Catalytic Aerobic Cross-Dehydrogenative Coupling of Phenols and

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A Catalytic Aerobic Cross-Dehydrogenative Coupling of Phenols and Catechols Wenbo Xu, Zheng Huang, Xiang Ji, and Jean-Philip Lumb ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04443 • Publication Date (Web): 18 Mar 2019 Downloaded from http://pubs.acs.org on March 18, 2019

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ACS Catalysis

A Catalytic Aerobic Cross-Dehydrogenative Coupling of Phenols and Catechols Wenbo Xu,1‡ Zheng Huang,1‡ Xiang Ji,1 and Jean-Philip Lumb1,2,* Department of Chemistry, McGill University, Montreal, QC H3A 0B8, Canada. KEYWORDS: Aerobic Copper Catalysis, Cross-Dehydrogenative Coupling, Aryl Ethers, Catechols, Phenols, Alkaloids

ABSTRACT: We describe a selective, catalytic aerobic cross-dehydrogenative coupling (CDC) reaction of phenols and catechols that creates aryl ethers. To avoid well-known challenges of selectivity, we employ copper (Cu) coordination to confine substrate redox to the inner coordination sphere of the metal. This minimizes non-selective radical chain processes to provide high levels of selectivity for cross over homo coupling, by C-O instead of C-C bond formation. The method remains efficient on synthetically useful substrates and scales, and enables a convergent synthesis of the tetrahydroisoquinoline alkaloid (S, S)-thalicarpine featuring diaryl ether formation in the late stages of the synthesis. Related molecules are difficult to prepare by traditional Ullman-type coupling, and provide a benchmark for evaluating the potential utility of our methodology.

Introduction Catechols are important functional groups of many essential and naturally occurring small molecules and materials (Fig. 1A).1-2 They are also building blocks for agrochemicals, pharmaceuticals, perfumes and resins, making their functionalization an important step in the

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chemical value chain.3-5 Electrophilic aromatic substitution (EArS) and nucleophilic displacement reactions are among the most common ways to functionalize the C-H and O-H bonds, respectively (Fig. 1B, left).1-2, 4 Both employ catechols as nucleophiles, and are thus limited to electrophilic coupling partners, and both can suffer poor regioselectivity.6 They also frequently employ stoichiometric amounts of activators or require an equivalent of base, creating an undesirable waste stream. A complementary, but underutilized approach to functionalize catechols is by aerobic oxidation (Fig. 1B, right).4, 7-15 This inverts their polarity, extends the potential scope of coupling partners to nucleophiles, and couples the energetic requirements of bond formation to the favorable reduction of molecular oxygen (O2) (Fig. 1B inset). Because of their atom efficiency, reactions of this more general family, namely catalytic aerobic cross-dehydrogenative coupling reactions (CDCs), have been extensively investigated.16-18


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ACS Catalysis

OH

A. Common Catechols OH

OH

OH

OH

OH

OH OH

OH

Privileged Structure OH HO

Me

HO

HO2C

NH2

natural products

O

HN

CO2H

adhesives / materials

H N

pharmaceuticals HO

agrochemicals

OH

pigments 4-methyl-catechol cross linker

L-DOPA neurotransmitter

DHICA precursor to melanin

adrenaline hormone

catechin constituent of tea

B. Catechol Functionalization OH

OH

OH

OH

R

O

electrophile

O

OH

R

OH O

Aerobic Oxidation

R

R

nucleophile

electrophile

R uncommon functionalization

challenges

potential advantages

regioselectivity

complementary coupling partners

atom economy

1/2 O2

C. Polymerization of Catechols

H2O is the only byproduct

H 2O

Redox Equilibrium OH

OH O

OH

i. C-C coupling

aerobic polymerization

OH

R

2

SQ

OH

OH

ii. tautomerization

R

R

1 e | 1 H+

OH 2

K1

R CAT

OH

Nucleophilic Addition

EArS

common functionalization

nucleophile

K1 increases at increasing pH

conproportionation K2

OH

disproportionation K3

OH

Polycatechols O

OH

OH

OH

O

poorly soluble mixture of regioisomers

R CAT

R OQ

OH

R

OH OH

R

metal chelating

OH OH

redox active R R

Figure 1. (A) Commonly encountered catechols. (B) Commonly employed functionalization reactions of catechols take advantage of their nucleophilicity functionalize C-H and O-H bonds (to left). A less common and complementary approach is by aerobic oxidation (to left). (C) The aerobic polymerization of catechols to polycatechols.

Catechols are challenging substrates for aerobic CDC reactions because they undergo polymerization in the presence of O2 (Fig. 1C).19-20 This can occur spontaneously at or above neutral pH, and it is catalyzed by a range of transition metals.7, 9, 21 Catechols (CAT) undergo facile 1 e |

1 H+ oxidation to afford an equilibrating mixture of ortho-semiquinone (SQ),

ortho-quinone (OQ) and CAT. By analogy to “free” radicals, “free” SQs are fleetingly stable,22 and undergo irreversible C-C bond formation. This leads eventually to poly-catechols: an often-


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complex mixture of materials with poor solubility.23-25 They are redox active and have a high affinity for transition metals,26 giving them multiple avenues to deteriorate a reaction’s mass balance. To avoid appreciable concentrations of SQs, most synthetically practiced catechol oxidations employ at least one oxidizing equivalent (2 e | 2 H+) of a strong oxidant (Fig. 2A). Examples include sodium periodate27 or silver (I) oxide,28 which either increase the rate of oxidation (K1) relative to conproportionation (K2), or oxidize SQ to OQ more rapidly than it can polymerize. This results in a net 2 e | 2 H+ oxidation of CAT to OQ that can be conducted on scales and substrates suitable for synthesis.29 It also represents the oxidative component of a CDC reaction, which would proceed by nucleophilic addition to OQ (Fig. 2A).10-14, 30-34 Following re-aromatization, this would afford substituted catechol (sCAT), which is the formal product of CDC coupling. In cases where sCAT is more electron rich than CAT, redox exchange between sCAT and OQ proceeds quickly (e.g. second order rate constants in excess of 106 M1s1).35-37 Since this is often faster than nucleophilic attack onto OQ, many addition reactions consume excess OQ to provide the more highly substituted quinone product (sOQ) along with reduced starting material (i.e. CAT). In our own experience, OQ functionalization under these conditions are low yielding. For example, the base promoted cyclization of acetamide 1 affords a mixture of products with a ~25% loss of mass balance that results from competitive redox exchange between 1 and 2 (Fig. 2B).36 Likewise, the addition of magnesium phenolate 5 to ortho-quinone (6) under the conditions of Barrow consumes excess 6 to provide only a 43% yield of 7, following redox exchange between 8 and 6.38 Finally, a bio-catalytic aerobic CDC reaction of 1,3-di-carbonyl 9 and catechol (10) mediated by a laccase was reported by Beifuss (Fig. 2D).32 Catechol 11 is produced in a high yield of 76% by a proposed sequence of successive C-C and C-O bond formations. It appears that the enzyme plays an important role in limiting the formation of any semi-quinone radicals, but mechanistic details have not been reported.


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ACS Catalysis

Figure 2. (A) Synthetically practiced catechol oxidations employ strong oxidants. The resulting CDC reactions with nucleophiles are complicated by competitive redox exchange between sCAT and OQ. (B) Base mediated cyclization of acetanilide 1 is complicated by competitive redox exchange of 1 and 2. (C) The nucleophilic addition of magnesium phenolate 5 to 6 consumes excess 6. (D) The bio-catalyzed catalytic aerobic CDC reaction of catechols and 1,3-dicarbonyls.

As part of a general program in aerobic Cu-catalysis,39-44 we became interested in CDC reactions of catechols, and the potential role that metals could play in controlling their selectivity. In previous work, we reported an aerobic oxygenation of phenols, in which we had observed high selectivity for coupled ortho-quinone 17 (Fig. 3A).45 It is interesting that two new C-O bonds form in this process. The first is a well-known oxygenation of 13 via 14 to afford 16, following a mechanism of atom transfer that mimics aspects of the enzyme


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tyrosinase.46 The second C-O bond formation, which installs the aryl ether, is less common.4749

Under oxidizing conditions, phenols favor C-C instead of C-O bond formation.7, 50 This

reflects their ease of oxidation to the phenoxyl radical, and the significant spin density that localizes on the less electronegative and more abundant carbon atoms.51 C-O bond formation has been attributed to metal coordination, most notably by Hay, to explain the selectivity of the Cu-catalyzed aerobic polymerization of phenols to (poly)phenylene ethers.52-54 This lead us to consider an oxidative coupling between semi-quinone radical 15 and phenolate 16, as a means of explaining the formation of 17 under the oxidizing conditions.


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ACS Catalysis

Figure 3. (A) Previous work on the oxygenative coupling of phenols. (B) Previous work on the catalytic aerobic CDC reaction of phenols and ortho-quinones. (C) This Work: a proposal for the catalytic aerobic CDC reaction of phenols and catechols.

Interested in the potential value of this aryl ether synthesis, but unable to extend our initial conditions to a cross coupling, we investigated an alternative CDC reaction between phenols and ortho-quinones (Fig. 3B).29 These conditions take advantage of a well-known redox process between Cu-(I) and ortho-quinones to produce semi-quinone radical 19. A similar mechanism of C-O bond formation with phenolate 16 could then provide quinone 20 as the product of cross coupling. While pleased about the improved versatility of this process, we were cognizant of certain drawbacks presented by the use of ortho-quinones. Because of their instability, ortho-quinones have limited commercial availability,55 they are incompatible with many common functional groups, and, as discussed above, they are most commonly synthesized by oxidation of the corresponding catechol using a synthetic oxidant. Consequently, a more efficient coupling reaction would unite the corresponding catechol with a phenol (Fig. 3C). This would replace a stoichiometric oxidation with a catalytic aerobic alternative, while also improving the commercial availability of the coupling partner. A catechol-phenol cross coupling presents several challenges that are not present in the polarity matched coupling of phenols and ortho-quinones. First, catechols and ortho-quinones are related by a 2 e | 2 H+ redox couple that requires a distinct oxidative mechanism in order to form the key semi-quinone radical 23 (Fig. 3C). While we anticipated 1 e oxidation of Cu(II)-catecholate 22 to be most straightforward, we also recognized the challenges of forming an electrophilic semi-quinone radical (e.g. 23) under standard catalytic conditions. This would create an inevitable competition between homo versus cross coupling, which ultimately requires preferential bond formation with phenolate 16 in the presence of catecholate 22. A second difference relates to the equilibrium between free and metal-bound quinone 18. This was not a complication in the quinone-phenol cross coupling, where the dissociation of 19 simply regenerated starting material (Fig. 3B). However, in a phenol-catechol cross coupling,


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dissociation of quinone 18 from semi-quinone radical 23 would create the possibility for conproportionation with the starting catechol 21, as discussed in Fig. 1C. Herein, we describe our efforts to address these challenges, and report conditions for a selective catalytic aerobic CDC of phenols and catechols that is selective for C-O bond formation. The reaction employs simple, commercially available components, proceeds within minutes at room temperature, and exhibits a relatively broad substrate scope. This includes the late-stage installation of (S, S)-thalicarpine’s diaryl ether, which benchmarks the efficiency of our new conditions relative to more traditional alternatives. The aerobic oxidation of phenols and catechols is a versatile, but underutilized transformation.44 We hope that our work provides a useful approach to address certain challenges of selectivity, which have historically limited its utility. Results and Discussion At the outset of our work, we investigated the oxidative coupling of guaiacol (25) and 4-methylcatechol (26) to coupled ortho-quinone 27 (Scheme 1). To bias the equilibrium towards Cu-(II) complexes 28 and 29, we employed excess CuCl2 (4 equiv) and 4-methoxy-pyridine (4-MeOPy) (8 equiv). The reaction mixture, including CH2Cl2 and 4 Å molecular sieves (4 Å MS) was assembled under an inert atmosphere of N2, before purging the headspace with O2 and applying a pressure of 1.2 atm. This triggered an immediate and pronounced darkening of the reaction mixture, which persisted for the duration of oxygenation (30 min). Aqueous acidic work-up delivered 27 in 73% NMR yield without observation of other products (entry 1). Consumption of catechol 26 was complete, whereas trace quantities of guaiacol (25) remained (~5 % by 1HNMR). This encouraging result appeared to support our mechanistic hypothesis. Because of their considerably lower oxidation potentials (Eox ~ 1V),56-57 a catecholate Cu-(II) complex should oxidize in preference to a phenolate Cu-II complex. In our case, this would selectively invert the polarity of 29 to electrophilic 30, while retaining the nucleophilicity of 28. C-O coupling should then proceed, by analogy to our previous work (Fig. 3A-B).


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ACS Catalysis

OH

O

CuCl2

OH

(4 equiv)

OH

MeO

OMe

Me

guaiacol (25) (1 equiv)

3 HX

4 Å M.S. CH2Cl2, rt

N

4-Me-catechol (26) (1 equiv)

O

O2 (1.2 atm) O OMe

4-MeO-Py (8 equiv)

Oxidation # 2 1 H+ | 3 e

3 HX

O

Cu

Oxidation # 1 1e

Ln

O

O

O

Cu

Cu

Ln

O

O Me

Me

27 (73% yield)

O X

Ln

Me

Me 29

28

O

Cu

X

Ln

Me

28

30

polarity reversal nucleophile

electrophile

Entry

Stoichiometric Conditions CuCl2 (4 equiv.) | 4-MeO-Py (8 equiv.)

1

Pre-mix reagents, then add O2 (1 atm) fo 30 min

Consumption (%)

Yield (%)

25

26

27

95

100

73

30

100

6

61

100

19

58

100

42

100

100

56

100

100

93

Change to reaction conditions: 2

No O2

3

4

No O2, use Cu(OAc)2

No O2, use

Py Cu Cl

5

CuCl 4-MeO-Py

6

CuCl 4-MeO-Py

O2

Me Cl O with 4-MeO-Py Cu O Py Me 31 sparge with N2

30 min

N2 30 min

then add solution of 25 and 26

then add solution of 25 and 26

O2 30 min

Scheme 1. Mechanistic proposal for the oxidative coupling of 26 and 27 in the presence of stoichiometric amounts of CuCl2.

To improve selectivity, we evaluated the effect of changing the oxidant (Scheme 1, entries 26). Under otherwise identical conditions, maintaining the N2 atmosphere and omitting O2 affords quinone 27 in only 6% NMR yield at complete consumption of catechol 26 and 30% consumption of guaiacol (25) (entry 2). No other discernable products were isolated, and we attribute poor mass balance to the polymerization of catechol 26, and to a lesser extent, guaiacol (25). It is important to note that with 4 equivalents of Cu(II), there is sufficient oxidizing capacity to produce 27 in the absence of O2. Recognizing that radical polymerization could initiate from outer sphere oxidation, we evaluated Cu salts with more basic counter anions,


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with the goal of driving ligand exchange towards Cu-II complexes 28 and 29. Consistent with this hypothesis, the yield of 27 improved to 19% when we employed Cu(OAc)2 (entry 3) and 42% when we employed bridged methoxy-chloride complex 31 (entry 4). Demmin and Rojic first described complex 31 in the 1970s,58-59 along with its preparation by aerobic oxidation of CuCl and pyridine (Py) in methanol. The same authors also demonstrated that a similar oxidation of CuCl, but in aprotic solvents, afforded a Brønsted basic Cu-(II) species, of undetermined structure.60-63 This led us to generate a similar Cu-(II) reagent in situ, by applying 1.2 atm of O2 to a solution of CuCl (4 equiv) and 4-MeO-Py (8 equiv) in CH2Cl2 possessing molecular sieves (entry 5). After 30 min, we discontinued oxygenation, and removed O2 by sparging with N2. To the resulting anaerobic mixture, we added a solution of catechol (26) (1 equiv) and guaiacol (25) (1 equiv), which was then allowed to react for an additional 30 min under an inert atmosphere of N2. This returned 27 in 56% yield at complete consumption of both substrates, demonstrating comparable reactivity between complex 31 and the Cu-(II) oxidant generated in situ from CuCl. While O2 is not required for C-O coupling it is beneficial, and if instead of sparging with N2, we simply add a 1:1 mixture of the substrates to the Cu-(II) reagent under an atmosphere of O2 (entry 6), the yield of quinone 27 improves to 93%. To account for this improvement to selectivity, we believe that aerobic oxidation of CuCl in an organic solvent produces a Brønsted basic, but not overly oxidizing, Cu-(II)-oxo. We believe that this species participates in a cleaner ligand exchange with catechol and phenol that minimizes electron transfer outside of the metal coordination sphere. We also believe that O2 accelerates the oxidation of 29, so that homocoupling between 30 and unoxidized 29 is limited. This then leaves 30 to react selectively with 28, and provide C-O coupled quinone 27.

The clean formation of quinone 27 takes an important first step towards a CDC of catechols and phenols, but extending these conditions to a catalytic alternative presented several challenges. Under catalytic conditions, Cu-(II) is not present in excess (Scheme 2). This creates a competition between phenol 25 and catechol 26 for binding to Cu-(II) that should favor the more thermodynamically favored catecholate complex 29. This creates a problem upon 1 e


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ACS Catalysis

oxidation of 29 to semi-quinone radical 30, since phenolate 28 would not be available for C-O coupling. Since we would anticipate poor selectivity under these conditions, we were not surprised to obtain only a 20% yield of 27 after a mixture consisting of CuCl (10 mol%), 4MeO-Py (20 mol%), catechol 26 (1 equiv.) and guaiacol (25) (1 equiv.) was oxidized with O2 (1.2 atm) for 1h. We do not recover starting material, and instead observe complex mixtures of varying solubility. LnCuX2 OH

O

OH OMe

OH

Me guaiacol (25) (1 equiv)


(10 mol %)

Cu

Ln

O

oxidation in the absence of 28 leads to polymerization

Me 29 formed preferentially

O2 (1.2 atm)

O

CuCl (10 mol%) 4-MeO-Py (20 mol%) guaiacol (25) (1 equiv)


CH2Cl2, rt, 1h

complete consumption of 25 and 26

O O OMe

Me 27 20% yield

Scheme 2. Preliminary attempts to catalyze the CDC of 26 and 27.

This result contrasts the very high levels of selectivity when we used four equivalents of Cu (Scheme 1), and led us to conclude that a high concentration of Cu-(II) relative to substrate was an important criterion for selectivity. To maintain this ratio while using only catalytic amounts of Cu, we considered a slow addition64 of substrate to match the introduction of catechol and phenol to the rate of a single turnover (Scheme 3). This would ensure a sufficiently high concentration of free Cu-(II) to coordinate both phenol and catechol, and thus avoid the coexistence of the electrophilic semi-quinone radical 30 with catechol 26 or catecholate 29.


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Scheme 3. Proposed mechanism for the catalytic aerobic CDC of 26 and 27 using a slow addition to control the relative concentrations of substrate and the Cu-(II) catalyst.

In practice, slow addition works remarkably well (Scheme 3). At an optimized rate of 0.6 mol / sec, the addition of a 1:1 mixture of catechol 26 and guaiacol (25) to a mixture of CuCl (10 mol%), 4-MeO-Py (20 mol%) and molecular sieves held under 1.2 atm of O2, provides a > 95% yield of quinone 27 (optimal conditions). There is a ~10% decrease in yield when molecular sieves are omitted (entry 1), and consistent with our hypothesis, the rate of substrate addition effects selectivity (entries 2 and 3). It is important to maintain a 1:1 ratio of catechol to phenol, as even slight deviation towards excess catechol leads to decreases in yield (entries 4 and 5). We observe a less pronounced sensitivity towards the stoichiometry of phenol (entries 6 and 7), suggesting that any pre-equilibrium between the phenol and Cu-(II) is reversible, and easily displaced towards catecholate 29. Finally, we highlight an important feature of the reaction setup that requires oxygenation of the pre-catalyst mixture for 2-3 minutes prior to the addition of substrate. We believe that this time allows a clean oxidation of CuCl to the unspecified Cu(II)-oxo. The lifetime of this in situ generated catalyst is not indefinite, and we observe


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ACS Catalysis

decreased yield if we oxygenate the pre-catalyst mixture for more than 30 min prior to the addition of substrate (entry 8). Because of our interest in forming the diaryl ether of (S, S)-thalicarpine (Scheme 5), we optimized conditions for a reductive work-up using NaBH4 in MeOH before exploring substrate scope (Scheme 4). This provides catechol 32 directly, with the new diaryl ether installed selectively at C4 (product numbering). We have conducted the procedure on scales of up to 8 mmols, which delivers 1.65 g of diaryl ether 32 in 89% isolated yield.

Scheme 4. Optimized conditions for the synthesis of diaryl ethers by oxidative coupling / reductive work-up.

This procedure remains selective for phenol itself (Figure 4, Entry 1), as well as a broad range of ortho-, meta- or para-substituted derivatives. Functional groups sensitive towards oxidation are tolerated. This includes 1o or 2o alcohols (Entries 8, 21 and 24), a 1o acetamide (Entry 7) and activated benzylic hydrogen atoms (Entries 9 and 13).65-66 A benzaldehyde is not oxidized to the corresponding carboxylic acid,65 and is preserved in the reductive work-up by using a modified protocol consisting of tert-butyl thiol and camphor sulfonic acid. The inclusion of an aryl bromide demonstrates complementarity with more traditional Ullman-type coupling reactions (Entry 5), and a boronic ester is tolerated, albeit in a reduced yield (Entry 6). Sterically encumbered diaryl ethers can be synthesized from the corresponding 3, 5-disubstituted catechol (Entry 26), and a preference is observed for the less sterically encumbered C5-position of a non-symmetric 3, 6-di-substituted derivative (Entry 25). Less highly substituted catechols are also tolerated (Entries 27-31), however, catechol itself is not a viable substrate. Substituents can include aliphatic groups bearing an ethyl ester, a Boc-protected 1o or 2o amine, or a free


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alcohol (Entries 22-24 and 31). Finally, successful coupling of 3-benzyl catechol demonstrates compatibility with easily oxidized and enolizable hydrogen atoms (Entry 30) that were not tolerated under our previous conditions employing ortho-quinones as coupling partners.29

Figure 4.

[a]Reaction

CH2Cl2/CH3CN;

performed in CH2Cl2;

[d]Reaction

[b]Reaction

performed in CH3CN;

performed on 4.0 mmol scale;

[e]Reductive

[c]Reaction

performed in a mixture of

work-up with tBuSH (3 equiv.)/TsOH (3

equiv); [f]Slow addition of 4-Me-catechol to a mixture of estradiol and catalyst.

Having evaluated scope, we turned our efforts to the diaryl ether adjoining the two halves of (S, S)-thalicarpine (32) (Scheme 5). Interest in this alkaloid peaked in the 1970’s, when it progressed to phase II clinical trials for the treatment of cancer (Scheme 5A).67 To support


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ACS Catalysis

biological studies, and to confirm the natural product’s structure, Kupchan and co-workers attempted to synthesize 33 by an Ullman coupling of phenol 34 and bromide 35 (Scheme 5a). These efforts were not successful, and ultimately required the group to synthesize the biaryl ether in the early stages of the synthesis from 36 and 37 by nucleophilic aromatic substitution.67 While Kupchan did not have access to more modern variants of the Ullman coupling, recent work of Opatz and co-workers, in the related total synthesis of (+)-tetramethylmagnolamine (39), highlight persistent challenges of late-stage diaryl ether synthesis (Scheme 5B).68-70 In this instance, cross coupling of phenol 38 with aryl bromide 35 using Ma’s di-methyl-glycine mediated conditions71 at 160 oC in the microwave led to only 50% yield of 39 on relatively small scale.


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Scheme 5. (A) Previous work towards the synthesis of (S, S)-thalicarpine (33) by Kupchan. (B) Late-stage Ullman coupling in the Opatz synthesis of (+)-tetramethylmagnolamine (39). (C) This work: total synthesis of 33 by phenolcatechol cross coupling. (D) Synthesis of thalicarpine analogues via late-stage derivatization of quinone 43. Conditions: a) MeI, Cs2CO3, DMSO; b) LAH, THF, reflux, 12 h | 74% over two-steps for 33; c) 3-pyroline (44) (1.2 equiv), 4 Å M.S. DCM | 63% for 45; d) 46 (2 equiv), DCM, 40 oC for 40 min, then, 100 oC for 4 h | 60% for 47.

The application of our methodology to a synthesis of thalicarpine requires cross coupling of aporphine 40 with catechol 41 (Scheme 5C). These are challenging substrates for a number of reasons. Both contain multiple sites for Cu coordination, aporphine 40 possesses a relatively


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planar biaryl bond that could delocalize spin density to weaken the putative Cu-(II)phenolate.42, 72 And there is potential for intramolecular oxidative cyclization of catechol 41 to form an aporphine.73-76 These challenges notwithstanding, the disconnection simplifies the natural product into two halves of comparable complexity, which we can prepare on multigram scale in high enantiopurity by capitalizing on Noyori’s asymmetric transfer hydrogenation77 and Fagnou’s aporphine synthesis78-79 (See Scheme S1 in the Supporting Information). Catalytic aerobic CDC under our standard conditions provides catechol 42 in 76% isolated yield, allowing us to complete an 11-step, longest linear sequence that delivers 33 in 20% overall yield. By contrast to Kupchan’s previous work,67 the point of convergence is only two steps from the end, which allows structural variation of the natural product’s two halves by fragment coupling (c.f. Entry 32 in Figure 4). The remaining central aromatic ring can be further diversified from the corresponding ortho-quinone 43 (Scheme 5D), which we can isolate in 68% yield on gram scale as the immediate product of dehydrogenative coupling. The two carbonyls of 43 are electronically differentiated as an enone and a vinylogous ester, allowing selective addition to the more electrophilic C4 carbonyl. Using 3-pyroline (44), redoxcondensation triggers C-sp2 | N-sp2 bond formation,55 and returns N-aryl-pyrrole 45 as a single regioisomer. Alternatively, coumarin 47 can be prepared as a single regioisomer by C-C bond formation with stabilized ylide 46,80 providing a synthesis of analogues that capitalizes on the restoration of aromaticity to drive aromatic C-N and C-C bond formation.81-82 Conclusion Catalytic aerobic CDC reactions provide a means of creating molecular complexity with high atom and step economy.16-18 Despite their efficiency, fundamental challenges of controlling their selectivity remain.83 In this work, we have described a new approach for promoting cross coupling between phenols and catechols, which remain particularly difficult substrates for this class of transformation. Our work takes advantage of Cu-catalysis to both stabilize reactive intermediates and promote a constructive cross coupling, and also exploits a slow substrate addition to approximate stoichiometric conditions while only using catalytic quantities of catalyst. This gives rise to a synthesis of diaryl ethers at room temperature, using inexpensive ACS Paragon Plus Environment

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starting materials, and simple, commercially available catalyst components.84-86 We hope that our work provides a platform from which to increase the use of catechols and phenols in fine chemical synthesis, since both are available from traditional petroleum and next-generation renewable feedstocks.87 As such, the current work provides a methodology that can bridge current and future sources of carbon. This is increasingly important as the field of chemical synthesis moves to a more sustainable future. ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at Additional information including reagent information; analytical information; experimental protocols; 1 H and 13C NMR spectra. AUTHOR INFORMATION Corresponding Author * [email protected] Author Contributions ‡

These Authors Contribute Equally

ACKNOWLEDGMENT Financial support was provided by the Natural Sciences and Engineering Council (NSERC) of Canada (Discovery Grant to J.-P. L.); the Fonds de Recherche Quebecois Nature et Technologies (FRQNT) (Team Grant to J.-P. L.); McGill University Faculty of Science (Milton Leong Fellowship in Science to Z. H.) the FRQNT Center for Green Chemistry and Catalysis (Fellowship to X. J.). REFERENCES


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1. Barner, B. A.; Bongat, A. F.; Demchenko, A. V. Catechol. In Encyclopedia of Reagents for Organic Synthesis. Weily: 2008. 2. Tyman, J. H. P. Chapter 14 Synthesis of Natural Phenols (and Their Derivatives) of Pharmaceutical, Medicinal or Technical Interest. In Studies in Organic Chemistry, Tyman, J. H. P., Ed. Elsevier: 1996; Vol. 52, pp 558-661. 3. Karakhanov, E. A.; Maximov, A. L.; Kardasheva, Y. S.; Skorkin, V. A.; Kardashev, S. V.; Ivanova, E. A.; Lurie-Luke, E.; Seeley, J. A.; Cron, S. L. Hydroxylation of Phenol by Hydrogen Peroxide Catalyzed by Copper(II) and Iron(III) Complexes: The Structure of the Ligand and the Selectivity of ortho-Hydroxylation. Ind. Eng. Chem. Res. 2010, 49, 4607-4613. 4. Fiege, H.; Voges, H.-W.; Hamamoto, T.; Umemura, S.; Iwata, T.; Miki, H.; Fujita, Y.; Buysch, H. J.; Garbe, D.; Paulus, W. Phenol Derivatives. In Ullmann's Encyclopedia of Industrial Chemistry. 5. Quinones and Heteroatom Analogues. In Category 4, Compounds with Two Carbon Heteroatom Bonds, 1st Edition ed.; Griesbeck, A. G., Ed. Georg Thieme Verlag: Stuttgart, 2006; Vol. 28. 6. Law, B. J. C.; Bennett, M. R.; Thompson, M. L.; Levy, C.; Shepherd, S. A.; Leys, D.; Micklefield, J. Effects of Active-Site Modification and Quaternary Structure on the Regioselectivity of Catechol-O-Methyltransferase. Angew. Chem. Int. Ed. 2016, 55, 26832687. 7. Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Aerobic CopperCatalyzed Organic Reactions. Chem. Rev. 2013, 113, 6234-6458. 8. Roduner, E.; Kaim, W.; Sarkar, B.; Urlacher, V. B.; Pleiss, J.; Gläser, R.; Einicke, W.-D.; Sprenger, G. A.; Beifuß, U.; Klemm, E.; Liebner, C.; Hieronymus, H.; Hsu, S.-F.; Plietker, B.; Laschat, S. Selective Catalytic Oxidation of C-H Bonds with Molecular Oxygen. ChemCatChem 2013, 5, 82-112. 9. Trammell, R.; Rajabimoghadam, K.; Garcia-Bosch, I. Copper-Promoted Functionalization of Organic Molecules: from Biologically Relevant Cu/O2 Model Systems to Organometallic Transformations. Chem. Rev. 2019, 119, 2954-3031.. 10. Hajdok, S.; Conrad, J.; Leutbecher, H.; Strobel, S.; Schleid, T.; Beifuss, U. The LaccaseCatalyzed Domino Reaction between Catechols and Heterocyclic 1,3-Dicarbonyls and the Unambiguous Structure Elucidation of the Products by NMR Spectroscopy and X-ray Crystal Structure Analysis. J. Org. Chem. 2009, 74, 7230-7237. 11. Hajdok, S.; Leutbecher, H.; Greiner, G.; Conrad, J.; Beifuss, U. Laccase Initiated Oxidative Domino Reactions for the Efficient Synthesis of 3,4-Dihydro-7,8-dihydroxy-2HDibenzofuran-1-ones. Tetrahedron Lett. 2007, 48, 5073-5076. 12. Leutbecher, H.; Greiner, G.; Amann, R.; Stolz, A.; Beifuss, U.; Conrad, J. Laccasecatalyzed Phenol Oxidation. Rapid Assignment of Ring-proton Deficient Polycyclic Benzofuran Regioisomers by Experimental 1H–13C Long-range Coupling Constants and DFTpredicted Product Formation. Org. Biomol. Chem. 2011, 9, 2667-2673. 13. Abdel-Mohsen, H. T.; Conrad, J.; Harms, K.; Nohr, D.; Beifuss, U. Laccase-catalyzed Green Synthesis and Cytotoxic Activity of Novel Pyrimidobenzothiazoles and Catechol Thioethers. RSC Adv. 2017, 7, 17427-17441.


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14. Emirdağ-Öztürk, S.; Hajdok, S.; Conrad, J.; Beifuss, U. Laccase-catalyzed Reaction of 3tert-Butyl-1H-pyrazol-5(4H)-one with Substituted Catechols Using Air as an Oxidant. Tetrahedron 2013, 69, 3664-3668. 15. For a related example using phenol and tyrosinase, see: Leutbecher, H.; Hajdok, S.; Braunberger, C.; Neumann, M.; Mika, S.; Conrad, J.; Beifuss, U. Combined Action of Enzymes: the First Domino Reaction Catalyzed by Agaricus Bisporus. Green Chem. 2009, 11, 676-679. 16. Liu, C.; Zhang, H.; Shi, W.; Lei, A. Bond Formations between Two Nucleophiles: Transition Metal Catalyzed Oxidative Cross-Coupling Reactions. Chem. Rev. 2011, 111, 17801824. 17. Girard, S. A.; Knauber, T.; Li, C.-J. The Cross-Dehydrogenative Coupling of Csp3-H Bonds: A Versatile Strategy for C-C Bond Formations. Angew. Chem. Int. Ed. 2014, 53, 74100. 18. Yeung, C. S.; Dong, V. M. Catalytic Dehydrogenative Cross-Coupling: Forming Carbon−Carbon Bonds by Oxidizing Two Carbon−Hydrogen Bonds. Chem. Rev. 2011, 111, 1215-1292. 19. Liu, Y.; Ai, K.; Lu, L. Polydopamine and Its Derivative Materials: Synthesis and Promising Applications in Energy, Environmental, and Biomedical Fields. Chem. Rev. 2014, 114, 5057-5115. 20. Maier, G. P.; Bernt, C. M.; Butler, A. Catechol Oxidation: Considerations in the Design of Wet Adhesive Materials. Biomater. Sci. 2018, 6, 332-339. 21. Dopamine undergoes spontaneous polymerization at pH > 7.5 in the presence of oxygen. The polymerization of catechol can also be catalyzed by enzymes or transition-metals, or be mediated electrochemically. For selected examples, see ref. 18-19 and 23-25. In control experiments, 60% of 4-methyl-catechol is polymerized in the presence of CuCl (10 mol%) after 2 min of oxygenation at rt. 22. Ulas, G.; Lemmin, T.; Wu, Y.; Gassner, G. T.; DeGrado, W. F. Designed Metalloprotein Stabilizes a Semiquinone Radical. Nature Chemistry 2016, 8, 354. 23. Šmejkalová, D.; Conte, P.; Piccolo, A. Structural Characterization of Isomeric Dimers from the Oxidative Oligomerization of Catechol with a Biomimetic Catalyst. Biomacromolecules 2007, 8, 737-743. 24. Ma, M.; Liu, H.; Xu, J.; Li, Y.; Wan, Y. Electrochemical Polymerization of oDihydroxybene and Characterization of Its Polymers as Polyacetylene Derivatives. J. Phys. Chem. C 2007, 111, 6889-6896. 25. Pezzella, A.; Vogna, D.; Prota, G. Synthesis of Optically Active Tetrameric Melanin Intermediates by Oxidation of the Melanogenic Precursor 5,6-Dihydroxyindole-2-carboxylic Acid Under Biomimetic Conditions. Tetrahedron: Asymmetry 2003, 14, 1133-1140. 26. Yuen, A. K. L.; Hutton, G. A.; Masters, A. F.; Maschmeyer, T. The Interplay of Catechol Ligands with Nanoparticulate Iron Oxides. Dalton Trans. 2012, 41, 2545-2559. 27. Takata, T.; Tajima, R.; Ando, W. Oxidation of Dihydroxyaromatics by Hypervalent Iodine Oxides: A Facil Quinone Synthesis. J. Org. Chem. 1983, 48, 4764-4766.


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28. Snyder, C. D.; Rapoport, H. Oxidative Cleavage of Hydroquinone Ethers with Argentic Oxide. J. Am. Chem. Soc. 1972, 94, 227-231. 29. Huang, Z.; Lumb, J.-P. A Catalyst-Controlled Aerobic Coupling of ortho-Quinones and Phenols Applied to the Synthesis of Aryl Ethers. Angew. Chem. Int. Ed. 2016, 55, 1154311547. 30. Abdel-Mohsen, H. T.; Conrad, J.; Beifuss, U. Laccase-Catalyzed Domino Reaction between Catechols and 6-Substituted 1,2,3,4-Tetrahydro-4-oxo-2-thioxo-5pyrimidinecarbonitriles for the Synthesis of Pyrimidobenzothiazole Derivatives. J. Org. Chem. 2013, 78, 7986-8003. 31. Leutbecher, H.; Hajdok, S.; Braunberger, C.; Neumann, M.; Mika, S.; Conrad, J.; Beifuss, U. Combined Action of Enzymes: the First Domino Reaction Catalyzed by Agaricus Bisporus. Green Chem. 2009, 11, 676-676. 32. Leutbecher, H.; Conrad, J.; Klaiber, I.; Beifuss, U. O-Heterocycles via Laccase-Catalyzed Domino Reactions with O2 as the Oxidant. Synlett 2005, 2005, 3126-3130. 33. For applications in bioconjugation, see ref. 33 and 34: Liu, B.; Burdine, L.; Kodadek, T. Chemistry of Periodate-Mediated Cross-Linking of 3,4-Dihydroxylphenylalanine-Containing Molecules to Proteins. J. Am. Chem. Soc. 2006, 128, 15228-15235. 34. Furst, A. L.; Smith, M. J.; Francis, M. B. Direct Electrochemical Bioconjugation on Metal Surfaces. J. Am. Chem. Soc. 2017, 139, 12610-12616. 35. Land, E. J.; Ito, S.; Wakamatsu, K.; Riley, P. A. Rate Constants for the First Two Chemical Steps of Eumelanogenesis. Pig. Cell Res. 2003, 16, 487-493. 36. Huang, Z.; Askari, M. S.; Esguerra, K. V. N.; Dai, T.-Y.; Kwon, O.; Ottenwaelder, X.; Lumb, J.-P. A Bio-inspired Synthesis of Oxindoles by Catalytic Aerobic Dual C–H Functionalization of Phenols. Chem. Sci. 2016, 7, 358-369. 37. Yu, W.; Hjerrild, P.; Jacobsen, K. M.; Tobiesen, H. N.; Clemmensen, L.; Poulsen, T. B. A Catalytic Oxidative Quinone Heterofunctionalization Method: Synthesis of Strongylophorine26. Angew. Chem. Int. Ed. 2018, 57, 9805-9809. 38. Zhang, M. Y.; Barrow, R. A. Accessing Polyoxygenated Dibenzofurans via the Union of Phenols and o-Benzoquinones: Rapid Syntheses of Metabolites Isolated from Ribes takare. Org. Lett. 2017, 19, 2302-2305. 39. Xu, B.; Lumb, J.-P.; Arndtsen, B. A. A TEMPO-Free Copper-Catalyzed Aerobic Oxidation of Alcohols. Angew. Chem. Int. Ed. 2015, 54, 4208-4211. 40. McCann, S. D.; Lumb, J.-P.; Arndtsen, B. A.; Stahl, S. S. Second-Order Biomimicry: In Situ Oxidative Self-Processing Converts Copper(I)/Diamine Precursor into a Highly Active Aerobic Oxidation Catalyst. ACS Cent. Sci. 2017, 3, 314-321. 41. Xu, B.; Hartigan, E. M.; Feula, G.; Huang, Z.; Lumb, J.-P.; Arndtsen, B. A. Simple Copper Catalysts for the Aerobic Oxidation of Amines: Selectivity Control by the Counterion. Angew. Chem. Int. Ed. 2016, 55, 15802-15806. 42. Esguerra, K. V. N.; Fall, Y.; Petitjean, L.; Lumb, J.-P. Controlling the Catalytic Aerobic Oxidation of Phenols. J. Am. Chem. Soc. 2014, 136, 7662-7668. 43. Esguerra, K. V. N.; Lumb, J.-P. Cu(III)-Mediated Aerobic Oxidations. Synthesis 2019, 51, 334-358.


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44. Huang, Z.; Lumb, J.-P. Phenol-Directed C–H Functionalization. ACS Catal. 2019, 9, 521555. 45. Esguerra, K. V. N.; Fall, Y.; Lumb, J.-P. A Biomimetic Catalytic Aerobic Functionalization of Phenols. Angew. Chem. 2014, 126, 5987-5991. 46. Askari, M. S.; Esguerra, K. V. N.; Lumb, J.-P.; Ottenwaelder, X. A Biomimetic Mechanism for the Copper-Catalyzed Aerobic Oxygenation of 4-tert-Butylphenol. Inorg. Chem. 2015, 54, 8665-8672. 47. Reinaud, O.; Capdevielle, P.; Maumy, M. Synthesis of New Bicyclic Quinones: 2H-1Benzopyran-5,8-quinones and Related Compounds. Synthesis 1987, 1987, 790-794. 48. Reinaud, O.; Capdevielle, P.; Maumy, M. Premiere Synthese Totale d'Une Hydroxymethoxy-quinone: la Dihydromaesanine. Tetrahedron Lett. 1985, 26, 3993-3996. 49. Sayre, L. M.; Nadkarni, D. V. Direct Conversion of Phenols to o-Quinones by Copper(I) Dioxygen. Questions Regarding the Monophenolase Activity of Tyrosinase Mimics. J. Am. Chem. Soc. 1994, 116, 3157-3158. 50. Shalit, H.; Dyadyuk, A.; Pappo, D. Selective Oxidative Phenol Coupling by Iron Catalysis. J. Org. Chem. 2019. 51. Quideau, S.; Deffieux, D.; Pouységu, L. 3.13 Oxidative Coupling of Phenols and Phenol Ethers. In Comprehensive Organic Synthesis II (Second Edition), Knochel, P., Ed. Elsevier: Amsterdam, 2014; pp 656-740. 52. Kobayashi, S.; Higashimura, H. Oxidative Polymerization of Phenols Revisited. Prog. Polymer Sci. 2003, 28, 1015-1048. 53. Hay, A. S. The SPE International Award Address—1975 Polymerization by Oxidative Coupling—an Historical Review. Polym. Eng. Sci . 1976, 16, 1-10. 54. Finkbeiner, H.; Hay, A. S.; Blanchard, H. S.; Endres, G. F. Polymerization by Oxidative Coupling. The Function of Copper in the Oxidation of 2,6-Dimethylphenol. J. Org. Chem. 1966, 31, 549-555. 55. Esguerra, K. V. N.; Xu, W.; Lumb, J.-P. Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling. Chem 2017, 2, 533-549. 56. Jazdzewski, B. A.; Holland, P. L.; Pink, M.; Young, V. G.; Spencer, D. J. E.; Tolman, W. B. Three-Coordinate Copper(II)−Phenolate Complexes. Inorg. Chem. 2001, 40, 6097-6107. 57. Verma, P.; Weir, J.; Mirica, L.; Stack, T. D. P. Tale of a Twist: Magnetic and Optical Switching in Copper(II) Semiquinone Complexes. Inorg. Chem. 2011, 50, 9816-9825. 58. Rogic, M. M.; Demmin, T. R.; Hammond, W. B. Cleavage of Carbon-Carbon Bonds. Copper(II)-induced Oxygenolysis of o-Quinones, Catechols, and Phenols. J. Am. Chem. Soc. 1976, 98, 7441-7443. 59. Demmin, T. R. Dichlorodi-μ-methoxybis(pyridine)dicopper. In Encyclopedia of Reagents for Organic Synthesis. 60. Rogic, M. M.; Demmin, T. R. Cleavage of Carbon-Carbon Bonds. Copper(II)-induced Oxygenolysis of o-Benzoquinones, Catechols, and Phenols. On the Question of Nonenzymic Oxidation of Aromatics and Activation of Molecular Oxygen. J. Am. Chem. Soc. 1978, 100, 5472-5487.


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74. Hara, H.; Hashimoto, F.; Hosino, O.; Umezawa, B. Studies on Tetrahydroisoquinolines. XXVIII. : Syntheses of (±)-N-Methyllaurotetanine, (±)-Cassythicine, (±)-9-Hydroxy-1, 2, 3, 10-tetramethoxyaporphine, (±)-Dicentrine, and (±)-Thalicsimidine. Chem. Pharm. Bull. 1986, 34, 1946-1949. 75. Landais, Y.; Rambault, D.; Robin, J. P. Ruthenium(IV) Tetrakis(trifluoroacetate), A New Oxidizing Agent. III. An Efficient Access to the Aporphine and Homoaporphine Skeletons and Their Structural Studies. Tetrahedron Lett. 1987, 28, 543-546. 76. Anakabe, E.; Carrillo, L.; Badía, D.; Vicario, J. L.; Villegas, M. Stereoselective Synthesis of Aporphine Alkaloids Using a Hypervalent Iodine-(III) Reagent-Promoted Oxidative Nonphenolic Biaryl Coupling Reaction-. Total Synthesis of (S)-(+)-Glaucine. Synthesis 2004, 2004, 1093-1101. 77. Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. Asymmetric Transfer Hydrogenation of Imines. J. Am. Chem. Soc. 1996, 118, 4916-4917. 78. Lafrance, M.; Blaquiere, N.; Fagnou, K. Aporphine Alkaloid Synthesis and Diversification via Direct Arylation. Eur. J. Org. Chem. 2007, 2007, 811-825. 79. Lafrance, M.; Blaquiere, N.; Fagnou, K. Direct Intramolecular Arylation of Unactivated Arenes: Application to the Synthesis of Aporphine Alkaloids. Chem. Commun. 2004, 28742875. 80. Nicolaides, D. N.; Adamopoulos, S. G.; Lefkaditis, D. A.; Litinas, K. E. Reactions of ortho-Quinones with Ethoxycarbonylmethylene(triphenyl)-phosphorane. Trapping of the ortho-Quinone Methanide Intermediates. J. Chem. Soc., Perkin Trans. 1 1990, 2127-2132. 81. Schreiber, S. L. Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery. Science 2000, 287, 1964-1969. 82. Karimov, R. R.; Sharma, A.; Hartwig, J. F. Late Stage Azidation of Complex Molecules. ACS Cent. Sci. 2016, 2, 715-724. 83. Esguerra, K. V. N.; Lumb, J.-P. Selectivity in the Aerobic Dearomatization of Phenols: Total Synthesis of Dehydronornuciferine by Chemo- and Regioselective Oxidation. Angew. Chem. Int. Ed. 2018, 57, 1514-1518. 84. Izawa, Y.; Pun, D.; Stahl, S. S. Palladium-Catalyzed Aerobic Dehydrogenation of Substituted Cyclohexanones to Phenols. Science 2011, 333, 209-213. 85. Campbell, A. N.; Stahl, S. S. Overcoming the “Oxidant Problem”: Strategies to Use O2 as the Oxidant in Organometallic C–H Oxidation Reactions Catalyzed by Pd (and Cu). Acc. Chem. Res. 2012, 45, 851-863. 86. Teles, J. H.; Hermans, I.; Franz, G.; Sheldon, R. A. Oxidation. In Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH Verlag GmbH & Co. KGaA: 2000. 87. Sun, Z.; Fridrich, B.; de Santi, A.; Elangovan, S.; Barta, K. Bright Side of Lignin Depolymerization: Toward New Platform Chemicals. Chem. Rev. 2018, 118, 614-678.


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Table of Contents Graphic | N

Me OMe

H O2

OH OH OH

OMe

MeO

CuCl (10 mol%) 4-MeO-Py (20 mol%)

OMe selective for cross C-O coupling simple catalyst components room temperature | 1h late-stage diaryl ether formation

OMe

O OMe

H

Me N

(S,S) thalicarpine MeO OMe


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Catalytic Aerobic Cross-Dehydrogenative Coupling of Phenols and

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