WO2011037929A2

WO2011037929A2 - Pd(ii)-catalyzed hydroxylation of arenes with o2 or air

Info

Publication number: WO2011037929A2
Application number: PCT/US2010/049680
Authority: WO
Inventors: Jin-Quan Yu
Original assignee: The Scripps Research Institute
Priority date: 2009-09-24
Filing date: 2010-09-21
Publication date: 2011-03-31
Also published as: WO2011037929A3

Abstract

Pd (II) -catalyzed ortho-hydroxylat ion of variously substituted aromatic carboxylic acids under O₂ or air is achieved under non-acidic conditions. Extensive labeling studies support a direct oxygenation of aryl C-H bonds with molecular oxygen.

Description

Pd (II) -CATALYZED HYDROXYLATION OF ARENES

WITH 0₂ OR AIR

Description

GOVERNMENTAL SUPPORT

The present invention was made with governmental support pursuant to grant NSF CHE- 0910014 from the National Science Foundation. The government has certain rights in the invention.

BACKGROUND ART

Catalytic hydroxylation of inert C-H bonds using environmentally benign hydrogen peroxide or molecular oxygen remains a significant task both in chemical industry and organic synthesis. [(a) Shilov et al., Chem. Rev. 1997, 97:2879; (b) Baik et al., Chem. Rev. 2003, 103:2385; (c) Lucke et al., Adv. Synth. & Catal. 2004, 346:1407; (d) Que et al.,

Nature 2008, 455:333: (e) Hartwig, Nature 2008,

455:314.] Among various metal [(a) Groves et al., J. Am. Chem Soc. 1989, 222:8537; (b) Grinstaff et al., Science 1994, 264:1311; (c) Larrow et al., J. Am. Chem Soc. 1994, 226:12129; (d) Breslow et al., J. Am. Chem Soc. 1997, 229:4535; (e) Punniyamurthy et al., Tetrahedron Lett. 1998, 39:8295; (f) Periana et al., Science 1998, 280, 560. (g) Lee et al., J. Am. Chem Soc. 2002, 224:13978; (h) Das et al., Science 2006, 322:1941; (i) Chen et al., Science 2007, 328:783; (j) Company et al . , J. Am. Chem Soc. 2007, 229:15766; (k) Herres-PawlisLyons et al., J. Am. Chem Soc. 2009,

232:1154] and non-metal [for dioxirane and radicals see: (a) Yang et al., J. Am. Chem Soc. 1998, 120:6611; (b) Curci 3et al., Acc.Chem. Res. 2005,

39:1; (c) Baran et al., Nature 2009, 455:824; (d) Kasuya et al., Org. Lett. 2009, 22:3630; for a single example of oxaziridine catalysts see: Litvinas et al., Angew. Chem. Int. Ed. 2009, 48:4513] catalytic systems, an early discovery by Fujiwara using Pd(OAc)₂ to convert benzene into phenol with molecular oxygen is especially intriguing, [Jintoku et al., Chemistry Lett. 1990, 1687, with corrected yields at: Chemistry Lett. 1991, 193)] but required harsh conditions and provided low yields (eq. 1) . In another pioneering study by Rybak-Akimova and Que, [Taktak et al . , Chem. Commun. 2005, 5301] the carboxylic group of benzoic acid was used to direct ortiio-hydroxylation with H₂0₂ in the presence of a stoichiometric amount of a reactive non-heme iron complex

[Fe (II) (BPMEN) (CH₃CN)₂] (C10₄)₂ (eq. 2).

The present inventor, his co-workers and others have also reported Pd-catalyzed C-H oxidation with various peroxides [(a) Giri et al . , Angew. Chem. Int. Ed. 2005, 4:7420] and oxone [(b) Desai et al., Org. Lett. 2006, 8:1141; for the use of PhI(OAc)₂ see: Desai et al., J. Am. Chem Soc. 2004, 126, 9542] using Ac₂0 as a crucial promoter. Recently, an important study by Vedernikov described a Pd ( II ) -catalyzed oxidation reaction of benzylic C-H bonds of

8-methylquinoline with molecular 0₂ in the presence of HOAC/AC₂O in which both hydroxylation and

acetoxylation were observed. [(a) Zhang et al.,

Chem. Commun. 2008, 3625.] However, this catalytic system is not compatible with aryl C-H bonds. [(b) Vedernikov, A. N. Chem. Commun. 2009, 4781]

The fundamental importance of hydroxylation with 0₂ and its applications related to drug discovery and natural product synthesis based on salicylic acids (o-hydroxybenzoic acids) prompted development of a Pd-catalyzed ortho-hydroxylation of benzoic acids with molecular 0₂ that is discussed hereinafter. Three of the top 200 retail dollar-producing drugs are derivatives of salicylic acid whose structures are shown below) .

Asacol Metoclopramide Flecainide Acetate

The present invention that is described hereinafter provides a highly selective Pd-catalyzed ort o-hydroxylation of aryl carboxyl compounds with 0₂ or air giving synthetically useful yields under non- acidic conditions (eq. 3) , thereby providing a route to salicylates and similar compounds.

35-95% BRIEF SUMMARY OF THE INVENTION

The present invention contemplates a method of preparing a hydroxylated aromatic compound. That method comprises the steps of contacting an aromatic carboxylic acid (aryl carboxylate or aryl carboxylic acid) compound of Formula I having a hydrogen at a

position ortho to the carboxyl group that is

dissolved in a tertiary amide of a C^-Cg carboxylic acid with oxygen in the presence of a Pd(II) catalyst and an excess of an alkali metal weak acid salt at a temperature of about 80° to about 140° C to form a reaction mixture. That reaction mixture is

maintained at that temperature for a time period sufficient to prepare an aromatic compound that is hydroxylated at the position of that hydrogen. Aside from having a carboxyl substituent and a hydrogen ortho to that carboxyl, a contemplated aryl compound can have three further substituents R¹, R2 and R3 that are defined hereinafter on the ring containing the carboxyl group. In addition, the aromatic ring system, A, that is also defined hereinafter can be bonded directly to the carboxyl group, as where "n" is zero, or can be bonded indirectly via a carbon atom, Q, that can itself be substituted or an unsubstituted methylene group (CH2), where "n" is one .

Pd (II) acetate is a preferred palladium ( II ) catalyst. Potassium acetate (KOAc) is the preferred alkali metal salt of a weak acid that is present. A preferred tertiary amide of a C1-C carboxylic acid is N, N-dimethylformamide (DMF) , N, -dimethylacetamide (DMA) or N, N-dimethylpropionamide (DMP) . It is also preferred but not required to include 0.2 to about 1 equivalents of benzoquinone per mole of starting aryl carboxylate. Once prepared, the hydroxylated

aromatic compound is preferably recovered, but need not be so and can be utilized in a further synthesis if desired.

The present invention has several benefits and advantages.

One benefit is that its use provides a facile preparation of hydroxylated aromatic product compound .

An advantage of the invention is that its use can provide a high yield of the hydroxylated product aromatic compound.

Still further benefits and advantages will be apparent to the skilled worker from the disclosure that follows .

The word "hydrocarbyl" is used herein as a short hand term to include aliphatic as well as alicyclic groups or radicals that contain only carbon and hydrogen. Thus, alkyl, alkenyl and alkynyl groups are contemplated as are aralkyl groups such as benzyl and phenethyl, and aromatic hydrocarbons such as phenyl and naphthyl groups are also included.

Where a specific hydrocarbyl substituent group is intended, that group is recited; i.e., C2-C4 alkyl, methyl or dodecenyl. Exemplary hydrocarbyl groups contain a chain of 1 to 6 carbon atoms, and

preferably one to about 4 carbon atoms.

A hydrocarbyloxy group is an ether containing a hydrocarbyl group linked to an oxygen atom. It is noted that a skilled worker would understand that an alkenyl or alkynyl substituent must have at least two carbon atoms.

An "acyl" group is a carbonyl-terminated radical usually derived from a carboxylic acid having the general structure RC(O), where R is a hydrocarbyl group.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The present invention contemplates a method of preparing a hydroxylated aromatic compound. A contemplated method comprises the steps of contacting an aromatic carboxylic acid compound of Formula I having a hydrogen at a position ortho to the carboxyl

group that is dissolved in a solvent of a tertiary amide of a C^-Cg carboxylic acid with oxygen in the presence of a Pd(II) catalyst and an excess of an alkali metal weak acid salt at a temperature of about

80° to about 140° C to form a reaction mixture. That reaction mixture is maintained at that temperature for a time period sufficient to prepare a

hydroxylated aromatic compound.

In a compound of Formula I , the starting aromatic ring system can contain 5 to about 14 ring atoms. Thus, in a compound of Formula I , A together with the bonded and depicted vinylene group forms an aromatic ring system containing 1, 2, or 3 rings that each has 5- or 6-members . Preferably, the aromatic ring system contains 5 to about 10 ring atoms in one to two rings. More preferably, there are six atoms in a single ring. A contemplated aromatic carboxylic acid is typically a hydrocarbyl carboxylic acid, but need not be so. Thus, aside from phenyl, naphthyl, anthracenyl, and phenanthryl compounds, pyridyl, pyrimidyl, pyrazinyl, furanyl, benzofuranyl,

isobenzofuranyl, benzoxazolyl , benzopyrazinyl, benzotriazinyl, quinolyl and isoquinolyl carboxylates and the like.

In addition to the carboxyl group and adjacent (ortho) hydrogen on the aromatic ring, a contemplated aromatic carboxylic acid can contain three further substituent groups R^ , and R^ on the ring containing the carboxyl group. Those

substituents are independently the same or different. Bonds to other rings are considered herein to be such substituents, so that for example, naphthalene

2-carboxylic acid is deemed to contain two

substituents in addition to the carboxyl group.

Each of R¹ , R2 and R^ can be hydrido.

However, the presence of at least one substituent wherein at least one of R^ , R2 and R^ is other than hydrido is preferred.

Electron donating substituents on the aromatic ring favor hydroxylation and include C^-Cg hydrocarbyl and C^-C hydrocarbyloxy substituents.

The hydroxylation reaction also proceeds with

electron withdrawing substituents such as halogens, cyano, nitro, trifluoromethyl , C]_-Cg acyl, benzoyl and C^-Cg acylamido groups as substituents . Yields are increased by raising the pressure of oxygen from one atmosphere up to about ten atmospheres,

particularly with electron withdrawing substituents. Several exemplary substituents are illustrated hereinafter in Table 2 and in the Experimental portion hereinafter.

Initial studies indicate that aromatic compounds in which the carboxyl group is bonded directly to the aromatic ring system such as benzoic acid or 1- or 2-naphthalenecarboxylic acid provide higher yields than do otherwise similar compounds in which the carboxyl is bonded indirectly to the ring system via a methylene or substituted methylene group, Q . Q can thus be represented as CR¾5, wherein each of R^ and is independently hydrido (H-) , which is preferred, straight chain C^-Cg- hydrocarbyl, branched chain Ci-Cg-hydrocarbyl or cyclic C_j-Cg-hydrocarbyl, or and R^ together with the carbon atom of the CR^ R5 group form a cyclic compound having a total of 5-7 carbon atoms. Q is present when "n" is one and absent when "n" is zero. Q is either present or absent, and ^λη" is thus one or zero .

Initial results indicate that starting compounds where Q one have somewhat lower yields of hydroxylated aromatic product. Additionally, the time required to achieve a given yield under the same the reaction conditions is also usually longer for a starting aromatic compound that contains a Q group than for an otherwise identical compound in which Q is absent. The oxygen that is contacted with the aryl carboxylate in a contemplated reaction can be present in atmospheric air, or as oxygen gas. The oxygen gas can be present admixed with another gas such as argon or nitrogen that does not interfere with the

reaction. It is preferred to use pure oxygen as is commercially available.

The oxygen is typically present at one atmosphere, whether in air or as pure oxygen. It is preferred to use pure oxygen at one atmosphere or at an elevated pressure of up to about ten atmospheres. A pressure of about five atmospheres of oxygen is preferred when electron a withdrawing substituent is present on the aromatic ring.

A contemplated reaction is carried out with the aryl carboxylate dissolved in a liquid solvent. That solvent is preferably a tertiary amide of a C^-Cg carboxylic acid. Preferred solvents include is

N, N-dimethylformamide (DMF) , N, N-dimethylacetamide (DMA) and N, N-dimethylpropionamide (DMP) as well as longer straight and branched chain carboxylic acid amides prepared using C_]_-Cg dihydrocarbyl-substituted amines or C5-C7 cyclic amines such as piperidine, pyrrolidine and the like such as Ν,Ν-diallyl iso- butyramide, N-ethyl-N-propylacetamide or piperidinyl formamide. N-C^-Cg hydrocarbyl lactams (cyclic amides) having up to 6 carbon atoms in the ring such as N-methyl pyrrolidone and N-methyl caprolactam are also contemplated solvents. Mixtures of the above tertiary amide compounds can also be used as solvent.

A contemplated hydroxylation is catalyzed by a Pd(II) compound that is present in a catalytic amount that is typically about 5 to about 15 mole percent and preferably about 10 mole percent based on the starting aryl carboxylic acid. Use of greater amounts of catalyst can hasten the reaction.

Illustrative useful palladium II compounds include Pd(II) acetate, a Pd(II) halide such as Pd(II) chloride , Pd(II) trifluoroacetate, Pd(II) oxide, Pd(II) hydroxide, Pd(II) nitrate, Pd(II) sulfate and the like that are well known and available

commercially .

The hydroxylation reaction is carried out in the presence of an alkali metal salt of a weak acid. Illustrative weak acid anions of that salt include a C^-Cg carboxylate such as acetate,

propionate, hexanoate, H2PO -, or CC>3⁼. Although sodium, potassium and cesium salts are useful, potassium is the preferred cation of the salt, and acetate is the preferred anion of the salt. A mixture of such salts can also be used.

The alkali metal salt of a weak acid is present in excess over the starting aryl carboxylic acid. The two materials are preferably present at a molar ratio of about 2:1 (salt to aryl carboxylic acid) .

A contemplated reaction is carried out at a temperature of about 80° to about 140° C. More preferably, the temperature is about 100° to about 120° C.

Once the reaction mixture of the before described materials is prepared at the above'

temperature, that reaction mixture is maintained at a temperature within an above-noted temperature range for a time sufficient to form the desired

hydroxylated compound. That time can be about 6 to about 24 hours, and is typically about 12 to about 18 hours .

Once formed, a hydroxylated aromatic compound can be and is preferably recovered after purification. Such recovery is not necessary when a further reaction is desired to be run on the reaction product .

The use of 0.2-1 equivalents of

benzoquinone present in the reaction mixture is found to significantly accelerate the reaction. The presence of benzoquinone or similar quinone such as naphthoquinone is not, however, required or

essential .

It is noted that the hydroxylation occurs exclusively at a single position ortho to the

carboxyl group even when two ortho positions are equally available. Additionally, when there is a substituent asymmetrically substituted on the

aromatic ring relative to the carboxyl group, the hydroxyl group is added to the ring at the least hindered ortho position relative to that carboxyl group .

Labeling studies using both ¹⁸C>2 and ¾¹⁸0 support a direct oxygenation of the arylpalladium intermediates instead of an acetoxylation/hydrolysis sequence. [For a Cu-catalyzed hydroxylation via acetoxylation/hydrolysis, see Chen et al., J. Am. Chem Soc. 2006, 128, 6790.]

Guided by an early observation that alkali metal and other cations promote palladation of proximate C-H bonds [Giri et al., J. Am. Chem Soc. 2008, 230:14082], it was discovered through extensive screening that potassium salts such as KOAc (OAc = acetate) or K2HPO4 promote Pd ( II ) -catalyzed ortho- hydroxylation of benzoic acids under 1 atm 0₂ in DMF, DMA and DMP. Although only two turnovers were observed (Table 1, entries 3-5) , the yield was increased to 55 -60% by performing this hydroxylation reaction under 5 atm 0₂ (Table 1, entries 6, 7 ) . It was also found that addition of 0 .2 and 1 equiv of benzoquinone increases the yield to 40% and 82% respectively under 1 atm 0₂ (Table 1, entries 8, 9) ·

Table 1

Screening of Reaction Conditions*

Entry Solvent Base BQ (equiv) %Yield^a % SM^a

1 f-BuOH KOAc (2 equiv) 0 0 100

2 THF KOAc (2 equiv) 0 0 100

3 DMF KOAc (2 equiv) 0 16 52

4 DMP KOAc (2 equiv) 0 12 60

5 DMA KOAc (2 equiv) 0 20 50

6 DMA KOAc (2 equiv) 0 55^ϋ 0

7 DMA K₂HP0₄ (3 equiv) 0 60" 0

8 DMA KOAc (2 equiv) 0.2 40 60

9 DMA KOAc (2 equiv) 1 82 12

10 DMA NaOAc (2 equiv) 1 25 70

11 DMA CsOAc (2 equiv) 1 80 16

12 DMA K₂HP0₄ (3 equiv) 1 45 45

13 DMA K₂C0₃ (3 equiv) 1 33 65

14 DMA KOAc (2 equiv) 1 62° 30

15 DMA KOAc (2 equiv) 1 0^d 100

* The yields were determined by ¹H NMR analysis of crude products using CH₂Br₂ as the internal standard; DMA is N,N- dimethylacetamide; DMP is N, N, -dimethylpropionaird.de; DMF is N, N-dimethylformamide; OAc is acetate ^b 5 atm. 0₂; ^c Air instead of 0₂; ^d Argon instead of 0₂. Among the bases screened, KOAc and CsOAc (entries 9, 11) are superior to NaOAc (Table 1, entry 10); however, K₂HP0₄ and K₂C0₃ are also compatible (Table 1, entry 12) . These combined data indicate that the acetate anion is not required.

Monitoring the reaction by ¹H NMR shows that benzoquinone significantly increases the rate of the hydroxylation (see the examples hereinafter) . [For recent dicussions on various roles of' benzoquninone on C-H functionalizations , see: (a) Boele et al., J. Am. Chem Soc. 2002, 224:1586; (b) Chen et al., J. Am. Chem Soc. 2005, 127:6970; (c) Chen et al., J. Am.

Chem Soc. 2006, 128:18; (d) Hull et al . , J. Am. Chem Soc. 2009, 231:9651.] It was pleasing to find that hydroxylation proceeds using 1 atm air as the sole oxidant (Table 1, entry 14). Notably, no reaction was observed using stoichiometric Pd(OAc)₂ under 1 atm argon, suggesting that 0₂ is likely to be involved in the product forming step rather than reoxidation of Pd(0) (Table 1, entry 15).

With these optimized conditions in hand, the substrate scope was established as shown by the products and yields in Table 2, below. Electron-rich arenes were readily hydroxylated to give the

anticipated products 1-9 in 60-82% yields. The hydroxylation product from 1-naphthoic acid was decarboxylated spontaneously to give 6.

Surprisingly, the well-known directing group

acetamide in 9 did not scramble the regioselectivity . Halides (10-13) , as well as other stronger electron- withdrawing groups such as trifluoromethyl, acetyl, cyanide and nitro (14-20) are reasonably well

tolerated, giving moderate yields. In these cases, 85-95% yields can be obtained by using 5 atm 0₂. Table 2

Pd-Catalyzed ortho-hydroxylation with 0₂ ^a

7 73% 8 61 % (10 moi% Pd(TFA)₂, 1 9 52%

equiv. KTFA and 1 equiv. CsOAc)

10 72% 11 52% 12 78%

95% (5 atm 0₂)

13 82% 1448% 15 50%

93% (5 atm 0₂) 86% (5 atm 0₂)

16 35% 17 51% 18 69%

85% (5 atm 0₂) 63% (5 atm 0₂) 85% (5 atm <¾)

19 50% 20 54%

91% (5 atm <¾)

Isolated yield. Similar results for aryl carboxylic acids in which the carboxyl functional group is indirectly bonded to the aromatic ring system via the Q group are shown below in Table 3.

Table 3

Pd-Catalyzed ortho-hydroxylation with 0₂

48% 48% 55%

Preliminary mechanistic investigations were carried out to shed light onto this hydroxylation pathway. Prior studies on Pd-catalyzed C-H oxidation using peroxides [(a) Giri et al., Angew. Chem. Int. Ed. 2005, 44:7420] and 0₂ as the oxygen source were initially inspired by seminal works regarding

organometallic reactions of carbon-Pd bonds with peroxides [(a) Alsters et al . , Organometallics 1993, 22:1629; (b) Alsters et al., Organometallics 1993, 22:4691] and carbon-Pt bonds with 0₂. [(a) Rostovtsev et al., Inorg. Chem. 2002, 42:3608; (b) Vedernikov et al., J. Am. Chem Soc. 2006, 128: 82; (c) Griceet al., Organometallics 2009, 28:953; (d) Taylor et al.,

Angew. Chem. Int. Ed. 2009, 46:5900.] These oxidants are shown to oxidize carbon-Pt (Pd) bonds to form Pt(IV) and Pd(IV) species I and II or directly insert oxygen atoms into carbon-Pt ( Pd) bonds to form III and IV. [(a) Giri et al., Angew. Chem. Int. Ed. 2005, 44:7420. ]

Pd^lv Ar-Pd^lv ArO ArOO-Pd¹ OH O

I II III IV

V VI

Although no data are currently available to distinguish among these reaction pathways, labeling experiments were performed to rule out the

involvement of carboxylation or lactonization intermediates V and VI, above. First, ¹⁸0₂ was incorporated into the products with high fidelity (eq. 4). Second, the decarboxylated product showed

(97)% that ¹⁸0₂ is incorporated into the hydroxyl rather than the carboxyl group (eq 5) . These observations

are inconsistent with carboxylation/hydrolysis pathway from the catalytic amount of OAc^~ or the benzoic acids. Finally, studies using 2 equivalents of H₂ ¹⁸0 (eq 6) or H₂0₂ (30% in H₂0) (eq 7) also rule out oxygen incorporation from H₂0 or H₂0₂ formed through a Pd(II)/Pd(0) catalysis. [(a ) Konnick et al.,2008, J. Am. Chem Soc. 130:5753; (b) Piera et al., Angew. Chem., Int. Ed. 2008, 47:2.]

C0₂H

.C0₂H

action

In summary, a versatile Pd-catalyzed ortho- hydroxylation of aryl carboxylic acids with 1 atm 0₂ or air under non-acidic conditions has been

developed. Mechanistic investigations point to a direct oxygenation of the aryl-Pd species by molecular 0₂. General Information :

Unless otherwise noted, all commercial materials were used without further purification.

Solvents were obtained from Acros or Sigma-Aldrich and used directly without further purification. ¹R and ¹³C chemical shifts are referenced to

tetramethylsilane at 0.0 ppm and residue CH₃COCH₃ at 205.0 or CHCI₃ at 77.0 ppm respectively unless

otherwise noted. Multiplicities are reported using the following abbreviations: s = singlet, d =

doublet, t = triplet, q = quartet, m = multiplet, br = broad resonance. High resolution mass spectra for new compounds were recorded at Mass Spectrometry Facilities, The Scripps Research Institute (TSRI) .

I . General procedure for screening

of reaction conditions :

A 50 mL Schlenk-type tube (with a Teflon high pressure valve and side arm) equipped with a magnetic stir bar was charged with Pd(OAc)₂ (11.2 mg, 0.05 mmol) , followed by jn-toluic acid (68.1 mg, 0.5 mmol) , benzoquinone (the amount listed in the table) , base (listed in the table) and solvent (1.5 mL) . The reaction tube was evacuated and back-filled with 0₂ (3 times, balloon) . After the reaction mixture was stirred at 115 °C for 15 hours, it was permitted to cool to ambient temperature. The reaction mixture was diluted with ethyl acetate and water and then filtered through a small pad of Celite. The filtrate was washed with aqueous HC1 (1.0 N, 5 mL) and brine (5 mL, twice) . The organic phase was dried (Na₂S0₄) and concentrated in vacuo. The yield was determined by ¹H NMR analysis of crude product using CH₂Br₂ as the internal standard. II. General procedure for Pd (II) -catalyzed

oartho-hydroxylation with 1 atm O₂ :

A 50 mL Schlenk-type tube (with a Teflon high pressure valve and side arm) equipped with a magnetic stir bar was charged with Pd(OAc)₂ (11.2 mg, 0.05 mmol) followed by benzoic acid (0.5 mmol) , benzoquinone (54.0 mg, 0.5 mmol), KOAc (98.0 mg, 1 mmol) and N, N-dimethylacetamide (1.5 mL) . The reaction tube was evacuated and back-filled with 0₂ (3 times, balloon) . After the reaction mixture was stirred at 115 °C for 15 hours, it was permitted to cool to ambient temperature. The reaction mixture was diluted with ethyl acetate and water and then filtered through a small pad of Celite. The filtrate was washed with aqueous HC1 (1.0 N, 5 mL) and brine (5 mL, twice) . The organic phase was dried (Na₂S0₄) and concentrated in vacuo. The residue was purified by silica gel flash column chromatography to give the corresponding product. The results are shown in Tables 1 and 2, above.

III. General procedure for Pd (II) -catalyzed

orfcho-hydroxylation with 5 atm 0₂ :

A 50 mL high pressure reactor equipped with a magnetic stir bar was charged with Pd(OAc)₂ (11.2 mg, 0.05 mmol), followed by the benzoic acid

substrate (0.5 mmol), benzoquinone (54.0 mg, 0.5 mmol), KOAc (98.0 mg, 1 mmol) and

N, N-dimethylacetamide (1.5 mL) . The reactor was filled with 0₂ (20 atm) , and then evacuated and backed-filled with 0₂ (5 atm, 2 times) . After the reaction mixture was stirred at 115 °C for 15 hours, it was permitted to cool to ambient temperature. The reaction was worked up and the crude product was purified following the procedure described above for hydroxylation with 1 atm O2.

IV. Preliminary mechanistic studies:

general procedure for the hydroxylation

reaction in 1 atm Argon or ¹⁸0:

,C0₂H argon

No

Reaction (1)

97.0% 3.0%

A 50 mL Schlenk-type tube (with a Teflon high pressure valve and side arm) equipped with a magnetic stir bar was charged with Pd(OAc)₂ (11.2 mg, 0.05 mmol) followed by the benzoic acid substrate (0.5 mmol), benzoquinone (54.0 mg, 0.5 mmol), KOAc (98.0 mg, 1 mmol) and N, N-dimethylacetamide (1.5 mL) . After the reaction mixture was cooled to -78 °C, the reaction tube was evacuated and back-filled with ¹⁸0₂ or argon (3 times, balloon) . The reaction mixture was stirred at 115 °C for 15 hours, and then it was permitted to cool to ambient temperature. The reaction was worked up and the crude product was purified following the procedure described above for hydroxylation with 1 atm O2.

Table 3

Influence of benzoquinone (BQ) on hydroxylation

2 hours 15 hours

Entry BQ (equiv)

%Yield^a % SM^a %Yield^a % SM^a

1 0 3 90 20 50

2 1 45 50 82 12

a The yields were determined by ^XH N R analysis of crude products using CH₂Br₂ as the internal standard. SM = starting material.

V. Characterization of the synthesized compounds

2-Hydroxy-5-methylbenzoic acid 1

^XH NMR (400 MHz, CD₃COCD₃) : δ 7.70 (s, 1 H) , 7.35 (d, J = 8.4 Hz, 1 H) , 6.85 (d, J = 8.4 Hz, 1 H) , 2.29 (s, 3 H); ¹³C NMR (100 MHz, CD₃COCD₃) : δ 171.48, 159.73, 136.36, 129.66, 127.78, 116.66, 111.52, 19.06. HRMS (ESI-TOF) m/z: calcd for C₈H₉0₃ ⁺ 153.0546 (M+H)⁺, found 153.0543.

2-Hydroxy-4-methylbenzoic acid 2

½ NMR (400 MHz, CD₃COCD₃) : δ 7.77 (d, J= 8.0 Hz, 1 H) , 6.78 (s, 1 H) , 6.77 (d, J= 8.0 Hz, 1 H) , 2.34 (s, 3 H) ¹³C NMR (100 MHz, CD₃COCD₃) : δ 171.47,

161.90, 146.87, 129.85, 119.94, 117.00, 109.32,

20.56. HRMS (ESI-TOF) m/z: calcd for C₈H₉0₃ ⁺ 153.0546 (M+H)⁺, found 153.0546.

2-Hydroxybenzoic aci 3

¾ NMR (400 MHz, CD₃COCD₃) : δ 7.91 (d, J= 8.0 Hz, H), 7.54 (t, J= 8.0 Hz, 1 H) , 6.97-6.93 (m, 2 H) ; NMR (100 MHz, CD₃COCD₃) : δ 171.44, 161.78, 135.51, 129.99, 118.70, 116.81, 111.89. HRMS (ESI-TOF) m/ calcd for C₇H₇0₃ ⁺ 139.0390 (M+H)⁺, found 139.0389.

2-Hydroxy-4 , 5-dimethylbenzoic acid 4

¹H NMR (400 MHz, CD₃COCD₃) : δ 7.62 (s, 1H) , 7.76 (s, 1 H) , 2.26 (s, 3 H) , 2.20 (s, 3 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 171.41, 160.06, 145.58, 129.91, 126.91, 117.46, 109.23, 19.05, 17.46. HRMS (ESI-TOF) m/z: calcd for 0₉Η_η0₃ ⁺ 167.0703 (M+H)⁺, found 167.0703.

3-Hydroxy-2-naphthoi acid 5

^XH NMR (400 MHz, CD₃COCD₃) : δ 8.63 (s, 1 H) , 7.96 (d, J= 8.0 Hz, 1 H) , 7.78 (d, J = 8.4 Hz, 1 H) , 7.55

(dd, J= 7.2 Hz, J= 8.4 Hz, 1 H) , 7.37 (dd, J= 7.2 Hz, J= 8.0 Hz, 1 H) , 7.33 (s, 1 H) , ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 171.08, 156.43, 137.61, 132.41, 128.82, 128.71, 126.62, 125.64, 123.41, 113.78,

110.64. HRMS (ESI-TOF) m/z: calcd for C_nH₇0₃ ^~ 187.0401

(M-H)^~, found 187.0394.

Naphthalen-2-ol 6

¹ti NMR (400 MHz, CDCI₃) : δ 7.77-7.73 (m, 2 H) , 7.67 (d, J= 8.4 Hz, 1 H) , 7.42 (t, J= 7.6 Hz, 1 H) , 7.32 (t, J= 7.6 Hz, 1 H), 7.15 (s, 1 H) , 7.11 (d, J= 8.8 Hz, 1 H) ; ¹³C NMR (100 MHz, CDCI₃) : δ 153.37, 134.56, 129.79, 128.85, 127.73, 126.47, 126.32, 123.54,

117.74, 109.43. HRMS (ESI-TOF) m/z: calcd for Ci₀H₉O⁺ 147.0699 (M+H)⁺, found 147.0693.

2-Hydroxy-5-methoxyb 7

¾ NMR (400 MHz, CD₃COCD₃) : δ 7.37 (s, 1 H) , 7.16 (d, J= 8.8 Hz, 1 H), 6.90 (d, J= 8.8 Hz, 1 H) , 3.79 (s, 3 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 171.20, 156.08, 151.73, 123.44, 117.81, 111.99, 111.54, 54.80. HRMS (ESI-TOF) m/z: calcd for C₈H₉0₄ ⁺ 169.0495 (M+H)⁺, found 169.0497.

¾ NMR (400 MHz, CD₃COCD₃) : δ 11.33 (s, 1H) , 7.80 (d, J = 8.8 Hz, 1 H) , 6.51 (d, J = 8.8 Hz, 1 H) , 6.47 (s, 1 H) , 3.86 (s, 3 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 171.31, 165.65, 164.11, 131.37, 106.81, 104.75,

100.22, 54.78. HRMS (ESI-TOF) m/z: calcd for C₈H₉0₄ ⁺ 169.0495 (M+H)⁺, found 169.0500.

4-Acetamido-2-hydroxybenzoic acid 9

½ NMR (400 MHz, CD₃COCD₃) : δ 11.20 (s, 1H) , 9.46 (s, 1 H) , 7.80 (d, J = 8.8 Hz, 1 H) , 7.49 (s, 1 H) , 7.10 (d, J = 8.8 Hz, 1 H) , 2.12 (s, 3 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 170.92, 168.33, 162.71, 145.61, 130.52, 109.49, 106.53, 105.52, 23.08. HRMS (ESI-TOF) m/z: calcd for C₉H₁₀NO₄ ⁺ 196.0604 (M+H)⁺, found 196.0599.

4-Fluoro-2-hydroxy-5 ic acid 10

¹H NMR (400 MHz, CD₃COCD₃) : δ 7.78 (d, J = 8.8 Hz, 1 H) , 6.65 (d, J = 11.2 Hz, 1 H) , 2.20 (s, 3 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 170.62, 164.86 (d, J_C-_F = 250.8 Hz), 161.63 (d, J_C-_F = 4.0 Hz), 132.46 (d, J_C-_F = 8.2 Hz), 115.36 (d, J_C-_F = 18.5 Hz), 108.20 (d, J_C-_F = 2.0 Hz), 102.77 (d, J_C-_F = 25.3 Hz), 12.11. HRMS (ESI-TOF) m/z: calcd for C₈H₆F0₃ ^~ 169.0306 (M-H)^~, found

169.0307. 5-Chloro-2-hydroxybenzoic acid 11

^XH NMR (400 MHz, CD₃COCD₃) : δ 7.84 (s, 1 H) , 7.52 (d, J = 8.4 Hz, 1 H) , 6.99 (d, J = 8.4 Hz, 1 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 169.93, 159.95, 134.75, 128.58, 122.39, 118.36, 112.75. HRMS (ESI-TOF) m/z: calcd for C₇H₄C10₃ ^" 170.9854 (M-H)^~, found 170.9859.

4-Chloro-2-hydroxybe 2

½ NMR (400 MHz, CD₃COCD₃) : δ 7.90 (d, J = 8.4 Hz, 1 H) , 7.02 (s, 1 H) , 6.98 (d, J = 8.4 Hz, 1 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 170.72, 162.21, 140.25, 131.31, 119.08, 116.59, 110.85. HRMS (ESI-TOF) m/z: calcd for C₇H₄CIO₃- 170.9854 (M-H) ^", found 170.9847.

4-Fluoro-2-hydroxybe 3

¹E NMR (400 MHz, CD₃COCD₃) : δ 7.97 (t, J = 7.2 Hz, 1 H) , 6.76-2.71 (m, 2 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 170.60, 166.49 (d, J-_F = 251.0 Hz), 163.58 (d, J_C-F = 14.2 Hz), 132.24 (d, J_C-_F = 11.4 Hz), 108.71 (d, J_C-F = 1.3 Hz), 106.27 (d, J_C-_F = 22.7 Hz), 103.08 (d, J_C-_F = 24.4 Hz). HRMS (ESI-TOF) m/z calcd for C₇H₄F0₃ ^~

155.0150 (M-H)^", found 155.0156. 2-Hydroxy-5- (trifluo nzoic acid 14

¹H NMR (400 MHz, CD₃COCD₃) : δ 8.19 (s, 1 H) , 7.84 (d, J = 8.8 Hz, 1 H) , 7.16 (d, J = 8.8 Hz, 1 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 169.94, 163.77, 131.35 (q, J_c-_F = 3.4 Hz), 126.91 (q, J_c-_F = 4.1 Hz), 123.28 (q, J_c-_F = 269.1 Hz), 119.96 (q, J_C__F = 33.0 Hz), 117.56, 111.65. HRMS (ESI-TOF) m/z: calcd for C₈H₄F₃0₃ ^~ 205.0118 (M-H)^~ , found 205.0117.

2-Hydroxy-4- (trifluo oic acid 15

^XH NMR (400 MHz, CD₃COCD₃) : δ 8.12 (d, J= 8.8 Hz, H) , 7.29-7.27 (m, 3H) ; ¹³C NMR (100 MHz, CD₃COCD₃)

171.06, 162.22, 136.40 (q, J_c-_F = 32.2 Hz), 131.89 123.66 (q, Jc-_F = 270.8 Hz), 115.78, 115.52 (q, J_c 3.7 Hz), 114.46 (q, J^" _C-_F = 4.0 Hz). HRMS (ESI-TOF) m/z: calcd for C₈H₄F₃(f 205.0118 (M-H)^", found

205.0126.

5-Acetyl-2-hydroxybe 16

^XH NMR (400 MHz, CD₃COCD₃) : δ 8.54 (s, 1 H) , 7.16 (d, J= 8.8 Hz, 1 H) , 7.06 (d, J= 8.8 Hz, 1 H) , 2.58 (s, 3 H) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 194.48, 171.02, 165.06, 135.04, 131.02, 128.63, 117.03, 111.62, HRMS (ESI-TOF) m/z: calcd for C₉H₉0⁺ 181.0495 found 181.0498.

4-Acetyl-2-hydroxybe 7

^XH NMR (400 MHz, CD₃COCD₃) : δ 8.01 (d, J= 8.0 Hz, 1 H ) , 7.50 (d, J = 8.0 Hz, 1 H) , 7.49 (s, 1 H) , 2.62 (s, 3 H ) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 196.26,

170.78, 161.47, 142.48, 130.32, 117.66, 116.38,

115.21, 25.68. HRMS (ESI-TOF) m/z: calcd for C₉H₈0₄Na⁺ 203.0315 (M+Na)\ found 203.0325.

4-Benzoyl-2-hydroxybenzoic acid 18

¾ NMR (400 MHz, CD₃COCD₃) : δ 8.08 (d, J= 8.0 Hz, 1 H) , 7.83 (d, J= 7.6 Hz, 2 H) , 7.69 (t, J= 7.6 Hz, 1 H) , 7.58 (t, J = 7.6 Hz, 1 H), 7.28-7.25 (m, 2 H ) ; ¹³C NMR (100 MHz, CD₃COCD₃) : δ 194.45, 171.05, 161.15, 143.58, 136.39, 132.53, 130.33, 129.36, 128.08,

119.12, 117.52, 115.14. HRMS (ESI-TOF) m/z: calcd for C₁₄Hn0⁺ 243.0652 (M+H)⁺, found 243.0654.

4-Cyano-2-hydroxyben

^XH NMR (400 MHz, CD₃SOCD₃ ) : δ 7.86 (br, 1 H) , 7.34 (s, 1H), 7.24 (br, 1 H) ; ¹³C NMR (100 MHz, CD₃SOCD₃ ) : δ 161.63, 132.23, 122.63, 121.46, 118.78, 116.99. HRMS (ESI-TOF) m/z: calcd for C₈H₄N0₃ ^~ 162.0197 ( M-H ) ^" , found 162.0199. 2-Hydroxy-4-nitroben

^XH NMR (400 MHz, CD₃COCD₃) : δ 8.15 (d, J = 8.4 Hz, 1 H) , 7.76 (d, J = 8.4 Hz , 1 H) , 7.72 (s, 1 H) ; ¹³C NMR (100 MHz , CD₃COCD₃) : δ 169.85, 161.62, 151.58, 131.39, 116.86, 112.76, 111.49. HRMS (ESI-TOF) m/z: calcd for C₇H₄N0₅ ^~ 182.0095 ( M-H ) ^~ , found 182.0087.

Each of the patents, patent applications and articles cited herein is incorporated by

reference. The use of the article "a" or "an" is intended to include one or more.

The foregoing description and the examples are intended as illustrative and are not to be taken as limiting. Still other variations within the spirit and scope of this invention are possible and will readily present themselves to those skilled in the art.

Claims

CLAIMS :

1. A method of preparing a hydroxylated aromatic compound that comprises the steps of:

a) contacting an aromatic carboxylic acid compound of Formula I having a hydrogen at a position ortho to the carboxyl group that is dissolved in a

solvent of a tertiary amide of a C_-Cg carboxylic acid with oxygen in the presence of a Pd(II) catalyst and an excess of an alkali metal weak acid salt at a temperature of about 80° to about 140° C to form a reaction mixture,

wherein

A together with the bonded and depicted vinylene group forms an aromatic ring system

containing 1, 2, or 3 rings that each has 5- or 6- members ;

Q is CR R⁵, where each of R⁴ and R⁵ is independently hydrido, straight chain C]_-Cg- hydrocarbyl, branched chain C]_-Cg-hydrocarbyl or cyclic Cij-Cg-hydrocarbyl, or R⁴ and R^ together with the carbon atom of the CR R^ group form a cyclic compound having a total of 5-7 carbon atoms;

n is one or zero;

R1, R2 and R^ are independently the same or different and are selected from the group consisting of hydrido, C_]_-Cg hydrocarbyl, Ci-C hydrocarbyloxy, halogen, cyano, nitro, trifluoromethyl, Ο -Cg acyl, benzoyl and C^-CQ acylamido groups; and

b) maintaining said reaction mixture at said temperature for a time period sufficient to prepare a hydroxylated aromatic compound product.

2. The method according to claim 1, wherein A together with the bonded and depicted vinylene group forms a aromatic ring system selected from the group consisting of phenyl, naphthyl, anthracenyl, and phenanthryl compounds, pyridyl, pyrimidyl, pyrazinyl, furanyl, benzofuranyl ,

isobenzofuranyl, benzoxazolyl, benzopyrazinyl , benzotriazinyl, quinolyl and isoquinolyl.

3. The method according to claim 2, wherein A together with the bonded and depicted vinylene group forms a hydrocarbyl aromatic ring system.

4. The method according to claim 1, wherein A together with the bonded and depicted vinylene group forms a single 6-membered ring system.

5. The method according to claim 1, wherein n is one.

6. The method according to claim 5, wherein each of R⁴ and is hydrido.

7. The method according to claim 1, wherein at least one of R1, R² and R³ is other than hydrido .

8. The method according to claim 1

including the further step of recovering said

hydroxylated aromatic compound product.

9. The method according to claim 1, wherein said carboxyl group is bonded directly to the aromatic ring.

10. The method according to claim 9, wherein said aromatic carboxylic acid compound contains up to three substituents in addition to said carboxyl group.

11. The method according to claim 9, wherein said tertiary amide of a C^-Cg carboxylic acid solvent is N, N-dimethylformamide,

N, N-dimethylacetamide or N, -dimethylpropionamide ,

12. The method according to claim 9, wherein said oxygen is present in air.

13. The method according to claim 9, wherein said oxygen is present as pure oxygen.

14. The method according to claim 9, wherein said Pd(II) catalyst is Pd(II) acetate.

15. The method according to claim 9, wherein said alkali metal weak acid salt is a potassium salt.

16. The method according to claim 9,.

wherein said reaction mixture further includes about

0.2 to about 1 equivalent of benzoquinone per equivalent of aromatic carboxylic acid compound.

17. The method according to claim 9 including the further step of recovering said hydroxylated aromatic compound product.

18. The method according to claim 9, wherein the temperature of said reaction mixture about 100° to about 120° C.