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Article

Synthesis of Novel s-Indacene-1,5-dione and Isoxazole Derivatives via NaNO2-Catalyzed/Involved Transformation of Cyclopentenone-MBH Acetates

by
Na Li
†,
Xiao-Tian Mo
†,
Min Li
,
Yi-Na Ma
and
Lin Jiang
*
National and Local Joint Engineering Research Center for Green Preparation Technology of Biobased Materials, School of Chemistry and Environment, Yunnan Minzu University, Kunming 650504, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Catalysts 2025, 15(2), 186; https://doi.org/10.3390/catal15020186
Submission received: 9 January 2025 / Revised: 10 February 2025 / Accepted: 14 February 2025 / Published: 17 February 2025
(This article belongs to the Section Catalysis in Organic and Polymer Chemistry)
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Abstract

:
A rapid synthesis of structurally novel s-indacene-1,5-dione and cyclopentanone-fused isoxazole derivatives in generally moderate yields was achieved through the NaNO2-catalyzed/involved transformation of cyclopentenone-MBH acetates. Under similar reaction conditions, two different reaction pathways were observed depending on the type of aryl substituent on MBH acetates. In the formation of s-indacene-1,5-diones, NaNO2 is proposed to act as a nucleophilic catalyst to initiate the stepwise dimeric cyclization/oxidative aromatization, whereas in the formation of isoxazole derivatives, it plays the role of nucleophilic reagent of (3+2) cycloaddition. Using NaNO2 as an inexpensive and readily available catalyst or reaction component, mild reaction conditions, operational simplicity, and metal-free transition are the main advantages of this work.

1. Introduction

Owing to the potential applications in polymers with unique optical and electronic properties, polynuclear transition metal complexes as well as biologically active compounds, molecules with s-indacene as the basic structural core, have captured the attention of the synthetic chemistry community [1,2]. For instance, bis-organogermanium compound A is used as a functional monomer in polymerization reactions to obtain organometallic materials [3]. s-indacene 1,5-dione B, having symmetrically substituted thiophene rings, displays thermally induced polymorphic transformations [4]. A nitrile derivative of s-indacene C possesses a high electron affinity, thus providing a candidate for π-conjugated molecular materials of the s-indacene system [5]. Sulfonylurea D exhibits prominent cytokine inhibitory activity [6] (Figure 1).
Tetrahydro-s-indacene-1,5-diones can be viewed as a practical synthon to incorporate s-indacene moiety into other complex structures by late-stage modification. However, very limited attention has been paid to its construction. A close inspection reveals that both the classic and modern synthetic approaches are rather rare, especially when it comes to such a scaffold not embedded into other ring-fused systems. Traditional methods for s-indacene-1,5-dione scaffold mainly rely on Friedel–Crafts reactions, by which the two fused cyclopentanone moieties can be built either simultaneously or stepwise [7,8]. Intramolecular Heck reactions provide another ring-closing method [9,10]. In addition, transition metal-catalyzed cyclocarbonylation and the [4+2] cycloaddition of arylacetylenes have been sporadically reported [11,12,13]. Despite existing achievements, studies in this field usually suffer from some limitations such as requiring sensitive and expensive reagents, harsh reaction conditions, and tedious work-up procedures.
Isoxazoles represent a class of five-membered N,O-containing heterocyclic compounds that occur widely in natural products and bioactive compounds. The intriguing biological activities such as antimicrobial, anticancer, analgesic, and anti-inflammation activities allow isoxazoles to be a privileged structural unit in medicinal and agricultural chemistry. In addition, isoxazoles are versatile intermediates in organic synthesis [14,15,16,17]. The cycloaddition of alkynes and nitrile oxides [18,19,20], transition metal-catalyzed cycloisomerization [21,22,23], and the conventionally used condensation reaction of β-dicarbonyl compounds with hydroxylamine [24,25] make up the main synthetic strategies to access to functionalized isoxazoles.
In the course of our ongoing interest in chemical transformations of Morita–Baylis–Hillman (MBH) adducts, we have reported the NaNO2-catalyzed synthesis of 2-methylene-3-cyclohexenones from cyclohexenone-MBH acetates [26]. As a continuation of this work, we wish to establish herein for the first time a substituent-controlled regioselective synthesis of structurally unprecedented tetrahydro-s-indacene 1,5-diones 2 and cyclopentanone-fused isoxazoles 3 via the NaNO2-catalyzed/involved transformation of cyclopentenone-MBH acetates (1, n = 0) (Scheme 1).

2. Results and Discussion

2.1. Optimization of Reaction Conditions

We started our trial by choosing cyclopentenone-MBH acetate 1a as a model substrate and NaNO2 as a catalyst and carrying out the reaction in DMF at 50 °C. Beyond our expectations, the tetrahydro-s-indacene-1,5-dione 2a was isolated in 35% yield (Table 1, entry 1). Being aware of this totally different reaction pathway from our previously reported results, we subsequently evaluated the effect of solvents, catalyst load, temperature, and so on with the aim of improving product yield. By keeping all other parameters unchanged, solvent screening revealed that a polar aprotic solvent such as DMF or DMSO proved to be pivotal, and this may be related to the enhanced nucleophilicity of -NO2− caused by a solvation effect (Table 1, entries 2–6). Next, additives were examined with DMF as a preferred choice of solvent, and NaHCO3 was found to be beneficial in increasing the yield to 52% (Table 1, entries 7–9). When a 4Å molecular sieve was added as a water scavenger, the yield could be slightly improved (Table 1, entry 10). Further efforts included altering the amount or the kind of catalyst, lowering the concentration of the substrate, and decreasing reaction temperature; however, these had no positive effect on boosting the yield (Table 1, entries 11–15). Hence, as depicted in Table 1, entry 10, conducting the reaction in DMF at 50 °C in the presence of 0.5 equiv. of NaNO2 as the catalyst combined with NaHCO3 and a 4Å molecular sieve as additives was regarded as the best-optimized reaction conditions presently.

2.2. Substrates Scope

With the optimal reaction conditions established, we subsequently investigated the efficacy of this protocol for the synthesis of s-indacene 1,5-dione derivatives 2 (Scheme 2, upper level). Generally, a range of cyclopentenone-MBH acetates 1 bearing an electron-donating group (EDG) on an aryl ring could react smoothly, delivering corresponding products 2b-e and 2i-l. Candidates like 2-furyl- or 2-thienyl-related MBH acetates could equally work well to produce 2m and 2n in relatively higher yields. When the substrates bearing an electron-withdrawing group (EWG) were examined, the outcomes became much more complex. An o-EWG made the corresponding substrate inert, whereas those with an m-halogen were converted into 2f-h in roughly equal yields. Interestingly, different reaction pathways were observed when the substrates with a p-EWG were tested. Compared with the formation of 1,5-dione 2o from p-Cl-substituted MBH acetate, p-Br-substituted substrate underwent a completely different reaction pathway to give rise to fused isoxazole 3p, albeit in low yields. We performed a rapid examination of the influence of the amount of NaNO2 on product yield and found that the maximum yield could be obtained on condition of increasing the amount of NaNO2 to 1.0 equiv. at the current stage. Being aware of this NaNO2-involved transformation route, MBH acetates in the same category, e.g., p-CN and p-NO2-bearing ones, were subjected to the reaction system, and corresponding isoxazoles 3q-t were furnished in 30–43% yields (Scheme 2, lower level). However, o-EWG-bearing substrates failed to produce corresponding products, and we deduced that this might be due to an obvious steric hindrance toward the benzyl site, thus making the direct nucleophilic attack by NO2− difficult to occur.
The structures of tetrahydro-s-indacene-1,5-dione 2i and cyclopentanone-fused isoxazole 3q were unambiguously confirmed by X-ray single-crystal diffraction analysis [27] (Figure 2).

2.3. Hypothetical Mechanism

Based on the experimental outcomes and earlier reports on using NaNO2 as a nucleophilic mediator [28,29], we proposed a plausible reaction mechanism. As indicated in Scheme 3, the reactions can follow two paths depending on the character of the substituent on the aryl moiety of MBH acetates 1. The reaction goes through path 1 when the aryl moiety is decorated with EDG(s), m-halogen, or p-Cl. In these cases, NO2− triggers an SN2′-type nucleophilic substitution at the β position of cyclopentenone moiety initially, yielding SN2′ adduct I after the liberation of AcO−. Next, Michael addition occurs between deprotonated II and neutral I, generating III-A after protonation. Subsequently, III-B, serving as deprotonated species of III-A, undergoes intramolecular Michael addition to produce III-C, featuring a six-membered ring. AcO− then neutralizes the neighboring proton of the nitro group, triggering the negative charge-driven twofold elimination of NO2− and completing the catalytic cycle. Finally, the so-formed cyclohexadiene intermediate IV aromatizes to s-indacene derivatives 2a-o via spontaneous aerobic oxidation.
In another scenario, when a strong EWG(s), e.g., Br, CN, or NO2 was located on the para position of the aryl moiety of MBH acetates, the inductive effect of aryl moiety seemed to make the benzyl position more electrophilic than the β site. Hence, direct SN2-substitution at the benzyl position dominantly occurs (path 2). In this situation, the rearrangement of the resulting intermediate V to VI followed by 6π-electrocyclization produces VII, which finally forms 3p-t upon the elimination of water (route a). To some extent, the conjecture on the shift in regioselectivity was proposed based on the experimental results of o-EWG-bearing substrates (route b).

3. Materials and Methods

3.1. General Information

Melting points were determined in open capillary tubes and were uncorrected. 1H NMR and 13C NMR spectra were recorded on a Bruker Advance III 400 MHz spectrometer (Bruker, Coventry, UK)with tetramethylsilane (TMS) as an internal reference and CDCl3 or DMSO-d6 as a solvent. Chemical shifts (δ) were given in parts per million (ppm) and the coupling constants (J) were in Hz. Infrared spectra were recorded on a Nicolet iS10 (Thermo Scientific, Waltham, MA, USA). High-resolution electrospray ionization mass spectrometry (ESI HRMS) was recorded on a Waters SYNAPT G2 (Waters, Manchester, UK). Cyclopentenone-MBH acetates 1 were prepared according to the literature procedure with slight modifications [30]. All chemicals were reagent-grade and used without purification as commercially available.

3.2. General Procedure for NaNO2-Catalyzed Synthesis of Tetrahydro-s-Indacene-1,5-diones

NaNO2 (13.8 mg, 0.2 mmol) was added to a solution of cyclopentenone-MBH acetates 1a-o (0.4 mmol), NaHCO3 (16.8 mg, 0.2 mmol), and 4 Å molecular sieve (50 mg) in DMF (4 mL), and this was stirred at 50 °C. After a full conversion, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic layer was successively washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate) to give products 2.

3.3. Characteristics of the Reaction Products 2a-o

4,8-Diphenyl-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2a). Yellow solid, 38.6 mg, 57% yield, mp. 260–263 °C. 1H NMR (400 MHz, CDCl3) δ 7.52–7.43 (m, 6H), 7.33–7.31 (m, 4H), 2.95–2.91 (m, 4H), 2.69–2.65 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 205.7, 153.9, 138.0, 137.4, 135.3, 128.8, 128.4, 128.1, 37.7, 24.4. IR (KBr): υ 2359, 2024, 1598, 1385, 1353, 1067 cm−1. ESI HRMS: calcd. for C24H18O2+Na [M+Na]+ 361.1204, found 361.1207.
4,8-Di-o-tolyl-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2b). Yellow solid, 22.7 mg, 31% yield, mp. 306–308 °C. 1H NMR (400 MHz, CDCl3) δ 7.38–7.28 (m, 6H), 7.13–7.10 (m, 2H), 2.95–2.86 (m, 2H), 2.71–2.62 (m, 6H), 2.07 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 205.9, 153.7, 138.0, 137.4, 135.6, 135.4, 130.2, 128.2, 128.1, 126.0, 37.4, 24.2, 19.9. IR (KBr): υ 2925, 1709, 1463, 1309, 1074, 763, 736 cm−1. ESI HRMS: calcd. for C26H22O2+Na [M+Na]+ 389.1517, found 389.1523.
4,8-Bis(2-methoxyphenyl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2c). Yellow solid, 38.3 mg, 48% yield, mp. 248–250 °C. 1H NMR (400 MHz, CDCl3) δ 7.46–7.42 (m, 2H), 7.22–7.15 (m, 2H), 7.09–7.04 (m, 4H), 3.77 (s, 6H), 2.97–2.80 (m, 4H), 2.66–2.63 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 205.9, 156.7, 154.2, 138.1, 134.0, 130.3, 129.7, 124.3, 120.7, 111.0, 55.7, 37.5, 24.1. IR (KBr): υ 2923, 1708, 1584, 1515, 1349, 844, 712 cm−1. ESI HRMS: calcd. for C26H22O4+H [M+H]+ 399.1596, found 399.1592.
4,8-Di-m-tolyl-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2d). Yellow solid, 24.9 mg, 34% yield, mp. 269–272 °C. 1H NMR (400 MHz, CDCl3) δ 7.39–7.35 (m, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.11 (s, 2H), 7.10 (d, J = 8.0 Hz, 2H), 2.93–2.90 (m, 4H), 2.67–2.64 (m, 4H), 2.42 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 205.8, 153.9, 138.1, 137.9, 137.3, 135.3, 129.4, 128.9, 128.2, 125.9, 37.7, 24.4, 21.7. IR (KBr): υ 2935, 1712, 1604, 1348, 1058, 793,700 cm−1. ESI HRMS: calcd. for C26H22O2+Na [M+Na]+ 389.1517, found 389.1521.
4,8-Bis(3-methoxyphenyl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2e). Yellow solid, 53.4 mg, 67% yield, mp. 309–311 °C. 1H NMR (400 MHz, CDCl3) δ 7.42–7.38 (m, 2H), 6.98 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0 Hz, 2H), 6.84 (s, 2H), 3.84 (s, 6H), 2.95–2.92 (m, 4H), 2.68–2.65 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 205.6, 159.6, 153.8, 137.8, 137.4, 136.7, 129.4, 121.2, 114.7, 113.4, 55.4, 37.7, 24.4. IR (KBr): υ 2918, 1703, 1606, 1225, 1044, 880, 784, 702 cm−1. ESI HRMS: calcd. for C26H22O4+K [M+K]+ 437.1155, found 437.1159.
4,8-Bis(3-chlorophenyl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2f). White solid, 27.7 mg, 34% yield, mp. 268–272 °C. 1H NMR (400 MHz, CDCl3) δ 7.44–7.42 (m, 4H), 7.31 (s, 2H), 7.22–7.18 (m, 2H), 2.94–2.91 (m, 4H), 2.73–2.70 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 205.3, 153.8, 137.4, 136.9, 136.8, 134.3, 129.7, 128.8, 128.4, 127.1, 37.6, 24.3. IR (KBr): υ 2922, 2354, 1704, 1594, 1293, 1067, 808, 697 cm−1. ESI HRMS: calcd. for C24H16Cl2O2+Na [M+Na]+ 429.0425, found 429.0431.
4,8-Bis(3-bromophenyl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2g). Yellow solid, 37.7 mg, 38% yield, mp. 262–265 °C.1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.0 Hz, 2H), 7.46 (s, 2H), 7.38–7.34 (m, 2H), 7.24 (d, J = 8.0 Hz, 2H), 2.93–2.89 (m, 4H), 2.70–2.66 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 205.2, 153.8, 137.4, 137.1, 136.6, 131.6, 131.2, 129.9, 127.5, 122.4, 37.5, 24.3. IR (KBr): υ 2924, 1633, 1591, 1384, 1353, 1185, 1073 cm−1. ESI HRMS: calcd. for C24H16Br2O2+Na [M+Na]+ 516.9415, found 516.9420.
4,8-Bis(3-iodophenyl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2h). Yellow solid, 41.3 mg, 35% yield, mp. 322–323 °C. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.0 Hz, 2H), 7.66 (s, 2H), 7.29–7.21 (m, 4H), 2.95–2.88 (m, 4H), 2.70–2.67 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 205.3, 153.8, 137.4, 137.4, 137.2, 137.2, 136.6, 130.1, 128.2, 94.2, 37.6, 24.3. IR (KBr): υ 2922, 2024, 1705, 1588, 1451, 1308, 1067, 800, 692 cm−1. ESI HRMS: calcd. for C24H16I2O2+Na [M+Na]+ 612.9137, found 612.9142.
4,8-Di-p-tolyl-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2i). Yellow solid, 26.4 mg, 36% yield, mp. 289–291 °C. 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 4H), 7.21 (d, J = 8.0 Hz, 4H), 2.94–2.91 (m, 4H), 2.68–2.64 (m, 4H), 2.45 (s, 6H). 13C NMR (100 MHz, CDCl3) δ 205.9, 154.1, 137.9, 137.8, 137.4, 132.3, 129.1, 128.8, 37.8, 24.4, 21.6. IR (KBr): υ 2924, 2025, 1708, 1601, 1359, 1068, 774 cm−1. ESI HRMS: calcd. for C26H22O2+Na [M+Na]+ 389.1517, found 389.1524.
4,8-Bis(4-methoxyphenyl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2j). Yellow solid, 53.4 mg, 67% yield, mp. 326–327 °C. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 8.0 Hz, 4H), 6.94 (d, J = 12.0 Hz, 4H), 3.80 (s, 6H), 2.87–2.84 (m, 4H), 2.60–2.58 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 206.0, 159.4, 154.3, 137.5, 137.4, 130.2, 127.3, 113.8, 55.4, 37.8, 24.4. IR (KBr): υ 2962, 1886, 1712, 1610, 1522, 1244, 1029, 831 cm−1. ESI HRMS: calcd. for C26H22O4+H [M+H]+ 399.1596, found 399.1599.
4,8-Bis(3,4-dimethoxyphenyl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2k). Yellow solid, 45.9 mg, 50% yield, mp. 305–307 °C. 1H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 2H), 6.82 (s, 2H), 3.95 (s, 6H), 3.88 (s, 6H), 2.97–2.94 (m, 4H), 2.69–2.66 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 205.8, 154.3, 148.9, 148.8, 137.7, 137.4, 127.6, 121.4, 112.5, 111.0, 56.1, 56.0, 37.8, 24.5. IR (KBr): υ 2930, 2025, 1709, 1586, 1467, 1244, 1022, 799 cm−1. ESI HRMS: calcd. for C28H26O6+Na [M+Na]+ 481.1627, found 481.1631.
4,8-Di(naphthalen-2-yl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2l). Yellow solid, 33.3 mg, 38% yield, mp. 240–241 °C. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 12.0 Hz, 2H), 7.96–7.94 (m, 2H), 7.91–7.88 (m, 2H), 7.84 (s, 2H), 7.58–7.52 (m, 4H), 7.46 (d, J = 8.0 Hz, 2H), 3.05–2.92 (m, 4H), 2.72–2.68 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 205.8, 154.2, 137.9, 137.6, 133.3, 133.1, 132.9, 128.3, 128.0, 127.9, 127.8, 127.1, 126.4, 126.3, 37.7, 24.6. IR (KBr): υ 2923, 2025, 1709, 1591, 1364, 1071, 805, 741 cm−1. ESI HRMS: calcd. for C32H22O2+K [M+K]+ 477.1257, found 477.1264.
4,8-Di(furan-2-yl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2m). Yellow solid, 45.8 mg, 72% yield, mp. 236–239 °C. 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 2H), 6.95 (d, J = 4.0 Hz, 2H), 6.61–6.59 (m, 2H), 3.25–3.22 (m, 4H), 2.77–2.75 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 204.9, 154.4, 147.5, 143.2, 137.4, 126.3, 113.7, 111.5, 37.8, 25.6. IR (KBr): υ 2926, 2360, 1703, 1491, 1434, 1286, 1069, 922, 750 cm−1. ESI HRMS: calcd. for C20H14O4+H [M+H]+ 319.0970, found 319.0975.
4,8-Di(thiophen-2-yl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2n). Yellow solid, 42.1 mg, 60% yield, mp. 264–265 °C. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 4.0 Hz, 2H), 7.19–7.17 (m, 2H), 7.10 (d, J = 4.0 Hz, 2H), 3.07–3.04 (m, 4H), 2.73–2.70 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 204.9, 155.4, 138.3, 134.5, 131.3, 128.1, 127.2, 126.9, 37.6, 24.6. IR (KBr): υ 2949, 2360, 1709, 1527, 1407, 1287, 849, 709 cm−1. ESI HRMS: calcd. for C20H14O2S2+Na [M+Na]+ 373.0333, found 373.0337.
4,8-Bis(4-chlorophenyl)-2,3,6,7-tetrahydro-s-indacene-1,5-dione (2o). White solid, 26.9 mg, 33% yield, mp. 281–284 °C. 1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.0 Hz, 4H), 7.25 (d, J = 8.0 Hz, 4H), 2.93–2.90 (m, 4H), 2.70–2.67 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 205.5, 153.9, 137.4, 137.0, 134.3, 133.5, 130.3, 128.7, 37.7, 24.4. IR (KBr): υ 2922, 2360, 1716, 1596, 1355, 1066, 817 cm−1. ESI HRMS: calcd. for C24H16Cl2O2+Na [M+Na]+ 429.0425, found 429.0431.

3.4. General Procedure for NaNO2-Involved Synthesis of Cyclopentanone-Fused Isoxazoles

DMF (4 mL) was added to a mixture of cyclopentenone-MBH acetates 1p-t (0.4 mmol), NaNO2 (27.6 mg, 0.4 mmol), NaHCO3 (16.8 mg, 0.2 mmol), and 4Å molecular sieve (50 mg). The solution was stirred at 50 °C. After completion, the reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The organic layer was successively washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Further purification by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate) afforded the pure products 3.

3.5. Characteristics of the Reaction Products 3p-t

3-(4-Bromophenyl)-5,6-dihydro-4H-cyclopenta[d]isoxazol-4-one (3p). Yellow solid, 50.1 mg, 45% yield, mp. 184–187 °C. 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 12.0 Hz, 2H), 3.30–3.27 (m, 2H), 3.15–3.12 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 197.9, 191.2, 157.0, 132.5, 130.0, 126.0, 125.9, 124.0, 44.5, 21.8. IR (KBr): υ 2831, 2025, 1700, 1596, 1365, 1069, 829 cm−1. ESI HRMS: calcd. for C12H8BrNO2+Na [M+Na]+ 299.9636, found 299.9639.
4-(4-Oxo-5,6-dihydro-4H-cyclopenta[d]isoxazol-3-yl)benzonitrile (3q). White solid, 28.7 mg, 32% yield, mp. 219–220 °C. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 3.34–3.32 (m, 2H), 3.20–3.18 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 198.3, 191.0, 156.4, 133.0, 131.2, 129.1, 124.1, 118.3, 114.8, 44.5, 21.9. IR (KBr): υ 2226, 1710, 1591, 1562, 1459, 1404, 1340, 1041, 860, 839 cm−1. ESI HRMS: calcd. for C13H8N2O2+H [M+H]+ 225.0664, found 225.0668.
3-(4-(Methylsulfonyl)phenyl)-5,6-dihydro-4H-cyclopenta[d]isoxazol-4-one (3r). Yellow solid, 47.7 mg, 43% yield, mp. 229–231 °C. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 8.0 Hz, 2H), 8.06 (d, J = 8.0 Hz, 2H), 3.35–3.33 (m, 2H), 3.21–3.19 (m, 2H), 3.09 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 198.3, 191.0, 156.3, 142.8, 132.2, 129.5, 128.3, 124.2, 44.5 (×2), 21.9. IR (KBr): υ 3004, 2362, 1708, 1590, 1461, 1150, 850, 776 cm−1. ESI HRMS: calcd. for C13H11NO4S+Na [M+Na]+ 300.0306, found 300.0308.
3-(4-Nitrophenyl)-5,6-dihydro-4H-cyclopenta[d]isoxazol-4-one (3s). White solid, 29.3 mg, 30% yield, mp. 221–222 °C. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.0 Hz, 2H), 8.32 (d, J = 12.0 Hz, 2H), 3.35–3.33 (m, 2H), 3.21–3.19 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 197.4, 190.0, 155.0, 148.4, 131.9, 128.5, 123.4, 123.1, 43.5, 20.9. IR (KBr): υ 3081, 2026, 1708, 1584, 1515, 1349, 844, 712 cm−1. ESI HRMS: calcd. for C12H8N2O4+Na [M+Na]+ 267.0382, found 267.0388.
3-(3,4-Dichlorophenyl)-5,6-dihydro-4H-cyclopenta[d]isoxazol-4-one (3t). White solid, 46.1 mg, 43% yield, mp. 191–192 °C. 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 8.08 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 3.31–3.28 (m, 2H), 3.17–3.15 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 198.1, 191.0, 155.5, 135.7, 133.6, 131.3, 130.0, 128.0, 126.9, 123.9, 44.5, 21.8. IR (KBr): υ 2924, 2024, 1706, 1460, 1187, 1081, 968, 723 cm−1. ESI HRMS: calcd. for C12H7Cl2NO2+Na [M+Na]+ 289.9752, found 289.9757.

4. Conclusions

In summary, we have demonstrated a facile construction of tetrahydro-s-indacene-1,5-diones and cyclopentanone-fused isoxazoles using cyclopentenone-MBH acetates as a synthetic platform and NaNO2 as an inexpensive catalyst or reagent. Depending on the substituent pattern on the aryl ring, the nucleophilic substitution of NO2− may take the form of SN2′- or SN2-type, and the corresponding intermediate, respectively, undergoes a sequential Michael addition-driven dimeric cyclization followed by oxidative aromatization to produce s-indacene derivatives or experiences intramolecular conversion with (3+2) cycloaddition as a critical step to produce cyclopentanone-fused isoxazoles. This protocol meets the swift rise in demand for new synthetic methods or complex molecule skeletons using inexpensive and readily available substrates and catalysts/reagents under mild transformation conditions and without the aid of a metallic catalyst. Though the yields are still synthetically dissatisfactory currently, these structurally interesting compounds might be promising for potential drug discovery or organic material usage.

Supplementary Materials

The following supporting information can be downloaded at https://www.mdpi.com/article/10.3390/catal15020186/s1: Synthesis and characterization data of cyclopentenone-MBH acetates 1. Copies of 1H NMR and 13C NMR spectra. Structural and other crystallographic details on data collection and refinement for compounds 2i and 3q.

Author Contributions

Investigation, N.L. and X.-T.M.; writing—original draft preparation, N.L.; methodology, X.-T.M.; formal analysis, M.L.; resources, Y.-N.M.; writing—review and editing, funding acquisition, and supervision, L.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research was founded by the National Natural Science Foundation of China (22161051, 21302163) and Yunnan XingDian Youth Talent Support Program (XDYC-QNRC-2022-0468).

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Conflicts of Interest

The authors declare no conflicts of interest.

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Catalysts 15 00186 g001
Figure 1. Classic molecule materials and bioactive compounds based on s-indacene framework.
Figure 1. Classic molecule materials and bioactive compounds based on s-indacene framework.
Catalysts 15 00186 g001
Catalysts 15 00186 sch001
Scheme 1. Reactions of 2-cycloenone-MBH acetates with NaNO2.
Scheme 1. Reactions of 2-cycloenone-MBH acetates with NaNO2.
Catalysts 15 00186 sch001
Catalysts 15 00186 sch002
Scheme 2. Substrate scope of tetrahydro-s-indacene-1,5-diones/isoxazoles. Reaction conditions: 1 (0.4 mmol), NaNO2 (13.8 mg, 0.2 mmol), NaHCO3 (33.6 mg, 0.4 mmol), and 4Å molecular sieve (MS, 50 mg) were stirred in DMF (4 mL) at 50 °C; isolated yield. a NaNO2 (27.6 mg, 0.4 mmol) was used.
Scheme 2. Substrate scope of tetrahydro-s-indacene-1,5-diones/isoxazoles. Reaction conditions: 1 (0.4 mmol), NaNO2 (13.8 mg, 0.2 mmol), NaHCO3 (33.6 mg, 0.4 mmol), and 4Å molecular sieve (MS, 50 mg) were stirred in DMF (4 mL) at 50 °C; isolated yield. a NaNO2 (27.6 mg, 0.4 mmol) was used.
Catalysts 15 00186 sch002
Catalysts 15 00186 g002
Figure 2. (a) Crystal structure of 2i (CCDC 2383585). (b) Crystal structure of 3q (CCDC 2383586). Ellipsoids are displayed at the 50%—probability level.
Figure 2. (a) Crystal structure of 2i (CCDC 2383585). (b) Crystal structure of 3q (CCDC 2383586). Ellipsoids are displayed at the 50%—probability level.
Catalysts 15 00186 g002
Catalysts 15 00186 sch003
Scheme 3. Plausible reaction mechanism.
Scheme 3. Plausible reaction mechanism.
Catalysts 15 00186 sch003
Table 1. Optimizing reaction parameters of NaNO2-catalyzed synthesis of 2a a.
Table 1. Optimizing reaction parameters of NaNO2-catalyzed synthesis of 2a a.
Catalysts 15 00186 i001
EntrySolventNaNO2 (equiv.)AdditiveTime (h)Yield (%) b
1DMF0.5/935
2DMSO0.5/928
3EtOH0.5/24N.R.
4Toluene0.5/24N.R.
5EtOH0.5/24N.R.
6MeCN0.5/24N.R.
7DMF0.5K2CO3842
8DMF0.5NaHCO3952
9DMF0.5LiBF4938
10DMF0.5NaHCO3/MS957
11DMF0.6NaHCO3/MS651
12DMF0.4NaHCO3/MS948
13 cDMF0.5NaHCO3/MS1056
14 dDMF0.5NaHCO3/MS1240
15 eDMF0.5NaHCO3/MS948
a Reaction conditions: unless otherwise noted, 1a (92.1 mg, 0.4 mmol), NaNO2 (13.8 mg, 0.2 mmol), additive (0.2 mmol), and 4Å molecular sieve (MS, 50 mg) were stirred in solvent (4 mL) at 50 °C; b isolated yield; c 8 mL of solvent; d at 40 °C; e KNO2 was used.
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Li, N.; Mo, X.-T.; Li, M.; Ma, Y.-N.; Jiang, L. Synthesis of Novel s-Indacene-1,5-dione and Isoxazole Derivatives via NaNO2-Catalyzed/Involved Transformation of Cyclopentenone-MBH Acetates. Catalysts 2025, 15, 186. https://doi.org/10.3390/catal15020186

AMA Style

Li N, Mo X-T, Li M, Ma Y-N, Jiang L. Synthesis of Novel s-Indacene-1,5-dione and Isoxazole Derivatives via NaNO2-Catalyzed/Involved Transformation of Cyclopentenone-MBH Acetates. Catalysts. 2025; 15(2):186. https://doi.org/10.3390/catal15020186

Chicago/Turabian Style

Li, Na, Xiao-Tian Mo, Min Li, Yi-Na Ma, and Lin Jiang. 2025. "Synthesis of Novel s-Indacene-1,5-dione and Isoxazole Derivatives via NaNO2-Catalyzed/Involved Transformation of Cyclopentenone-MBH Acetates" Catalysts 15, no. 2: 186. https://doi.org/10.3390/catal15020186

APA Style

Li, N., Mo, X.-T., Li, M., Ma, Y.-N., & Jiang, L. (2025). Synthesis of Novel s-Indacene-1,5-dione and Isoxazole Derivatives via NaNO2-Catalyzed/Involved Transformation of Cyclopentenone-MBH Acetates. Catalysts, 15(2), 186. https://doi.org/10.3390/catal15020186

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