Palladium catalyzed C–H bond acetoxylation: isoxazolinyl as a directing group

Abstract

Pd(OAc)₂-catalyzed acetoxylations of 3-aryl or 3-alkyl groups mounted on a 2-isoxazoline ring were studied. Ortho-selective C–H bond activation directed by an isoxazolinyl group was realized. 2-Isoxazoline rings without and with one or two alkyl substituents in the 5-position were effective directing groups. The substituent effect on reactivity and regioselectivity was examined. The acetoxylation was applied to the synthesis of useful intermediates.

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C–H bond functionalization catalyzed by transition metals is experiencing a renaissance. Over the past decade, numerous reactions commencing with a key C–H bond activation step have been developed.¹ Pd(II), Rh(III) and Ru(II) were among the most often studied transition metals in C–H bond functionalization reactions. A popular strategy to accomplish regioselective C–H bond activation relies on the presence of a preexisting or in situ formed directing group, which is necessary for the transition metal to be anchored in proximity to the C–H bond to be functionalized and to stabilize the metallacyclic intermediates (Scheme 1a).² Common directing groups include sp² N containing groups, such as aromatic heterocycles, oxazoline, imine or oxime ethers, and carbonyl groups of carboxamide or carboxylic acid.^3,4 Though Fahey reported a PdCl₂ catalyzed ortho-chlorination of azobenzene in 1970,⁵ preparations and stoichiometric reactions of ortho-metallacyclic compounds had been a mainstream in studies for over three decades since the late 1960s. An easily accessible and removable directing group containing sp² N, such as an imine or oxime ether group, is attractive from the point of view of practicality, because such a group could be easily converted back into a versatile carbonyl group.^1g,6 In the 1980s, Baldwin prepared palladacyclic compounds from ketoximes and Na₂PdCl₄, and reported stoichiometric reactions of these palladacyclic compounds with Pb(OAc)₄ giving rise to products of acetoxylation of C–H bonds (Scheme 1b).⁷ Two decades later, Sanford developed a catalytic version of similar transformations using a catalytic amount of Pd(OAc)₂ and a stoichiometric amount of phenyliodoso diacetate, PhI(OAc)₂, as the terminal oxidant (Scheme 1c).⁸ Both aryl and alkyl C–H bonds could be acetoxylated in a catalytic way. In a further attempt, Sanford could realize the Pd(OAc)₂ catalyzed C–H bond acetoxylation reactions in a solvent composed of acetic acid and acetic anhydride using Oxone or K₂S₂O₈ instead of PhI(OAc)₂ as the oxidant.^8d Besides the C–H bond acetoxylation reactions,⁹ a diverse collection of C–H bond functionalizations mediated by a transition metal and directed by a ketoxime ether or an aldoxime ether group were reported.^10–13

Scheme 1 Directed C–H bond functionalization and acetoxylation.

Recently, our group became interested in catalytic asymmetric syntheses of chiral 2-isoxazolines.¹⁴ Due to the highly similar structural unit present in a 2-isoxazolinyl group and a ketoxime ether group (Scheme 1c and d) and the versatilities of isoxazolinyl groups in organic syntheses,¹⁴ we hope to investigate Pd(II) catalyzed C–H bond functionalizations directed by a 2-isoxazolinyl group. To the best of our knowledge, only one example of a Pd(OAc)₂ catalyzed acetoxylation directed by a 2-isoxazolinyl group was reported by Sanford.^8d

We chose 3-phenyl-2-isoxazoline (1a) as a model compound to check the influences caused by variations of the reaction parameters. In light of the results of the Pd(II) catalyzed acetoxylation reactions conducted by Sanford,⁸ PhI(OAc)₂ and acetonitrile were arbitrarily selected as the acetoxy source and the solvent, respectively. The influence of the amount of PhI(OAc)₂ on the conversions was first studied. Initially, the loading of Pd(OAc)₂ was set to 5 mol%. When 1.2 equivalents of PhI(OAc)₂ was used, the only product observed was a monoacetoxylation product 2a. The isolated yield of 2a based on the recovered starting material (brsm) was 70%, but the conversion of 1a was only 41% (Table 1, entry 1). When 2.0 or 3.0 equivalents of PhI(OAc)₂ were used, the conversions of 1a were both 60%. The total isolated yields of 2a and 2a′ were 78% and 86%, respectively (Table 1, entries 2 and 3). When the loading of Pd(OAc)₂ was reduced to 2 mol%, the conversion after 17 h at 100 °C was only 36%. Only 2a was isolated in 64% yield (Table 1, entry 4). When 10 mol% of Pd(OAc)₂ was used, the conversion of 1a was improved to 78%. The isolated yields of 2a and 2a′ were 65% and 24%, respectively (Table 1, entry 5). An extension of the reaction time from 12 h to 24 h did not improve the conversion (Table 1, entry 7 vs. 6). But a slightly higher total yield (89%) of 2a and 2a′ was obtained at 17 h in comparison with 82% at 12 h. Thus, the optimal reaction time (17 h), catalyst loading (10 mol%), and amount of oxidant (3.0 equiv.) for the acetoxylations in acetonitrile were established. Next, the solvent was varied in order to improve the conversion of 1a while keeping good selectivity toward the acetoxylation products (2a and 2a′). Solvents composed of sole acetic acid (AcOH), 1,2-dichloroethane, 1,4-dioxane, 1,2-dimethoxyethane, THF, DMF, DMSO, CH₃NO₂, or binary components of acetic anhydride/AcOH (v/v = 1 : 1), CH₃CN/AcOH (1 : 1) or toluene/AcOH (1 : 1) were tested under otherwise identical conditions. Disappointingly, all of the solvents other than only CH₃CN turned out to be less effective when taking into account both the conversion and selectivity toward acetoxylation products. The reaction conducted in CH₃CN/AcOH (1 : 1) gave almost the same conversion (79%) of 1a and total yield (87%) of 2a and 2a′ as that in only CH₃CN (Table 1, entry 8). In nitromethane, the conversion was 56% and the isolated yield of the acetoxylation products was only 64%. In 1,4-dioxane, the conversion was 58% and the selectivity was 94% (Table 1, entry 10). In 1,2-dichloroethane, the conversion was 100%, but the selectivity was only 67%. When the reaction was carried out in CH₃CN using Oxone or K₂S₂O₈ as the oxidant, the conversion was very low and only a trace amount of 2a was observed.

Table 1 Optimization of the reaction parameters using 1a ^a,b

Entry	X	Y	Solvent	Time (h)	Convn^c (%)	Yield^c^,^d (%)
a Reactions were conducted under N2. Under an atmosphere of air or O2, similar results were obtained.b Solvents were used as purchased.c Conversions and isolated yields were based on recovered starting material.d Yields in parentheses are for 2a′.
1	5	1.2	CH3CN	17	41	70(0)
2	5	2	CH3CN	17	60	67(11)
3	5	3	CH3CN	17	60	75(11)
4	2	3	CH3CN	17	36	64(0)
5	10	3	CH3CN	17	78	65(24)
6	10	3	CH3CN	12	76	60(22)
7	10	3	CH3CN	24	76	60(22)
8	10	3	CH3CN/AcOH (1 : 1)	17	79	61(26)
9	10	3	CH3NO2	17	56	57(7)
10	10	3	Dioxane	17	58	84(10)
11	10	3	ClCH2CH2Cl	17	100	33(34)

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With the optimal conditions in hand, we started to investigate the acetoxylation reactions of different arenes bearing a simple 2-isoxazolinyl group (Scheme 2). When an electron-donating group para to the isoxazolinyl group was introduced into the phenyl ring, the conversion of 1b was 72%. 2b and 2b′ were isolated in 46% and 14% yields, respectively. When a para-Cl was introduced, the conversion of 1c was 32% and the isolated yield of 2c was 59%. When a strong electron-withdrawing group was introduced on the para-position, 40% of 1d was converted, and 2d was isolated in only 5% yield. Possibly, a NO₂ group para to the isoxazolinyl group decreased the coordination capability of the sp² N, and thus hampered the formation of the palladacyclic intermediate and led to a low conversion. Naphthalene, furan or thiophene bearing a 2-isoxazolin-3-yl group were also tested. The conversions of 1e, 1f and 1g were 94%, 85% and 77% respectively. The isolated yields of 2e, 2f and 2g were 72%, 13% and 18%, respectively. Possibly the coordinating oxygen or sulfur atom in the furan or thiophene molecules disturbed the desired C–H bond activation process mediated by Pd(OAc)₂, which resulted in low yields of the acetoxylation products.

Scheme 2 Isoxazolinyl group directed acetoxylations of arenes.

A 5-substituted 2-isoxazoline ring as the directing group was then examined (Scheme 3). When a phenyl group was present in the 5-position of the isoxazoline ring (3a), the mono- (4a) and diacetoxylation (4a′) products were obtained in 66% and 28% yields, respectively, with a 68% conversion of 3a. When a hydroxymethyl group was present in the 5-position of the isoxazoline ring, the reaction did not proceed at all. Protection of the free hydroxyl group was necessary. When a methoxymethyl group was present in the 5-position of the isoxazoline ring (3b), the conversion was 78%. The mono- (4b) and diacetoxylation (4b′) products were isolated in 55% and 18% yields, respectively. When the methyl protection group in 3b was replaced with a tetrahydropyranyl (THP) group (3c), the conversion was 61%, and the mono- (4c) and diacetoxylation (4c′) products were isolated in 62% and 21% yields, respectively. When the methyl in 3b was replaced with a benzoyl group (3d), a conversion of 83% was obtained while the mono- (4d) and diacetoxylation (4d′) products were isolated in 66% and 17% yields, respectively. When an ortho-, meta- or para-methyl group was introduced into the phenyl ring to be functionalized (3e–3g), acetoxylations proceeded smoothly. For substrate 3e, the conversion was 93%. Monoacetoxylation occurred at the ortho-position of the phenyl ring (4e) and the ortho-methyl group (4e′′). ¹H NMR indicated that the ratio of 4e to 4e′′ was ca. 52 : 48. The total yield of the two monoacetoxylation products was 72%. Diacetoxylation occurred at both the ortho-position of the phenyl ring and the ortho-methyl group. The diacetoxylation product 4e′ was isolated in 16% yield. For substrate 3f, only the monoacetoxylation product 4f was isolated in 82% yield. This is similar to the results reported by Sanford et al. when using a pyridine or a ketoxime ether as the directing group.⁸ For substrates 3g and 3h, the monoacetoxylation products were isolated in 54% (4g) and 53% yields (4h), respectively. When a 1-naphthyl ring was mounted on the isoxazoline ring, the 2-acetoxylation product 4i was isolated in 73% yield with a small amount (3%) of the 2,8-diacetoxylation product (4i′). When an isoxazoline ring fused with a cyclohexane ring acted as the directing group, the monoacetoxylation product 4j was isolated in 38% yield with a full conversion of 3j. While spatially well-disposed alkyl C–H bonds could be activated by Pd(II) with the aid of a proximal directing group, we also tested the acetoxylation of a tert-butyl group under the optimal conditions. Compound 3k was prepared from pivaldehyde. The monoacetoxylation product 4k was isolated in 51% yield with a conversion of 47%.

Scheme 3 Acetoxylations directed by a 5-substituted 2-isoxazolinyl group^a,b,c. ^a CH₃CN, 100 °C, 17 h. ^b Conversions and isolated yields were based on recovered starting materials. ^c Yields in parentheses were for diacetoxylation products. ^d Total yield of the phenyl and methyl monoacetoxylation products. ^e Yield for the 2,8-diacetoxylation product.

Except for the isoxazoline rings bearing a phenyl or alkyl group, those bearing a carbonyl group in the 5-position were also examined. When a carboximide, ester or ketone group was present in the 5-position of the directing isoxazoline ring (Scheme 4), low conversions (19% to 73%) of the substrates (5a–5g) were observed. Only the monoacetoxylation products (6a–6g) were isolated. The isolated yields ranged from 21% to 58%. Obviously, a carbonyl group present in the directing isoxazoline ring was unfavorable for the desired Pd(II) mediated C–H bond activation reactions. When compound 5g was subjected to the acetoxylation reaction, the monoacetoxylation product 6g was isolated in 35% yield with a conversion of 34%.

Scheme 4 Acetoxylations directed by a 5-carbonyl-2-isoxazolinyl group^a,b,c. ^a CH₃CN, 100 °C, 17 h. ^b Conversions and isolated yields were based on recovered starting materials. ^c Only monoacetoxylation products were isolated.

An isoxazoline ring bearing two substituents in the 5-position was then used as the directing group (Scheme 5). These substrates (7a–7h) were prepared via cycloadditions of 2-ethylacrolein or methacrolein with nitrile oxides followed by reduction with NaBH₄ and esterification. When 7a was subjected to the acetoxylation reaction, the mono- (8a) and diacetoxylation (8a′) products were isolated in 72% and 13% yields, respectively, with a conversion of 79%. When a meta-methyl group was introduced to the phenyl ring to be functionalized, the monoacetoxylation product 8b was isolated in 75% yield with a conversion of 87%. The reaction results of 7a and 7b resemble those of substrates 3d and 3f, respectively. We then prepared several 3-phenyl-2-isoxazolines from methacrolein to examine the substituent effect on the acetoxylations. When an ortho-methyl group was present in the phenyl ring to be functionalized, monoacetoxylation occurred at both the methyl group (8c′′) and the phenyl ring (8c). The two monoacetoxylation products were isolated in a total yield of 58%. The diacetoxylation product was not observed. When a meta-methyl group was present, only the monoacetoxylation product 8d was isolated in 69% yield with a conversion of 90%. When a para-methyl group was present, the mono- (8e) and diacetoxylation (8e′) products were isolated in 58% and 40% yields, respectively, with a conversion of 87%. When a meta-methoxy group was present, the mono- (8f) and diacetoxlyation (8f′) products were isolated in 66% and 14% yields, respectively, with a full conversion of substrate 7f. When an electron-withdrawing Cl or CF₃ group was present in the meta-position (7g, 7h), the reaction became sluggish. Low conversions (54%, 20%) and low yields (24%, 25%) of the acetoxylations were observed. When an even stronger electron-withdrawing nitro group was present in the meta-position, the substrate was not converted at all.

Scheme 5 Acetoxylations directed by a 5,5-disubstituted 2-isoxazolinyl group^a,b,c. ^a CH₃CN, 100 °C, 17 h. ^b Conversions and isolated yields were based on recovered starting materials. ^c Yields in parentheses were for the diacetoxylation products. ^d Total yield of the phenyl and methyl monoacetoxylation products. Ratio of the phenyl monoacetoxylation to the methyl monoacetoxylation product was 55 : 45. ^e Yield for the 2,6-diacetoxylation product.

To demonstrate the usefulness of the present acetoxylations, compound 11, which is a potential precursor for the synthesis of the tricyclic core of marticin,¹⁵ was prepared from 4h in five steps (Scheme 6). PTSA-catalyzed deacetylation of 4h gave 9 in 83% yield. Oxidation of 9 with CAN followed by reduction with Na₂S₂O₄ provided the hydroquinone compound 10 in 78% yield.^16–18 The phenolic hydroxyl group meta to the isoxazolinyl ring was allylated with allyl bromide in 58% yield. A subsequent Claisen rearrangement gave 11 in complete regioselectivity and 100% yield.¹⁹ The ortho instead of para position of the allyl group to the isoxazolinyl group in 11 was confirmed by the two doublets in the NMR spectrum of the two protons on the phenyl ring bearing the allyl group.^15,19

Scheme 6 Preparations of 9–11. (i) PTSA, MeOH, 83%; (ii) (a) CAN, CH₃CN/H₂O; (b) Na₂S₂O₄, acetone/H₂O, 78% for the two steps; (iii) (a) allyl bromide, K₂CO₃, acetone, 58%; (b) decalin, 200 °C, 100%.

The mechanism of Pd(II) catalyzed benzoxylations of aryl C–H bonds with PhI(OBz)₂ was already investigated by Sanford.²⁰ A Pd(II)/Pd(IV) cycle was involved in the catalytic process. An isoxazolinyl group directed acetoxylation of 1a is shown in Scheme 7.

Scheme 7 Catalytic cycle of acetoxylations directed by a 2-isoxazolinyl group.

In summary, we investigated isoxazolinyl group assisted and Pd(OAc)₂ catalyzed acetoxylations of C–H bonds using PhI(OAc)₂ as the oxidant. 2-Isoxazolin-3-yl without and with one or two 5-subsituents could act as an effective directing group facilitating ortho-selective acetoxylations. Both aryl and alkyl C–H bonds could be activated with the assistance of an isoxazolinyl group. An electron-withdrawing substituent para or meta to the isoxazoline ring was disadvantageous to the C–H bond activation step, and usually gave a low conversion of the substrate. A 5-carbonyl group in the isoxazoline ring was deleterious for the desired C–H bond activation. Though an isoxazolinyl group is not as easily hydrolyzed as an oxime ether or imine group, in comparison with a N containing heteroaromatic cycle, it seems more like a directing group when considering the synthetic usefulness. More C–H bond functionalizations directed by a 2-isoxazolinyl group will be reported in due course.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and compound characterization data. See DOI: 10.1039/c6ra07793e

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