Palladium-catalyzed base-accelerated direct C–H bond alkenylation of phenols to synthesize coumarin derivatives

Abstract

A palladium-catalyzed base-accelerated ortho-selective C–H alkenylation of phenols to synthesize bioactive coumarin derivatives was developed. The reaction condition was mild and the substrate scope was broad with both electron-neutral and electron-deficient phenols, which is complementary to the previous methods to synthesize electron-rich coumarins. Several bioactive molecules were functionalized and several coumarins with bioactive properties were synthesized. Mechanistic studies showed that this reaction underwent C–H bond activation via direct metallation rather than the Friedel–Crafts pathway.

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Phenols are important motifs in natural products and drugs¹ and the direct functionalization of phenols is useful for organic synthesis. Although the hydroxyl group has been used as an efficient directing group in C–H bond activation,² phenols cannot form five- or six-membered metallacycles, which are important intermediates for directing strategies.³ As a result, they are usually transformed to their derivatives with proper directing groups, like carbamate,⁴ ester,⁵ amide,⁶ carboxylic acid,⁷N-heterocycle⁸ and silyl groups.⁹ For unprotected phenols, the selective ortho-functionalization requires specific structures (2-phenylphenol¹⁰ and naphthalen-1-ol¹¹), acceleration by phosphines¹² or other methods.¹³ For the transition metal-catalyzed direct ortho-functionalization of phenols, only limited examples were reported, including the additions to alkynes and alkenes,¹⁴ oxidative couplings,¹⁵ and others.¹⁶

Coumarin derivatives¹⁷ are one kind of important natural products in plants and display good biological and pharmacological activity, including antitumor,¹⁸ anti-HIV,¹⁹ antioxidant,²⁰ antibacterial,²¹ and anti-inflammatory²² activity. In addition, they also have good optical properties and are widely used in laser devices, light-emitting diodes, as fluorescent probes and in other areas²³ (Scheme 1).

Scheme 1 Selected coumarin derivatives with bio-activities and photochromic properties.

Traditional synthesis of coumarin derivatives is based on condensation reactions, such as Pechmann,²⁰ Perkin, Knoevenagel, Wittig,²⁴ Ponndorf, Horner–Wittig, Houben–Hoesch, and so on.²⁵ Although these methods are widely used and efficient, harsh conditions and stoichiometric quantities of strong Lewis or Brønsted acids are usually required, and the regioselectivity is not ideal and leads to mixtures. Transition metal-catalyzed intermolecular or intramolecular coupling reactions (Heck reaction, carbonylation, etc.) partially solved this problem.²⁶ However, prefunctionalization of the starting materials (halides and organometallic reagents) made these reactions non-economic. Transition metal-catalyzed direct C–H bond addition to alkynes developed by Trost and Fujiwara is more atom economic and has seen wide application in recent years^14d,e,27 (Scheme 2, (2)). However, this reaction is generally limited to electron-rich phenols and a Friedel–Crafts pathway rather than a C–H activation pathway cannot be ruled out clearly. Direct C–H bond alkenylation provide another strategy for the synthesis of coumarins. This reaction was first realized in 2005 by Pd catalysis with TFA (trifluoroacetic acid) as solvent, although only electron-rich phenols can be adopted²⁸ (Scheme 2, (3)). Very recently, a tandem reaction starting from cyclohexanone with phenol as intermediate was reported.²⁹ Again, the reaction was conducted in acid and the Friedel–Crafts pathway rather than C–H activation cannot be ruled out clearly. As we were preparing our manuscript, a Pd-catalyzed alkenylation of phenols to synthesis benzofurans and coumarins was reported by Maiti.³⁰ Here, we report a base-accelerated alkenylation reaction of phenol to synthesize coumarins under mild conditions (without acid as solvent) and good functional group tolerance (Scheme 2).

Scheme 2 Synthesis of coumarins by transition metal catalysis.

Initially, we selected 4-(tert-butyl)phenol (1a) and methyl acrylate (2a) as model substrates to screen the conditions (Table 1). When Pd(OAc)₂ was used as catalyst and Cu(OAc)₂ as oxidant, the alkenylation/cyclization product 6-(tert-butyl)-2H-chromen-2-one (3a) was obtained in 11% NMR yield (Table 1, entry 1). Screening of other palladium catalysts showed that Pd(CH₃CN)₄(BF₄)₂ gave the best yield (Table 1, entry 3). We proposed that addition of proper base may promote the formation of phenolic anion, which will coordinate with the palladium catalyst more readily and thus promote the ortho-C–H bond activation. Screening of a series of bases showed that many of the bases could accelerate the reaction to different degrees, and NaOPiv and KOPiv showed the highest activity (Table 1, entries 6 to 12). Changing the solvent from DCE to mesitylene further promoted the yield to 67% (Table 1, entry 14). Increasing or decreasing the temperature showed inferior results (Table 1, entries 15 and 16). No product was obtained in the absence of the catalyst (Table 1, entry 17). Replacement of the palladium catalyst by Lewis acids, Cu(OTf)₂ or Sc(OTf)₃, all showed no reaction, ruling out the Friedel–Crafts reaction pathway (Table 1, entries 18 and 19).

Table 1 Condition screening^a

Entry	Catalyst (10 mol%)	Solvent	Additive	Yield^b (%)
a Reaction conditions: 1a (0.20 mmol, 1.0 equiv.), methyl acrylate 2a (0.40 mmol, 2.0 equiv.), Pd catalyst (0.020 mmol, 10 mol%), Cu(OAc)2 (0.40 mmol, 2.0 equiv.) and additive were reacted in solvent (2.0 mL) at 120 °C for 20 h under N2 atmosphere. DCE (1,2-dichloroethane). b NMR yield with CH2Br2 as internal standard. c Isolated yield. d 140 °C. e 90 °C.
1	Pd(OAc)2	DCE	None	11
2	Pd(OTFA)2	DCE	None	<10
3	Pd(CH3CN)4(BF4)2	DCE	None	14
4	Pd(CH3CN)2(OTs)2	DCE	None	8
5	Pd(dba)2	DCE	None	<5
6	Pd(CH3CN)4(BF4)2	DCE	Na2CO3 (100 mol%)	19
7	Pd(CH3CN)4(BF4)2	DCE	K2CO3 (100 mol%)	19
8	Pd(CH3CN)4(BF4)2	DCE	Cs2CO3 (100 mol%)	15
9	Pd(CH3CN)4(BF4)2	DCE	K3PO4 (100 mol%)	9
10	Pd(CH3CN)4(BF4)2	DCE	NaOPiv (100 mol%)	30
11	Pd(CH3CN)4(BF4)2	DCE	KOPiv (100 mol%)	30
12	Pd(CH3CN)4(BF4)2	DCE	NaOPiv (80 mol%)	33
13	Pd(CH3CN)4(BF4)2	Decalin	NaOPiv (80 mol%)	53
14	Pd(CH3CN)4(BF4)2	Mesitylene	NaOPiv (80 mol%)	67 (70)^c
15^d	Pd(CH3CN)4(BF4)2	Mesitylene	NaOPiv (80 mol%)	48
16^e	Pd(CH3CN)4(BF4)2	Mesitylene	NaOPiv (80 mol%)	38
17	None	Mesitylene	NaOPiv (80 mol%)	0
18	Cu(OTf)2	Mesitylene	NaOPiv (80 mol%)	0
19	Sc(OTf)3	Mesitylene	NaOPiv (80 mol%)	0

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With the reaction conditions in hand, we first investigated the substrate scope of phenol derivatives (Table 2). Both electron-rich and electron-deficient phenols could be tolerated, and electron-deficient ones (3ea, 3ga, 3ka, 3ja, 3la, 3oa, 3qa) are better than electron-rich ones (3fa, 3na). This kind of electronic effect complements the developed methods, which makes this transformation synthetically useful.^14e,27b,31 Apart from alkyl (3aa, 3ba, 3ma) and aryl (3da) substituents, functional groups like nitro (3ea), halide (3ga to 3ia), acetyl (3ja), formyl (3ka), and ester (3la) could all be well tolerated, providing access to synthesize more complex molecules by further transformation of these functional groups.³²Meta-substituted phenols underwent this reaction selectively at the less sterically hindered position (3ma to 3oa), avoiding the difficult separation of regioisomers.^27b,e Di-substituted phenols also reacted smoothly to give moderate to good yields (3ra to 3ua). The tolerance of the OTs group (3va) also provided the possibility for further cross-coupling reactions.^26a,33 It should be noted that this reaction can even be conducted on a 1.0 mmol scale without a decrease in yield (3aa), further suggesting its synthetic applications.

Table 2 Substrate scope of phenol derivatives^a

a Reaction conditions: 1 (0.20 mmol, 1.0 equiv.), methyl acrylate (0.40 mmol, 2.0 equiv.), [Pd(CH₃CN)₄](BF₄)₂ (0.020 mmol, 10 mol%), Cu(OAc)₂ (0.40 mmol, 2.0 equiv.) and NaOPiv (0.16 mmol, 0.80 equiv.) were reacted in mesitylene (2.0 mL) at 120 °C for 20 h under N₂ atmosphere. Isolated yields were reported. b 1.0 mmol scale in 10.0 mL of mesitylene.

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Next, we began to investigate the substrate scope of the alkenes (Table 3). Variation of the protecting groups of the ester showed a reduced activity of more sterically hindered acrylate (Table 3, entries 1 to 6). Apart from mono-substituted alkenes, 1,2-di-substituted alkenes can also show acceptable to moderate yields (Table 3, entries 7 to 9). The reactivity of methyl cinnamate (2g) provided a method to synthesize 4-aryl coumarins with bioactivity.³⁴ However, the 1,1-di-substitued alkenes showed no reactivity (Table 3, entry 10).

Table 3 Substrate scope of olefin^a

Entry	2	3	Yield
a Reaction conditions: 1 (0.20 mmol, 1.0 equiv.), alkene (0.40 mmol, 2.0 equiv.), [Pd(CH3CN)4](BF4)2 (0.020 mmol, 10 mol%), Cu(OAc)2 (0.40 mmol, 2.0 equiv.) and NaOPiv (0.16 mmol, 0.80 equiv.) were reacted in mesitylene (2.0 mL) at 120 °C for 20 h under N2 atmosphere. Isolated yields were reported. b NMR yield.
1–6			R = Me, 70%^b; Bu, 52%^b
			R = Et, 32%^b; Ph, 5%^b
			R = ^tBu, 20%^b; Bn, 36%^b
7			R^1 = Ph, 3sg, 57%
8			R^1 = Me, 3sh, 37%
9			R^1 = ^nPr, 3si, 21%^b
10			3sj, Trace

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When [1,1′-biphenyl]-4,4′-diol (4) was selected as the substrate, di-functionalization occurred and the product 5 with more complexity was obtained in 34% yield (Scheme 3, Eq. 1). Interestingly, for 2-phenylphenol (6) as substrate, the compound 8 was produced via an oxidative alkenylation/oxidative cyclization sequence rather than the alkenylation/Michael addition product reported in the literature (Scheme 3, Eq. 2).³⁵

Scheme 3 Synthesis of complex and interesting molecules.

To verify whether this reaction was initiated by alkenylation or esterification, we conducted the reaction with phenyl acrylate (9) or (E)-methyl 3-(2-hydroxyphenyl)acrylate (10) as starting materials in parallel with the standard reaction (Scheme 4, Eq. 3–5). (E)-Methyl-3-(2-hydroxyphenyl)acrylate (10) can be converted to the product in comparable yield with the standard reaction while only a trace amount of product can be obtained from phenyl acrylate, indicating the C–H bond alkenylation occurs first. A tandem process of C–H activation, olefin insertion, proto-demetalation, condensation and oxidation was also ruled out by using 11 (chroman-2-one) as the starting material under the standard conditions (Scheme 4, Eq. 6).³⁶

Scheme 4 Control experiments to identify the reaction pathway.

An intramolecular deuterium labeling experiment showed a kinetic isotopic effect (KIE) value of 1.9 (Scheme 5, Eq. 7), showing that the C–H activation was involved in the rate-determining step. When 4-methylphenol (1b) was conducted under the conditions in the presence of 4.0 equivalents of D₂O but in the absence of alkene, no deuterium exchange we observed in the recovered starting material (Scheme 5, Eq. 8).

Scheme 5 Deuterium labeling experiments.

Competing experiments between phenols with different electronic factors showed that electron-rich phenols reacted faster than electron-deficient ones (Scheme 6).

Scheme 6 Competing reaction.

Based on these results and the literature reports,^13,14c,37 we proposed the mechanism as shown in Scheme 7. In the presence of base, phenol was transformed to its sodium salt I, which coordinated with the palladium catalyst to form intermediate II. Palladium 1,3-migration viaIII generated the C–H bond metalation intermediate IV. Alkene insertion and β-H elimination released the alkenylated product and the PdH species VI, which was oxidized to the Pd(II) species to furnish the catalytic cycle. Intramolecular esterification produced the final product.

Scheme 7 Proposed catalytic cycle.

With our method, several bioactive molecules can also be functionalized to synthesize more complex structures (Scheme 8). Estrone (1,3,5(10)-estratrien-3-ol-17-one)³⁸ and Phth-Me-D-tyrosine³⁹ all reacted smoothly under the standard conditions to afford moderate yields.⁴⁰ In addition, with this methodology, several bio-active molecules can also be constructed (Scheme 9). Apart from the herniarin (7-methoxy-2H-chromen-2-one, 3na) with anti-inflammatory activity,⁴¹ deprotection of 2-oxo-2H-chromen-7-yl-4-methylbenzenesulfonate (3va) can also generate the natural umbelliferone molecule with anti-oxidant activity.^17m,42

Scheme 8 Functionalization of bio-active molecules and natural products.

Scheme 9 Synthesis of natural products with bioactivity.

In summary, a palladium-catalyzed base-accelerated ortho-selective phenol C–H alkenylation reaction was developed without acid as solvent. The substrate scope for the phenol was very wide and both electron neutral and electron-deficient phenols were well tolerated, which is complementary to the previous methods to synthesize electron-rich coumarins. Several bioactive molecules were functionalized and several coumarins with bioactive or fluorescent properties were synthesized. Mechanistic studies showed that this reaction underwent C–H bond activation via metallation but not the Friedel–Crafts pathway. Expansion of this chemistry to synthesize other useful molecules is undergoing in our laboratory.

Experimental section

General procedures

To a 50 mL of Wattecs (a Chinese company making chemical apparatuses) reaction tube with a stirring bar was added 4-(tert-butyl)phenol 1a (0.2 mmol, 1.0 equiv., 30.0 mg), Cu(OAc)₂ (0.4 mmol, 2.0 equiv., 72.5 mg) and NaOPiv (0.16 mmol, 0.8 equiv., 19.9 mg) under air atmosphere. After adding Pd(CH₃CN)₄(BF₄)₂ (0.02 mmol, 8.9 mg) in a glove box, methyl acrylate 2a (0.4 mmol, 2.0 equiv., 34.4 mg) and solvent (mesitylene) were added and the tube was sealed and heated to 120 °C for 12 h. After cooling to room temperature, the system was purified by column chromatography with hexane–EtOAc (6 : 1) to afford the product as a white solid in 70% yield (28.5 mg).

Acknowledgements

Support of this work by the “973” Project from the MOST of China (2009CB825300) and NSFC (Nos. 20925207 and 21002001) is gratefully acknowledged.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3qo00010a

‡ These authors contributed equally.

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