Palladium-catalyzed C(sp³)–H nitrooxylation of masked alcohols

Abstract

A palladium-catalyzed β-C(sp³)–H nitrooxylation of aliphatic alcohols with AgNO₂ is reported. An 8-formylquinoline-derived oxime is installed as an exo-type directing group for sp³ C–H activation and selectfluor acts as the oxidant. The reaction tolerates a variety of functional groups and shows good selectivity for β-C–H nitrooxylation of alcohols.

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Introduction

Nitrate esters are of significant interest to synthetic chemists because they are widespread in pharmaceuticals and energetic materials.¹ Examples include vasodilators, such as glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN), postcoital antifertility agents, antidiabetes agents and so on (Scheme 1a).² The classical ways to prepare nitrate esters are mainly based on two strategies: one is the nitration of alcohols using a mixture of HNO₃/H₂SO₄,^1a,3 which causes pollution to the environment. The other is the reaction of a suitable alkyl halide with silver nitrate.⁴ Recently, a variety of new methods have been developed, including nucleophilic displacement,^1a,4a,b,5 ring opening of epoxides,^1a,6 alkene difunctionalization,⁷ diazo compound trapping⁸ and radical based hydrogen-atom-transfer (HAT) reactions.⁹ A photocatalytic approach has also been reported with the help of a novel high-valent iodine derivative.¹⁰ Despite the successes achieved in the above-mentioned methods, methods to synthesize organic nitrates in a more efficient and straightforward way are still needed.

Scheme 1 Pharmaceuticals containing the nitrate group, C–H nitrooxylation reactions and C–H oxidation of alcohols.

The strategy of transition metal catalyzed C–H activation has become more and more popular in synthetic chemistry due to its high atom economy and selectivity particularly towards unreactive C–H bonds. Lots of studies on palladium catalyzed C–O bond formation through C–H activation have been reported, mainly including acyloxylation, alkoxylation, or sulfonyloxylation of different substrates.¹¹ In 2020, the Shi group reported the first C(sp³)–H nitrooxylation of carboxylic acids assisted by a bidentate 2-pyridinylisopropyl (PIP) directing group (Scheme 1b).¹² Recently, we reported a palladium-catalyzed β-C(sp³)–H nitrooxylation of ketones and amides using practical oxidants (Scheme 1b).¹³ As far as we know, the direct C(sp³)–H nitrooxylation of alcohols has never been reported via C–H activation.^9b

Alcohols are common and ubiquitous structural motifs found in small molecules to complex natural products and materials. The direct C–H bond conversion of alcohols to high value-added molecules is always an attractive choice in synthetic chemistry.¹⁴ Various auxiliaries on alcohols have been discovered to promote different C–C and C–X (X = O, N, F and so on) bond formations.¹⁵ In terms of C–O bond formation, the Dong group developed β-C(sp³)–H acetoxylation^15a and later sulfonyloxylation^15b of oxime-masked alcohols via a five-membered exo-palladacycle intermediate. The method was then extended to synthesize cyclic ethers of different ring sizes using a pendant alcohol as an internal nucleophile.^15c The Xu group also reported the acetoxylation on primary methyl, methylene, and benzylic C(sp³)–H bonds of alcohol using a different bidentate auxiliary (Scheme 1c).^15d Inspired by the above successes, we postulated that the β-C(sp³)–H nitrooxylation of alcohols could be achieved using an appropriate exo-oxime directing group (Scheme 1d).

Results and discussion

We started to verify the hypothesis with oxime-derived 2-butanol (1a) as the initial substrate. Fortunately, the desired product 2a was obtained in 62% yield using AgNO₂ as the nitrate source (entry 1, Table 1). Other commonly used nitrate reagents were also screened (entries 2–5). Surprisingly, AgNO₃ was less efficient than AgNO₂. Then, we explored the efficiency of different aldoxime groups (entries 6–8). DG₁ was proved to be the best. Many oxidants were used to improve the yield (entries 9–11), and selectfluor showed better oxidation performance. The addition of 1.0 equiv. of tetrabutyl ammonium hydrogen sulfate (TBAHS) improved the yield to 68% (entry 12). Other phase transfer catalysts were also screened as additives for the reaction, but none of them showed better performance than TBAHS (Table 1, entries 13–15).

Table 1 Optimization of reaction conditions^a,b

Entry	DG	Nitrate reagent	Oxidant	Additive	Yield^b [%]
a Reaction conditions: 1a (0.1 mmol), Pd(OAc)2 (10 mol%), nitrate reagent (3.0 equiv.), oxidant (1.5 equiv.), additive (1.0 equiv.), DCE (1.5 mL), 80 °C, air, 18 h. b Isolated yield.
1	DG1	AgNO2	Selectfluor	—	62
2	DG1	AgNO3	Selectfluor	—	34
3	DG1	TBN	Selectfluor	—	Trace
4	DG1	Al(NO3)3·9H2O	Selectfluor	—	Trace
5	DG1	Fe(NO3)3·9H2O	Selectfluor	—	Trace
6	DG2	AgNO2	Selectfluor	—	Trace
7	DG3	AgNO2	Selectfluor	—	19
8	DG4	AgNO2	Selectfluor	—	0
9	DG1	AgNO2	BQ	—	0
10	DG1	AgNO2	NFSI	—	34
11	DG1	AgNO2	AgF	—	31
12	DG1	AgNO2	Selectfluor	Bu4NHSO4(TBAHS)	68
13	DG1	AgNO2	Selectfluor	Me4NHSO4	66
14	DG1	AgNO2	Selectfluor	(NH4)2SO4	48
15	DG1	AgNO2	Selectfluor	NH4OAC	49

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With the optimized conditions in hand, we then explored the scope of the alcohol substrates (Table 2). A variety of nitrooxylation products could be achieved in moderate to excellent yields and with good selectivity for primary β-methyl groups. Various secondary and tertiary aliphatic alcohols with different alkyl chain lengths (2a–2d), tertiary alkyl groups (isopropyl, 2f–2g) and cyclic alkyl groups (cyclohexyl, 2h, and cyclopentyl, 2i) were smoothly nitrooxylated. The di-nitrooxylation product (2e′) was observed with the substrate containing three β-methyl groups, while only the mono-nitrooxylation product (2d) was isolated for the substrate containing two β-methyl groups. For phenyl containing alcohol substrates, nitrooxylation products were obtained in moderate yields (2j–2k) without any C–H functionalization or substitution on the phenyl ring. Methoxy (2l), chloro (2m) and ester (2n–2w) groups were all compatible in the nitrooxylation reaction. Different substituents on the aryl ester groups (2n–2s) were allowed in the reaction. Substrates containing naphthyl ester (2t), styrenyl ester (2u), thiophenyl ester (2v) and cyclopropyl ester (2w) all gave moderate to good yields.

Table 2 Scope of aliphatic alcohols^a,b

a Reaction conditions: substrate (0.1 mmol), AgNO₂ (3.0 equiv.), Pd(OAc)₂ (10 mol%), selectfluor (1.5 equiv.), TBAHS (1.0 equiv.), DCE (1.5 mL), 80 °C, 18 h. b All yields are isolated yields. c The di-nitrooxylation product 2e′ was isolated in 23% yield.

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The nitrate group in the products could be easily converted into other functional groups through substitution reactions. For example, the reaction with NaN₃ converted the alkyl nitrate to an alkyl azide (Scheme 2).^9a The aldoxime directing group could be efficiently removed via hydrogenation with commercial Pd/C to deliver 1,2-diol and 1,2-amino alcohol which are important structural motifs in organic synthesis.^15b

Scheme 2 The conversion of alkyl nitrate and the synthesis of 1,2-diol and 1,2-amino alcohol.

Based on our previous work and literature reports,^12,13,15b we have proposed a putative Pd(II)/Pd(IV) catalytic cycle for the nitrooxylation reaction (Scheme 3). Substrate coordination followed by C–H bond cleavage gives the bicyclic palladacycle A. The attempt to trap this intermediate to get a stable crystallographic structure failed. Selectfluor could oxidize Ag(I) to Ag(III), which may undergo single electron transfer (SET) to give NO₂ radicals.^16,17 The NO₂ radical could dimerize to form the NO⁺NO₃⁻ ion pair,¹⁸ which could oxidize the Pd(II) species A to give the Pd(IV) species B. The nitrosyl-organopalladium(IV) complex B could deliver 2a directly via reductive elimination (the nitrooxylation reaction gave 34% yield of the desired product under a N₂ atmosphere, see the ESI†) or react with O₂ to afford the O-bound nitrate complex C.¹⁹ The more reactive Pd(IV) intermediate C could then undergo reductive elimination to provide 2a.

Scheme 3 Plausible mechanism.

Conclusions

We have developed a palladium-catalyzed direct alcohol C(sp³)–H nitrooxylation under mild reaction conditions. This protocol was enabled by using selectfluor as the oxidant and AgNO₂ as the nitrate source. The reaction shows excellent chemoselectivity, functional group tolerance, and a broad substrate scope. The method provides a new synthetic strategy for the construction of C–O bonds via transition metal catalysis.

Author contributions

Y. X. and R.-B. Z. contributed equally to this work.

Conflicts of interest

The authors declare no competing financial interest.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC) (Grant No. 21772092 and 22075144). We thank Y.-H. Liu and T.-T. Zhao for preliminary studies on nitrooxylation of alcohols.

References

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d2ob01919a

‡ These authors contributed equally to this work.

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