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Article

Inverting the Regioselectivity of 1,3-Dipolar Cycloaddition Reaction Between Nitrones and Enal Derivatives

by
Yuki Maeda
,
Yoshimitsu Hashimoto
*,
Yuriko Oshita
,
Sayuri Yuhara
,
Osamu Tamura
and
Nobuyoshi Morita
*
Department of Pharmacy, Showa Pharmaceutical University, 3-2-1 Higashi-Tamagawagakuen, Machida 194-8543, Tokyo, Japan
*
Authors to whom correspondence should be addressed.
Reactions 2026, 7(2), 26; https://doi.org/10.3390/reactions7020026
Submission received: 3 March 2026 / Revised: 19 March 2026 / Accepted: 26 March 2026 / Published: 2 April 2026
(This article belongs to the Special Issue Cycloaddition Reactions at the Beginning of the Third Millennium, 2nd Edition)
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Versions Notes

Abstract

The 1,3-dipolar cycloaddition of nitrones with hydrazones affords 5-iminoisoxazolidines as the major products, in contrast to the reaction with enals, which exclusively afford 4-acylisoxazolidines. This reversal of regioselectivity can be explained in terms of frontier orbital theory. The 5-iminoisoxazolidines are easily converted to 5-acylisoxazolidines.

Graphical Abstract

1. Introduction

Isoxazolidines are saturated five-membered heterocycles containing adjacent nitrogen and oxygen atoms [1]. Although they are uncommon in natural products [2,3] due to their intrinsically unstable N–O bond, they have been reported to possess a variety of biological activities [4,5,6,7,8]. Furthermore, they can be used as valuable intermediates for the synthesis of 1,3-aminoalcohols [9,10,11,12,13], amino acids [14,15,16], and lactams [17,18] via cleavage of the N–O bond. Thus, the development of efficient and versatile synthetic methods for diverse isoxazolidine derivatives would be useful for the total synthesis of various natural products and pharmaceuticals [19]. General methods for the synthesis of isoxazolidines include 1,3-dipolar cycloaddition of nitrones [3,20,21,22] with alkenes [23,24,25,26,27] and the cyclization reaction of unsaturated hydroxylamines [20,28]. In particular, 1,3-dipolar cycloaddition is a versatile technique widely used in the synthesis of various heterocyclic compounds [29,30,31,32,33,34,35,36]; however, the 1,3-dipolar cycloaddition reaction of nitrones with enals has limitations. For example, 1,3-dipolar cycloaddition of nitrones with crotonaldehyde tends to give 4-acylisoxazolidines as the main products due to the interaction between the LUMO of crotonaldehyde and the HOMO of the nitrones [37,38].
Umpolung is a strategy in organic synthesis to invert the polarity of a compound [39,40]. For example, converting the electron-withdrawing carbonyl group of α,β-unsaturated carbonyl into an electron-donating hydrazone activates the HOMO, enabling the α,β-unsaturated hydrazone to react as a nucleophile [41,42,43,44,45]. Our group previously reported inverse regioselective 1,3-dipolar cycloaddition reactions of nitrones with cyclic enone derivatives by converting an electron-withdrawing carbonyl group into an oxime group, which is structurally analogous to a hydrazone, based on the electron-donating character of O-substituted oxime groups (Scheme 1, top) [46]. This carbonyl-to-oxime conversion raises the HOMO of the dipolarophile, leading to the selective formation of 5-iminoisoxazolidines as the major products. It is noteworthy that the corresponding α,β-unsaturated dimethylhydrazone failed to yield the desired compound (Appendix A), likely due to steric hindrance between the methyl group and the methylene of the ring, which reduces electron-donation to the olefin [47]. Building on that work, we turned our attention to acyclic α,β-unsaturated aldehyde derivatives as dipolarophiles (Scheme 1, bottom). For enals, hydrazones can be used because the steric hindrance caused by substituents on the amino nitrogen of the hydrazones is reduced. However, although introducing various substituents at the α- and β-positions of acyclic enals expands the substrate range, the application of acyclic enal derivatives as dipoles poses additional challenges. For example, following cycloaddition, isomerization may occur via keto-enol tautomerism. Additionally, whereas the reaction with cyclic enone derivatives affords exclusively exo products due to steric repulsion between the ring and the cyclic nitrone, the reaction with enal is expected to afford endo products because of the reduced steric hindrance in acyclic substrates. Furthermore, steric factors have a greater influence on the regioselectivity of acyclic compounds than cyclic compounds [48,49,50]. Herein, we report the 1,3-dipolar cycloaddition of cyclic electron-deficient nitrones with α,β-unsaturated oximes and hydrazones, providing a regio- and stereoselective approach for the synthesis of isoxazolidine derivatives.

2. Results and Discussion

To investigate the regioselectivity arising from the HOMO activation of enal derivatives, we performed 1,3-dipolar cycloaddition reaction of electron-deficient nitrones 1 with various acyl- and imino-substituted olefins 2 (Table 1). First, the reaction of nitrone 1a [51] with crotonaldehyde (2a) as an enal with an alkyl substituent at the β-position at room temperature for 10 h exclusively afforded 4-acyl-endo-isoxazolidines 4aa (91% yield, trans:cis = 66:34) (entry 1). Next, the reaction with a benzyl oxime derivative 2b [52] was conducted at 90 °C for 24 h, affording 5-imino-trans-isoxazolidines 3ab as the main products with slight endo selectively (93% yield, 5-imino:4-imino = 67:33) (entry 2), reflecting the electron-donating nature of the oxime. The reaction of oxime 2c bearing a TBDPS group also exhibited similar regioselectivity to that observed with the benzyl oxime (5-imino:4-imino = 62:38), and the diastereomeric ratio of 5-imino-trans-exo to 5-imino-trans-endo was 56:44, indicating a reversal in stereoselectivity (entry 3). The conversion of the oxime group to hydrazones is expected to enhance the electron-donating ability and to improve regioselectivity. Indeed, the reaction of α,β-unsaturated dimethylhydrazone 2d [53] with nitrone 1a proceeded at 50 °C with high regioselectivity (5-imino:4-imino = 93:7) (entry 4), consistent with the more electron-donating character of hydrazone as compared to oxime. Additionally, the reaction was exo-stereoselective (exo:endo = 77:23), as discussed later. The reaction with hydrazone 2e containing a piperidine ring gave a similar result (5-imino:4-imino = 91:9) (entry 5), and the reaction with diisopropylhydrazone 2f [54] afforded complete regioselectivity (entry 6). These results confirm the HOMO activation of the acyclic enal by converting the formyl group to an oxime or hydrazone moiety, leading to a complete reversal of regioselectivity in the case of hydrazones.
The stereochemistry of the cycloadducts was determined by means of NOESY experiments, as shown in Figure 1.
Here, we consider the stereoselectivity of the resulting 5-imino-trans-isoxazolidine from the perspective of the transition states (Figure 2). In the reaction of the benzyl oxime derivative 2b with the nitrone 1a, there is no significant difference in steric hindrance between the endo- and exo-transition states. However, for the reaction with dimethylhydrazone 2d, steric hindrance occurs between one of the methyl groups of the hydrazone and the methylene of the cyclic nitrone in the endo-transition state, but not in the exo-transition state. This accounts for the preferential formation of the exo isomers as the major products.
Next, we investigated the effect of the β-substituent on the reactions (Table 2). In contrast to the preceding results, substrates bearing a bulky substituent at the β-position afforded the endo isomer as the major product. Although trans-diisopropylhydrazone 2f proved to be the most efficient substrate in Table 1, dimethylhydrazone was employed in subsequent investigations owing to its greater availability. The reaction of the nitrone 1a with trans-cinnamaldehyde derivative 2g [54] afforded a mixture of 5-imino and 4-imino trans-isoxazolidines in a ratio of 44:56, with exclusive endo selectivity (entry 1). The reactions of 2h [54], with an electron-donating 4-methoxyphenyl group, and trans-2i, with a cyclohexyl group, gave the cycloadducts with slightly better regioselectivity and exclusive endo selectivity (entries 2 and 3).
These results indicate that the bulkiness of the β-substituent critically influences the stereoselectivity (Figure 3). To rationalize this, we conducted frontier molecular orbital (FMO) analysis. When 5-imino-trans-isoxazolidine is formed through interaction between the LUMO of the nitrone and the HOMO of the α,β-unsaturated hydrazone, the largest orbital interaction occurs between the carbon atom of the nitrone and the β-position of the α,β-unsaturated hydrazone, leading to an asynchronous transition state in which these positions preferentially approach. Consequently, steric repulsion between the nitrone and the large β-substituent in the exo transition state becomes more severe than that between the nitrone and the dimethyamino group in the endo transition state, resulting in preferential formation of the endo isomer. In contrast, when 4-imino-trans-isoxazolidine arises from the interaction between the HOMO of the nitrone and the LUMO of the α,β-unsaturated hydrazone, the dominant orbital interaction is established between the oxygen atom of the nitrone and the β-position of α,β-unsaturated hydrazone. This interaction enforces an approach geometry that increases steric repulsion between the methylene of the nitrone and the β-substituent of the α,β-unsaturated hydrazone, favoring formation of the endo isomer.
Subsequently, the reaction was carried out with a more electron-deficient lactone type nitrone 1b [55] (Scheme 2). The reaction of the nitrone 1b with a trans-cinnamaldehyde derivative 2g gave the cycloadducts only 30% yield. However, the regioselectivity was 5-imino:4-imino = 82:18 with 5-imino-trans-isoxazolidines 3bg as the major products, although the regioisomeric ratio of the reaction between lactam type nitrone 1a and trans-cinnamaldehyde dervative 2g is only 44:56 (Table 2, entry 1). This result suggests that the reactions of more electron-deficient nitrones with hydrazone derivatives give 5-imino-trans-isoxazolidines with better regioselectivity. Although it is unclear whether the reaction is slightly exo-selective, the α-phenyl group of nitrone 1b may exert a steric influence on the cycloaddition, mainly affecting facial selectivity rather than exo-selectivity and regioselectivity.
Finally, the hydrazone group of the resulting 5-imino-trans-isoxazolidine exo-3ad was removed (Scheme 3). The removal of the hydrazone group in the presence of formaldehyde and hydrochloric acid in THF provided the desired 5-acyl-trans-isoxazolidine exo-3aa in 75% yield. This two-step sequence, consisting of a nitrone cycloaddition reaction with the hydrazone derivatives followed by dehydrazonation, enables indirect synthesis of 5-acylisoxazolidines that are difficult to obtain via nitrone cycloaddition reaction with enals.

3. Conclusions

1,3-Dipolar cycloaddition of electron-deficient cyclic nitrones with acyclic α,β-unsaturated imines with a β-substituent gave 5-iminoisoxazolidines as the major products. This regioselectivity is the reverse of that in the reaction with acyclic enals, owing to polarity inversion induced by replacement of the carbonyl group with an imino group. Consistently with this rationale, the use of hydrazones, which are more strongly electron-donating than oximes, increased the regioselectivity. The stereoselectivity of the cycloaddition reaction is influenced not only by the substituent of the imines, but also by the β-substituent of the conjugated olefin. Increasing the steric bulkiness of the imino substituent promotes the formation of the exo-cycloadduct, while the presence of a sterically bulky β-substituent increases the endo-selectivity. The obtained 5-iminoisoxazolidines were easily converted to 5-acylisoxazolidines, providing an efficient synthetic route enabled by polarity inversion. The present work provides an uncommon example of regioselectivity reversal in 1,3-dipolar cycloadditions achieved through electronic control imparted by a electron-donating imine functionality [46,56,57].

4. Experimental Section

4.1. General Information

1H- and 13C-NMR spectra were recorded on Bruker-600M (Billerica, MA, USA), JEOL JNM-AL300 (Akishima, Tokyo, Japan) and ECZ400S spectrometers. Chemical shifts (δ) were reported in parts per million (ppm) on an internal standard (tetramethylsilane, 0.0 ppm for 1H, CDCl3, 77.0 ppm, acetone-d6, 206.3 ppm and C6D6, 128.1 ppm for 13C). Coupling constants (J) were given in Hertz (Hz). IR spectra were recorded on Shimadzu FTIR 8200A (Kyoto, Kyoto, Japan). High-resolution MS (HRMS) were recorded on JEOL JMS-700 and JMS T100LP spectrometers. Melting points (mp) were recorded on Yanaco melting point apparatus MP-S3 (Chiyoda, Tokyo, Japan). Flash chromatography was performed on Kanto Chemical silica gel 60 N (spherical, neutral, size 40–50 µm) (Chuo, Tokyo, Japan) and Fuji Silysia Chemical BW-127ZH (Kasugai, Aichi, Japan). TLC was performed on Merck silica gel 60 F254 (0.25 mm thickness) (Darmstadt, Germany). Preparative TLC was performed on Merck silica gel 60 F254 (1.0 mm thickness).

4.2. Synthesis of Enal Derivatives

(1E,2E)-but-2-enal O-(tert-butyldiphenylsilyl) oxime (trans-2c). Crotonaldehyde (2a) (0.330 mL, 4.02 mmol) was added to a solution of O-(tert-butyldiphenylsilyl)hydroxylamine (1.00 g, 3.68 mmol) in CH2Cl2 (3.7 mL) at 0 °C. After the reaction mixture was stirred at room temperature for 1 h, the solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (hexane/CHCl3 = 4/1 to 3/1 to CHCl3) to afford oxime trans-2c (805 mg, 68% yield) as a colorless oil. 1H NMR (600 MHz, CDCl3) δ 8.01 (1H, d, J = 9.6 Hz), 7.70 (4H, dd, J = 7.8, 1.2 Hz), 7.41–7.34 (6H, m), 6.21–6.16 (1H, m), 6.05 (1H, dq, J = 15.6, 6.7 Hz), 1.82 (3H, dd, J = 6.7, 1.5 Hz), 1.10 (9H, s); 13C NMR (150 MHz, CDCl3) δ 156.1, 137.4, 135.5, 133.6, 129.6, 127.5, 125.7, 27.1, 19.3, 18.5; IR (KBr) 2961, 2858, 1653, 1473, 1429, 1115 cm−1; HRMS (ESI) m/z: Calcd for C20H25NOSiNa[M+Na]+, 346.1603. Found: 346.1614.
(1E,2E)-N-(piperidin-1-yl)but-2-en-1-imine (trans-2e) and (1E,2Z)-N-(piperidin-1-yl)but-2-en-1-imine (cis-2e). Acetic acid (1.10 mL, 20.0 mmol) and crotonaldehyde (2a) (0.720 mL, 10.0 mmol) were added to a solution of 1-aminopiperidine (2.20 mL, 20.0 mmol) in CH2Cl2 (20 mL) at 0 °C. After the reaction mixture was stirred at room temperature for 23 h, the solution was diluted with CH2Cl2, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (CH2Cl2/AcOEt = 5/1) to afford hydrazone 2e (801.6 mg, 53% yield, trans:cis = 87:13) as a yellow oil. 1H NMR (300 MHz, CDCl3, signals from the minor isomer are marked with an asterisk) δ 7.57* (1H, d, J = 9.3 Hz), 7.28 (1H, d, J = 8.7 Hz), 6.30–6.08 (1H + 1H*, m), 5.94–5.77 (1H, m), 5.76–5.61* (1H, m), 3.05* (4H, t, J = 6.0 Hz), 3.00 (4H, t, J = 5.7 Hz), 1.82 (3H + 3H*, dd, J = 6.6, 1.5 Hz), 1.77–1.64 (4H + 4H*, m), 1.57–1.43 (2H + 2H*, m); 13C NMR (75 MHz, CDCl3, weak signals of the minor isomer were omitted) δ 138.5, 131.5, 130.3, 52.2, 25.0, 24.0, 18.1; IR (NaCl) 2936, 2854, 2804, 1450, 1374, 1096, 1074 cm−1; HRMS (EI) m/z: Calcd for C9H16N2 [M]+ 152.1313, Found 152.1309.
(E)-2-((E)-3-cyclohexylallylidene)-1,1-dimethylhydrazine (trans-E-2i) and (Z)-2-((E)-3-cyclohexylallylidene)-1,1-dimethylhydrazine (trans-Z-2i). (2E)-3-cyclohexyl-2-propenal (426 mg, 3.08 mmol) was added to a solution of 1,1-dimethylhydrazine (0.700 mL, 9.24 mmol) and MgSO4 (445 mg, 3.70 mmol) in CH2Cl2 (1.5 mL) at 0 °C. After the reaction mixture was stirred at room temperature for 19 h, the solution was filtered, washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (toluene/AcOEt = 15/1) to afford hydrazone trans-2i (344 mg, 62% yield, E:Z = 87:13) as a yellow oil. 1H NMR (300 MHz, CDCl3, signals from the minor isomer are marked with an asterisk) δ 7.02 (1H, d, J = 8.7 Hz), 7.01* (1H, d, J = 7.8 Hz), 6.16 (1H, ddd, J = 15.6, 9.0, 1.2 Hz), 6.15–6.04* (1H, m), 5.79 (1H, dd, J = 15.6, 6.3 Hz), 5.68* (1H, dd, J = 15.0, 6.9 Hz), 2.86* (6H, s), 2.82 (6H, s), 2.14–1.97 (1H + 1H*, m), 1.82–1.58 (5H + 5H*, m), 1.39–1.01 (5H + 5H*, m); 13C NMR (75 MHz, CDCl3, weak signals of the minor isomer were omitted) δ 141.7, 137.5, 126.4, 42.9, 40.6, 32.6, 26.1, 26.0; IR (NaCl) 2924, 2850, 2784, 1470, 1447, 1269, 1134 cm−1; HRMS (EI) m/z: Calcd for C11H20N4 [M]+ 180.1626, Found 180.1623.

4.3. General Procedure for 1,3-Dipolar Cycloaddition Reaction of Nitrones and Enal Derivatives

A nitrone was added to an enal derivative, and the reaction mixture was stirred at room temperature or heated as required until complete consumption of the nitrone was confirmed by TLC analysis. The mixture was then directly purified by column chromatography on silica gel to afford the corresponding isoxazolidines.

4.4. Synthesis of Cycloadducts

(2R*,3S*,3aS*)-5-benzyl-2-methyl-4-oxohexahydro-2H-isoxazolo[2,3-a]pyrazine-3-carbaldehyde (trans-endo-4aa) and (2R*,3R*,3aS*)-5-benzyl-2-methyl-4-oxohexahydro-2H-isoxazolo[2,3-a]pyrazine-3-carbaldehyd (cis-endo-4aa). Following the general procedure, 4aa (80.9 mg, 91% yield, trans:cis = 66:34) with a small amount of impurity was afforded from nitrone 1a (50.0 mg, 0.245 mmol) and crotonaldehyde (2a) (40.0 μL, 0.490 mmol) at room temperature for 10 h followed by column chromatography on silica gel (hexane/AcOEt = 1/1). Yellow oil; 1H NMR (600 MHz, C6D6, signals from the minor isomer are marked with an asterisk) δ 9.82 (1H, d, J = 0.8 Hz), 9.40* (1H, d, J = 2.4 Hz), 7.16–7.02 (5H + 5H*, m), 4.58–4.54 (1H + 1H*, m), 4.48 (1H, d, J = 14.4 Hz), 4.35* (1H, d, J = 14.4 Hz), 4.26 (1H, d, J = 9.8 Hz), 4.23* (1H, d, J = 14.4 Hz), 4.05* (1H, dq, J = 8.6, 6.6 Hz), 4.01 (1H, d, J = 14.4 Hz), 3.40* (1H, ddd, J = 8.6, 6.6, 2.4 Hz), 2.88 (1H, ddd, J = 9.8, 7.2, 0.8 Hz), 2.85–2.50 (4H + 4H*, m), 1.03 (3H, d, J = 6.6 Hz), 0.97* (3H, d, J = 6.6 Hz); 13C NMR (150 MHz, C6D6) δ 198.1, 197.8, 167.3, 165.5, 137.2, 136.8, 129.0, 128.9, 128.5, 128.4, 73.7, 72.9, 67.6, 64.3, 64.2, 61.6, 49.7, 49.5, 47.7, 47.6, 42.3, 42.1, 19.6, 16.5 (several signals overlapped); IR (NaCl) 2972, 1722, 1645, 1494, 1263 cm−1; HRMS (EI) m/z: Calcd for C15H18N2O3 [M]+ 274.1317, Found 274.1312.
(E)-(2S*,3S*,3aS*)-5-benzyl-3-methyl-4-oxohexahydro-2H-isoxazolo[2,3-a]pyrazine-2-carbaldehyde O-benzyl oxime (trans-exo-3ab), (E)-(2R*,3R*,3aS*)-5-benzyl-3-methyl-4-oxohexahydro-2H-isoxazolo[2,3-a]pyrazine-2-carbaldehyde O-benzyl oxime (trans-endo-3ab) and (E)-(2R*,3R*,3aS*)-5-benzyl-2-methyl-4-oxohexahydro-2H-isoxazolo[2,3-a]pyrazine-3-carbaldehyde O-benzyl oxime (trans-endo-4ab). Following the general procedure, 3ab and 4ab (86.5 mg, 93% yield, trans-exo-3ab:trans-endo-3ab:trans-endo-4ab = 29:38:33) were afforded from nitrone 1a (50.0 mg, 0.245 mmol) and oxime 2b (85.9 mg, 0.490 mmol) at 90 °C for 24 h followed by column chromatography on silica gel (hexane/AcOEt = 5/1 to 3/2 to AcOEt). A mixture of 3ab and 4ab was further purified by flash column chromatography on silica gel (toluene/Et2O/acetonitrile = 30/1/10) to afford 3ab (exo:endo = 52:48) as a yellow oil and 4ab as a pale white oil with a small amount of impurity.
Compound trans-3ab (exo:endo = 52:48): 1H NMR (300 MHz, CDCl3, signals from the endo isomer are marked with an asterisk) δ 7.41 (1H, d, J = 7.2 Hz), 7.36–7.21 (10H + 11H*, m), 5.10 (2H + 2H*, s), 4.81 (1H, d, J = 14.5 Hz), 4.59* (2H, s), 4.43 (1H, d, J = 14.5 Hz), 4.35 (1H, t, J = 7.0 Hz), 4.23 (1H, d, J = 9.3 Hz), 4.16* (1H, dd, J = 7.3, 6.7 Hz), 3.75* (1H, d, J = 7.3 Hz), 3.46–3.13 (4H + 4H*, m), 3.01 (1H, m), 2.79* (1H, m), 1.39* (3H, d, J = 6.7 Hz), 1.26 (3H, d, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 167.6, 165.9, 148.2, 148.0, 137.0, 136.9, 136.2, 136.1, 128.8, 128.4, 128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 82.5, 81.0, 76.3, 76.2, 70.2, 67.2, 49.7, 49.6, 49.4, 48.7, 46.3, 45.3, 42.2, 16.5, 14.9 (several signals overlapped); IR (NaCl) 2929, 1651, 1454, 1359, 1259 cm−1; HRMS (EI) m/z: Calcd for C22H25N3O3 [M]+ 379.1896, Found 379.1893.
Compound trans-endo-4ab: 1H NMR (600 MHz, CDCl3) δ 7.61 (1H, d, J = 6.0 Hz), 7.36–7.25 (10H, m), 5.08 (2H, s), 4.82 (1H, d, J = 14.6 Hz), 4.64–4.60 (1H, m), 4.37 (1H, d, J = 10.2 Hz), 4.27 (1H, d, J = 14.6 Hz), 3.33–3.27 (2H, m), 3.18–3.07 (3H, m), 1.35 (3H, d, J = 6.0 Hz); 13C NMR (150 MHz, CDCl3) δ 165.4, 148.4, 137.6, 136.0, 128.8, 128.4, 128.3, 128.2, 127.8, 127.8, 75.9, 75.1, 67.5, 53.2, 49.4, 47.8, 42.9, 18.6; IR (NaCl) 2926, 2361, 1651, 1454, 1359, 1014 cm−1; HRMS (EI) m/z: Calcd for C22H25N3O3 [M]+ 379.1896, Found 379.1894.
(E)-(2R*,3R*,3aR*)-5-benzyl-3-methyl-4-oxohexahydro-2H-isoxazolo[2,3-a]pyrazine-2-carbaldehyde O-(tert-butyldiphenylsilyl) oxime (trans-exo-3ac), (E)-(2R*,3R*,3aS*)-5-benzyl-3-methyl-4-oxohexahydro-2H-isoxazolo[2,3-a]pyrazine-2-carbaldehyde O-(tert-butyldiphenylsilyl) oxime (trans-endo-3ac) and (E)-(2R*,3R*,3aS*)-5-benzyl-2-methyl-4-oxohexahydro-2H-isoxazolo[2,3-a]pyrazine-3-carbaldehyde O-(tert-butyldiphenylsilyl) oxime (trans-endo-4ac). Following the general procedure, 3ac and 4ac (106 mg, 82% yield, trans-exo-3ac:trans-endo-3ac:trans-endo-4ac = 35:27:38) were afforded from nitrone 1a (50.0 mg, 0.245 mmol) and oxime 2c (159 mg, 0.490 mmol) at 70 °C for 7 h followed by column chromatography on silica gel (hexane/AcOEt = 5/1 to 2/3 to acetonitrile). A mixture of 3ac and 4ac was further purified by flash column chromatography on silica gel (toluene/Et2O/acetonitrile = 15/1/5) to afford 3ac (exo:endo = 47:53) as a yellow oil with a small amount of impurity and 4ac as a colorless oil.
Compound trans-3ac (exo:endo = 47:53): 1H NMR (300 MHz, CDCl3, signals from the exo isomer are marked with an asterisk) δ 7.69–7.64 (5H + 5H*, m), 7.43–7.23 (11H + 11H*, m), 4.77 (1H, d, J = 14.5 Hz), 4.61* (1H, d, J = 14.7 Hz), 4.53* (1H, d, J = 14.7 Hz), 4.42 (1H, d, J = 14.5 Hz), 4.36 (1H, t, J = 7.2 Hz), 4.21 (1H, d, J = 9.3 Hz), 4.18* (1H, dd, J = 7.9, 6.9 Hz), 3.73* (1H, d, J = 7.9 Hz), 3.42–3.01 (4H + 4H*, m), 3.00 (1H, m), 2.79* (1H, m), 1.31* (3H, d, J = 6.9 Hz), 1.17 (3H, d, J = 7.2 Hz), 1.10 (9H + 9H*, s); 13C NMR (75 MHz, CDCl3) δ 167.5, 166.0, 153.8, 153.6, 136.2, 135.5, 135.4, 133.1, 133.0, 129.7, 128.8, 128.7, 128.1, 128.0, 127.8, 127.6, 82.6, 81.0, 77.2, 70.2, 67.2, 49.7, 49.6, 48.7, 46.2, 45.5, 42.4, 42.2, 27.0, 26.9, 19.3, 19.2, 16.2, 14.7 (several signals overlapped); IR (NaCl) 2931, 2858, 1651, 1429, 1359, 1114 cm−1; HRMS (ESI) m/z: Calcd for C31H37N3O3SiNa [M+Na]+ 550.2502, Found 550.2492.
Compound trans-endo-4ac: 1H NMR (600 MHz, CDCl3) δ 7.90 (1H, d, J = 4.8 Hz), 7.63 (4H, dd, J = 12.6, 8.4 Hz), 7.40–7.37 (2H, m), 7.33–7.21 (9H, m), 4.81 (1H, d, J = 14.4 Hz), 4.60 (1H, dq, J = 12.6, 6.0 Hz), 4.37 (1H, d, J = 9.6 Hz), 4.28 (1H, d, J = 14.4 Hz), 3.32–3.26 (2H, m), 3.11–3.08 (1H, m), 3.03–2.95 (2H, m), 1.23 (3H, d, J = 6.0 Hz), 1.11 (9H, s); 13C NMR (150 MHz, CDCl3) δ 165.5, 153.4, 136.0, 135.6, 135.5, 129.6, 128.9, 128.3, 127.8, 127.5, 74.7, 67.4, 53.1, 49.4, 47.5, 43.0, 27.1, 19.3, 18.4; IR (NaCl) 2961, 2858, 1651, 1488, 1429, 1263, 1114 cm−1; HRMS (EI) m/z: Calcd for C31H37N3O3Si [M]+ 527.2604, Found 527.2599.
(2R*,3R*,3aR*)-5-benzyl-2-((E)-(2,2-dimethylhydrazineylidene)methyl)-3-methyltetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-exo-3ad), (2R*,3R*,3aS*)-5-benzyl-2-((E)-(2,2-dimethylhydrazineylidene)methyl)-3-methyltetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-3ad), (2S*,3R*,3aS*)-5-benzyl-2-((E)-(2,2-dimethylhydrazineylidene)methyl)-3-methyltetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (cis-exo-3ad) and (2R*,3R*,3aS*)-5-benzyl-3-((E)-(2,2-dimethylhydrazineylidene)methyl)-2-methyltetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-4ad). Following the general procedure, 3ad and 4ad (70.7 mg, 91% yield, trans-exo-3ad:trans-endo-3ad:cis-exo-3ad:trans-endo-4ad = 63:19:11:7) were afforded from nitrone 1a (50.0 mg, 0.245 mmol) and hydrazone 2d (55.0 mg, 0.490 mmol, trans:cis = 10:1) at 50 °C for 48 h followed by column chromatography on silica gel (hexane/AcOEt = 5/1 to acetonitrile). A mixture of 3ad and 4ad was further purified by PTLC (Et2O) to afford trans-exo-3ad as a yellow oil and trans-endo-4ad as a yellow oil with a small amount of impurity, which was purified by PTLC (CHCl3/acetonitrile = 2/1) to afford trans-endo-3ad as a yellow solid and cis-exo-3ad as a yellow oil.
Compound trans-exo-3ad: 1H NMR (600 MHz, CDCl3) δ 7.35–7.25 (5H, m), 6.39 (1H, d, J = 6.0 Hz), 4.80 (1H, d, J = 15.0 Hz), 4.45 (1H, d, J = 15.0 Hz), 4.40 (1H, t, J = 7.2 Hz), 4.29 (1H, d, J = 9.0 Hz), 3.40 (1H, m), 3.29–3.20 (3H, m), 2.99–2.93 (1H, m), 2.86 (6H, s), 1.27 (3H, d, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) δ 166.3, 136.2, 130.9, 128.8, 128.2, 127.7, 84.6, 67.8, 49.6, 48.8, 45.6, 42.6, 42.5, 14.9; IR (NaCl) 3030, 2874, 2360, 1645, 1265, 1031 cm−1; HRMS (EI) m/z: Calcd for C17H24N4O2 [M]+ 316.1899, Found 316.1893.
Compound trans-endo-3ad: mp 116.3–117.3 °C (hexane–AcOEt); 1H NMR (600 MHz, CDCl3) δ 7.34–7.25 (5H, m), 6.29 (1H, d, J = 6.6 Hz), 4.64 (1H, d, J = 14.4 Hz), 4.61 (1H, d, J = 14.4 Hz), 4.17 (1H, dd, J = 7.8, 6.6 Hz), 3.75 (1H, d, J = 6.6 Hz), 3.55–3.51 (1H, m), 3.28–3.26 (2H, m), 3.18–3.14 (1H, m), 2.83 (6H, s), 2.78–2.72 (1H, m), 1.38 (3H, d, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) δ 168.5, 136.4, 130.3, 128.7, 128.1, 127.7, 86.0, 70.4, 49.8, 49.3, 46.8, 42.5, 42.1, 16.7; IR (KBr) 2895, 1637, 1445, 1267, 1040 cm−1; HRMS (EI) m/z: Calcd for C17H24N4O2 [M]+ 316.1899, Found 316.1896.
Compound cis-exo-3ad: 1H NMR (600 MHz, CDCl3) δ 7.35–7.24 (5H, m), 6.41 (1H, d, J = 7.8 Hz), 4.81 (1H, dd, J = 8.4, 7.8 Hz), 4.61 (2H, s), 3.75 (1H, d, J = 7.8 Hz), 3.35–3.28 (2H, m), 3.23–3.12 (1H, m), 3.16–3.12 (1H, m), 3.05–3.00 (1H, m), 2.84 (6H, s), 1.30 (3H, d, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) δ 168.0, 136.2, 130.2, 128.7, 128.1, 127.7, 80.5, 71.1, 49.6, 48.5, 44.7, 42.7, 42.6, 15.3; IR (NaCl) 2927, 2856, 1658, 1456, 1261, 1029 cm−1; HRMS (EI) m/z: Calcd for C17H24N4O2 [M]+ 316.1899, Found 316.1898.
Compound trans-endo-4ad: 1H NMR (600 MHz, CDCl3) δ 7.33–7.20 (5H, m), 6.63 (1H, d, J = 3.6 Hz), 4.98 (1H, d, J = 15.0 Hz), 4.70 (1H, dq, J = 12.6, 6.0 Hz), 4.38 (1H, d, J = 9.9 Hz), 4.19 (1H, d, J = 15.0 Hz), 3.41–3.25 (4H, m), 3.15–3.12 (1H, m), 2.75 (6H, s), 1.36 (3H, d, J = 6.0 Hz); 13C NMR (150 MHz, CDCl3) δ 166.2, 136.3, 128.7, 128.1, 127.7, 76.0, 68.4, 55.5, 49.3, 48.1, 43.3, 43.0, 30.0, 18.7; IR (NaCl) 2930, 2856, 1633, 1456, 1259, 1029 cm−1; HRMS (ESI) m/z: Calcd for C17H25N4O2 [M+H]+ 317.1977, Found 317.1964.
(2R*,3R*,3aR*)-5-benzyl-3-methyl-2-((E)-(piperidin-1-ylimino)methyl)tetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-exo-3ae), (2R*,3R*,3aS*)-5-benzyl-3-methyl-2-((E)-(piperidin-1-ylimino)methyl)tetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-3ae), (2S*,3R*,3aS*)-5-benzyl-3-methyl-2-((E)-(piperidin-1-ylimino)methyl)tetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (cis-exo-3ae) and (2R*,3R*,3aS*)-5-benzyl-2-methyl-3-((E)-(piperidin-1-ylimino)methyl)tetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-4ae). Following the general procedure, 3ae and 4ae (82.9 mg, 95% yield, trans-exo-3ae:trans-endo-3ae:cis-exo-3ae:trans-endo-4ae = 53:26:12:9) were afforded from nitrone 1a (50.0 mg, 0.245 mmol) and hydrazone 2e (74.6 mg, 0.490 mmol, trans:cis = 87:13) at 60 °C for 19 h followed by column chromatography on silica gel (AcOEt). A mixture of 3ae and 4ae was further purified by PTLC (hexane/AcOEt = 1/10) to afford trans-exo-3ae as a yellow oil, trans-endo-3ae as a yellow oil, cis-exo-3ae as a yellow oil and trans-endo-4ae as a yellow oil.
Compound trans-exo-3ae: 1H NMR (300 MHz, CDCl3) δ 7.40–7.21 (5H, m), 6.70 (1H, d, J = 6.6 Hz), 4.81 (1H, d, J = 14.7 Hz), 4.44 (1H, d, J = 14.7 Hz), 4.39 (1H, dd, J = 7.8, 6.6 Hz), 4.27 (1H, d, J = 9.3 Hz), 3.46–3.13 (4H, m), 3.11–2.87 (5H, m), 1.77–1.63 (4H, m), 1.56–1.44 (2H, m), 1.27 (3H, d, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 166.4, 136.3, 133.2, 128.8, 128.2, 127.8, 84.8, 67.9, 51.8, 49.6, 48.8, 45.6, 42.6, 25.0, 24.0, 15.0; IR (NaCl) 2935, 2855, 2810, 1651, 1489, 1453, 137, 1260 cm−1; HRMS (ESI) m/z: Calcd for C20H28N4O2Na [M+Na]+ 379.2110, Found 379.2099.
Compound trans-endo-3ae: 1H NMR (300 MHz, CDCl3) δ 7.40–7.20 (5H, m), 6.61 (1H, d, J = 6.6 Hz), 4.64 (1H, d, J = 14.7 Hz), 4.58 (1H, d, J = 14.7 Hz), 4.18 (1H, dd, J = 8.1, 6.6 Hz), 3.75 (1H, d, J = 6.9 Hz), 3.50 (1H, dt, J = 12.0, 5.4 Hz), 3.26 (2H, t, J = 5.4 Hz), 3.23–3.11 (1H, m), 3.08–2.91 (4H, m), 2.77 (1H, qdd, J = 6.9, 6.9, 6.6 Hz), 1.76–1.63 (4H, m), 1.56–1.44 (2H, m), 1.38 (3H, d, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) δ 168.3, 136.4, 132.8, 128.7, 128.1, 127.7, 86.2, 70.4, 51.8, 49.8, 49.4, 46.7, 42.2, 25.0, 24.0, 16.8; IR (NaCl) 2934, 2855, 1650, 1489, 1454, 1355, 1261 cm−1; HRMS (ESI) m/z: Calcd for C20H28N4O2Na [M+Na]+ 379.2110, Found 379.2095.
Compound cis-exo-3ae: 1H NMR (300 MHz, CDCl3) δ 7.42–7.17 (5H, m), 6.71 (1H, d, J = 7.2 Hz), 4.80 (1H, dd, J = 8.7, 7.2 Hz), 4.61 (2H, s), 3.75 (1H, d, J = 7.5 Hz), 3.41–2.98 (5H, m), 3.01 (4H, t, J = 5.6 Hz), 1.76–1.64 (4H, m), 1.56–1.44 (2H, m), 1.30 (3H, d, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 168.0, 136.2, 132.6, 128.8, 128.1, 127.7, 80.7, 71.1, 51.9, 49.6, 48.6, 44.9, 42.7, 25.0, 24.0, 15.3; IR (NaCl) 2934, 2854, 2808, 1652, 1488, 1453, 1357, 1260, 1166, 1084 cm−1; HRMS (ESI) m/z: Calcd for C20H28N4O2Na [M+Na]+ 379.2110, Found 379.2099.
Compound trans-endo-4ae: 1H NMR (300 MHz, CDCl3) δ 7.39–7.26 (3H, m), 7.26–7.20 (2H, m), 6.93 (1H, d, J = 5.1 Hz), 4.95 (1H, d, J = 14.7 Hz), 4.81–4.67 (1H, m), 4.39 (1H, d, J = 9.9 Hz), 4.22 (1H, d, J = 14.7 Hz), 3.42–3.22 (4H, m). 3.15–3.06 (1H, m), 2.89 (4H, t, J = 5.7 Hz), 1.75–1.62 (4H, m), 1.54–1.43 (2H, m), 1.36 (3H, d, J = 6.0 Hz); 13C NMR (75 MHz, CDCl3) δ 166.2, 136.3, 134.6, 128.7, 128.2, 127.7, 75.9, 68.3, 55.6, 52.3, 49.4, 48.0, 43.4, 25.1, 24.1, 18.8; IR (NaCl) 2933, 2855, 1652, 1490, 1454, 1357, 1261, 1163, 1084 cm−1; HRMS (ESI) m/z: Calcd for C20H28N4O2Na [M+Na]+ 379.2110, Found 379.2094.
(2R*,3R*,3aR*)-5-benzyl-2-((E)-(2,2-diisopropylhydrazineylidene)methyl)-3-methyltetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-exo-3af), (2R*,3R*,3aS*)-5-benzyl-2-((E)-(2,2-diisopropylhydrazineylidene)methyl)-3-methyltetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-3af) and (2S*,3R*,3aS*)-5-benzyl-2-((E)-(2,2-diisopropylhydrazineylidene)methyl)-3-methyltetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (cis-exo-3af). Following the general procedure, 3af (92.6 mg, quant, trans-exo-3af:trans-endo-3af:cis-exo-3af = 68:20:12) was afforded from nitrone 1a (50.0 mg, 0.245 mmol) and hydrazone 2f (82.5 mg, 0.490 mmol, trans:cis = 86:14) at 50 °C for 24 h followed by column chromatography on silica gel (CH2Cl2/AcOEt = 1/4). A mixture of 3af was further purified by PTLC (hexane/AcOEt = 1/3) to afford trans-exo-3af as a yellow oil, trans-endo-3af as a yellow oil and cis-exo-3af as a yellow oil with a small amount of impurity.
Compound trans-exo-3af: 1H NMR (300 MHz, CDCl3) δ 7.39–7.22 (5H, m), 6.37 (1H, d, J = 6.0 Hz), 4.88 (1H, d, J = 14.7 Hz), 4.43 (1H, t, J = 7.5 Hz), 4.40 (1H, d, J = 14.7 Hz), 4.28 (1H, d, J = 9.3 Hz), 3.74 (2H, sept, J = 6.6 Hz), 3.47–3.11 (4H, m), 2.97 (1H, m), 1.26 (3H, d, J = 7.2 Hz), 1.13 (12H, dd, J = 6.6, 0.9 Hz); 13C NMR (75 MHz, CDCl3) δ 166.7, 136.4, 128.8, 128.2, 127.7, 123.9, 85.8, 68.0, 49.6, 48.8, 47.2, 45.3, 42.7, 20.6, 20.4, 15.0; IR (NaCl) 3446, 2971, 2932, 2874, 1648, 1490, 1455, 1362, 1208 cm−1; HRMS (ESI) m/z: Calcd for C21H32N4O2Na [M+Na]+ 395.2423, Found 395.2422.
Compound trans-endo-3af: 1H NMR (300 MHz, CDCl3) δ 7.40–7.15 (5H, m), 6.34 (1H, d, J = 5.7 Hz), 4.67 (1H, d, J = 14.7 Hz), 4.57 (1H, d, J = 14.7 Hz), 4.22 (1H, dd, J = 8.4, 5.7 Hz), 3.77 (1H, d, J = 7.5 Hz), 3.72 (2H, sept, J = 6.6 Hz), 3.55–3.42 (1H, m), 3.41–3.07 (3H, m), 2.81 (1H, m), 1.38 (3H, d, J = 6.6 Hz), 1.12 (12H, t, J = 6.3 Hz); 13C NMR (75 MHz, CDCl3) δ 168.7, 136.5, 128.7, 128.0, 127.6, 123.4, 87.1, 70.5, 49.7, 49.6, 47.2, 46.3, 42.3, 20.7, 20.4, 16.7; IR (NaCl) 2970, 2929, 1652, 1489, 1456, 1362, 1207 cm−1; HRMS (ESI) m/z: Calcd for C21H32N4O2Na [M+Na]+ 395.2423, Found 395.2407.
Compound cis-exo-3af: 1H NMR (300 MHz, CDCl3) δ 7.40–7.20 (5H, m), 6.36 (1H, d, J = 7.2 Hz), 4.85 (1H, dd, J = 8.4, 7.2 Hz), 4.70 (1H, d, J = 14.4 Hz), 4.54 (1H, d, J = 14.4 Hz), 3.76 (1H, d, J = 8.1 Hz), 3.74 (2H, sept, J = 6.6 Hz), 3.39–3.08 (4H, m), 2.99 (1H, m), 1.29 (3H, d, J = 6.9 Hz), 1.13 (12H, dd, J = 7.5, 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ 168.3, 136.3, 128.8, 128.1, 127.7, 123.1, 81.9, 71.3, 49.5, 48.6, 47.3, 44.7, 42.9, 20.8, 20.3, 15.4; IR (NaCl) 2970, 2930, 2873, 1653, 1489, 1455, 1362, 1208, 1141 cm−1; HRMS (ESI) m/z: Calcd for C21H32N4O2Na [M+Na]+ 395.2423, Found 395.2416.
(2R*,3R*,3aS*)-5-benzyl-2-((E)-(2,2-dimethylhydrazineylidene)methyl)-3-phenyltetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-3ag) and (2S*,3R*,3aS*)-5-benzyl-3-((E)-(2,2-dimethylhydrazineylidene)methyl)-2-phenyltetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-4ag). Following the general procedure, 3ag and 4ag (59.6 mg, 64% yield, trans-endo-3ag:trans-endo-4ag = 44:56) were afforded from nitrone 1a (50.0 mg, 0.245 mmol) and hydrazone 2g (85.3 mg, 0.490 mmol) at 90 °C for 48 h followed by column chromatography on silica gel (hexane/AcOEt = 5/1 to AcOEt). A mixture of 3ag and 4ag was further purified by PTLC (AcOEt) to afford 3ag as a pale white oil and 4ag as a pale yellow oil.
Compound trans-endo-3ag: 1H NMR (300 MHz, CDCl3) δ 7.46 (2H, d, J = 7.2 Hz), 7.35–7.21 (8H, m), 6.34 (1H, d, J = 6.6 Hz), 4.74–4.67 (2H, m), 4.58 (1H, d, J = 14.7 Hz), 4.16 (1H, d, J = 4.1 Hz), 4.02 (1H, dd, J = 7.2, 4.1 Hz), 3.85–3.78 (1H, m), 3.57–3.50 (1H, m), 3.37–3.27 (1H, m), 3.11–3.04 (1H, m), 2.81 (6H, s); 13C NMR (75 MHz, CDCl3) δ 168.8, 140.6, 136.5, 128.7, 128.4, 128.1, 127.9, 127.6, 127.1, 86.0, 71.5, 57.9, 50.2, 47.9, 42.4, 41.4 (several signals overlapped); IR (NaCl) 2924, 1651, 1456, 1269, 1028 cm−1; HRMS (EI) m/z: Calcd for C22H26N4O2 [M]+ 378.2056, Found 378.2057.
Compound trans-endo-4ag: 1H NMR (600 MHz, CDCl3) δ 7.43 (2H, d, J = 6.8 Hz), 7.36–7.26 (6H, m), 7.22, (2H, d, J = 6.8 Hz), 6.7 2 (1H, d, J = 4.4 Hz), 5.82 (1H, d, J = 7.2 Hz), 5.03 (1H, d, J = 14.7 Hz), 4.55 (1H, d, J = 9.6 Hz), 4.21 (1H, d, J = 14.7 Hz), 3.69 (1H, ddd, J = 9.6, 7.2, 4.4 Hz), 3.56–3.54 (1H, m), 3.44–3.40 (1H, m), 3.32–3.30 (1H, m), 3.24–3.22 (1H, m), 2.77 (6H, s); 13C NMR (150 MHz, CDCl3) δ 166.0, 139.9, 136.2, 132.0, 128.7, 128.5, 128.0, 127.9, 127.7, 126.5, 80.9, 68.8, 56.9, 49.3, 48.1, 43.5, 42.9; IR (NaCl) 2856, 1651, 1493, 1454, 1261, 1170 cm−1; HRMS (EI) m/z: Calcd for C22H26N4O2 [M]+ 378.2056, Found 378.2059.
(2R*,3R*,3aS*)-5-benzyl-2-((E)-(2,2-dimethylhydrazineylidene)methyl)-3-(4-methoxyphenyl)tetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-3ah) and (2S*,3R*,3aS*)-5-benzyl-3-((E)-(2,2-dimethylhydrazineylidene)methyl)-2-(4-methoxyphenyl)tetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-4ah). Following the general procedure, 3ah and 4ah (79.8 mg, 80% yield, trans-endo-3ah:trans-endo-4ah = 56:44) were afforded from nitrone 1a (50.0 mg, 0.245 mmol) and hydrazone 2h (100 mg, 0.490 mmol) at 90 °C for 48 h followed by column chromatography on silica gel (hexane/AcOEt = 1/1). A mixture of 3ah and 4ah was further purified by PTLC (CH2Cl2/AcOEt = 4/1) to afford 3ah as a pale yellow oil and 4ah as a pale yellow oil.
Compound trans-endo-3ah: 1H NMR (300 MHz, CDCl3) δ 7.42–7.23 (7H, m), 6.87 (2H, d, J = 8.7 Hz), 6.33 (1H, d, J = 6.0 Hz), 4.71 (1H, d, J = 14.7 Hz), 4.65 (1H, dd, J = 7.5, 6.0 Hz), 4.57 (1H, d, J = 14.7 Hz), 4.11 (1H, d, J = 4.2 Hz), 3.96 (1H, dd, J = 6.0, 4.2 Hz), 3.88–3.70 (1H, m), 3.79 (3H, s), 3.52 (1H, dt, J = 14.1, 3.6 Hz), 3.39–3.23 (1H, m), 3.08 (1H, dt, J = 11.7, 3.6 Hz), 2.81 (6H, s); 13C NMR (75 MHz, CDCl3) δ 168.8, 158.7, 136.5, 132.6, 128.9, 128.7, 128.6, 128.1, 127.6, 114.1, 86.0, 71.6, 57.2, 55.3, 50.2, 48.0, 42.4, 41.4; IR (NaCl) 2932, 2858, 2836, 1645, 1611, 1513, 1491, 1454, 1354, 1250, 1178, 1032 cm−1; HRMS (ESI) m/z: Calcd for C23H28N4O3Na [M+Na]+ 431.2059, Found 431.2049.
Compound trans-endo-4ah: 1H NMR (300 MHz, CDCl3) δ 7.36 (2H, d, J = 8.7 Hz), 7.34–7.17 (5H, m), 6.88 (2H, d, J = 8.7 Hz), 6.70 (1H, d, J = 4.8 Hz), 5.75 (1H, d, J = 7.2 Hz), 5.03 (1H, d, J = 14.7 Hz), 4.56 (1H, d, J = 9.9 Hz), 4.20 (1H, d, J = 14.7 Hz), 3.80 (3H, s), 3.69 (1H, ddd, J = 9.9, 7.2, 4.8 Hz), 3.55 (1H, td, J = 10.2, 3.3 Hz), 3.42 (1H, td, J = 12.0, 3.3 Hz), 3.29 (1H, dt, J = 12.0, 3.3 Hz), 3.21 (1H, dt, J = 10.2, 3.3 Hz), 2.76 (6H, s); 13C NMR (75 MHz, CDCl3) δ 166.1, 159.4, 136.2, 132.0, 131.6, 128.7, 128.0, 127.9, 127.6, 113.9, 80.8, 69.0, 56.7, 55.3, 49.3, 48.1, 43.5, 42.9; IR (NaCl) 2954, 2858, 2786, 1651, 1611, 1514, 1494, 1454, 1250, 1175, 1032 cm−1; HRMS (ESI) m/z: Calcd for C23H28N4O3Na [M+Na]+ 431.2059, Found 431.2049.
(2R*,3R*,3aS*)-5-benzyl-3-cyclohexyl-2-((E)-(2,2-dimethylhydrazineylidene)methyl)tetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-3ai) and (2R*,3R*,3aS*)-5-benzyl-2-cyclohexyl-3-((E)-(2,2-dimethylhydrazineylidene)methyl)tetrahydro-2H-isoxazolo[2,3-a]pyrazin-4(5H)-one (trans-endo-4ai). Following the general procedure, 3ai and 4ai (58.5 mg, 62% yield, trans-endo-3ai:trans-endo-4ai = 52:48) were afforded from nitrone 1a (50.0 mg, 0.245 mmol) and hydrazone 2i (88.3 mg, 0.490 mmol, E:Z = 87:13) at 80 °C for 22 h followed by column chromatography on silica gel (hexane/AcOEt = 1/2). A mixture of 3ai and 4ai was further purified by PTLC (hexane/AcOEt = 1/2) to afford 3ai as a pale yellow oil and 4ai as a pale yellow oil.
Compound trans-endo-3ai: 1H NMR (300 MHz, CDCl3) δ 7.39–7.21 (5H, m), 6.24 (1H, d, J = 6.9 Hz), 4.70 (1H, d, J = 14.4 Hz), 4.56 (1H, d, J = 14.4 Hz), 4.42 (1H, t, J = 6.9 Hz), 3.95–3.75 (2H, m), 3.48 (1H, br d, J = 14.4 Hz), 3.30–3.14 (1H, m), 2.98 (1H, dd, J = 12.0, 3.3 Hz), 2.82 (6H, s), 2.60 (1H, ddd, J = 7.8, 6.9, 2.7 Hz), 1.98–1.53 (5H, m), 1.37–0.93 (6H, m); 13C NMR (75 MHz, CDCl3) δ 169.9, 136.6, 130.9, 128.6, 128.0, 127.6, 81.9, 66.4, 58.6, 50.3, 47.3, 42.5, 40.9, 40.1, 31.9, 30.9, 26.4, 26.2 (several signals overlapped); IR (NaCl) 2925, 2852, 2789, 1645, 1489, 1448, 1352, 1268, 1030 cm−1; HRMS (ESI) m/z: Calcd for C22H32N4O2Na [M+Na]+ 407.2423, Found 407.2403.
Compound trans-endo-4ai: 1H NMR (300 MHz, CDCl3) δ 7.37–7.15 (5H, m), 6.63 (1H, d, J = 5.1 Hz), 4.99 (1H, d, J = 14.7 Hz), 4.49 (1H, t, J = 6.9 Hz), 4.29 (1H, d, J = 9.9 Hz), 4.16 (1H, d, J = 14.7 Hz), 3.56–3.43 (1H, m), 3.46–3.27 (2H, m), 3.27–3.02 (2H, m), 2.72 (6H, s), 1.96–1.48 (5H, m), 1.38–0.80 (6H, m); 13C NMR (75 MHz, CDCl3) δ 166.2, 136.3, 133.6, 128.7, 128.1, 127.6, 83.9, 68.8, 51.7, 49.2, 47.8, 43.7, 43.0, 41.7, 29.3, 26.5, 26.0, 25.8 (several signals overlapped); IR (NaCl) 2924, 2852, 2785, 1654, 1490, 1450, 1341, 1261, 1031 cm−1; HRMS (ESI) m/z: Calcd for C22H32N4O2Na [M+Na]+ 407.2423, Found 407.2406.
(2R,3R,3aR,7R)-2-((E)-(2,2-dimethylhydrazineylidene)methyl)-3,7-diphenyltetrahydroisoxazolo [3,2-c][1,4]oxazin-4(2H)-one (trans-exo-3bg), (2S,3S,3aR,7R)-2-((E)-(2,2-dimethylhydrazineylidene)methyl)-3,7-diphenyltetrahydroisoxazolo [3,2-c][1,4]oxazin-4(2H)-one (trans-endo-3bg) and (2R,3S,3aR,7R)-3-((E)-(2,2-dimethylhydrazineylidene)methyl)-2,7-diphenyltetrahydroisoxazolo [3,2-c][1,4]oxazin-4(2H)-one (trans-endo-4bg). Following the general procedure, 3bg and 4bg (28.7 mg, 30% yield, trans-exo-3bg:trans-endo-3bg:trans-endo-4bg = 53:29:18) were afforded from nitrone 1b (50.0 mg, 0.262 mmol) and hydrazone 2g (91.3 mg, 0.524 mmol) at 70 °C for 24 h followed by column chromatography on silica gel (hexane/AcOEt = 4/1). A mixture of 3bg and 4bg was further purified by PTLC (hexane/AcOEt = 2/1) to afford trans-exo-3bg as a pale yellow oil, trans-endo-3bg as pale yellow with a small amount of impurity and trans-endo-4bg as a pale yellow oil with a small amount of impurity.
Compound trans-exo-3bg: 1H NMR (300 MHz, CDCl3) δ 7.58–7.25 (10H, m), 6.39 (1H, d, J = 5.1 Hz), 5.01 (1H, t, J = 6.0 Hz), 4.91 (1H, d, J = 10.2 Hz), 4.60 (1H, dd, J = 10.2, 3.3 Hz), 4.42–4.31 (1H, m), 4.36–4.13 (2H, m), 2.79 (6H, s); 13C NMR (75 MHz, CDCl3) δ 167.1, 136.5, 135.4, 129.2, 128.9, 128.8, 128.76, 128.74, 127.7, 82.5, 69.9, 68.0, 61.3, 56.9, 42.4 (several signals overlapped); IR (NaCl) 3031, 2953, 2859, 1751, 1455, 1217, 1051 cm−1; HRMS (ESI) m/z: Calcd for C21H23N3O3Na [M+Na]+ 388.1637, Found 388.1622.
Compound trans-endo-3bg: 1H NMR (400 MHz, acetone) δ 7.63–7.59 (2H, m), 7.50–7.45 (2H, m), 7.44–7.39 (2H, m), 7.39–7.32 (3H, m), 7.30–7.25 (1H, m), 6.47 (1H, d, J = 6.6 Hz), 4.64 (1H, d, J = 6.6 Hz), 4.54 (1H, dd, J = 9.9, 6.6 Hz), 4.46–4.37 (3H, m), 4.27 (1H, dd, J = 9.0, 6.6 Hz), 2.74 (6H, s); 13C NMR (150 MHz, acetone) δ 170.4, 140.2, 138.2, 129.7, 129.48, 129.47, 129.3, 129.1, 128.7, 128.2, 87.3, 70.3, 69.9, 66.0, 55.6, 42.6; IR (NaCl) 2924, 2855, 2790, 1751, 1456, 1396, 1317, 1225, 1040 cm−1; HRMS (ESI) m/z: Calcd for C21H23N3O3Na [M+Na]+ 388.1637, Found 388.1627.
Compound trans-endo-4bg: 1H NMR (600 MHz, CDCl3) δ 7.58–7.21 (10H, m), 6.65 (1H, d, J = 4.8 Hz), 5.58 (1H, d, J = 6.9 Hz), 4.86 (1H, dd, J = 10.2, 4.2 Hz), 4.80 (1H, d, J = 9.9 Hz), 4.38–4.21 (2H, m), 3.85–4.74 (1H, m), 2.86 (6H, s); 13C NMR (150 MHz, CDCl3) δ 167.8, 138.8, 135.3, 130.3, 128.9, 128.64, 128.55, 128.2, 127.9, 126.6, 81.7, 70.9, 67.9, 60.0, 57.5, 42.9; IR (NaCl) 2924, 2854, 2788, 1748, 1456, 1217, 1094, 1048 cm−1; HRMS (ESI) m/z: Calcd for C21H23N3O3Na [M+Na]+ 388.1637, Found 388.1633.

4.5. Synthesis of 5-acylisoxazolidine exo-3aa

(2R*,3R*,3aR*)-5-benzyl-3-methyl-4-oxohexahydro-2H-isoxazolo[2,3-a]pyrazine-2-carbaldehyde (trans-exo-3aa). To a solution of trans-exo-3ad (4.6 mg, 14.5 µmol) in THF (2.0 mL) were added 37% HCHO aq. (37 µL) and conc. HCl (36%, 29 µL) at 0 °C. After the reaction mixture was stirred at room temperature for 26 h, the reaction was quenched with water. The aqueous layer was extracted with CH2Cl2, and the organic layer was washed with brine. The resulting solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by PTLC (AcOEt) afforded trans-exo-3aa (3.0 mg, 75% yield) as a pale yellow oil. 1H NMR (300 MHz, CDCl3) δ 9.66 (1H, d, J = 1.5 Hz), 7.39–7.21 (5H, m), 4.77 (1H, d, J = 14.4 Hz), 4.50 (1H, d, J = 14.4 Hz), 4.11 (1H, d, J = 9.0 Hz), 3.98 (1H, dd, J = 4.8, 1.5 Hz), 3.72–3.59 (1H, m), 3.47–3.06 (4H, m), 1.30 (3H, d, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 201.3, 165.8, 136.2, 128.8, 128.2, 127.8, 86.8, 65.7, 50.1, 48.9, 43.4, 41.4, 16.1; IR (NaCl) 3393, 2926, 1636, 1496, 1456, 1340, 1286, 1029 cm−1; HRMS (ESI) m/z calcd for C15H18N2O3 [M]+ 274.1317, found 274.1318.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/reactions7020026/s1, 1H, 13C-NMR and NOESY spectrum.

Author Contributions

Conceptualization, Y.H.; methodology, Y.H.; validation, Y.M. and Y.H.; formal analysis, Y.M., Y.O. and S.Y.; investigation, Y.M., Y.O. and S.Y.; data curation, Y.M.; writing—original draft preparation, Y.M.; writing—review and editing, Y.H., O.T. and N.M.; supervision, Y.H. and N.M.; project administration, Y.H. and N.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

1H, 13C NMR, and NOESY spectra are provided in the Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
EIElectron ionization
ESIElectrospray ionization
HOMOHighest occupied molecular orbital
LUMOLowest unoccupied molecular orbital
NMRNuclear magnetic resonance
NOESYNuclear Overhauser effect spectroscopy
TBDPStert-Butyldiphenylsilane
THFTetrahydrofuran
TLCThin layer chromatography

Appendix A

The reaction of the corresponding dimethylhydrazone with nitrone 1a at 60 °C for 30 h did not afford the desired product and gave a complex mixture.

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Reactions 07 00026 sch001
Scheme 1. Regioselective inverse 1,3-dipolar cycloaddition of imines.
Scheme 1. Regioselective inverse 1,3-dipolar cycloaddition of imines.
Reactions 07 00026 sch001
Reactions 07 00026 g001
Figure 1. Structure determination by NOESY experiments.
Figure 1. Structure determination by NOESY experiments.
Reactions 07 00026 g001
Reactions 07 00026 g002
Figure 2. Stereoselectivity: Steric hindrance in transition states.
Figure 2. Stereoselectivity: Steric hindrance in transition states.
Reactions 07 00026 g002
Reactions 07 00026 g003
Figure 3. Steric hindrance between β-substituent and nitrone in transition states.
Figure 3. Steric hindrance between β-substituent and nitrone in transition states.
Reactions 07 00026 g003
Reactions 07 00026 sch002
Scheme 2. Reaction with lactone nitrone.
Scheme 2. Reaction with lactone nitrone.
Reactions 07 00026 sch002
Reactions 07 00026 sch003
Scheme 3. Dehydrazonation to give 5-acylisoxazolidine.
Scheme 3. Dehydrazonation to give 5-acylisoxazolidine.
Reactions 07 00026 sch003
Table 1. Cycloaddition reactions of nitrones with enal derivatives.
Table 1. Cycloaddition reactions of nitrones with enal derivatives.
Reactions 07 00026 i001
EntryXtrans:cis aTemp.TimeYield5-imino
:4-imino
(5-acyl:4-acyl)		exo:endo b
1O (2a)only transr.t.10 h91%
(0:0:0:66:34 c)		N.D.:>99only endo
2(E)-NOBn (2b)only trans90 °C24 h93%
(29:38:0:33:0)		67:3343:57
3(E)-NOTBDPS (2c)only trans70 °C7 h82%
(35:27:0:38:0)		62:3856:44
4(E)-NNMe2 (2d)85:1550 °C48 h91%
(63:19:11:7:0)		93:777:23
5(E)-NN(CH2)5 (2e)87:1360 °C19 hca. 95%
(53:26:12:9:0)		91:967:33
6(E)-NNi-Pr2 (2f)86:1450 °C24 hQuant
(68:20:12:0:0)		only 5-imino77:23
a Ratio of trans and cis isomers of the enal derivatives used for cycloaddition reactions. b Ratio of exo to endo isomers of the 4-acylisoxazolidines or the 5-trans-iminoisoxazolidines. c Partial isomerization from trans-endo-4aa to cis-endo 4aa was observed after the reaction.
Table 2. Effects of β-substituent.
Table 2. Effects of β-substituent.
Reactions 07 00026 i002
EntryRTemp.TimeYield5-imino:4-iminoendo:exo
1Ph (2g)90 °C48 h64%
(0:44:56)		44:56>99:N.D.
24-OMeC6H4 (2h)90 °C48 h80%
(0:56:44)		56:44>99:N.D.
3c-Hex (2i) *80 °C22 h62%
(trace:52:48)		52:48>99:trace
* E:Z = 87:13.
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Maeda, Y.; Hashimoto, Y.; Oshita, Y.; Yuhara, S.; Tamura, O.; Morita, N. Inverting the Regioselectivity of 1,3-Dipolar Cycloaddition Reaction Between Nitrones and Enal Derivatives. Reactions 2026, 7, 26. https://doi.org/10.3390/reactions7020026

AMA Style

Maeda Y, Hashimoto Y, Oshita Y, Yuhara S, Tamura O, Morita N. Inverting the Regioselectivity of 1,3-Dipolar Cycloaddition Reaction Between Nitrones and Enal Derivatives. Reactions. 2026; 7(2):26. https://doi.org/10.3390/reactions7020026

Chicago/Turabian Style

Maeda, Yuki, Yoshimitsu Hashimoto, Yuriko Oshita, Sayuri Yuhara, Osamu Tamura, and Nobuyoshi Morita. 2026. "Inverting the Regioselectivity of 1,3-Dipolar Cycloaddition Reaction Between Nitrones and Enal Derivatives" Reactions 7, no. 2: 26. https://doi.org/10.3390/reactions7020026

APA Style

Maeda, Y., Hashimoto, Y., Oshita, Y., Yuhara, S., Tamura, O., & Morita, N. (2026). Inverting the Regioselectivity of 1,3-Dipolar Cycloaddition Reaction Between Nitrones and Enal Derivatives. Reactions, 7(2), 26. https://doi.org/10.3390/reactions7020026

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