Phenol-Directed C-H Functionalization

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Review

Phenol-Directed C-H Functionalization Zheng Huang, and Jean-Philip Lumb ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04098 • Publication Date (Web): 05 Dec 2018 Downloaded from http://pubs.acs.org on December 5, 2018

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ACS Catalysis

Phenol-Directed C-H Functionalization Zheng Huang, Jean-Philip Lumb*

Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, QC H3A 0B8, Canada

Abstract: Phenols are important starting materials, intermediates and functional elements of a very broad range of chemicals and materials. They are large volume products of benzene oxidation, and are increasingly available from biomass. Investment into methodologies that improve the efficiency of their use can have both immediate and future impact on chemical upgrading. This review summarizes recent phenol-directed C-H functionalization reactions, which provide efficient increases in molecular complexity. Catalytic methodologies play an increasingly important role in addressing long-standing challenges of chemo- and regioselectivity, setting the stage for increased use of phenols

ACS Paragon Plus Environment

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in fine-chemical synthesis. We discuss these advances, while underscoring persistent challenges, with the goal of motivating increased interest in this versatile functional group.

KEYWORDS: Phenol, C-H Functionalization, Transition-Metal Catalysis, Oxidation, Selectivity

TOC Graphic:

OH

OH

OH

C2

C3

OH

H H

C-H Functionalization

H

C4

Methods: OH

H

 EArS  1,3-Migration  C-H Insertion  Dearomatization

OH

OH

external readily available building blocks

multi-site

high value products

1. General Introduction

1.1. Occurrence, Synthesis and Classical Functionalization of Phenols


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ACS Catalysis

Phenols are a highly conserved functional group in natural and synthetic chemistry.1-5 Tyrosine is an essential amino acid that plays important roles in the primary function and secondary structure of enzymes, including molecular recognition, electron transfer and catalysis (Figure 1A).6-8 It is also a precursor to co-factors produced by posttranslational oxidation.9-14

Natural products derived from or containing phenols are numerous, and

include hormones, antibiotics, vitamins and neurotransmitters (Figure 1B).1 Ten percent of the top 200 selling pharmaceuticals contain a phenol, and numerous others employ phenols as synthetic intermediates (Figure 1C).15-18 Phenols are also key components of or precursors to materials, including the biopolymers melanin19-21 and lignin,22 as well as synthetic phenol-formaldehyde resins23 and polyphenylene oxides (PPOs)24 (Figure 1D). They are a functional group whose study bridges small and macromolecular chemistry, as well as one- and two-electron reactivity.


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a) Tyrosine and its Post-Translational Derivatives OH

O

Tyr

Tyr

Tyr OH OH

Post Translational Modification

H 2N

O

CO2H tyrosine amino acid

O NHis Cu NHis O

OH2 OH2 NHis Cu His N NHis

Cys H S H R

Copper Amine Oxidase amine dehydrogenation

Galactose Oxidase alcohol dehydrogenation

b) Representative Naturally Occuring Phenols I

H

O

H

I

H

OH

HO

I

Me

O Cl

H

O H

Cl

O O

HO

OH

H 2N

O CO2H

O O

levothyroxine thyroid hormone estradiol estrogen hormone

HO

I

HO

OH

OH

NH2

Me

Me OH

O

OH OH

H N

H N HN

O

CO2H

O

O

H N

N H H2NOC

NHMe

N H

O

iPr

HO NH2 O

HO

OH

OH

vancomycin antibiotic

dopamine neurotransmitter

-tocopherol essential vitamin

OH

c) Representative Phenol-Containing Pharmaceuticals

OH OH

H N

O HO Me

HO O

HN

N

OMe

formoterol asthma controller

OH

R

MeO

HN OH

HO

Me

HO

MeO

OH

OH

representative substructure of lignin

Me

Me

O Me

HN OH

O OH

OH O

N

morphine analgesic

ezetimibe cardiovascular drug

d) Phenol Containing and Phenol Derived Materials

HO

Me

O

F

HO

F

R

polyphenylene oxide (PPO)

R = H or CO2Me representative structure of melanin

Figure 1. Occurrence of Phenols in Biology, Pharmacy and Materials Science.


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ACS Catalysis

Methodologies that selectively functionalize phenols can dramatically alter molecular form and function. Phenols are more electron rich and less aromatic than benzene [Eox phenol = 2.10 V (CH3CN vs Fc/Fc+);25-26 Eox benzene = 2.48 V (CH3CN vs SCN)],27 allowing reactions that proceed by dearomatization to occur at lower activation energies. The physical properties of phenols, including their redox-potential, their acidity and their OH bond-dissociation energies, are dramatically impacted by substituents

(Figure 2),

offering a broad range of reactivity, but one that can limit the scope of methodologies. Phenols have a strong electronic bias for electrophilic aromatic substitution (EArS) at their

ortho- and para-positions;2, 28 however, controlling selectivity between these two positions can be difficult. A steric bias exists for substitution in the para-position, while a statistical preference exists for substitution in the ortho-position. The capability of H-bonding and metal-coordination offers an additional avenue for biasing reactivity to the ortho-position. Phenolates are also nucleophilic on oxygen and participate in a range of C-O bond forming reactions by substitution2 (e.g. Williamson ether synthesis, -allyl chemistry) or cross-coupling reactions29-31 (e.g. Cham-Lam, Buchwald-Hartwig and Ullman Coupling). Phenols are also readily converted into pseudo-halides, and are thus attractive


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electrophiles for traditional cross-coupling platforms.32 They are thus strong directing groups for C-H functionalization, as well as versatile functional handles, from which a broad range of derivatives are readily prepared.

OH

OH

NO2

NO2

OH

OH

O2N

pKa (DMSO)

5.1

NMe2

10.8

18.0

19.8

Eox

2.74 V

2.1 V

0.84 V

BDE

94.7 kcal/mol

90 kcal/mol

80.3 kcal/mol

increasing electron density | decreasing oxidation potential

increasing acidity

Figure 2. Physical Properties of Phenols

Most large-volume and relatively simple phenols are downstream of the Hock Process, which converts benzene and isoprene into phenol and acetone by aerobic oxidation (Figure 3A).33 Production exceeds 106 tons per year, representing a remarkable production velocity of no less than 287 kg per second. A range of substituted derivatives are then readily prepared by Friedel-Crafts reactions, including acid promoted substitution


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ACS Catalysis

of alcohols, substitution of alkyl chlorides, acid promoted addition to olefins or carbonyls, and halogenation. Well-known and highly dispersed examples include butylated hydroxytoluene (BHT) and bisphenol A (BPA).28 More structurally diverse phenols are available from natural resources, and aromatic fractions of depolymerized lignin are increasingly popular targets of integrated bio-refineries (Figure 3B).34-35 Commercially relevant examples include guaiacol and vanillin, although production from benzene is still favored.

Phenols required for fine chemical synthesis can be prepared by a number of

methods, with commonly practiced examples including nucleophilic aromatic substitution or transition metal catalyzed cross coupling (Figure 3C).16-18, 36-37 While common place, many of these conditions require elevated temperatures and strong base, limiting their utility in complex molecule settings. In this context, recent work of Fier and Maloney, developing hydroxide surrogates, is noteworthy, since it has enabled the synthesis of phenols under much milder conditions.16-18 One example is provided in Scheme 1a, in which Ullmann-type hydroxylation of a base-sensitive substrate is made possible by using oxime as a hydroxide equivalent in conjunction with an elegantly optimized Cu-catalyst.17 The strength of the ortho / para electronic bias makes the synthesis of meta-substituted


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phenols more difficult, but recent strategies beginning from non-aromatic precursors have alleviated some of these limitations and provide an interesting blueprint for future development (Figure 3D).38-42 Recent work of Stahl is illustrated in Scheme 1B, in which oxidative coupling of cyclohexanone and an arylboronic acid affords the corresponding

meta-functionalized phenol following aerobic dehydrogenation (Scheme 1b).40 Finally, the synthesis of phenols via direct C-H oxygenation has seen recent development. This is a challenging transformation, because the product of oxygenation is typically more reactive than the starting material. Nevertheless, several conditions have been developed to oxygenate C-H bonds to protected forms of phenols possessing electron withdrawing groups on oxygen. Free phenols can then liberated in a subsequent step (Figure 3E).4345

Recent work of Ritter is illustrated in Scheme 1C, whose of use of bis(methanesulfonyl)

peroxide enables the synthesis of a broad range of phenols following basic deprotection, including a number of heterocyclic derivatives.44


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ACS Catalysis

OH

a) Industrial Synthesis of Phenol | Hock Process H

OH

H+

O2

Me common derivatization via SEAr

HO

OH cresols

bisphenol A

C-H oxidation

benzene petrochemical

cumene

phenol

7 106 tonnes produced in 2003

OH t

OH

OH

t

Bu

Bu

Cl

Me

Cl

BHT

chlorophenols

b) Production of Phenols from Biomass OH

OH

OH

OMe

MeO

OMe

depolymerization

OMe

lignin CHO

O guaiacol

vanillin

d) From Non-aromatic Compounds

c) Hydrolysis of Arylhalides X

O OH

O

OH SNAr or R1

R2

Pd (cat.)

Cs2CO3 R1

e) C-H oxygenation

F

O

R2

R1

R2

O O

EWG

OH

[O] C-H Oxygenation

CO2R

O2

transition-metal catalyzed hydrolysis

H

syringaldehyde

[O] =

cat. Pd(OAc) HNO3, HOAc O2

deprotection

O O

MsO

OMs

O

Figure 3. Standard Methods for the Production of Phenols


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a) Hydroxylation of aryl halide on a complex molecule setting CO2Me N

O

CO2Me CuI (5 mol%)

Boc Ph

N

(2.0 equiv)

Br

Me

N N

Me

b) Synthesis of meta-functionalized phenol

Boc

HO

O

H N

N H O

N

O

OH

PMB 94% yield

O (5 mol%)

Cs2CO3 (2.5 equiv) DMSO (0.2 M) 80 oC, 18 h

O2 (1 atm) [Pd(CH3CN)4](BF4)2 (5 mol%)

O

B(OH)2

N Me

+

OH

N

(5 mol%)

Me

O

NH2

c) Late-stage C-H Oxygenation H N

O

1. NMP, 50 oC, 24 h 2. DMSO, 80 oC, 36 h 1-pot process, 72% yield O

Me

O S

O

O

CF3

S

O

O

Cl

NH2

anthraquinone-2-sulfonate (10 mol%)

O

HFIP, 23 oC 36%

OMs

Me O Cl

OH

H N

O O CF3

LDA THF, - 78 oC

efavirenz

80%

Cl

H N

O O CF3

8-OH-efavirenz

Scheme 1. Representative remarkable examples for Recent Advancements

1.2. Organization of Review

Given their availability, phenols are important starting materials for methodology development. Their functionalization affects many different points of the chemical value chain, and existing transformations that are either non-regioselective or super


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ACS Catalysis

stoichiometric in promoter would be improved by selective, catalytic alternatives. Obtaining high selectivity between ortho and para positions remains challenging, as is the direct preparation of meta substituted phenols by directed C-H functionalization. These opportunities have motivated improvements to the C-H functionalization toolbox, which we survey in this review. We have attempted to catalogue successful examples of direct C-H functionalization reactions that conserve aromaticity, with an emphasis placed on recent examples from the literature. We have limited the number of examples in which products of C-H functionalization are non-aromatic, since the area of oxidative phenolic dearomatization has been surveyed by excellent reviews of Porco46 and Quideau.3,

47

Likewise, more recent, and very elegant bio-catalytic platforms for phenolic dearomatization are not covered, despite their clear impact on the field.48-49 More recently, the isohypsic, or redox neutral, dearomatization of phenols has gained in popularity,50-57 but these examples also go beyond the scope of this work. Recent examples of aryl-ether synthesis,58 either by nucleophilic substitution or cross-coupling, are also not covered. The breadth of phenol-directed C-H functionalization will invariably lead to omissions.


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Nevertheless, we hope to have suitably sampled the current literature to provide a meaningful overview of the field that will motivate continued development.

We have organized this review by the position of functionalization (Scheme 2), and treat (1) ortho-, (2) meta-, and (3) para-positions of phenol successively, followed by (4) external functionalization. Phenol-directed C-H functionalization reactions can take a number of different mechanistic forms. We have loosely defined these classes as (1) Electrophilic Aromatic Substitution (EArS), (2) Rearrangement of Aryl Ethers, (3) Transition-Metal Mediated Cross-Coupling and (4) 1- or 2-Electron Oxidation. These categories are not mutually exclusive, and a given transformation may exhibit mechanistic features of more than one class. Nevertheless, this categorization provides a convenient means of organizing transformations within each regiochemical category.


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ACS Catalysis

a) Classification of Phenol-Directed C-H Functionalization by Position OH

OH

C2

C3

OH

OH H C-H functionalization

H H

C4

OH

OH

external

multi-site

OH

H b) Methods and Strategies i) Electrophilic Aromatic Substitution OH

OH

O

ii) 1,3-Migration

H

TM H

O TM

iv) Oxidative Functionalization

OH

O

iii) C-H Insertion

O

O /

/

Scheme 2. Classification of Phenol-Directed C-H Functionalization

2. C2-Functionalization

2.1. Methods based on Electrophilic Aromatic Substitution (EArS)

Historically, C-H functionalization of phenols employing mechanisms of EArS exhibit poor selectivity between ortho- and para-positions in the absence of blocking substituents


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(Figure 4).2 However, recent catalyst development has achieved good to excellent C2selectivity when both C2 and C4 positions are unsubstituted. While detailed mechanistic studies of these catalyst systems are still required, a working model, accounting for their increased levels of ortho-selectivity through bi-functional catalysis, is illustrated in Figure 4. In this scenario, a Lewis-basic functionality on the catalyst activates the phenol towards EArS through hydrogen-bonding, while an electrostatic interaction or a discrete covalent bond positions the electrophile in close proximity of the ortho-position. We believe that this working model provides a convenient means of rationalizing regioselectivity for many of the examples included below in Section 2.

Figure 4. General Model for the Catalytic ortho-Selective Functionalization H-bonding accelerates EArS

OH E E

statistically favored

bifunctional catalyst control

O

H

E electrostactic interaction or covalent bonding

sterically and electronically favored

traditional EArS suffers from poor regioselectivity

B

favors ortho-functionalization

Perhaps the most well established reaction in this area is the catalyst-controlled

ortho-halogenation reaction (Scheme 3), which affords valuable products that can be further functionalized by traditional cross coupling. In 1993, Fujisaki et al. discovered that


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ACS Catalysis

simple secondary amines dramatically increased ortho-selectivity for the bromination of 2-substituted phenols with NBS.59 The selectivity for the generation of 6-bromo-2-cresol improved from ~ 4:1 to > 200:1 in the presence of only 10 mol% of diisopropylamine. In 1995, Sheldon et al. observed a similar amine effect for the ortho-chlorination of phenol with SO2Cl2,60 in which the addition of diisobutylamine was crucial to maintain good selectivity for the generation of 2-chlorophenol. These conditions were further developed by Snider for the synthesis of maldoxin,61 where 2,2,6,6-tetramethylpiperidine was found to be a better amine catalyst, albeit with limited substrate scope, with general ortho : para selectivity of ~ 4:1. In 2016, Gustafson et al. developed a thiourea-catalyzed orthochlorination of phenol using N-chlorosuccinimide as the terminal chlorine source, and included 11 examples with overall > 10:1 ortho : para selectivity.62 The authors also demonstrated catalyst-controlled para-selectivity with an alternative thiourea catalyst. More recently, Yeung et al. reported a simple ammonium salt-catalyzed ortho-selective halogenation of phenol.63 In the presence of catalytic amounts of diisopropylammonium chloride, phenols with different substituents can be selectively ortho-chlorinated with 1,3dichloro-5,5-dimethylhydantoin (DCDMH). 3-Substituted phenols possessing a non-


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Lewis basic group (e.g. F); are selective for C6, whereas substituents capable of engaging in H-bonding (e.g. aldehyde or boronic ester) promote chlorination at C2. In addition,

ortho-selenylation could also be achieved with similar ammonium catalysts using a (N(phenylseleno)phthalimide (NPSP) as the electrophilic source of selenium.


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ACS Catalysis

OH

OH H

"

X

R

OH X

"

or

R

R

H ortho-

X para-

major

minor

Fujisaki 1993 OH

OH

NBS (1 equiv)

Me

OH

Me

Br

Me

CH2Cl2, rt, 1h Br without amine: with 10 mol% NHiPr2: Sheldon 1995

75.4

21.1

96.5

0.4

Snider 2014 OH

O

N H

Cl

(7.9 mol%) + SO2Cl2 (1.25 equiv)

OH Cl

N H (1 - 10 mol%) +

79% 66:1 (o:p)

53% 3.7:1 (o:p)

SO2Cl2

1 example

7 examples

F 3C

CF3 OH

OH Ph S

NH NH

CF3

F

S

75% 10:1 (o:p)

N H

N H

73% 16:1 (o:p)

CF3 Gustafson 2016

(10 mol%) +

11 examples

NCS OH

Cl

o' N H

Cl

Cl

OH o Cl

o'

CHO

H

o'

BPin

93% 20:1:0 (o:o':p)

(0.01 - 5 mol%)

OH o Cl F 80% >50:1:0 (o:o':p) OH

64% 15:1:0 (o:o':p) OH

+ I

DCDMH

MeO

Yeung 2018

79%

75% > 50:1 (o:p) O

Cl

SePh

Cl

75 examples

o Cl

N

N

with NPSP O

Cl

O DCDMH

N

SePh

O NPSP

Scheme 3. Catalyst-Controlled ortho-Halogenation


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A remarkable example, demonstrating the potential for catalyst control to effect selective phenol-directed C-H functionalization in a complex molecule setting, was recently reported by Miller’s group, in which site-selective bromination of vancomycin with

N-bromophthalimide was mediated by a small-peptide catalyst (Scheme 4). Using BocAsn(Me2)-DAla-DAla-OH, the team was able to generate 7d-Br as the major product of bromination, and proposed a multi-site hydrogen-bonding network between the substrate and the peptide to account for regiocontrol. In contrast, 7f-Br was formed as the major product of bromination when using excess guanidine as the mediator, underscoring the important role of molecular recognition.


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ACS Catalysis

Me

OH

OH

NH2

Me HO O

H

O

O H

Cl

Me

O

O HN

H

O

H N O

N H H2NOC

O

O H

Cl

O

Cl O

O OH

N H CO2H

O

Cl

HO O

HO

O

O

OH

OH

NH2

Me HO

HO

HO O

H N O

NHMe

N H

OH O

catalyst O

N H CO2H

O iPr

HN N

Br

O

H N O

N H

O

H N

H2NOC

NHMe

N H

O

iPr

Rf HO

O

OH OH

HO

vancomycin

Rd = H, Rf = Br, 7f-Br Rd = Br, Rf = H, 7d-Br Rd = Br, Rf = Br, 7d,f-Br

OH OH Rd

catalyst

conv.%

7f-Br

Boc-Asn(Me2)-DAla-DAla-OH (1 equiv.)

98

1.0

:

7d-Br 14.6

:

7d,f-Br 2.8

guanidine (18 equiv.)

85

12.7

:

1.0

:

10.8

Scheme 4. Catalyst-controlled Site-selective Bromination on Vancomycin

With the development of chiral catalysts, asymmetric EArS reactions of 2-naphthols have recently emerged. One of the most developed systems is the atropo-selective synthesis of biaryl bonds by conjugate addition to para-quinones (Scheme 5).64-66 This process has been catalyzed by chiral Brønsted-acids, chiral amines, as well as chiral cobalt complexes. These methods provide an alternative approach to unsymmetrical BINOLs, which are more commonly prepared by oxidative coupling (see Section 4).


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Page 20 of 129

R2

O

R2

HO O

chiral catalyst

OH

OH

OH atropo-selective biaryl synthesis

R1

i i

Pr i

O

i

HO

HO OH

EtO2C

Pr

O i

Pr

R1

OH

Br MeO

OH

O

OH

P OH

Pr

88% yield 99% e.e.

72% yield 96% e.e.

Pr i

(5 mol%) CH2Cl2, - 78 oC

Pr

21 examples Liu & Tan 2015

H

HO

Br

HO

Br

OH

Cl

HO N

OH

OH

MeO

OH Br

N 82% yield 60% e.e.

(30 mol%) THF, 4 oC - rt

70% yield 80% e.e.

18 examples

Salvio & Bella 2016 HO

O i

Pr

NH i

N

N

O

O

i

Pr

Pr

(10 mol%)

Scheme 5.

MeO2C O HN

i

OMe OH OH

Pr MeO 84% yield 85% e.e.

Co(ClO4)2 · 6H2O (10 mol%)

36 examples, 75 - 95% e.e.

CH2Cl2, - 78 oC

Liu & Feng 2017

Asymmetric Addition of 2-Naphthol to para-Quinone

Recently, organocatalysts capable of synergistic activation of the electrophile and the phenol by H-bonding have emerged. Mechanistically, protons of the thioamide or squaric amide groups are proposed to activate Lewis basic functionalities of the electrophile for 1,2- or 1,4-addition, while a Lewis basic amine activates the phenol by H-


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ACS Catalysis

bonding (Scheme 6).67-69 α-Ketoaldehyde hydrates,67 nitroalkenes68 as well as isatins69 are suitable electrophiles, producing chiral phenols with good control of chirality at the newly formed benzylic position. Methods are currently limited to phenols with strong electron-donating substituents, naphthols or hydroxyindoles, but the process affords an attractive approach for asymmetric ortho-selective C-H functionalization.

OH

OH

H-bonding catalyst

" E

*E

" OH

OH HO

OH

OH

Ph

O

O

Vila & Pedro 2016

Ar

OH

Wang & Zeng 2017

O

Ar

- only 3,5-dimethoxyphenol was shown - Ar = aryl, naphthyl, thiophenyl furanyl - 16 examples up to 98% e.e.

N

OH

Type II

- only hydroxyindoles were shown - 15 examples up to 96% e.e.

O OH

Pedro 2017

N H

common catalyst structure: S

95% e.e.

Bn

O NBn

At least 1 donating group required

NO2 OMe

MeO

O

MeO

up to 99% e.e.

Type I

NO2

OH

Ar

Type I

Ar

mode of action: O

O

ArHN

Q

N ArHN

Q

Type I

Ar =

CF3

S

Type II Ar

N Q= H

F 3C

H

H OMe N H

OMe H N

N E

O

H

N

N

Scheme 6. Organo-Catalytic 1,2- and 1,4-addition


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ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 22 of 129

In 2015, Wang and Tang et al. reported an asymmetric synthesis of dihydrobenzofuranones by EArS with trifluoromethyl-pyruvates (Scheme 7).70 Their method employed Cu(OTf)2 as a catalyst in conjunction with a chiral bisoxazole ligand, displayed good scope in phenol, and was applied to the decagram scale synthesis of an enantio-pure biologically active compound. The method is currently limited by the scope of the electrophilic coupling partner.

O N

O OH

O N

OR

F 3C

TfO

R = Me or Et

O O CF3

Bu

O

CF3 OH

OH

R' = H, 83%, 85% e.e. t Bu, 94%, 94% e.e. OMe, 81%, 95% e.e. Et, 88%, 95% e.e.

OMe 58%, 96% e.e.

74%, 95% e.e. O

O

O

O

O Me

O CF3

OH

R'

CF3 OH

Wang & Tang 2015

O t

O

OTf

(10 mol%)

O

O

O

Cu

CF3

O CF3 OH

OH

CF3 OH

O

Me

O 76%, 97% e.e.

58%, 91% e.e.

75%, 99% e.e.

Scheme 7. Asymmetric Synthesis of Benzofuranones


22

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ACS Catalysis

In 2017, You et al. reported the asymmetric synthesis of dihydrobenzopyranones by

N-heterocyclic carbene (NHC) catalyzed oxidative coupling of phenols and α,β-unsaturated aldehydes (Scheme 8).71 Over 19 examples were included, with enantiomeric excess of up to 97%. Current limitations include poor scope for the -substituent of the aldehyde, and the requirement of an electron-rich phenol with electron donating oxygen or nitrogen substituents in the ortho- or para-position.

Ph

OH

Ph

BF4 N

N N H

R1

O t

t

Bu

Bu

CHO

R2

R1

(10 mol%)

OH

O

19 examples up to 81% yield 85-97% e.e.

You 2017 t

Bu

t

Bu

(1.2 equiv)

O

R2 O

LiHMDS (20 mol%) OMe

OMe

MeO

MeO

O

OMe

O

MeO O

O

Ph

O

O2N

70%, 96% e.e.

O O

50%, 85% e.e.

NMe2

52%, 96% e.e. OMe

O O

Br O

O

MeO

MeO

N

R2

N N *R

R

62%, 92% e.e.

36%, 94% e.e.

R1

Proposed Mechansim:

Ar

O MeO

32%, 92% e.e.

OH

O

MeO O

O

O

-

- 2e | H

H

O

+

Ar N

R2

N

OH O

R1 R2

N

N *R

Ar N N

R

*R

R


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ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 129

Scheme 8. Chiral NHC-Catalyzed Dihydrobenzopyranone Synthesis

In 2017, Tong et al. reported a chiral phosphine-catalyzed addition of naphthols to allenic esters for the synthesis of dihydrobenzofurans with two adjacent chiral centers (Scheme 9).72 In their proposed mechanism, the phosphine attacks the central carbon of the allene with the loss of the acetate to generate a phosphonium salt, on which the naphthol can than perform a 1,6-addition followed by cyclization.


24

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ACS Catalysis

OAc

R1

R1

(R)-SITCP (10 mol%)

R2  H

O

R2

K2CO3 PhMe, 0 oC

CO2Et OH

CO2Et

O

Ph

I

O

O

Me

O

Ph Me CO2Et

CO2Et 75% 87% e.e.

CO2Et 94% 92% e.e.

70% > 20:1 d.r.

CO2Et

27% 85% e.e.

Proposed Mechanism:

P

*PR3 =

R

OAc

Ph

OH

*PR3

R 

* R 3P

CO2Et

proton transfer R R 3P

O

R H

H

O

CO2Et

* R 3P CO2Et

R

O

O

R

* R 3P

[1,2]-proton shift

O EtO

(R)-SITCP

O

R

OEt

O

R 3P CO2Et

CO2Et

Scheme 9. Chiral Phosphine-Catalyzed Dihydrobenzofuran Synthesis

In limited cases, EArS reactions affording alkylated products can be highly orthoselective for simple phenols lacking multiple substituents. In 2016, a Lewis-acid catalyzed

ortho-selective alkylation of phenols with α-diazoesters was reported by Zhang et al


25

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Page 26 of 129

(Scheme 10).73 Tris(pentafluorophenyl)borane was found to be the most efficient catalyst, and provided a 75 : 13 ratio of ortho- vs para-functionalized products when using phenol as the substrate. The ratio was further increased to 90 : 8.5 when the α-diazoester was changed from methyl to isopropyl. The author’s proposed a hydrogen-bonding interaction between the -OH of phenol and the fluorine atoms on the tris(pentafluorophenyl)borane catalyst to account for the ortho-selectivity. Over 50 examples were demonstrated, providing ortho-substituted phenols in yields of up to 92%.

OH R1

CO2R2

Ar

OH

(C6F5)3B (5 mol%)

N2

Ar CO2R2

R1

CH2Cl2, rt metal-free

> 50 examples up to 92% OH

Br

Ph

OH

CO2R

Ph CO2iPr

F

OH OH

CO2iPr I

CO2iPr

R = Me, 75/13 (o/p) i Pr, 90/8.5 (o/p)

81% (o/p = 10.3/1)

71% (o/p = 10.1/1)

73% (o/p = 10.4/1) F F

F

F

F F

F O

H Ar

B

F

F F

F F F

N

N CO2R2

F

F F

F

F F

F

F

F

O

H H

B

F

F F F F

Ar

N

F F

F

N CO2R2

hydrogen-bonding directed

Scheme 10. Lewis-Acid Catalyzed ortho-Selective Alkylation with α-Diazoesters


26

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ACS Catalysis

Finally, a conceptually distinct approach to ortho-arylation involving a pericyclic process is the ortho-CH functionalization of phenols with benzynes, which proceeds via an ene-type mechanism (Scheme 11). Recently, Hoye et al. reported an elegant extension of this protocol by intercepting arynes generated in situ from the thermolysis of triynes.74 Regioselectivity was explained by preferential attack of the nucleophilic carbon of the phenol onto the carbon of the benzyne that possessed the largest internal bond angle. This led to exclusive formation of the 5-arylated indole. The method is relatively broad with regards to the scope of phenol, and can include catechols, resorcinols and hydroquinones, as well as hydroxyindoles. While somewhat limited to electron rich phenols, this work provides a conceptually new approach for the ortho-selective C-H arylation of phenols.


27

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Me

Page 28 of 129

Me HO

o

DCE, 85 C

H

18 examples 26-77%

NMs

85 oC Me

R

HO Me

Me

R

NMs

tautomerize

138o

R

Me

Me

R

Me

phenol-ene reaction H NMs aryne-intermediate R' =

H

O 117

H

o

NMs

Me HO Me OMe

NMs

HO Me

R'

71% OH

21%

80%

57% NMs

HO Me

OMe

R'

R'

R'

CO2Me

NMs

HO Me

NMs

Me

HO Me

R'

O

OH

NMs

HO Me R'

75%

NH

NMs

68%

Scheme 11. The Phenol-Ene Reaction with Arynes

2.2. Methods Based on Oxygen to Carbon Rearrangements An alternative approach to functionalize the C-H bonds of phenols is by initial O-H functionalization, followed by O to C rearrangement.28, 75 Well-known examples include the Fries rearrangement, which can occur via charge separated, radical or anionic76-77 pathways (Scheme 12). The first two can suffer poor ortho-, para-selectivity, reflecting the delocalization of charge or spin-density throughout the aromatic ring. Nevertheless, their


28

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ACS Catalysis

utility is exemplified by the Mulzer-Magauer total synthesis of kendomycin,78 in which the natural product’s macrocycle was constructed by an O-C migration via photo-Fries rearrangement.

The anionic rearrangement of aryl sulfonates promoted by strong base

provides an alternative pathway via a non-resonance stabilized arene anion, and is selective for migration of sulfur to the ortho-position.76 This provides a convenient entry into aryl sulfones by thio-Fries rearrangement, albeit under relatively forcing conditions.

a) Cationic Fries Rearrangement R O

d) Recent Application in Mulzer's Kendomycin synthesis

2

R O Lewis-acid

R1

2

OLi R2

OLi

O

O

O

R1

O 2

R O para-

ortho-

O

R2 O

OLi

O

O

O

O O

HO

HO2C

O OMe

OMe h

Photo-Fries

O

R1 R2 O para-

ortho-

OH O

c) Anionic Fries Rearrangement R2 O R

Lactonization

R2

O

h R1

OLi

O

O

b) Radical Fries Rearrangement R2

EDCI DMAP

1

S

R2 O

O

O LDA R

1

S

OLi

O O Li

S

O O

O

O O

HO

R2

R1

O O

HO O kendomycin

HO OMe

ortho-

Scheme 12. Three Types of Mechanisms for the Fries Rearrangement


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Page 30 of 129

The aromatic Claisen rearrangement provides a well-known approach to functionalize the C-H bonds of phenols by O to C rearrangement.79 This can take place via a concerted [3, 3]-sigmatropic rearrangement, in which a closed transition state relays absolute stereochemistry from the allylic ether to the newly formed benzylic stereocenter. In 1998, Trost et al. reported the first example of an asymmetric O-allylation / rearrangement protocol to generate 2-allylphenols bearing benzylic stereocenters with high levels of enantiocontrol (Scheme 13).80 The first step employs well-established conditions for the Pd-catalyzed asymmetric O-allylation of phenols using Trost’s chiral diphosphine ligands. In the second step, a Lewis-acidic europium catalyst (EuFOD) promotes Claisen rearrangement at 50 oC, with good chirality transfer.


30

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ACS Catalysis

R1

R1

cat. Pd2dba3/L* CH2Cl2, rt

R2 R4O2CO

R3

step 1

R3

Eu(fod)3 CHCl3, 50 oC

R2 O

R3

OH

OH

step 2

R1 R2

R R

R

OH H

O

85% (step 1) 86% (step 2) 93% e.e.

L*=

OCH3

O NH

HN

PPh2 Ph2P OH

OH

Me

OH H

F 88% (step 1) 83% (step 2) 94% e.e.

H3CO H

Me

CHO 83% (step 1) 84% (step 2) 80% e.e.

Me

Me

Me 89% (step 1) 83% (step 2) 91% e.e.

Scheme 13. Asymmetric O-Allylation Followed by 1,3-Migration

It is also possible for the aromatic Claisen rearrangement to proceed via a non-concerted mechanism, in which heterolytic cleavage produces an ion pair. Trauner proposed such a mechanism to account for the ring contraction of (±)-smenochromene D in the course of a synthesis of smenochromene B (Scheme 14).81


31

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

O

Me

OMe

Page 32 of 129

Me

OMe

O

Concerted Claisen Rearangement OH

O Not Observed (±-smenochromene D = (±)-likonide B

likonide A

o-C6H4Cl2, w (95%) Me

Me O

O

OMe

OMe (Z)

OH (E)

O isomerization

ring contraction

Scheme 14. A Non-Concerted 1, 3-Transposition

Related, but non-classical Claisen rearrangements have also recently been reported for the construction of biaryl bonds (Scheme 15). Kurti et al. reported a new synthesis of 2-arylated phenols by acid-catalyzed coupling of phenols and para-quinone ketals.82 Their proposed mechanism involves acid-promoted ketal exchange to provide the allylvinyl ether necessary for aromatic Claisen rearrangement, which generates the corresponding biaryl bond with good ortho-selectivity. The authors reported the synthesis of more than 30 unsymmetrical biaryls in generally high yields. N-Sulfonyl iminoquinone ketals were also shown to be effective coupling partners to provide the corresponding protected anilines. More recently, an asymmetric version of this methodology has


32

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ACS Catalysis

appeared, catalyzed by chiral phosphoric acids.83 In 2016, Kita et al. demonstrated that a competition existed between substitution on oxygen and substitution on carbon,84 where the latter was favored when using methane sulfonic acid (MeSO3H). The result was direct C-C bond formation at the para-position of the phenol, to provide the corresponding 4aryl phenols. Finally, Kaicharla and Biju showed that the stronger triflic acid (TfOH) promoted cyclization of the initially formed binol, creating an attractive entry into dibenzofurans by dehydration.85

Ar

MeO

R1

MeO

P

O

OH

OH Ar

X X = O or NSO2R''

H

TFA, (PhO)2PO2H or chiral phosphoric acid MeO

Ar = 2,4,6-tri-iPr-Ph chiral phosphoric acid

R2

R1

H+ X

TfOH

MeSO3H

O

MeO

R1

OH

OH

OH

MeO MeO

R2

R2 R1

[3,3] MeO

O

O

(S)-

H

R2

X

acid-promoted cyclization

EArS

R1

MeO R1 OH

XH OH

R2 Kurti and Xu 2016

up to 97% e.e.

MeO

O R2 R1

XH Kita 2016

R2 Kaicharla and Biju 2017

Scheme 15. Biaryl Synthesis via 1,3-Migration


33

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 34 of 129

In 2016, Yorimitsu et al. reported a novel synthesis of 2-aryl phenols by cross coupling of phenols and aryl sulfoxides (Scheme 16).86 Similar to the Claisen rearrangement, migration of the aryl sulfonium group from oxygen to the ortho-carbon can proceed via a six-membered transition state. The reaction proceeds at room temperature, and requires only trifluoroacetic anhydride to activate the sulfoxide. More than 35 examples, encompassing both electron rich and electron poor phenols were demonstrated, including a broad scope of aryl and heteroaryl substituted sulfoxides. In cases were the ortho-position of the phenol was blocked, a further 1,2- or 1,3-migration occurred, to produce a 15 to 1 mixture of the meta- and para- substituted products.


34

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ACS Catalysis

R2

R2

S R1

O OH

R2

S

(CF3CO)2O (1.5 equiv)

R1

S R1

O

OH

o

CH2Cl2, 25 C R3

R3

39 examples up to 97%

R3 Ts N

Ts N

SMe

MeO

S

SMe

SMe SMe

OH

OH

OH

OH MeO

O2N

Bpin 76%

t

Bu

84%

83%

S SMe

Me

TFA (20 mol%)

O

Me

92% Me

Me

25 oC

OH

OH Me Me

S SMe

58%

82% (m/p = 15/1) C3-functionalization

S

SMe

C4-functionalization

Scheme 16. ortho-Aylation of Phenols with Aryl Sulfoxides

In a somewhat related, albeit mechanistically distinct process, Schaus et al. reported a BINOL-catalyzed three-component coupling between phenols, aldehydes and vinyl borates

for

the

synthesis

of

chiral

2-allylphenols

or

2,

4-disubstitued

tetrahydrobenzopyranes (Scheme 17).87 Their proposed mechanism involves a chiral boronate, which co-localizes the phenol, the aldehyde and the vinyl boronic ester within the asymmetric influence of BINOL. The resulting cyclic boronate results from orthoselective C-C bond formation before migration of the vinyl group installs the benzylic stereocenter of the corresponding 2-allyl-phenol. These products can undergo additional


35

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 36 of 129

cyclization to produce the corresponding 2, 4-disubstituted tetrahydrobenzopyranes with excellent enantioselectivity.

R2 R2

R3

R1

CHO

OH

R1 OH

OiPr i

PrO

21 examples 44-100% yield up to 98:2 e.r.

X

B

R3

R2

OH OH R1 X X = Br or I (15 mol%)

R2

R2 O

R1 O

R3 O 6 examples up to 72%, 99:1 e.r.

O

R1

B OR*

R3

O

H

B OR*

R2

R3

R2

R1

R3

R1 O

R3

OH

Scheme 17. Chiral BINOL-Catalyzed ortho-Selective Multi-Component Coupling

A related rearrangement within this category is the migration of aryl groups from phenolate-metal complexes (Scheme 18). Barton introduced Pb (IV)88 and Bi (V)-


36

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ACS Catalysis

reagents89 for this purpose as early as 1985. More recently, Yamamoto has reported asymmetric variants that employ chiral amine ligands to install biaryl bonds with good atropo-selectivity.90 In general, arylation reactions employing Pb- or I-based reagents91 are selective for ortho-arylation of the phenol. It is noteworthy that these high-valent metals are selective for aryl transfer, since related reagents are well known to oxidize phenols to the corresponding phenoxyl radical or phenoxonium cation, to provide products of phenolic dearomatization (Scheme 18D).3, 46-47


37

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 38 of 129

a) General Concept:

OH Ar R

Ln

OH

Ar-M-X

H

O

base

R

M

[2,3] migration

Ar

mono-aryl OH

O-metallation

R

Ar

Ar

R di-aryl b) Early Discovery

i. Ph3BiCl2 NH

OH Ph

Me2N

ii. heat

t

t

Bu

Bu

OH

82%

OH PhPb(OAc)3 (4 equiv)

NMe2 t

t

Bu

Bu

Barton 1985

Ph

t pyridine Bu CHCl3, 25 oC Barton 1994

c) Atropo-Selective Biaryl Synthesis OH

Pb(OAc)3 R1

R1 N

OH iPr MeO i

Ph Me

Me

H H

Pr

H

H

MeO

68% > 99% d.r. 83% e.e.

Bu

R2

PhMe - 40 to - 20 oC OH Ph

t

64%

OH R2

brucine (6 equiv)

R2

Ph

OMe

N

MeO

82% > 99% d.r. 54% e.e.

O

O brucine

d) I-(III)-Mediated Arylation / Dearomatization OH Me

OPh Me

Ph2ICl (1.3 equiv) t BuOK BuOH, rt

Me

O Me

Me Me

Ph

t

Me

Me 7%

Me 42%

O Me

Me

Me Ph 7%

Scheme 18. The Migration of Aryl Groups From High-Valent Metals

2.3. Methods Based on Transition Metal Catalysis In addition to their strong ortho-, para-directing effects, phenols can serve as good ligands to transition metals through their corresponding phenolates. This has given rise to a number of transition metal catalyzed C-H functionalization reactions. An early


38

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ACS Catalysis

example comes from Trost and Toste, who reported a Pd-catalyzed addition of phenols to propionic esters to provide the corresponding coumarins (Scheme 19).92-93 This reaction provides an atom-economic way of making coumarins from readily available starting materials, albeit with some limitations in the scope of the phenol, which must have strong meta-donating groups. Two mechanistic pathways have been proposed, both involving a phenolate-bound Pd(II)-hydride. The first invokes a hydro-palladation of the alkyne to afford a vinyl-Pd-(II)-phenolate 19-2, before 1,3-migragtion to the ortho-carbon and reductive elimination provide ortho-vinyl phenol 19-4. Double bond isomerization and lactonization then lead to the coumarin. Alternatively, phenolate-bound Pd-(II)-hydride 191 could isomerize to a C-bound Pd-intermediate 19-5, before carbo- palladation, reductive elimination and tautomerization afford a similar ortho-vinyl phenol en route to the product. More recently, Maiti has reported a related coumarin synthesis by oxidative coupling of phenols and α,β-unsaturated esters.94


39

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

O

R'

OH

Page 40 of 129

Pd2dba3 (cat.) NaOAc

O

HCO2H rt, 16 h

R CO2Et

O

O

O

O O

O

O

R'

R

O

R MeO

O

OMe

MeO

O

R = Ph, 69% CH3, 51%

67%

Me

61%

72%

H O

Pd

CO2Et

O

1,3migration

H Pd

CO2Et

H 19-2 H

19-3

pathway I

O

CO2Et

Pd

H

O

O

H

CO2Et

19-1

19-4 H

pathway II H

O

O

CO2Et

Pd

Pd

CO2Et

1,3migration

H

H 19-6

19-5 OH

R

O

isomerization / cyclization

C-H activation

O

O Pd(OAc)2 (cat.) 1,10-phen

O

MeO

Maiti 2013

Cu(OAc)2 (1 equiv) NaOAc, air 110 oC

R

Scheme 19. Palladium-Catalyzed Coumarin Synthesis from Phenol

A similar vinylation protocol was recently reported by Yi and co-workers, who developed a cationic ruthenium-catalyzed ortho-vinylation of phenols with ketones (Scheme 20).95-96 The reaction proceeds via OH-directed ortho- C-H activation to form an aryl-ruthenium intermediate, which can then undergo a migratory insertion with the enol


40

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ACS Catalysis

tautomer of the ketone. The cationic ruthenium can then perform a β-elimination to cleave the C-O bond. Subsequent exchange with another equivalent of the starting material liberates the product and closes the catalytic cycle. While both aromatic and aliphatic ketones are tolerated, only electron-rich phenols as well as naphthols have been employed. The reaction between 3,5dimethoxyphenol and an α,β-unsaturated ketone can also produce a dihydrobenzopyrane. OH

R1

R3

R2

OH

Ph

R3

Me

OH

MeO

Me OMe

MeO

OMe

95% OH

R1

1,2-DCE 125 oC

OH

Me OMe

MeO

R2

OH

[Ru] (3 mol%)

O

H

78%

77% (Z:E = 1.4:1)

Ph OH

OH Me OMe

MeO

MeO

OMe 58%

62%

55% OH

 H2 [Ru] = Cy3P

Ru H

CO

H R1

BF4

R3 HO

HO

H 2O

HO

R2

R2

R3

HO

[Ru] OH

[Ru]

H

R1

O

R1

HO

R1

R1

R2

OH

R3

[Ru]

R2

R3

OH HO

H

[Ru]

R1 R1

R2

HO

OH R3

HO

[Ru] R3

R2

R1

Me OH H Ph MeO

[Ru] (3 mol%)

O

OMe

Me

O Ph

annulation MeO

OMe

Scheme 20. Cationic Ruthenium-Catalyzed ortho-Vinylation of Phenols


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Page 42 of 129

In 1997, Rawal et al. reported an intramolecular C-H functionalization of phenols by Pd-catalyzed coupling of tethered aryl iodides or bromides (Scheme 21).97 Mechanistically, the reaction hinges on an EArS-type mechanism for C-H functionalization by nucleophilic addition of the phenol or phenolate to the Pd-(II) that forms upon oxidative addition. Optimization efforts led to relatively mild conditions for C-H arylation, consisting of Herrmann’s catalyst and a carbonate base in a polar aprotic solvent at temperatures of 80 – 115 oC. The reaction is typically regioselective for the ortho-position of the phenol, and can produce six-membered rings containing carbon, nitrogen or oxygen in the tether between the two aromatic rings. This strategy was extended by Cuny to the synthesis of aporphine alkaloids and later by Fagnou,98-99 who employed Buchwald’s Pd-pre-catalysts (e.g. XPhos-Pd-G1).100-102 In 2008, Daugulis reported a similar reaction without a transition metal catalyst, however, these conditions require a stronger base (tBuOK), higher temperatures (140 oC) and exhibit diminished regiocontrol.103


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ACS Catalysis

OH OH

OH conditions

X R

1

R

R1

R2

R1

2

n

n n ortho-cyclization major

R2 para-cyclization minor

Ar

Me

OH

Ar

P

O

O

O

O

Pd

OH

Pd P Ar

O

O

Ar

Me Ar = o-tol (5 mol%)

X = Br, 73% (o/p = 3.2/1) t

BuOK (2.5 equiv) 1,4-dioxane, 140 oC

Cs2CO3, DMA, 80 oC

X = I, 97%

Rawal 1997

Daugulis 2008

OH 1st generation

2nd generation

Pd(OAc)2 (20 mol%) PCy3 (40 mol%) Cs2CO3, DMA, 110 oC, 24 h

XPhos-Pd-G1 (5 mol%) Cs2CO3, DMA, 110 oC, 1 h

NTs

56%

X =Br

93%

Cuny 2003 & 2004

aporphine common isoquinoline alkalods core structure

Cuny 2012

O

O

Ln Pd

R1

ortho-palladation

n

Ln Pd

R1

R2

X

H

X

R2 n

Scheme 21. Palladium-Catalyzed Intramolecular Cyclization of Phenols and Aryl Halides

Despite early successes in the intramolecular C-H arylation of phenols, similar conditions are problematic for the intermolecular coupling of phenols and aryl halides (Scheme 22). In 1988, Bois-Choussy reported a photo-induced, transition-metal free arylation of phenoxides via SRN1, albeit with a limited substrate scope and poor ortho- /

para-selectivity.104

In 1999, Miura et al. reported a phenol-directed ortho-arylation of

phenols with aryl bromides catalyzed by Pd(OAc)2 and PPh3;105 however, these reactions


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Page 44 of 129

suffer poor chemoselectivity, and could not be stopped after the first C-H functionalization. Instead, products of poly-arylation were observed, resulting from sequential orthodirected and external phenol-directed C-H functionalization. More recently, Daugulis reported a related Ag-catalyzed process, which exhibits higher degrees of selectivity for the mono-arylated product (Scheme 22).106

OH

Ph

Pd(OAc)2 (5 mol%) PPh3 (20 mol%) Ph-Br (8 equiv) Cs2CO3 (8 equiv) o-xylene , refulx

Ph

Ph 58%

Miura 1999

C2-activation

OH

Ph Ph Ln

OH

Ln Pd

OH

Pd

OH

external activation

OH

OH AgOAc, tBuONa

Daugulis 2013

Ph-Cl 1,4-dioxane, 155 oC

OH Ph

78% 1.8 equiv PhCl

Ph

Ph

60% 5 equiv PhCl

Scheme 22. Intermolecular Phenol / Aryl Halide Coupling

To mitigate issues of over arylation, Bedford and co-workers introduced a transient directing group strategy for the Rh-catalyzed ortho-arylation of phenols by employing an


44

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ACS Catalysis

aryl phosphite co-catalyst (Scheme 23).107-108 The authors propose a fast and reversible exchange between the phosphite co-catalyst and the phenol to create a directing group for ortho-selective C-H arylation. Subsequent exchange of the phosphite with the less sterically encumbered starting phenol releases the directing group to close the catalytic cycle, and provides the ortho-arylated product. The authors have demonstrated a broad scope of both phenol and aryl halide coupling partners, and in 2008, they reported a more practical phosphine chloride co-catalyst.109 A similar strategy was also reported by Oi and Inoue, who employed hexamethylphosphorous triamide (HMPT) as a more readily available co-catalyst.110 More recently, this strategy has also been adopted by Ye for the rapid derivatization of BINOL.111


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Page 46 of 129

Rh-catalyst P(III)-co-catalyst

OH

OH

ArBr R

Ar R

Cs2CO3 or K2CO3 PhMe, 100 oC - reflux

O

Cl

P

N

P N

P

N

R co-catalyst

co-catalyst

co-catalyst

RhCl(PPh3)3

[RhCl(cod)]2

[RhCl(cod)]2

Bedford 2003

Bedford 2008

Oi & Inoue 2003

OH

O

X-PR2

PR2 C-H activation

R

R

Ar Br

exchange R OH

R

oxidative addition

P

O Ar

R

Rh Ln ArBr

R Ln Rh

P

Ar

R Rh

Ln

Ar

R

R

reductive elimination

NMe2

OH

O

OH t

Bu

86%, with PiPr2(OAr) 77%, with PiPr2Cl

OH N

Bu

t

t

Bu

41% with PiPr2(OAr)

83% with PiPr2Cl Ph

OH Ph

OH OH

F 3C 75% with HMPA

Ph

82% with PtBu2Cl

Scheme 23. Rhodium-Catalyzed Intermolecular Coupling of Phenols and Aryl Bromides Mediated by a Transient Directing Group

In addition to ortho-C-H-arylation, significant efforts have been directed to related

ortho- C-H allylation reactions (Scheme 24). Hamada112 as well as Wu and You113


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ACS Catalysis

independently reported the Pd-catalyzed intramolecular asymmetric ortho-allylation of phenols for the synthesis of dihydrophenanthrenes and tetrahydroisoquinolines, respectively. In both cases, Trost’s phosphine ligands for asymmetric allylation were found to be most efficient, giving both good yield and e.e. for the desired products. In the case of intermolecular allylation, Feng and Zhang recently reported a Rh-catalyzed, diastereoselective ortho-allylation of phenols with chiral vinyl aziridines.114 Breit has reported a complementary Rh-catalyzed allylation of phenols with achiral allylic carbonates that employs the chiral DIOP biphosphine to induce moderate levels of enantioselectivity.115 In both of these examples, high selectivity for the branched products was observed. In a related, albeit transition-metal free allylation, Harran reported an intramolecular phenol allylation that provided macrocyclic phenols with interesting pharmaceutical properties.116


47

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

a) Intramolecular Cyclization

b) Intermolecular Coupling R2 N

OCO2Me

R1

Page 48 of 129

cat. Pd2dba3 Trost L*

R4 OH

Hamada 2012

R2

R4

OH

OCO2Me

substrate -controlled

R3

OH

R5

R1

Breit 2016 OH

NBn

Wu & You 2015

NBn

OH

catalyst -controlled

R1

Feng & Zhang 2017

OH

R

R

[Rh(cod)Cl]2 (2.5 mol%) L* (5 mol%)

OH

[Rh(NBD)2](BF4) (5 mol%)

R1 cat. Pd2dba3 Trost L*

MeO2CO

R3

NHR2

R2

OH

OH

R5

R1

Ph

OH

NHNs

n

C5H11

NHTs

OH

MeO O

MeO

O N H PPh2

O

HN

OMe

Me OMe

94%, 71% e.e.

O NH

H

HN

95%, 97% e.e. from 97% e.e. aziridine

Ph2P PPh2

70%, 87% e.e.

Ph2P

O

77%, 97% e.e. from 98% e.e. aziridine

O

PPh2 PPh2

H L* = (S,S)-DIOP

commonly used Trost ligands F

c) Macrocycle Formation OBoc

H

H OH N

F

N

O N H O

H N O

Me

N H OH

N

1) AcOH, H2O

O NH2 O

2) MeSO3H MeNO2, 23 oC (73%)

BocN

O O

HN

Me OH

O

OH

HN

Harran 2015

NH2 O

Scheme 24. ortho- C-H Allylation of Phenol

In 2015, Magauer et al. reported an unusual and conceptually distinct Au-catalyzed

ortho-allylation of phenols (Scheme 25).117 While the method is somewhat limited in scope, it provides a unique mechanistic approach to the ortho-alkylation of phenols.


48

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ACS Catalysis

H

t

Bu3PAuNTf2 (5 mol%)

OH

Br OH

CH2Cl2 0 - 23 oC 15 examples 13-77% yield

R Br

R

Br

[Au]

elimination

H O Br

Br

[Au]

R isolated intermediate

Br

Br

Br

Br

OH

OH

OH

OH

Cl

TBDPSO 76%

70% (o:p = 2.1:1)

59%

62%

Scheme 25. Gold-Catalyzed ortho-Allylation

Hu recently reported a related asymmetric propargylation of phenols for the synthesis of chiral dihydrobenzofurans (Scheme 26).118 The reaction is believed to proceed via a chiral Cu- allenylidene complex, which is susceptible to EArS. The resulting 2propargylated phenols, which were formed with good enantio- and regioselectivity, underwent a subsequent 5-exo-dig cyclization to provide the final cyclized dibenzofurans.


49

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

SiMe3

Page 50 of 129

Cu(OAc)2·H2O (5 mol%)

H OH

R1

(S)-L (5.5 mol%)

O

i

Pr2NEt (1.2 equiv) MeOH, - 40 oC 26 examples up tp 98%, 96% e.e.

R1 R2

OAc racemic

R2

CuL* CuL*

CuL* 

ligand-induced facial selective addition

CuL* R1



OH

R1

R1 OAc

chiral copper allenylidene complex

R2 F 3C

Ph

CF3

Ph O

O

O N

OH 52%, 91% e.e.

82%, 80% e.e.

PPh2 92%, 93% e.e.

N

L*

Scheme 26. Synthesis of Dihydrobenzofurans via ortho-Propargylation

Recently, Wang et al. reported a Cu-catalyzed ortho-aminomethylation of phenols employing potassium amino-methyl-borontrifluoride (Scheme 27).119 Their conditions utilized a simple Cu(OAc)2 catalyst, sodium acetate as a base and air as the terminal oxidant. These conditions exhibited broad scope in the phenol, which can include a range of substitution patterns, including both electron-rich and electron-deficient substituents. The amine-coupling partner is generally limited to cyclic secondary amines, whereas acyclic derivatives did not perform well. The method was applied to the synthesis of serine hydrolase inhibitor analogues. In a conceptually related example, Patureau and co-


50

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ACS Catalysis

workers have demonstrated a cross dehydrogenative coupling of phenols and methyl amines to provide similar products.120


51

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Page 52 of 129

OH Cu(OAc)2·H2O (5 mol%)

H

R1 KF3B

O

NaOAc·3H2O (3 equiv)

N

R2

R3

Cu(II) R1 N R2

OH

N

BF3K

PhMe, 80 oC 38 examples 21 - 98%

OH

R3 R1

R1

OH

OH

N

N O

OMe

N O

Cl 81%

MeO2C 96%

OH

NHBoc

OH

O

N

N

O NO2

62%

58%

OH N

N NBoc

CO2Et

R2

96%

NBoc 71% (after O-methylation) serine hydrolase inhibitor analogues

Scheme 27. ortho-Aminomethylation of Phenol

2.4. Methods Based on Phenol-Directed C-H Insertion While the directed insertion of transition metals into C-H bonds has provided many powerful, complexity-generating tools, phenols remain underutilized directing groups for this family of reactions. An important exception is the Ir-catalyzed hydroxy directed orthoborylation protocol of phenols reported by Maleczka, Singleton and Smith (Scheme 28).121 The authors attribute high ortho-selectivity to an electrostatic attraction between the substrate and the bipyridyl ligand, which was enhanced by using the ethylene glycolate on boron instead of the more commonly employed and sterically encumbered


52

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ACS Catalysis

pinacolate. Hartwig has developed an alternative and complementary silyl-directed orthoborylation from the corresponding silanes of phenols (See Scheme 29).122 In this case, the Ir catalyst is placed in close proximity to the ortho-position of the silyl ether by initial insertion into the Si-H bond.

i. [Ir(cod)(OMe)] (1.5 mol%) dtbpy (3 mol%) NEt3, PhMe, 80 oC

OH O

O

H

B

B

Bpin

ii. pinacol

O

O

OH

R

R OH

OH

OH

Bpin

Bpin

Me

Bpin

EtO2C

F 50%

65%

OH Bpin

56%

73% OH

OH

OH Bpin

OH

Bpin

Bpin MeO

Bpin

Cl

MeO 80%

60%

t

67%

73%

Bpin

Bu N





N

t

Bu

O O 

Bpin

Ir H

Bpin

B O

O

O

O =

B

B O

O

B O

proposed model: Directed by Electrostatics

Bpin

Beg

less C2-selective

more C2-selective

Scheme 28. Ir-Catalyzed ortho-Selective Borylation of Phenol


53

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Et O

OH

[Ir(cod)Cl]2 (0.5 mol%)

H

Et2SiH2, PhH R

Page 54 of 129

Et Si

Et

H

[Ir(cod)Cl]2 (1 mol%) dtbpy (2 mol%) HBpin (5 mol%)

H

O

OH MeO

BF3K

96%

R

OH Cl

BF3K

89%

OH BF3K

100%

OH

OH

Ph

86% BF3K

O

t

Bu

O 82%

N t

Bu

94%

Bpin

Bu N

Ir H

BF3K

OH

BF3K

BF3K

t

BF3K

KHF2

R

OH

Me

OH

H BPin

B2pin2 (1 equiv) THF, 80 oC

R

Et Si

79%

t

Bpin SiEt2

N

O

t

Bu

t

Bpin

Bu

silyl-directed borylation

N

Bpin

Bu

Bpin

Ir H

SiEt2 O

N t

N

Bu

Ir Bpin

H SiEt2 O

Scheme 29. ortho-Borylation of Phenol with a Silyl Directing Group

A conceptually related, albeit mechanistically distinct, ortho-borylation of phenols was reported by Vedejs et al. in 2013 (Scheme 30).123 In this case, a stepwise C2borylation of phenols occurred by an addition to chloro-diisopropyl-phosphine, before the addition of borane. Subsequent C-B bond formation occurred by an EArS type mechanism, requiring strong acid and elevated temperatures to promote the extrusion of H2. Subsequent work up using KHF2 afforded the corresponding products as their stable potassium trifluoroborate salts.


54

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ACS Catalysis

OH

i

H

Pr2PCl NEt3

O

PiPr2 H

OH

i. BH3·THF

BF3K

o

ii. Tf2NH, 140 C iii. KHF2

R

R

R

OH BF3K

Me

OH

OH

OH

BF3K

BF3K

BF3K

Cl 75%

88%

56%

34%

Scheme 30. Phosphorous-Directed ortho-Borylation

Because of their poor directing abilities, phenols are typically modified with an appended directing group in order to promote ortho-selective C-H insertion (Scheme 31).124-136 In recent years, a range of groups for this relay-direction have been introduced, including silyl, acyl, 2-pyridyl and carboxylate groups, and the most common catalysts are Ru, Rh, Pd and Pt. While the majority of examples install 2-aryl or 2-vinyl substituents, it is also possible to install oxygen or silicon heteroatoms. While this approach suffers poor atom and step economies, due to the installation and removal of directing groups, they provide important inroads into metal-mediated C-H insertion for substrates possessing the unique electronic properties of phenols and their ether derivatives.


55

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

OH

DG

O installation

O

Page 56 of 129

DG

C-H activation

OH FG deprotection

FG

O

O DG =

Me

N

O

cat. [Pd]

Ar

Ar-H Na2S2O8 Dong 2010

Me

O

R O

cat. [Rh]

O

R'

NMe2

NMe2

O

NMe2

H

R' Cu(OAc)2 Fu & Liu 2011

R

O

OPiv

DG = Bu

OPiv

cat. [Pd] Ar2IOTf

H

t

R

Ar

R

Fu & Liu 2010

R

cat. [Pd] DG =

O

CO2K

CO2H

O

CO2Et

CO2H

H

Yu 2013

CO2Et

R

KHCO3 O2

R t

DG =

Bu

t

t

Bu

Bu Si

cat. [Pd]

OH

PhI(OAc)2

Gevorgyan 2011 Bu

Bu

R

Si

cat. [Pd]

OH

OPy

O

R

N

Si

OH R'

R

OPy

cat. [Ru] / MesCO2H K2CO3

H

Bu

Bu

Ag(OAc) Li2CO3

R

t

t

R'

H

DG =

Bu

t

t

O

t

O Si O

Ar R

Ar-Br Ackermann 2012 cat. [Ru] / Cu(OAc)2 air

R2

OPy H H

R1

CONHtBu

R1

CONHtBu Me

O DG =

Lan & You 2018

R2

OPy

OAc H

Me Jeon 2016

R1

cat. [Ir] / [Rh]

O

O SiEt2

H2SiEt2

R1

Scheme 31. Directing Group Strategies for ortho-Selective C-H Insertion


56

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ACS Catalysis

2.5. Methods Based on Oxidative Coupling The oxidative homo coupling of phenols is an industrially relevant C-H functionalization that is used to produce 2, 2′- and 4, 4′-biphenols (Scheme 32).137 Since the oxidative coupling of phenol itself is not selective, the process requires tert-butylation to block ortho- or para-positions, as needed.138 Cu-catalyzed aerobic coupling of the resulting 2, 4- or 2,6-di-tert-butyl phenols affords the corresponding diphenoquinones, which can be reduced to the corresponding bi-phenols by a variety of methods. Removal of the tert-butyl groups affords the corresponding biphenols along with iso-butylene, which can be recovered and reused.

O OH

OH

Al(OPh)3

t

t

Bu

t

Bu

OH

Bu

OH t

t

Bu

Bu

t



t

Bu

Bu

O

Al(OPh)3

reduction t

t

Bu

OH

t

Bu

cat. [Cu] O2

Bu

OH

Scheme 32. Industrial Synthesis of 4, 4′-Biphenols


57

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 58 of 129

While significant effort to control the chemo- and regioselectivity of phenolic oxidative coupling reactions has led to certain advances, the majority require blocking substituents to ensure high degrees of regioselectivity. This underscores the well-known challenges of controlling free phenoxyl radicals, which form easily under oxidizing conditions, and undergo non-selective C-C coupling at either ortho- or para-positions with 2nd order rate constants that can approach the diffusion limit (~108 M1s1 in benzene) (Scheme 33).139 In light of these challenges, work of Kozlowski,140-142 Pappo143-148 and Waldvogel149-151 places the state of the art into context, since they have provided the first examples of an oxidative cross coupling reaction between two, non-identical phenols. To avoid freeradicals, Kozlowski and Pappo confine electron transfer to the inner coordination sphere of a Cr-(IV) or Fe-(IV)-phenolate, generating only catalytic quantities of a metal-(III)phenoxy radical that remains within the metal’s coordination sphere. Selectivity is determined by preferential coordination of one phenol to the metal catalyst, so that radical capture occurs between a metal-bound phenoxyl radical and a non-associated partner. Kozlowski differentiates phenols by the steric demands of their ortho-substituents, requiring relatively encumbered 2,6-di-substituted phenols to be the non-associating


58

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ACS Catalysis

substrate.142 Pappo, on the other hand, discriminates phenols by their relative affinity for an Fe-(III)-porphyrin, which appears to favor phenols with higher oxidation potentials and lower global nucleophilicities in hexafluoroisopropoanol.146 This requires at least one methoxy group on the weaker of the two associating phenols, suggesting an important role for the strongly hydrogen bonding solvent. Waldvogel and Pappo have also demonstrated selectivity for radical-based couplings between phenols with different redox potentials and global nucleophilicities, relying on electrochemical and Fe-mediated oxidations, respectively. While each of these methods makes an important advance, they continue to struggle with phenols that have multiple sites available for coupling, and isolated yields are frequently less than 60%. In addition to these transition-metal mediated or electrochemical conditions, Kita has reported a hypervalent iodine-catalyzed process.152 This system requires phenols with electron-donating substituents, as well as blocking groups, to ensure high degrees of site-selectivity. The prevalence of biphenols in natural products has led to recent applications in total synthesis. Examples include Quideau’s asymmetric synthesis of ()-vescalin,153 Baran’s synthesis of acrylomycin


59

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Page 60 of 129

derivatives,154 and Kozlowski’s atropo-selective total synthesis of (S)-bisoranjidiol,155 and chaetoglobin A.156


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ACS Catalysis

HO

a) Oxidative Phenolic Coupling K = 6.3 x 108 M-1s-1 (Benzene)

O

O OH

O

O -

1e |1H

K = 6.4 x 109 M-1s-1 (H2O) Rate of Diffusion in H2O

O

+

OH homo-coupling

EDG

O phenoxy radical EDG EDG = OH, OMe, NMe2, etc. b) Cr-Catalyzed Cross-coupling Between Phenols

c) Fe-Catalyzed Cross-Coupling Between Phenols OH

OH Me

O2 (1 atm) 1,2-DCE, 50 - 85 oC

Me

BuOOH (1.1 equiv) HFIP, rt

OH Me

iPr Cy

Cy

N tBu

t

OH Me

iPr 1 equiv.

Cy

N

tBu

O Cl O

OH tBu

2 equiv.

Cr Cl Me

O Ln

N Ph

H

H

tBu

Ln

tBu

Me

iPr

OH

HO

Fe O

Cr (III) - phenoxy radical

OMe 77%

Ph

Me Cr (IV) - phenolate

tBu

N

tautomerization

Cr Cl

Me

radical-phenol coupling

iPr

iPr

OMe 1 equiv.

OH

Me

Me

Cl Fe

N

tBu

O tBu

O

O

HO

N

Cr (IV) Ln

Ln

Ph

HO

2 Cr (III)

tBu

Me

Ph

Me OH 74%

Cy

(5 mol%)

Cr Cl

(1 mol%)

Me 2-3 equiv.

Cr

Me

Ln

OH cross-coupling

OMe

Me

O

tBu

Me

OMe

Fe-phenoxy / Me free phenoxy coupling

H-atom abstraction

Fe (IV) - oxyl radical

Me

O

O

Fe

O

H

H

tBu

Me

OMe

OH d) Electrochemical Oxidative Coupling of Phenols

e) Hypervalent Iodine-Catalyzed Cross Coupling OH

O

MeO

O O

OH

OMe

OH

R

R

O

74% homo-coupling

Ar-I = OMe

R-O

OMe

MeO

H+

OMe

90%

OAc

boron-doped diamond (BDD) anode

Ar

I

2,6-dimethoxy Ar OAc phenol MeO

I

O AcOH

OMe

Ar-I

OAc Me

I

OMe

OMe R-OH

MeO

MeO

MeO

OMe OH

OMe

AcOH HFIP, rt

OMe

OH O

OH

MeO

Ar-I (10 mol%) 18-crown-6 Oxone

AcOH

47%

cross-coupling

Oxone

AcOH

f) Applications to Complex Molecules

OH

Cu(MeCN)4(PF6) (2 equiv) TMEDA (2 equiv) O2, MeCN 60%, 5 g scale

OH OH

HO

O

HO CuCl2 (5 equiv) (-)-sparteine (20 equiv) 68%

O O O O O S R

OH HO

OH OH OH (-)-Vescalin

HO

OH

OH

O N

Me H

HO

OH O O

OH CuCl2 (5 equiv) bispidine (20 equiv) 41%

Boc

N Me

H N

HN

OH

CO2Me O

O Me Acrylomycin A2 core

N

Cu

H I

OH (10 mol%) O2, 40 oC 62%, 87% e.e.

Me OH

O

(S)-Bisoranjidiol


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Page 62 of 129

Scheme 33. Biaryl Formation via Oxidative Phenolic Coupling

The oxidative cross coupling of phenols and olefins has also been extensively developed, resulting in the concise synthesis of dihydrobenzofurans or benzofurans via a formal [3+2] cycloaddition (Scheme 34). In 2013, Lei reported the first example of FeCl3catalyzed coupling between phenols and styrene derivatives with DDQ as the terminal oxidant.157 Since then, many research groups including those of Wang,158 Pappo159, Yoon160 and Chiba161 have developed transition-metal free, photochemical or electrochemical methods.94, 162-163 In 2016, Xia et al. applied this type of transformation to the total synthesis of (+)-decursivine, in which the key step involves an Fe-mediated intramolecular [3+2] oxidative cyclization to form the key [8.5]-ring system of the natural product.164 In addition, Canesi reported a related [3+2] cycloaddition between phenols and arenes in which the authors noted a stabilizing effect of a para-sulfone substituent on the phenol.165 They attributed its beneficial effects to a favorable n-π* interaction. The resulting cyclohexadiene product could then be re-aromatized with acid to produce 2arylphenols as the final product.


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ACS Catalysis


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Page 64 of 129

R4

OH R1

R2

R3

R

O

oxidant

O

R2 R1

[3+2]

R4

R

R3 or

R

R a) Conditions Ph O

Ph

O

O

O

Me

Me

Me

OMe cat. Ru(bpz)3(PF6)2 visible light (NH4)2S2O8

OMe

cat. FeCl3 / DTBP

OMe cat. FeCl3 / DDQ

Ar

Ph

Ph

DDQ Wang 2017

Pappo 2013

Lei 2013

Yoon 2014 O

O

Ph

O O

OMe NO2

LiTFSI/MeNO2 electro-oxidation

BF3 Et2O DDQ

cat. Pd(OAc)2 Cu(OAc)2

Dong & Zhou 2017

Maiti 2013

Chiba 2017 b) Synthesis of (+)-Decursivine

O O

O

O

O

O

DDQ FeCl3

O

NCbz

HO

R2 N

H

R1

H

HFIP 66%

CO2Me

Xia 2016

N H

N H R1 = CO2Me, R2 = Cbz steps

R1 = H, R2 = H (+)-decursivine

c) With Arenes

X

OH

R

O X PhI(OAc)2

H

R PhO2S

X = H or I

O R

S

O

PhO2S

X=I TFA

OH

X

O

stablized by n-* interaction

R

PhO2S

Scheme 34. Oxidative Coupling Between Phenols and Olefins


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ACS Catalysis

In addition to olefins, the pyrrole rings of indoles can also couple with phenols in a similar fashion (Scheme 35). Danishefsky was the first to demonstrate this transformation in 2006 during a biomimetic total synthesis of pharlarine.166 These authors observed an oxidative coupling between 3,4-dimethoxyphenol and indole 35-1 mediated by phenyliodo-trifluoroacetate (PIFA). The regio-selectivity of this process was further studied by Vincent, who developed complementary conditions to access the two possible regioisomeric products of oxidative coupling.167-168 Similar phenol-indole coupling reactions have subsequently been applied to the synthesis of natural products including a biomimetic synthesis of azonazine by Yao,169 and Vincent’s synthesis of the voacalgine A core.170 Nicolaou et al. applied a similar transformation to the total synthesis of haplophytine171-172 and Harran et al. developed both chemical and electrochemical oxidations to produce the macrocyclic core of diazonamide and related biologically active molecules.173


65

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Page 66 of 129

R R

R3

R O

R2

[3+2]

N

or N

R2

N

OH

R1

R2

R1 R1 both common core structures in indole alkaloids

a) Initial Study

b) Selective Generation of Two Regio-isomers

OMe

OMe

MeO

MeO

R

N

O

E

Danishefsky 2006

35-1

E

N

N H

R2

Ac

R2

N

Vincent 2012

FeCl3 DDQ

R3

FeCl3 OH

50 - 86%

R

R3 O

R3

oxidation

E = CO2Me O N

R

R

R3

PIFA OH

N H

R3 O

R3

oxidant

R2

24 - 99%

OH

N

27 - 62%

N

Ac

C2-unsubstitution required

Vincent 2014

Ac

H

Ac

c) Applications in Complex Molecule Synthesis O

H O

H Me

N

H

Me

NH PIDA TFE

O

H

N

MeO

NH

OMe

CF3

O

NIS O O

12% + 16% ent

N H

OH

CF3

N

O

biomimetic oxidative cyclization

H

OH

N H

26%

N H

N

R2 CO2Me

N

R1

O

O

R1HN

R2 CO2Me

R1 = OAc, R2 = Cbz R1 = H, R2 = CO2Me

R1

N H

R3 O

O

R4

R4

O N

N

HN

R3

PIFA 23%

N

R1HN

OH

OH

N H

R2 N

HN

N

OH

H

Voacalgine A core

(+)-Azonazine precursor

CO2Me

O

O N

AgBF4 SnCl4

O

N H

HO R2 CO2Me

NH

Generation 1: PhI(OAc)2 R1 = ArSO2, R2 = iPr, R3 = CO2Me, R4 = 7-Br Generation 2: electrochemical oxidation

Precursor for Haplophytine

R1 = Cbz, R2 = tBu R4 = 5-F

O

20 - 25% ~ 3:1 d.r. Core of Diazonamide-based Drug Candidates

O 35%, d.r. = 2.7:1

R3 = N

H

OH

Scheme 35. Oxidative Coupling Between Phenols and Indoles

More recently, a concise biomimetic total synthesis of bipleiophyline was reported by Poupon, Evanno and Vincent (Scheme 36).174 Two sequential oxidative coupling reactions between 3-carboxylic acid catechol and the indole natural product


66

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ACS Catalysis

pleiocarpamine, consisting of 1,4- or 1,6-additions to the oxidized ortho-quinone afforded the natural product along biosynthetic lines.


67

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H

N

Page 68 of 129

H HCO2

N OH MeO2C O

OH HO

H

CO2H

Ag2O

O

O

HO

Me

pleiocarpamine formate salt

CO2H

N

O Me

O H N

O

H

N Me

O H

Ag2O

H

N

CO2Me

1,4-addition

CO2Me N

21%

N

O

voacalgine A

H Me

H

CO2Me OH N

O

O

H

N Me

O N

H HCO2

N

H N

N

H CO2Me

bipleiophylline

MeO2C

H

Me

pleiocarpamine formate salt 1,6-addition 3% over 2 steps, one pot

Scheme 36. Total Synthesis of bipleiophyline

In addition to double bonds, the triple bonds of alkynes can be used in oxidative cross coupling reactions with phenols to provide the corresponding benzofurans (Scheme 37). Many transition-metal catalysts have been developed for this process, including Rh, Pd, Cu, Au and Zn based systems.175-180 It can be difficult to control regiochemistry when using non-symmetric alkynes, and aryl substituents on the alkyne are better tolerated than alkyl substituents. A related, transition-metal free oxidative coupling has also been


68

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ACS Catalysis

reported by Dong and Zhou;181 however, the method is currently limited to 2-naphthols and aryl substituted terminal acetylenes to produce 2-arylated naphthofurans.

OH

R1

R1

H

oxidant

R2

[3+2]

R2

R

O

R Ar

1

R

O

1

R1

O

O

Ar2

R2

R

Ar

R

R

cat. [Cp*Rh(MeCN)3](SbF6)2 Cu(OTf)2 AgPF6, 120 oC

R1, R2 = alkyl or aryl

R1 = alkyl or aryl

cat. Pd2dba3 AgOAc 130 oC

cat. Cu(OTf)2 ZnCl2, O2 120 oC

Shi 2013

Sahoo 2013

Jiang 2013

Ar

Ar

O

O Ar

Ar

R

R

R

cat. Au(PPh3)Cl / AgSbF6 O2, 100 oC Guo 2016

R1 O

BF3·Et2O DDQ 80 oC Dong & Zhou 2016

R1 = alkyl or aryl ZnCl2 140 oC Satyanarayana 2017

Scheme 37. Oxidative Coupling Between Phenols and Alkynes

Enolizable ketones are also suitable coupling partners for oxidative cross coupling with phenols (Scheme 38). Li et al. reported an early example of this transformation in 2009,182 which described an oxidative coupling between phenols and β-ketoesters to afford the corresponding benzofuran using FeCl3 as a catalyst and di-tert-butyl peroxide


69

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Page 70 of 129

(DTBP) as the terminal oxidant. Pappo has continued to refine these conditions for the synthesis of dihydrofurans, including efforts to induce asymmetry.148, 183-184 In addition, a related transition-metal-free dihydrobenzofuranone synthesis mediated by I2 was reported by Wu in 2014.185

OH

OH

O

O

oxidant R3

R2

R2

R2

O

R3

R3

or

H

R1

R

R HO

Ph

OMe

O

O

OMe

OEt CO2Me

O

cat. FeCl3·6 H2O (tBuO)2, 100 oC Li 2009 OH

O OMe

cat. FeCl3·6 H2O 2,2'-bpy or 1,10-phen

O

Fe(ClO4)3 (10 mol%) 1,10-phen (10 mol%)

(tBuO)2, 70 oC Pappo 2012

Ph

O O

Me HO O L* =

O O

I2, DMSO, 100 oC Wu 2014

(tBuO)2 TFE/HFIP (1:1) rt - 40 oC Pappo 2015

O O

O P OH

Fe(ClO4)3 (5 mol%) L* (15 mol%) CaCO3 (15 mol%) (tBuO)2, 50 oC Pappo 2017

Scheme 38. Oxidative Coupling of Phenols and Ketones

The ortho-oxygenation of phenols is an important subclass of phenolic oxidations that is practiced on both small and large scales (Scheme 39). The industrial production


70

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ACS Catalysis

of catechol and hydroquinone derives from the oxidation of phenol with H2O2 in the presence of an acid or metal catalyst.28 Product ratios range from 2 - 4 : 1 in favor of the catechol, but the oxidation must be stopped at short conversion, in order to avoid over oxidation of the catechol or hydroquinone products, and product mixtures must be separated by distillation. A mechanistically distinct ortho-oxygenation of phenols is catalyzed by the enzyme tyrosinase, which activates O2 as a characteristic di-Cu(II)-µ,η2,η2peroxo to achieve complete

selectivity

for

the

corresponding

ortho-quinone.186

Mechanistically, oxygenation is believed to take place from a discrete phenolatecoordinated intermediate, from which oxygen atom transfer occurs by way of an EArStype mechanism. Many biomimetic Cu-complexes, emulating the unique coordination sphere of the enzyme have been reported, but few have recapitulated the enzyme’s catalytic activity.187-190 In 2014, Lumb and co-workers demonstrated that a remarkably simple catalytic system, consisting of simple 3o amines and Cu(PF6)(CH3CN)4, could mediate selective ortho-oxygenation.191-192 A more robust and functional group tolerant system employing N,N′-di-tert-butyl-ethylene diamine as a ligand to Cu was developed contemporaneously,191,

193-194

and recently applied to the total synthesis of


71

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Page 72 of 129

dehydronornuciferine.195 In the key step, a regioselective ortho-oxygenation triggers additional dehydrogenation, to provide ortho-quinone 39-1 as a single product in high yield. A conceptually related oxygenation can also be conducted with hypervalent iodine. In 2002, Pettus and co-workers demonstrated that IBX successfully delivered orthoquinones from the corresponding phenols across a relatively broad scope.196 In subsequent studies, Quideau and co-workers introduced SIBX197 as a safer alternative to IBX, and in 2012, Uyanik and co-workers described a related process using IBS.198


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ACS Catalysis

a) Industrial Synthesis of Catechol OH

OH

OH OH

acid or metal catalyst H2O2

OH catechol hydroquinone 1.5 - 4.1 : 1 ration separated by distillation

large excess stop at low conversion b) Biomimetic Oxidation OH

O

tyrosinase mimicry

OH reduction

O

R

OH R

R or I (V) reagents O

O

OH

I

OH

Ln

I O

(IBX)

O (IBS)

O

Cu

O

Ln

O

--peroxy-dinucleo

O

copper complex tyrosinase mimicry

S O

Cu

c) Mechanism of Atom Transfer OH

Ln

Cu

O O

H Cu

H

Ln

Bu

NH

Ln =

Bu

N

Bu

Cu

t

O

H

N t

Bu

Bu

HN

N

Cu

O

t

t

H

O

Bu

t

t

N

H

DBED

EArS tBu O

H O

N

dissociation O

Cu

N

tBu

H

O Cu (II) semi-quinone radical complex d) Recent Examples OH

[Cu(MeCN)4](PF6) (8 mol%) NEt3 (50 mol%)

t

Bu

Bu

O

CH2Cl2, O2, rt 4 Å M.S. ligandless condition

t

Bu

OH

O t

smaller substituent

t Bu 95%

O

[Cu(MeCN)4](PF6) (8 mol%) DBED (15 mol%)

Me

CH2Cl2, O2, rt

t

Bu

O Bu

regio-selective oxygenation OH

71%

O [Cu(MeCN)4](PF6) (20 mol%) DBED (40 mol%)

Me

t

OMe

O

MeO

CH2Cl2, O2, rt N Boc

dehydrogenated

N Boc 39-1 not isolated

N H 70% over 3-steps dehydronomuciferine

Scheme 39. ortho-Oxygenation of Phenol


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Page 74 of 129

The related synthesis of hydroquinone can be accomplished by para-hydroxylation of phenol (Scheme 40), although competitive catechol formation is often observed. Many catalytic systems have been developed in order to increase regio-selectivity for the 4position.28 Most notably, para-oxygenation of phenol can be conducted using O2 as the terminal oxidant with a salcomine catalyst, in which case para-quinones are produced preferentially.199

OH

OH

O

para-oxygenation R

or

R

R

OH heterogeneous catalyst + H2O2

O N O

Co

N O

+ O2

Scheme 40. para-Oxygenation of Phenol

The ortho-amination of phenols is an additional sub-class of phenolic oxidations that is widely practiced on both small and large scales. The corresponding 2-aminophenols are versatile synthetic intermediates, and important precursors to a broad range of medicinally relevant heterocycles (Scheme 41). Traditionally, the ortho-amination of


74

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ACS Catalysis

phenols is carried out in a two-step sequence, requiring nitration with HNO3 before reduction of the corresponding ortho-nitro-phenol.200 Recent advances have focused on direct amination that can bypass the intermediate nitro-arene, occurring via different mechanisms for C-N bond formation that can include oxidative coupling, EArS, or photoinduced coupling. In 2006, Jorgensen demonstrated an asymmetric ortho-amination of 2naphthols with diazo coupling partners, mediated by an organocatalyst and electrostatic interactions.201 In 2008, Luo demonstrated the ortho-amination of 2-naphthols with substituted hydrazines, taking advantage of a conceptually distinct C-N bond formation.202 More direct, oxidative C-N coupling reactions employing amines were reported by Patureau203 in 2015 and Xia204 in 2016, in which the nitrogen center is believed to be oxidized to the corresponding N-centered radical.205-206 In general, most of these methods are limited to naphthols or phenols with para-substitution, and the nitrogen coupling partner can be limited in scope. An alternative strategy, employing a 1-pot, sequential process consisting of ortho-oxygenation followed by amine condensation was reported by Lumb and co-workers.194, 207-208 Condensation onto the more electrophilic carbonyl of the ortho-quinone triggers re-aromatization via a [1,5]-hydrogen atom shift. This protocol


75

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Page 76 of 129

has been used for the synthesis of 2-aminophenols, 2-diazophenols, 2-pyrrolylphenols, as well as benzoxazole and benzoxazinone heterocycles. While versatile, the method suffers from a limited scope in the phenol, since most reported cases employ phenols with relatively pronounced electronic or steric bias.

OH

OH R1

N

R1

conditions

R2

N

R2

X R

R

a) Traditional Approach

c) Concerted Amination OH

OH

OH

R

Ph

NH2

reduction R

R

OH

OH

NO2

HNO3

R NO2

O

O

H

Br 94%

Luo 2008

S d) EArS-type Amination

cueme + O2

CF3

N H

OH

CF3

90% 88% e.e.

67% o-/p- = 57/43

H

Boc N

N

HO

H

Boc NH2

HO

NR*3

N H

O N H

N

OH

chiral amine

MeO SO42-

S

OH

S

MeO

N

e) Amine Condensation on orho-Quinones H

N

O

OH

69%

H

OH

Xia 2017 Ar2

OH

S

S



Xia 2016

N H

PC, (NH4)2K2O8 blue LED -

-e |H

Ar1

N

OH

R

Ph

Ar2

OR

Ph

Ar2

O

BF4

O

R1

N

R2

OH

N

OBz R

R1

R

OH R2

N

R

N

[1,5]-H shift

R1 N

N

R2

OH N R

Ar

OH N

N R

OH

O R

R [Fe]

N R

R' R' N

FeCl3

H

condensation

O

Ph

O

OR

Luo 2016

O R

H

PC =

Ar1

limited to para-oxygen substituted phenols

R

orthooxygenation

O

See Scheme 37 for more details

(Ar-OH)

+

N

OH

Boc

N

Jorgensen 2006

S N

SO4

NH2

N

Boc

OH

N

h

N

OH

OH

S2O82-

N

NH2

F 3C

H

Boc

Boc

*NR3

Patureau 2015

Ar1

OH

80 oC limited to naphthols and quinolinols

b) Radical Amination

NH2

Me

Br

NH2

NH2

N

OH

R

R

R1, R2 = alkyl


76

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ACS Catalysis

Scheme 41. ortho-Amination of Phenol

A mechanistically distinct protocol for the perfluoroalkylation of phenols was recently reported by Melchiorre (Scheme 42)209

involving the excited state of the phenoxide

anion, which is generated by visible light photo-excitation. While only moderate levels of

ortho- / para-selectivity, as well as mono- and di-functionalization were observed for electron deficient phenols, the method does provide a non-traditional approach to C-H functionalization via a radical mechanism under redox-neutral conditions.

NH Me2N

OH RF

R

OH

NMe2

(2.5 equiv)

I

R

MeCN, 25 oC 23 W CFL

OH

RF

OH

MeO2C

C6F13

C6F13

OH C6F13

C6F13

CHO

50%

C6F13

40%

OH

O

30% *

O

RF

R

R

R

R RF

chain propagation O

H+ work-up

R

O

R RF

O

I

h

base

O

O

Me

RF

R RF

RF

I

I

I

O RF R


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Page 78 of 129

Scheme 42. Perfluoroalkylation of Phenol Using Visible Light Photo-redox

3. C3-Functionalization The meta functionalization of phenol is challenging because C3 and C5 are not electronically activated, nor are they easily accessible via chelate assisted metalation. As a result, examples of meta-C-H functionalization are limited. In 2013, Yu et al. reported a stepwise approach for meta-olefination by the incorporation of a nitrile template for remote, directed C-H activation (Scheme 43).128 The method achieved remarkably high selectivity for the meta position, with ratios of up to 98:2, favoring meta functionalization of over

ortho or para. Phenols with ortho-, meta- or para-substituents were compatible, although a relatively limited scope of substituents was demonstrated. While α,β-unsaturated esters were the best coupling partners, substituted styrenes could also be used to provide moderate yields of the vinyl-substituted products. In 2016, the same group also developed a meta-functionalization of phenol derivatives using a consecutive ortho- C-H activation strategy.210 With the pyridyl directing group installed on the oxygen atom of the phenol starting material, an ortho- C-H palladation can occur with Pd(OAc)2, followed by migratory insertion into the double bond of norbornene, which set the stage for a secondary C-H activation of the meta- C-H bond of the original phenol molecule. A final oxidative addition into the aryl iodide on the Pd(II) intermediate


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ACS Catalysis

followed by reductive elimination affords the final product. Yields of up to 91% were reported for 12 substrates.

R cat. Pd(OAc)2 / Ac-Gly-OH

OH

R

OH

R

AgOAc, HFIP, 90 oC

H

R

Yu 2013 T

O

i. installation of template

O

iii. removal of template

T

O

ii. directedmeta-arylation

O

R

R H

R

T

O

T

O Me

O

O

NC

CO2Et

CO2Et

60% m:others = 95;5

O

T

O

T

O

Me

Br

O

O

CO2Et

PO(OEt)2

OMe

77% m:others = 87:13

83% m:others = 89:11

O

Ar-I, Norbornene AgOAc

R

CF3

36%

cat. Pd(OAc)2/L

DG

O

NC

86% m:others = 98:2

T

O

N

T=

DG

R

Yu 2016

H

Ar Me

O

DG

DG =

DG Pd

N

OAc

L=

H

Ar N

DG

O

H

R H

O

H

R

NHAc

R

O

DG O

O

H

R

Pd L n OAc

H

Pd L n

O

DG

Pd L n I

OH DG

H

H

DG I

Cl MeO2C

O

Ar

Ar

O 53%

81%

Ar OMe

Ar-I

58%


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Page 80 of 129

Scheme 43. Directed meta-Functionalization of Phenol

In 2014, Larrosa et al. reported a one-pot meta-functionalization procedure using carboxylate as a traceless directing group (Scheme 44).211 Their strategy installs a carboxylate at C2 by a Kolbe-Schmitt reaction, prior to carboxylate directed C-H arylation.

In situ Ag promoted decarboxylation then provided the formal product of a meta-arylation. Both electron-rich and electron-deficient phenols were tolerated, and exclusive formation of the meta-functionalized products was observed. The conditions do require relatively harsh conditions for the carboxylation, which must be conducted at high pressures of CO2 and elevated reaction temperatures.

OH

OH

KOH, CO2 (25 atm) 190 oC, 2h, then

H R

R

ArI, PEPPSI-IPr (2 mol%) Ag2CO3 AcOH, 130 oC, 16 h

H

Ar

OH

i. orthocarboxylation

OH CO2H

ii. directedortho-arylation

CO2H

R

iii. decarboxylation

R

H or para-carboxylic acid OH

Ar

OH

OH

R = OMe, 63% F, 46% Cl, 65% R Ph, 56% CHO, 50% NO2, 54%

Cl N 48%

Cl

R

Me

R = Me, 75% MeO, 25% Me OCF3, 69% Br, 60%


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ACS Catalysis

Scheme 44. meta-Functionalization of Phenol with a Traceless Directing Group

Whereas the meta-position of phenols is not electronically activated, the corresponding de-aromatized quinone ketal becomes electrophilic at this position. This allows nucleophilic addition followed by elimination to restore aromaticity, and provides a conceptually distinct approach to meta-functionalization. This mode of reactivity was described as early as 1907 during biochemical investigations on the oxidative metabolism of tyrosine to homogentisic acid.212 In 1952, Witkop and Goodwin described related rearrangements during Pb(OAc)4-mediated Wesley oxidations of para-cresol.213 Subsequent studies have dramatically improved synthetic utility, and modern methods now employ hypervalent iodine (PIDA) in MeOH to create the initial quinone ketal (Scheme 45).214-220 Subsequent conjugate addition of nucleophiles, including indoles, enolates or aryl radicals followed by re-aromatization via the elimination of MeOH provide the corresponding meta-functionalized products.


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O

Page 82 of 129

O OMe

R

OMe

R

MeO

OMe

OH

OH

O

Nu-H

PhI(OAc)2 R

nucleophile

MeOH

1,4-addition

oxidative umpolung

then acid or heat - MeOH

R

OMe

R Nu

common dearomatized intermediates electrophile OH

OMe OMe

CO2Me

NH indole 96% nucleophile Liao 1999

OH MeO

MeOH condensation

HO

Me

NH

NH 80% Chittimalla 2014

53% Fan 2011

OH

OH MeO

O

OH

N 46% Ghorai 2016

OMe

Me

O

86% Chittimalla 2014 OH

O Bu3SnH AIBN O

enolate nucleophile

MeO

EtO2C

MeO

OBn

MeO

I

radical addition

H+ MeO

O

- MeOH Clive 2004

O

Scheme 45. Hypervalent Iodine-Mediated meta-Functionalization of Phenol

A conceptually related, but mechanistically distinct approach to functionalize the

meta-position of phenols can be triggered by ortho-oxygenation (Scheme 46). This leads to the net functionalization of two aromatic C-H bonds, and provides a rapid entry into polyfunctional aromatic rings. In 2016, Lumb et al. described a catalytic aerobic functionalization of phenols with pendant amides that provided oxindoloquinones in high


82

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ACS Catalysis

yields across a broad substrate scope.221 Because of its electronic differentiation, the resulting ortho-quinone could be selectively functionalized at the more electron deficient carbonyl, to provide a range of C2, C5-difunctionalized oxindoles with complete regiocontrol. Mechanistic studies support the formation of a Cu(II) semiquinone radical complex as the immediate product of ortho-oxygenation, which undergoes oxidative C-O coupling with the starting phenol. Subsequent cyclization by a mechanism of addition/elimination closes the lactam and liberates the starting material, which can reenter the catalytic cycle. In a more recent contribution, the same team reported an efficient protocol for the synthesis of polyfunctional indoles from inexpensive and commercially available Boc-Tyr-OMe. ortho-Oxygenation affords coupled ortho-quinones, which can be directly cyclized by careful adjustment of pH in an alcoholic solvent to provide 5,6difunctionalized indoles on scales of up to 13 g.222 By capitalizing upon the complementary directing abilities of the C5-OH and the indole N-H, the team could then direct C-H functionalization to C4 and C7, selectively. Indoles of this family are found in many natural products, pharmaceuticals and bio-materials, making these polyfunctional indoles attractive synthetic platforms.


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Page 84 of 129


84

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ACS Catalysis

a) Difunctionalization OH

OH H

R

2,5-difunctionalization

H

X

= (ArOH)

HX X = O, NTs

Oxygenation / C-O Coupling

Selective Functionalization

O

O

O

Cyclization by Substitution

ArO

O

 ArOH re-enters cycle

HX

X

b) Oxindole Synthesis OH

OH H

OH F

OAc

OAc

OH

1. oxidation Ph

H 2. further functionalization

PhHN O

Ph

N O

O C-F

bond formed:

Ph

N

N O

C-O

C-C

c) Indole Synthesis OH

OMe 1. Cu / O2 2. MeOH / H2SO4

HN

BocHN CO2Me Boc-Tyr-OMe

OMe OH

MeO2C

OH

OH Directed C-H Bromination or Borylation

HN

MeO2C

66% 13.4 g prepared in a single pass

= Br or Bpin

Scheme 46. Catalytic Aerobic Poly-Functionalization of Phenols

4. C4-Functionalization Methods for para-functionalization can capitalize on the strong electronic effects of the phenol, as well as the reduced sterics of C4 relative to either C2 or C6. In 2011, Gaunt

et al. reported a para-selective, Cu-catalyzed arylation of phenols or their corresponding aryl ethers with diaryliodonium salts (Scheme 47).223 While para-arylated products are


85

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Page 86 of 129

formed preferentially, ortho-arylation is also observed when the para-position is substituted.224

OR2 Ar2IOTf or Ar2IBF4

R1

OR2

Cu(OTf)2 (20 mol%) R1

1,2-DCE 40-70 oC

Ar O

OMe

OMe

Ph

Ph

OH

NHPiv Ph 75%

80%

Ph 76%

Me O

52% OR2

H

Ph

R1 H

Ar

H

I

HO

Ar 64%

steric-driven

Scheme 47. Cu-Catalyzed para-Selective Arylation

In 2014, Zhang et al. reported a gold-catalyzed para-selective C-H alkylation between phenols and α-diazoesters (Scheme 48).225 The method remained efficient across a broad scope of coupling partners, resulting in 39 examples with yields of up to 99%. ortho-Functionalization is also possible when the para-position is blocked, however


86

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ACS Catalysis

this results in the corresponding lactone, following spontaneous lactonization of the phenol onto the ester.


87

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Page 88 of 129

tBu OH

OH LAuCl (5 mol%) AgSbF6 (5 mol%)

R1

CO2R2

P

OAr

Au

L = (2,4-tBu2C6H3O)3P 39 examples up to 99%

OH

R1

O ArO

DCM, rt

N2 Ar

tBu

CO2R2

Ar

OH

CO2R2

Ar

OH

OH

Cl Ph

O

CO2Et

CO2Me

CO2Me S

NH 99%

91%

85%

56%

OH

O

OH

OH

Ph

R

Ph

CO2Et 83%

Ph

R = Me, 98% Cl, 83% I, 92% allyl, 68% CO2Me

H

O

H

H

O 97% (1;1 d.r.)

Scheme 48. Au-Catalyzed para-Alkylation with α-Diazoesters

In 2013, Zhou et al. reported a Pd-catalyzed arylation of phenols with aryl iodides in the presence of AgOTFA that is selective for para-functionalization (Scheme 49).226 Interestingly, in their first generation conditions, the iodoarene required an orthosubstituent. The authors proposed the oxidative addition of Pd(II) into the Ar-I bond, in which case the additional chelation could help to stabilize the Pd(IV) intermediate. Additional refinement in 2015 expanded the scope of iodoarenes to substrates lacking this coordinating group.227


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ACS Catalysis


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OH

Page 90 of 129

OH

cat. Pd(OAc)2 Ar

R1

I

R1

AgOTFA TsOH H2O, 25 oC

Ar OH

OH

OH OAc

I HO

I

O CO2H

85%

proposed Pd(IV) intermediate

65%

OH

O R

Modified Conditions: cat. Pd(OAc)2, AgOAc, TsOH, HOAc/H2O, 70 oC OH

L

CO2H

NMe2

69%

Pd

OH

OH Br

Cl

Ph

72% (p:o = 17:1)

NO2 87%

55%

Br 82%

Scheme 49. para-Arylation of Phenol

Although para-selective allylation of phenol is challenging due to the competitive Oand ortho-allylation, several examples of direct para-allylation have been reported (Scheme 50). In 1999, Kocovsky reported a Mo-catalyzed para-selective allylation of phenol with allylic acetates that afforded an 88:12 ratio between para- and ortho-allylated products.228 A similar transformation was reported by Pregosin in 2006, in which the authors developed a catalytic system based upon Ru that generated an 84:16 ratio of the

para-allylated product to all other regioisomers.229 More recently, Discolo reported a Pdcatalyzed allylation that is para-selective when employing electron deficient allyl coupling


90

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ACS Catalysis

partners.230 These conditions require a relatively high catalyst loading and excess phenol (2 equiv) to minimize competitive O-allylation. These conditions have also led to good chirality transfer when employing a chiral allyl carbonate starting material.


91

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OCO2Et

Me OH

[Mo(CO)4Br2]2 (5 mol%) Kocovsky 1999 Me

94% 88:12 (p:o)

CO2Et

OAc

Ph

Page 92 of 129

OH

S

OH

Pd(PPh3)4 (8 mol%) Discolo 2017 CO2Et

Ph S

OBoc (PF6)2

DMF Ru DMF Ph Ru complex

Ph Ru complex (3 mol%)

41%

OH

Pregosin 2006 Ph 100% C-C selectivity 84:6:10 (p:m:o)

Scheme 50. para-Allylation of Phenol

Recently, Wen and Xu reported a para-selective amination of phenols with iminoquinone ketals catalyzed by a Brønsted acid (Scheme 51).231 A broad range of phenols can be converted to the corresponding protected biaryl anilines with good yields and regioselectivity. However, the scope of the iminoquinone ketal coupling partner was relatively limited. The authors proposed a [5,5]-sigmatropic rearrangement of a mixed ketal in order to explain the high selectivity for para-functionalization, but did not comment on the possibility of a competitive [3,3]-rearrangement leading to ortho-functionalization (for example, see Scheme 15).


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ACS Catalysis

OH N

OH

PG (PhO)2POOH (1 mol%)

R2

R1

R1

CH2Cl2, 0 oC PG

MeO

N

R2

OMe OMe

OH

Boc

OH

Me

N Me

OMe 85%

Ms

Me

N

O Me

N Ms Me

MeO Me

OMe 98%

[5,5]-sigmatropic rearrangement

Scheme 51. Para-Amination of Phenol via Rearrangement

In 2017, Hwang et al. reported a Cu-catalyzed visible light-promoted para-selective carbonylation of phenol with terminal alkynes under aerobic conditions (Scheme 52).232 The para-selective oxygenation of phenol was involved, which produces the para-quinone intermediate. Subsequent [2+2] cycloaddition with a Cu(II) acetylide followed by further ring opening / oxidative cleavage provides the one-carbon degraded product. A broad range of aryl- and alkyl-substituted alkynes were shown to be compatible, as were phenols with either 2- or 3-substitution. More recently, the mechanism of this transformation was interrogated by computations.233


93

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OH

Page 94 of 129

OH

CuCl (5 mol%) R

R

R CH3CN, O2 rt, blue LEDs

H

R OH

OH

O OH

Me

Me

Me Me

Me Ph

O

Ph

from 2-Me-phenol, 82% from 3-Me-phenol, 88%

O

OH

HO

Ph

80% OH

O

O 74% OH

HO

O

O

S 88%

82% CuCl

CuI

Ph

CuI

H

Ph

blue LEDs Ph

84%

*

O2

O

O2CuII

Ph

O

paterno-Buchi type [2+2] cycloaddition O

CuCl O2 h

O

OH O2 Ph

Ph

O

O CuII

CuII O

H O

OH

O

Ph O

Ph

OH

Ph

O

OH

Scheme 52. para-Selective Carbonylation by Aerobic / Photoredox Catalysis

Recently, Faber and Glueck reported a one-pot process for the enzymatic paraselective hydroxyethylation of phenol (Scheme 53).234 Four enzyme-catalyzed


94

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ACS Catalysis

transformations sequentially convert phenols into tyrosine derivatives, cinnamic acids, styrenes, and finally chiral secondary alcohols. The process combines four distinct enzymatic processes, and is conducted under buffered conditions (pH 8) using sodium pyruvate and ammonium chloride to provide alcohols in yields of up to 84% and enantiomeric excess of 92% e.e.

a) hydroxyethylation sequence

OH

OH

OH

O

R

CO2H

TAL

R

TPL

H 2N

H 2O

R

NH3 CO2H

NH3

CO2H

OH

OH FDC

TPL: tyrosine phenol lyase TAL: torosine ammonia lyase FDC: ferulic acid decarboxylase FDC*: FDC - hydratase variant

FDC*

R

CO2

R

H 2O OH

b) Substrate scope for the hydroxyethylation sequence OH OH

R

OH

OH

TPL/TAL/ FDC/FDC*

OH

F

Br

R sodium pyruvate NH4Cl pH 8 buffer

F OH OH

84% 78% e.e.

OH 58% 88% e.e.

OH 72% 85% e.e.

Scheme 53. para-Selective Enzymatic Hydroxyethylation of Phenol

5. External-Functionalization


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Page 96 of 129

Phenols are also suitable directing groups for C-H functionalization reactions of substituents at C2 or C6. Because these C-H bonds are not part of the same aromatic nucleus as the phenol itself, we have categorized this family as external functionalization. Because of the more favorable ring sizes that can form by metalation under these conditions, external C-H functionalization can often be favored over the corresponding internal C-H functionalization (see Scheme 22 for a previously discussed example). Among all of the substrates that have been examined for external C-H functionalization, 2-arylphenols are among the most popular, and have been employed in both intermolecular coupling reactions as well as intramolecular cyclizations (Scheme 54 - 57). In 2004, Zhou et al. reported an intramolecular borylation of 2-arylphenol that proceeded through the di-chloro-boron-phenolate (Scheme 54).235 Subsequent borylation via EArS was promoted by AlCl3, which afforded the corresponding boronate as a single regioisomer following a hydrolytic work up. Subsequent diversification by either arylation or carbonylation proceeds smoothly to produce the corresponding biaryls or lactones, respectively.


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ACS Catalysis

Scheme 54. External C-H Borylation of 2-Arylphenol

OH R

R1

O

O

BCl3

OH

BCl2

2

cat. AlCl3 R2

R1

OH

OH

B

B

O

O

then H2O

B

R2

R1 OH

Me

O

B

F CH3

99%

80%

98%

O Me

O

Pd(OAc)2 CO

Pd(PPh3)4 PhI, K2CO3

Me

OH

futher diversification 96%

Ph 81%

In 1997, Miura et al. reported the first example of a Pd-catalyzed, phenol-directed CH arylation of 2-arylphenol with aryl iodides (Scheme 55).236 Mechanistically, the reaction is consistent with C-H insertion to afford a six-membered palladacycle, form which oxidative addition and reductive elimination can afford the corresponding biaryl. Under similar conditions, the authors also found that C8-arylation of 1-naphthol was possible, even when the C2 position of naphthol was not substituted. In 2013, Manabe demonstrated compatibility for a similar arylation using aryl-nonaflates.237 Because of their complementary reactivity with aryl iodides, their introduction allowed for the


97

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Page 98 of 129

synthesis of more complex poly-arylated products by sequential arylation/Nf protection steps.

cat. Pd(OAc)2

OH Ar

OH

I Cs2CO3 100 oC

H

Ar

53-1

53-2 OH

NO2

Ph

OH

Ph

Ph

63%

72%

70%

53-2 Cs Ln O

OH

OH

Ln

70%

OMe Ar-I

Pd

Ar Pd

Ln Pd

Ar Ln Pd

Ar

I

O 53-1

CsHCO3

Cs2CO3 Cs2CO3

CsI CsHCO3

Iterative chain growth with Ar-ONf for polymer synthesis: ONf MeO

standard condition

NfF, NEt3

Ph

OH

MeO OH

standard condition

=

64%

Pd(OAc)2 PCy3 Cs2CO3 Mesitylene, reflux

ONf

MeO 86% Pd(OAc)2 OH SPhos, KF

NfF, NEt3

OH

MeO

97%

(HO)2B

ONf MeO standard condition 73%

OH

MeO

Ph OH

64%

Scheme 55. External C-H Arylation of 2-Arylphenol


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ACS Catalysis

Miura’s group also reported the external C-H olefination of 2-arylphenols (Scheme 56), demonstrating migratory insertion from the corresponding palladacycle.238 Subsequent β-hydride elimination affords the product of vinylation and a Pd-hydride, from which Pd(OAc)2 is regenerated by a Cu(OAc)2/O2 couple. In cases where electron-deficient olefins were employed, additional cyclization of the OH group led to the corresponding cyclic ether. In 2014, Sun reported a similar vinylation that employed benzoquinone as the terminal oxidant.239

R OH O

cat. Pd(OAc)2

OH R H

or

Cu(OAc)2·H2O 4 Å MS, air 80 - 120 oC

56-1 CO2Et

56-2

56-3

R

CO2nBu

CONMe2

OH O

O

O

Ph 56%

44%

H 2O

56-2 or 56-3 Ln H R

2 Cu(OAc)2 H Pd OAc

27%

Cl

53%

1/2 O2 2 HOAc

2 Cu(OAc)

56-1

R

LnPd(OAc)2

HOAc

HOAc R Ln

Ln Pd O

AcO

Pd

O

R

R Ln Pd O

Ln O

Pd

HOAc

Scheme 56. External C-H Vinylation of 2-Arylphenol


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In 2011, Liu et al. reported a Pd-catalyzed intramolecular dehydrogenative coupling of 2-arylphenols to afford the corresponding dibenzofurans (Scheme 57).240 The authors proposed a reductive elimination from the 6-membered ring palladacycle to account for C-O bond formation, which was promoted by the electron rich and sterically encumbered NHC-ligand. To close the catalytic cycle, Pd-(0) is then re-oxidized by air to Pd(OAc)2. The authors reported a broad substrate scope that tolerated electron donating and withdrawing substituents throughout the substrate. In the same year, Yoshikai et al. reported a similar Pd-catalyzed dibenzofuran synthesis, but proposed an alternative Pd(II)/Pd(IV) cycle on account of using tert-butyl peroxybenzoate as the terminal oxidant.241 In 2012, Zhu et al. reported that Cu could promote a similar dibenzofuran synthesis from 2-arylphenol (Scheme 57),242-243 however, this system required an electron withdrawing substituent at C4 of the phenol or a directing group ortho- to the site of C-H activation, for good yields.


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OH

H

cat. Pd(OAc)2

R2

oxidant

R1

R1

Liu 2011 | cat. Pd(OAc)2 / IPr, air SiMe3 O

R Cl

O O

O

82%

R2

O

Ts

48%

O H

N

67%

IPr

Pd

O

Pd (II) - Pd (0) cycle

Yoshikai 2011 | cat. Pd(OAc)2 / 3-NO2-py, BzOOtBu O

Br

O O

O

40%

Cl

55%

Cu-based conditions: special substrates required

O

O

Ln Pd

X

O

Pd (IV) - Pd (II) cycle

55%

AcHN

o-DG

O cat. CuBr air 72%

NO2

X

cat. Cu(OAc)2 O2

R1 = p-EWG

EWG

56%

R2 = o-DG

F

Scheme 57. Dibenzofuran Synthesis

In addition to the Csp2-H bonds of aromatic rings, phenol directed C-H insertions into vinyl or heteroaryl substituents have been reported. In 2014, Liu et al. reported a Cucatalyzed, Ag-mediated synthesis of 2-sulfonylbenzofurans by the addition of sodium sulfonates to 2-hydroxycinnamic acids using a tandem decarboxylative sulfonylation / oxidative cyclization cascade (Scheme 58).244 Good substrate scope was demonstrated for both the phenol and sulfonate coupling partners, to provide more than 25 examples


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with yields of up to 79%. Mechanistically, a proto-decarboxylation occurred followed by an oxidative sulfonylation of the terminal alkene. Subsequent phenol-directed C-H metalation followed by oxidative insertion and reductive elimination gave the benzofuran product.

R2-SO2Na CuCl2·2H2O (50 mol%) AgTFA (2.5 equiv)

O OH

R1

Cs2CO3 (2.0 equiv) DMF, 80-100 oC

OH

O R1

S

F

O

Ts

S

Ts

O

BnO

O

O 51%

67% O S

O R2

O

O Me

72%

O R = Me, 79% OMe, 77% F, 56% Br, 52% NHAc, 72%

O

Ts O 81%

R O OH

[Ag] or [Cu] protodecarboxylation

OH

OH

SO2R

RSO2 2 Ag

SO2R

OH

2 Ag

OH [Cu] SO2R

SO2R

O2 O [Cu]

[Cu] O

SO2R O

Scheme 58. Benzofuran Synthesis via External C-H Functionalization of Phenol


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In 2015, Nachtsheim et al. reported a Rh-catalyzed alkynylation of 2-vinylphenols, using a hypervalent I-(III)-alkyne transfer agent (TIPS-EBX*) as the electrophilic source of the alkyne (Scheme 59).245 This chemistry has shown good scope on both the vinyl and aromatic components, and control experiments demonstrated the requirement of a free phenol for successful C-H functionalization.

TIPS

TIPS

H R'

R

2.5 mol% [(Cp*RhCl2)2] 1.5 equiv DIPEA

I

MeCN, rt OH

R

CH3

OH

TIPS-EBX*

TIPS

X

TIPS

Cl

CH3

O

R'

1.5 equiv TIPS-EBX*

TIPS

O

CH3

OH

OH

X = F, 86%, 3 h X= Cl, 90%, 2 h X = Br, 93%, 2 h X = NO2, 92%, 2 h

Ph OH

MeO

Cl 98%, 20 min

TIPS

84%, 3 h

TIPS

TIPS OH CH3 H 3C

HO

95%, 2 h

CH3

CH3

S

OCH3 0%, 8 h

0%, 8 h

Scheme 59. Alkynylation of 2-Vinylphenol

In 1998, Larock et al. reported a novel dihydrobenzofuran and dihydrobenzopyran synthesis via a Pd-catalyzed vinylation / cyclization cascade between 2-vinyl or 2-


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allylphenol and vinyl halides (Scheme 60).246 Good substrate scope in both components provided

a

direct

entry

into

structurally

diverse

dihydrobenzofuran

and

dihydrobenzopyran products. The proposed mechanism began by oxidative addition into the vinyl halides by Pd-(0), followed by migratory insertion and β-hydride elimination. Reinsertion of the Pd-H led to a -allyl complex, from which C-O bond formation could occur by coordination and reductive elimination or direct attack onto the allyl fragment.

cat. Pd(OAc)2 Na2CO3

OH R

R1

2

n = 0, 1

R1

n Bu4Cl DMF, 80 oC

X

n

n

X = Br, I, OTf

O

Ph

R2

O

major O

O

Ph Me

X =Br, 82%

X = Br, 75% cis/trans = 77/23

X = I, 68%

O

Me

O

Ph

O Ph

X = OTf, 76%

X = Br, 56% OH

OH

X

PdX

X = Br, 56%

-hydride elimination

OH Pd(H)X

migratory insertion Pd

migratory insertion

oxidative addition

X

Pd0

OH O

O - Pd (0) -X-

deprotonation

PdX

PdX

Scheme 60. Tandem Vinylation / Cyclization of 2-Vinyl or 2-Allylphenol


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7. Conclusion In surveying the recent literature on transformations that directly functionalize the CH bonds of phenols, we have identified a number of methodologies that are increasingly capable of overcoming longstanding challenges of selectivity. These include hydrogen bonding or electrostatic interactions between the phenol and a substrate-catalyst complex to direct C-H functionalization to the ortho-position. Metal-catalyzed C-H insertion, directed by increasingly sophisticated templates, has given rise to selective metafunctionalization, which remains an important area for future development. In this context, the temporary disruption of aromaticity by oxidation can provide a complementary means of activating the meta-position of phenols that can offer advantages to synthetic efficiency when O2 is employed as the terminal oxidant. Selective functionalization of the paraposition has also been addressed, and appears to follow classical considerations of sterics. Since phenols affect all stages of the chemical value chain, methodologies for their diversification can have wide-ranging impact. This can include the efficient preparation of versatile feedstocks, the late-stage functionalization of complex and biologically active natural products or polymer synthesis. While the primary source of


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phenols is currently benzene derived from petroleum, efforts to valorize the lignin fraction of biomass have led to an increasingly well-defined stream of phenolic building blocks. Successfully incorporating these small molecules into the existing chemical value chain is a requirement for the economic viability of emergent integrated bio-refineries. This will require increasingly efficient manipulation of phenols and their derivatives under conditions that are practical, low-cost and environmentally benign. We hope to have highlighted the current state of the art in phenol-directed C-H functionalization reactions, with the goal of motivating these continued developments.

AUTHOR INFORMATION

Corresponding Author *[email protected]

ACKNOWLEDGMENTS 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


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Nature et Technologies (FRQNT) (Team Grant to J.-P. L.); McGill University Faculty of Science (Milton Leong Fellowship in Science to Z. H.).

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