Abstract
A method to synthesize 3-hydroxyquinoline N-oxides from ketones having a 2-nitrophenyl group at the α-position relative to the carbonyl group was developed. The substrates were easily prepared via a SNAr reaction or a Sonogashira coupling, and treatment with sodium tert-butoxide in dimethyl sulfoxide produced the corresponding quinoline N-oxides. The method was successfully applied to the total synthesis of aurachins A and B. On the basis of the quinoline N-oxide synthesis, related reactions of α-(2-nitrophenyl)ketones, including nitrone formation and photoinduced rearrangement, were also investigated. These investigations provided clues about the reaction mechanism, and the following mechanism for the quinoline N-oxide synthesis is proposed: Deprotonation of the α-position of α-(2-nitrophenyl)ketone with tert-butoxide generates an enolate, which reacts with a nitro group via single-electron transfer to form an α-hydroxyketone having a nitroso group. An intramolecular alkoxide-mediated hydride shift reduces the nitroso group, and condensation of the resultant hydroxylamine and diketone moieties produces a 3-hydroxyquinoline N-oxide.
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17.1 Discovery of the Quinoline N-Oxide Synthesis
We investigated a reaction of a compound that had ketone and 2-nitrobenzenesulfonamide (nosyl amide) moieties (Scheme 17.1). Upon treatment of compound 1 with potassium carbonate in dimethyl sulfoxide (DMSO) at 90 °C, Smiles rearrangement occurred. Thus, formation of enolate 2 under basic conditions, followed by the enolate attacking the electron-deficient benzene ring of the sulfonamide, led to Meisenheimer complex 3, which collapsed into ketone 4, which had a nitrophenyl group. Under these conditions, the sulfonamide was converted into an amine, which was reacted with the ketone, and the resultant enamine 5 was obtained as a product. Reduction of the nitro group of 5 with zinc in aqueous acetic acid produced tryptamine 6, an indole having a 2-aminoethyl group at the 3-position of the indole moiety. This two-step process produces tryptamines from ketones having a nosyl amide moiety, and we speculated that this process might be useful for the synthesis of indole alkaloids.
Investigation on tryptamine synthesis
The shortcoming of the process, at that time, was the low yield of the first step. To improve the yield, we investigated various basic conditions. When sodium tert-butoxide in dimethyl sulfoxide (DMSO) was used at room temperature, the starting material was smoothly consumed but the desired enamine 5 was not obtained. Instead, another compound (compound A) was obtained; analysis of this compound by electrospray ionization mass spectrometry (ESI–MS) showed that its molecular weight was the same as that of enamine 5 (m/z 337). Thus, under the conditions using sodium tert-butoxide, the Smiles rearrangement occurred to form aminoketone 4, which underwent a dehydrative transformation. IR spectroscopic analysis of compound A confirmed the presence of functional groups. The resultant IR spectrum unexpectedly showed the absence of peaks for both carbonyl and nitro groups.
We considered likely reactions after the Smiles rearrangement under these conditions to elucidate the structure of compound A. Deprotonation of the ketone by tert-butoxide would form enolate 7 (Scheme 17.2). Because the nitro group had to disappear, the enolate likely reacted with the nitro group as in an aldol condensation, during which water is eliminated, to form a C–N double bond. Enolization of the resultant ketone 8 would generate an aromatic compound. The structure that would be obtained is a 3-hydroxyquinoline N-oxide, which can explain the results of the MS and IR analyses showing m/z 337 and a lack of nitro and carbonyl groups, respectively. The structure, however, was so unfamiliar to us that we did not trust our assumptions. To determine whether related molecules were known, we searched a database (SciFinder). As a result, we found a natural product: aurachin B [1].
Discovery of the quinoline N-oxide synthesis
The 1H-NMR data reported for aurachin B in the literature are similar to those of our compound [2]. The chemical shift of the proton at the 8-position of the quinoline core in aurachin B was reported to be 8.75 ppm, whereas the corresponding peak in the 1H-NMR spectrum of our compound was observed at 8.76 ppm. We speculate that these peaks were substantially shifted downfield because of the influence of the N-oxide. After obtaining additional spectroscopic data, including 2D-NMR spectra, we concluded that compound A was a quinoline N-oxide.
Although intramolecular reactions of a nitro group with a carbanion have been reported to form quinoline N-oxides [3,4,5,6,7,8,9], reports on reactions of ketones that have a 2-nitrophenyl group are limited. Zaki and Iskander disclosed a reaction of ketoester 9 with sodium ethoxide to produce substituted naphthalene 10 in 1943 (Scheme 17.3) [10]. Loudon and Tennant pointed out in 1964 that the structure of the product should be a quinoline N-oxide [11].
A related reaction in the literature
17.2 Application of the Quinoline N-Oxide Synthesis and Total Synthesis of Aurachins a and B
Ketones having a 2-nitrophenyl group were easily prepared (Scheme 17.4). A SNAr reaction of 2-fluoronitrobenzene (11) with β-ketoesters and subsequent dealkoxycarbonylation produced ketones 12a [12, 13]. Alternatively, 2-alkynylnitrobenzenes 14, which were synthesized via Sonogashira coupling, could be converted into the requisite ketones 12b via addition of pyrrolidine onto the alkyne moiety, followed by acidic hydrolysis of the resultant enamines 15 [14]. Alkylation of ketones 12 with alkyl halides under basic conditions occurred selectively at the benzylic position (Scheme 17.5). Treatment of the resultant compounds 16 with sodium tert-butoxide in DMSO produced quinoline N-oxides 17 in moderate to good yields. Primary or secondary alkyl groups were introduced onto the 2- or 4-position of the quinoline N-oxides. A methoxy or nitro group on the benzene ring was tolerated in this transformation. Alkylation with farnesyl bromide, followed by treatment with sodium tert-butoxide in DMSO, afforded aurachin B in good yield (Scheme 17.6) [15]. When the alkylation was performed using epoxy iodide 18 in the presence of sodium hydride in N,N-dimethylformamide (DMF), the alkylation, the cyclization to form the quinoline N-oxide core, and cleavage of the epoxide proceeded sequentially to afford aurachin A in 38% yield.
Preparation of substrates for quinoline N-oxide synthesis
Substrate scope of quinoline N-oxide synthesis
Total syntheses of aurachins A and B
17.3 Mechanistic Insight into the Quinoline N-Oxide Synthesis
Starting from unexpected observations, we developed a quinoline N-oxide synthesis and successfully applied it to the synthesis of aurachins A and B. We were next interested in the mechanism of the reaction. One attractive idea involved an electrocyclic reaction (Scheme 17.7a). Under basic conditions, enolate 19 and/or 19’ would be formed via deprotonation; further deprotonation would generate dianion 20, which would undergo an electrocyclic reaction. Our observations, however, ruled out this possibility. Even when the reaction was performed with 0.5 equivalents of sodium tert-butoxide, the quinoline N-oxide formation occurred to afford the product in 49% yield, indicating that formation of the dianion was unlikely. In addition, the 2-nitrophenyl group could apparently not facilitate the second deprotonation because the appropriate conformations are disrupted by the steric repulsion of the nitro group with the substituent.
Discussion on reaction mechanism of quinoline N-oxide synthesis
These considerations led us to speculate that the reaction might proceed via the formation of enolate 19’, which would react with the nitro group to form a C–N bond (Scheme 17.7b). However, this idea has a serious problem. The benzylic position of the alkylated ketone (compound 16) is apparently highly acidic because of the carbonyl and 2-nitrophenyl groups. Indeed, the alkylation of ketone 12a occurred selectively at the benzylic position.
To confirm the acidity, we conducted deuteration experiments. Upon treatment of ketone 12a, which has no alkyl group at the benzylic position, with diisopropylamine in methanol-d4, deuteration selectively occurred at the benzylic position and was completed within 15 min. By contrast, deuteration of ketone 16a, which has an alkyl group at the benzylic position, under the same conditions proceeded much more slowly; only partial deuteration was observed even after 120 min. More notably, both α-positions of the ketone were almost equally deuterated, clearly showing that the acidity of the benzylic position changes upon the introduction of an alkyl group at the benzylic position. This behavior can be rationalized as follows (Scheme 17.8). In the absence of an alkyl group at the benzylic position, the ketone can adopt a conformation in which both the carbonyl and 2-nitrophenyl groups can activate the benzylic position. After the alkyl group is introduced at the benzylic position, the 2-nitrophenyl cannot adopt a conformation in which the 2-nitrophenyl group activates the benzylic position because of the steric repulsion between the alkyl and nitro groups. In the favorable conformation, the benzene ring and the C–H bond at the benzylic position are coplanar [16,17,18].
Conformational analysis
These results lead to the conclusion that deprotonation of the ketone occurs equally at both α-positions of the ketone. Deprotonation at the benzylic position might be a non-productive pathway, and deprotonation at the other α-position is followed by a reaction with the nitro group to form a C–N bond.
17.4 Nitrone Formation
The conclusion in Sect. 17.3 leads to a question: Does the reaction between the enolate and the nitro group occur without the proton at the benzylic position? The product of such a reaction was assumed to be a nitrone. We speculated that the reaction might support the mechanism of the quinoline N-oxide synthesis and therefore attempted it [19].
The requisite substrate was prepared as shown in Scheme 17.9. Sequential alkylations of 2-nitrophenylacetate 22 gave product 23, which had a quaternary carbon. A reduction–oxidation sequence afforded aldehyde 24, and an aldol reaction with tert-butyl propionate, followed by oxidation with Dess–Martin periodinane, gave ketoester 26. Cleavage of the tert-butyl group with trifluoroacetic acid (TFA) and subsequent decarboxylation by heating in toluene produced the requisite ketone 27.
Preparation of substrate for nitrone formation
Unfortunately, treatment of ketone 27 with sodium tert-butoxide in DMSO did not produce the desired nitrone; however, a reaction with sodium hydroxide in diluted methanol (1.25 mM) produced nitrone 28 in 71% yield, accompanied by the formation of N-hydroxyindolinone 29 in 17% yield (Scheme 17.10). Interestingly, when the reaction was run at a higher concentration (12.5 mM), nitrone 28 was only obtained in 8% yield and N-hydroxyindolinone 29 was obtained in 65% yield instead.
Formation of a nitrone and an N-hydroxyindolinone
17.5 Closer Consideration of the Reaction Mechanism
The results presented in Sect. 17.4 indicate that the enolate is capable of reacting with a nitro group. How does this reaction between the enolate and nitro group occur? There are two possible positions for the reaction of a nitro group with a nucleophile: N-attack or O-attack (Scheme 17.11). Although not fully conclusive, according to the reported results, O-attack, which occurs via single-electron transfer followed by coupling of the resultant radical and radical anion, is likely [20,21,22]. In our cases, the O-attack produces seven-membered intermediate 32, which is converted into α-hydroxyketone X with a nitroso group. For the further transformation of X, the nitroso aldol reaction, involving nucleophilic attack of the nitroso group by enolate 33 derived from the α-hydroxyketone under basic conditions, is a possible pathway. Subsequent elimination of a hydroxy group leads to the nitrone. However, deuteration experiments, in which α-hydroxyketone 34 was reacted under the same conditions for nitrone formation in methanol-d4, showed that formation of the enolate occurred only partially. This result indicates that the aforementioned nitroso aldol reaction is not a major pathway for forming the nitrone. Another plausible mechanism involves a hydride shift from the alkoxide to the nitroso group, forming 1,2-diketone 35 having a hydroxylamine moiety, whose condensation with the carbonyl group produces the nitrone.
Discussion on reaction mechanism of nitrone formation
Although the α-hydroxyketone could not be isolated or detected as an intermediate, isolation of N-hydroxyindolinone 29 under the same conditions supported formation of the α-hydroxyketone. A plausible mechanism for the formation of N-hydroxyindolinone 29 via the α-hydroxyketone is shown in Scheme 17.12. Nucleophilic attack on the carbonyl group by the nitrogen atom in the nitroso group, accompanied by C–C bond cleavage promoted by electron donation from the alkoxide anion, produces N-hydroxyindolinone 29. According to this mechanism, an aldehyde should be formed in the reaction mixture. When a 2-pyridylmethyl ketone (R' = 2-pyridyl) was used as a substrate, formation of the corresponding aldehyde 36 was detected. Using density functional theory (DFT) calculations, we successfully obtained the transition states for the N-hydroxyindolinone formation with appropriate activation barriers (+10.7 kcal/mol) [19].
Formation of N-hydroxyindolinone
17.6 Consideration of an Alternative Mechanism
We mentioned in Sect. 17.3 that deprotonation of the substrate at the benzylic position might be a nonproductive pathway. After investigating the nitrone formation, we realized that a mechanism starting from the deprotonation at the benzylic position could be drawn as shown in Scheme 17.13. Under this alternative mechanism, the reaction of enolate 19 with a nitro group gives α-hydroxyketone 38 having a nitroso group, which is attacked intramolecularly by an enolate to form a C–N bond. Subsequent elimination of a hydroxide ion and aromatization produce quinoline N-oxide 17.
Alternative reaction mechanism
To evaluate the feasibility of the alternative mechanism, we attempted a reaction of tert-butyl ketone 16b, which has only one α-proton at the benzylic position (Scheme 17.14) [23]. Photoirradiation of the tert-butyl ketone in methanol at −78 °C gave cyclic hydroxamate 44 in 83% yield. In general, photoirradiation of an o-alkylnitrobenzene induces oxygen transfer via hydrogen abstraction by the excited nitro group to produce a nitroso compound having a hydroxy group at the benzylic position [24, 24,25,26]. When tert-butyl ketone 16b was used as a substrate, α-hydroxyketone 38b having a nitroso group would be generated as an intermediate. Reaction of the α-hydroxyketone moiety with the nitroso group, like that of compound X, gave cyclic hydroxamate 44 via acyl transfer and hemiacetal formation. Upon treatment with sodium hydroxide in methanol, cyclic hydroxamate 44 was converted into benzoisoxazole 45.
Attempted reactions of an α-(2-nitrophenyl)ketone
Treatment of tert-butyl ketone 16b with sodium hydroxide in methanol afforded benzisoxazole 45 in 47% yield. The reaction of o-pentylnitrobenzene (46) did not give benzisoxazole 45 at all, ruling out deacylation of tert-butyl ketone 16b to form o-pentylnitrobenzene (46) as a reaction mechanism [27]. The reaction of enolate 19b with a nitro group in an O-attack manner would form α-hydroxyketone 38b. A subsequent sequence involving the acyl transfer, hemiacetal formation, and hydrolysis might produce benzisoxazole 45.
Photoirradiation of ethyl ketone 16a also produced, via α-hydroxyketone 38a, cyclic hydroxamate 44a in a comparable yield (Scheme 17.15). The formation of cyclic hydroxamates occurred even at −78 °C under neutral conditions. When the enolate is reacted with a nitro group in an O-attack manner at the benzylic position under the conditions for the quinoline N-oxides synthesis, the hydroxamate 44a or benzoisoxazole 45 might form. However, in the quinoline N-oxide synthesis, these products were not detected. These considerations and observations ruled out the reaction pathway involving O-attack at the benzylic position in the quinoline N-oxide synthesis.
Photoinduced rearrangement of an ethyl ketone
17.7 Conclusion
A method to synthesize 3-hydroxyquinoline N-oxides from ketones having a 2-nitrophenyl group at the α-position of the carbonyl group was developed. The reaction was unexpectedly discovered and was successfully applied to the synthesis of various quinoline N-oxides, including aurachins A and B. On the basis of the quinoline N-oxide synthesis, related reactions of α-(2-nitrophenyl)ketones, including nitrone formation and photoinduced rearrangement to afford cyclic hydroxamates, were also investigated. These investigations provided clues about the reaction mechanism, leading us to propose the following mechanism (Scheme 17.16). Deprotonation of the α-position of α-(2-nitrophenyl)ketone with tert-butoxide forms an enolate. Single-electron transfer from the enolate to the nitro group generates a radical and a radical anion, which are coupled to form a C–O bond. Subsequent cleavage of a N–O bond produces an α-hydroxyketone having a nitroso group. An alkoxide-mediated hydride shift reduces the nitroso group, and condensation of the resultant hydroxylamine and diketone moieties, followed by tautomerization, produces a 3-hydroxyquinoline N-oxide.
Quinoline N-oxide synthesis
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Acknowledgements
This work was supported by JSPS KAKENHI (JP17H01523) and by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research; BINDS) from the Japan Agency for Medical Research and Development (AMED) under Grant Number JP20am0101099 and JP22ama121044.
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Yokoshima, S. (2024). Construction of Quinoline N-Oxides and Synthesis of Aurachins A and B: Discovery, Application, and Mechanistic Insight. In: Nakada, M., Tanino, K., Nagasawa, K., Yokoshima, S. (eds) Modern Natural Product Synthesis. Springer, Singapore. https://doi.org/10.1007/978-981-97-1619-7_17
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