Efficient route to 4H-1,3-oxazines through ring expansion of isoxazoles by rhodium carbenoids

Abstract

Studies related to the total synthesis of elisabethin C led to the discovery of a rhodium-catalyzed cascade sequence involving isoxazole ring expansion and a [4 + 3] cycloaddition. The scope of the isoxazole ring expansion was explored, resulting in the synthesis of a range of 4H-1,3-oxazines in 47–96% yield

1. Introduction

The metal-catalyzed reactions of diazo compounds are capable of a diverse array of transformations.¹ With the advent of new catalysts and the recognition that different classes of carbenoids can open up new vistas of reactivity, the field continues to expand.² We have had a long-standing interest in developing new synthetic methods derived from the chemistry of donor/acceptor-substituted carbenoids. This paper describes the discovery of an unexpected but highly efficient ring expansion of isoxazoles by rhodium carbenoid intermediates.

A recent focus of our group has been the synthesis of biologically active marine natural products utilizing the enantiodivergent combined C–H activation/Cope rearrangement methodology.³ This reaction occurs during allylic C–H functionalization using rhodium-stabilized vinylcarbenoids. Recent total syntheses completed using this methodology include (+)-erogorgiaene (3),⁴ (−)-elisapterosin B (4),⁵ and (−)-colombiasin A (5).⁵ This strategy has been successful at rapidly introducing three of the stereocenters common in these natural products by differentiating between the enantiomers of the racemic dihydronaphthalene derivative 1. One enantiomer of the substrate undergoes the combined C–H activation/Cope rearrangement while the other is cyclopropanated (Scheme 1).

Scheme 1.

Synthesis of Marine Natural Products

In seeking to broaden the scope of this methodology, we focused our attention on the marine bisnor-diterpenoid elisabethin C (6),^6,7 using the fused isoxazole 8 as the substrate for the combined C–H activation/Cope rearrangement (Scheme 2). The isoxazole subunit would be used as a protecting group for the diketone functionality of elisabethin C, to be unmasked at a late stage of the synthesis.

Scheme 2.

Retrosynthesis of Elisabethin C

2. Results and discussion

The synthesis of fused isoxazole 8 was achieved using a relatively straightforward approach starting from β-diketone 9, which in turn was readily prepared by literature procedures^8,9 from the commercially available mono-protected 1,4-cyclohexadione (Scheme 3). If the isoxazole forming reaction was allowed to run to completion, the resulting regioisomeric mixture of isoxazoles proved inseparable by chromatography at all subsequent steps. Fortunately, if the reaction was stopped after 10 min, the regioisomeric oxime intermediates 10 and 11 could be chromatographically separated. Treatment of each isomer separately with warm acetic acid furnished the corresponding isoxazoles in isomerically pure form. Regioisomer 11 was chosen initially to carry through the sequence to test the key carbenoid reaction. Cyclization to form isoxazole 12 and subsequent acetal deprotection to ketone 13 proceeded smoothly. The remaining two steps to form vinyl triflate 15 using Comins’ reagent 14¹⁰ followed by a palladium-catalyzed reduction¹¹ gave 8 in good overall yield.

Scheme 3.

Synthesis of Dihydrobenzoisoxazole 8

The Rh₂(R-DOSP)₄-catalyzed reaction¹² of the fused isoxazole 8 with vinyldiazoacetate 2 (3 equiv) gave a most unusual result (Scheme 4). Instead of the expected reaction to form 7, the major isolable product was an unprecedented tricyclic derivative 16, which was formed as a 1 : 1 mixture of diastereomers in 62% yield. Each diastereomer was formed with low enantioinduction (19% ee). This material has incorporated into isoxazole 8 two equivalents of the vinylcarbenoid derived from 2. Compound 16 can be considered as formally derived from a carbenoid insertion into the isoxazole N–O bond and a tandem cyclopropanation/Cope rearrangement between another carbenoid and the diene component of the substrate.

Scheme 4.

Reaction of 8 with a Vinylcarbenoid

The formation of 16 is an unusual transformation and we were intrigued by this novel carbenoid reactivity. Formal [4 + 3] cycloadditions between vinylcarbenoids and dienes by a tandem cyclopropanation/Cope rearrangement are well precedented,¹³ but the carbenoid insertion into the isoxazole N–O bond is not an established process. Rhodium carbenoids containing isoxazoles have been used in intermolecular cyclopropanations without any side reaction on the isoxazole ring.¹⁴ Additionally, intramolecular C–H insertion reactions have been successfully achieved on substrates containing an isoxazole ring.¹⁵ It is known, however, that isoxazolium ylides, typically generated by deprotonation of an isoxazolium salt, undergo rearrangements to generate either 4H-1,3-oxazines or 3-imino-2-en-1-ones, depending on the substitution of the isoxazolium salt.¹⁶ Consequently, we decided to explore further the scope of the N–O insertion chemistry using rhodium carbenoids and various isoxazole substrates.

The first series of experiments studied the effect of the carbenoid structure on the efficiency of the N–O insertion, using 3,5-dimethylisoxazole (18) as a reference substrate (Table 1). In recent years we have shown that donor/acceptor-substituted carbenoids are capable of higher selectivity than the conventional carbenoids lacking a donor group. In this case all three of the prototypical types of carbenoids, derived from 17a–c, induced an N–O insertion into the isoxazole, although the reaction with the donor/acceptor-substituted carbenoid (entry 3) was the most efficient (88% yield).

Table 1.

Reaction of Rhodium Carbenoids with 3,5-Dimethylisoxazole

entry	R1	R2	19	yield, %a
1	H	Et	19a	56
2	CO2Me	Me	19b	47
3	Ph	Me	19c	88

^aReported yields are of isolated products.

The next series of reactions were conducted to determine what types of functionality on the isoxazole would be compatible with the N–O insertion (Table 2). Methyl phenyldiazoacetate (17c) was used as the carbenoid source because it had resulted in the highest yield of product in the initial evaluation. Further studies were performed with a range of isoxazoles (Table 2). All four isoxazoles 20a–d produced the 4H-1,3-oxazine products 21a–d, respectively in high yield (67–96%). These studies demonstrate that siloxy, halo and even ester functionalities are compatible with this chemistry. The ester derivative 20d gave a tautomeric mixture of the ring expansion products 21d and 22d (Entry 5). Compound 21d was formed cleanly in the carbenoid reaction, but is prone to isomerization to 22d during silica gel chromatography, illustrating the relative mildness of the carbenoid reaction conditions.

Table 2.

Reaction of diazoacetate 17c with isoxazoles

entry	isoxazole	product	yield, %a
1			83
2			93
3			96
4			67b

^aReported yields are of isolated products.

^bDuring attempted purification, product formed a 1:1 inseparable mixture with its tautomer 22d.

Having discovered that isoxazoles could be effectively ring-expanded, it became of interest to determine if the reaction could be extended to other heterocyclic systems. Benzisoxazoles were found to be similarly reactive with carbenoids, although further transformations occurred in certain cases (Scheme 5). The reaction with 1,2-benzisoxazole 23 produced the ring expansion product 24 cleanly in 72% yield if 23 was used in excess, and aziridine 25 in 94% yield if 3 equiv of the diazo component was used. In the case of anthranil 26, aldehyde 27, formally the result of a 6π-electrocyclic ring-opening of the expected N–O insertion product, was isolated along with epoxide 28. Compound 28 could be obtained exclusively if 3 equiv of the diazoacetate was used in the reaction. 5-Chloro-3-phenylanthranil (29) cleanly produced ketone 30, which did not readily undergo epoxide formation.

Scheme 5.

Reaction of Diazoacetate 17c with Benzisoxazoles

Another system worthy of study was benzoisothiazoles (Scheme 6). Previously it had been shown that the related 2-substituted isothiazol-3(2H)-ones undergo N–S insertion with carbenoids lacking an electron-donating group.¹⁷ The reaction of 17c with 3-chloro[d]benzoisothiazole (31) was a very efficient process resulting in the formation of 2H-1,3-benzothiazine 32 in 88% yield.

Scheme 6.

Ring Expansion of an Isothiazole

The reaction mechanism for the transformations described above likely proceeds through an isoxazolium ylide intermediate 33, formed by attack of the isoxazole nitrogen onto the rhodium carbenoid (Scheme 7). At this point, two reasonable pathways could lead to the ring-expanded product 35. The ylide 33 could undergo a 1,2-shift to generate 35 directly, as previously proposed for the ring expansion of 2-substituted isothiazol-3(2H)-ones.¹⁷ Alternatively, ylide 33 could undergo a ring opening to 34, followed by a 6π electrocyclization to give 35 as proposed for the ring expansion of isoxazolium ylides derived from deprotonation of isoxazolium salts.^16c

Scheme 7.

Possible Mechanistic Pathways for Isoxazole Ring Expansion

3. Conclusion

In summary, the reactions of various isoxazoles with rhodium carbenoids have been examined and found to produce 4H-1,3-oxazines through a ring expansion in good to excellent yields. These reactions are likely to proceed via ylide intermediates which then either expand through a 1,2-shift, or open up to 3-imino-2-en-1-ones which subsequently undergo a 6π electrocyclization to 4H-1,3-oxazines. Studies toward applications of this transformation in heterocycle synthesis are currently underway.

4. Experimental

4.1. General

All experiments were performed under anhydrous conditions in an atmosphere of argon except where stated, using flame dried glassware. 2,2-Dimethylbutane (DMB) was purified by distillation over sodium. DCM and THF were dried by a solvent purification system (passed through activated alumina). The vinyldiazoacetate 2,⁴ dimethyl diazomalonate 17b,¹⁸ methyl phenyldiazoacetate 17c,¹⁹ and methyl 2-(3-methylisoxazol-5-yl)acetate 20d⁸ were prepared by their respective literature procedures. The synthesis of compounds 9–13, 15, and 8 is described in the supplementary information. Unless otherwise noted, all other reagents were obtained from commercial sources and used as received. Mass spectral determinations were carried out by LC-MS (ESI), or electron impact ionization (EI). Melting points are uncorrected. Flash column chromatography was performed on silica gel 60Å (230–400 mesh) using a pentane/diethyl ether mixture as the eluent unless otherwise specified.

4.2. Synthesis of ring expansion/[4 + 3]-cycloaddition product 16

4.2.1. (16)

To a flame dried 25 mL round bottom flask under argon and charged with a stir bar was added 8 (0.0500 g, 0.306 mmol), Rh₂(R-DOSP)₄ (0.017 g, 0.0092 mmol, 0.03 eq) and 2,2 DMB (2 mL). A reflux condenser was attached to the flask and the solution was heated to reflux. A solution of 2 (0.172 g, 1.23 mmol) in 2,2-DMB (3 mL) was added via syringe pump addition over 20 min. The solution was refluxed for another 5 min, then allowed to cool to ambient temperature. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 5:1-2:1 pentane:diethyl ether) to give the diastereomeric products 16a (0.038 g, 32% yield) and 16b (0.036 g, 30% yield) as clear oils.

16a

R_f 0.16 (2:1 pentane:diethyl ether); FTIR (neat): 2930, 1746, 1711, 1640, 1436, 1236, 1193, 1066, 1028, 1006, 970 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.89 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 4.5 Hz, 1H), 5.77 (d, J = 15.5 Hz, 1H), 5.55 (dq, J = 15.5, 6.5 Hz, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.55 (m, 1H), 2.67-2.60 (m, 3H), 2.29-2.20 (m, 2H), 1.68 (d, J = 6.5 Hz, 3H), 1.24 (t, J = 7.5 Hz, 3H), 1.19-1.15 (m, 1H), 0.91 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.8 (C), 167.3 (C), 165.4 (C), 145.5 (CH), 135.9 (CH), 132.9 (CH), 129.9 (C), 127.9 (CH), 126.1 (C), 89.0 (C), 77.6 (C), 52.9 (CH₃), 52.1 (CH₃), 48.5 (CH), 38.6 (CH₂), 37.8 (CH), 31.2 (CH), 27.7 (CH₂), 21.5 (CH₃), 17.6 (CH₃), 14.6 (CH₃), 12.1 (CH₃); LRMS (EI) m/z (relative intensity): 387 (24) [M]⁺, 328 (100) [M-CO₂CH₃]⁺; HRMS (EI) Calcd for [C₂₂H₂₉NO₅]⁺ 387.2040, Found 387.2041; HPLC analysis: 19% ee (Chiralpak AD-H, 1% i-PrOH in hexanes, 0.8 mL/min, λ = 254 nm, t_R = 17.3 min, major; 18.4 min, minor).

16b

R_f 0.31 (2:1 pentane:diethyl ether); FTIR (neat): 2919, 1741, 1710, 1641, 1435, 1234, 1065, 1026, 1003, 970 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 6.90 (d, J = 7.5 Hz, 1H), 6.69 (d, J = 5.0 Hz, 1H), 6.11 (dq, J = 15.5, 6.5 Hz, 1H), 5.91 (d, J = 15.5 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 3.57 (m, 1H), 2.72-2.58 (m, 2H), 2.54-2.48 (m, 1H), 2.27-2.21 (m, 2H), 1.78 (d, J = 6.5 Hz, 3H), 1.27-1.20 (m, 4H), 0.80 (d, J = 6.0 Hz, 3H), 0.78 (d, J = 7.5 Hz, 3H); ¹³C NMR (125 MHz, CDCl₃) δ 170.2 (C), 167.3 (C), 165.0 (C), 145.3 (CH), 135.7 (CH), 131.6 (CH), 130.1 (C), 128.5 (CH), 126.0 (C), 87.8 (C), 77.9 (C), 52.3 (CH₃), 52.1 (CH₃), 48.4 (CH), 38.6 (CH₂), 38.4 (CH), 31.2 (CH), 27.5 (CH₂), 18.8 (CH₃), 17.7 (CH₃), 15.0 (CH₃), 11.6 (CH₃); LRMS (ESI) m/z (relative intensity): 388 (100) [M+H]⁺; HRMS (ESI) Calcd for [C₂₂H₃₀NO₅]⁺ 388.2118, Found 388.2121; HPLC analysis: 19% ee (Regis R,R-Whelk, 0.5% i-PrOH in hexanes, 1.0 mL/min, λ = 254 nm, t_R = 20.8 min, major; 24.7 min, minor).

4.3 Synthesis of isoxazole 20a

4.3.1 2-(3-Methylisoxazol-5-yl)ethanol

To a flame dried round bottom flask under argon and charged with a stir bar was added methyl 2-(3-methylisoxazol-5-yl)acetate 20d⁸ (0.62 g, 4.0 mmol) and THF (10 mL). The solution was cooled to 0 °C in an ice bath and a solution of LAH (2.0 M in THF, 1 mL) was added by syringe. The solution was stirred for 10 min and then slowly quenched with water. The solution was then extracted with ether (3 × 15 mL) and the combined organic extracts dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, diethyl ether as eluent, visualized with KMnO₄ stain) to give 2-(3-methylisoxazol-5-yl)ethanol as a clear oil (0.252 g, 50% yield). The characterization data were in agreement with the literature values.²⁰

4.3.2 5-(2-(tert-Butyldimethylsilyloxy)ethyl)-3-methylisoxazole (20a)

To a flame dried round bottom flask under argon and charged with a stir bar was added 2-(3-methylisoxazol-5-yl)ethanol (0.105 g, 0.83 mmol), TBSCl (0.149 g, 0.99 mmol), DMAP (0.003 g, 0.025 mmol) and DCM (10 mL). Imidazole (0.062 g, 0.91 mmol) was then added and the solution stirred overnight. The solution was then washed with brine, dried over anhydrous MgSO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 7:1 pentane:diethyl ether) to give the product as a clear oil (0.107 g, 54% yield). R_f 0.25 (7:1 pentane:diethyl ether); FTIR (neat): 2929, 1607, 1472, 1417, 1255, 1101, 835, 776 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ 5.89 (s, 1H), 3.88 (t, J = 6.5 Hz, 2H), 2.92 (t, J = 6.5 Hz, 2H), 2.26 (s, 3H), 0.87 (s, 9H), 0.02 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 170.4 (C), 159.5 (C), 102.5 (CH), 60.6 (CH₂), 30.4 (CH₂), 25.7 (CH₃), 18.1 (C), 11.3 (CH₃), −5.6 (CH₃); LRMS (EI) m/z (relative intensity): 226 (9) [M]⁺, 184 100 [M-^tBu]⁺; HRMS (EI) Calcd for [M-CH₃]⁺ [C₁₁H₂₀NO₂Si]⁺ 226.1258, Found 226.1249.

4.4. General Procedure for the rhodium catalyzed isoxazole/isothiazole ring expansion reactions

To a flame dried 25 mL round bottom flask under argon and charged with a stir bar was added the isoxazole substrate, Rh₂(OAc)₄ and solvent (DCM or 1,2-DCE, 5 mL). A water-cooled condenser was attached to the flask and the solution was heated to reflux. A solution of diazoacetate in solvent (DCM or 1,2-DCE, 5 mL) was then added by syringe pump over 45 min. The solution was refluxed another 15 min and then cooled to ambient temperature. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography to give the product.

4.4.1. Ethyl 4,6-dimethyl-2H-1,3-oxazine-2-carboxylate (19a)

The reaction was performed with 3,5-dimethylisoxazole 18 (0.146 g, 1.5 mmol), Rh₂(OAc)₄ (6.6 mg, 0.015 mmol) and ethyl diazoacetate 17a (0.057 g, 0.5 mmol) in 1,2-DCE. Purified by flash chromatography (silica gel, 1:1 pentane:diethyl ether) to give 19a as a clear oil (0.051 g, 56% yield). R_f 0.13 (1:1 pentane:diethyl ether); FTIR (neat): 2983, 1743, 1619, 1575, 1443, 1385, 1202, 1096, 1023 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.59 (s, 1H), 5.37 (s, 1H), 4.36-4.26 (m, 2H), 2.04 (s, 3H), 1.98 (s, 3H), 1.34 (t, J = 7.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 168.1 (C), 165.8 (C), 162.9 (C), 100.7 (CH), 85.9 (CH), 61.8 (CH₂), 23.7 (CH₃), 19.0 (CH₃), 14.0 (CH₃); LRMS (ESI) m/z (relative intensity): 206 (100) [M+Na]⁺, 184 (36) [M+H]⁺; HRMS (ESI) Calcd for [C₉H₁₄NO₃]⁺ 184.0968, Found 184.0970.

4.4.2. Dimethyl 4,6-dimethyl-2H-1,3-oxazine-2,2-dicarboxylate (19b)

The reaction was performed with 3,5-dimethylisoxazole 18 (0.049 g, 0.5 mmol), Rh₂(OAc)₄ (6.6 mg, 0.015 mmol), dimethyldiazomalonate 17b¹⁸ (0.111 g, 0.70 mmol) and 1,2-DCE. The solution was refluxed for 2 h after the diazo addition was complete. Purified by flash chromatography (silica gel, 1:5 pentane:diethyl ether) to give 19b as a clear oil (0.053 g, 47% yield). R_f 0.24 (diethyl ether); FTIR (neat): 2950, 1748, 1654, 1574, 1435, 1294, 1259, 1134, 1056, 784, 706 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 5.39 (s, 1H), 3.86 (s, 6H), 2.10 (s, 3H), 2.02 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 166.6 (C), 166.2 (C), 162.1 (C), 100.5 (CH), 53.5 (CH₃), 24.1 (CH₃), 19.2 (CH₃), missing C attributed to excessive peak broadening/quadrupolar effect due to N; LRMS (ESI) m/z (relative intensity): 477 (39) [2M+Na]⁺, 250 (51) [M+Na]⁺; HRMS (ESI) Calcd for [C₁₀H₁₃NO₅Na]⁺ 250.0686, Found 250.0680.

4.4.3. Methyl 4,6-dimethyl-2-phenyl-2H-1,3-oxazine-2-carboxylate (19c)

The reaction was performed with 3,5-dimethylisoxazole 18 (0.049 g, 0.5 mmol), Rh₂(OAc)₄ (6.6 mg, 0.015 mmol), 17c (0.132 g, 0.75 mmol) and DCM. Purified by flash chromatography (silica gel, 1.5:1 pentane:diethyl ether) to give 19c as a white solid (0.109 g, 89% yield). mp = 72–73 °C, R_f 0.19 (1:1 pentane:diethyl ether); FTIR (neat): 2954, 1742, 1659, 1574, 1235, 729 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.74 (dd, J = 8.0, 1.5 Hz, 2H), 7.40-7.35 (m, 3H), 5.36 (s, 1H), 3.72 (s, 3H), 2.13 (s, 3H), 2.01 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 170.3 (C), 164.7 (C), 162.2 (C), 138.8 (C), 128.6 (CH), 127.9 (CH), 126.2 (CH), 100.7 (CH), 52.7 (CH₃), 23.9 (CH₃), 19.2 (CH₃), missing C attributed to excessive broadening/quadrupolar effect due to N; LRMS (ESI) m/z (relative intensity): 246 (100) [M+H]⁺; Anal. Calcd for C₁₄H₁₅NO₃: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.42; H, 6.17; N, 5.60.

4.4.4. Methyl 6-(2-(tert-butyldimethylsilyloxy)ethyl)-4-methyl-2-phenyl-2H-1,3-oxazine-2-carboxylate(21a)

The reaction was performed with 20a (0.073 g, 0.30 mmol), Rh₂(OAc)₄ (4.0 mg, 0.009 mmol), 17c (0.064 g, 0.36 mmol) and DCM. Purified by flash chromatography (silica gel, 4:1-3:1 pentane:diethyl ether) to give 21a as a clear oil (0.098 g, 83% yield). R_f 0.11 (5:1 pentane:diethyl ether); FTIR (neat): 2954, 2928, 2856, 1745, 1658, 1574, 1235, 1098, 1006, 833, 776, 729, 696 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.73 (dd, J = 8.0, 1.5 Hz, 2H), 7.40-7.35 (m, 3H), 5.43 (s, 1H), 3.87-3.85 (m, 2H), 3.70 (s, 3H), 2.49 (t, J = 7.0 Hz, 2H), 2.15 (s, 3H), 0.86 (s, 9H), 0.03 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 170.5 (C), 164.8 (C), 162.9 (C), 138.8 (C), 128.8 (CH), 128.1 (CH), 126.4 (CH), 101.3 (CH), 78.9 (C), 59.4 (CH₂), 52.8 (CH₃), 37.0 (C), 25.7 (CH₃), 24.1 (CH₃), 18.1 (CH₂), −5.5 (CH₃); LRMS (ESI) m/z (relative intensity): 390 (100) [M+H]⁺; HRMS (ESI) Calcd for [C₂₁H₃₂NO₄Si]⁺ 390.2095, Found 390.2091.

4.4.5. Methyl 4-(chloromethyl)-6-methyl-2-phenyl-2H-1,3-oxazine-2-carboxylate (21b)

The reaction was performed with 3-chloromethyl-5-methylisoxazole 20b (0.066 g, 0.5 mmol), Rh₂(OAc)₄ (6.6 mg, 0.015 mmol), 17c (0.115 g, 0.65 mmol) and DCM. Purified by flash chromatography (silica gel, 5:1 pentane:diethyl ether) to give 21b as a clear oil (0.130 g, 93% yield). R_f 0.14 (5:1 pentane:diethyl ether); FTIR (neat): 1743, 1655, 1572, 1434, 1369, 1238, 1031, 727, 697 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.73 (dd, J = 8.0, 1.5 Hz, 2H), 7.41-7.38 (m, 3H), 5.66 (s, 1H), 4.22 (s, 2H), 3.73 (s, 3H), 2.08 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 169.8 (C), 164.7 (C), 163.0 (C), 138.1 (C), 129.1 (CH), 128.2 (CH), 126.3 (CH), 98.0 (CH), 53.1 (CH₃), 45.5 (CH₂), 19.7 (CH₃), missing C attributed to excessive broadening/quadrupolar effect due to N; LRMS (ESI) m/z (relative intensity): 581 (17) [2M+Na]⁺, 302 (100) [M+Na]⁺; HRMS (ESI) Calcd for [C₁₄H₁₄NO₃ClNa]⁺ 302.0554, Found 302.0557.

4.4.6. Methyl 5-bromo-4,6-dimethyl-2-phenyl-2H-1,3-oxazine-2-carboxylate (21c)

The reaction was performed with 4-bromo-3,5-dimethylisoxazole (0.088 g, 0.5 mmol), Rh₂(OAc)₄ (4.4 mg, 0.01 mmol), 17c (0.115 g, 0.65 mmol) and DCM. Purified by flash chromatography (silica gel, 7:1 pentane:diethyl ether) to give 21c as a clear oil (0.155 g, 96% yield). R_f 0.21 (5:1 pentane:diethyl ether); FTIR (neat): 1746, 1638, 1564, 1432, 1376, 1309, 1241, 1137, 1011, 908, 726, 696 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.72 (dd, J = 7.5, 1.5 Hz, 2H), 7.40-7.38 (m, 3H), 3.72 (s, 3H), 2.34 (s, 3H), 2.22 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 169.9 (C), 163.1 (C), 160.2 (C), 137.9 (C), 129.0 (CH), 128.8 (C), 128.2 (CH), 126.3 (CH), 97.4 (C), 53.1 (CH₃), 24.4 (CH₃), 19.2 (CH₃); LRMS (ESI) m/z (relative intensity): 324 (10) [M+H]⁺; HRMS (ESI) Calcd for [C₁₄H₁₅BrNO₃]⁺ 324.0230, Found 324.0234.

4.4.7. (21d) and (22d)

The reaction was performed with 20d (0.078 g, 0.5 mmol), Rh₂(OAc)₄ (6.6 mg, 0.015 mmol), 17c (0.132 g, 0.75 mmol) and DCM. ¹H NMR analysis of the crude reaction mixture in CD₂Cl₂ did not contain 22d. Purified by flash chromatography (silica gel, 1:1 pentane:diethyl ether) to give a 1:1 mixture of 21d and 22d as a sticky white solid (0.102 g, 67% yield). R_f 0.17 (1:1 pentane:diethyl ether); ¹H NMR (500 MHz, CDCl₃) δ 7.73-7.71 (m, 2H), 7.57-7.56 (m, 2H), 7.40-7.39 (m, 6H), 6.45 (s, 1H), 6.00 (s, 1H), 5.45 (s, 1H), 5.19 (s, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.72 (s, 3H), 3.65 (s, 3H), 3.33 (s, 2H), 2.24 (s, 3H), 2.03 (s, 3H); LRMS (ESI) m/z (relative intensity): 629 (85) [2M+Na]⁺, 326 (100) [M+Na]⁺; HRMS (EI) Calcd for [C₁₆H₁₇NO₅]⁺ 303.1101, Found 303.1111.

4.4.8. Methyl 2-phenyl-2H-benzo[e][1,3]oxazine-2-carboxylate (24)

The reaction was performed with freshly purified 1,2-benzisoxazole 23 (0.065 g, 0.55 mmol, purified by passing through a silica gel pipet column eluted with 5:1 pentane:diethyl ether), Rh₂(OAc)₄ (7 mg, 0.016 mmol), 17c (0.044 g, 0.25 mmol) and DCM. Purified by flash chromatography (silica gel, 2:1-1:1 pentane:diethyl ether) to give 24 as a clear oil (0.048 g, 72% yield). R_f 0.23 (1:1 pentane:diethyl ether); FTIR (neat): 2950, 1745, 1633, 1608, 1229, 1050, 1035, 1003, 759, 727, 697 cm⁻¹; ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 7.76 (d, J = 7.0 Hz, 2H), 7.42-7.32 (m, 4H), 7.22 (dd, J = 7.5, 1.5 Hz, 1H), 7.08 (d, J = 8.5 Hz, 1H), 6.98 (appt t, J = 7.0 Hz, 1H), 3.76 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 169.1 (C), 157.5 (CH), 153.2 (C), 138.6 (C), 134.5 (CH), 128.8 (CH), 128.1 (CH), 127.4 (CH), 126.4 (CH), 122.0 (CH), 116.7 (C), 116.5 (CH), 91.7 (C), 53.1 (CH₃); LRMS (ESI) m/z (relative intensity): 268 (27) [M+H]⁺; HRMS (ESI) Calcd for [C₁₆H₁₄NO₃]⁺ 268.0968, Found 268.0969.

4.4.9. Aziridine 25

The reaction was performed with freshly purified 1,2-benzisoxazole 23 (0.065 g, 0.55 mmol, purified by passing through a silica gel pipet column eluted with 5:1 pentane:diethyl ether), Rh₂(OAc)₄ (7 mg, 0.016 mmol), 17c (0.291 g, 1.65 mmol) and DCM. Purified by flash chromatography (silica gel, 3:1–2:1 pentane:diethyl ether) to give 25 as a white solid (0.215 g, 94% yield). mp 147–149 °C; R_f 0.36 (1:1 pentane:diethyl ether); FTIR (neat): 2950, 1742, 1491, 1281, 1208, 1128, 1074, 1045, 1031, 986, 759, 727, 696 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) . 7.84 (d, J = 7.0 Hz, 2H), 7.80 (d, J = 7.0 Hz, 2H), 7.44-7.36 (m, 3H), 7.29-7.15 (m, 5H), 7.04 (d, J = 8.0 Hz, 1H), 6.95-6.92 (m, 1H), 3.83 (s, 3H), 3.60 (s, 3H), 3.36 (s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 168.6 (C), 167.4 (C), 149.5 (C), 137.5 (C), 137.0 (C), 128.9 (CH), 128.6 (CH), 128.3 (CH), 128.0 (CH), 127.7 (CH), 127.0 (CH), 122.8 (CH), 120.3 (C), 118.5 (CH), 89.5 (C), 53.0 (CH₃), 52.7 (C), 52.3 (CH₃), 44.4 (CH), 2 missing CH resonances attributed to overlapping signals; LRMS (ESI) m/z (relative intensity): 853 (100) [2M+Na]⁺, 438 (36) [M+Na]⁺; Anal. Calcd for C₂₅H₂₁NO₅: C, 72.28; H, 5.10; N, 3.37. Found: C, 71.92; H, 5.09; N, 3.33.

4.4.10. Methyl 2-(2-formylphenylimino)-2-phenylacetate (27)

The reaction was performed with anthranil 26 (0.179 g, 1.5 mmol), Rh₂(OAc)₄ (6.6 mg, 0.015 mmol), 17c (0.085 g, 0.5 mmol) and 1,2-DCE. Purified by flash chromatography (silica gel, 5:1 pentane:diethyl ether) to give 27 (0.089 mg, 67% yield) and 28 (0.034 g, 16% yield) as yellow oils. 27: R_f 0.30 (2:1 pentane:diethyl ether); FTIR (neat): 1733, 1690, 1624, 1592, 1450, 1302, 1273, 1226, 1192, 1174, 1155, 1009, 764, 689, 669 cm⁻¹; ¹H NMR (400 MHz, CD₂Cl₂) δ 10.20 (s, 1H), 7.90 (d, J = 7.5 Hz, 2H), 7.86 (d, J = 7.5 Hz, 1H), 7.60-7.49 (m, 4H), 7.26 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 3.58 (s, 3H); ¹³C NMR (75 MHz, CD₂Cl₂) δ 190.3 (CH), 164.7 (C), 161.7 (C), 152.7 (C), 135.1 (CH), 133.5 (C), 132.8 (CH), 129.2 (CH), 128.6 (CH), 128.3 (CH), 127.0 (C), 125.5 (CH), 119.4 (CH), 52.4 (CH₃); LRMS (ESI) m/z (relative intensity): 557 (52) [2M+Na]⁺, 290 (100) [M+Na]⁺, 268 (68) [M+H]⁺; HRMS (EI) Calcd for [C₁₆H₁₃NO₃]⁺ 267.0890, Found 267.0903.

4.4.11. (E)-Methyl3-(2-(2-methoxy-2-oxo-1-phenylethylideneamino)phenyl)-2-phenyloxirane-2-carboxylate (28)

The reaction was performed with anthranil 26 (0.060 g, 0.5 mmol), Rh₂(OAc)₄ (6.6 mg, 0.015 mmol), 17c (0.255 g, 1.5 mmol) and 1,2-DCE. Purified by flash chromatography (silica gel, 5:1 pentane:diethyl ether) to give 28 as a yellow oil (0.201 g, 97% yield). R_f 0.24 (2:1 pentane:diethyl ether); FTIR (neat): 1734, 1449, 1434, 1298, 1234, 1197, 1171, 1009, 763, 739, 691 cm⁻¹; ¹H NMR (400 MHz, CD₂Cl₂) δ 7.87 (d, J = 7.0 Hz, 2H), 7.57-7.54 (m, 1H), 7.49-7.45 (m, 5H), 7.31-7.17 (m, 5H), 6.80 (d, J = 8.0 Hz, 1H), 4.33 (s, 1H), 3.64 (s, 3H), 3.48 (s, 3H); ); ¹³C NMR (75 MHz, CD₂Cl₂) δ 167.6 (C), 165.3 (C), 160.6 (C), 148.9 (C), 135.8 (C), 133.9 (C), 132.5 (CH), 129.2 (CH), 129.1 (CH), 128.9 (CH), 128.52 (CH), 128.48 (CH), 127.5 (CH), 126.5 (CH), 126.2 (C), 125.3 (CH), 117.4 (CH), 66.8 (C), 63.1 (CH), 52.4 (CH₃), 52.3 (CH₃); LRMS (ESI) m/z (relative intensity): 438 (100) [M+Na]⁺, 416 (41) [M+H]⁺; HRMS (EI) Calcd for [C₂₅H₂₁NO₅]⁺ 415.1414, Found 415.1416.

4.4.12. Methyl 2-(2-benzoyl-4-chlorophenylimino)-2-phenylacetate (30)

The reaction was performed with 5-chloro-3-phenylanthranil 29 (0.115 g, 0.5 mmol), Rh₂(OAc)₄ (6.6 mg, 0.015 mmol), 17c (0.106 g, 0.6 mmol) and DCM. Purified by flash chromatography (silica gel, 5:1 pentane:diethyl ether) to give 30 as a sticky yellow oil (0.185 g, 98% yield). R_f 0.24 (5:1 pentane:diethyl ether); FTIR (neat): 1734, 1664, 1449, 1283, 1226, 1195, 1173, 1009, 688 cm⁻¹; ¹H NMR (500 MHz, C₆D₆) δ 7.81 (d, J = 7.0 Hz, 2H), 7.54 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 2.5 Hz, 1H), 7.05-6.95 (m, 5H), 6.92-6.89 (m, 2H), 6.66 (d, J = 8.5 Hz, 1H), 3.10 (s, 3H); ¹³C NMR (75 MHz, CD₂Cl₂) δ 195.1 (C), 164.7 (C), 160.4 (C), 147.2 (C), 137.7 (C), 133.6 (C), 133.3 (CH), 132.9 (C), 132.5 (CH), 131.8 (CH), 130.7 (C), 130.1 (CH), 129.9 (CH), 128.9 (CH), 128.7 (CH), 128.3 (CH), 120.8 (CH), 52.5 (CH₃); LRMS (ESI) m/z (relative intensity): 777 (100) [2M+Na]⁺, 400 (100) [M+Na]⁺, 378 (18) [M+H]⁺; HRMS (EI) Calcd for [C₂₂H₁₆NO₃Cl]⁺ 377.0813, Found 377.0826.

4.4.13. Methyl 4-chloro-2-phenyl-2H-benzo[e][1,3]thiazine-2-carboxylate (32)

The reaction was performed with 3-chloro-1,2-benzisothiazole 31 (0.085 g, 0.5 mmol), Rh₂(OAc)₄ (6.6 mg, 0.015 mmol), 17c (0.115 g, 0.65 mmol) and DCM (5 mL). Purified by flash chromatography (silica gel, 3:1 pentane:diethyl ether) to give 32 as a clear oil (0.140 mg, 88% yield). R_f 0.25 (2:1 pentane:diethyl ether); FTIR (neat): 2966, 1736, 1446, 1434, 1234, 1007, 819, 764, 733, 693 cm⁻¹; ¹H NMR (500 MHz, CDCl₃) δ 7.65-7.62 (m, 2H), 7.55-7.54 (m, 2H), 7.51-7.46 (m, 2H), 7.34 (m, 3H), 3.85 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 167.6 (C), 137.8 (CH), 136.8 (C), 133.7 (CH), 133.2 (C), 132.3 (CH), 130.3 (CH), 129.2 (CH), 128.2 (CH), 127.0 (CH), 120.5 (C), 117.0 (C), 82.3 (C), 54.3 (CH₃); LRMS (EI) m/z (relative intensity): 317 (5) [M]⁺, 121 (100); HRMS (EI) Calcd for [C₁₆H₁₂ClNO₂S]⁺ 317.0272, Found 317.0265.

Supplementary Material

01. Supplementary data.

Synthesis of compounds 9–13, 15, and 8 and the method for structural assignment of 13 and its regioisomer. gHSQC and gHMBC correlations for 16. Supplementary data associated with this article can be found in the online version, at