:2	31
5	AlCl3 (20)	24	rt	1:2	0
6	BF3·Et2O (40)	24	rt	1:2	15
7	BF3·Et2O (20)	24	rt	1:2	22
8	BF3·Et2O (10)	24	rt	1:2	32
9	BF3·Et2O (5)	24	rt	1:2	29
10	BF3·Et2O (10)	48	rt	1:2	40
11	BF3·Et2O (10)	48	reflux	1:2	63
12	BF3·Et2O (10)	48	reflux	2:1	70
13d	BF3·Et2O (10)	48	reflux	2:1	79e

Conditions: 0.40 mmol limiting reagent in CH2Cl2 (0.05 M), in glovebox.

DCE as solvent.

Determined by GC relative to tetradecane as an internal standard.

Conditions: 1a (2.0 mmol) and 2a (1.0 mmol) in CH2Cl2 (0.05 M), outside glovebox.

Isolated yield.

Having established efficient conditions for the BF3·Et2O-catalyzed transformation, the reaction scope was examined using a variety of substituted nitrosobenzenes (Table 2). Electron-neutral (3a), electron-rich (3b–3g, 3l–3n), and even modestly electron-deficient (3h–3k) aromatics reacted efficiently. However, the site of substitution of the electronegative chloro group was crucial for reaction success. While 3-nitrosochlorobenzene provided the benzisoxazole 3h in good yield, the regioisomeric 4-nitrosochlorobenzene gave only trace product. This pronounced sensitivity to the placement of the chloro group is consistent with an electrophilic aromatic substitution reaction pathway where electronegative halogen substituents are known to be deactivating but, due to resonance stabilization, also strongly ortho-/para-directing.

Table 2

Examination of Substrate Scopea,b,c

Conditions: nitrosoarene (2.0 mmol), aldehyde (1.0 mmol), BF3·Et2O (10%) in CH2Cl2 (0.05 M).

Isolated yield of all regioisomers after silica gel chromatography. Ratio of regioisomers determined by 1H NMR of crude product.

Isolated as an inseparable mixture of regioisomers.

Substitutions at the para and meta positions of the aromatic ring were well-tolerated. In contrast, 2-nitrosotoluene resulted in <10% yield of the desired benzisoxazole (not shown). The regioselectivity of the transformation was examined by employing a number of meta-substituted nitrosoarenes. While only moderate regioselectivity was observed for alkyl and chloro groups (3d, 3e, 3h, 3i), a fluoro substituent at the meta position provided significantly higher regioselectivity, with the major site of addition being that most remote from the fluoro group (3j, 3k). Reaction with a meta-methoxy group resulted in a single regioisomer (3m, 3n). Notably, a single benzisoxazole regioisomer was also observed from reaction with 2-nitrosonaphthalene (3l). This result parallels the regioselectivity observed in electrophilic aromatic substitution reactions.[7]

While other glyoxylate esters react efficiently under the optimized conditions (3o), less electrophilic aldehydes such as benzaldehyde did not give 2,1-benzisoxazole products.

We next aimed to shed light on the reaction mechanism by employing an 18O labeling study to determine the origin of the oxygen in the isoxazole product. First, 18O-enriched 4-tert-butyl-nitrosobenzene (4) was prepared and subjected to the reaction conditions to give benzisoxazole 5 (eq 1). The 18O-nitrosobenzene was generated by oxidation of the corresponding aniline with H218O2 in the presence of a diphenyldiselenide catalyst, and 18O incorporation into the nitroso product was confirmed by GCMS analysis.[8] In order to work with the low concentrations of aqueous H218O2 that are commercially available,[9] we opted to label 4-tert-butyl-nitrosobenzene for this study to alleviate issues with nitrosobenzene sublimation on a small scale. Importantly, reaction of the 18O-labeled nitrosoarene with ethyl glyoxylate resulted in almost complete incorporation of the 18O label in the 2,1-benzisoxazole product 5 as determined by LCMS analysis (eq 1).[10]

To verify that the isoxazole oxygen originates from nitrosobenzene, a control reaction was conducted with 18O-labeled ethyl glyoxylate. Labeling of the glyoxylate ester was achieved by exchange with H218O. Because ethyl glyoxylate not only readily hydrates and oligomerizes but also poorly ionizes, direct GCMS and LCMS analyses were not effective for accurately quantitating the extent of 18O labeling of the ethyl glyoxylate. Instead, the 18O-labeled glyoxylate was subjected to Sakurai allylation with allyltrimethylsilane to give alcohol 7 for which a high level of 18O incorporation was confirmed by LCMS analysis (eq 2).[11] Notably, when the labeled glyoxylate 6 was subjected to the reaction conditions, minimal 18O incorporation was observed in benzisoxazole 8 by LCMS (eq 3). Taken together, the results of the described labeling experiments clearly establish that the isoxazole oxygen originates from the nitrosoarene partner rather than from the aldehyde.

We propose a mechanism shown in Scheme 1 that is based on the 18O incorporation experiments and the clear parallel between this reaction and electrophilic aromatic substitutions in terms of substrate reactivity and regioselectivity. Enol 9b is proposed to add to the nitroso oxygen upon activation with BF3 to provide adduct 10. This step is consistent with previously reported O-selective nucleophilic additions of carbon nucleophiles, including silyl enol ethers, to Lewis acid activated nitrosoarenes.[12] The O-selectivity is postulated to result from coordination of the nitroso nitrogen to the Lewis acid to increase electrophilicity at oxygen.[12−14] Although the proposed umpolung reactivity of the glyoxylate ester upon hydration does not have direct precedent, it is highly analogous to the acid-catalyzed addition of glyoxylate-derived silyl ketene acetals to a variety of electrophiles, including carbonyls and alkyl halides.[15] Following dehydration of addition product 10 to regenerate the carbonyl 11, an intramolecular Friedel–Crafts cyclization gives bicyclic intermediate 12, which provides the 2,1-benzisoxazole product 3 upon aromatization.

Scheme 1

Proposed Reaction Mechanism

To test this mechanistic pathway, we prepared Boc derivative 13 that, upon acidic Boc cleavage, should provide intermediate 11, with the only difference being a proton in place of BF3. Indeed, upon treatment of 13 with trifluoroacetic acid, 2,1-benzisoxazole 3a was observed as the major reaction product (eq 4). The acid not only removed the Boc group but presumably also promoted Friedel–Crafts cyclization. The yield of 3a from 13 is limited by a competing Bamberger rearrangement to give the 4-aminophenol side product in 20% yield.[16] We also explored cyclization of the less electrophilic benzoate analogue of pyruvate 13. However, upon acid treatment, benzisoxazole was not detected, and 4-aminophenol and benzoic acid from competing Bamberger rearrangement were instead observed as the sole reaction products.

Conclusion

A practical annulation to give 2,1-benzisoxazoles from previously unexplored inputs has been developed. A range of electron-neutral, electron-rich, and modestly electron-deficient nitrosobenzenes serve as efficient inputs for the reaction. On the basis of mechanistic studies that include 18O labeling, substrate scope and regioselectivities, and preparation of a putative reaction intermediate, the reaction likely proceeds by an unusual BF3·Et2O-catalyzed umpolung addition of glyoxylates to nitrosobenzenes with high O-selectivity. A new type of Friedel–Crafts cyclization then occurs, followed by aromatization to give the desired 2,1-benzisoxazole products. Studies are currently underway to capitalize on the uncovered novel reactivity to access other heterocyclic motifs.

Experimental Section

General Experimental Methods

Unless otherwise indicated, all reactions were set up under an inert atmosphere (N2) using flame-dried glassware. Dichloromethane and all other solvents were purified by elution through a column of activated alumina under N2 before use. Triethylamine was distilled from CaH2 under nitrogen immediately before use. Dichloromethane-d2, benzene-d6, acetone-d6, and chloroform-d were all used as received. Unless otherwise noted, all reagents were purchased from commercial sources and used without further purification. Products and starting materials were visualized on TLC using UV or by staining with KMnO4. NMR chemical shifts are reported in ppm relative to CDCl3 (7.26 ppm 1H and 77.16 ppm 13C), C6D6 (7.16 ppm 1H), (CD3)CO (29.84 ppm 13C), or CD2Cl2 (5.32 ppm 1H and 54.00 ppm 13C). Trifluoroacetic acid (−76.55 pm in CDCl3) was used as an external standard for determining 19F NMR chemical shifts. For IR spectra, only partial data are provided. Melting points are reported uncorrected. High-resolution mass spectra (HRMS) and low-resolution mass spectra (LRMS) data for the benzisoxazole products were obtained using electrospray ionization (ESI) on a time-of-flight (TOF) mass spectrometer. HRMS data for the nitrosoarene starting materials were obtained using an APGC ion source. GC analysis was performed using an Agilent J&W HP-5 column (5%-phenyl)-methylpolysiloxane.

Ethyl Glyoxylate (2a)

Purification of ethyl glyoxylate was adapted from a literature procedure.[17] A 50% technical solution of ethyl glyoxyate in toluene (purchased form Aldrich) was purified by flash chromatography on silica gel (hexanes/ethyl acetate 20:1 to 1:1) and then distilled through a vacuum-jacketed vigereux column under N2 (90 °C, 60 mmHg) to give a pale yellow oil. The freshly distilled ethyl glyoxylate was stored under N2 in a Schlenk flask at −20 °C and warmed to ambient temperature before use.

Benzyl Glyoxylate (2b)

Benzyl glyoxyate was prepared according to a literature procedure[18] and purified by distillation using a Kugelrohr apparatus (95 °C, 20 mmHg) to give a yellow oil.

BF3·Et2O Catalyst

Boron trifluoride diethyl etherate was purchased from Aldrich and purified according to a literature procedure.[19] The reagent was stored under N2 in a Schlenk flask at −20 °C and warmed to ambient temperature before use.

Nitrosoarenes (1)

Nitrosobenzene, which was used to prepare 3a and 3o, is commercially available. The nitrosoarenes used to prepare 2,1-benzisoxazoles 3b,[20]3c,[21]3d,[22]3e,[23]3g,[24] and 3m(20) were prepared according to the cited recently published methods.

General Procedure for the Preparation of Nitrosobenzenes[25]

In a round-bottom flask equipped with a stir bar, the indicated aniline (3.7–24 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.26 M) and added to a solution of oxone (11–72 mmol, 3.0 equiv) in water (0.60 M). The reaction mixture was stirred at room temperature with vigorous stirring. After 4 h, the reaction mixture was extracted with CH2Cl2 (3 × 1 mL/mmol aniline), dried over MgSO4, and concentrated under reduced pressure. Purification by silica gel column chromatography provided the indicated nitrosobenzene.

1-Isopropyl-3-nitrosobenzene (1e)

The general procedure was followed with 3-isopropyl-benzeneamine (2.7 g, 20 mmol, 1.0 equiv) with purification by silica gel chromatography eluting using hexanes/ether (15:1). The product 1h (1.3 g, 45% yield) was obtained as an amorphous tan paste. 1H NMR (500 MHz, CDCl3) δ 7.77 (d, J = 7.7 Hz, 1H), 7.73 (s, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 3.18–2.91 (m, 1H), 1.32 (d, J = 6.9 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 166.7, 150.6, 134.1, 129.3, 119.3, 118.7, 34.1, 23.9. The analytical data for this compound are consistent with previously reported data.[26]

1-2-3-Trimethyl-5-nitrosobenzene (1f)

The general procedure was followed with 3,4,5-trimethyl-benzeneamine (0.50 g, 3.7 mmol, 1.0 equiv) with purification by silica gel chromatography eluting using hexanes/ether (20:1). The product 1f (0.14 g, 25% yield) was obtained as a pale blue solid. (mp: 36–39 °C). IR (film) 3082, 2915, 1793, 1590, 1511, 1482, 1415, 1343, 1260, 1092, 965, 901, 747, 701 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.55 (s, 2H), 2.42 (s, 6H), 2.25 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 165.7, 144.9, 137.7, 120.5, 20.8, 16.6; HRMS (APGC/[M + H]+) calcd. for C9H12NO+: 150.0913. Found: 150.0920.

1-Chloro-3-nitrosobenzene (1h)

The general procedure was followed with 3-chloro-benzeneamine (3.1 g, 24 mmol, 1.0 equiv) with purification by silica gel chromatography eluting using hexanes/ether (20:1). The product 1h (2.0 g, 60% yield) was obtained as a white solid (69–73 °C, lit.[27a] 72–73 °C). 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.66–7.60 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 165.2, 136.2, 135.1, 130.9, 121.6, 118.9. The analytical data for this compound are consistent with previously reported data.[27b]

2-Chloro-1-methyl-4-nitrosobenzene (1i)

The general procedure was followed with 3-chloro-4-methyl-benzeneamine (3.4 g, 24 mmol, 1.0 equiv) with purification by silica gel chromatography eluting using hexanes/dichloromethane (20:1). The product 1i (0.74 g, 20% yield) was obtained as a white solid. (mp: 66–68 °C). IR (film) 3089, 2930, 1917, 1580, 1480, 1380, 1249, 1215, 1049, 869, 824, 766, 703, 555 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, J = 8.0, 1.8 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 2.47 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 165.1, 144.8, 136.0, 131.7, 121.1, 120.2, 20.9; HRMS (APGC/[M + H]+) calcd. for C7H7ClNO+: 156.0211. Found: 156.0220.

1-Fluoro-3-nitrosobenzene (1j)

The general procedure was followed with 3-fluoro-benzeneamine (2.7 g, 24 mmol, 1.0 equiv) with purification by silica gel chromatography eluting using hexanes/ether (10:1). The product 1j (2.1 g, 67% yield) was obtained as a white solid. (mp: 52–56 °C) IR (film) 3060, 3039, 1602, 1479, 1446, 1412, 1392, 1234,1144, 1011, 905, 830, 782, 691, 519, 479 cm–1; 1H NMR (500 MHz, CDCl3) δ 8.17 (dt, J = 7.8, 1.0 Hz, 1H), 7.70 (td, J = 8.0, 5.3 Hz, 1H), 7.48–7.40 (m, 1H), 7.16 (dt, J = 8.3, 2.1 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 165.9 (d, J = 4.7 Hz), 163.3 (d, J = 251.8 Hz), 131.3 (d, J = 7.7 Hz), 122.3 (d, J = 22.4 Hz), 121.2 (d, J = 2.7 Hz), 103.7 (d, J = 22.6 Hz); 19F NMR (376 MHz, CDCl3) δ −106.95 (q, J = 7.6 Hz); HRMS (APGC/[M + H]+) calcd. for C6H5FNO+: 126.0350. Found: 126.0356.

2-Fluoro-1-methyl-4-nitrosobenzene (1k)

The general procedure was followed with 3-fluoro-4-methyl-benzeneamine (2.0 g, 16 mmol, 1.0 equiv) with purification by silica gel chromatography eluting using hexanes/ether (20:1). The product 1k (1.4 g, 63% yield) was obtained as a green oil. IR (neat) 3073, 1593, 1502, 1478, 1400, 1226, 1184, 1065, 879, 821, 784, 745 cm–1; 1H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 7.9, 1.7 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.11 (dd, J = 9.2, 1.7 Hz, 1H), 2.37 (d, J = 2.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 165.7 (d, J = 4.8 Hz), 161.6 (d, J = 250.6 Hz), 134.1 (d, J = 18.2 Hz), 132.2 (d, J = 4.8 Hz), 121.5, 103.2 (d, J = 23.0 Hz), 15.5 (d, J = 3.5 Hz); 19F NMR (376 MHz, CDCl3) δ −115.82 (ddd, J = 9.6, 7.3, 2.4 Hz); HRMS (APGC/[M + H]+) calcd. for C7H7FNO+: 140.0506. Found: 140.0512.

1-Chloro-2-methoxy-4-nitrosobenzene (1n)

The general procedure was followed with 4-chloro-3-methyoxy-benzeneamine (1.0 g, 6.4 mmol, 1.0 equiv) with purification by silica gel chromatography eluting using hexanes/ether (20:1). The product 1n (0.52 g, 48% yield) was obtained as a pale yellow solid (mp: 115–120 °C). IR (film) 3093, 2935, 1583, 1482, 1281, 1245, 1030, 768, 690 cm–1; 1H NMR (500 MHz, CDCl3) δ 8.08 (dd, J = 8.2, 2.0 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 1.9 Hz, 1H), 3.97 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 164.9, 156.0, 131.6, 131.3, 120.7, 98.1, 56.5; HRMS (APGC/[M + H]+) calcd. for C7H7ClNO2+: 172.0160. Found: 172.0163.

2-Nitrosonaphthalene (1l)[28]

In a round-bottom flask positioned in a water bath at ambient temperature, NOBF4 (174 mg, 1.49 mmol, 1.03 equiv) was added in one portion, with vigorous stirring, to a white slurry of potassium naphthalene-2-trifluoroborate (340 mg, 1.45 mmol, 1.00 equiv) in acetonitrile (4.40 mL, 0.330 mL). The reaction mixture immediately turned black and was stirred for 20 s before the addition of H2O (20 mL) and then CH2Cl2 (20 mL). The reaction mixture was extracted with CH2Cl2 (3 × 20 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by SiO2 column chromatography eluting with hexanes/ethyl acetate (4:1) to give 1l (34.0 mg, 14.9% yield) as a tan solid (mp: 58–63 °C). IR (film) 3089, 3054, 2925, 1596, 1425, 1381, 1347, 868, 814, 751, 566 cm–1; 1H NMR (500 MHz, CDCl3) δ 9.52 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 7.76–7.71 (m, 1H), 7.71–7.66 (m, 1H), 7.01 (dd, J = 8.9, 1.8 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 164.0, 137.5, 136.7, 133.2, 131.3, 130.7, 129.3, 128.3, 127.9, 108.5; GCMS (EI/[M]+) calcd. for C10H6NO+: 157.1. Found: 157.1.

General Procedure for the BF3·Et2O-Catalyzed 2,1-Benzisoxazole Synthesis

In a flame-dried Schlenk flask equipped with a stir bar, ethyl glyoxylate (90–110 mg, 0.88–1.1 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.067 M) under an atmosphere of N2. To the solution was added BF3·Et2O (13–15 mg, 0.088–0.11 mmol, 0.10 equiv), followed by a solution of the indicated nitrosobenzene (1.8–2.2 mmol, 2.0 equiv) in CH2Cl2 (0.40 M). The Schlenk flask was equipped with a reflux condenser under positive N2 pressure and placed in a temperature-controlled oil bath set to 45 °C. After 48 h, the flask was removed from the oil bath and cooled to ambient temperature. The mixture was pushed through a plug of SiO2 with EtOAc and then concentrated under reduced pressure. The crude reaction product was purified via silica gel column chromatography to afford the indicated product.

Ethyl Benzo[c]isoxazole-3-carboxylate (3a)

The general procedure was followed with ethyl glyoxylate (110 mg, 1.08 mmol, 1.00 equiv) and nitrosobenzene (1a) (230 mg, 2.16 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (4:1) afforded 3a (165 mg, 79% yield) as a very pale, pink solid (mp: 94–96 °C). IR (film) 3078, 2976, 1731, 1606, 1545, 1476, 1451, 1373, 1310, 1207, 1153, 1105, 1016, 947, 853, 765, 752, 625 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.3 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 156.6, 152.9, 151.0, 140.6, 128.2, 125.9, 122.2, 111.8, 63.4, 14.3; HRMS (ESI/[M + H]+) calcd. for C10H10NO3+: 192.0655. Found: 192.0661.

Ethyl 5-Methylbenzo[c]isoxazole-3-carboxylate (3b)

The general procedure was followed with ethyl glyoxylate (102 mg, 1.00 mmol, 1.00 equiv) and 4-methyl-1-nitrosobenzene (1b) (242 mg, 2.00 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (8:1) afforded 3b (154 mg, 75% yield) as a pale pink solid (mp: 81–84 °C). IR (film) 2989, 1729, 1599, 1541, 1371, 1313, 1245, 1218, 1163, 1112, 1022, 857, 814, 780, 605 cm–1; 1H NMR (400 MHz, CD2Cl2) δ 7.73 (d, J = 8.3 Hz, 1H), 7.47 (m, 1H), 7.36–7.21 (m, 1H), 4.49 (q, J = 7.1 Hz, 2H), 2.52 (s, 3H), 1.45 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 156.7, 152.4, 151.3, 139.2, 138.5, 127.4, 121.5, 111.7, 63.3, 22.2, 14.3; HRMS (ESI/[M + H]+) calcd. for C11H12NO3+: 206.0812. Found 206.0805.

Ethyl 5-(tert-Butyl)benzo[c]isoxazole-3-carboxylate (3c)

The general procedure was followed with ethyl glyoxylate (102 mg, 1.00 mmol, 1.00 equiv) and 4-tert-butyl-1-nitrosobenzene (1c) (326 mg, 2.00 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (4:1) afforded 3c (178 mg, 72% yield) as a yellow solid (mp: 45–47 °C). IR (film) 2962, 2909, 2875, 1741, 1621, 1547, 1368, 1302, 1192, 1152, 1112, 1016, 954, 930, 859, 829, 779, 659 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.76 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.49 (dd, J = 8.6, 1.7 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.35 (s, 9H); 13C NMR (126 MHz, (CD3)2CO) δ 157.0, 153.8, 153.3, 152.0, 139.3, 124.6, 121.8, 109.0, 63.3, 36.1, 31.8, 14.4; HRMS (ESI/[M + H]+) calcd. for C14H18NO3+: 248.1281. Found 248.1255.

Ethyl 6-Methylbenzo[c]isoxazole-3-carboxylate (3d)

The general procedure was followed with ethyl glyoxylate (110 mg, 1.08 mmol, 1.00 equiv) and 1-methyl-3-nitrosobenzene (1d) (260 mg, 2.16 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (4:1) afforded 3d and 3d′ (150 mg, 67% yield) as an inseparable mixture of two regioisomers in a ratio of 2.6:1 as a pale yellow solid. IR (film) 2994, 2914, 1730, 1606, 1545, 1475, 1375, 1343, 1309, 1298, 1208, 1157, 1113, 1014, 952, 854, 809, 781, 758, 635 cm–1; 1H NMR (600 MHz, CDCl3) major regioisomer δ 7.65 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) major regioisomer δ 156.7, 152.9, 149.3, 140.8, 136.0, 129.7, 121.8, 111.2, 63.4, 21.7, 14.4; HRMS (ESI/[M + H]+) calcd. for C11H12NO3+: 206.0812. Found 206.0803.

Ethyl 6-Isopropylbenzo[c]isoxazole-3-carboxylate (3e)

The general procedure was followed with ethyl glyoxylate (110 mg, 1.08 mmol, 1.00 equiv) and 1-isopropyl-3-nitrosobenzene (1e) (321 mg, 2.16 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (4:1) afforded 3e and 3e′ (211 mg, 84% yield) as an inseparable mixture of two regioisomers in a ratio of 4:1 as a red solid. IR (film) 2973, 2953, 2869, 1738, 1606, 1553, 1461, 1367, 1294, 1228, 1154, 1108, 1016, 957, 853, 802, 658 cm–1; 1H NMR (400 MHz, CDCl3) major regioisomer δ 7.69 (d, J = 1.3 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.41–7.37 (m, 2H), 4.53 (q, J = 7.2 Hz, 2H), 3.04 (p, J = 6.9 Hz, 1H), 1.47 (t, J = 7.1 Hz, 3H), 1.29 (d, J = 6.9 Hz, 6H); 13C NMR (101 MHz, CDCl3) major regioisomer δ 156.7, 152.9, 149.4, 147.2, 140.8, 127.4, 119.1, 111.3, 63.3, 34.3, 24.4, 14.3; HRMS (ESI/[M + H]+) calcd. for C13H16NO3+: 234.1125. Found 234.1146.

Ethyl 4,5,6-Trimethylbenzo[c]isoxazole-3-carboxylate (3f)

The general procedure was followed with ethyl glyoxylate (95.0 mg, 0.931 mmol, 1.00 equiv) and 1,2,3-trimethyl-5-nitrosobenzene (1f) (278 mg, 1.86 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (8:1) afforded 3f (98 mg, 44% yield) as a white solid (mp: 119–123 °C). IR (film) 2982, 1726, 1537, 1373, 1287, 1231, 1197, 1157, 1027, 881, 857, 781, 652, 627 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 1H), 4.53 (q, J = 7.1 Hz, 2H), 2.51 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 157.0, 152.1, 149.6, 137.7, 136.3, 135.1, 120.0, 119.2, 63.2, 21.5, 15.9, 14.4, 13.0; HRMS (ESI/[M + H]+) calcd. for C13H16NO3+: 234.1125. Found 234.1109.

Ethyl 4,6-Dimethylbenzo[c]isoxazole-3-carboxylate (3g)

The general procedure was followed with ethyl glyoxylate (95.0 mg, 0.931 mmol, 1.00 equiv) and 1,3-dimethyl-5-nitrosobenzene (1g) (251 mg, 1.86 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (4:1) afforded 3g (66 mg, 32% yield) as an off-white solid (mp: 78–80 °C). IR (film) 2925, 1729, 1625, 1547, 1446, 1368, 1307, 1290, 1212, 1155, 1129, 1111, 1024, 958, 848, 637 cm–1; 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.12 (s, 1H), 4.54 (q, J = 7.1 Hz, 2H), 2.54 (s, 3H), 2.44 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 156.9, 152.8, 148.8, 140.5, 135.9, 130.6, 121.8, 119.0, 63.2, 21.6, 15.3, 14.4; HRMS (ESI/[M + H]+) calcd. for C12H14NO3+: 220.0968. Found 220.0953.

Ethyl Chlorobenzo[c]isoxazole-3-carboxylates (3h and 3h′)

The general procedure was followed with ethyl glyoxylate (110 mg, 1.08 mmol, 1.00 equiv) and 1-chloro-3-nitrosobenzene (1h) (304 mg, 2.16 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (5:1) afforded 3h (129 mg, 52% yield) as a tan solid and 3h′ (40.3 mg, 16% yield) as an off-white solid. Characterization for ethyl 6-chlorobenzo[c]isoxazole-3-carboxylate (3h, major): (mp: 79–80 °C). IR (film) 3067, 2984, 1734, 1601, 1546, 1472, 1449, 1371, 1305, 1210, 1159, 1113, 1053, 1012, 921, 852, 828, 704, 636 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.50 (dd, J = 8.8, 2.1 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 156.3, 154.0, 149.5, 141.6, 131.6, 128.84, 122.03, 112.74, 63.66, 14.30; HRMS (ESI/[M + H]+) calcd. for C10H9ClNO3+: 226.0265. Found 226.0285. Characterization for ethyl 4-chlorobenzo[c]isoxazole-3-carboxylate (3h′, minor): (mp: 84–86 °C). IR (film) 3003, 1742, 1610, 1549, 1471, 1444, 1375, 1310, 1252, 1197, 1140, 1109, 1018, 963, 854, 787, 734, 634 cm–1; 1H NMR (600 MHz, CDCl3) δ 7.79 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 4.57 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 156.1, 153.2, 147.7, 141.7, 128.4, 126.6, 120.7, 117.2, 63.7, 14.3; HRMS (ESI/[M + H]+) calcd. for C10H9ClNO3+: 226.0265. Found 226.0294.

Ethyl Chloro-5-methylbenzo[c]isoxazole-3-carboxylate (3i and 3i′)

The general procedure was followed with ethyl glyoxylate (102 mg, 1.00 mmol, 1.00 equiv) and 2-chloro-1-methyl-4-nitrosobenzene (1i) (310 mg, 2.00 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (5:1) afforded 3i (121 mg, 51% yield) as a pale pink solid and 3i′ (68 mg, 28% yield) as a pale orange solid. Characterization for ethyl 4-chloro-5-methylbenzo[c]isoxazole-3-carboxylate (3i, major): (mp: 110–115 °C). IR (film) 3071, 2997, 1737, 1595, 1544, 1448, 1370, 1297, 1247, 1158, 1109, 1007, 950, 851, 781, 691, 650, 626, 509 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.86 (s, 1H), 7.52 (s, 1H), 4.55 (q, J = 7.2 Hz, 2H), 2.52 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 156.4, 153.4, 149.8, 139.7, 137.2, 132.2, 121.9, 113.0, 63.5, 21.4, 14.3; HRMS (ESI/[M + H]+) calcd. for C11H11ClNO3+: 240.0422. Found 240.0414. Characterization for ethyl 6-chloro-5-methylbenzo[c]isoxazole-3-carboxylate (3i′, minor): (mp: 85–86 °C). IR (film) 3086, 2994, 2943, 1744, 1592, 1551, 1479, 1365, 1330, 1297, 1246, 1202, 1135, 1107, 1030, 943, 854, 809, 633, 599 cm–1; 1H NMR (600 MHz, CDCl3) δ 7.66 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 2.54 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ 156.2, 152.8, 148.2, 139.6, 136.9, 128.5, 119.7, 116.6, 63.5, 19.7, 14.3; HRMS (ESI/[M + H]+) calcd. for C11H11ClNO3+: 240.0422. Found 240.0395.

Ethyl 6-Fluorobenzo[c]isoxazole-3-carboxylate (3j and 3j′)

The general procedure was followed with ethyl glyoxylate (102 mg, 1.00 mmol, 1.00 equiv) and 1-fluoro-3-nitrosobenzene (1j) (150 mg, 2.00 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (4:1) afforded 3j and 3j′ (80 mg, 38% yield) as an inseparable mixture of two regioisomers in a ratio of 14:1 as a pale yellow solid. IR (film) 3074, 2922, 2852, 1734, 1608, 1553, 1473, 1448, 1437, 1369, 1346, 1302, 1262, 1221, 1148, 1114, 1016, 962, 884, 854, 808, 779, 637, 512 cm–1; 1H NMR (400 MHz, C6D6) major regioisomer δ 7.25 (dd, J = 8.1, 2.6 Hz, 1H), 6.76 (dd, J = 9.0, 4.3 Hz, 1H), 6.62 (td, J = 9.1, 2.6 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 0.93 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3) major regioisomer δ 160.7 (d, J = 243.5 Hz), 156.3, 154.4, 147.4 (d, J = 1.0 Hz), 141.4 (d, J = 13.3 Hz), 116.7 (d, J = 26.8 Hz), 112.5 (d, J = 10.0 Hz), 108.2 (d, J = 25.4 Hz), 63.6, 14.30; 19F NMR (376 MHz, CDCl3) δ −116.16 (td, J = 8.5, 4.1 Hz); HRMS (ESI/[M + H]+) calcd. for C10H9FNO3+: 210.0561. Found 210.0569.

Ethyl Fluoro-5-methylbenzo[c]isoxazole-3-carboxylate (3k and 3k′)

The general procedure was followed with ethyl glyoxylate (110 mg, 1.08 mmol, 1.00 equiv) and 2-fluoro-1-methyl-4-nitrosobenzene (1k) (300 mg, 2.16 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (8:1) afforded 3k (182 mg, 73% yield) as a pale pink solid and 3k′ (5 mg, 2% yield) as an orange solid. Characterization for ethyl 6-fluoro-5-methylbenzo[c]isoxazole-3-carboxylate (3k, major): (mp: 100–104 °C). IR (film) 3036, 2925, 1731, 1601, 1546, 1460, 1375, 1318, 1280, 1215, 1143, 1098, 1026, 1006, 865, 782, 631, 512 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 6.1 Hz, 1H), 4.55 (q, J = 7.1 Hz, 2H), 2.44 (d, J = 2.3 Hz, 3H), 1.49 (t, J = 7.2 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 159.5 (d, J = 242.9 Hz), 156.4, 153.7, 147.4, 139.3 (d, J = 13.5 Hz), 127.4 (d, J = 21.7 Hz), 113.0 (d, J = 5.8 Hz), 107.4 (d, J = 26.7 Hz), 63.4, 15.9 (d, J = 4.5 Hz), 14.3; 19F NMR (376 MHz, CDCl3) δ −118.88 (tt, J = 6.0, 2.6 Hz); HRMS (ESI/[M + H]+) calcd. for C11H11FNO3+: 224.0717. Found 224.0690. Characterization for ethyl 4-fluoro-5-methylbenzo[c]isoxazole-3-carboxylate (3k′, minor): (mp: 95–98 °C). IR (film) 2926, 1739, 1602, 1561, 1506, 1469, 1369, 1306, 1256, 1232, 1171, 1076, 1012, 954, 819, 777, 693, 607, 540 cm–1; 1H NMR (600 MHz, C6D6) δ 7.24 (d, J = 8.2 Hz, 1H), 6.58 (t, J = 7.3 Hz, 1H), 4.00 (q, J = 7.1 Hz, 1H), 1.95 (s, 1H), 0.92 (t, J = 7.2 Hz, 2H); 13C NMR (151 MHz, CD2Cl2) δ 156.5 (s), 153.3 (s), 145.9 (d, J = 251.1 Hz), 142.1 (d, J = 1.0 Hz), 139.1 (d, J = 12.0 Hz), 129.0 (d, J = 3.1 Hz), 125.4 (d, J = 12.5 Hz), 117.4 (d, J = 4.8 Hz), 63.8 (s), 14.8 (d, J = 3.2 Hz), 14.5 (s); 19F NMR (376 MHz, C6D6) δ −138.26 (dq, J = 6.8, 2.3 Hz); HRMS (ESI/[M + H]+) calcd. for C11H11FNO3+: 224.0717. Found 224.0746.

Ethyl Naphtho[2,1-c]isoxazole-1-carboxylate (3l)

The general procedure was followed with ethyl glyoxylate (90.0 mg, 0.882 mmol, 1.00 equiv) and 2-nitroso-naphthalene (1l) (276 mg, 1.76 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (5:1) afforded 3l (79 mg, 37% yield) as a red solid (mp: 90–92 °C). IR (film) 3055, 2976, 2909, 1729, 1654, 1582, 1537, 1374, 1322, 1247, 1204, 1145, 1023, 815, 754, 636, 561 cm–1; 1H NMR (500 MHz, CDCl3) δ 8.38 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.68 (m, 1H), 7.63 (m, 1H), 4.59 (q, J = 7.2 Hz, 2H), 1.52 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 156.6, 152.3, 147.7, 137.5, 133.2, 128.9, 127.6, 127.4, 127.1, 121.2, 120.5, 119.4, 63.3, 14.4; HRMS (ESI/[M + H]+) calcd. for C14H12NO3+: 242.0812. Found 242.0787.

Ethyl 6-Methoxybenzo[c]isoxazole-3-carboxylate (3m)

The general procedure was followed with ethyl glyoxylate (102 mg, 1.00 mmol, 1.00 equiv) and 1-methoxy-3-nitrosobenzene (1m) (274 mg, 2.00 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (2:1) afforded 3m (115 mg, 52% yield) as a pale pink solid (mp: 80–83 °C). IR (film) 2978, 2944, 2843, 1733, 1608, 1550, 1485, 1434, 1366, 1311, 1257, 12222, 1151, 1105, 1022, 959, 850, 803, 779, 643, 554, 529 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 9.0, 2.6 Hz, 1H), 4.54 (q, J = 7.2 Hz, 2H), 3.87 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 158.3, 156.6, 153.5, 145.8, 141.6, 118.2, 112.1, 103.7, 63.3, 56.1, 14.3; HRMS (ESI/[M + H]+) calcd. for C11H12NO4+: 222.0761. Found 222.0751.

Ethyl 5-Chloro-6-methoxybenzo[c]isoxazole-3-carboxylate (3n)

The general procedure was followed with ethyl glyoxylate (102 mg, 1.00 mmol, 1.00 equiv) and 1-chloro-2-methoxy-4-nitrosobenzene (1n) (342 mg, 2.00 mmol, 2.00 equiv). Purification via silica gel column chromatography eluting with hexanes:ethyl acetate (4:1) afforded 3n (114 mg, 45% yield) as a tan solid (mp: 115–120 °C). IR (film) 3101, 3077, 2970, 2951, 1733, 1603, 1544, 1469, 1437, 1375, 1320, 1278, 1226, 1149, 1042, 1018, 991, 954, 863, 837, 779, 694, 627, 546 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 1H), 7.34 (s, 1H), 4.55 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 156.2, 154.1, 153.6, 144.9, 140.0, 124.7, 113.2, 103.3, 63.4, 56.9, 14.3; HRMS (ESI/[M + H]+) calcd. for C11H11ClNO4+: 256.0371. Found 256.0378.

18O Labeling Studies

Synthesis of 1-(tert-Butyl)-4-(nitroso)benzene (18O) (4)[8]

In an oven-dried one dram vial with a Teflon cap, cooled to room temperature in a desiccator, diphenyldiselenide (0.97 mg, 3.1 μmol, 0.10 equiv) and 4-(tert-butyl)aniline (5.0 μL, 31 μmol, 1.0 equiv) were dissolved in CHCl3 (100 μL, 0.31 M). Finally, a 2.5% aqueous solution of 18O-labeled hydrogen peroxide9 (100 mg, 65.8 μmol, 2.10 equiv) was added, and the reaction mixture was stirred vigorously in a water bath at ambient temperature under an atmosphere of air for 5 h. The reaction mixture was extracted with CHCl3 (3 × 0.5 mL) and concentrated under reduced pressure. The crude mixture was purified via SiO2 column chromatography, eluting with hexanes/dichloromethane (4:1) to give 1-(tert-butyl)-4-nitrosobenzene-(18O) (4) as a yellow-green oil (0.5 mg, 10% yield). GCMS (EI/[M]+) calcd. for C10H13N18O+: 165.1. Found: 165.1.

BF3·Et2O-Catalyzed Reaction with 1-(tert-Butyl)-4-(nitroso)benzene (18O) (eq 1)

In a N2-filled glovebox, a solution of ethyl glyoxylate (2a) in CH2Cl2 (0.025 M, 59 μL, 1.5 μmol, 1.0 equiv) was added to 1-(tert-butyl)-3-(nitroso)benzene-18O (4) (0.50 mg, 2.9 μmol, 2.0 equiv) in an oven-dried one dram vial with a Teflon cap. To the reaction mixure was added BF3·Et2O (0.02 μL, 0.2 μmol, 0.1 equiv). The vial was capped tighly, removed from the glovebox, and placed into a temperature-controlled oil bath set to 40 °C with stirring for 48 h. The reaction solution was cooled to ambient temperature, pushed through a SiO2 plug with ethyl acetate, and concentrated under reduced pressure. A reaction yield was determined by GC using tetradecane as an external standard (14%). The crude reaction mixture was purified by prep-TLC with hexanes/ethyl acetate (3:1), and product was collected as a fluorescent band at R 0.68. LCMS (ESI/[M + H]+) calcd. for C14H18NO218O+: 250.1324. Found: 250.1253.

Ethyl 2-(Oxo-18O)acetate (6)

In a flame-dried 5 mL Schlenk flask under positive N2 pressure, ethyl glyoxylate (2a) (52.5 mg, 0.514 mmol, 1.00 equiv) was dissolved in H218O (262 mg, 13.1 mmol, 25.5 equiv).[29] The solution was stirred in an ambient temperature water bath under N2 for 12 h. After 12 h, the mixture was frozen with liquid N2 and then placed onto the lyophilizer to remove water. Ethyl 1-(oxo-18O)acetate (6) was recovered after lyophilization for 4 h (20 mg, 38% yield).

Trapping of 6 To Give Ethyl 2-(Hydroxyl)pent-4-enoate-2-18O (7) (eq 2)[11]

In the same flame-dried 5 mL Schlenk flask used for the preparation of 6, under positive N2 pressure, 18O-ethyl glyoxyate (6) (18 mg, 0.17 mmol, 1.0 equiv) was dissolved in CH2Cl2 (0.86 mL, 0.20 M). Allyltrimethylsilane (60 μL, 0.35 mmol, 2.0 equiv) was added to the solution, which was then cooled to 0 °C. BF3·Et2O (40 μL, 0.35 mmol, 2.0 equiv) was added dropwise over 15 min. The reaction mixture was stirred at 0 °C for 15 min before warming slowly to ambient temperature and stirring for an additional 2 h in an ambient temperature water bath. The reaction was quenched with a saturated solution of NH4Cl (1.2 mL), extracted with CH2Cl2 (3× 1.5 mL), washed with brine (3× 1.5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 7 as a pale yellow oil (20.2 mg, 80%). LCMS (ESI/[M + H]+) calcd. for C7H13O218O+: 147.0902. Found: 147.0956.

BF3·Et2O-Catalyzed Reaction with Ethyl 2-(Oxo-18O)acetate (3a) (eq 3)

In a flame-dried 10 mL Schlenk flask under positive N2 pressure, 18O-ethyl glyoxylate (6) (20 mg, 0.20 mmol, 1.0 equiv) was dissolved in CH2Cl2 (3 mL). A solution of nitrosobenzene (1a) (43 mg, 0.40 mmol, 1.0 equiv) in CH2Cl2 (1 mL) was added to the reaction mixture, followed by BF3·Et2O (2.8 μL, 0.020 mmol, 0.10 equiv). The Schlenk flask was fitted with a reflux condenser under positive N2 pressure and placed in a temperature-controlled oil bath set to 45 °C. After stirring at a gentle reflux for 48 h, the reaction mixture was cooled to ambient temperature, pushed through a SiO2 plug with ethyl acetate, and concentrated under reduced pressure. The crude mixture was purified via SiO2 column chromatography eluting with hexanes/ethyl acetate (4:1) to give a pale pink solid (34 mg, 88% yield). LCMS (ESI/[M + H]+) cacld. for C10H10NO3+: 192.0655. Found: 192.0873.

Preparation of N-Boc-O-acylphenylhydroxylamine and Conversion to 2,1-Benzisoxazole

Ethyl 2-(((tert-Butoxycarbonyl)(phenyl)amino)oxy)-2-oxoacetate (13)

In a flame-dried round-bottom flask, N-Boc-phenylhydroxylamine[30] (1.0 g, 4.8 mmol, 1.0 equiv) was dissolved in THF (50 mL, 0.10 M) under a N2 atmosphere and cooled to 0 °C. Triethylamine (1.3 mL, 9.6 mmol, 2.0 equiv) was added dropwise, and the reaction mixture was stirred at 0 °C for 15 min before dropwise addition of ethyl oxalyl chloride (1.2 mL, 5.7 mmol, 1.2 equiv). A white gas evolved, and the reaction mixture warmed slowly to rt over 1.5 h. After stirring for an additional 6 h in a rt water bath, the reaction mixture was diluted with ether (20 mL) and washed with saturated NaHCO3 (2 × 25 mL), water (2 × 25 mL), and brine (2 × 25 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give a yellow oil (1.43 g, 97%). IR (neat) 2981, 2939, 1803, 1750, 1730, 1596, 1492, 1346, 1300, 1157, 1094, 1004, 852, 747, 692 cm–1; 1H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 7.7 Hz, 2H), 7.38 (t, J = 7.9 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.50 (s, 9H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 156.3, 152.1, 139.8, 129.1, 128.0, 124.8, 121.1, 84.3, 63.9, 28.1, 14.0; LRMS (ESI/[M + H]+) calcd. for C16H19NO6+: 310.1. Found: 310.1.

Deprotection of N-Boc-O-acylphenylhydroxylamine To Give 3a (eq 4)

In a flame-dried round-bottom flask, 13 (124 mg, 0.400 mmol, 1.00 equiv) was dissolved in CH2Cl2 (12 mL, 0.030 M) with 3 Å MS and cooled to 0 °C under N2. TFA (0.80 mL, 10 mmol, 26 equiv) was added dropwise with stirring at 0 °C, and the reaction mixture slowly warmed to rt over 1.5 h. After stirring for an additional 6.5 h in a rt water bath, the crude reaction mixture was washed with water (2 × 20 mL) and brine (2 × 20 mL), dried over Na2SO4, and concentrated. The crude mixture was purified by SiO2 column chromatography eluting with hexanes/ethyl acetate (4:1) to give 3a as a white solid (32 mg, 42%). 1H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H), 4.56 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 156.6, 152.9, 151.0, 140.7, 128.3, 125.9, 122.3, 111.9, 63.4, 14.3.