A redox-neutral catechol synthesis

Abstract

Ubiquitous tyrosinase catalyses the aerobic oxidation of phenols to catechols through the binuclear copper centres. Here, inspired by the Fischer indole synthesis, we report an iridium-catalysed tyrosinase-like approach to catechols, employing an oxyacetamide-directed C-H hydroxylation on phenols. This method achieves one-step, redox-neutral synthesis of catechols with diverse substituent groups under mild conditions. Mechanistic studies confirm that the directing group (DG) oxyacetamide acts as the oxygen source. This strategy has been applied to the synthesis of different important catechols with fluorescent property and bioactivity from the corresponding phenols. Finally, our method also provides a convenient route to ¹⁸ O-labelled catechols using ¹⁸ O-labelled acetic acid.

ARTICLE

Received 13 Sep 2016 | Accepted 9 Dec 2016 | Published 27 Jan 2017

Qian Wu1,*, Dingyuan Yan2,*, Ying Chen1,*, Ting Wang3, Feng Xiong2, Wei Wei2, Yi Lu2, Wei-Yin Sun2, Jie Jack Li4 & Jing Zhao1,2

Ubiquitous tyrosinase catalyses the aerobic oxidation of phenols to catechols through the binuclear copper centres. Here, inspired by the Fischer indole synthesis, we report an iridium-catalysed tyrosinase-like approach to catechols, employing an oxyacetamide-directed CH hydroxylation on phenols. This method achieves one-step, redox-neutral synthesis of catechols with diverse substituent groups under mild conditions. Mechanistic studies conrm that the directing group (DG) oxyacetamide acts as the oxygen source. This strategy has been applied to the synthesis of different important catechols with uorescent property and bioactivity from the corresponding phenols. Finally, our method also provides a convenient route to 18O-labelled catechols using 18O-labelled acetic acid.

DOI: 10.1038/ncomms14227 OPEN

A redox-neutral catechol synthesis

1 Guangdong Key Lab of Nano-Micro Material Research, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China. 2 State Key Laboratory of Coordination Chemistry, Department of Chemistry, Institute of Chemistry and BioMedical Sciences, School of Chemistry and Chemical Engineering, Collaborative Innovation Centre of Chemistry for Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China. 3 School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China.

4 Department of Chemistry, University of San Francisco, 2130 Fulton Street, San Francisco, California 94117, USA. * These authors contributed equally to this work. Correspondence and requests for materials should be addressed to J.Z. (email: mailto:[email protected]

Web End [email protected] ).

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Catechols are essential bioactive molecules in human metabolism and normal physiological activities, acting as effective structural units in many bronchodilator,

adrenergic, anti-parkinsonian and anti-hypertensive drugs (Fig. 1a)1. For example, L-dopa is a well-known drug used for the treatment of Parkinsons disease and is converted from

L-tyrosine via catalysis by tyrosine hydroxylase in the central nervous system under mild conditions. The dopamine system plays a central role in several signicant medical conditions, including attention decit hyperactivity disorder (ADHD), schizophrenia and addictions2. On the other hand, estradiol is important in the regulation of the female oestrous and menstrual reproductive cycles3.

Synthesis of catechols usually requires lengthy steps and harsh reaction conditions, with low selectivity and conversion rates4. To develop efcient routes to synthesize catechols, we aim to construct a new CO bond at the ortho position of phenols through directed CH bond oxygenation. The catalytic transformation of the CO bond from benzene to phenol is considered to be one of the greatest challenges in catalytic chemistry5. Tremendous progress has been achieved in directed CH hydroxylation/oxygenation by metal catalysis with O2 (refs 69), H2O (refs 1012), peroxides1318 or the in situ hydrolysis of newly installed acyloxy groups as oxygen sources such as OAc, OTFA and so on refs 1930 (Fig. 1b). Notably, Yu and colleagues6 rst developed a versatile Pd-catalysed orthohydroxylation of benzoic acids at 1 atm of O2 or air under non-acidic conditions. Gevorgyan and colleagues31 recently reported an ingenious silanol-directed Pd-catalysed CH oxygenation of phenols followed by desilylation of the silacyle with tetrabutylammonium uoride (TBAF), furnishing catechols with PhI(OAc)2 as the oxygen source. Rao and colleagues32

demonstrated the efcient ruthenium(II)- and palladium(II)-catalysed CH hydroxylation of aryl carbamates and a subsequent deprotection to afford catechols in good yields. These pioneering works used TFA/TFAA as the oxygen source26.

We have recently reported a number of metal-catalysed CH bond functionalizations based on a powerful directing group, -ONHAc (oxyacetamide), which can act as an internal oxidant to yield versatile phenol derivatives33,34. A variety of substituted substrates with -ONHAc directing group were easily prepared from phenols or aryl boronic acid compounds3538. Inspired by the classic Fischer indole synthesis3941, we hypothesized that catechols would be furnished from N-phenoxyacetamides provided that the acetamide group could function as an intramolecular oxygen source. By choosing appropriate metal catalysts, the acetamide group could function as a directing group, an internal oxidant and an oxygen source simultaneously (Fig. 1c)38,4245. This design would avoid the need for an external oxidant, which could be detrimental to the fragile polyphenols. Notably, seminar reports from the Cheung and Buchwald46, and Zhao and colleagues47 clearly established that the acetamide group could participate in CO bond formation.

Herein, we report an iridium-catalysed, one-step, mild and redox-neutral synthesis of catechols from acetamide-protected phenols, employing a bioinspired intramolecular oxygen transfer strategy.

ResultsModel studies. We rst explored Zn-, Al-, Fe-, Cu-, Pd- and Ru-catalysed systems to N-phenoxyacetamides (1a). Unfortunately, the target product (2a) was not detected. The same result was shown in the common Rh-catalysed system for -ONHAc (Table 1, entries 110 and Supplementary Table 1). Considering

a

Important catechols in biology and medicine

Previous work on catechol synthesis

DG-directed, oxidizing conditions, external oxygen source

O N H

O

O

HO HO HO

Dopamine

Levodopa Estradiol

CO2H

NH2 HO

NH2

H

H

H

HO

HO

b

ODG

H

ODG

OH

-DG

R R

oxygen source: O2, R'OOH, H2O

or

R DG

O

O

R

OH

OH

Pd, Ru

DG = Si-OH, CONMe2

c

Our design inspired by Fischer indole synthesis

Fischer indole synthesis:

HN N

HN NH

[3,3] H+

NH3

NH2

NH

H N

ONHAc-directed, redox-neutral condition, internal oxygen source

O NH

[3,3]

O NH

OH

OH

O

Figure 1 | A new approach to catechol synthesis inspired by Fischer indole synthesis. (a) Important catechols in biology and medicine. (b) Previous work on catechol synthesis. (c) Our design inspired by Fischer indole synthesis.

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Table 1 | Screening of reaction conditions.

O

O

H

N

H

Catalyst

Additive, Solvent

Oxygen source

T

OH OH

1a 2a

Entry Catalyst* Additive Solvent O source T (C) % yieldw 1 ZnCl2 2.5 eq. AcOH Dioxane 80/r.t. ND2 AlCl3 2.5 eq. AcOH Toluene 80/r.t. ND3 FeCl3 2.5 eq. AcOH MeOH 80/r.t. ND4 TsOH MeOH 80/r.t. ND5 Pd(OAc)2 2 eq. KOAc/1 eq. BQ DMA 1 atm O2 90 ND6 Pd(OAc)2 2 eq. PhI(OAc)2 PhMe PhI(OAc)2 90 ND7 [Ru(p-cymene)Cl2]2 2 eq. K2S2O8 TFA/TFAA TFA/TFAA 80 ND8 Pd(OAc)2 2 eq. K2S2O8 TFA/TFAA TFA/TFAA 80/r.t. ND9 Pd(OAc)2 10 mol% PPh3 DCE 1.2 eq. oxone 90 ND 10 [Cp*RhCl2]2 MeOH 2 eq. DTBP 70 ND11 [Cp*IrCl2]2 2 eq. KOAc MeOH 2 eq. DTBP 70 ND12 [Cp*IrCl2]2 MeOH 2 eq. DTBP 70 2513 [Cp*IrCl2]2 2.5 eq. AcOH MeOH 70 3014 [Cp*IrCl2]2 2.5 eq. AcOH MeOH r.t. 6715 [IrCl(COD)]2 2.5 eq. AcOH MeOH 70/r.t. ND16 IrCl3.H2O 2.5 eq. AcOH MeOH 70/r.t. ND17 [Ir(COD)OMe]2 2.5 eq. AcOH MeOH 70/r.t. ND18 [Cp*IrCl2]2 2.5 eq. HCOOH MeOH r.t. ND19 [Cp*IrCl2]2 2.5 eq. CH2(COOH)2 MeOH r.t. 92 20 [Cp*IrCl2]2 2.5 eq. CH2BrCOOH MeOH r.t. 7521 [Cp*IrCl2]2 2.5 eq. TFA MeOH r.t. ND 22 [Cp*IrCl2]2 2.5 eq. TFA/TFAA MeOH r.t. ND 23 2.5 eq. CH2(COOH)2 MeOH r.t. ND

ND, not detected; r.t., room temperature.*Reaction conditions: 0.2 mmol 1a, 5% mol catalyst, X mol additive in 0.1 M solvent under N .

wIsolated yield.

the design of the internal oxidation pathway, we made further attempts using other metal catalysts in the absence of an external oxidant. Gratifyingly, using 5 mol% [Cp*IrCl2]2 as catalyst and 2 equiv. of di-tert-butyl peroxide (DTBP) as a possible oxygen source and heating in MeOH at 70 C for 12 h, the target product catechol 2a was obtained in 25% yield (Table 1, entry 12). Concurrently, a mixture of phenol byproducts from the self-decomposition of N-phenoxyacetamides was detected. According to the literature and our past experience, the reaction temperature and acidalkali environment are important factors in the self-decomposition of N-phenoxyacetamides. It was surprising to nd that target product was synthesized in the absence of DTBP when one equivalent of AcOH was added (Table 1, entry 13). Lowering the temperature greatly improved the yield. At room temperature, the reaction proceeded to give 67% yield (Table 1, entry 14). Next, various acids and alkalis were tested to improve the yield. As a whole, acids were conducive to this reaction, whereas alkalis were not. Malonic acid was preferred, with a 95% gas chromatography (GC) yield and a 92% isolated yield (Table 1, entry 19). Bromoacetic acid was slightly inferior (Table 1, entry 20), whereas HCOOH, TFA and TFA/TFAA failed to afford the product (Table 1, entries 18, 2122). When alkali was added, no product was observed (Table 1, entry 11). In the absence of [Cp*IrCl2]2,

no product was detected (Table 1, entry 23). In addition, there was no distinction under N2, O2 and air as the reaction environment. Ultimately, optimal reaction conditions to carry the ortho-hydroxylation are: 5 mol% [Cp*IrCl2]2 and 2.5 equiv. of

CH2(COOH)2 in MeOH at room temperature in air with no external oxidant.

Scope of Ir-catalysed ortho-hydroxylation. The scope of the one-step neutral ortho-hydroxylation from N-phenoxyacetamides 1 to obtain catechols 2 was investigated (Table 2). Signicantly, electron-neutral and electron-rich substituents such as Me, Et, tBu and OMe groups (2a2e, 2o and 2p), all afforded excellent selectivity and good yields. The hydroxylation of substrates with electron-withdrawing substituents such as COOH, COOMe and halogen (F, Cl, Br and I with good yield) were also well tolerated (2f2n). Ortho-, meta- and para-substituents on N-phenoxyacetamides provided similarly good yields. Remarkably, meta- and para-substituents on N-phenoxyacetamides shared the same products. This nding showed a good selectivity of hydroxylation in the ortho position, which was far away from the meta-substituents (2c and 2d, 2j and 2k). In particular, the ortho-ethyl substituent substrate showed CH activation on the aromatic ring rather than the aliphatic chain (2e).

The synthesis of uorescent and bioactive catechols. Our method provided the possibility of one-step synthesis of complicated catechols (Table 3). Recently, we reported a new method to afford different uorescent heteroarylated phenols by N-phenoxyacetamides34. When ortho-heteroarylated N-phenoxyacetamide 1u was subject to the standard orthohydroxylation conditions, the desired product 2-(2,3-

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Table 2 | Scope of Ir-catalysed ortho-hydroxylation*.O

H

O

5 mol% [Cp*IrCl2]2

2.5 equiv. CH2(COOH)2

N

H

R R

1 2

OH OH

MeOH, r.t., 10 h

Entry Product Yield Entry Product Yield Entry Product Yield

90%

OH OH

OH OH

OH OH

OH OH

OH OH

OH OH

OH OH

OH OH

OH OH

OH OH

OH OH

OH OH

OH OH

OH OH

1

7

75%

13

90%

HOOC

2a

F

2g

2m

Cl

8

14

2

90%

73%

95%

MeOOC

2b

2h

2n

3

90%

9

78%

15

80%

Cl

2c

2i

2o

Br

MeO

4

95%

10

16

72%

75%

2p

2d

2j

11

OH OH

OH OH

70%

5

88%

Br

2e

2k

I

6

68%

12

80%

F

2f

2l

*Reaction conditions: 0.2 mmol 1, 5 mol% [Cp*IrCl ] , 2.5 equiv. CH (COOH) in 0.1 M MeOH at room temperature in air with no external oxidant. wIsolated yield.

dihydroxyphenyl)benzothiazole derivative 2u with green uorescence was obtained in 76% yield. Our method could be a general strategy to prepare uorescent dihydroxyl heterocycle scaffold48,49. Next, we prepared the ONHAc-containing coumarins, the 7,8-dihydroxyl products 2v and 2w, with complete chemoselectivity in 87% and 81% yield, respectively. The product 7,8-dithydroxycoumarin 2v was commonly called Daphnetin and is an important natural product from Zushima with good anti-inammatory and anti-oxidant activities50,51. Our reaction could provide a powerful tool in the chemical synthesis

of Daphnetin derivatives. Finally, bioactive catechols natural products such as L-dopa and estradiol were tested under the standard reaction conditions, the protected L-dopa 2x, protected dopamine 2y and estradiol 2z were successfully obtained directly with high selectivity and excellent yields, highlighting the methods mild conditions,excellent functional group tolerance and selectivity.

DiscussionTo understand the reaction mechanism, we rst attempted to identify the oxygen source of the catechol products. With the

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Table 3 | Scope of uorescent and bioactive catechols.

Entry Substrate Product Yield*,

O

HO

OH

O

NH

1u

N

2u

N

76%

1

S

S

Fluorescent 2-DHPBT

O

OH

2

O

O

HO

O

N

H

1v 2v 87%

Daphentin

O

OH

O

O

HO

O

3

N

H

1w

2w

81%

COOMe

COOMe

Substituted Daphentin

4

HO

H

N

CO2Me NHBoc

1x

CO2Me NHBoc

2x

80%

O

HO

O

Protected L-dopa

NHBoc

HO

NHBoc

5

H

N

1y

2y

85%

O

HO

O

Protected Dopamine

O

O

6

1z

HO

2z

72%

H

N

O

HO

O

Estradiol

*Reaction conditions: 0.2 mmol 1, 5 mol% [Cp*IrCl ] , 2.5 equiv CH (COOH) in 0.1 M MeOH at room temperature in air for 16 h. wIsolated yield.

standard condition, using 18O-MeOH as the solvent (Fig. 2a, eq. 1), the product detected by high resolution mass spectroscopy (HRMS) did not show the 18O-labelled catechol, which meant the oxygen of the product did not come from the solvent. After that, 50 ml 18O-H2O was added under the standard conditions (Fig. 2a, eq. 2). The results showed that the addition of water had no effect

on the yield of catechol, but still no 18O-labelled product could be detected. It seemed as though that the oxygen of catechol did not come from the water that might be generated in the reaction. When 18O-labelled acetic acid (CH3C18O18OH) was added instead of malonic acid (Fig. 2a, eq. 3), the 18O-labelled product was still not detected, which showed that the acid was also not the

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a

5 mol% [Cp*IrCl2]22.5 equiv. CH3C18O18OH

1a 2a (67%)

O N H

18O 5 mol% [Cp*IrCl2]22.5 equiv. CH2(COOH)2

MeOH, r.t., N2

O N H

O 5 mol% [Cp*IrCl2]22.5 equiv. CH2(COOH)2

Me18OH, r.t., N2

OH

OH

eq. 1

OH

OH

eq. 3

MeOH, r.t., N2

1a 2a (90%)

1a 2a (90%)

O N H

O

5 mol% [Cp*IrCl2]22.5 equiv. CH2(COOH)2

OH

18OH

1a-18O 2a-18O (90%)

eq. 4

O N H

O

eq. 2

MeOH, H218O (50 l) r.t., N2

OH

OH

b

18O

1) KOtBu/MSH

2)CH3C18O18OH,EDCI

One pot

O

5 mol% [Cp*IrCl2]22.5 equiv. CH2(COOH)2

MeOH, r.t., N2

OH

OH

R

R N

H

R

18OH

c

O O

1a 3, 95%

O N H

O

0.5 equiv. [Cp*IrCl2]22.0 equiv. Ag2CO3

MeCN/DCM r.t., N2

N

Ir

2.5 equiv. CH2(COOH)2

MeOH, r.t., N2

OH

OH

CCDC 1491482

d

O N

O 5 mol% [Cp*IrCl2]2

2.5 equiv. CH2(COOH)2

MeOH, r.t., N2

1q

OH

OH

2a

eq. 5

O N

H

O

5 mol% [Cp*IrCl2]22.5 equiv. CH2(COOH)2

MeOH, r.t., N2

OH

OH

2a (78%)

eq. 6

1r

Figure 2 | Mechanistic study. (a) Isotope labelling experiments. (b) Synthesis of 18O-labelled catechols. (c) Seeking the active intermediate. (d) The importance of the NH bond in the substrates.

oxygen source of the reaction. Based on the aforementioned results, we inferred that the oxygen of the product could only come from the carbonyl of the -ONHAc group. Finally, we synthesized the substrate PhONHAc with the carbonyl labelled with 18O. Under the standard conditions, we obtained the catechol with one 18O-labelled hydroxyl (Fig. 2a, eq. 4). The 18O-labelled substrate and product were conrmed by HRMS (Fig. 3), suggesting that the reaction was an intramolecular process and that the carbonyl of the -ONHAc group was the oxygen source. This method may be a powerful tool to access a variety of

18O-labelled catechols, which could then be used to investigate the metabolic pathways of catechol-derived bioactive compounds.

To probe the active intermediate in the reaction, we treated the substrate N-phenoxyacetamide (1 equiv.) and [Cp*IrCl2]2 (0.5

equiv.) with Ag2CO3 (2 equiv.) in MeCN at room temperature for 10 h, and the ve-membered iridium species 3 was obtained in 95% yield. The structure of complex 3 was conrmed by nuclear magnetic resonance spectroscopy, HRMS and X-ray crystal-lography. However, no product was obtained when 2.5 equiv. malonic acid was added in MeOH (Fig. 2c), implying that species 3 is not an active intermediate of the reaction. Furthermore, N-methyl-substituted phenoxyacetamide 1q did not give the desired product (Fig. 2d, eq. 5) and most of the starting material was recovered. However, the reaction proceeded smoothly when the acetamide was replaced by hexanamide (Fig. 2d, eq. 6), highlighting the important role of the NH bond.

We proposed that the seven-membered [IrIII] species A might be the active intermediate, which underwent the reductive

elimination process to form a CO bond and afforded [IrI] complex B (Fig. 4). Subsequently, the ON bond oxidatively added to the iridium complex B, generating the [IrIII] complex C. Protonation of the intermediate C regenerated the original catalyst and the imine compound D, which would be hydrolysed to catechols.

The acid might play several roles such as preventing the generation of inactive intermediate 3, consuming the byproduct ammonia and protonating the intermediate C. Further theoretical calculations revealed that when acid additives were introduced, the free energy of species A underwent a signicant reduction from 22.4 to 2.1 kcal mol 1, highlighting the crucial role of acids in stabling species A and protonation (Supplementary Fig. 1).

Mass spectrometric experiments were carried out to explore the interaction between [Cp*IrCl2]2 and different acids (HCOOH,

CH2COOH and CH2(COOH)2) (Supplementary Fig. 2). Interestingly, in the Ir/HCOOH/MeOH system, HCOOH was detected losing a molecule CO2 fragment when interacted with [Cp*IrCl2]2, whereas CH2COOH or CH2(COOH)2 dissociated one molecule CH3COOH and CH2(COOH)2, respectively, by collision-induced dissociation. This result might explain why HCOOH was ineffective in promoting the reaction.

In summary, we have described the rst examples of an iridium-catalysed synthesis of catechols from phenols through the formation of N-phenoxyacetamide intermediates. This bio-inspired route allows efcient, selective synthesis of catechols, which are useful building blocks for amino acids and pharmaceuticals. Our method also provides a convenient

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a

[M+H]

[MH]

O

2,323

2,200 2,000 1,800 1,600 1,400 1,200 1,000

800 600 400 200

OH

N

H

O

6,000 5,500 5,000 4,500 4,000 3,500 3,000 2,500 2,000 1,500 1,000

500 0

65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 m/z, Da

OH

1a- O

2a- O

138 140 142 144 146 148 150 152 154 156 158 160 162 164 166 168 170 m/z, Da

b

[M+H]

[M-H]

1,100 1,000

900 800 700 600 500 400 300 200 100

0

120 125 130 135 140 145 150 155 160 165 170 175 180 185 m/z, Da

8,355

8,000

7,500

7,000

6,500

6,000

5,500

5,000

4,500

4,000

3,500

3,000

2,500

2,000

1,500

1,000

500

0 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 m/z, Da

OH

O N

H

O

OH

1a 2a

Figure 3 | HRMS contrast of O18-labelled and non-O18-labelled substrate and product. (a) HRMS of O18-labelled substrate and product. (b) HRMS of non-O18-labelled substrate and product.

Cp*

O

IrIII

N

2 HCl

O

C

OH

OH

Catechol

Hydrolysis

O IrI Cp*

[Cp*IrIIIL2]2

O

N

B

Acid, MeOH

O-N bond broken

OH

OH

OH

C-H activation

O

N

Catechol

Ir

O

Cp*

N

Cp*

O

IrIIIO

3

A

Phenol

Pathway of seven-membered [IrIII] species under acid Pathway of five-membered [IrIII] species under base

Figure 4 | Proposed mechanism. A plausible mechanism illustrating how catechols are formed in acidic condition (left) and phenols are formed in alkaline condition (right).

route to 18O-labelled catechols using 18O-labelled acetic acid. Further applications of the Ir/malonic acid/MeOH system and mechanistic studies of the reaction are under investigation and will be reported in due course.

Methods

Materials. For NMR spectra of compounds in this study, see Supplementary Figs 127. For the crystallographic data of compound 3, see Supplementary

Tables 12 and Supplementary Fig. 28. For the representative experimental procedures and analytic data of compounds synthesized, see Supplementary Methods.

General procedure (2a). N-phenoxyacetamide (1) (0.2 mmol), [Cp*IrCl2]2(5 mol%) and CH2(COOH)2 (5.0 mmol) without external oxidant were weighed into a 10 ml pressure tube, to which was added anhydrous MeOH (1 ml) in a glove box. The reaction vessel was stirred at room temperature for 10 h in air. The mixture was then concentrated under vacuum and the residue was puried by

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column chromatography on silica gel with a gradient eluent of petroleum ether and ethyl acetate to afford the corresponding product.

Data availability. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC14911482. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif

Web End =www.ccdc.cam.ac. http://www.ccdc.cam.ac.uk/data_request/cif

Web End =uk/data_request/cif . The authors declare that all other data supporting the ndings of this study are available within the article and Supplementary Information les, and also are available from the corresponding author upon reasonable request.

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Acknowledgements

Financial support was provided by the Shenzhen Government (JCYJ20150626110741712 and GJHZ20140417144118026), the Guangdong Government (S20120011226), the National Science Foundation of China (21622103 and 21571098) and the MOST of China (2014AA020512).

Author contributions

Y.C. performed most of the reaction optimization. The experimental work was conducted by Y.C., D.Y.Y. and Q.W. Q.W. prepared most of the manuscript and

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supporting information. J.Z. conceived the initial ideas of this work, supervised all the experiments and coordinated with Y.L. and W.Y.S.

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How to cite this article: Wu, Q. et al. A redox-neutral catechol synthesis. Nat. Commun. 8, 14227 doi: 10.1038/ncomms14227 (2017).

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