Synthesis of 4-Oxoisoxazoline N-Oxides via Pd-Catalyzed Cyclization

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Synthesis of 4‑Oxoisoxazoline N‑Oxides via Pd-Catalyzed Cyclization of Propargylic Alcohols with tert-Butyl Nitrite Kai-Wen Feng, Yong-Liang Ban, Pan-Feng Yuan, Wen-Long Lei, Qiang Liu,* and Ran Fang* State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 South Tianshui Road, Lanzhou 730000, P.R. China

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S Supporting Information *

ABSTRACT: A cyclization of propargylic alcohols with tertbutyl nitrite at room temperature in air was achieved using Pd(OAc)2 as catalyst. The first reported 4-oxoisoxazoline Noxides could be directly accessed from a range of multisubstituted propargylic alcohols in moderate to excellent yields under mild conditions. Density functional theory calculations indicated that the reaction proceeds through a palladiumcatalyzed NO2 addition that efficiently generates a ketoxime radical, which eventually produces 4-oxoisoxazoline N-oxide.

N

Table 1. Optimization of Reaction Conditionsa

itrogenous organic molecules play a crucial role in enriching the carbon-based natural world and are

Scheme 1. Protocol of the Synthesis of 4-Oxoisoxazoline NOxides

entry

cat. (mol %)

solvent

time (h)

TBN (equiv)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13c 14d

Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (10) Pd(OAc)2 (5) Pd(OAc)2 (2) Pd(OAc)2 (2) Pd(OAc)2 (2) Pd(OAc)2 (2) Pd(PPh3)4 (2) Pd(PPh3)2Cl2 (2) PdCl2 (2)

CH3CN THF CH2Cl2 CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

12 12 12 12 12 16 16 16 16 16 16 16 16 16

2.5 2.5 2.5 2.5 2.5 2.5 2.0 1.5 2.0 2.0 2.0 2.0 2.0 0

95 74 68 86 85 95 93 80 trace 16 67 0 75 37

Pd(OAc)2 (2) Pd(OAc)2 (2)

a

Reaction conditions: 1a (0.2 mmol), TBN (0.4 mmol), solvent (2 mL), at room temperature under air in a closed bottle. bYields of isolated products. cReaction exposed to the air. d2.0 equiv of NaNO2 and 2.0 equiv of CF3COOH instead of TBN.

prevalent in compounds investigated in the pharmaceutical industry,1 the agriculture industry,2 organic synthesis,3 and biological research.4 Moreover, aza-heterocyclic compounds, a class of representative nitrogenous compounds, have drawn extensive attention for their potential biological and pharmaceutical activities.5 In particular, isoxazoline N-oxides exhibit unique reactivity for the particular structure in this family and are well-known to be versatile building blocks in chemical synthesis.6 There are several methods for synthesizing isoxazoline Noxides on the basis of relevant literature. In general, isoxazoline N-oxides can be prepared from functionalized aliphatic nitro compounds via intramolecular O-alkylation.7 However, no general strategy can be used to afford the functionalized nitro © XXXX American Chemical Society

precursors. Thus, intermolecular connection synthesis strategies have been developed, and there are two main types: (1) formal [3 + 2] cascade approaches8 and (2) formal [4 + 1] annulation approaches.9 In addition, it is reported that βhydroxy ketoximes can be candidates to generate isoxazoline N-oxides, which undergo an intramolecular N−O coupling process by some additive oxidants.10 In this regard, although Received: March 5, 2019

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DOI: 10.1021/acs.orglett.9b00811 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 2. Reaction Scopea,b

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DOI: 10.1021/acs.orglett.9b00811 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Table 2. continued a

Reaction conditions: 1 (0.2 mmol), TBN (0.4 mmol), and Pd(OAc)2 (2.0 mol %) in CH3CN (2.0 mL) were stirred at room temperature under air in a closed bottle. bYields of isolated products. cThe amount of 1q is 0.1 mmol.

to air.11 Propargylic alcohols are widely researched for the excellent reactivity and abundant functional group transformations. 12 In recent years, many combinations of propargylic alcohols and CO2 have been developed, which ordinarily generate five-membered ring lactones.13 As a consequence, we envisioned that NO2 and propargylic alcohols can build isoxazoline N-oxide analogues. Herein, we report the first synthesis of 4-oxoisoxazoline N-oxides from propargylic alcohols and tert-butyl nitrite using Pd(OAc)2 as catalyst (Scheme 1). We initiated our investigations with cyclic propargylic alcohol 1a as the model substrate to react with TBN (Table 1). Considering both that TBN can release NO2 smoothly in air and the volatility of NO2, an acetonitrile solution dissolving 1a (1.0 equiv), TBN (2.5 equiv), and Pd(OAc)2 (0.1 equiv) in an air atmosphere vessel with a plug was designed. After 12 h of stirring under room temperature, 4-oxoisoxazoline N-oxide 2a was obtained in 95% yield. THF and CH2Cl2 were evaluated in this reaction (entries 2 and 3), which indicated CH3CN is the best candidate solvent. When Pd(OAc)2 was employed in a smaller amount (entries 4 and 5), the yields reduced by almost 10%. To our delight, a longer reaction time can improve the efficiency (entry 6). In addition, the amount of TBN could be decreased to 2.0 equiv with a negligible influence on the yields (entries 7 and 8). Several typical palladium catalysts were also studied for their efficiency (entries 9−11), and Pd(OAc)2 is still the best catalyst for the cyclization. Not surprisingly, no desired product could be obtained when Pd(OAc)2 was absent (entry 12) and the reaction in a bottle exposed in air gave lower yield than that in a closed bottle containing air (entry 13). We also used NaNO2 and CF3COOH instead of TBN to react with 1a and obtained 2a in a lower yield, which proved NO2 was the actual reagent (entry 14). With the optimized conditions in hand, we next investigated the substrate scope of this Pd-catalyzed synthesis of 4oxoisoxazoline N-oxides (Table 2). First, we tested sixmembered ring propargylic alcohols with different substitutions on the alkynyl moiety. In the case of n-butyl- and benzyloxymethyl-substituted alkynylcyclohexanols 1b and 1c, the system performed well and the corresponding products 2b and 2c were obtained in 84% and 43% yields, respectively. For phenyl-substituted alkynyl cyclohexanols, cyclizations with TBN afforded the desired products 2d−f in 65−96% yields. We were glad to see that the thienyl group had excellent compatibility in this approach, and 2g was isolated in 93% yield. While spiro-ring propargylic alcohol 1h is also an excellent substrate for this reaction, bridged-ring propargylic alcohol 1i reluctantly reacted with TBN under the standard conditions. Moreover, heterocyclic propargylic alcohol 1j and other sizes of cyclic propargylic alcohols 1k,l performed well, and the corresponding products were obtained in moderate to high yields. We also examined the scope of propargylic alcohols with phenyl and alkyl chain substitutions instead of the cycloalkyl moiety. As expected, annulations with TBN took place smoothly and delivered 4-oxoisoxazoline N-oxides 2m−o in good to high yields. In addition, heteroaromatics were tolerated well in the transformations, and cyclic products 2p

Scheme 2. Scaled-up Reaction of 1a and Reduction of 2a

Scheme 3. Biologically Active Compound 4 and Synthesis of Compound 9

Figure 1. Calculated reaction pathway for the cyclization.

various substituted isoxazoline N-oxides can be delivered, there is no report about 4-oxoisoxazoline N-oxide synthesis. It is well-known that tert-butyl nitrite (TBN) is used to serve as a NO source in various synthesis reactions. In fact, TBN can also release NO2 in reaction systems, especially when exposed C

DOI: 10.1021/acs.orglett.9b00811 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters and 2q were isolated in high yields. Last but not least, it should be mentioned that some special propargylic alcohols, such as terminal alkynes 1r−t, primary alcohol 1u, and secondary alcohol 1v, were incompatible with the reaction conditions. A gram-scale reaction of propargylic alcohol 1a (10 mmol) with TBN (25 mmol) was designed to demonstrate the inherent value of this transformation, and the desired product 2a was obtained in 71% yield. Additionally, 4-oxoisoxazoline N-oxide 2a could be readily converted into the corresponding isoxazoline 3a in good yield (Scheme 2). It is notable that 4oxoisoxazoline compounds derived from the present transformations are not only potentially bioactive but also excellent precursors to bioactive compounds. For instance, 4-oxoisoxazoline 9 could be easily transformed to compound 4, a CRAC (calcium release-activated calcium channels) modulator.14 To further extend the utility of this annulation reaction, we chose commercially available aniline 5 as the raw material to synthesize compound 9 in four steps (Scheme 3). After a diazotization, iodination, and Sonogashira cross-coupling sequence, aniline 5 was transformed to aromatic propargylic alcohol 7 in 76% yield. Subsequently, cyclization of the resulting alcohol 7 with TBN under standard conditions afforded 4-oxoisoxazoline N-oxide 8 in 80% yield. Finally, reduction of 8 with triethyl phosphite gave the desired 4oxoisoxazoline 9 in 50% yield. To gain some insight into the mechanism, density functional theory (DFT) calculations were implemented (Figure 1).15 First, propargylic alcohol 1a is activated by Pd(OAc)2 to form intermediate 10, and TBN releases NO2 into the vessel. Then, DFT calculations indicated that intermediate 10 undergoes an addition reaction to deliver intermediate 11 through TSa1, where C−N bond formation resulted from the N atom connecting with the methyl side alkyne C atom. That the activation energy of this process was lower than the energy of the other addition paths favored this view, and a value up to 20.8 kcal/mol revealed that this conversion was the ratedetermining step. Immediately, the generated nitro alkene intermediate 11 transformed to ketoxime radical 12 through a cyclic four-membered TS2, and Pd(OAc)2 was recovered at the same time. The O-centered ketoxime radical 12 behaves as N-centered radical 13,16 which could be nucleophilically attacked by the adjacent hydroxyl group. With the N−O bond-forming cyclization of radical 13 and the aid of t-BuO•, the desired product 2a was eventually obtained. In summary, we have developed a convenient strategy for the construction of 4-oxoisoxazoline N-oxides from propargylic alcohols and TBN mediated by Pd(OAc)2 catalysis. The system achieves cyclization of various propargylic alcohols with TBN in moderate to excellent yields under mild conditions. The resulting 4-oxoisoxazoline N-oxides can be easily transformed to 4-oxoisoxazolines which are found in a variety of biologically active molecules. As little known compounds, 4oxoisoxazoline N-oxides have unexplored potential in biologically active research, application of organic synthesis, and industry.

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Experimental procedures and detailed characterization data of all products (PDF) Accession Codes

CCDC 1898980−1898981 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Qiang Liu: 0000-0001-8845-1874 Ran Fang: 0000-0001-6804-6572 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (No. 21871123). REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00811. D

DOI: 10.1021/acs.orglett.9b00811 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b00811 Org. Lett. XXXX, XXX, XXX−XXX