Palladium-catalysed regioselective aroylation and acetoxylation of 3,5-diarylisoxazole via ortho C–H functionalisations

Abstract

The higher directing ability of N over O in 3,5-diarylisoxazole is demonstrated during the construction of C–C and C–O bonds. Out of the four ortho sp² C–Hs and one internal sp² C–H in 3,5-diarylisoxazoles, regioselective aroylation and acetoxylation take place at one of the ortho-C–Hs proximal to the N atom using Pd(OAc)₂ as the catalyst in the presence of suitable oxidants and solvents.

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Introduction

Recently, a number of C–H functionalisation methods with a high level of accuracy and predictability for systematising the synthesis of a diverse array of complex organic molecules have been reported.¹ Among the various methods, the cross-dehydrogenative coupling (CDC)² and directing group-assisted approaches³ are the two most powerful strategies for the site selective C–H functionalisations. Donor heteroatoms like nitrogen (N) and oxygen (O) have been employed to direct the metallation at the proximal site for achieving the desired ortho-C–H functionalisations. In this field, Pd-catalysed directing group-assisted C–H functionalisation methods have received much recent attention for the construction of C–C or C–X (X = heteroatom) bonds.⁴

Transition metal catalysed ortho-aroylations have been achieved using aldehydes,⁵ benzyl alcohols⁶ or even inert alkylbenzenes⁷ as aroyl surrogates assisted by N and O bearing directing groups such as 2-phenylpyridine,^5a,b,6a,7a anilides,^{5c,d,e,6b,7b,c} benzamides,^5f O-methyl oxime,^5g,7a and 2-arylbenzazoles.^5h Recently, a variety of ortho-aroylation strategies have been demonstrated using different directing groups via the decarboxylation of alpha-keto acids.⁸ In a similar fashion, various directing group-containing substrates have also been employed for Pd-catalysed oxidative C–O bond formation, in particular o-hydroxylation or o-acetoxylation.⁹

It is pertinent to mention here that there are numerous examples of sp² N atoms in heterocycles acting as chelating ligands in ortho-directed functionalisations.^5–10 However, the directing (chelating) ability of sp² oxygen¹¹ in ketones and acids and sp³ oxygen¹² in ethers and alcohols can hardly be ignored. 3,5-Diarylisoxazole possessing both N and O-chelating atoms in a rigid framework may provide a competitive cyclometallated intermediate either through N or O atoms by anchoring the metal selectively to one of the proximal ortho C–H bonds. There is only one instance where 3,5-diarylisoxazole is ortho-arylated using phenylboronic acid as the arylating partner in the presence of stoichiometric Pd salt.¹³ Apart from this, there is not a single report on catalytic ortho C–H functionalisation using this moiety. The 3,5-diarylisoxazole scaffold is an important pharmacophore having a diverse array of biological activities.¹⁴ The reductive N–O bond cleavage of 3,5-disubstituted isoxazoles leads to various bifunctional molecules¹⁵ that can be utilized for the synthesis of other important heterocycles.¹⁶ Thus, any further functionalisation of this important moiety is likely to generate further interest. There are two o-hydrogens, each proximal to a N and O atom in 3,5-diarylisoxazole that can be activated (o-palladated). Furthermore, functionalisation of the isoxazolyl internal sp² C4–H by a non-directing metallation path cannot be ruled out. o-C–H functionalisation in isoxazoles having dual-directing atoms such as N and O has not been investigated so far. Thus, it would be interesting to see whether the palladation would occur through the –N donor ortho-site or –O donor ortho-site or at the C4 position in 3,5-diarylisoxazoles.

Results and discussion

An initial experiment for the aroylation of 3,5-diphenylisoxazole was performed using an aromatic aldehyde as the aroyl source. Thus 3,5-diphenylisoxazole (1) (1 equiv.) was reacted with an equivalent of benzaldehyde (a) in the presence of Pd(OAc)₂ (5 mol%) and oxidant tert-butylhydroperoxide (TBHP, 1 equiv.) in toluene solvent. A product having a lower retention factor (R_f) was isolated with a mere yield of 18% (entry 1, Table 1). Spectroscopic (¹H and ¹³C NMR) analysis of the product (1a) showed the presence of an aroyl group and retention of the internal C4 hydrogen in its ¹H NMR at 6.54 ppm. Thus, the aroylation is taking place most probably at one of the ortho positions proximal to either the N or O donor site of the isoxazole moiety. In the pursuit to improve the yield of the product (1a), the reaction was again performed under identical conditions using 1,4-dioxane as the solvent. No product formation (entry 2, Table 1) was observed and the starting material was recovered completely. Switching the solvent to acetic acid provided an improved yield of 27% (entry 3, Table 1). Further screening of solvents such as DMSO, DMF, and dichloroethane (DCE) (entries 4–6, Table 1) revealed DCE to be the better solvent giving a moderate yield (41%) of the product. The use of 10 mol% of the catalyst increased the yield up to 53% (entry 7, Table 1). Improvement in the yield up to 64% (entry 8, Table 1) was observed when the oxidant quantity was increased to 1.2 equivalents. No further enhancement in the yield was observed even when the catalyst loading was increased to 15 mol % (entry 9, Table 1). Other palladium(II) catalysts such as PdBr₂, PdCl₂ and Pd(TFA)₂ were found to be not so effective compared with Pd(OAc)₂ (entries 10–12, Table 1). The use of hydrogen peroxide (H₂O₂) and benzoyl peroxide (PhCOO)₂ as oxidants were unsuccessful in giving the anticipated product.

Table 1 Screening of reaction conditions for C–C bond formation

Entry	Catalyst (mol%)	Solvent	Oxidant	Yield^a^b (%)
a Isolated yield of o-aroylated product (1a) after 12 h, TBHP (1.2 equiv.) was added in 4 portions at 3 h intervals.b All reactions were performed under an air atmosphere using 1.2 equiv. of benzaldehyde at 110 °C.
1	Pd(OAc)2 (5.0)	Toluene	TBHP (1.0)	18
2	Pd(OAc)2 (5.0)	1,4-Dioxane	TBHP (1.0)	00
3	Pd(OAc)2 (5.0)	AcOH	TBHP (1.0)	27
4	Pd(OAc)2 (5.0)	DMSO	TBHP (1.0)	00
5	Pd(OAc)2 (5.0)	DMF	TBHP (1.0)	00
6	Pd(OAc)2 (5.0)	DCE	TBHP (1.0)	41
7	Pd(OAc)2 (10.0)	DCE	TBHP (1.0)	53
8	Pd(OAc)2 (10.0)	DCE	TBHP (1.2)	64
9	Pd(OAc)2 (15.0)	DCE	TBHP (1.2)	65
10	PdCl2 (10.0)	DCE	TBHP (1.2)	8
11	PdBr2 (10.0)	DCE	TBHP (1.2)	16
12	Pd(TFA)2 (10.0)	DCE	TBHP (1.2)	22

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The scope and generality of this aroylation reaction was further explored using various aromatic aldehydes and 3,5-diarylisoxazoles. The 3-aryl ring of 3,5-diarylisoxazoles possessing electron-donating substituents such as p-Me (2) and p-OMe (3) coupled efficiently with benzaldehyde (a) giving the corresponding o-aroylated products (2a) and (3a), respectively, in moderate yields. However, the presence of electron-withdrawing substituents such as o-NO₂, m-F and p-Cl in the 3-aryl ring of 3,5-diarylisoxazole were completely unproductive under these present reaction conditions. Due to the deactivating nature of 3-phenyl rings, they are reluctant to form a palladacycle intermediate, thereby preventing the aroylation process.

Aromatic aldehydes possessing electron-donating substituents such as p-Me (b), p-^tBu (c) and p-OMe (d) served as excellent aroyl precursors toward the aroylation of 3,5-diphenylisoxazole (1) giving products (1b), (1c) and (1d), respectively, in moderate yields. The structure of the product (1d) has been confirmed by X-ray crystallographic analysis (Fig. 1).¹⁷ As can be clearly seen from the crystal structure of (1d), an aroyl moiety has been incorporated into the 3-aryl ring of 3,5-diarylisoxazole (1) proximal to the N atom. Aromatic aldehydes possessing electron-withdrawing substituents such as m-Cl (e), p-Ph (f), p-CO₂Me (g) and 2,6 di-Cl (h) underwent reactions giving better yields of their o-aroylated products (1e), (1f), (1g) and (1h) compared with the aldehydic substrates possessing electron-donating substituents as shown in Table 2. The structure of the product (1g) has been reconfirmed by X-ray crystallography (Fig. 2).¹⁸ Here again, the aroylation is directed by the N atom in the 3,5-diarylisoxazole. The fused aromatic aldehyde (i) provided a better yield of o-aroylated product (1i) compared to heteroaromatic aldehydes (j) and (k) in giving their corresponding products (1j) and (1k). The reductive N–O bond cleavage of 3,5-disubstituted isoxazoles provides β-aminoenones or 1,3-diketones,^15d thus these ortho-aroylated products may be useful precursors to triketones.

Fig. 1 ORTEP molecular diagram of (1d).¹⁷

Table 2 Scope of substrates for ortho-aroylation of 3,5-diarylisoxazole^a

a Yields of pure isolated products after silica gel column chromatography.

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Fig. 2 ORTEP molecular diagram of (1g).¹⁸

Substrate-directed Pd-catalysed oxidative C–O bond formation, viz. o-hydroxylation and o-acetoxylation, has been well explored.⁹ Analogous to the C–C bond formation in 3,5-diarylisoxazoles directed by the N atom, it is also of interest to see whether a C–O bond can similarly be constructed. From the literature reports, it is well established that directing group-promoted hydroxylation/acetoxylation proceeds better with a combination of diacetoxyiodobenzene (DIB), AcOH and Pd(OAc)₂.⁹ To reassess the better directing ability of N in 3,5-diarylisoxazoles for o-acetoxylation, substrate (1) (1 equiv.) was treated with Pd(OAc)₂ (5.0 mol%), DIB (1.2 equiv.) in AcOH (2 mL) at 110 °C, which provided the o-acetoxylated product (1a′) in 44% isolated yield. With this initial result in hand, further optimisations in terms of solvent, catalyst and their quantities were examined. Details of the optimisation reactions that were performed are summarised in Table 3. The most surprising aspect of the optimisation reaction is the use of the combination of solvents AcOH : toluene (3 : 1), which gave the best possible yield. The other ratios of AcOH : toluene [(1 : 1), (2 : 1) and (1 : 2)] tried were found to be less effective. Thus all further reactions were performed taking the substrate (1 equiv.), DIB (1.2 equiv.), Pd(OAc)₂ (0.1 equiv.) in a mixture of AcOH :  toluene (3 : 1) at a temperature of 110 °C.

Table 3 Screening of reaction conditions for C–O bond formation

Entry	Catalyst (mol%)	Solvent	Oxidant	Yield^a^b (%)
a Isolated yield of o-acetoxyted product (1a′) after 12 h.b All reactions were performed under an air atmosphere at 110 °C.c AcOH : toluene used in a 3 : 1 ratio.
1	Pd(OAc)2 (5.0)	AcOH	DIB (1.2)	44
2	Pd(OAc)2 (5.0)	1,4-Dioxane	DIB (1.2)	00
3	Pd(OAc)2 (5.0)	Toluene	DIB (1.2)	00
4	Pd(OAc)2 (5.0)	DMSO	DIB (1.2)	00
5	Pd(OAc)2 (5.0)	DMF	DIB (1.2)	00
6	Pd(OAc)2 (5.0)	DCE	DIB (1.2)	00
7	Pd(OAc)2 (10.0)	AcOH	DIB (1.2)	45
8	Pd(OAc)2 (10.0)	AcOH	DIB (1.5)	53
9	Pd(OAc)2 (10.0)	AcOH : toluene	DIB (1.2)	62^c
10	Pd(OAc)2 (15.0)	AcOH : toluene	DIB (1.2)	66^c
11	PdBr2 (10.0)	AcOH	DIB (1.2)	27
12	Pd(TFA)2 (10.0)	AcOH	DIB (1.2)	30
13	PdCl2 (10.0)	AcOH	DIB (1.2)	18

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The above optimised conditions were then applied toward the o-acetoxylation of various 3,5-diphenylisoxazoles. It was observed that electron-donating substituents such as p-Me (2) and p-OMe (3) present in the 3-aryl ring of 3,5-diarylisoxazole afforded their corresponding o-acetoxylated products (2a′) and (3a′) in good yields. The electron-withdrawing substituent of o-NO₂ (4) present in the 3-aryl ring of 3,5-diarylisoxazole underwent a slow reaction giving a poor yield (43%) of the product (4a′). Other substrates possessing electron-withdrawing substituents such as m-F and p-Cl were completely unproductive under these optimised reaction conditions. Barring the exception of o-NO₂ (4) for o-acetoxylation, the results of o-aroylation and o-acetoxylation are identical (Table 2 and 4) for substrates possessing electron-withdrawing groups in their 3-aryl rings. The substrate having p-NO₂ did not yield any product supporting our argument for the unreactive nature of a substrate having deactivating groups for o-acetoxylation and o-aroylation reactions. The unusual reactivity of (4) which, in spite of possessing a deactivating o-NO₂ group, gives an o-acetoxylated product (4a′) can not be ascertained at this moment. Interestingly, 3-benzyl-5-phenylisoxazole afforded the desired ortho-acetoxylated product (5a′) in a modest yield. The reaction in the latter case is expected to proceed via a 6-membered palladacycle intermediate.

Table 4 Scope of substrates in the Pd-catalysed ortho-acetoxylation of 3,5-diarylisoxazole^a

a Yields of pure isolated products after silica gel column chromatography.

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Recently alkylbenzenes have been demonstrated to be the synthetic equivalent of an aroyl moiety during substrate directed o-aroylation.⁷ In this case, even though an alkylbenzene (toluene) is used as the solvent, no aroylation was observed. This is because of the inability of toluene to be converted into an alcohol and aldehyde under the reaction conditions. It is clear from Table 2 that the presence of electron-withdrawing substituents results in completely unproductive reactions, while the presence of electron-donating substituents facilitates the reactions. Thus, if an electron-withdrawing substituent is placed in the 3-aryl ring (towards the N side) and an electron-donating group in the 5-aryl ring (towards the O side), can oxygen in 3,5-diarylisoxazole direct the o-aroylation? With this objective the designed substrate (9), Fig. 3, was subjected to the present o-aroylation conditions but no aroylation whatsoever was observed suggesting the inability of O as directing group in this case.

Fig. 3 Competitive metallation paths.

Although we have not thoroughly probed the mechanisms of these reactions, the mechanisms are expected to be similar to those recently proposed by us^5,9e–h,l and others for these C–C and C–O bond forming reactions (Scheme 1). The presence of a radical scavenger such as 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) greatly suppressed the rate of this o-aroylation reaction and only a trace amount (8%) of ortho-aroylated product was formed along with the formation of a benzoyl-TEMPO adduct (A) in 66% isolated yield. Thus, a plausible mechanism can be depicted for this o-aroylation reaction. The first step of the o-aroylation reaction involves the cyclopalladation to form an intermediate (I) towards the N side, i.e. 3-aryl ring in 3,5-diarylisooxazole. The aroyl radical generated in situ by the reaction of an aldehyde and TBHP undergoes oxidative addition with the intermediate (I) to form either a reactive Pd(IV)¹⁹ or a dimeric Pd(III)²⁰ intermediate (II) (Scheme 1, path A). In the final stage, reductive elimination affords C–C bond formation leading to the ortho-aroylated product and regenerating the Pd(II) catalyst, which maintains the subsequent catalytic cycle (Scheme 1, path A). The C–O bond forming path (o-acetoxylation) is illustrated in (Scheme 1, path B). This mechanism is identical to our Pd(II) catalysed o-hydroxylation of 2-arylbenzothiazole and compounds with other directing groups.^9e–h,l

Scheme 1 Plausible mechanisms for C–C and C–O bond formation.

Conclusions

In conclusion, we have demonstrated the higher directing ability of N over O in 3,5-diarylisoxazole via a chelation-assisted approach in accomplishing site selective ortho-functionalisations. In spite of the higher acidic character of the isoxazolyl, sp² C4–H directed o-metallation is preferred over the non-directed metallation pathway. This is the first report of catalytic o-functionalisation of this scaffold for the construction of C–C and C–O bonds.

Experimental section

General remarks

All the reagents were commercial grade and purified according to the established procedures. Organic extracts were dried over anhydrous sodium sulphate. Solvents were removed in a rotary evaporator under reduced pressure. Silica gel (60–120 mesh size) was used for the column chromatography. Reactions were monitored by TLC on silica gel 60 F₂₅₄ (0.25 mm). NMR spectra were recorded in CDCl₃ with tetramethylsilane as the internal standard for ¹H NMR (400 MHz, 600 MHz) and CDCl₃ solvent as the internal standard for ¹³C NMR (100 MHz, 150 MHz). HRMS spectra were recorded using ESI mode (TOF). IR spectra were recorded neat or in KBr.

(A) General experimental procedure for the preparation of phenyl(2-(5-phenylisoxazol-3-yl)phenyl)methanone (1a) from 3,5-diphenylisoxazole (1)

An oven-dried flask was charged with Pd(OAc)₂ (22 mg, 0.10 mmol), benzaldehyde (127 mg, 1.2 mmol), 3,5-diphenylisoxazole (1) (221 mg, 1.0 mmol) and 1,2-dichloroethane (2 mL). The reaction vessel was then subjected to reflux in an oil bath preheated to 110 °C and stirring was maintained for the stipulated period of time. TBHP (1.2 mmol) was then added in 4 equal portions over a period of 12 h. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled and admixed with water (5 mL). The product was extracted with ethyl acetate (3 × 10 mL) and the combined organic layer was washed with saturated sodium bicarbonate (NaHCO₃) solution. The organic layer was dried over anhydrous sodium sulphate (Na₂SO₄), and evaporated under reduced pressure. Further purification of the crude product was done through silica gel column chromatography (8% EtOAc–hexane) to yield the pure phenyl(2-(5-phenylisoxazol-3-yl)phenyl)methanone (1a) (208 mg, yield 64%). The identity and purity of the product was confirmed by spectroscopic analysis.

(B) General experimental procedure for the preparation of 2-(5-phenylisoxazol-3-yl)phenyl acetate (1a′) from 3,5-diphenylisoxazole (1)

An oven-dried flask was charged with 3,5-diphenylisoxazole (1) (221 mg, 1.0 mmol), diacetoxyiodobenzene (DIB) (386 mg, 1.2 mmol), Pd(OAc)₂ (22 mg, 0.10 mmol), and acetic acid : toluene (2 mL in 3 : 1 ratio). After that the reaction mixture was subjected to reflux in a preheated oil bath at 110 °C and stirring was maintained for the stipulated period of time. The progress of the reaction was monitored by TLC. After the completion of the reaction as judged from TLC, the reaction mixture was cooled and admixed with water (5 mL). The product was extracted with ethyl acetate (2 × 10 mL) and the combined organic layer was washed with saturated sodium bicarbonate (NaHCO₃) solution. The organic layer was dried over anhydrous sodium sulphate (Na₂SO₄), and evaporated under reduced pressure. The crude product obtained here was further purified through silica gel column chromatography (10% EtOAc–hexane) to yield the pure 2-(5-phenylisoxazol-3-yl)phenyl acetate (1a′) (172 mg, yield 62%). The identity and purity of the product was confirmed by spectroscopic analysis.

Crystallographic description. Crystal data were collected using graphite monochromated Mo K_α radiation (λ = 0.71073 Å) at 298 K. Cell parameters were retrieved using SMART²¹ software and refined with SAINT²¹ on all observed reflections. Data reduction was performed with the SAINT software and corrected for Lorentz and polarization effects. Absorption corrections were applied with the program SADABS.²² The structure was solved by direct methods implemented in the SHELX-97²³ program and refined by full-matrix least-squares methods on F². All non-hydrogen atomic positions were located in difference Fourier maps and refined anisotropically. The hydrogen atoms were placed in their geometrically generated positions. Colourless crystals were isolated in rectangular shapes from acetonitrile at room temperature.

Phenyl(2-(5-phenylisoxazol-3-yl)phenyl)methanone (1a). Gummy: 208 mg, isolated yield 64%; ¹H NMR (400 MHz, CDCl₃): δ 8.03 (d, 1H, J = 7.2 Hz), 7.80 (d, 1H, J = 7.6 Hz), 7.73 (d, 1H, J = 7.2 Hz), 7.67–7.63 (m, 2H), 7.60 (d, 1H, J = 7.2 Hz), 7.57–7.53 (m, 1H), 7.50–7.46 (m, 2H), 7.43 (d, 2H, J = 7.6 Hz), 7.41–7.34 (m, 3H), 6.54 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 197.7, 170.2, 162.2, 139.5, 137.2, 133.9, 133.5, 130.5, 130.2, 129.6, 129.5, 129.1, 128.7, 128.6, 128.0, 127.4, 125.9, 100.0; IR (KBr): 3120, 3063, 2918, 2846, 1789, 1736, 1667, 1596, 1573, 1486, 1449, 1400, 1315, 1287, 1264, 1229, 1177, 1149, 1089, 1069, 1025, 1000, 946, 929, 803, 763, 731, 709, 690, 636 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₅NO₂ (M + H⁺) 326.1176, found 326.1175.

(5-Methyl-2-(5-phenylisoxazol-3-yl)phenyl)(phenyl) methanone (2a). Gummy: 210 mg, isolated yield 62%; ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, 1H, J = 6.8 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.66–7.63 (m, 2H), 7.47 (t, 2H, J = 7.4 Hz), 7.42–7.33 (m, 6H), 7.29 (s, 1H), 6.50 (s, 1H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 198.0, 170.1, 162.1, 140.0, 139.4, 137.3, 133.5, 131.2, 130.3, 130.2, 129.4, 129.2, 129.1, 128.6, 127.4, 125.9, 125.1, 99.9, 21.5; IR (KBr): 3060, 2922, 2846, 1672, 1611, 1593, 1568, 1491, 1447, 1403, 1317, 1292, 1260, 1209, 1179, 1155, 1069, 1023, 961, 946, 919, 846, 833, 791, 752, 766, 752, 711, 689, 648 cm⁻¹; HRMS (ESI) calcd for C₂₃H₁₇NO₂ (M + H⁺) 340.1332, found 340.1331.

(5-Methoxy-2-(5-phenylisoxazol-3-yl)phenyl)(phenyl) methanone (3a). Gummy: 253 mg, isolated yield 71%; ¹H NMR (400 MHz, CDCl₃): δ 7.80 (d, 1H, J = 7.2 Hz), 7.74 (d, 1H, J = 8.4 Hz), 7.65–7.63 (m, 2H), 7.49–7.45 (m, 2H), 7.39–7.33 (m, 5H), 7.11 (d, 1H, J = 8.8 Hz), 6.98 (s, 1H), 6.47 (s, 1H), 3.86 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 197.5, 170.0, 161.8, 160.6, 140.8, 137.0, 133.6, 130.9, 130.3, 130.2, 129.1, 128.6, 127.4, 125.9, 120.1, 116.2, 113.9, 99.8, 55.8; IR (KBr): 2921, 2840, 1786, 1733, 1666, 1604, 1566, 1492, 1449, 1402, 1316, 1286, 1257, 1231, 1168, 1086, 1064, 1026, 965, 946, 839, 801, 764, 688 cm⁻¹; HRMS (ESI) calcd for C₂₃H₁₇NO₃ (M + H⁺) 356.1281, found 356.1273.

(2-(5-Phenylisoxazol-3-yl)phenyl)(p-tolyl)methanone (1b). Gummy: 227 mg, isolated yield 67%; ¹H NMR (400 MHz, CDCl₃): δ 7.93 (d, 2H, J = 8.4 Hz), 7.76 (d, 1H, J = 7.6 Hz), 7.63–7.60 (m, 2H), 7.55 (t, 1H, J = 7.6 Hz), 7.49 (d, 1H, J = 7.4 Hz), 7.41 (d, 1H, J = 7.6 Hz), 7.36–7.33 (m, 2H), 7.21–7.19 (m, 2H), 7.06 (d, 1H, J = 8.0 Hz), 6.48 (s, 1H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 197.5, 172.4, 162.2, 144.8, 139.7, 134.7, 130.4, 130.3, 129.6, 129.5, 129.4, 129.0, 128.6, 127.8, 127.4, 126.8, 125.9, 100.0, 21.9; IR (KBr): 2972, 2857, 2652, 1786, 1663, 1610, 1572, 1447, 1418, 1402, 1286, 1182, 1152, 1116, 1020, 949, 927, 833, 757, 714, 688, 606, 541 cm⁻¹; HRMS (ESI) calcd for C₂₃H₁₇NO₂ (M + H⁺) 340.1332, found 340.1321.

(4-tert-Butylphenyl)(2-(5-phenylisoxazol-3-yl)phenyl) methanone (1c). Gummy: 259 mg, isolated yield 68%; ¹H NMR (400 MHz, CDCl₃): δ 7.81 (d, 1H, J = 7.6 Hz), 7.72 (d, 2H, J = 8.4 Hz), 7.68–7.65 (m, 2H), 7.59 (t, 1H, J = 7.6 Hz), 7.53 (t, 1H, J = 7.4 Hz), 7.47 (d, 1H, J = 7.6 Hz), 7.43–7.38 (m, 5H), 6.54 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 197.4, 170.1, 161.9, 157.4, 141.5, 139.8, 134.6, 130.3, 129.6, 129.1, 128.7, 128.0, 126.0, 125.7, 124.7, 122.9, 122.2, 100.3, 35.3, 31.2; IR (KBr): 2962, 2923, 2862, 1785, 1733, 1667, 1607, 1603, 1573, 1459, 1450, 1363, 1314, 1286, 1266, 1185, 1155, 1106, 1017, 949, 931, 851, 803, 763, 690 cm⁻¹; HRMS (ESI) calcd for C₂₆H₂₃NO₂ (M + H⁺) 382.1802, found 382.1805.

(4-Methoxyphenyl)(2-(5-phenylisoxazol-3-yl)phenyl) methanone (1d). White solid: 191 mg, isolated yield 54%; m.p. 132 °C, ¹H NMR (400 MHz, CDCl₃): δ 8.08 (d, 1H, J = 8.8 Hz), 7.81 (d, 1H, J = 7.2 Hz), 7.75 (d, 2H, J = 8.8 Hz), 7.68–7.65 (m, 2H), 7.58 (t, 1H, J = 7.6 Hz), 7.54 (t, 1H, J = 7.4 Hz), 7.45 (d, 1H, J = 7.6 Hz), 7.42-7.37 (m, 2H), 6.98 (d, 2H, J = 9.2 Hz), 6.54 (s, 1H), 3.79 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 196.3, 170.0, 163.9, 162.2, 139.8, 132.9, 132.5, 130.3, 130.1, 129.5, 129.4, 128.9, 128.3, 127.6, 127.3, 125.9, 113.9, 99.9, 55.5; IR (KBr): 2925, 2842, 2570, 1655, 1596, 1573, 1504, 1464, 1448, 1419, 1398, 1301, 1288, 1257, 1149, 1070, 1046, 1016, 951, 929, 843, 806, 771, 757, 713, 691, 610 cm⁻¹; HRMS (ESI) calcd for C₂₃H₁₇NO₃ (M + H⁺) 356.1281, found 356.1287.

(3-Chlorophenyl)(2-(5-phenylisoxazol-3-yl)phenyl)methanone (1e). Gummy: 251 mg, isolated yield 70%; ¹H NMR (400 MHz, CDCl₃): δ 7.74–7.71 (m, 2H), 7.65–7.62 (m, 2H), 7.61–7.55 (m, 2H), 7.52 (t, 1H, J = 7.4 Hz), 7.45–7.35 (m, 5H), 7.24 (t, 1H, J = 8.0 Hz), 6.52 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 196.2, 170.5, 162.0, 138.9, 138.8, 134.9, 133.3, 130.9, 130.5, 129.9, 129.8, 129.6, 129.1, 128.8, 128.3, 127.9, 127.3, 126.0, 99.6; IR (KBr): 3127, 3069, 2917, 1667, 1614, 1589, 1569, 1492, 1463, 1448, 1426, 1403, 1286, 1254, 1154, 1068, 1050, 1026, 948, 920, 895, 840, 824, 802, 780, 734, 687, 635 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₄ClNO₂ (M + H⁺) 360.0786, found 360.0783.

[1,1′-Biphenyl]-4-yl(2-(5-phenylisoxazol-3-yl)phenyl) methanone (1f). Gummy: 265 mg, isolated yield 66%; ¹H NMR (400 MHz, CDCl₃): δ 7.84 (t, 2H, J = 9.4 Hz), 7.69–7.66 (m, 2H), 7.63 (t, 2H, J = 8.0 Hz), 7.59–7.50 (m, 6H), 7.46–7.35 (m, 6H), 6.58 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 197.3, 170.3, 162.2, 156.2, 146.2, 139.9, 139.7, 135.9, 130.8, 130.5, 130.4, 129.7, 129.6, 129.1, 128.7, 128.4, 127.9, 127.5, 127.3, 126.0, 100.0; IR (KBr): 3049, 3027, 2923, 2846, 1786, 1728, 1663, 1600, 1566, 1484, 1448, 1399, 1314, 1283, 1261, 1185, 1149, 1070, 949, 930, 761, 743, 691 cm⁻¹; HRMS (ESI) calcd for C₂₈H₁₉NO₂ (M + H⁺) 402.1489, found 402.1481.

Methyl 4-(2-(5-phenylisoxazol-3-yl)benzoyl)benzoate (1g). White solid: 280 mg, isolated yield 73%; m.p. 156–157 °C,¹ H NMR (400 MHz, CDCl₃): δ 7.99 (d, 2H, J = 8.4 Hz), 7.80 (d, 2H, J = 8.8 Hz), 6.39 (s, 1H), 7.67–7.62 (m, 3H), 7.58 (t, 1H, J = 7.4 Hz), 7.51 (d, 1H, J = 7.6 Hz), 7.40–7.39 (m, 3H), 6.56 (s, 1H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 196.9, 170.4, 166.2, 161.9, 140.6, 138.9, 133.9, 130.8, 130.4, 129.8, 129.7, 129.4, 129.0, 128.8, 127.9, 127.1, 125.9, 99.5, 52.5; IR (KBr): 2951, 2923, 2851, 1717, 1664, 1574, 1445, 1438, 1403, 1280, 1195, 1106, 1015, 952, 932, 864, 821, 795, 764, 723, 689 cm⁻¹; HRMS (ESI) calcd for C₂₄H₁₇NO₄ (M + H⁺) 384.1230, found 384.1237.

(2,6-Dichlorophenyl)(2-(5-phenylisoxazol-3-yl)phenyl) methanone (1h). Gummy: 287 mg, isolated yield 73%; ¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, 2H, J = 8.0 Hz), 7.71 (t, 2H, J = 5.8 Hz), 7.68–7.65 (m, 2H), 7.57–7.53 (m, 2H), 7.49–7.43 (m, 2H), 7.33–7.31 (m, 2H), 6.68 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 192.3, 169.3, 163.4, 137.9, 135.7, 133.5, 132.5, 132.1, 131.6, 131.2, 130.7, 130.2, 130.1, 129.1, 128.4, 128.3, 127.6, 126.9, 126.0, 101.1; IR (KBr): 3065, 2925, 2852, 1818, 1750, 1684, 1613, 1588, 1574, 1489, 1429, 1400, 1259, 1211, 1195, 1163, 1115, 1091, 1070, 1026, 988, 948, 926, 805, 781, 761, 736, 689, 662 cm⁻¹; HRMS (ESI) calcd for C₂₂H₁₃Cl₂NO₂ (M + H⁺) 394.0396, found 394.0393.

(Naphthalen-2-yl)(2-(5-phenylisoxazol-3-yl)phenyl)methanone (1i). Gummy: 270 mg, isolated yield 72%; ¹H NMR (400 MHz, CDCl₃): δ 8.14 (s, 1H), 7.99 (d, 1H, J = 8.8 Hz), 7.85 (t, 2H, J = 7.6 Hz), 7.81 (d, 2H, J = 8.4 Hz), 7.67–7.59 (m, 4H), 7.55 (t, 3H, J = 7.9 Hz), 7.47 (t, 1H, J = 7.9 Hz), 7.36–7.35 (m, 2H), 6.56 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 197.7, 170.2, 162.2, 139.7, 136.1, 135.9, 134.7, 132.9, 132.5, 130.5, 130.3, 129.9, 129.6, 129.1, 128.9, 128.8, 128.7, 128.6, 128.5, 127.9, 126.8, 125.9, 125.6, 124.9, 99.9; IR (KBr): 3053, 2924, 2852, 1662, 1626, 1593, 1572, 1463, 1445, 1399, 1353, 1293, 1233, 1198, 1150, 1114, 1020, 949, 920, 866, 850, 823, 760, 710, 688 cm⁻¹; HRMS (ESI) calcd for C₂₆H₁₇NO₂ (M + H⁺) 376.1332, found 376.1326.

(2-(5-Phenylisoxazol-3-yl)phenyl)(thiophen-2-yl)methanone (1j). Gummy: 169 mg, isolated yield 51%; ¹H NMR (400 MHz, CDCl₃): δ 7.83 (d, 1H, J = 7.6 Hz), 7.70 (d, 2H, J = 8.4 Hz), 7.64 (d, 1H, J = 5.2 Hz), 7.60 (d, 1H, J = 9.2 Hz), 7.57–7.55 (m, 2H), 7.43–7.39 (m, 3H), 7.34 (d, 1H, J = 3.6 Hz), 7.01 (t, 1H, J = 4.4 Hz), 6.58 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 189.7, 171.1, 163.9, 144.6, 139.3, 135.9, 135.5, 130.7, 130.4, 129.7, 129.6, 129.1, 128.5, 128.4, 127.8, 127.5, 126.0, 100.2; IR (KBr): 3085, 2925, 2852, 1722, 1641, 1571, 1513, 1489, 1448, 1410, 1353, 1293, 1260, 1226, 1149, 1070, 1049, 948, 913, 888, 843, 803, 761, 725, 687, 640 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₃NO₂S (M + H⁺) 332.0740, found 332.0740.

(Furan-2-yl)(2-(5-phenylisoxazol-3-yl)phenyl)methanone (1k). Gummy: 123 mg, isolated yield 39%; ¹H NMR (400 MHz, CDCl₃): δ 7.80 (t, 1H, J = 6.8 Hz), 7.72–7.70 (m, 1H), 7.64–7.53 (m, 5H), 7.45–7.36 (m, 3H), 6.95 (d, 1H, J = 4.0 Hz), 6.59 (s, 1H), 6.43 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 169.9, 162.9, 162.8, 159.1, 155.9, 147.8, 140.4, 135.4, 131.1, 129.8, 129.2, 126.1, 121.5, 120.1, 112.7, 110.0, 100.1; IR (KBr): 3125, 3062, 2923, 2851, 1793, 1727, 1655, 1613, 1569, 1463, 1400, 1306, 1261, 1227, 1186, 1152, 1081, 1020, 950, 889, 762, 689, 650 cm⁻¹; HRMS (ESI) calcd for C₂₀H₁₃NO₃ (M + H⁺) 316.0968, found 316.0970.

2,2,6,6-Tetramethylpiperidin-1-yl benzoate (A). White solid: 172 mg, isolated yield 66%; ¹H NMR (600 MHz, CDCl₃): δ (ppm) 1.12 (s, 6H), 1.26 (s, 6H), 1.42–1.45 (m, 1H), 1.55–1.58 (m, 2H), 1.66–1.78 (m, 3H), 7.43 (t, 2H, J = 7.8 Hz), 7.54 (t, 1H, J = 7.8 Hz), 8.03–8.06 (m, 2H); ¹³C NMR (150 MHz, CDCl₃): δ (ppm) 17.2, 21.0, 32.1, 39.2, 60.6, 128.6, 129.7, 129.9, 133.0, 166.6; IR (KBr): 3007, 2973, 2940, 1741, 1641, 1452, 1365, 1253, 1238, 1083, 1062, 1026, 913, 718 cm⁻¹; HRMS (ESI) calcd. for C₁₆H₂₃NO₂ (M + H⁺) 262.1802; found 262.1801.

2-(5-Phenylisoxazol-3-yl)phenyl acetate (1a′). Gummy: 172 mg, isolated yield 62%; ¹H NMR (400 MHz, CDCl₃): δ 8.12 (d, 1H, J = 7.2 Hz), 7.84–7.79 (m, 2H), 7.51–7.46 (m, 4H), 7.37 (t, 1H, J = 7.0 Hz), 7.22 (d, 1H, J = 8.0 Hz), 6.79 (s, 1H), 2.35 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 170.2, 169.7, 160.3, 148.5, 133.9, 131.1, 130.4, 130.0, 129.2, 128.7, 126.7, 126.0, 123.8, 99.3, 21.4; IR (KBr): 3065, 2928, 2846, 1766, 1621, 1593, 1572, 1495, 1464, 1445, 1400, 1369, 1207, 1192, 1088, 948, 913, 820, 803, 762, 689 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₃NO₃ (M + H⁺) 280.0968, found 280.0977.

5-Methyl-2-(5-phenylisoxazol-3-yl)phenyl acetate (2a′). Gummy: 187 mg, isolated yield 64%; ¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, 2H, J = 8.0 Hz), 7.67 (d, 1H, J = 8.0 Hz), 7.48–7.43 (m, 3H), 7.16 (d, 1H, J = 8.0 Hz), 7.01 (s, 1H), 6.74 (s, 1H), 2.40 (s, 3H), 2.33 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 170.2, 169.7, 162.2, 150.0, 133.9, 131.1, 130.4, 130.0, 129.2, 128.7, 126.7, 126.0, 122.8, 99.3, 21.8, 21.1; IR (KBr): 2928, 2846, 1768, 1618, 1569, 1522, 1495, 1450, 1368, 1204, 1086, 969, 949, 807, 766, 690 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₅NO₃ (M + H⁺) 294.1125, found 294.1127.

5-Methoxy-2-(5-phenylisoxazol-3-yl)phenyl acetate (3a′). Gummy: 210 mg, isolated yield 68%; ¹H NMR (400 MHz, CDCl₃): δ 7.83–7.80 (m, 2H), 7.72 (d, 1H, J = 8.4 Hz), 7.48–7.45 (m, 3H), 6.90 (d, 1H, J = 8.8 Hz), 6.79–6.75 (m, 1H), 6.74 (s, 1H), 3.86 (s, 3H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 169.8, 164.9, 161.7, 149.6, 130.4, 129.2, 127.6, 125.9, 123.7, 121.7, 115.1, 112.6, 109.4, 99.0, 55.8, 21.4; IR (KBr): 2937, 2843, 1767, 1690, 1617, 1572, 1525, 1494, 1450, 1390, 1369, 1251, 1203, 1157, 1080, 948, 811, 765, 690, 630, 608 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₅NO₄ (M + H⁺) 310.1074, found 310.1078.

3-Nitro-2-(5-phenylisoxazol-3-yl)phenyl acetate (4a′). Gummy: 139 mg, isolated yield 43%; ¹H NMR (400 MHz, CDCl₃): δ 7.97 (d, 1H, J = 8.0 Hz), 7.93 (d, 1H, J = 7.6 Hz), 7.80–7.77 (m, 1H), 7.75–7.69 (m, 1H), 7.65–7.61 (m, 1H), 7.48 (d, 2H, J = 9.6 Hz), 7.37 (t, 1H, J = 7.6 Hz), 6.64 (s, 1H), 2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 170.4, 163.2, 160.2, 149.4, 133.2, 131.8, 129.3, 128.2, 126.2, 124.1, 120.5, 119.5, 113.4, 100.4, 22.0; IR (KBr): 2922, 2851, 1766, 1736, 1615, 1572, 1531, 1450, 1401, 1349, 1186, 1094, 949, 789, 765 cm⁻¹; HRMS (ESI) calcd for C₁₇H₁₂N₂O₅ (M + H⁺) 325.0819, found 325.0817.

2-((5-Phenylisoxazol-3-yl)methyl)phenyl acetate (5a′). Gummy: 196 mg, isolated yield 67%; ¹H NMR (400 MHz, CDCl₃): δ 7.70–7.68 (m, 2H), 7.43–7.37 (m, 3H), 7.30 (t, 2H, J = 7.8 Hz), 7.23–7.19 (m, 1H), 7.08 (d, 1H, J = 8.0 Hz), 6.23 (s, 1H), 3.96 (s, 2H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 170.1, 169.5, 162.8, 149.2, 130.9, 130.2, 129.5, 129.0, 128.5, 127.5, 126.6, 125.9, 122.9, 99.5, 27.5, 20.9; IR (KBr): 2922, 2840, 1760, 1647, 1486, 1448, 1419, 1378, 1218, 1171, 1094, 816, 766, 743, 699, 690 cm⁻¹; HRMS (ESI) calcd for C₁₈H₁₅NO₃ (M + H⁺) 294.1125, found 294.1121.

Acknowledgements

B. K. P. acknowledges the support of this research by the Department of Science and Technology (DST) (SR/S1/OC-79/2009), New Delhi, and CSIR (02(0096)/12/EMR-II). AB, SKS and SG thank CSIR for fellowships. Thanks are due to Central Instruments Facility (CIF) IIT Guwahati for NMR spectra.

References

1. (a) F. Kakiuchi and S. Murai, Acc. Chem. Res., 2002, 35, 826; (b) I. V. Seregin and V. Gevorgyan, Chem. Soc. Rev., 2007, 36, 1173; (c) L.-C. Campeau and K. Fagnou, Chem. Soc. Rev., 2007, 36, 1058; (d) O. Daugulis, H.-Q. Do and D. Shabashov, Acc. Chem. Res., 2009, 42, 1074; (e) X. Chen, K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (f) L. Ackermann, R. Vicente and A. R. Kapdi, Angew. Chem., Int. Ed., 2009, 48, 9792; (g) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624; (h) L.-M. Xu, B.-J. Li, Z. Yang and Z.-J. Shi, Chem. Soc. Rev., 2010, 39, 712; (i) L. Ackermann, Chem. Rev., 2011, 111, 1315; (j) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem. Rev., 2011, 111, 1293; (k) F. Bellina and R. Rossi, Chem. Rev., 2010, 110, 1082; (l) I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and J. F. Hartwig, Chem. Rev., 2010, 110, 890; (m) G. Dyker, Handbook of C–H Transformations, Wiley-VCH, Weinheim, 2005; (n) D. R. Stuart and K. Fagnou, Science, 2007, 316, 1172; (o) A. N. Verdernikov, Acc. Chem. Res., 2012, 45, 803; (p) K. Godula and D. Sames, Science, 2006, 312, 67; (q) R. J. Phipps and M. J. Gaunt, Science, 2009, 323, 1593; (r) D.-H. Wang, K. M. Engle, B.-F. Shi and J.-Q. Yu, Science, 2010, 327, 315; (s) J. Wencel-Delord, T. Dröge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; (t) L. McMurray, F. O'Hara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885; (u) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960; (v) M. C. White, Science, 2012, 335, 807; (w) J. Wencel-Delord and F. Glorius, Nat. Chem., 2013, 5, 369.
2. (a) C.-J. Li, Acc. Chem. Res., 2009, 42, 335; (b) J. A. Ashenhurst, Chem. Soc. Rev., 2010, 39, 540; (c) C. J. Scheuermann, Chem.–Asian J., 2010, 5, 436.
3. (a) N. Chatani, Directed Metallation, Springer, Berlin, Germany, 2008; (b) O. Daugulis, H. Q. Do and D. Shabashov, Acc. Chem. Res., 2009, 42, 1074; (c) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010, 110, 624; (d) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord and F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 10236.
4. (a) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012, 45, 788; (b) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174; (c) E. M. Beccalli, G. Broggini, M. Martinelli and S. Sottocornola, Chem. Rev., 2007, 107, 5318; (d) J. D. Neukom, A. S. Aquino and J. P. Wolfe, Org. Lett., 2011, 13, 2196; (e) D. Kim and S. Hong, Org. Lett., 2011, 13, 4466; (f) S. R. Neufeldt and M. S. Sanford, Acc. Chem. Res., 2012, 45, 936; (g) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215.
5. (a) X. Jia, S. Zhang, W. Wang, F. Luo and J. Cheng, Org. Lett., 2009, 11, 3120; (b) O. Baslé, J. Bidange, Q. Shuai and C.-J. Li, Adv. Synth. Catal., 2010, 352, 1145; (c) Y. Wu, B. Li, F. Mao, X. Li and F. Y. Kwong, Org. Lett., 2011, 13, 3258; (d) C. Li, L. Wang, P. Li and W. Zhou, Chem.–Eur. J., 2011, 17, 10208; (e) C.-W. Chan, Z. Zhou and W.-Y. Yu, Adv. Synth. Catal., 2011, 353, 2999; (f) J. Park, E. Park, A. Kim, Y. Lee, K. W. Chi, J. H. Kwak, Y. H. Jung and I. S. Kim, Org. Lett., 2011, 13, 4390; (g) C.-W. Chan, Z. Zhou, A. S. C. Chan and W.-Y. Yu, Org. Lett., 2010, 12, 3926; (h) A. Banerjee, S. K. Santra, S. Guin, S. K. Rout and B. K. Patel, Eur. J. Org. Chem., 2013, 1367.
6. (a) F. Xiao, Q. Shuai, F. Zhao, O. Baslé, G. Deng and C.-J. Li, Org. Lett., 2011, 13, 1614; (b) Y. Yuan, D. Chen and X. Wang, Adv. Synth. Catal., 2011, 353, 3373.
7. (a) S. Guin, S. K. Rout, A. Banerjee, S. Nandi and B. K. Patel, Org. Lett., 2012, 14, 5294; (b) Y. Wu, P. Y. Choy, F. Mao and F. Y. Kwong, Chem. Commun., 2013, 49, 689; (c) Z. Yin and P. Sun, J. Org. Chem., 2012, 77, 11339.
8. (a) H. Wang, L.-N. Guo and X.-H. Duan, Org. Lett., 2012, 14, 4358; (b) M. Kim, J. Park, S. Sharma, A. Kim, E. Park, J. H. Kwak, Y. H. Jung and I. S. Kim, Chem. Commun., 2013, 49, 925; (c) P. Fang, M. Li and H. Ge, J. Am. Chem. Soc., 2010, 132, 11898; (d) J. Park, M. Kim, S. Sharma, E. Park, A. Kim, S. H. Lee, J. H. Kwak, Y. H. Jung and I. S. Kim, Chem. Commun., 2013, 49, 1654; (e) S. Sharma, A. Kim, E. Park, J. Park, M. Kim, J. H. Kwak, S. H. Lee, Y. H. Jung and I. S. Kim, Adv. Synth. Catal., 2013, 355, 667; (f) C.-D. Pan, H.-M. Jin, X. Liu, Y.-X. Cheng and C.-J. Zhu, Chem. Commun., 2013, 49, 2933.
9. (a) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010, 110, 1147; (b) S. H. Kim, H. S. Lee, S. H. Kim and J. N. Kim, Tetrahedron Lett., 2008, 49, 5863; (c) F.-R. Gou, X.-C. Wang, P.-F. Huo, H.-P. Bi, Z.-H. Guan and Y.-M. Liang, Org. Lett., 2009, 11, 5726; (d) L. Wang, X.-D. Xia, W. Guo, J.-R. Chen and W.-J. Xiao, Org. Biomol. Chem., 2011, 9, 6895; (e) D. Kalyani and M. S. Sanford, Org. Lett., 2005, 7, 4149; (f) A. Company and S. Enthaler, Chem. Soc. Rev., 2011, 40, 4912; (g) D. A. Alonso, C. Nájera, I. M. Pastor and M. Yus, Chem.–Eur. J., 2010, 16, 5274; (h) X. Zheng, B. Song and B. Xu, Eur. J. Org. Chem., 2010, 2010, 4376; (i) X. Yang, G. Shan and Y. Rao, Org. Lett., 2013, 15, 2334; (j) Y. Yan, P. Feng, Q.-Z. Zheng, Y.-F. Liang, J.-F. Lu, Y. Cui and N. Jiao, Angew. Chem., Int. Ed., 2013, 52, 5827; (k) F. Mo, L. J. Trzepkowski and G. Dong, Angew. Chem., Int. Ed., 2012, 51, 13075; (l) A. Banerjee, A. Bera, S. Guin, S. K. Rout and B. K. Patel, Tetrahedron, 2013, 69, 2175.
10. (a) L. V. Desai, K. J. Stowers and M. S. Sanford, J. Am. Chem. Soc., 2008, 130, 13285; (b) T. W. Lyons, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2011, 133, 4455.
11. For recent examples of ketone directed C–H functionalisation: (a) E. M. Simmons and J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 17092; (b) F. Kakiuchi, T. Kochi, E. Mizushima and S. Murai, J. Am. Chem. Soc., 2010, 132, 17741; (c) K. Muralirajan, K. Parthasarathy and C.-H. Cheng, Angew. Chem., Int. Ed., 2011, 50, 4169; (d) K. Padala and M. Jeganmoham, Org. Lett., 2011, 13, 6144; (e) N. Schröder, J. Wencel-Delord and F. Glorius, J. Am. Chem. Soc., 2012, 134, 8298; (f) B. Xiao, T.-J. Gong, J. Xu, Z.-J. Liu and L. Liu, J. Am. Chem. Soc., 2011, 133, 1466; (g) F. W. Patureau, T. Besset and F. Glorius, Angew. Chem., Int. Ed., 2011, 50, 1064; (h) For recent examples of acid directed C–H functionalisation: B.-F. Shi, Y.-H. Zhang, J. K. Lam, D.-H. Wang and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 460; (i) K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int. Ed., 2010, 49, 6169; (j) K. M. Engle, D.-H. Wang and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 14137; (k) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L. B. Saunders and J.-Q. Yu, J. Am. Chem. Soc., 2007, 129, 3510.
12. For recent examples of ether/phenol directed C–H functionalisation: (a) G. Li, D. Leow, L. Wan and J.-Q. Yu, Angew. Chem., Int. Ed., 2013, 52, 1245; (b) X. Wang, Y. Lu, H.-X. Dai and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 12203; (c) Y. Lu, D.-H. Wang, K.-M. Engle and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 5916; (d) X. Wang, Y. Lu, H.-X. Dai and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 12203; (e) Y. Li, D. Leow, X. Wang, K. M. Engel and J.-Q. Yu, Chem. Sci., 2011, 2, 967.
13. J.-H. Chu, C.-C. Chen and M.-J. Wu, Organometallics, 2008, 27, 5173.
14. (a) J. J. Talley, D. L. Brown, J. S. Carter, M. J. Craneto, C. M. Koboldt, J. L. Masferrer, W. E. Perkins, R. S. Rogers, A. F. Shaffer, Y. Y. Zhang, B. S. Zweifel and K. Seibert, J. Med. Chem., 2000, 43, 775; (b) M. P. Giovannoni, C. Vergelli, C. Ghelardini, N. Galeotti, A. Bartolini and V. D. Piaz, J. Med. Chem., 2003, 46, 1055; (c) M. S. Malamas, E. S. Manas, R. E. McDevitt, I. Gunawan, Z. B. Xu, M. D. Collini, C. P. Miller, T. Dinh, R. A. Henderson, J. C. Keith Jr and H. A. Harris, J. Med. Chem., 2004, 47, 5021; (d) M. B. Soellner, K. A. Rawls, C. Grundner, T. Alber and J. A. Ellman, J. Am. Chem. Soc., 2007, 129, 9613.
15. (a) M. Nitta and T. Kobayashi, J. Chem. Soc., Perkin Trans. 1, 1985, 1401; (b) J. W. Bode and E. M. Carreira, Org. Lett., 2001, 3, 1587; (c) G. K. Tranmer and W. Tam, Org. Lett., 2002, 4, 4101; (d) M. Nitta and T. Kobayashi, J. Chem. Soc., Chem. Commun., 1982, 877; (e) D. Donati, S. Ferrini, S. Fusi and F. Ponticelli, J. Heterocycl. Chem., 2004, 41, 761; (f) C. Kashima, S. Tobe, N. Sugiyama and M. Yamamoto, Bull. Chem. Soc. Jpn., 1973, 46, 310; (g) N. R. Natale, Tetrahedron Lett., 1982, 23, 5009; (h) J. V. Greenhill, Chem. Soc. Rev., 1977, 6, 277.
16. (a) A. P. Tulloch, Chemistry of Waxes of Higher Plants, in Chemistry and Biochemistry of Natural Waxes, ed. P.E. Kolattukkudy, Elsevier, Amsterdam, 1976, p. 235; (b) B. Ramaroson-Raonizafinimanana, E. M. Gaydou and I. Bombarda, J. Agric. Food Chem., 2000, 48, 4739.
17. Crystallographic description of 1d: crystal dimension (mm): 0.38 × 0.28 × 0.24. C₂₃H₁₇NO₃, M_r = 355.38. Triclinic, space group P1̄; a = 8.8993 (11) Å, b = 10.4759 (13) Å, c = 11.0032 (14) Å; α = 70.634(7)°, β = 72.001 (5)°, γ = 73.148 (7)°, V = 900.14 (19) ų; Z = 2; ρ_cal = 1.311 mg m⁻³; μ (mm⁻¹) = 0.087; F(000) = 372.0; reflection collected/unique = 2964/2188; refinement method = full-matrix least-squares on F²; final R indices [I > 2σ_l ] R₁ = 0.1770, wR₂ = 0.4251, R indices (all data) R₁ = 0.1980, wR₂ = 0.4315; goodness of fit = 1.131 (see ESI.†).
18. Crystallographic description of 1g: crystal dimension (mm): 0.54 × 0.42 × 0.30. C₂₄H₁₇NO₄, M_r = 241.31. Triclinic, space group P1̄; a = 6.2208 (3) Å, b = 12.7931 (5) Å, c = 13.3551 (5) Å; α = 113.491(2)°, β = 91.551 (2)°, γ = 97.433 (2)°, V = 962.95 (7) ų; Z = 2; ρ_cal = 1.322 mg m⁻³; μ (mm⁻¹) = 0.091; F(000) = 400.0; reflection collected/unique = 1645/1333; refinement method = full-matrix least-squares on F²; final R indices [I > 2σ_l] R₁ = 0.0338, wR₂ = 0.0825, R indices (all data) R₁ = 0.0441, wR₂ = 0.0893; goodness of fit = 1.070 (see ESI.†).
19. (a) N. R. Deprez and M. S. Sanford, J. Am. Chem. Soc., 2009, 131, 11234; (b) J. M. Racowski, A. R. Dick and M. S. Sanford, J. Am. Chem. Soc., 2009, 131, 10974; (c) P. A. Sibbald, C. F. Rosewall, R. D. Swartz and F. E. Michael, J. Am. Chem. Soc., 2009, 131, 15945; (d) S. R. Whitfield and M. S. Sanford, J. Am. Chem. Soc., 2007, 129, 15142.
20. (a) D. C. Powers, M. A. L. Geibel, J. E. M. N. Klein and T. Ritter, J. Am. Chem. Soc., 2009, 131, 17050; (b) D. C. Powers and T. Ritter, Nat. Chem., 2009, 1, 302.
21. SMART V 4.043 Software for the CCD Detector System, Siemens Analytical Instruments Division, Madison, WI, 1995.
22. SAINT V 4.035 Software for the CCD Detector System, Siemens Analytical Instruments Division, Madison, WI, 1995.
23. G. M. Sheldrick, SHELXL-97, Program for the Refinement of Crystal Structures, University of Göttingen, Göttingen (Germany), 1997.

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Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra and HRMS spectra. CCDC reference numbers are 945394 and 945395. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ra45403g

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