Methylene Insertion into Nitrogen‐Heteroatom Single Bonds of 1,2‐Azoles via a Zinc Carbenoid: An Alternative Tool for Skeletal Editing

Abstract The nitrogen‐heteroatom single bonds of 1,2‐azoles and isoxazolines underwent methylene insertion in the presence of CH2I2 (6 equiv.) and diethylzinc (3 equiv.) to produce a wide variety of the ring‐expanded six‐membered heterocycles. Density functional theory calculations suggest that the methylene insertion proceeds via cleavage of nitrogen‐heteroatom single bonds followed by ring closure.


Introduction
Skeletal editing is the precise modification of molecular skeletons to facilitate the rapid diversification of complex molecular architectures. [1]This strategy for modifying arenes and heterocycles involves three main transformations: ring expansion, ring contraction, and atom exchange.In particular, ring expansion with a single carbon insertion, one of the skeletal editing techniques, has been achieved through [2+1]-cycloaddition of a carbon-carbon double bond with a carbene or metal carbenoid followed by isomerization. [2]n the other hand, ring expansion by insertion of a carbon atom into a single bond is still less common.Diazo compounds are known as the most widely used carbene or transitional DOI: 10.1002/advs.202307563metal carbenoid precursors [3] and the corresponding reactive intermediates insert into various types of single bonds, including C─C, [4] C─O, [5] C─Si, [6] and C─S [7] bonds in cyclic compounds.Nitrogenheteroatom single bonds in heteroarenes also undergo thering expansion with a single carbon insertion.Rhodium carbenoids insert into the N─X (X = N, O, S) single bonds of 1,2-azoles [8] to give the corresponding six-membered products with a single carbon atom inserted (Scheme 1-A).Although these strategies using diazo precursors lead to various transformations of the compounds, the diazo compounds have structural limitations to stabilize themselves.
Diazirines are alternative practical carbene precursors.The stability of diazirines allows their application in photoaffinity probes. [9]Although the free carbenes generated from diazirines by UV light have been reported to insert C─H, N─H, O─H, and Si─H single bonds, [10] the reactivity of diazirines with other types of single bonds remains unknown.Recently, Levin et al. reported ring expansion from pyrazoles to pyrimidines via benzyl carbenes generated from chlorodiazirines (Scheme 1-B). [11]inc carbenoids are well-known reagents for cyclopropanation of carbon-carbon double bonds, called Simmons-Smith cyclopropanation.Especially, Furukawa et al. reported the reliable and reproducible iodomethylzinc reagent (EtZnCH 2 I) prepared from diethylzinc (Et 2 Zn) and CH 2 I 2 . [12]Further development of zinc carbenoid reagents has improved their reactivity with unreactive olefines [13] and enabled their application in asymmetric synthesis. [14]However, zinc carbenoid insertion into single bonds in cyclic compounds has not been reported.
We have developed direct functionalization of isoxazoles to access multi-functionalized or heteroarene-fused isoxazoles. [15]15f] In this study, we demonstrate methylene insertion into nitrogen-heteroatom (N─X: X = N, O, S) single bonds of 1,2-azoles I via a zinc carbenoid (EtZnCH 2 I) to afford the corresponding ring-expanded products II (Scheme 1-C).Furthermore, we examined the mechanism of this ring expansion by density functional theory (DFT) calculations to elucidate the unique reactivity of the iodomethylzinc reagent.Since the resulting 2H-1,3-oxazines are labile under acidic or heating conditions, their general synthetic methods have not been established. [16,17]cheme 1. Methylene insertion into nitrogen-heteroatom single bonds of 1,2-azoles.

Methylene Insertion into N─O Single Bonds of Isoxazoles
We first examined the methylene insertion into 3,5diphenylisoxazole (1a) (Table 1).Treatment of 1a with excess amount of CH 2 I 2 (10 equiv.)and Et 2 Zn (5 equiv.) in CH 2 Cl 2 gave the corresponding ring-expanded product 2a in 63% yield (entry 1).Although the reduction of the amount of CH 2 I 2 and Et 2 Zn to one-fifth resulted in the poor yield of 2a (5%: entry 2), the use of CH 2 I 2 (4 equiv.)and Et 2 Zn (2 equiv.)gave the product 2a in moderate yield (56%, entry 3).Next, solvent effects on the methylene insertion were examined (entries 4-7).Although oxazine 2a was not obtained in THF and ethyl acetate (entries 4 and 5, respectively), oxazine 2a was generated in moderate yield in toluene (42%, entry 6) and in good yield in 1,2-dichloroethane (62%, entry 7).Diluted condition (in 0.05 m) increased the yield of 2a (68%, entry 8).When the reaction was carried out at 10 °C, oxazine 2a was obtained in the better yield (86%, entry 9).However, longer reaction time did not improve the yield of 2a but afforded several unidentified by-products (entry 10).Finally, the use of CH 2 I 2 (6 equiv.)and Et 2 Zn (3 equiv.)gave the best result: oxazine 2a was obtained in 91% yield with 6% recovery of 1a (entry 11).To clarify the importance of zinc species, control conditions were examined by using several types of zinc species.However, no other zinc species than Et 2 Zn gave oxazine 2a (Table S1, Supporting Information).Needless to say, 1a was not consumed in the absence of Et 2 Zn (entry 12).
With the optimized conditions (Table 1, entry 11), we examined the methylene insertion into various di-or tri-substituted isoxazoles 1 (Table 2).Although oxazine 2a was labile on silica gel, its decomposition was suppressed by deactivation of silica gel using triethylamine (1% v/v in the eluent), and oxazine 2a was isolated in 80% yield by preparative thin-layer chromatography.The reaction was applicable to a 1.0 mmol scale reaction, and 2a was obtained without a significant decrease in yield (76%).With the established procedures, isoxazoles having aryl groups gave oxazines 2b-d in good yields.Isoxazole 1e having   a sterically hindered 2-tolyl group at the C-3 position (R 1 ) gave oxazine 2e in low yield (36%).Although alkyl groups such as cyclohexyl (1f) and tert-butyl (1 g) were tolerated to give the corresponding oxazines 2f and 2 g in 26% and 62% yields, respectively, an electron withdrawing group such as an ethoxy carbonyl group gave oxazine 2 h in high yield (85%).Aryl groups at the C-5 position gave the products 2i-l in moderate yields (42-52%).Although tert-butyl group and ester group were also tolerated at the C-5 position, oxazine 2n having an ethyl ester group was obtained in lower yield (2h: 85% vs 2n: 42%).We carefully examined the difference in yields between products 2 h and 2n.A total of three experiments were performed for each, and the average yields were 81% and 41%, respectively (for each of yields, see Supporting Information).These results indicate that the difference in yields is due to the substituent effects.Furthermore, silyl substituents as R 3 gave oxazines 2o and 2p in high yields.Trisubstituted isoxazoles 1q and 1r gave the corresponding oxazines 2q and 2r in 56% and 39% yields, respectively, without affecting the bromo and ester substituents in the molecule.Benzoisoxazoles 1s and 1t were also converted to the corresponding bicyclic oxazines in moderate to high yield (2s: 61%, 2t: 88%).Furthermore, we applied the methylene insertion to the late-stage skeletal editing of drug molecules.Zonisamide (1u), [18] a drug approved by the FDA in 2000, afforded the prod-uct 2u in 17% yield.Benzioxazole 1v, [19] a histone deacetylase (HDAC) inhibitor also underwent the methylene insertion selectively into the N─O bond of isoxazole in the presence of a 1,2,3-triazole ring in the molecule, giving the corresponding product 2v in 16% yield.As for unsuccessful experiments, [20] isoxazoles with nonsubstituted (1w) and monosubstituted at the C-3 (1x) or C-5 (1y) position did not afford the corresponding oxazines 2w-y, suggesting that substituents R 1 and R 3 strongly affect this reaction (for further unsuccessful examples, see: Figure S1, Supporting Information).The DFT calculations suggest the possibility of oxazine formation, although the presence or absence of substituents affects the activation barrier to N-alkylation.These results suggest that unsubstituted isoxazoles can lead to ring expansion products, but the products formed may be unstable.In fact, these oxazine derivatives have not been reported.Furthermore, complex mixtures were also obtained with mono 3-or mono 5-substitutions.Substrates that were not successful are listed in Figure S1 (Supporting Information).

Methylene Insertion into N─X Single Bonds of 1,2-Azoles and Cyclic Oximes
We next investigated ring-expansion of other 1,2-azoles and related heterocycles (Table 3).When the 3,5-diphenylisothiazole 3a was exposed to the optimized conditions, the ring-expanded product 4a was generated in 35% yield with 65% recovery of the starting material 3a.We also examined methylene insertion of EtZnCH 2 I into N─N single bonds of pyrazoles.Although N-tosylated pyrazole 3b gave dihydropyrimidine 4b in 19% yield, pyrazoles having other substituents (R = H, acetyl, tertbutoxycarbonyl, methanesulfonyl) did not give the corresponding products.Indazoles having methoxy (3c), benzyloxy (3d), or 2,4,6-trimethylbenzoyloxy (3e) groups afforded the corresponding bicyclic dihydropyrimidines 4c-e in 31-39% yields.Increasing the reaction temperature or the amount of the iodomethylzinc reagent did not improve the reaction yield.On the other hand, unsubstituted indazole (R = H) gave N-methyindazole in 74% yield via methylene insertion into N─H single bond (Scheme S1, Supporting Information).Furthermore, the current methylene insertion mediated by zinc carbenoid was applicable to fivemembered cyclic oximes.Indeed, diphenyl dihydrooxazine 4f was produced in 80% yield from diphenylisoxazoline 3f.The ring-expanded products 4 g and 4 h were also obtained albeit in 30% and 57% yields, respectively.The low yields of 4 g and 4 h are probably due to the instability of dihydro oxazine structures which were readily converted to -keto alcohols via hydrolysis.In fact, the hydrolyzed products 5i and 5j were obtained from 3i and 3j, respectively, and the desired 4i and 4j were not observed.In the same manner, the methylene insertion into the six-membered oxime 3k was attempted, resulting in only -keto alcohol 5k in 74% yield.

Mechanistic Investigation
To clarify the mechanism of the methylene insertion, we conducted DFT calculations on the ring-expansion of isoxazole 1a and cyclic oxime 3f.All calculations were performed by the Gaussian 16 program at the level of B3LYP-D3/LANL2DZ for I and Zn and 6-31G(d,p) for other elements in 1,2-dichloroethane (polarizable continuum model, PCM).MeZnCH 2 I [21] was used as a model of zinc carbenoid for the calculations.We first examined the possibility of concerted insertion of zinc carbenoid into the N─O single bond, similar to the well-known mechanism of Simmons-Smith reaction. [22]However, no desired transition state structures were obtained, and the candidates converged to N-or O-alkylated structures.Therefore, we focused on the stepwise path (Figure 1 conditions: 1a (0.20 mmol), CH 2 I 2 (X equiv.),Et 2 Zn (Y equiv.),solvent (2 mL), 4 h; b) NMR yield using dibromomethane as an internal standard; c) DCE (4 mL, 0.05 m) was used; d) reaction time: 12 h; Ph = phenyl, THF = tetrahydrofuran, EtOAc = ethyl acetate, DCE = 1,2-dichloroethane.
-a).Isoxazole 1a and MeZnCH 2 I formed the complex Int1, and S N 2-like N-alkylation occurred between the nitrogen of isoxazole 1a and MeZnCH 2 I, leading to the intermediate Int2 via the transition state TS1.The energy barrier required for this N-alkylation (ΔG ‡ 1a→TS1 ) is 14.5 kcal mol −1 (also see entry 1 in Figure1-b).After the N-alkylation, the zinc moiety (IZnMe) was eliminated from the intermediate Int2 to afford the ylide intermediate Int3, followed by the N─O single bond cleavage to give the intermediate Int4 through the transition state TS2.The energy barrier required for the N─O single bond cleavage (ΔG ‡ Int3→TS2 ) is 0.5 kcal mol −1 , and this

Figure 1 .
Figure 1.a) Gibbs free energy profile of methylene insertion into the N─O single bond of isoxazole 1a; b) the summary of activation energies and product yield of each 1,2-azole and c) Gibbs free energy profile of methylene insertion into the N─O single bond of cyclic oxime 3f via MeZnCH 2 I.All calculations were conducted at the level of B3LYP-D3/LANL2DZ for Zn, I, and 6-31G(d,p) for other elements in 1,2-dichloroethane (PCM).

Table 1 .
Optimization of methylene insertion into N─O single bond of isoxazole 1a.