Palladium-catalysed ortho-acylation of 6-anilinopurines/purine nucleosides via C–H activation

Abstract

Purinyl N1 directed ortho-acylation of 6-anilinopurines was achieved via C(sp²)–H bond activation in the presence of [Pd]-catalyst using aldehydes or α-oxocarboxylic acids as the acylating source. A wide variety of purine appended 2′-aminoacetophenones/benzophenones are isolated in good to excellent yields. These catalytic transformations are also successfully applied to 6-anilinopurine nucleosides.

---

Introduction

Aryl ketones are important building blocks in several biologically active natural products, pharmaceuticals and agrochemicals.¹ Thus, construction of these motifs always attracts considerable attention from synthetic chemists. Among the numerous methods developed for the synthesis of aryl ketones, Friedel–Crafts acylation is the most accepted synthetic procedure.² However, poor regioselectivity, limited functional group tolerance and using an over-stoichiometric amount of Lewis acid catalyst limit the scope of this reaction. Therefore, it is highly desirable to develop a mild and efficient method for the synthesis of aryl ketones.

Recently transition metal catalysed direct C–H bond acylation of arenes has been reported by several pioneering groups using aldehydes,³ α-oxocarboxylic acids,⁴ alcohols,⁵ toluene derivatives,⁶ benzylamines,⁷ benzyl chlorides/bromides,⁸ carboxylic acids,⁹ diketones¹⁰ or benzylic ethers¹¹ as acylating source with the aid of directing groups. This direct acylation reaction is more atom economic and environmentally friendly alternative to the Friedel–Crafts acylation, which is commonly used for the synthesis of aryl ketones. Purine could also be used as a directing group for the ortho-C–H functionalization of aryl moieties.¹² As our ongoing work on C–H activation¹³ and modification of nucleoside derivatives,¹⁴ we herein report the palladium-catalysed ortho-acylation of 6-anilinopurines with aldehydes/α-oxocarboxylic acids via purinyl N1 directed C–H bond activation. More importantly, this study provides the purine appended 2′-aminoacetophenones/benzophenones, which may be used as active pharmaceutical ingredients.¹⁵

Results and discussion

To achieve ortho-acylation, we have initiated our studies by performing the reaction of 6-anilinopurine 1a with 1-heptanal in the presence of Pd(OAc)₂ (5 mol%) with TBHP (3 equiv.) as an oxidant under neat conditions at 110 °C for 24 h. We were happy to find that ortho-acylated purine derivative 2a was obtained in 38% isolated yield (Table 1, entry 1). Inspired by this result, we proceeded to maximise the yield of the product 2a by varying the reaction parameters as depicted in Table 1. Among the solvents DMF, NMP, CH₃CN, DCE, dioxane, toluene, xylene and AcOH, only dioxane gave moderate yield (44%). In the remaining cases, product 2a yield was poor or negligible (Table 1, entries 2–9). Among the palladium catalysts, only palladium acetate gave better conversion to the acylated product 2a (Table 1, entries 10–12). Proper oxidant is also crucial for this reaction. Compared to TBHP, benzoyl peroxide or H₂O₂ or benzoquinone gave lower yields of the product 2a (Table 1, entries 13–15). Gratifyingly, further optimisation revealed that reaction proceeds better in dioxane/AcOH/DMSO (7/2/1, v/v/v) solvent mixture to afford the ortho-acylated product in good yield of 62%. Increasing the amount of catalyst Pd(OAc)₂ from 5 mol% to 10 mol% improved the yield of the product 2a to 74% after isolation (Table 1, entry 17). Thus, the optimised reaction conditions for the present reaction were: Pd(OAc)₂ (10 mol%), TBHP (3 equiv.) and dioxane/AcOH/DMSO (7/2/1, v/v/v, 3 mL) at 110 °C (oil bath temperature) for 24 h.

Table 1 Optimisation study for the [Pd]-catalysed ortho-acylation of 6-anilinopurines with aldehydes^a

Entry	Catalyst (5 mol%)	Oxidant	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 1-heptanal (0.6 mmol), oxidant (3 equiv.), solvent (3 mL), 110 °C (oil bath temperature).b Isolated yields. ND = not detected.c This solvent system was earlier used by Ge and coworkers.^4b
1	Pd(OAc)2	TBHP	—	38
2	Pd(OAc)2	TBHP	DMF	Trace
3	Pd(OAc)2	TBHP	NMP	21
4	Pd(OAc)2	TBHP	CH3CN (90 °C)	Trace
5	Pd(OAc)2	TBHP	DCE (90 °C)	23
6	Pd(OAc)2	TBHP	Dioxane	44
7	Pd(OAc)2	TBHP	Toluene	10
8	Pd(OAc)2	TBHP	Xylene	32
9	Pd(OAc)2	TBHP	AcOH	Trace
10	PdCl2	TBHP	Dioxane	18
11	PdCl2(CH3CN)2	TBHP	Dioxane	24
12	PdCl2(PPh3)2	TBHP	Dioxane	Trace
13	Pd(OAc)2	Benzoyl peroxide	Dioxane	ND
14	Pd(OAc)2	H2O2	Dioxane	31
15	Pd(OAc)2	Benzoquinone	Dioxane	16
16	Pd(OAc)2	TBHP	Dioxane/AcOH/DMSO (7/2/1, v/v/v)	62
17	Pd(OAc)2 (10 mol%)	TBHP	Dioxane/AcOH/DMSO (7/2/1, v/v/v)^c	74

---

After having the optimised reaction conditions in hand, we examined the substrate scope by varying the 6-anilinopurine derivatives and aldehydes (Table 2). Anilines bearing electron-donating or withdrawing substituents underwent cross-dehydrogenative coupling (CDC) with heptanal smoothly and produced the corresponding acylated derivatives 2a–2h in good to excellent yields (61–74%). Bromo and chloro functional groups were well tolerated and afforded ortho-acyl derivatives 2d and 2e. These products can pave way for further manipulation via cross-coupling reactions utilising the –Br/–Cl functionalities. The reaction is highly regioselective when performed with meta-substituted amines. In these cases, only one regioisomer was observed and the sterically less hindered C–H position was acylated. Under these catalytic conditions ortho-substituted 6-anilinopurines did not furnish the corresponding acylated derivatives.^4a,5b We have also examined the effect of purine N9-substituent on the course of the reaction. Thus, the reaction of (9-isopropyl-9H-purin-6-yl)-phenyl-amine 1i with heptanal afforded the ortho-acylated derivative 2i in good yield (70%). The generality of the methodology was then extended to 6-anilinopurine nucleoside 1j with 1-heptanal and 1-hexanal; in both the cases we have isolated the corresponding ortho-acylated nucleosides 2j and 2k respectively, in decent yields (54–56%). The reaction worked well in the case of simple 2-anilinopyrimidine, though.

Table 2 Scope of the ortho-acylation reaction with 6-anilinopurines and aldehydes^a

Entry no.	Substrate	Product	Yield^b (%)
a Reaction conditions: amine 1 (0.3 mmol), aldehyde (0.6 mmol), Pd(OAc)2 (10 mol%), TBHP (3 equiv.) and dioxane/AcOH/DMSO (7/2/1, v/v/v, 3 mL) at 110 °C (oil bath temperature) for 24 h.b Isolated yield.
1			74
2			71
3			72
4			66
5			62
6			68
7			61
8			63
9			70
10			56
11	1j		54
12			68
13	1a		71
14	1a		68
15	1a		60
16	1a		54

---

We then investigated the effect of a wide range of alkyl aldehydes. The reaction worked well with isovaleraldehyde (a branched aldehyde) and produced the acylated derivative 2n in good yield (68%). Cyclohexane carboxaldehyde also participated in this coupling and gave the corresponding ketone 2o in 60% yield. It is noteworthy that citronellal, a monoterpenoid could also provide the acylated derivative 2p in moderate yield (54%). Rather surprisingly, aryl aldehydes underwent oxidation to the corresponding carboxylic acids under these conditions. Thus, we observed the reactivity difference between the other directing group assisted cross dehydrogenative coupling (CDC) reaction of aryl aldehydes with the purine directed CDC reactions.³ The structure of one of the acylated derivatives (2m) was further confirmed by using X-ray crystallography (Fig. 1).

Fig. 1 Molecular structure of compound 2m. Selected bond lengths [Å] with esd's in parentheses: C(24)–O(1) 1.2263(17), C(24)–C(23) 1.490(2), N(10)–C(18) 1.3964(19), N(10)–C(6) 1.3621(18), N(9)–C(11) 1.4604(18).

Plausible mechanistic pathway for the ortho-acylation using aldehydes

Based on previous reports,³ a plausible pathway is outlined for Pd-catalysed ortho-acylation in Scheme 1. Initially, through the chelate-directed C–H activation of purine N1 atom, the six-membered cyclopalladated intermediate I is formed. The reaction of aldehyde with TBHP generates reactive acyl and OH radicals which react with intermediate I to produce the Pd(IV) intermediate II.³ Finally, species II undergoes reductive elimination leading to the formation of acylated derivative 2a (or 2b–2p). The active Pd(II) is regenerated for next catalytic cycle.

Scheme 1 Plausible reaction pathway for the formation of ortho-acylated derivatives from 6-anilinopurines with aldehydes.

Palladium-catalysed C(sp²)–H bond acylation of 6-anilinopurines with α-oxocarboxylic acids

The above Pd(OAc)₂/TBHP catalytic system was applicable to alkyl aldehydes only; aryl aldehydes under those catalytic conditions were oxidized to the corresponding carboxylic acids. We overcame this drawback by choosing α-oxocarboxylic acid as the acylating source. Ag₂O and K₂S₂O₈ were used as oxidant and co-oxidant respectively (Scheme 2), under conditions similar to that available in the literature.^4b Thus, the reaction of 6-anilinopurine 1a with phenylglyoxylic acid in the presence of PdCl₂ (10 mol%) afforded the corresponding acylated derivative 3a in good yield (64%). Although Pd(OAc)₂ also worked, the yield was lower (50%). Under these catalytic conditions, we have examined the substrate scope with respect to 4-Cl and 3-OMe substituted anilinopurines (1e and 1j) also. In both the cases, the corresponding ortho-aroyl derivative was isolated in good yield. Arylglyoxylic acids containing Me, F or Br functional groups are well tolerated under these conditions and afford the ortho-aroyl derivatives 3d–3g in good yields. It is noteworthy that the reaction also proceeded smoothly with 2-ketobutyric acid (an alkyl α-oxocarboxylic acid) by furnishing the ortho-acyl derivative 3h in 63% yield. Thus, our protocol is applicable for both aryl and alkyl α-oxocarboxylic acids.

Scheme 2 Synthesis of ortho-aroyl 6-anilinopurines using α-oxocarboxylic acid as acylating source.

Conclusions

In summary, we have developed an efficient method for the Pd-catalysed oxidative ortho-acylation of 6-anilinopurines with alkyl aldehydes via C–H bond activation. A broad range of functional groups and a variety of alkyl aldehydes were well tolerated under these catalytic conditions. This protocol was also successfully applied on 6-anilinopurine nucleoside. 2′-Aminobenzophenones are synthesized by using α-oxocarboxylic acids as the acylating source. Further studies on the mechanistic pathway are currently going on in our laboratory.

Experimental section

General comments

Solvents were dried according to known methods as appropriate.^{16 1}H, ¹³C spectra (¹H, 400 MHz; ¹³C, 100 MHz) were recorded using a 400 MHz spectrometer in CDCl₃ with shifts referenced to SiMe₄ (δ = 0). IR spectra were recorded on an FTIR spectrophotometer. Melting points were determined by using a local hot-stage melting point apparatus and are uncorrected. Elemental analyses were carried out on a CHN analyser. Mass spectra were recorded using LC-MS and HRMS (ESI-TOF analyser) equipment.

General procedure for the ortho-acylation of 6-anilinopurine derivatives with aldehydes: synthesis of compounds 2a–2p

A mixture of 6-anilinopurine (0.3 mmol) and Pd(OAc)₂ (10 mol%) was taken in a Schlenk tube under N₂. To this, dioxane/AcOH/DMSO (7/2/1, v/v/v, 3 mL) solvent mixture was added and stirring was continued at rt for 10 min. To this mixture, aldehyde (0.6 mmol) and TBHP (0.9 mmol) were added. The contents were heated with stirring at 110 °C (oil bath temperature) for 24 h. After cooling to rt, the reaction mixture was extracted with EtOAc (3 × 30 mL) and water. The combined organic phase was washed with brine solution (30 mL), dried over anh. Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using n-hexane–EtOAc (4 : 1) mixture as the eluent.

Compound 2a. Yield 0.092 g (74%); white solid; mp = 164–168 °C; IR ν_max (KBr): 3284, 3059, 1615, 1576, 1480, 1449, 1256, 1151, 1024, 891, 725, 700 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.66 (s, 1H), 9.27 (d, J = 8.4 Hz, 1H), 8.63 (s, 1H), 7.99–7.97 (m, 1H), 7.93 (s, 1H), 7.63–7.58 (m, 1H), 7.37–7.29 (m, 5H), 7.07 (t, J ∼ 7.4 Hz, 1H), 5.42 (s, 2H), 3.06 (t, J ∼ 7.4 Hz, 2H), 1.81–1.76 (m, 2H), 1.40–1.26 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.8, 152.7, 152.2, 150.1, 142.4, 141.5, 135.7, 134.5, 131.2, 129.1, 128.4, 127.7, 121.8, 121.6, 120.9, 120.8, 47.3, 40.0, 31.7, 29.1, 24.8, 22.6, 14.1; HRMS (ESI): calcd for C₂₅H₂₈N₅O [M⁺ + H]: m/z 414.2295. Found: 414.2302.

Compound 2b. Yield 0.091 g (71%); white solid; mp = 154–158 °C; IR ν_max (KBr): 3079, 2915, 1611, 1567, 1534, 1463, 1299, 1178, 784, 723 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.49 (s, 1H), 9.12 (d, J = 8.8 Hz, 1H), 8.61 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.37–7.27 (m, 5H), 5.42 (s, 2H), 3.05 (t, J ∼ 7.4 Hz, 2H), 2.40 (s, 3H), 1.81–1.78 (m, 2H), 1.43–1.31 (m, 6H), 0.91–0.88 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.7, 152.7, 152.2, 149.9, 141.2, 139.9, 135.7, 135.2, 131.2, 130.3, 129.1, 128.4, 127.6, 121.8, 121.6, 120.8, 47.2, 39.9, 31.7, 29.1, 24.7, 22.6, 20.9, 14.1; HRMS (ESI): calcd for C₂₆H₃₀N₅O [M⁺ + H]: m/z 428.2451. Found: 428.2450.

Compound 2c. Yield 0.096 g (72%); white solid; mp = 132–136 °C; IR ν_max (KBr): 3441, 3083, 2952, 1608, 1586, 1478, 1350, 1248, 1175, 1047, 979, 840, 726 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.20 (s, 1H), 9.15 (d, J = 9.6 Hz, 1H), 8.59 (s, 1H), 7.89 (s, 1H), 7.47 (d, J = 3.2 Hz, 1H), 7.35–7.29 (m, 5H), 7.21 (dd, J ∼ 9.4 Hz, ∼3.0 Hz, 1H), 5.42 (s, 2H), 3.87 (s, 3H), 3.03 (t, J = 7.6 Hz, 2H), 1.81–1.77 (m, 2H), 1.40–1.30 (m, 6H), 0.89 (t, J ∼ 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.4, 153.6, 152.8, 152.2, 149.9, 141.1, 135.9, 135.8, 129.1, 128.4, 127.7, 123.0, 122.5, 121.5, 120.1, 116.0, 55.9, 47.3, 40.1, 31.7, 29.1, 24.7, 22.6, 14.1; HRMS (ESI): calcd for C₂₆H₃₀N₅O₂ [M⁺ + H]: m/z 444.2400. Found: 444.2399.

Compound 2d. Yield 0.098 g (66%); white solid; mp = 170–174 °C; IR ν_max (KBr): 3429, 3079, 2952, 1612, 1581, 1525, 1486, 1381, 1300, 1184, 1023, 837, 731 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.53 (s, 1H), 9.25 (d, J = 9.2 Hz, 1H), 8.63 (s, 1H), 8.06 (br, 1H), 7.93 (s, 1H), 7.67 (dd, J ∼ 9.0 Hz, ∼ 2.2 Hz, 1H), 7.38–7.28 (m, 5H), 5.43 (s, 2H), 3.03 (t, J ∼ 7.4 Hz, 2H), 1.83–1.76 (m, 2H), 1.42–1.26 (m, 6H), 0.90 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 203.7, 152.6, 151.9, 150.3, 141.7, 141.4, 137.1, 135.6, 133.5, 129.2, 128.5, 127.7, 123.1, 122.7, 121.9, 113.0, 47.4, 40.0, 31.7, 29.0, 24.5, 22.6, 14.1; HRMS (ESI): calcd for C₂₅H₂₇BrN₅O [M⁺ + H]: m/z 492.1400. Found: 492.1399.

Compound 2e. Yield 0.083 g (62%); white solid; mp = 184–188 °C; IR ν_max (KBr): 3449, 3106, 2928, 1614, 1583, 1525, 1466, 1405, 1351, 1327, 1298, 1139, 1018, 837, 725 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.53 (s, 1H), 9.30 (d, J = 9.2 Hz, 1H), 8.62 (s, 1H), 7.93 (s, 1H), 7.92 (d, J = 2.4 Hz, 1H), 7.54 (dd, J = 9.2 Hz, =2.4 Hz, 1H), 7.37–7.29 (m, 5H), 5.43 (s, 2H), 3.03 (t, J ∼ 7.4 Hz, 2H), 1.83–1.75 (m, 2H), 1.42–1.32 (m, 6H), 0.91–0.89 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 203.7, 152.6, 151.9, 150.2, 141.7, 141.0, 135.6, 134.3, 130.6, 129.1, 128.5, 127.7, 125.7, 122.6, 122.3, 121.8, 47.3, 40.0, 31.7, 29.0, 24.5, 22.6, 14.1; HRMS (ESI): calcd for C₂₅H₂₇ClN₅O [M⁺ + H]: m/z 448.1905. Found: 448.1903.

Compound 2f. Yield 0.088 g (68%); white solid; mp = 132–136 °C; IR ν_max (KBr): 3453, 3100, 2930, 1620, 1588, 1472, 1328, 1259, 1175, 1023, 833, 726 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.40 (s, 1H), 9.29 (dd, J = 9.2 Hz, 5.2 Hz, 1H), 8.61 (s, 1H), 7.92 (s, 1H), 7.64 (dd, J ∼ 9.4 Hz, ∼ 3.0 Hz, 1H), 7.37–7.28 (m, 6H), 5.43 (s, 2H), 3.02 (t, J = 7.6 Hz, 2H), 1.81–1.75 (m, 2H), 1.42–1.26 (m, 6H), 0.89 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 203.7, 156.5 (d, J_(C–F) = 240.5 Hz), 152.6, 152.0, 150.1, 141.5, 138.7, 135.7, 129.2, 128.5, 127.7, 122.8, 122.7, 122.5, 121.7, 121.6, 121.5, 116.9, 116.6, 47.3, 40.1, 31.7, 29.1, 24.6, 22.6, 14.1; HRMS (ESI): calcd for C₂₅H₂₇FN₅O [M⁺ + H]: m/z 432.2200. Found: 432.2200.

Compound 2g. Yield 0.088 g (61%); white solid; mp = 160–164 °C; IR ν_max (KBr): 3463, 2931, 2849, 1731, 1616, 1589, 1468, 1233, 1123, 1025, 729 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.81 (s, 1H), 9.49 (d, J = 8.8 Hz, 1H), 8.67 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.38–7.29 (m, 5H), 5.44 (s, 2H), 3.10 (t, J ∼ 7.4 Hz, 2H), 1.85–1.78 (m, 2H), 1.44–1.33 (m, 6H), 0.92–0.90 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.0, 152.5, 151.7, 150.5, 145.2, 142.0, 135.5, 130.9, 129.2, 128.6, 128.2, 127.8, 122.1, 121.0, 120.8, 47.4, 40.0, 31.7, 29.0, 24.5, 22.6, 14.1; HRMS (ESI): calcd for C₂₆H₂₇F₃N₅O [M⁺ + H]: m/z 482.2168. Found: 482.2167.

Compound 2h. Yield 0.093 g (63%); white solid; mp = 152–156 °C; IR ν_max (KBr): 2937, 2849, 1644, 1605, 1567, 1463, 1408, 1025, 882 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.72 (s, 1H), 9.63 (s, 1H), 8.67 (s, 1H), 7.93 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.38–7.27 (m, 5H), 7.19 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 5.43 (s, 2H), 3.02 (t, J ∼ 7.4 Hz, 2H), 1.82–1.75 (m, 2H), 1.41–1.31 (m, 6H), 0.89 (t, J ∼ 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.2, 152.7, 151.8, 150.3, 143.4, 141.8, 135.6, 132.2, 129.4, 129.2, 128.5, 127.7, 123.9, 123.5, 121.9, 120.0, 47.3, 40.1, 31.7, 29.1, 24.7, 22.6, 14.1; HRMS (ESI): calcd for C₂₅H₂₇BrN₅O [M⁺ + H]: m/z 492.1400. Found: 492.1399.

Compound 2i. Yield 0.077 g (70%); white solid; mp = 88–92 °C; IR ν_max (KBr): 3096, 2948, 1616, 1584, 1534, 1447, 1238, 975 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.62 (s, 1H), 9.26 (d, J = 8.8 Hz, 1H), 8.60 (s, 1H), 8.00 (s, 1H), 7.98 (s, 1H), 7.63–7.59 (m, 1H), 7.09–7.05 (m, 1H), 4.94–4.84 (m, 1H), 3.06 (t, J = 7.6 Hz, 2H), 1.88–1.78 (m, 2H), 1.64 (d, J = 6.8 Hz, 6H), 1.42–1.31 (m, 6H), 0.89 (t, J ∼ 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.8, 152.2, 152.1, 149.6, 142.5, 139.1, 134.5, 131.2, 122.3, 121.7, 120.9, 120.8, 47.2, 40.1, 31.8, 29.2, 24.8, 22.8, 22.6, 14.1; HRMS (ESI): calcd for C₂₁H₂₈N₅O [M⁺ + H]: m/z 366.2295. Found: 366.2293.

Compound 2j. Yield 0.065 g (56%); gummy liquid; IR ν_max (neat): 2948, 2860, 1753, 1560, 1447, 1353, 1227, 1096 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.69 (s, 1H), 9.26 (d, J = 8.4 Hz, 1H), 8.62 (s, 1H), 8.11 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.64 (t, J ∼ 7.6 Hz, 1H), 7.12 (t, J ∼ 7.6 Hz, 1H), 6.25 (d, J = 5.2 Hz, 1H), 6.02 (t, J = 5.6 Hz, 1H), 5.73–5.71 (m, 1H), 4.50–4.39 (m, 3H), 3.09 (t, J ∼ 7.4 Hz, 2H), 2.18–2.17 (m, 6H), 2.10 (s, 3H), 1.86–1.79 (m, 2H), 1.43–1.29 (m, 6H), 0.93–0.91 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.9, 170.5, 169.7, 169.4, 152.9, 152.3, 149.6, 142.2, 139.9, 134.6, 131.2, 122.5, 121.8, 121.2, 120.9, 86.3, 80.5, 73.1, 70.9, 63.2, 40.1, 31.7, 29.1, 24.8, 22.6, 20.9, 20.6, 20.5, 14.1; HRMS (ESI): calcd for C₂₉H₃₆N₅O₈ [M⁺ + H]: m/z 582.2565. Found: 582.2568.

Compound 2k. Yield 0.061 g (54%); gummy liquid; IR ν_max (neat): 2953, 2931, 1753, 1605, 1447, 1227, 1096, 1047, 756 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.67 (s, 1H), 9.24 (d, J = 8.4 Hz, 1H), 8.60 (s, 1H), 8.11 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.62 (t, J ∼ 7.8 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.24 (d, J = 5.6 Hz, 1H), 6.01 (t, J = 5.6 Hz, 1H), 5.71 (t, J ∼ 4.8 Hz, 1H), 4.50–4.38 (m, 3H), 3.07 (t, J = 7.6 Hz, 2H), 2.16 (s, 3H), 2.15 (s, 3H), 2.08 (s, 3H), 1.83–1.80 (m, 2H), 1.41–1.37 (m, 4H), 0.94–0.90 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.9, 170.4, 169.6, 169.4, 152.8, 152.3, 149.6, 142.1, 139.9, 134.5, 131.1, 122.4, 121.7, 121.1, 120.8, 86.2, 80.4, 73.1, 70.8, 63.2, 40.0, 31.6, 24.5, 22.6, 20.8, 20.6, 20.4, 14.0; HRMS (ESI): calcd for C₂₈H₃₄N₅O₈ [M⁺ + H]: m/z 568.2408. Found: 568.2404.

Compound 2l. Yield 0.058 g (68%); white solid; mp = 80–84 °C; IR ν_max (KBr): 3216, 2931, 2849, 1655, 1573, 1562, 1523, 1441, 1304, 1162, 975, 800, 745 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 11.89 (s, 1H), 8.90 (d, J = 8.4 Hz, 1H), 8.60 (s, 1H), 8.52–8.50 (m, 1H), 7.95 (dd, J = 8.0 Hz, 1.6 Hz, 1H), 7.58–7.54 (m, 1H), 7.04–7.00 (m, 1H), 6.81–6.78 (m, 1H), 3.05 (t, J ∼ 7.4 Hz, 2H), 1.80–1.73 (m, 2H), 1.45–1.32 (m, 6H), 0.93–0.90 (m, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.3, 160.2, 157.9, 142.7, 134.3, 131.1, 121.3, 120.1, 119.5, 113.4, 40.0, 31.8, 29.1, 24.8, 22.6, 14.1; HRMS (ESI): calcd for C₁₇H₂₂N₃O [M⁺ + H]: m/z 284.1764. Found: 284.1763.

Compound 2m. Yield 0.085 g (71%); white solid; mp = 132–136 °C; IR ν_max (KBr): 3447, 3083, 2952, 1603, 1583, 1531, 1448, 1349, 1303, 1250, 1192, 1022, 972, 727 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.68 (s, 1H), 9.29 (d, J = 8.4 Hz, 1H), 8.65 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.94 (s, 1H), 7.62 (t, J ∼ 7.8 Hz, 1H), 7.38–7.30 (m, 5H), 7.08 (t, J = 7.6 Hz, 1H), 5.44 (s, 2H), 3.07 (t, J ∼ 7.4 Hz, 2H), 1.84–1.80 (m, 2H), 1.41–1.38 (m, 4H), 0.92 (t, J ∼ 7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.8, 152.6, 152.1, 150.0, 142.4, 141.4, 135.7, 134.5, 131.1, 129.1, 128.4, 127.6, 121.8, 121.6, 120.9, 120.7, 47.2, 39.9, 31.6, 24.5, 22.6, 14.0; HRMS (ESI): calcd for C₂₄H₂₆N₅O [M⁺ + H]: m/z 400.2138. Found: 400.2130. X-ray structure was determined for this compound.

Compound 2n. Yield 0.079 g (68%); white solid; mp = 134–138 °C; IR ν_max (KBr): 3079, 2959, 1611, 1584, 1523, 1457, 1304, 1200, 1025 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.68 (s, 1H), 9.30–9.28 (m, 1H), 8.65 (s, 1H), 8.00–7.97 (m, 1H), 7.95 (s, 1H), 7.64–7.60 (m, 1H), 7.38–7.30 (m, 5H), 7.11–7.06 (m, 1H), 5.44 (s, 2H), 2.94 (d, J = 6.8 Hz, 2H), 2.46–2.36 (m, 1H), 1.03 (d, J = 6.4 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 204.5, 152.6, 152.1, 150.0, 142.4, 141.4, 135.6, 134.5, 131.3, 129.1, 128.9, 128.4, 127.6, 121.9, 121.8, 120.9, 120.7, 48.8, 47.2, 25.5, 22.9; HRMS (ESI): calcd for C₂₃H₂₄N₅O [M⁺ + H]: m/z 386.1982. Found: 386.1978.

Compound 2o. Yield 0.074 g (60%); white solid; mp = 268–272 °C; IR ν_max (KBr): 3085, 2932, 2860, 1605, 1584, 1452, 1310, 1162, 981, 723 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.75 (s, 1H), 9.29 (d, J = 7.6 Hz, 1H), 8.65 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.95 (s, 1H), 7.65–7.61 (m, 1H), 7.39–7.29 (m, 5H), 7.11 (t, J = 7.6 Hz, 1H), 5.45 (s, 2H), 3.44–3.39 (m, 1H), 1.99–1.86 (m, 4H), 1.69–1.60 (m, 2H), 1.47–1.25 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 208.0, 152.6, 152.1, 150.0, 142.8, 141.4, 135.6, 134.4, 130.9, 129.0, 128.3, 127.6, 121.7, 120.9, 120.5, 47.2, 46.6, 29.8, 25.9; HRMS (ESI): calcd for C₂₅H₂₆N₅O [M⁺ + H]: m/z 412.2138. Found: 412.2141.

Compound 2p. Yield 0.073 g (54%); white solid; mp = 82–86 °C; IR ν_max (KBr): 2964, 2926, 1720, 1605, 1529, 1447, 1304, 1238, 1025 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.68 (s, 1H), 9.29 (d, J = 8.4 Hz, 1H), 8.67 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.95 (s, 1H), 7.65–7.62 (m, 1H), 7.39–7.27 (m, 5H), 7.12–7.08 (m, 1H), 5.45 (s, 2H), 5.13–5.10 (m, 1H), 3.08 (dd, J = 15.4 Hz and J = 5.2 Hz, 1H), 2.85 (dd, J = 15.4 Hz and J = 8.4 Hz, 1H), 2.35–2.27 (m, 1H), 2.10–2.00 (m, 2H), 1.69 (s, 3H), 1.62 (s, 3H), 1.49–1.42 (m, 1H), 1.38–1.29 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 204.7, 152.7, 152.2, 150.1, 142.4, 141.5, 135.7, 134.6, 131.6, 131.3, 129.2, 128.5, 127.7, 124.5, 122.1, 121.9, 121.0, 120.8, 47.3, 37.4, 30.0, 25.8, 25.6, 20.2, 17.8; HRMS (ESI): calcd for C₂₈H₃₂N₅O [M⁺ + H]: m/z 454.2608. Found: 454.2610.

General procedure for the ortho-acylation of 6-anilinopurine derivatives with α-oxocarboxylic acids: synthesis of compounds 3a–3h

A mixture of 6-anilinopurine (0.3 mmol), PdCl₂ (10 mol%), Ag₂O (0.3 mmol), K₂S₂O₈ (0.3 mmol) and α-oxocarboxylic acid (0.6 mmol) was taken in a Schlenk tube under N₂ atmosphere. To this, dioxane/AcOH/DMSO (7/2/1, v/v/v, 3 mL) mixture was added and the contents stirred at 110 °C (oil bath temperature) for 24 h. After cooling to rt, the reaction mixture was extracted with EtOAc (3 × 30 mL) and washed with water (30 mL). The combined organic phase was washed with brine solution (30 mL), dried over anh. Na₂SO₄ and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using n-hexane–EtOAc (3 : 2) mixture as the eluent.

Compound 3a. Yield: 0.077 g (64%); white solid; mp = 190–194 °C; IR ν_max (KBr): 3299, 3058, 1622, 1573, 1474, 1321, 1249, 1156, 1025, 756 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 11.76 (s, 1H), 9.14 (d, J = 8.8 Hz, 1H), 8.66 (br, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.93 (br, 1H), 7.79 (d, J = 7.6 Hz, 2H), 7 69–7.65 (m, 2H), 7.61–7.58 (m, 1H), 7.51–7.48 (m, 2H), 7.40–7.29 (m, 4H), 7.09 (t, J = 7.6 Hz, 1H), 5.45 (s, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 199.4, 152.7, 152.0, 150.1, 141.8, 141.3, 138.9, 135.6, 134.1, 134.0, 132.2, 130.1, 129.1, 128.4, 128.1, 127.7, 123.1, 121.5, 121.2, 120.9, 47.2; HRMS (ESI): calcd for C₂₅H₂₀N₅O [M⁺ + H]: m/z 406.1669. Found: 406.1667.

Compound 3b. Yield: 0.072 g (55%); white solid; mp = 202–206 °C; IR ν_max (KBr): 3423, 2920, 1615, 1521, 1479, 1323, 1249, 1026, 823, 764 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 8.43 (s, 1H), 8.29 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H), 7.72 (dd, J = 7.2 Hz and 2.0 Hz, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.58–7.55 (m, 1H), 7.46–7.43 (m, 3H), 7.36–7.33 (m, 2H), 7.30–7.27 (m, 3H), 5.41 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 195.7, 151.9, 151.5, 150.3, 143.1, 138.2, 137.5, 137.2, 133.0, 132.8, 130.9, 129.9, 129.2, 128.7, 128.3, 128.1, 128.0, 126.9, 125.5, 122.6, 120.4, 46.8; HRMS (ESI): calcd for C₂₅H₁₉ClN₅O [M⁺ + H]: m/z 440.1279. Found: 440.1279.

Compound 3c. Yield 0.09 g (63%); white solid; mp = 232–236 °C; IR ν_max (KBr): 3443, 2920, 1602, 1585, 1467, 1338, 1264, 1240, 1098, 1027, 906, 722 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 13.13 (s, 1H), 9.08 (d, J = 2.4 Hz, 1H), 8.70 (s, 1H), 7.97 (s, 1H), 7.37–7.30 (m, 6H), 6.90 (s, 2H), 6.46 (dd, J ∼ 9.0 Hz and ∼2.6 Hz, 1H), 5.46 (s, 2H), 3.98 (s, 3H), 2.35 (s, 3H), 2.14 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 202.8, 165.1, 152.6, 152.3, 150.2, 145.5, 141.7, 138.2, 137.6, 136.3, 135.6, 134.1, 129.2, 128.5, 127.7, 122.0, 116.1, 108.1, 104.4, 55.7, 47.3, 21.2, 19.4; HRMS (ESI): calcd for C₂₉H₂₈N₅O₂ [M⁺ + H]: m/z 478.2244. Found: 478.2240.

Compound 3d. Yield 0.08 g (60%); white solid; mp = 220–224 °C; IR ν_max (KBr): 2926, 1748, 1605, 1584, 1452, 1249, 1151, 1019, 915 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.82 (s, 1H), 9.37 (d, J = 8.4 Hz, 1H), 8.71 (s, 1H), 8.00 (s, 1H), 7.67–7.63 (m, 1H), 7.44 (d, J = 8.4 Hz, 2H), 7 37–7.29 (m, 5H), 6.98–6.92 (m, 2H), 5.47 (s, 2H), 2.36 (s, 3H), 2.15 (s, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 204.8, 152.6, 152.2, 150.2, 143.0, 141.6, 138.5, 137.3, 135.6, 135.4, 134.1₃, 134.0₉, 129.1, 128.4, 128.3, 127.7, 122.1, 121.9, 121.2, 120.4, 47.3, 21.2, 19.5; HRMS (ESI): calcd for C₂₈H₂₆N₅O [M⁺ + H]: m/z 448.2138. Found: 448.2134.

Compound 3e. Yield 0.077 g (61%); white solid; mp = 204–208 °C; IR ν_max (KBr): 3298, 3052, 1632, 1583, 1501, 1462, 1358, 1254, 1029, 925, 772 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 11.62 (s, 1H), 9.06 (d, J = 8.0 Hz, 1H), 8.63 (s, 1H), 7.92 (s, 1H), 7.71–7.62 (m, 4H), 7.36–7.26 (m, 7H), 7.11–7.07 (m, 1H), 5.44 (s, 2H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 198.9, 152.8, 152.0, 150.0, 143.1, 141.4, 141.3, 136.1, 135.6, 133.7₄, 133.6₉, 130.5, 130.2, 129.2, 129.1, 128.9, 128.5, 127.7, 123.9, 121.4, 121.0, 47.3, 21.7; LC-MS: m/z = 420 [M + 1]⁺; anal. calcd for C₂₆H₂₁N₅O: C, 74.44; H, 5.05; N, 16.70; found: C, 74.53; H, 5.12; N, 16.75.

Compound 3f. Yield 0.084 g (66%); white solid; mp = 222–226 °C; IR ν_max (KBr): 3128, 2975, 1616, 1578, 1528, 1495, 1353, 1260, 1150, 1090, 931, 843 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 11.53 (s, 1H), 9.07 (dd, J = 8.5 Hz and 2.0 Hz, 1H), 8.64 (s, 1H), 7.92 (s, 1H), 7.84–7.81 (m, 2H), 7.68–7.62 (m, 2H), 7.38–7.28 (m, 5H), 7.18–7.14 (m, 2H), 7.12–7.09 (m, 1H), 5.44 (s, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 197.7, 165.3 (d, J_(C–F) = 252.6 Hz), 152.8, 152.0, 150.1, 141.6, 141.4, 135.6, 135.0₁, 134.9₈, 134.1, 133.5, 132.8₃, 132.7₆, 129.2, 128.5, 127.7, 123.4, 121.5₂, 121.4₅, 121.1, 115.6, 115.5, 115.3, 47.3; LC-MS: m/z = 424 [M + 1]⁺; anal. calcd for C₂₅H₁₈FN₅O: C, 70.91; H, 4.28; N, 16.54; found: C, 70.82; H, 4.23; N, 16.45.

Compound 3g. Yield 0.084 g (58%); white solid; mp = 234–238 °C; IR ν_max (KBr): 3156, 2991, 1676, 1616, 1588, 1495, 1446, 1353, 1265, 1183, 1073, 936, 750 cm⁻¹; ¹H NMR (500 MHz, CDCl₃): δ 11.58 (s, 1H), 9.07 (dd, J = 8.5 Hz, 1H), 8.64 (s, 1H), 7.96–7.94 (m, 1H), 7.67–7.61 (m, 6H), 7.39–7.30 (m, 5H), 7.12–7.09 (m, 1H), 5.45 (s, 2H); ¹³C NMR (125 MHz, CDCl₃): δ 198.1, 152.8, 152.0, 150.1, 141.7, 141.5, 137.6, 135.5, 134.3, 133.6, 131.9, 131.7, 131.5, 129.2, 128.5, 127.8, 127.3, 123.2, 121.6, 121.4, 121.2, 47.4; LC-MS: m/z = 486 [M + 2]⁺; anal. calcd for C₂₅H₁₈BrN₅O: C, 61.99; H, 3.75; N, 14.46; found: C, 61.85; H, 3.81; N, 14.38.

Compound 3h. Yield 0.067 g (63%); white solid; mp = 140–144 °C; IR ν_max (KBr): 3156, 2991, 1660, 1583, 1490, 1451, 1380, 1298, 1205, 1134, 1079, 953 cm⁻¹; ¹H NMR (400 MHz, CDCl₃): δ 12.68 (s, 1H), 9.29 (d, J = 8.0 Hz, 1H), 8.65 (s, 1H), 8.01 (dd, J = 8.0 Hz and 1.6 Hz, 1H), 7.94 (s, 1H), 7.65–7.60 (m, 1H), 7.38–7.29 (m, 5H), 7.11–7.07 (m, 1H), 5.44 (s, 2H), 3.14 (qrt, J = 7.2 Hz, s), 1.29 (t, J = 7.2 Hz); ¹³C NMR (100 MHz, CDCl₃): δ 205.0, 152.7, 152.2, 150.1, 142.4, 141.5, 135.7, 134.6, 131.0, 129.1, 128.5, 127.7, 121.8, 121.5, 121.0, 120.8, 47.3, 33.2, 8.7; LC-MS: m/z = 358 [M + 1]⁺; anal. calcd for C₂₁H₁₉N₅O: C, 70.57; H, 5.36; N, 19.59; found: C, 70.45; H, 5.41; N, 19.48.

X-ray data

X-ray data for compound 2m was collected using Mo K_α (λ = 0.71073 Å) radiation. The structure was solved and refined by standard methods.¹⁷

Compound 2m. C₂₄H₂₅N₅O, M = 399.49, triclinic, space group P1̄, a = 8.249(3), b = 9.685(3), c = 14.060(5) Å, α = 94.073(6), β = 91.653(6), γ = 107.489(6), V = 1067.2(6) ų, Z = 2, μ = 0.079 mm⁻¹, data/restraints/parameters: 3797/0/276, R indices (I > 2σ(I)): R₁ = 0.0443, wR₂ (all data) = 0.1258. CCDC no. 1423000.†

Acknowledgements

We thank Department of Science & Technology (DST, New Delhi) for financial support, single crystal X-ray diffractometer and HRMS facility, KCK thanks DST for a J. C. Bose fellowship and UGC for a one-time grant. ASR thanks CSIR (New Delhi) for a fellowship.

References

1. (a) Y. Deng, Y.-W. Chin, H. Chai, W. J. Keller and A. D. Kinghorn, J. Nat. Prod., 2007, 70, 2049; (b) P. J. Harrington and E. Lodewijk, Org. Process Res. Dev., 1997, 1, 72; (c) K. R. Romines, G. A. Freeman, L. T. Schaller, J. R. Cowan, S. S. Gonzales, J. H. Tidwell, C. W. Andrews, D. K. Stammers, R. J. Hazen, R. G. Ferris, S. A. Short, J. H. Chan and L. R. Boone, J. Med. Chem., 2006, 49, 727; (d) H. Ogita, Y. Isobe, H. Takaku, R. Sekine, Y. Goto, S. Misawa and H. Hayashi, Bioorg. Med. Chem., 2002, 10, 3473.
2. G. A. Olah, Friedel–Crafts Chemistry, Wiley, New York, 1973.
3. (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) C.-W. Chan, Z. Zhou and W.-Y. Yu, Adv. Synth. Catal., 2011, 353, 2999; (d) Y. Wu, B. Li, F. Mao, X. Li and F. Y. Kwong, Org. Lett., 2011, 13, 3258; (e) C. Li, L. Wang, P. Li and W. Zhou, Chem.–Eur. J., 2011, 17, 10208; (f) F. Szabó, J. Daru, D. Simkó, T. Z. Nagy, A. Stirling and Z. Novák, Adv. Synth. Catal., 2013, 355, 685; (g) C.-W. Chan, Z. Zhou, A. S. C. Chan and W.-Y. Yu, Org. Lett., 2010, 12, 3926; (h) H. Li, P. Li and L. Wang, Org. Lett., 2013, 15, 620; (i) S. Sharma, J. Park, E. Park, A. Kim, M. Kim, J. H. Kwak, Y. H. Jung and I. S. Kim, Adv. Synth. Catal., 2013, 355, 332; (j) X.-B. Yan, Y.-W. Shen, D.-Q. Chen, P. Gao, Y.-X. Li, X.-R. Song, X.-Y. Liu and Y.-M. Liang, Tetrahedron, 2014, 70, 7490; (k) M. Sun, L.-K. Hou, X.-X. Chen, X.-J. Yang, W. Sun and Y.-S. Zang, Adv. Synth. Catal., 2014, 356, 3789; (l) M. Yi, X. Cui, C. Zhu, C. Pi, W. Zhu and Y. Wu, Asian J. Org. Chem., 2015, 4, 38; (m) Q. Zhang, C. Li, F. Yang, J. Li and Y. Wu, Tetrahedron, 2013, 69, 320; (n) A. Banerjee, S. K. Santra, S. Guin, S. K. Rout and B. K. Patel, Eur. J. Org. Chem., 2013, 1367; (o) S. K. Santra, A. Banerjee and B. K. Patel, Tetrahedron, 2014, 70, 2422; (p) A. Banerjee, A. Bera, S. K. Santra, S. Guin and B. K. Patel, RSC Adv., 2014, 4, 8558; (q) Q. Tian, P. He and C. Kuang, Org. Biomol. Chem., 2014, 12, 7474; (r) G. Kumar and G. Sekar, RSC Adv., 2015, 5, 28292; (s) J. Zhao, H. Fang, C. Xie, J. Han, G. Li and Y. Pan, Asian J. Org. Chem., 2013, 2, 1044; (t) J.-H. Chu, S.-T. Chen, M.-F. Chiang and M.-J. Wu, Organometallics, 2015, 34, 953; (u) Z.-J. Cai, C. Yang, S.-Y. Wang and S.-J. Ji, J. Org. Chem., 2015, 80, 7928; (v) X.-F. Wu, Chem.–Eur. J., 2015, 21, 12252.
4. (a) P. Fang, M. Li and H. Ge, J. Am. Chem. Soc., 2010, 132, 11898; (b) M. Li and H. Ge, Org. Lett., 2010, 12, 3464; (c) H. Li, P. Li, H. Tan and L. Wang, Chem.–Eur. J., 2013, 19, 14432; (d) Z.-Y. Li, D.-D. Li and G.-W. Wang, J. Org. Chem., 2013, 78, 10414; (e) J. Yao, R. Feng, Z. Wu, Z. Liu and Y. Zhang, Adv. Synth. Catal., 2013, 355, 1517; (f) C. Pan, H. Jin, X. Liu, Y. Cheng and C. Zhu, Chem. Commun., 2013, 49, 2933; (g) H. Li, P. Li, Q. Zhao and L. Wang, Chem. Commun., 2013, 49, 9170; (h) B. Xu, W. Liu and C. Kuang, Eur. J. Org. Chem., 2014, 2576.
5. (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; (c) H. Tang, C. Qian, D. Lin, H. Jiang and W. Zeng, Adv. Synth. Catal., 2014, 356, 519; (d) J. Park, A. Kim, S. Sharma, M. Kim, E. Park, Y. Jeon, Y. Lee, J. H. Kwak, Y. H. Jung and I. S. Kim, Org. Biomol. Chem., 2013, 11, 2766; (e) M. Kim, S. Sharma, J. Park, M. Kim, Y. Choi, Y. Jeon, J. H. Kwak and I. S. Kim, Tetrahedron, 2013, 69, 6552; (f) L. Hou, X. Chen, S. Li, S. Cai, Y. Zhao, M. Sun and X.-J. Yang, Org. Biomol. Chem., 2015, 13, 4160; (g) Q. Zhang, F. Yang and Y. Wu, Tetrahedron, 2013, 69, 4908.
6. (a) S. Guin, S. K. Rout, A. Banerjee, S. Nandi and B. K. Patel, Org. Lett., 2012, 14, 5294; (b) Z. Xu, B. Xiang and P. Sun, RSC Adv., 2013, 3, 1679; (c) Z. Yin and P. Sun, J. Org. Chem., 2012, 77, 11339; (d) Y. Wu, P. Y. Choy, F. Mao and F. Y. Kwong, Chem. Commun., 2013, 49, 689; (e) J. Weng, Z. Yu, X. Liu and G. Zhang, Tetrahedron Lett., 2013, 54, 1205; (f) F. Xiong, C. Qian, D. Lin, W. Zeng and X. Lu, Org. Lett., 2013, 15, 5444; (g) H. Song, D. Chen, C. Pi, X. Cui and Y. Wu, J. Org. Chem., 2014, 79, 2955; (h) Y. Zheng, W.-B. Song, S.-W. Zhang and L.-J. Xuan, Tetrahedron, 2015, 71, 1574.
7. Q. Zhang, F. Yang and Y. Wu, Chem. Commun., 2013, 49, 6837.
8. (a) G. Zhang, S. Sun, F. Yang, Q. Zhang, J. Kang, Y. Wu and Y. Wu, Adv. Synth. Catal., 2015, 357, 443; (b) A. Behera, W. Ali, S. Guin, N. Khatun, P. R. Mohanta and B. K. Patel, RSC Adv., 2015, 5, 33334.
9. J. Lu, H. Zhang, X. Chen, H. Liu, Y. Jiang and H. Fu, Adv. Synth. Catal., 2013, 355, 529.
10. W. Zhou, H. Li and L. Wang, Org. Lett., 2012, 14, 4594.
11. S. Han, S. Sharma, J. Park, M. Kim, Y. Shin, N. K. Mishra, J. J. Bae, J. H. Kwak, Y. H. Jung and I. S. Kim, J. Org. Chem., 2014, 79, 275.
12. (a) M. K. Lakshman, A. C. Deb, R. R. Chamala, P. Pradhan and R. Pratap, Angew. Chem., Int. Ed., 2011, 50, 11400; (b) H.-M. Guo, L.-L. Jiang, H.-Y. Niu, W.-H. Rao, L. Liang, R.-Z. Mao, D.-Y. Li and G.-R. Qu, Org. Lett., 2011, 13, 2008; (c) H.-M. Guo, W.-H. Rao, H.-Y. Niu, L.-L. Jiang, G. Meng, J.-J. Jin, X.-N. Yang and G.-R. Qu, Chem. Commun., 2011, 47, 5608; (d) R. R. Chamala, D. Parrish, P. Pradhan and M. K. Lakshman, J. Org. Chem., 2013, 78, 7423; (e) H. J. Kim, M. J. Ajitha, Y. Lee, J. Ryu, J. Kim, Y. Lee, Y. Jung and S. Chang, J. Am. Chem. Soc., 2014, 136, 1132; (f) A. B. Pawar and S. Chang, Org. Lett., 2015, 17, 660; (g) M. A. Ali, X. Yao, H. Sun and H. Lu, Org. Lett., 2015, 17, 1513.
13. (a) R. Rama Suresh and K. C. Kumara Swamy, J. Org. Chem., 2012, 77, 6959; (b) S. Allu and K. C. Kumara Swamy, J. Org. Chem., 2014, 79, 3963; (c) R. N. P. Tulichala and K. C. Kumara Swamy, Chem. Commun., 2015, 51, 12008; (d) S. Allu and K. C. Kumara Swamy, Adv. Synth. Catal., 2015, 357, 2665.
14. (a) K. C. Kumara Swamy, S. Allu, V. Srinivas, E. Balaraman and K. V. P. Pavan Kumar, Cryst. Growth Des., 2011, 11, 2302; (b) K. C. Kumara Swamy, E. Balaraman and N. Satish Kumar, Tetrahedron, 2006, 62, 10152.
15. (a) V. Gayakhe, Y. S. Sanghvi, I. J. S. Fairlamb and A. R. Kapdi, Chem. Commun., 2015, 51, 11944; (b) A. Nayak, G. Chandra, I. Hwang, K. Kim, X. Hou, H. O. Kim, P. K. Sahu, K. K. Roy, J. Yoo, Y. Lee, M. Cui, S. Choi, S. M. Moss, K. Phan, Z.-G. Gao, H. Ha, K. A. Jacobson and L. S. Jeong, J. Med. Chem., 2014, 57, 1344; (c) M. Legraverend and D. S. Grierson, Bioorg. Med. Chem., 2006, 14, 3987; (d) V. E. Marquez and M.-I. Lim, Med. Res. Rev., 1986, 6, 1.
16. D. D. Perrin, W. L. F. Armarego and D. R. Perrin, Purification of Laboratory Chemicals, Pergamon, Oxford, 1986.
17. (a) G. M. Sheldrick, SADABS, Siemens Area Detector Absorption Correction, University of Göttingen, Germany, 1996; (b) G. M. Sheldrick, SHELX-97 – A program for crystal structure solution and refinement, University of Göttingen, 1997; (c) G. M. Sheldrick, SHELXTL NT Crystal Structure Analysis Package, Analytical X-ray System, Version 5.10, Bruker AXS, WI, USA, 1999.

---

Footnote

† Electronic supplementary information (ESI) available: ¹H and ¹³C NMR spectra. CCDC 1423000. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra18447a

---