Process for the synthesis of phenols from arenes

Details Process for the synthesis of phenols from arenes Process for the synthesis of phenols from arenes

2003-07-15

2004-12-07

Shippen, Michael L. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C546S303000, C560S065000, C560S067000, C564S442000, C568S650000, C568S651000, C568S765000, C568S774000, C568S775000, C568S800000

Reexamination Certificate

active

06828466

ABSTRACT:

REFERENCE TO A “COMPUTER LISTING APPENDIX SUBMITTED ON A COMPACT DISC”
Not Applicable.
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a process for synthesizing various substituted phenols such as those of the general formula RR′R″Ar(OH) wherein R, R′, and R″ are each independently hydrogen or any group which does not interfere in the process for synthesizing the substituted phenol including, but not limited to, halo, alkyl, alkoxy, carboxylic ester, amine, amide; and Ar is any variety of aryl or hetroaryl by oxidation of substituted arylboronic esters. In particular, the present invention relates to a metal-catalyzed C—H activation/borylation reaction, which when followed by direct oxidation in the same or separate reaction vessel affords phenols without the need for any intermediate manipulations. More particularly, the present invention relates to the Ir-catalyzed borylation of arenes using pinacolborane (HBPin) followed by oxidation of the intermediate arylboronic ester by OXONE to produce the substituted phenols.
(2) Description of Related Art
Phenols serve as synthetic building blocks for construction of compounds ranging from polymers to pharmaceuticals (Tyman, Synthetic and Natural Phenols; Elsevier: New York, (1996). Despite numerous phenol syntheses (Hanson et al., J. Chem. Soc., Perkin Trans 2: 1135-1150 (2002); George et al., J. Chem. Soc., Perkin Trans 1: 2529-2574 (2000); Sweeney, Contemp. Org. Synth. 4: 435-453 (1997);For more recent innovative approaches see: Hoarau and Pettus, Synlett 127-137 (2003); Guo et al., Org. Lett. 3: 1177-1180 (2001); Marchueta et al., Org. Lett. 3: 3197-3200 (2001); Serra et al., J. Org. Chem. 66: 7883-7888 (2001); Hashmi et al., J. Am. Chem. Soc. 122: 11553-11554 (2000); Gevorgyan and Yamamoto, J. Organomet. Chem. 576: 232-247 (1999)), straightforward routes to 3,5-disubstituted phenols bearing ortho/para-directing groups are lacking (For an alternative approach, see Keil et al., Ger. Offen. DE2344925 (1975)).
Traditional approaches to such phenols are obstructed by the fact that electronic effects typically govern regioselectivities in aromatic substitution chemistry. Thus, the 5-position in 1,3-disubstituted benzenes is notoriously inert when the substituents are ortho/para directors. Illustrative of this problem is 3-bromo-5-chlorophenol (1). To the best of our knowledge, the only two descriptions of this potentially useful (Höger et al., J. Am. Chem. Soc. 123: 5651-5659 (2001)) and versatile molecule dates back to 1926 (Hodgson and Wignall, J. Chem. Soc. 2077-2079 (1926); Kohn and Zandman, Monatsh. Chem. 47: 357-377 (1926)), including a synthesis by Hodgson and Wignall that requires ten steps starting from TNT!
Other methods for the synthesis of phenols, include electrophilic hydroxylation of aromatics, oxidation of aryl organometallic compounds, hydrolysis of aryl halides, hydrolysis of diazonium salts, and reduction of quinones. Of these, the hydrolysis of diazonium salts by aqueous acids or in the presence of cuprous oxide (see, for example: Cohen et al., J. Org. Chem. 42: 2053 (1977)) is an often used method and serves as a representative example of a previous approach.
While the hydrolysis of the diazonium salt can be high yielding, the salts themselves are often explosive and can be hard to manipulate. Furthermore, producing the above salts involves multiple steps. The diazonium salts are synthesized from the corresponding anilines by reaction with nitrous acid (HONO), which is generated in situ from a nitrate salt. The aniline is derived from the nitro compound via a reduction. The nitroaromatic is synthesized from the arene by electrophilic aromatic nitration, which is traditionally performed in nitric and sulfuric acids. Electrophilic nitration, like all electrophilic aromatic substitution reactions, is governed by electronics. Thus, certain functional groups (hydroxy, amino, alkoxy, alkyl, and halo) are ortho-/para-directing, while other functional groups (nitro, carboxy, and nitrilo) are meta-directing. Those experienced in the art will recognize the limitations of this approach in terms of product mixtures and the inability to access certain substitution patterns.
Another method for phenol synthesis involves the oxidation of an arylboronic acid or ester by means of hydrogen peroxide or OXONE. These methods require the pure boronic acid or ester as a starting material, which, in turn, are “traditionally” synthesized by a multi-step approach from an aryl halide. Again, those experienced in the art will recognize the limitations of this approach as it relies on electrophilic aromatic substitution to access the aryl halide.
A demonstrative example with 3-chloro-5-methylphenol will illustrate the inherent difficulties of the “traditional” approach and the benefit of this invention. As illustrated below, a “traditional” synthesis of 3-chloro-5-methylphenol might involve initial electrophilic chlorination of m-nitrotoluene to give a mixture of the desired 3-chloro-5-nitrotoluene and other isomers. Separation of the desired material from the other isomers by methods known to those experienced in the art would be followed by a reduction to give 3-chloro-5-methylaniline, which would then be converted into the diazonium salt and subsequently hydrolyzed to give 3-chloro-5-methylphenol.
Alternative approaches involving electrophilic chlorination of 3-methylphenol or Friedel-Crafts alkylation of 3-chlorophenol, as illustrated below, would not give the desired phenol. Electrophilic aromatic substitution reactions on various arenes is shown below.
As can be seen, there remains a need for a process for synthesizing substituted phenols that is safer and less laborious than the prior art methods.
SUMMARY OF THE INVENTION
The present invention provides a process for producing a substituted phenol which comprises (a) reacting an arene with a borane selected from the group consisting of a borane with a B—H, B—B, and B—Si bond in the presence of a catalytically effective amount of an iridium or rhodium complex with three or more substituents, and with or without an organic ligand selected from the group consisting of phosphorus, carbon, nitrogen, oxygen, and sulfur organic ligands to produce an arylboronic ester; and (b) oxidizing the arylboronic ester with a hydrogenating oxidizing compound to produce the substituted phenol.
The present invention further provides a process for producing a substituted phenol which comprises (a) reacting in a reaction vessel an arene with a borane selected from the group consisting of a borane with a B—H, B—B, and B—Si bond in the presence of a catalytically effective amount of an iridium or rhodium complex with three or more substituents, and an organic ligand selected from the group consisting of phosphorus, carbon, nitrogen, oxygen, and sulfur organic ligands to produce an arylboronic ester; and (b) oxidizing the arylboronic ester formed in the reaction vessel with a hydrogenating oxidizing compound to produce the substituted phenol.
In a further embodiment of the above processes, the oxidizing compound is a peroxy compound selected from the group consisting of peroxymonosulfuric acid and salts thereof.
In a further embodiment, the oxidizing compound is taken from the group consisting of organic peroxides and salts thereof.
In a further embodiment of the above processes, the oxidizing agent is hydrogen peroxide.
In a further embodiment of the above processes, the oxidizing compound is an alkali metal peroxymonosulfate, preferably potassium peroxymonosulfate, most preferably 2KHSO
5
.KHSO
4
.K
2
SO
4
.
In a further embodiment of the above processes, the iridium complex is selected from the group consisting of (Cp*)Ir(H)
2
(Me
3
P), (Cp*)Ir(H) (BPin) (Me
3
P), (Cp*)Ir(H) (C
6
H
5
) (Me
3
P), (Ind)Ir(COD), (Ind)Ir(dppe), (MesH)Ir(BPin) (B(OR)
2
)
2
, ((R
1
)
3
P)
3
Ir(B(OR
2
)
2
)
3
, (R
1
)
2
P)
2
Ir(BPin)
3
, (((R
1
)
2
P)
3
Ir((R
2
O)
2
B)
3
)
2
, ((R
1
)
3
P)
4
Ir(BPin), ((R
1
)
3
P)
2
Ir(BPin)
3
, (MesH)Ir(BPin)
3
, and (IrCl(COD)

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