Palladium-catalysed synthesis of aryl ethers

ES 2 200 162 T3

DESCRIPTION

Synthesis of Aryl Ethers, Methods and Related Reagents.

The present invention relates to improved methods for preparing aryl ethers, which are useful intermediates and end products in pharmaceutical and agricultural applications.

Recently, aryl bromides have been reported to react with primary and secondary simple amines in the presence of a palladium catalyst, supporting ligands and Na (OtBu) (base) to form the corresponding arylamine in good yields. See, Guram et al. Angew. Chem. 34 (12): 1348 (1995).

Despite recent success with palladium-catalyzed cross-coupling reactions of Ar-X with amines, it is still difficult to achieve comparable coupling of aryl halides with alcohols, and this, despite their obvious utility in organic synthesis. . Aryl ethers, which include oxygen heterocycles, feature in a large number of pharmaceutically important molecules and are found in numerous secondary metabolites.

Existing methods for the conversion of Ar-X to aryl ethers often require harsh or restricted reaction conditions and / or the presence of activating groups on the arene ring. For example, Cu (I) catalyzed syntheses of aryl and vinyl ethers commonly require large amounts of freshly prepared sodium alkoxides and / or greater excess of the corresponding alcohol in order to achieve reasonable yields from the corresponding aryl halides and vinyl halides. See, Keegstra et al. Tetrahedron 48 (17): 3633 (1992).

Cramer and Coulson also reported limited success with Ni (II) catalyzed synthesis of diphenyl ether using sodium phenolate at reaction temperatures greater than 200 ° C. See, J. Org. Chem. 40 (16): 2267 (1975). Christau and Desmurs describe the nickel-catalyzed reactions of alcohols with aryl bromides in the presence of a base. Good yields (around 80%) were reported only for reactions with primary alcohols with 7% by mole of nickel catalyst at 125 ° C. See, Ind. Chem Lib. 7: 240 (1995). Christau and Desmurs also reported that the synthesis of aryl ethers was only possible for primary and secondary alcohols. Houghton and Voyle reported the Rh (III) catalyzed cyclization of 3- (2-fluorophenyl) propanols to activated chromans via n-bonding to the metal center; however, the reaction required a very high loading of rhodium catalyst (17 mol%). See, J. Chem. Soc. Perkin Trans. l, 925 (1984).

Ether formation has been reported as a minor by-product in palladium-catalyzed carbonylation reactions of highly activated aromatic compounds such as substituted α-quinolines. Due to the highly reactive nature of the α site, it is possible for the reaction to proceed by direct nucleophilic substitution, without promotion or catalysis by the palladium metal center. See, Cacchi et al. Tetrahedron Lett. 27 (33): 3931 (1986).

Bates et al. J Org. Chem. 1982,47,4374-6, refers to a high yield benzine synthesis of diaryl ethers in the absence of a catalyst agent and suggests that the reaction will not be possible in an aromatic solvent.

Therefore, the need for an effective method to prepare a wide range of aryl ethers under moderate conditions and in high yields still remains. There is also a need for an efficient catalyst system with high efficiencies and quantity capacity for the synthesis of aryl ethers. Furthermore, the need for an effective method for the arylation of tertiary alkoxides still remains.

Compendium of the invention

The present invention provides general and attractive pathways to a wide range of aryl ethers. The methods facilitate several improvements over hitherto known methods, namely the efficient synthesis of aryl ethers under moderate conditions and in high yields, especially, the method of the present invention can be used to couple reactions using tertiary alcohols. In other aspects of the invention, the present invention provides a class of transition metal complexes that are useful in the catalytic reactions of the invention, which up to now have not been known to be useful for the preparation of aryl ethers.

Brief description of the invention

Figure 1. Scheme illustrating the possible reaction steps in the synthesis of aryl ethers according to the method of the invention.

Figure 2. Representative first-order graphs of the disappearance of 4 in THF-d₈ at 23 (v), 37 (Δ), 47 (O), and 55 ° C (x), where [KOCH₂CMe₃]² 0.002 M. The error bars correspond to ± 5% integration error in the NMR spectrum ¹Corresponding H.

Figure 3. Second-order graph of the disappearance of 4 in THF-d₈ at 47 ° C.

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Figure 4. Eyring plot of thermolysis of 4 in THF-d₈ in a temperature range of 23-57 ° C.

Figure 5. Dependence of potassium neopentoxide concentration on the reductive elimination rate of 4 in THF-d8 at 47 ° C.

Figure 6. Dependence of potassium neopentoxide concentration on the exchange rate of alkozide 4 in THF-d₈ at 47 ° C.

Detailed description of the invention

General information

According to a first aspect of the present invention there is provided a method for preparing an aryl ether, comprising: reacting an alcohol with an aromatic compound comprising an activated substituent, X, in an aromatic hydrocarbon solvent, in the presence of a base and a catalyst selected from the group consisting of nickel, palladium, and platinum complexes; where X is a moiety whose conjugated acid, HX, has a pKa of less than 5.0.

According to a second aspect of the present invention there is provided a method for preparing an aryl ether, comprising: reacting an alkoxide salt with an aromatic compound comprising an activated substituent, X, in an aromatic hydrocarbon solvent, in the presence of a catalyst selected from the group consisting of nickel, palladium, and platinum complexes; where X is a moiety whose conjugated acid, HX, has a pKa of less than 5.0.

In preferred embodiments, the synthetic reaction subject of the present invention may be characterized by the general reaction schemes (Scheme 1a):

catalytic etherification

R-YH + ArX base metal catalyst Scheme la:

> Ar-YR 3 where: Ar represents an aryl group (whose substitution can be promoted beyond X): X represents a leaving group (such as a halide or a sulfonate), which can be displaced by oxygen from nucleophilic alcohol, such as in a metal dependent etherification reaction; Y represents O; R represents, as valence and stability permit, a substituted or unsubstituted alkyl or alkenyl group, or - (CH2) m-R8 where R8 represents a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocyclic or polycyclic , and m is zero or an integer in the range 1 to 8.

According to Scheme 1a, an alcohol 2 (eg, Y = 0) is reacted with an aromatic compound 1 having an activated substituent, X, to form an aryl ether 3. The reaction is carried out in the presence of at least a catalytic amount of a transition metal catalyst agent, which promotes the cross-coupling of the alcohol and the activated aryl nucleus to form the ether product, 3. The reaction generally proceeds in the presence of a transition metal complex (with or without a supporting ligand) and a suitable base.

The reaction can be either an intermolecular or an intramolecular reaction. In the case of the latter, it will be noted that, with reference to scheme 1a, RYH is a substituent for Ar, and the reaction scheme can be represented by the following formula:

catalytic esterification

<img file="ES2200162T3_D0001.tif" />

Ar — R + HY-R-ArX base metal catalyst in which R-YH represents a substituent of Ar, eg, an alkyl or alkenyl group substituted by a hydroxyl, which provides Y from 2 to 10 bond lengths away from the substituted position on Ar, more preferably 2 to 5

ES 2 200 162 T3 joining lengths. Consequently, in intramolecular etherification. Y is attached to R and the site replaced by X in Ar. Preferably Y, R and the bridging portion of Ar form a fused ring with Ar having 4 to 8 ring atoms, more preferably 5, 6 or 7 atoms. Reframing slightly, the intermolecular and intramolecular reaction comprising an aryl substrate can be represented in the following two schemes:

<img file="ES2200162T3_D0002.tif" />

Although not intended to be limited by any particular theory, the reaction most likely continues with the oxidative addition of the aromatic compound 2 to a zero valence catalyst metal center, the substitution of X for alcohol 1 at the metal center, followed of reductive elimination to generate the aryl ether 3. The base presumably promotes the formation of a metal-oxygen bond, in which the metal is the metal center of the catalyst, presumably facilitating the abstraction of the hydrogen proton from the alcohol.

Although not limited by any particular mode of operation, it is hypothesized that the preferred Pd-catalyzed synthesis mechanism of aryl ethers can continue along the same pathway as that described in Figure 1. Figure 1 presents a pathway proposed reaction for the synthesis of an aryl ether by an intermolecular reaction. Any ligand that may be present on the palladium atom during this procedure has been omitted for the sake of clarity. According to the figure, the oxidative addition of the Pd (0) complex to the aryl halide produces the organo-metal complex Pd (II) intermediate A. In the presence of a suitable base, the reaction of the alcohol moiety (or alkoxide) with A could, after de-protonization, generate B, producing intermediate C, which would then undergo reductive elimination to produce the aryl ether product. and regenerating the active catalyst agent. The reaction sequence is likely to be similar for intramolecular reactions. Alternatively, and especially for nickel catalysts, the transition metal species active in the oxidative addition step may comprise the metal in the +1 oxidation state.

In preferred embodiments of the present invention, there is no need to use large amounts of any of the reactants be it alcohol or aromatic compound. The reaction proceeds rapidly and in high yield of aryl ether product using substantially stoichiometric amounts of reactants. Therefore, the alcohol can be present in amounts as small as twice and preferably in no greater than 20% excess relative to the aromatic compound. Alternatively, the aromatic compound may be present in amounts as little as twice and preferably in no greater than 20% excess relative to the alcohol.

The reaction can continue at moderate temperatures and pressures to give high yields of the aryl ether product. Therefore, yields greater than 45%, preferably greater than 75% and even more preferably greater than 80% can be obtained by the reaction at moderate temperatures according to the present invention. The reaction can be carried out at a temperature lower than 120 ° C, and preferably in the range of 50-120 ° C. In a preferred embodiment, the reaction is carried out at a temperature in the range of 80-100 ° C.

The reaction is carried out in an aromatic hydrocarbon solvent.

The ability to provide an ether synthesis scheme that can be carried out under mild conditions and / or with non-polar solvents has wide application, especially in the pharmaceutical and agricultural industries, as well as in the polymer industry. In this regard, the subject reaction of the present invention is more feasible to use reactants or products that include sensitive functionalities, eg, which might otherwise be labile under harsh reaction conditions.

The subject etherification reactions of the present invention can be used as part of a combinatorial synthesis scheme to produce aryl ethers. Similarly, another aspect of the present invention relates to the use of the subject method of the present invention to generate varied libraries of aryl ethers of the general formula Ar-OR, and with the libraries themselves. Libraries can be soluble or attached to insoluble supports, eg, either through substituents on the aryl group or through R.

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Definitions

For convenience, before delving into the description of the present invention, certain terms used in the specification, examples, and claims included last are grouped together.

The term "substrate aryl group" refers to an aryl group containing an electrophilic atom, which is susceptible to the subject cross-coupling reaction of the present invention, eg, the electrophilic atom carries a leaving group. In Reaction Scheme 1, the substrate aryl is represented by Ar-X, and X is the leaving group. The aryl group, Ar, is said to be substituted if, in addition to X, it is substituted in still other positions. The substrate aryl group can be a single ring molecule, or it can be a larger molecule substituent.

The term "reactive alcohol group" refers to an alcohol group that can attack the electrophilic atom of the substrate aryl group and displace the leaving group in the subject cross-coupling reaction of the present invention. In reaction schemes 1 a and 1 b, the nucleophilic aryl group is represented by ROH. The reactive alcohol group can be a component of a molecule other than the substrate aryl group, or a substituent on the same molecule (eg, for intramolecular condensation). A "reactive linden" and a "reactive selenol" have similar meanings.

The term "nucleophile" is recognized in the art, and as used herein means a chemical moiety that has a reactive electron pair.

The term "electrophilic" is recognized in the art and refers to chemical moieties that can accept an electron pair from a nucleophile as defined above. Electrophilic moieties useful in the method of the present invention include halides and sulfonates.

The terms "electrophilic atom", "electrophilic center" and "reactive center" as used herein refer to the atom of the substrate aryl moiety, which is attacked by, and forms a new bond with, the oxygen of the alcohol. . In most (but not all) cases, this will also refer to the atom of the aryl ring from which the leaving group originates.

The term "electron taking group" is recognized in the art, and denotes the tendency of a substituent to attract valent electrons from neighboring atoms, that is, the substituent has a negative electrical charge relative to neighboring atoms. The Hammett constant sigma (s) gives the quantification of the level of electron taking capacity.

This constant is well known and is described in many references, for example, J. March, Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1977) pp. 251-259. Hammett's constant values ​​are generally negative for electron donor groups (s [P] = -0.66 for NH₂) and positive for electron withdrawing groups (s [P] = 0.78 for nitro group), s [P] indicating para-substitution. As an example, electron withdrawing groups include nitro, ketone, aldehyde, sulfonyl, trifluoromethyl, -CN, chloride, and the like. As an example, electron donating groups include amino, methoxy, and the like.

The term "reaction product" means a compound that results from the reaction of an alcohol and the substrate aryl group. In general, the term "reaction product" will be used herein to refer to a stable isolatable aryl ether adduct, and not to unstable or transition intermediate states.

The term "catalytic amount" is recognized in the art and means a stoichiometric amount of the reactant relative to the reactant. As used herein, a catalytic amount means 0.0001 to 90 mole percent of reactive agent relative to a reactant, more preferably 0.001 to 50 mole percent, still more preferably 0.01 to 10 mole percent. percent, and even more preferably 0.1 to 5 mole percent reactant to reactant.

The term "alkyl" refers to the radical of saturated aliphatic groups, including straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or less carbon atoms on its backbone (eg, C1-C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or less . Likewise, preferred cycloalkyls have 3 to 10 carbon atoms in their ring structure, and more preferably have 5, 6, or 7 carbons in their ring structure.

Furthermore, the term "alkyl" (or "lower alkyl") as used throughout the present specification and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls"; the latter, referring to alkyl moieties that have substituents that replace a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an ester, a formyl, or a ketone), a thiocarbonyl (such as a thioester, atioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl , a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. Those skilled in the art will understand that substituted moieties in the hydrocarbon chain can be substituted, if appropriate. For example, the substituents of a substituted alkyl can include substituted and unsubstituted forms of amino, azido, imino, amido, groups.

ES 2 200 162 T3 phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl, and sulfonate), and silyl, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN and the like. As an example, substituted alkyls are described below. Cycloalkyls can still be substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl substituted alkyls, -CF3, -CN, and the like.

The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).

The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double or triple bond respectively.

Unless a different number of carbons is specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having one to ten carbons, more preferably one to six carbon atoms. carbon in its central axis structure. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is lower alkyl.

The term "aryl" as used herein includes 5-, 6-, and 7-membered single ring aromatic groups that can include zero to four heteroatoms, eg, benzene, pyrol, furan, thiophene, imidazole, oxazole, thiazole , triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like. Those aryl groups that have heteroatoms in the ring structure can also be referred to as "aryl heterocycles" or "heteroaromatic". The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido , phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems that have two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") in which at least one of the rings it is aromatic, eg, the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, and / or heterocyclyls.

The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, which ring structures include one or more heteroatoms. Heterocycles can also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indole. purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, fenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolan, thiolan, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted in one or more positions with such substituents as described above, as for example halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

The terms "polycyclyl" or "polycyclic group" refer to two or more rings (eg, cycloalkyls, cycloalkenyls, cycloalkyls, aryls, and / or heterocyclyls) in which two or more carbons are common to two or more adjoining rings, eg the rings are "cast rings". Rings that are linked through non-adjacent atoms are called "bridged" rings. Each of the rings of the polycycle can be substituted with such substituents as described above, such as, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate , carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

The term "carbocycle", as used herein, refers to an aromatic or non-aromatic ring in which each atom of the ring is a carbon.

The term "heteroatom" as used herein, means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur, and phosphorus.

As used herein, the term "nitro" means NO2; the term "halogen" designates -F, -Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO2-,

The terms "amine" and "amino" are recognized in the art and refer to both substituted and unsubstituted amines, eg, a moiety that can be represented by the general formula:

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<img file="ES2200162T3_D0003.tif" />

R'.o I +

N — Rio

<img file="ES2200162T3_D0004.tif" />

wherein R9, R10, and R'10 each independently represent hydrogen, alkyl, alkenyl, - (CH2) m -R8, or R9 and R10 taken together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure; R8 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range 1 to 8. In preferred embodiments, only one of R9 or R10 can be a carbonyl, eg, R9, R10 and the nitrogen together do not form an imide. In even more preferred embodiments, R9 and R10 (and optionally R'10) each independently represent hydrogen, alkyl, alkenyl, or - (CH2) m R8. Accordingly, the term "alkylamine" as used herein means an amine group, as defined above, that has a substituted or unsubstituted alkyl attached to it, that is, at least one of R9 and R10 is an alkyl group.

The term "acylamino" is recognized in the art and refers to a moiety that can be represented by the following general formula:

<img file="ES2200162T3_D0005.tif" />

wherein R9 is as defined above, and R'11 represents hydrogen, alkyl, alkenyl, or - (CH2) m -R8, wherein m and R8 are as defined above.

The term "amido" is recognized in the art as an amino substituted carbonyl and includes a moiety that may be represented by the following general formula:

<img file="ES2200162T3_D0006.tif" />

wherein R9, R10 are as defined above. Preferred embodiments of the amides will not include imides that can be unstable.

The term "alkylthio" refers to an alkyl group, as defined above, that has a sulfur radical attached to it. In preferred embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S- (CH2) m R8, where m and R8 are further defined above. Representative alkylthio groups include methylthio, ethylthio, and the like.

The term "carbonyl" is recognized in the art and includes moieties such as those that can be represented by the following general formula:

<img file="ES2200162T3_D0007.tif" />

where X is a bond or represents oxygen or sulfur, and R11 represents hydrogen, alkyl, alkenyl, - (CH2) m R8 or a pharmaceutically acceptable salt, R'11 represents hydrogen , an alkyl, an alkenyl or - (CH2) m -R8, where m and R8 are as defined above. If X is an oxygen and R11 or R'11 is not

ES 2 200 162 T3 a hydrogen, the formula represents an "ester". If X is oxygen, and R11 is as defined above, the remainder is referred to herein as a carbonyl group, and especially when R11 is hydrogen, the formula represents a "carboxylic acid". If X is oxygen and R'11 is hydrogen, the formula represents a "format". In general, if the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiolcarbonyl" group. If X is a sulfur and R11 or R'11 is not hydrogen, the formula represents a "thiol ester". If X is sulfur and R11 is hydrogen, the formula represents a "thiolcarboxylic acid." If X is sulfur and R'11 is hydrogen, the formula represents a "thiolformat." On the other hand, if X is a bond, and R11 is not a hydrogen, the above formula represents a "ketone" group. If X is a bond, and R11 is hydrogen, the above formula represents an "aldehyde" group.

The terms "alkoxy" or "alkoxy" as used herein refer to an alkyl group, as defined above, that has an oxygen radical attached to it. Representative alkoxy groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently linked by means of oxygen. Similarly, the substituent of an alkyl that converts said alkyl to an ether is or resembles an alkoxy, as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O - (CH2) m-R8, where m and R8 are described above.

The term "sulfonate" is recognized in the art and includes a moiety that may be represented by the following general formula:

OR

II —S — OR41

II

Or in which R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term "sulfate" is recognized in the art and includes a moiety that may be represented by the following general formula:

—O — S — OR41 in which R41 is as defined above.

The term "sulfonamido" is recognized in the art and includes a moiety that may be represented by the following general formula:

OR

II —N — S — R'11

I II

R9 Or where R9, and R'11 are as defined above.

The term "sulfamoyl" is recognized in the art and includes a moiety that may be represented by the following general formula:

<img file="ES2200162T3_D0008.tif" />

<img file="ES2200162T3_D0009.tif" />

wherein R9, and R10 are as defined above.

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The terms "sulfoxide" or "sulfinyl", as used herein, refer to a moiety that may be represented by the following general formula:

OR

II wherein R44 is selected from a group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

A "phosphoryl" can generally be represented by the following formula:

Q1

II —P— |

OR46 in which Q, represented S or O, and R46 represents hydrogen, a lower alkyl or an aryl. When used to substitute, eg, an alkyl, the phosphoryl group of the phosphorylalkyl can be represented by the following general formula:

Q1 Q1

II II —Q2 — P —O— or —Q2 — P —OR46 ² | ² | ⁴⁶^OR46 ^OR46 in which Q1 represents S or O, and each R46 independently represents hydrogen, a lower alkyl or an aryl, O2 represents O, S or N. When Q1 is an S, the phosphoryl moiety is a "phosphorothioate".

A "phosphoramidite" can be represented by the following general formula:

OO

II II —Q2 — P —O— or —Q2 — P —OR46 ||

N (R9) R10 N (R9) R10 in which R9 and R10 are as defined above, and O2 represents O, S or N.

A "phosphonamidite" can be represented by the following general formula:

^R48 ^R48 || —Q2 — P —O— or —Q2 — P —OR46 ||

N (R9) R10 N (R9) R10 in which R9 and R10 are as defined above, O2 represents S or N and R46 represents lower alkyl or aryl, O2 represents O, S or N.

A "selenoalkyl" refers to an alkyl group that has a substituted selene group attached to it. Examples of "selenoethers" that may be substituted on alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and -Se- (CH2) m -R7, m and R7 having been further defined. above.

Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, alkenyls or alkynyl substituted by carbonyls.

The phrase "protecting group" as used herein means substituents that protect the reactive functional group from unwanted chemical reactions. Examples of such protecting groups include carboxylic acid esters, ethers of alcohols and acetals, and ketals of aldehydes and ketones.

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It will be understood that "substitution" or "substituted with" includes the implicit condition that such substitution is in accordance with the allowable valence of the substituted atom and the substituent, and that the substitution results in a stable compound, eg, not undergoing spontaneously transformation such as by rearrangement, cyclization, elimination, etc.

As used herein, the term "substituted" is considered to include all permissible substituents of organic compounds. In a broader aspect, permissible substituents include non-cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for the corresponding organic compounds. For the purpose of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible organic compound substituents described herein that can satisfy the valences of the heteroatoms. The present invention is not intended to be limited in any way by the permissible substituents of organic compounds.

A "polar solvent" means a solvent having a di-polar moment (s) of 2.9 or greater, such as DMF, TMF, ethylene glycol dimethyl ether, DMSO, acetone, acetonitrile, methanol, ethanol, isopropanol , n-propanol, t-butanol or 2-methoxyethyl ether. Preferred solvents are DMF, diglyme, and acetonitrile.

A "polar, aprotic solvent" means a polar solvent as defined above, which does not have any hydrogen available to exchange with the compounds of the present invention during the reaction, for example, DMF, acetonitrile, diglyme, DMSO, or THF.

An "aprotic solvent" means a non-nucleophilic solvent having a boiling point range greater than room temperature, preferably from about 25 ° C to about 190 ° C, more preferably from about 80 ° C to about 160 ° C, as most preferred option from about 80 ° C to 150 ° C, at atmospheric pressure. Examples of such solvents are acetonitrile, toluene, DMF, diglyme, THF, or DMSO.

For the purpose of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, back cover. Also for the purpose of the present invention, the term "hydrocarbon" is considered to include all permissible compounds having at least one hydrogen and one carbon atom. In a broader aspect, permissible hydrocarbons include non-cyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds that may be substituted or unsubstituted.

Examples of catalyzed reactions

As described above, the present invention features a general cross-coupling reaction which comprises combining an alcohol with an aryl group (a "substrate aryl") having an electrophilic center susceptible to attack by the oxygen of the alcohol. In embodiments where the cross-coupling is catalyzed by a transition metal, the reaction will also include at least a catalytic amount of the transition metal catalyst agent and the combination is maintained under conditions suitable for the metal catalyst agent to catalyze the nucleophilic addition of the reactive alcohol to the electrophilic atom of the substrate aryl.

In one embodiment, the subject method of the present invention can be used to cause the formation of an intramolecular ether bond, eg, to form oxygen. In an exemplary embodiment, the subject method of the present invention can be used to perform the Pd-catalyzed intramolecular substitution of an activated aryl itself:

<img file="ES2200162T3_D0010.tif" />

As illustrated in the examples included below, five-, six- and seven-membered heterocycles were obtained in good yield from the corresponding halides. In addition, a variety of functional groups were found to be compatible with the reaction conditions, including acetals, silyl ethers, and amides.

The subject method of the present invention can also be used for the intermolecular formation of carbon and oxygen bonds. As an exemplary embodiment, the subject method of the present invention can be used to catalyze reactions such as:

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To illustrate in more detail, the examples describe, among other things, that the reaction of 2-propanol, 4-bromobenzonitrile and NaH in the presence of 1.5 mol% Pd2 (dba) 3 and 3 mol% (S ) - (-) - 2,2'-bis (di-p-tolylphosphino) -1,1'binaphthyl (Tol-BINAP) at 50 ° C produced 4-isopropoxy-benzonitrile in 80% isolated yield.

Substrate aryl compounds include compounds derived from single aromatic rings (single or polycyl), such as, benzene, naphthalene, anthracene, and phenanthracene; or heteroaromatic rings (simple or polycyl), such as pyrrole, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatiin, pyrrole, imidazole, pyrazole, thiazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine , isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, fenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolan, thiolan, oxazole, piperidine, piperazine, morpholine, and the like. In a preferred embodiment, the reactive group, X, is substituted on a five-, six-, or seven-membered ring (although it may be part of a larger polycyl).

In preferred embodiments, the aryl substrate can be selected from the group consisting of phenyl and phenyl derivatives, heteroaromatic compounds, polycyclic aromatic and heteroaromatic compounds, and their functionalized derivatives. Suitable aromatic compounds derived from single aromatic rings and heteroaromatic rings include, but are not limited to, pyridine, imidizole, quinoline, furan, pyrrole, thiophene, and the like. Suitable aromatic compounds derived from fused ring systems include, but are not limited to, naphthalene, anthracene, tetralin, indole, and the like.

Suitable aromatic compounds may have the formula ZPPAr-X, where X is an activated substituent. X, as an activated substituent, is characterized as a good leaving group. In general, the leaving group is a group such as a halide or sulfonate. For the purposes of the present invention, an activated substituent is that moiety whose conjugated acid, HX, has a pKa of less than 5.0. Suitable activated substituents include, by way of example only, halides such as chloride, bromide and iodide, triflate, mesylate, and tosylate. In certain embodiments, the leaving group is a halide selected from iodine and bromine. Chlorine and fluorine can also be used as leaving groups, although another negative electric charge substitution on the aryl group may be necessary to activate those halogens as leaving groups in the subject metal cross-coupling reactions of the present invention.

Z represents one or more optional substituents on the aromatic ring, although each occurrence of Z (p&gt; 1) is independently selected. By way of example only, each occurrence of substitution may independently, as valence and stability allow, be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (e.g., an ester, a carboxylate , or a formate), a thiocarbonyl (e.g., a thiol ester, a thiolcarboxylate, or a thiolformat), a cetyl, an aldehyde, an amino, an acylamino, an amido, an amidino, a cyano, a nitro, an azide , u sulfonyl, a sulfoxide, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a phosphoryl, a phosphonate, a phosphinate, - (CH2) -R8, - (CH2) m-OH, - (CH2) m O-lower alkyl, - (CH2) mO-lower alkenyl, - (CH2) mO- (CH2) n-R8, - (CH2) m-SH, - (CH2) mS-lower alkyl, - (CH2) mS-lower alkenyl, - (CH2) m S - (CH2) nR8, or protecting groups of those mentioned above or a solid or polymeric support; R8 represents a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; y and n are independent for each occurrence of zero or an integer within the range of 1 to 6. P is preferably within the range of 0 to 5. For fused rings, in which the number of substitution sites on the aryl group increases, p can be adjusted appropriately.

In certain embodiments, suitable Z substituents include alkyl, aryl, acyl, heteroaryl, amino, carboxylic ester, carboxylic acid, hydrogen group, ether, thioether, amide, carboxamide, nitro, phosphonic acid, hydroxyl, sulfonic acid, halide, groups pseudo-halides, and their substituted derivatives, and n is in the range of 0 to 5. In particular, the reaction has been found to be compatible with acetal ethers, amides and silyl as functional groups. For fused rings, where the number of substitution sites on the aromatic ring increases, n can be suitably adjusted. Furthermore, the moieties mentioned above can be covalently linked to an alcohol moiety in intramolecular reactions.

In preferred embodiments, the resonance structure of the aryl group Ar, or at least one substituent Z, is electron withdrawing from the substituted position of X.

A wide variety of substrate aryl groups are useful in the methods of the present invention. The choice of substrate will depend on factors such as the alcohol to be used and the desired product, and for a seasoned craftsman the

A suitable aryl substrate will be apparent. It will be understood that the aryl substrate will preferably not contain any interfering functionality. It is also understood that not all activated aryl substrates will react with all alcohols.

The reactive alcohol group can be a molecule apart from the substrate aryl group, or a substituent on the same molecule (eg, for intramolecular condensation).

The alcohol is selected to provide the desired reaction product. In general, the alcohol can be any alcohol such as, but not limited to, alkyl alcohols, including primary, secondary, and tertiary alcohols, and phenols. Alcohol can be functionalized. The alcohol can be selected from a wide variety of structural types, including, but not limited to, non-cyclic, cyclic, or heterocyclic compounds, fused ring compounds, or phenol derivatives. The aromatic compound and the alcohol can be included as moieties of a single molecule, in which the arylation reaction proceeds as an intramolecular reaction.

The reactive alcohol group that is used in the subject coupling reaction of the present invention may be represented by the general formula ROH; R represents, as valence and stability permit, a substituted or unsubstituted alkyl or alkenyl group, or (CH2) m -R8, where R8 represents a substituted or unsubstituted aryl cycloalkyl, cycloalkenyl, heterocycle or polycycle, and m is zero or an integer in the range 1 to 8. In other embodiments, R is a linker to a solid support. In which R is substituted, it is preferably substituted with an electron withdrawing group in a way that would substantially reduce the nucleophilicity of the hydroxyl group. For example, R will not include any electron withdrawing group linkages within less than two linkages of the hydroxyl substituted carbon.

In certain embodiments, the alcohol is generated in situ, eg, by conversion of a precursor under the reaction conditions.

Alternatively, the corresponding alkoxide salt, eg, NaOR, LiOR, KOR, etc., can be prepared and used in place of the alcohol. When the corresponding alkoxide is used in the reaction, an additional base may not be necessary. The active form of the transition metal catalyst is not well characterized. Therefore, it is contemplated that the "transition metal catalyst agent" of the present invention, as that term is used herein, will include any transition metal catalyst agent and / or catalyst precursor as it is introduced into the reaction vessel, and which, if necessary, is converted in situ into the active phase, as well as the active form of the catalyst agent participating in the reaction.

In preferred embodiments, the transition metal catalyst agent complex is provided in the reaction mixture in a catalytic amount. In certain embodiments, said amount is within the range of 0.0001 to 20% by mole, and preferably 0.05 to 5% by mole, most preferably 1-3% by mole, relative to the limiting reactive agent. , which can be either an aromatic compound or the alcohol (or alkoxide) or both, depending on which reactive agent is in stoichiometric excess. In the case where the molecular formula of the catalyst agent complex includes more than one metal, the amount of the catalyst agent complex used in the reaction can be suitably adjusted. By way of example, Pd2 (dba) 3 has two metal centers; and therefore, the molar amount of Pd2 (dba) 3 used in the reaction can be halved without sacrificing catalytic activity.

Furthermore, heterogeneous catalysts containing forms of these elements are also suitable catalysts for any of the transition metal catalyzed reactions of the present invention. Catalysts containing palladium and nickel are preferred. These catalyst agents are expected to perform similarly as they are known to undergo similar reactions, namely oxidative addition reactions and reductive elimination reactions, which are thought to be related to the formation of the aryl ethers herein. invention. However, the different ligands are thought to modify the performance of the catalyst, for example by modifying the reactivity and avoiding unwanted side reactions.

While suitable, the catalyst agents employed in the subject method of the present invention comprise the use of metals that can act as mediators in the cross-coupling of the aryl groups Ar-X and the alcohol as defined above. For example, suitable metals include platinum, palladium, and nickel. The particular form of metal to be used in the reaction is selected to provide, under the reaction conditions, metal centers that are not coordinate saturated and are not in their maximum oxidation state. The metal center of the catalyst should be a zero valence transition metal such as Pd or Ni with the ability to undergo oxidative addition at the Ar-X linkage. The zero valence state, M⁰ , can be generated in situ from _M+2_.

To further illustrate, transition metal catalysts include soluble complexes of platinum, palladium, and nickel. Nickel and palladium are especially preferred and palladium is most preferred. A zero valence metal center is presumed to participate in the catalytic bond formation sequence of carbon and oxygen. Therefore, it is desirable that the metal center is in the zero valence state or is capable of being reduced to metal (0). Soluble palladium complexes include, but are not limited to, tris (dibenzylideneacetone) dipalladium [Pd2 (dba) 3], bis (dibenzylideneacetone) palladium [Pd (dba) 2], and palladium acetate. Alternatively, and especially for nickel catalysts, the active species in the oxidative addition step can be found in the oxidative addition state (+1) in the metal.

ES 2 200 162 T3

Catalysts containing palladium and nickel are preferred. These catalyst agents are expected to perform comparably as they are known to undergo similar reactions, namely cross-coupling reactions, which may be related to the formation of the aryl ethers of the present invention.

The coupling may be catalyzed by a palladium catalyst, which may take the form of, as an illustrative example, PdCl2, Pd (OAc) 2, (CH3CN) 2PdCl2, Pd [P (C6H5) 3] 4, and Pd (0 ) supported by polymer. In other embodiments, the reaction may be catalyzed by means of a nickel catalyst, such as Ni (acac) 2, NiCl2 [P (C6H5)] 2, Raney's nickel, and the like, where "acac" represents acetyletonate.

In some cases, it may be necessary or include additional reactive agents in the reaction to promote the reactivity of the transition metal catalyst agent or activated aryl nucleus. In particular, it may be advantageous to include a suitable base. In general, a variety of bases can be used in the practice of the present invention. Preferably, the base is capable of extracting a proton to promote the formation of the metal alkoxide. It has not been determined whether de-protonization occurs before or after oxygen coordination. The base may optionally be spatially inhibited to discourage metallic coordination of the base in those circumstances where such coordination is possible, ie, alkali metal alkoxides. Example bases include such as for example: an alkoxide such as sodium tert-butoxide, an alkali metal amide such as sodium amide, lithium diisopropylamide, or an alkali metal bis (trialkyl silyl) amides, e.g. such as bis- (trimethylsilyl) amide lithium or sodium bis- (trimethylsilyl) amide, a tertiary amide (eg, triethylamine, trimethylamine, N, N-dimethylaminopyridine, 1,5-diazabicycl [4.3.0] nonene-5 (DBN), 1, 5-diazabicycl [5-4.0] undecene-5 (DBU), alkali, alkaline earth carbonate, bicarbonate, or hydroxide (eg, sodium, magnesium, calcium, barium, potassium carbonate, hydroxide and bicarbonate). By way of example only, suitable bases include NaH, LiH, KH, K2CO3, Na2CO3, Tl2CO3, Cs2CO3, K (OtBu), Ll (OtBu), Na (OtBu) K (OPh), Na (OPh), triethylamine or their mixes. NaH, Na (OtBu) and K2CO3 have been found to be useful in a wide variety of aryl ether bond formation reactions. Preferred bases include Cs2CO3, DBU, NaH, KOt-Bu, KN (SiMe3) 2, NaN (SiMe3) 2, and LiN (SiMe3) 2.

The base is used in approximately stoichiometric proportions in the reaction using alcohol. The present invention has shown that there is no need for large excesses of base to obtain good yield of aryl ether under moderate reaction conditions. No more than four equivalents are needed and preferably no more than four equivalents. Furthermore, in reactions using the corresponding alkoxide as the reactant, there may be no need for additional base.

In this way, a wide range of aryl ethers can be prepared from the available alcohols. The reaction can be accomplished using a wide range of alcohols, which can be commercially available or can be obtained from conventional syntheses using a variety of methods known in the art.

As is clear from the discussion above, the products that can be produced by the etherification reaction of the present invention may undergo further reaction / s to produce their desired derivatives. Such allowable derivatization reactions can be carried out according to conventional procedures known in the art. For example, potential derivatization reactions include esterification, oxidation of alcohols to aldehydes and acids, N-alkylation of amides, reduction of nitrile, acylation of ketones by esters, acylation of amines, and the like.

III. Reaction conditions

The etherification reactions of the present invention can be carried out under a wide variety of conditions, although it will be understood that the solvents and temperature ranges described herein are not limiting and correspond only to a preferred mode of a process of the present invention. invention.

In general, it will be preferred that the reactions be carried out using mild conditions which will not adversely affect the reactants, the catalyst, or the product. For example, the reaction temperature influences the rate of the reaction, as well as the stability of the reactants and the catalyst. The reactions will generally be carried out at temperatures within the range of 25 ° C to 300 ° C, more preferably within the range of 25 ° C to 150 ° C.

In general, the reactions subject of the present invention are carried out in a liquid reaction medium. The reactions are carried out in an inert solvent, preferably one in which the reaction ingredients, including the catalyzing agent, are substantially soluble. Suitable solvents are aromatic hydrocarbon solvents such as benzene, xylene, and toluene, or combinations of two or more solvents.

The present invention also contemplates the reaction in a biphasic mixture of solvents, in an emulsion or suspension, or the reaction in a lipid vesicle or bi-layer. In certain embodiments, it may be preferred to perform the solid phase catalyzed reactions with one or more reactants anchored to a solid support.

In certain embodiments, it is preferred to carry out the reactions under an inert atmosphere of a gas such as nitrogen or argon.

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The reaction processes of the present invention may be conducted in a continuous, semi-continuous or batch mode and may comprise a liquid recycling operation as desired. The processes of the present invention are preferably performed in a batch mode. Likewise, the mode or order of adding the reaction ingredients, catalyst and solvent are generally also not critical and can be achieved according to any conventional modality.

The reaction may be conducted in a single reaction zone or in a plurality of reaction zones, in series or in parallel, or it may be conducted batchwise or continuously in an elongated tubular zone or a series of such zones. The construction materials used must be inert to the starting materials during the reaction and the manufacture of the equipment must be able to withstand the temperatures and pressures of the reaction. Means of introducing and / or adjusting the amount of the starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction may be conveniently used during the processes, especially to maintain the rate. desired molar of the starting materials. The stages of the reaction can be affected by the gradual addition of one of the starting materials to the other. Furthermore, the reaction steps can be combined by the joint addition of the starting materials to the metal catalyst agent. If complete conversion is not desired or cannot be obtained, the starting materials can be separated from the product and recycled back to the reaction zone.

The processes can be conducted either in reaction equipment lined with glass, stainless steel or the like. The reaction zone may be equipped with one or more external and / or internal heat exchanger (s) to control undue temperature fluctuations, or to avoid any possible "blowout" reaction temperatures.

In addition, one or more reactants can be immobilized or incorporated into a polymer or other insoluble matrix, for example, by derivatization with one or more of the aryl group substituents.

IV. Combinatorial libraries

The etherification reaction subject of the present invention readily lends itself to the creation of combinatorial libraries of aryl ethers for the identification of pharmaceutical, agrochemical, or other biological or medicine-related activity or material-related qualities. A combinatorial library, for the purposes of the present invention, is a mixture of chemically related compounds which can be jointly identified for the desired property. The preparation of many related compounds in a single reaction greatly reduces and simplifies the number of identification processes that need to be carried out. The identification of the appropriate biological, pharmaceutical, agrochemical or physical property is carried out by means of conventional methods.

Diversity in the library can be created on a variety of levels. For example, the substrate aryl groups used in the combinatorial reactions can be diverse in terms of the aryl moiety in the center, eg, a variation in terms of the ring structure, and / or can be varied with respect to the other substituents. .

There are a variety of techniques available in the art for generating combinatorial libraries of small organic molecules such as the subject arylamines of the present invention. See, for example, Blondelle et al. (1995) Trends Anal. Chem. 14:83; Affymax patents US 5 359 115 and 5 362 899: the Eliman patent US 5 288 514: the publication Still et al. PCT WO 94/08051; Chen et al. (1994) JACS 116: 2661: Kerr et al. (1993) JACS 115: 252; PCT publications WO 92/10092, WO 93/09668 and WO 91/07087; and the publication by Lerner et al. PCT WO 93/20242). Similarly, a variety of libraries in the order of about 100 to 1,000,000 or more diversomers of the aryl ethers subject of the present invention can be synthesized and identified by a particular activity or property.

In an exemplary embodiment, a library of substituted diversomers can be synthesized using the subject alcohol cross-coupling reaction of the present invention adapted to the techniques described in the Still et al. Publication. PCT WO 94/08051, eg, being attached to a polymer bead by means of a hydrolyzable or photolyzable group, eg, located at one of the positions of the aryl group or an alcohol substituent. According to the technique of Still et al., The library is synthesized in a set of beads, each bead includes a set of tags that identify the particular diversomer in said bead. In one embodiment, which is especially suitable for detecting enzyme inhibitors, the beads can be dispersed on the surface of a permeable membrane, and the diversomers are released from the beads by lysis of the bead linker. The diversomer from each bead will diffuse across the membrane into a test zone, where it will interact with an enzyme assay.

Exemplification

The invention can be understood with reference to the following examples, which are presented for illustrative purposes only and are not limiting. All aromatic and alcohol compounds were commercially available for intermolecular reactions. Substrates used in intramolecular reactions were prepared by standard synthetic organic methods in approximately 3-5 synthetic steps. All palladium catalysts were commercially available.

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Example 1-11

Examples 1-11 demonstrate the versatility of the synthetic aryl ether pathway of the present invention. A variety of alcohol moieties substituted aromatics were subjected to palladium catalyzed cross-coupling to produce variously substituted heterocyclic ethers. The aromatics and starting alcohols are recorded in Table 1. The reactions were carried out as described in the legend.

As shown in Table 1, five-, six- and seven-membered heterocycles were obtained in good yields from the corresponding aryl halide. Furthermore, a number of functional groups were found to be compatible with the reaction conditions including acetals (Example 3), silyl ethers (Example 4), and amides (Example 7). Reactions performed by method A were significantly slower (24-36 h) than reactions performed by method B (1-6 h), however, reactions using method A were slightly cleaner. Cyclization of the aryl iodide substrate (Example 2) was extremely slow in toluene, but in 1,4-dioxane, complete conversion occurred within 24-36 h. Two equivalents of ligand relative to palladium (P: Pd = 4) and two equivalents of base relative to substrate were used to achieve reasonable yields in the cyclization reactions of Example 11 containing a secondary alcohol. Observed by-products included dehalogenation of the aryl halides and in the case of substrates containing secondary alcohols, along with oxidation of the alcohol to a ketone.

(Table goes to next page)

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TABLE 1

Pd-Catalyzed Synthesis of Cyclic Aryl Ethers

Input Substrate Method * Product Yield (%)^b

<td> 1</td><td></td><td>TO</td><td></td><td> 89</td>

<td> 2</td><td></td><td>TO</td><td>Ox;</td><td> 60</td>

<td> 3</td><td>MOMO OH 02</td><td>TO</td><td>Momo or M</td><td> 93</td>

<td> 4</td><td>TBOMSO OH or-</td><td>TO</td><td>TBOMSO ΟψτΜ.</td><td> 90</td>

<td> 5</td><td>Ha m.</td><td>TO</td><td>030 M »</td><td> 65</td>

<td> 6</td><td>m »</td><td>TO</td><td>Oct&gt;</td><td> 73</td>

<td> 7</td><td>ei? &lt;AA_&amp;</td><td>TO</td><td>or</td><td> 66</td>

<td> 8</td><td> ¿2</td><td>Q</td><td>QQcm.</td><td> 69</td>

<td> 9</td><td>orf</td><td>B</td><td>° Q-</td><td> 64</td>

<td>UJ</td><td>HO Μ. OQÓ</td><td>B</td><td> 033</td><td> 73</td>

<td> 11</td><td>OCO</td><td>C</td><td>033 H</td><td> 66</td>

<td> 12</td><td>a to/·</td><td>C</td><td> 03.</td><td> 32</td>

^to Method A: 7 mol% Pd (OAc)₂, 6 mol% Tol-BINAP, 1.2 equiv of K₂CO₃ in toluene at 100 ° C. Method B: 3 mole% Pd (Oac)₂, 3.6 mole% DPPF, 1.2 equiv NaOt-Bu in toluene at 80 ° C. Method C: 7 mole% Pd (OAc)₂, 10 mole% DPPF, 2.0 equiv of NaOt-Bu in toluene at 90 ° C.^b Performance refers to the average isolated performance of two or more cycles. The reaction was carried out in 1,4-dioxane.

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Comparative Example 1

This example demonstrates the palladium catalyzed intermolecular synthesis of the aryl ether, 4-t-butoxybenzonitrile.

A Schlenk tube was loaded with Na (OtBu) (97 mg, 1.00 mmol), Pd (OAc) 2 (5.6 mg, 0.025 mmol), (R) (+) 2,2'-bis (di- ptoylphosphino) -1,1'-binaphthyl (Tol-BINAP) (20.4 mg, 0.030 mmol), 4-bromobenzonitrile (91 mg, 0.50 mmol), and toluene (3 mL). The mixture was heated at 100 ° C for 30 h under an argon atmosphere. The mixture was cooled to room temperature and diethyl ether (20 mL) and water (20 mL) were added. The organic layer was separated, washed in brine (20 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (19/1 hexanes / ethyl acetate) to yield 4-t-butoxybenzonitrile as a yellow oil (39 mg, 45% yield).

Comparative Example 2

This example demonstrates the palladium-catalyzed intermolecular synthesis of aryl ether, 4-f-butylphenyl-t-butyl ether.

An oven-dried Schlenk equipped with a Teflon-coated stir bar was loaded with Na (Ot-Bu) (97 mg, 1.00 mmol), Pd (OAc) 2 (5.6 mg, 0.025 mmol), and Tol -BINAP (20.4 mg, 0.030 mmol). The Schlenk was emptied, refilled with argon, and charged with toluene (3 mL) and 4-t-butyl bromobenzene (87 µ / L-, 0.50 mmol). The mixture was heated at 100 ° C for 40 h, at which time the mixture was cooled to room temperature and diethyl ether (20 mL) and water (20 mL) were added. The organic layer was separated, washed in brine (20 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (99/1 hexanes / ethyl acetate) to yield 4-t-butylphenyl-t-butyl ether as a yellow oil (59 mg, yield of the 53%).

Comparative example 3

This example demonstrates the palladium catalyzed intermolecular synthesis of aryl ether, 4-benzonitrile cyclopentyl ether.

A Schlenk tube was charged with NaH (80.0 mg, 60% dispersion in mineral oil, 2.00 mmol), cyclopentanol (182 // µ, 2.00 mmol), and toluene (2.5 mL). The mixture was heated at 70 ° C for 30 minutes under an argon atmosphere followed by the addition of Pd (OAc) 2 (6.7 mg, 0.030 mmol), (R) - (+) - 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) (27.2 mg, 0.040 mmol), 4-bromobenzonitrile (182 mg, 1.00 mmol), and toluene (2.5 mL) . The mixture was heated at 100 ° C for 1.5 h and at that time diethyl ether (30 mL) and water (30 mL) were added at room temperature. The organic layer was separated, washed in brine (20 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (19/1 hexanes / ethyl acetate) to yield 4-benzonitrile cyclopentyl ether as a colorless oil (140 mg, 75% yield).

Comparative Example 4

This example demonstrates the palladium catalyzed intermolecular synthesis of aryl ether, 4-benzonitrile isopropyl ether.

An oven-dried Schlenk equipped with a Teflon-coated stir bar was charged with NaH (60% dispersion in mineral oil, 40 mg, 1.00 mmol), placed under vacuum, and refilled with argon. To this was added 2-propanol (46 µ / L-, 0.60 mmol) and toluene (2 mL). The mixture was heated to 50 ° C for 15 min, at which time 4-bromobenzonitrile (91 mg, 0.50 mmol), Pd2 (dba) 3 (6.9 mg, 0.0075 mmol), (R ) - (+) - 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) (12.2 mg, 0.018 mmol), and 1 mL of toluene. The mixture was heated to 50 ° C under an argon atmosphere. After 22 h, water (50 mL) and diethyl ether (50 mL) were added and the aqueous layer was separated and extracted with diethyl ether (50 mL). Organics were combined, washed with brine (50 mL), and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel (19/1 hexanes / ethyl acetate) to yield 4-benzonitrile isopropyl ether as a white solid (65 mg, 80% yield).

Comparative Example 5

This example demonstrates the palladium-catalyzed intermolecular synthesis of aryl ether, 1-naphthyl-cyclohexyl ether.

An oven-dried Schlenk equipped with a Teflon-coated stir bar was loaded with NaH (40 mg, 1.50 mmol), toluene (2 mL), and cyclohexanol (94 µ / Ι, 0.90 mmol). The mixture was heated at 70 ° C for 10 min under an argon atmosphere. To this was added 1-bromonaphthalene (104 μ / Ι ,, 0.75 mmol), Pd₂(dba)₃ (10.3 mg, 0.0113 mmol), (R) - (+) 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 2 mL of toluene. The mixture was heated at 70 ° C for 20 h and at that time diethyl ether (60 mL) and water (60 mL) were added. The aqueous layer was separated and extracted with diethyl ether (60 mL). The organics were combined, washed with brine (60 mL), and dried over anhydrous MgSO4. The drying agent was removed by filtration, and the mother alcohol was concentrated in vacuo. The crude product was purified by gel flash chromatography

ES 2 200 162 T3 of silica (50/1 hexanes / ethyl acetate) to yield 1-naphthyl cyclohexyl ether as a colorless oil (101 mg, 60% yield).

Comparative Example 6

This example demonstrates the palladium catalyzed intermolecular synthesis of aryl ether, 3-pentyl- (4-trifluoromethyl phenyl) ether.

An oven-dried Schlenk equipped with a Teflon-coated stir bar was charged with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol), placed under vacuum, and refilled with argon. Toluene (2 mL) and 3-pentanol (98 µL, 0.90 mmol) were added to this. The mixture was heated to 70 ° C for 10 min, at which time 4-bromobenzotrifluoride (105 μL, 0.75 mmol), Pd₂(dba)₃ (10.3 mg, 0.0113 mmol), (R) - (+) - 2,2'-bis (dip-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 1 mL of toluene. The mixture was heated at 70 ° C for 18 h and at that time diethyl ether (60 mL) and water (60 mL) were added. The aqueous layer was separated and extracted with diethyl ether (60 mL). Organics were combined, washed with brine (60 mL), and dried over anhydrous MgSO4. The drying agent was removed by filtration, and the mother alcohol was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (19/1 hexanes / ethyl acetate) to yield 3-pentyl- (4-trifluoromethylphenyl) ether as a colorless oil (114 mg, 54% yield) .

Comparative Example 7

This example demonstrates the palladium catalyzed intermolecular synthesis of aryl ether, 9-anthryl cyclopentyl ether.

An oven-dried Schlenk equipped with a Teflon-coated stir bar was charged with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol), placed under vacuum, and refilled with argon. Toluene (2 mL) and cyclopentanol (109 μL, 0.90 mmol) were added to this. The mixture was heated to 70 ° C for 15 min, at which time 9-bromoanthracene (193 μL, 0.75 mmol), Pd₂(dba)₃ (10.3 mg, 0.0113 mmol), (R) - (+) - 2,2'bis (di-p-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 2 mL of toluene. I know mixture was heated to 100 ° C under an argon atmosphere. After 20 hours diethyl ether (30 mL) and brine (30 mL) were added. The organic layer was separated and dried over anhydrous MgSO4. The drying agent was removed by filtration, and the mother alcohol was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (99/1 hexanes / ethyl acetate) to yield 9-anthryl cyclopentyl ether as a yellow solid (135 mg, 68% yield).

Comparative Example 8

This example demonstrates the palladium catalyzed intermolecular synthesis of aryl ether, 4-benzonitrile benzyl ether.

An oven-dried Schlenk equipped with a Teflon-coated stir bar was charged with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol), placed under vacuum, and refilled with argon. Toluene (2 mL) and benzyl alcohol (93 μL, 0.90 mmol) were added to this. The mixture was heated to 70 ° C for 10 min, at which time 4-bromobenzonitrile (139 μβ, 0.75 mmol), Pd₂(dba)₃ (10.3 mg, 0.0113 mmol), (R) - (+) - 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) (18.3 mg , 0.027 mmol), and 1 mL of toluene. The mixture was heated to 70 ° C under an argon atmosphere. After 14 hours diethyl ether (50 mL) and water (50 mL) were added. The aqueous layer was separated and extracted with diethyl ether (50 mL). Organics were combined, washed with brine (50 mL), and dried over anhydrous MgSO4. The drying agent was removed by filtration, and the mother alcohol was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (19/1 hexanes / ethyl acetate) to yield 9-benzonitrile benzyl ether as a white solid (113 mg, 72% yield).

Comparative Example 9

This example demonstrates the palladium-catalyzed intermolecular synthesis of aryl ether, 4-benzonitrile methyl ether.

An oven-dried Schlenk equipped with a Teflon-coated stir bar was charged with NaH (60% dispersion in mineral oil, 60 mg, 1.50 mmol), placed under vacuum, and refilled with argon. Toluene (2 mL) and methyl alcohol (87 µL, 0.90 mmol) were added to this. The mixture was heated to 70 ° C for 10 min, at which time 4-bromobenzonitrile (136 μg, 0.75 mmol), Pd₂(dba)₃ (10.3 mg, 0.0113 mmol), (R) - (+) - 2,2'bis (di-p-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 1 mL of toluene. The mixture was heated to 70 ° C under an argon atmosphere. After 20 hours diethyl ether (50 mL) and water (50 mL) were added. The aqueous layer was separated and extracted with diethyl ether (50 mL). The organics were washed with brine (50 mL), and dried over MgSO4. The drying agent was removed by filtration, and the mother alcohol was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (19/1 hexanes / ethyl acetate) to yield 9-benzonitrile methyl ether as a white solid (77 mg, 77% yield).

ES 2 200 162 T3

Comparative Example 10

Direct observation of reductive removal of CO from palladium (aryl) alkoxide complexes to form aryl ethers.

The reaction of KOCH2CMe3 with [(R) -Tol-BINAP] Pd (p-C6H4CN) Br (1) or (dppf) Pd (p-C6H4CN) Br (2) formed the complexes of palladium (p-cyanophenyl) neopentoxide [ PP] Pd (p-C6H4CN) (OCH2CMe3) [PP = Tol-BINAP (4), dppf (6)] as exclusive products. Thermolysis of 4 in THF-d₈ at 55 ° C formed p-neopentoxybenzonitrile (5) in 85% yield (t_1/2 = 2.7 min). Thermolysis of 6 in THF-d₈ at 55 ° C it formed 5 in 60% yield and pivaldehyde in 23% yield (t1 / 2 = 8.8 min). The kinetic analysis of the decomposition of 4 in the presence of excess alkoxide established the two-time rate law: Rate = k [4] + k [4] [KOCN2CMe3]. The alkoxide-independent pathway coincides with the direct reductive elimination of 4 to generate 5 and [(R) -Tol-BINAP] Pd (I). The alkoxide-dependent pathway coincides with the attack of the alkoxide on palladium followed by the reductive elimination of a bis (alkoxide) complex coordinated with five or coincides with the attack of the alkoxide on the carbon atom of the aryl group attached to palladium followed by elimination from {[(R) -Tol-BINAP] Pd (OCH2CMe3)}^- (1a).

Reductive removal from a metal center of a low valence group to form an aryl CC linkage represents the key linkage formation step in a variety of synthetically relevant catalytic cross-coupling protocols. ⁱ As a result, the mechanisms of reductive elimination of CC from well-defined Pd, Ni, and Pt complexes has been intensively investigated. ² Similarly, reductive elimination of CX [X = N, S] presumably serves as the key bond formation step in palladium-catalyzed cross-coupling protocols, ^3,4 and both reducing eliminations of C-NS and CS have been directly observed⁶ from well characterized group 10 metal complexes. Despite the numerous examples of group 10 metal (aryl) alkoxide complexes,⁷ Direct thermal reductive elimination to form an aryl CO bond has not been observed. ^8,9 Recently, we have developed a palladium-catalyzed process for the formation of aryl ethers from aryl bromides and sodium alkoxides which employ mixtures of Pd (OAc) 2 and bulky chelating bis (phosphine) ligands such as 1,1 ' -bis (diphenylphosphino) ferrocene (dppf) or (R) (+) - 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl [(R) -Tol-BINAP].ⁱ⁰Significantly, this system appeared to provide an opportunity to observe the reductive elimination of (aryl) CO from a group 10 metal center. In this paper, we report the generation of thermally unstable palladium (aryl) alkoxide complexes which undergo elimination. reductive to form aryl ethers.

Our approach to generating palladium (aryl) alkoxide complexes with bis (phosphine) chelating ligands involved direct displacement of the bromide ligand from a palladium (p-cyanophenyl) bromide complex with potassium neopentoxide. Neopentoxide was used due to its diagnostic signs in the NMR spectrumⁱH and because neopentanol couples efficiently with aryl bromides under catalytic conditions.ⁱⁱ The necessary complexes of chelating bis (phosphine) palladium (p-cyanophenyl) palladium bromide Pd [(R) -Tol-BINAP] (p-C6H4CN) (Br) (1) and Pd (dppf) (p-C6H4CN) were prepared ) (Br) (2) in good yield (&gt; 75%) from the quencher reaction palladium tri (o-tolylphosphine) {Pd [P (o-tolyl)₃] (PC₆H₄CN) (uBr)}₂ (3) with (q-Tol-BINAP or dppf, respectively. Complexes 1-3 were characterized by standard spectroscopic techniques and elemental analysis (Scheme 21.1).

<img file="ES2200162T3_D0012.tif" />

Treatment of a pale yellow solution of 1 in THF-d₈ with a small excess of (~ 1.1 equiv.) potassium neopentoxide formed an orange solution of palladium neopentoxide complex [(q-TolBINAP] Pd (p-C6H4CN) (OCH2CMe3) (4) in quantitative yield (NMR ⁱH; PhSiMe3 internal standard). Solutions of 4 darkened within a few minutes at room temperature and attempts to isolate 4 from the corresponding preparatory scale reaction were unsuccessful. As a result, the alkoxide complex 4 was characterized by NMR spectroscopy.ⁱH and ³ⁱP without insulation. The NMR spectrumⁱH of 4 in THF-d8 showed a 1: 1 1: 1 ratio of p-tolyl peaks at δ 2.38, 2.19, 1.98, and 1.93 and a simple tert-butyl resonance at 0.17; the ratio of these resonances established the 1: 1 rate of the neopentoxide ligands to the [(R) -Tol-BINAP] PdAr groups. A pair of doublets at 2.76 and 2.62 (J = 8.8 Hz) assigned to the diastereotopic methylene protons of the alkoxide ligand confirmed the binding of the alkoxide to the chiral metal fragment. The NMR spectrum³ⁱP of 4 showed two doublets at 25.1 and 12.1 (Jpp = ~ 36 Hz), which established the bidentate coordination of the phosphine ligand to the palladium alkoxide fragment.

ES 2 200 162 T3

<img file="ES2200162T3_D0013.tif" />

Thermolysis of a freshly prepared solution of 4 in THF-d₈ at 55 ° C led to rapid decomposition (t_1/22.7 min).¹² NMR analysis ¹H and GCMS from the resulting black solution revealed the formation of p-neopentoxybenzonitrile (5.85%), 4,4'-dimethylbiphenyl (~ 10%), and traces of benzonitrile (&lt;5%).¹³ No resulting products were observed from aryl exchange Pd / P ^14,15 such as p-neopentoxytoluene or 4-methyl-4'-cyano-biphenyl. Thermolysis of 4 in the presence of PPh3 did not lead to any increase in the yield of 5 but instead decreased the yield of 4,4'-dimethylbiphenyl (&lt;2%). This behavior opposes that of the reductive elimination of CS from palladium (aryl) tert-butylsulfide complexes which require the presence of a capture agent to generate high thioether yields.⁵ Furthermore, these observations suggest that the PC binding separation reaction to form 4,4'-dimethyl biphenyl occurs following reductive removal of CO from the reactive species bis (phosphine) Pd (O) [( R) -Tol-BINAP] Pd (I); PPh3 presumably captures I prior to oxidative addition of PC. Thermolysis of 4 in the presence of 30.04 M KOCH2CMe3 led to an almost quantitative formation of 5 (³94 ± 5%).

The addition of 1.1 eq of KOCH2CMe3 to a suspension of 2 in THF-d8 formed Pd (dppf) (p-6H4CN) (OCH2CMe3) (6) as the only palladium species as indicated in NMR spectroscopy. ¹H and ³¹P; 6 was characterized by NMR¹H and ³¹P without insulation. The decomposition of the neopentoxide complex 6 at 55 ° C was 4 times slower (t_1/2 = 8.8 min) than decomposition of 4. NMR analyzes ¹H and GC from the resulting black solution revealed the presence of 5 (60%), pivaldehyde (23%), benzonitrile (30%), and biphenyl (~ 10%) (Table 21.1, Scheme 21.2). Presumably, the lower reductive removal rate of 6 over 4 leads to competitive removal of β-hydrogen in the case of 6 with pivaldehyde formation.^l6

TABLE 21.1

<td colspan="4">First-order rate constants and yields of 5 for the decomposition of 4 ([Pd] A 1 x 10^-2 M) in THF-d₈.</td>

<td>Temp</td><td>[KOCH2CH3]</td><td>(104) kobsS^-1</td><td>ArOR yield (± 5%)</td>

<td> 23</td><td> 0,0017</td><td> 1,42 ± 0,01</td><td> 76</td>

<td> 23</td><td> 0,0017</td><td> 1,43 ± 0,09</td><td> -</td>

<td> 23</td><td> 0,0017</td><td> 1,45 ± 0,02</td><td> 72^to</td>

<td> 35</td><td> 0,0017</td><td> 5,2 ± 0,2</td><td> -</td>

<td> 37</td><td> 0,0017</td><td> 6,3 10,2</td><td> -</td>

<td> 47</td><td> 0,0017</td><td> 15,7 ± 0,2</td><td> 84</td>

<td> 47</td><td> 0,0017</td><td> 14,9 10,5</td><td> 86</td>

<td> 47</td><td> 0,0017</td><td> 16,1 ± 0,3</td><td>_-b</td>

<td> 47</td><td> 0,043</td><td> 11,8 ± 0,6</td><td> 97</td>

<td> 47</td><td> 0,11</td><td> 20,9 ± 0,6</td><td> 97</td>

<td> 47</td><td> 0,12</td><td> 23,010,9</td><td> -</td>

<td> 47</td><td> 0,17</td><td> 23,2 ± 0,3</td><td> 94</td>

<td> 47</td><td> 0,20</td><td> 25,5 ± 0,9</td><td> -</td>

<td> 47</td><td> 0,26</td><td> 33 ± 1</td><td> -</td>

<td> 47</td><td> 0,28</td><td> 33 ± 1</td><td> -</td>

ES 2 200 162 T3

TABLE 21.1 (continued)

<td colspan="4">First-order rate constants and yields of 5 for the decomposition of 4 ([Pd] A 1 x 10^-2 M) in THF-d₈.</td>

<td>Temp</td><td>[KOCH2CH3]</td><td>(104) kobsS^-1</td><td>ArOR yield (± 5%)</td>

<td> 52</td><td> 0,0017</td><td> 30 ± 1</td><td> 85</td>

<td> 55</td><td> 0,0017</td><td> 43 ± 2</td><td> -</td>

<td> 55</td><td> 0,0017</td><td> 45 ± 3</td><td> 87^to</td>

<td> 57</td><td> 0,0017</td><td> 58 ± 2</td><td> 86</td>

^to contained PPh3 (0.15 M). ^b it contained KBr in excess.

The kinetics of the reductive removal of 4 was investigated in greater detail in an effort to probe the mechanism of palladium-mediated CO-binding formation. Thermolysis of a freshly prepared solution of 4 {[4]₀ = 17 mM} in THF-d₈ at 47 ° C led to first-order deterioration of 4 over&gt; 3 half-lives with a constant velocity of k_obs = 1.52 ± 0.05 x 10^-3 s^-1,12,17,18. The decomposition rate of 4 in THF-d8 was not significantly altered (&lt;10%) by the presence of PPh3 (0.15 M) or KBr (saturated) but was accelerated by the addition of an excess of KOCH2CMe3. In order to determine the rate dependence on the alkoxide concentration, the rate constants observed for the decomposition of 4 were measured as a function of the KOCH2CMe3 concentration of 0.0017 to 0.30 M at 47 ° C in THF- d8. The graph of kobs versus alkoxide concentration was linear with a significant positive intercept of the ordinate which established the two-time velocity law shown in eq 1, in which k = 1.50 ± 0.07 x 10³ s^-1 [AG * = 22.9 ± 0.1 kcal mol^-1] and k = 6.2 ± 0.4 x 10³ s^-1 M^-1[AG * = 22.0 ± 0.1 kcal mol^-1].¹⁷ In addition, the rate constants observed for the disappearance of 4 in the absence of KOCH2CMe were measured.₃¹² added at temperatures between 23 and 57 ° C in THF-d₈. The Eyring plot of the data provided the activation parameters for the independent alkoxide pathway: AIk = 19.8 ± 0.8 kcal mol^-1; AS '= -9 ±

17.19 speed = -^d—^] = k [4] + k '[4] [KOCH₂CMe₃] _dt (1)

Neopentoxide ligand 4 underwent simple associative exchange with KOCH₂CMe₃ free at 47 ° C in THFd₈. At a low concentration of KOCH_ZCMe₃ (&lt;2 mM), the NMR spectrum¹H at 4 at 47 ° C showed a marked tert-butyl resonance (1/2 &lt;2 Hz) without any loss of coupling between the diastereotopic benzyl protons. However, in the presence of the excess KOCH2CMe3, the tert-butyl peak widened considerably. The observed rate constants for alkoxide exchange were determined from the enlargement of the excess line (Δω1 / 2 = k / Π)²⁰ as a function of the alkoxide concentration from 0.0017 to 0.3 M KOCH2CMe₃at 47 ° C. A graph of kobs, versus [KOCH_zCMe₃] established a first order dependence of the exchange rate on the alkoxide concentration and the second order rate law shown in eq 2, where kex = 1.0 ± 0.1 x 10² s^-1 M^-1 ^ G * = 15.8 ± 0.1 kcal mol^-1].¹⁷ (2) alkoxide exchange rate = Kex [4] [KOCH2CMe3]

<img file="ES2200162T3_D0014.tif" />

ES 2 200 162 T3

Reductive elimination from square planar d8 metals to form DC bonds has been proposed to occur from coordinate complexes three, four, or five. ¹ The speed law of the experiment for the decomposition of 4 (eq 1) coincides with the reductive elimination of CO by opposing the alkoxide-dependent and alkoxide-independent pathways. The activation parameters for the alkoxide-independent pathway coincide with the unimolecular reductive elimination directly from 4 to form 5 and presumably to the Pd (0) I species (Scheme 21.3), in which the empirical rate constant k = k1 (Scheme 21.3).¹⁵ We cannot strictly rule out a mechanism initiated by the rapid and reversible dissociation of a single phosphoric center. However, the rate of reductive removal of CS from palladium (aryl) tert-butylsulfide complexes was not effected by the rigidity of the chelating phosphine ligand, which suggested that ligand cleavage did not precede reductive removal.⁵

The alkoxide-dependent pathway could be produced by a rapid and reversible attack of the alkoxide on palladium to generate the five-coordinate bis (alkoxide) intermediate {Pd [(R) -Tol-BINAP] (p-C6 H4 CN) (OCH2 CMe3) 2 }^- (II) or a related isomer. ²¹ Reductive rate limiting elimination from II could then generate 5 and presumably the three coordinate palladium alkoxide fragment {[(R) -Tol-BINAP] Pd (OCH2 CMe3)}^- (1a). The intermediate position of II is supported by the simple associative alkoxide exchange observed for 4 in the presence of KOCH2 CMe3. The stationary speed law for this road (eq 3) is in the same way as the second term of the speed law of the experiment (eq 1), where k '= k2 k3 / (k2 + k3). In contrast, the alkoxide-dependent pathway could be produced by the direct attack of the alkoxide on the palladium-bound aryl group's own carbon atom to form the Meisenheimer III complex. The collapse of III would then generate 5 and the. The stationary speed law for this path (eq 4) is also in the same form as the second term of the speed law of the experiment (eq 1), where k '= k4 k5 / (k4 + k5).²² speed = - ^^-4 = τ—— © [4] [KOCH₂CMe₃] dt k-2 + k3 velocity = -⁴⁴ = ^⁵. | 4] | KOCH-CMe.1 dt k-4 + k5 (3) (4)

In conclusion, we have presented the first examples of the reductive elimination of CO from group 10 metal (aryl) alkoxide complexes to form aryl ethers. Kinetic analysis of the decomposition of 4 in the presence of excess alkoxide established the two-time rate law which consisted of the presence of both an alkoxide-independent and an alkoxide-dependent pathway for reductive elimination of CO. We continue to investigate the mechanism of this important transformation. ^11b In particular, we are probing the electronic and stearic effects of both the palladium-linked aryl group and the chelating phosphine ligand on the rate and efficiency of reductive CO removal.

Experiment protocol for comparative example 9

General methods

All manipulations and reactions were carried out under a nitrogen or argon atmosphere in a glove box or by standard Schlenk techniques. Preparatory scale reactions were carried out in oven- or flame-dried Schlenk tubes equipped with a stir bar, a side sleeve joint, and a septum. NMR spectra were obtained in oven-dried 5 mm thin-walled NMR tubes covered with a rubber septum on a Varian XL-300 spectrometer at 22 ° C unless otherwise noted. Gas chromatography was performed on a Hewlett-Packard model 5890 gas chromatograph using a 25 µm capillary polymethylsiloxane column. GC response factors were determined from mixtures of pure compounds. Elemental analyzes were carried out by E + R Microanalytical Laboratories (Corona, NY). Diethyl ether, hexane, and TNF-d8 were distilled from sodium benzophenone cetyl solutions under argon or nitrogen. Pd2 (DBA) 3, P (o-tol) 3, (R-Tol-BINAP, dppf (Strem), 4-bromobenzonitrile, pivaldehyde, biphenyl, 4,4'-dimethylbiphenyl, and benzonitrile (Aldrich) were used as they were received. KOCH2CMe3 was synthesized from the reaction of anhydrous neopentanol (Aldrich) and 1 equiv of KH in THF.

Kinetic measurements

Samples for kinetic analysis were prepared from broth solutions of the appropriate aryl halide palladium complex and run in oven-dried 5 mm thin-walled NMR tubes covered with rubber baffles. The volume of the solvent in the NMR tubes was calculated from the height of the solvent measured at 25 ° C according to the relationship V (mL) = H (mm) x 0.01384 - 0.006754 and from the dependence of the temperature of the density of benzene.²³ Kinetic data were obtained by NMR spectroscopy. ¹H on the heated probe of a Varian XL-300 spectrometer. Probe temperatures were measured with an ethylene glycol thermometer and were maintained at ± 0.5 ° C during the data acquisition period. The syringes used for the measurement of liquids for kinetic measurements were calibrated by means of mercury displacement and had a

ES 2 200 162 T3&gt; 95% accuracy. The limits of error for the rate constants refer to the standard deviation of the corresponding least squares fit line.

{Pd [P (o-toUl)₃] (pC₆H₄CN) fa-Br)}₂ (3)

A purple solution of Pd2 (DBA) 3 (1.0 g, 1.1 mmol), P (o-tol) 3 (1.3 g, 4.3 mmol) and p-bromobenzonitrile (2.0 g , 11 mmol) in benzene (60 mL) at room temperature for 1 h. The resulting green / brown solution was filtered through Celite and the benzene was evaporated in vacuo. The oily residue was dissolved in Et2O (25 mL) and allowed to rest at room temperature overnight. The resulting yellow precipitate was filtered, washed with Et2O and dried under vacuum to give 3 (0.95 g, 75%) as a yellow powder. NMR¹H (CHCl3, 55 ° C): δ 7.33, 7.13, 6.90, 6.73, 2.10.³¹P {¹H} NMR (CDCl3, 55 ° C): δ -22.5 (br s). IR (THF): vcn 2222 cm^-1. Anal: calcd. (found) for C56H₅₀Br₂N₂P₂P.S₂: C, 56.73 (56.57); H, 4.25 (4.51).

Pd [(R) -Tol-BINAP] (p-C6H4CN) (Br) (1)

A solution of 3 (200 mg, 0.17 mmol), and (R) -Tol-BINAP (240 mg, 0.35 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 5 h and then evaporated in vacuo . The oily residue was dissolved in Et2O (10 mL) and allowed to rest at room temperature for 4 h. The resulting precipitate was filtered, washed with Et2O, and dried under vacuum to give 1 (308 g, 94%) as a yellow solid containing trace amounts of ether (&lt;5%) by NMR analysis.¹H. NMR ¹H (THF): δ 8.26 (dd, J = 8.73, 10.5), 8.04, (t, J = 8.2 Hz), 7.98 (t, J = 9.3 Hz ), 7.91 (q, J = 7.7 Hz), 7.77-7.60 (m, 7H), 7.38 (m, 4H), 7.28-7.14 (m, 5H), 6.90 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 6.8 Hz, 2H, C6H4CN), 6.67 (d, J = 7, 0 Hz, 2H, C6H4CN), 2.76 (s, 3H, p-tolyl), 2.56, (s, 3H, p-tolyl), 2.31, (s, 3H, p-tolyl) , 2.29 (s, 3H, p-tolyl). ³¹P {¹H} NMR: δ 26.7 (d, J = 38.1 Hz), 11.4 (d, J = 37.9 Hz). IR (THF): vcn 2219 cm^-1. Anal: calcd. (found) for C₅₅H₄₄BrNp₂Pd: C, 68.30 (68.36); H, 4.59 (4.87).

Pd (dppf) (pC6H4 CN) (Br) (2)

A solution of 3 (200 mg, 0.17 mmol), and dppf (258 mg, 0.47 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 12 h. The resulting solution was concentrated under vacuum. The addition of Et2O (10 mL) formed a precipitate which was filtered, washed with Et2O and dried under vacuum to give 2 (280 mg, 79%) as a bright yellow solid containing trace amounts of ether (&lt;5%) by NMR analysis¹H. NMR ¹H (CDCl3): δ 8.01 (dt, J = 2.7, 9.7 Hz), 7.47 (m, 6H), 7.33 (t, J = 11.2 Hz, 6H) , 7.12 (dt, J = 1.7, 15.4 Hz, 6H), 6.76 (d, J = 7.54 Hz, 2H), 4.68 (d, J = 1.95 Hz, 2H, Cp), 4.51 (s, 2H, Cp), 4.14 (d, J = 2.23 Hz, 2H, Cp), 3.59 (d, J = 1.74 Hz, 2H, Cp). ³¹P {¹H} NMR (CDCl3): S 30.0 (d, J = 29.2 Hz), 10.8 (d, J = 31.6 Hz). IR (CH2CU): V [c = n] 2220 cm^-1 .Anal: calcd. (found) for C41H₃₂BrFeNP₂Pd: C, 58.43 (58.41); H, 3.83 (3.98).

Pd [(R) -Tol-BINAP] (p-C6H4CN) (OCH2CMe3) (4)

A 0.54 M KOCH solution was added₂I₃ in THF-d₈ (25 μ / L-, 1.35 x 10^-2 mmol) by means of a syringe to a colorless solution of 2 (12 mg, 1.25 x 10^-2 mmol) and PhSiMe3 (1.75 mg, 1.16 x 10^-2 mmol) in THF-d8 (0.70 mL). The tube was briefly shaken at room temperature and centrifuged to form an orange solution of 4 in quantitative yield (98 ± 5%) by NMR spectroscopy.¹H versus PhSiMe3 internal standard. 4 was thermally unstable and was analyzed without isolation by NMR spectroscopy.¹ H and ³¹ P. ¹H NMR (THF-d8): in addition to a small resonance corresponding to the free alkoxide (δ 0.85), resonances were observed at δ 7.83 (t, J = 8.4 Hz), 7.78 - 7.59 ( m), 7.51 - 7.25 (m), 7.12 (t, J = 7.4 Hz), 7.04-6.93 (m), 6.81 (d, J = 7.0 Hz), 6.44 (d, J = 7.4 Hz), 6.29 (d, J = 7.4 Hz) 2.76 (d, J = 9.0 Hz, 1 H, -OCH2CMe3), 2.62 (d, J = 8.8 Hz, 1H, -OCH2CMe3), 2.38 (s, 3H, p-tolyl), 2.19 (s, 3H, p-tolyl), 1, 98 (s, 3H, p-tolyl), 1.93 (s, 3H, p-tolyl), 0.17 (s, 9H, CMe3), ³¹P {¹H} NMR (THF-d8): S 29.3 (d, J = 36.6 Hz), 14.1 (d, J = 36.7 Hz). IR (THF): v_CN 2218 cm^-1. Pd (dppf) (p-C8H4CN) (OCH2CMe3) (6)

A yellow suspension of 2 (11 mg, 1.3 x 10^-2 mmol) in THF-d8 (0.70 mL) with aliquots of KOCH2Me3 in THF-d8. Addition of 1.1 equiv alkoxide formed an orange solution of 6 and a small amount of free KOCH2Me3 as unique products by NMR spectroscopy.¹H. Despite the relatively slow decomposition of 6 at room temperature (t 1/2 At 4 h) attempts to isolate 6 from the corresponding set-up reaction gave only impure brown solids. NMR¹H (22 ° C, THF-d8): δ 8.21 (m, 4 H), 7.46 (m), 7.40 (d J = 11.5 Hz), 7.37 (dd, J = 1.2, 11.6 Hz), 7.31 (t, J = 7.3 Hz), 7.09 (dt, J = 2.1, 8.0 Hz), 6.75 (dd, J = 2.2, 8.2 Hz, 2H), 4.82 (q, J = 2.0 Hz, 2H, Cp), 4.58 (br s, 2H, Cp), 4.20 (t , J = 1.6 Hz, 2H, Cp), 3.55 (q, J = 1.8 Hz, 2H, Cp), 2.68 (s, 2H, OCH2CMe3), 0.23 (s , 9 H, OCH2CMe3), ³¹P {¹H} NMR (22 ° C, THF-d8): δ 30.9 (d, J = 32 Hz), 11.9 (d, J = 31.7 Hz). IR (THF): v_[C=_N] 2218 cm^-1.

Thermolysis kinetics of 4

An NMR tube containing a freshly prepared solution of 4 (12 mg, 1.2 x 10^-2 mmol) and PhSiMe₃ (1.75 mg, 1.16 x 10^-2 mmol) in THF-d₈ (0.70 mL) {[KOCH₂CMe₃] At 1.7 mM} in an NMR spectrometer probe heated to 47 ° C. The concentrations of 4, and p-neopentoxybenzonitrile, were determined by integrating the tert-butyl resonance for 4 (δ 0.17) and p-neopentoxybenzonitrile (δ 1.06) versus

ES 2 200 162 T3 the trimethylsilyl resonance of PhSiMe3 (δ 0.25) in the NMR spectrum ¹H. The concentrations of 4,4'-dimethylbiphenyl and benzonitrile were determined by integrating the peaks for 4,4'-dimethylbiphenyl, benzonitrile, and PhSiMe3 in the GC spectrum. The first order rate constant for the disappearance of 4 was determined from a plot of In [4] versus time (Figure 2, Table 21.1). The corresponding plot of reciprocal concentration versus time (Figure 3) deviated considerably from linearity.

First order rate constants were also obtained for the disappearance of 4 in the absence of the addition of KOCH₂CMe₃ (&lt;2 mM) at 23, 35, 37, 52, and 57 ° C (Figure 2, Table 21.1); Activation parameters were obtained from a graph In [k / T] versus 1 / T (Figure 4). First order rate constants for the disappearance of 4 were also measured as a function of [KOCH₂CMe₃] from 0.043 to 0.30 M at 47 ° C in THF-d8 (Table 21.1). Solutions of 4 with KOCH2CMe3 concentrations ranging from 0.43 to 0.12 M were obtained by a procedure analogous to that described above. Solutions of 4 with KOCH2CMe3 concentrations&gt; 0.12 M were prepared by adding a 4 (17 mM) THF-d8 solution (via syringe) to an NMR tube containing solid KOCH2CMe3. The first order rate constant k was obtained as the intercept of a graph of kobs versus [KOCH2CMe3] (Figure 5). The second order rate constant k was obtained from the slope of this graph.

Kinetics of alkoxide exchange with 4

An NMR tube containing a freshly prepared solution of 4 (12 mg, 1.2 x 10^-2 mmol, 19 mM), PhSiMe3 (1.75 mg, 1.16 x 10^-2 mmol), and KOCH2CMe3 (3.4 mg, 0.0271 mmol, 0.043 mM) in THF-d8 (0.63 mL) in the probe of a NMR spectrometer heated to 47 ° C. The amplification of the excess line (Δω1 / 2) of the 4-tert-butyl resonance was determined by measuring the maximum width at the mean height (ω1 / 2) for the 4-tert-butyl resonance (δ 0.17 ) relative to ω1 / 2 for the trimethylsilyl resonance of PhSiMe3 (δ 0.25) in the NMR spectrum¹H [Δω1 / 2 (4) = ω_1/2 (4) - ω_1/2 (PhTMS)]. Because the separation of the tert-butyl peaks for PdOCH₂CMe₃ and KOCH₂CMe₃ (Δν&gt; 200 Hz) was much larger than the excess magnification of the tertbutyl resonance of 4 (ω_1/2 = 5.5 Hz), the slow exchange approximation (ω_1/2 = k_obs/ n) to convert Δω_1/2 ak_obs.²⁴The rate constants observed for alkoxide exchange were also determined in concentrations of KOCH2CMe3 that ranged from 0.0017 to 0.30 M. The second order rate constant kex for alkoxide exchange with 4 was determined from the slope of a graph of kobs, versus [KOCH2CMe3] (Figure 6, Table 21.2).

TABLE 21-2

First-order rate constants for alkoxide exchange 4 at 47 ° C in THF-d₈

<td>[KOCH2CH3]</td><td>k_obs s^-1</td><td>[KOCH2CH3</td><td>kobs s^-1</td>

<td> 0,0017</td><td> 0,62</td><td> 0,12</td><td> 16</td>

<td> 0,0082</td><td> 1,6</td><td> 0,17</td><td> 18</td>

<td> 0,019</td><td> 3,0</td><td> 0,20</td><td> 22</td>

<td> 0,030</td><td> 4,2</td><td> 0,26</td><td> 26</td>

<td> 0,043</td><td> 6,1</td><td> 0,28</td><td> 29</td>

<td> 0,11</td><td> 17</td><td></td><td></td>

Thermolysis kinetics 6

An NMR tube containing a freshly prepared solution of 6 (11 mg, 1.2 x 10^-2 mmol, 18 mM) in THF-d8 (0.70 mL) and mesitylene (1.72 mg, 1.14 x 10^-2 mmol) in a probe of a NMR spectrometer pre-heat to 55 ° C. The concentrations of 6, and p-neopentoxybenzonitrile, and pivaldehyde were determined by integrating the tert-butyl resonances for 6 (δ 0.23), p-neopentoxybenzonitrile (δ 1.06) and pivaldehyde (δ 1.04) versus the mesitylene methyl resonance (δ 2.12) in the NMR spectrum¹H. Biphenyl and benzonitrile concentrations were determined by integrating the peaks for biphenyl, benzonitrile, and mesitylene in the GC spectrum. The first order rate constant was determined for the disappearance of 6 (kobs = 1.33 ± 0.04 x 10^-3 s^-1) from a graph of In [6] versus time.

References for Comparative Example 9

1) (a) Stille, JK Angew. Chem. Int. Ed. Engl. 1986, 25,508. (b) Miyaura, N .; Suzuki, A. Chem. Rev. 1995, 95, 2457. (c) de Meijere, A .; Meyer, FE Angew. Chem. Int. Ed. Engl. 1994, 33, 2379.²

2) (a) Collman, JP; Hegedus, LS; Norton, JR; Finke, RG Principles and Applications of Organotransition Metal Chemistry; University Science: Mill Valley, CA, 1987: p 322.

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3) (a) Kosugi, M .; Ogata, T .: Terada. M .; Sano, H .; Migita, T. Bull Chem. Soc. Jpn. 1985, 58, 3657. (b) Dickens, MJ; Gilday, JP; Mowlem T J .; Widdowson, DA Tetrahedron, 1991, 47, 8621 and their accompanying references.

4) (a) Wolfe, JP; Wagaw, S .; Buchwald, SLJ Am. Chem. Soc. 1996, 118, 7215 and their accompanying references. (b) Louie, J .; Hartwig, JF Tetrahedron LetL 1995, 36, 3609.

5) Baranano, D .; Hartwig, JFJ Am. Chem. Soc. 1995, 117, 2937.

6) (a) Driver, MS; Hartwig, JFJ Am. Chem. Soc. 1996, 118, 7217. (b) Villanueva, LA; Abboud, KA; Boncella, JM Organometallics, 1994, 13, 3921.

7) Bryndza, HE; Tam, W. Chem. Rev. 1988, 88, 1163.

8) The oxidation of nickel oxametalacycles has been shown to form C bonds (sp³) -O.Koo, K .; Hillhouse, GL; Rheingold, AL Organometallics, 1995, 14, 456.

9) Reductive elimination from Pd and Ni has been found to form a C (O) -O: Komiya ester linkage. S .; Akai, Y .; Tanaka, K .; Yamamoto, T; Yamamoto, A. Organometallics 1985,4,1130.

10) (a) Palucki, M .; Wolfe, JP; Buchwald, SLJ Am. Chem. Soc. 1996,118,10333. (b) Palucki, M .; Buchwald, SL filed.

11) (a) L. unpublished results. (b) We investigate a range of alkoxides and will report the results of these studies in a full paper.

12) The solution contained a small amount (&lt;2 mM) of free KOCH2CMe3.

13) (a) The final destination of palladium is not yet clear. The NMR spectrumⁱH of the reaction mixture revealed a broad resonance at δ 2.1 possibly corresponding to palladium (R) Tol-BINAP complexes while the NMR spectrum ³¹P showed a small resonance for (R) -Tol-BINAP free (16,1) and a wide resonance at δ -2. No resonance was observed in the expected region for Pd [(R) -Tol-BINAP]₂ {δ 25 for Pd [(R) BlNAP]₂}^13b. (b) Ozawa, F .; Kubo, A .; Hayashi, T Chem. Lett. 1992, 2177.

14) Morita, DK; Stille, JK; Norton, J. R, J. Am. Chem. Soc. 1995, 117, 8576.

15) Braterman, PS; Cross, RJ; Young, GBJ Chem. Soc., Dalton Trans. 1977, 1892.

16) (a) Bryndza, HE; Calabrese, JC; Marsi, M .; Roe, DC; Tam, W .; Bercaw, JEJ Am. Chem. Soc. 1986, 108,4805. (b) Hoffman, D. M,; Lappas, D .; Wierda, DAJ Am. Chem. Soc. 1993, 115, 10538. (c) Blum, O .; Milstein, D. Angew. Chem., Int. Ed. Engl. 1995, 34, 229.

17) See experiment protocol above.

18) The corresponding second-order graphs (see Supporting Information) deviated significantly from linearity. Velocity measurements using different batches of 4 and KOCH2CMe3 yielded values ​​for kobs that were &lt;7.5% different.

19) Under these conditions {[KOCH2CMe3] &lt;2 mM}, k&gt;&gt; k [KOCH2CMe3], and kobs A k.

20) Bovey, FA Nuclear Magnetic Resonance Spectroscopy, 2nd Ed. Academic Press: San Diego, CA, 1988.

21) The proposed II structure assumes that the Tol-BINAP ligand will extend into equatorial-axial sites (90 °) rather than equatorial-equatorial sites (120 °) in the trigonal bi-pyramid due to the preferred bite angle of - 92 °; Hayashi, T .; Konishi, M .; Kobori, Y; Kumada, M .; Higuchi, T; Hirotsu, KJ Am. Chem. Soc. 1984, 106, 158.

22) This speed law assumes the speed limitation collapse of III. The velocity law for the velocity limiting formation of III, followed by rapid collapse to form 5 (velocity = k4 [4] [KOCH2CMe3]) is also in the same form as the second term of the velocity law of the experiment.

23) International Critical Tables of Numerical Data, Physics, Chemistry, and Technology, Volume III, Washburn, EW, Ed .; McGraw-Hill: London, 1928; pp 29, 39,221.²⁴

24) Bovey, FA Nuclear Magnetic Resonance Spectroscopy, 2nd Ed. Academic Press: San Diego, CA, (1988).

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Example 13

Palladium-catalyzed intermolecular carbon-oxygen bonding formation: A new synthesis of aryl ethers.

The synthesis of aryl ethers through intermolecular formation of a carbon and oxygen bond can be catalyzed by a combination of Pd2 (dba) 3 or Pd (OAc) 2 and Tol-BINAP in toluene. This procedure produces aryl ethers in moderate to good yields. While little or no conversion is observed in control reactions performed in toluene, it was found that for some electron-poor aryl bromides nucleophilic aromatic substitution could be carried out in DMF in the absence of a metal catalyst under mild conditions.

Aryl ethers are ubiquitous structural constituents in pharmacologically important molecules, and consequently much research has been directed toward their synthesis.^l

Available methods for the synthesis of aryl ethers by direct or Cu (I) catalyzed nucleophilic substitution of an aryl halide with an alcohol typically require high reaction temperatures and / or a large excess of alcohol and are found limited in the field of application of the substrate.^2,3,4 The need to use HMPA, DMSO or DMF as a solvent further diminishes the applicability of these methods, especially for large-scale procedures.

Recently, we have reported the first example of palladium catalyzed aromatic carbon and oxygen bonding; the Pd-catalyzed intramolecular substitution of an aryl halide with an alcohol to give oxygen heterocycles.^5-6 This method was used to synthesize five-, six-, and seven-membered oxygen heterocycles in moderate to good yields.⁷ We attempted to determine if a related catalyst agent system could be used for the synthesis of aryl ethers by intermolecular coupling of alcohols and aryl bromides (eq 1).⁸ Here, we report our initial results, which demonstrate the feasibility of using palladium catalysis for the intermolecular formation of carbon and oxygen bonds in a process that takes place under moderate conditions.

<img file="ES2200162T3_D0015.tif" />

The conditions used for the intramolecular procedure (see above) were not immediately applicable to the intermolecular version. However, we found that the reaction of 2-propanol, 4-bromobenzonitrile and NaH in the presence of 1.5 mol% of Pd2 (dba) 3 and 3 mol% of (S) - (-) - 2,2 ' -bis (di-p-tolylphosphino) -1,1'binaphthyl (Tol-BINAP) at 50 ° C produced 4-isopropoxy-benzonitrile in an isolated yield of 80%.⁹ Although Pd (OAc) 2 was found to be an effective catalyst precursor, the use of Pd2 (dba) 3 gave higher product rates for reduced by-products (benzonitrile) as determined by GC analysis. ¹⁰ Aryl bromides containing electron-withdrawing substituents (Table 1, entries 1-5) were effectively coupled with a wide variety of alcohols, including 2-propanol, 3-pentanol, (1 R, 2S, 5R) - (-) -menthol, ¹¹ benzyl alcohol and methanol within 24 hours using 1.5 mol% Pd₂(dba)₃ and 3.6 mol% Tol-BINAP at 70 ° C. ¹² The Pd-catalyzed coupling of methanol with 4-bromobenzonitrile is of interest because methanol in combination with catalytic amounts of Pd (PPh3) 4 has previously been shown to be effective in reducing aryl halides to de-arene products. halogenated with the concomitant formation of HCHO. ¹³ The application of this technology using electron-rich or neutral aryl bromides and different alcohols produces the desired coupling products in good yields only when tertiary alcohol alkoxides or cycloalkanols are used. For example, the reaction of 4-bromo-t-butylbenzene with 2-propanol or cyclopentanol produced predominantly the reduction product t-butylbenzene. However, reaction with NaOt-Bu produced the aryl ether product in an isolated yield of 53% (entry 6). ¹⁴ A similar reaction of 1-bromonaphthalene with 2-propanol produced naphthalene as the main product, while the use of cyclohexanol produced the aryl ether product in 65% yield (entry 7). Higher rates of aryl ether to anthracene were observed for the reaction of 9-bromoanthracene with tetrahydro-4-H-pyran-4-ol than with cyclopentanol (entries 8 and 9).¹⁵

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TABLE 22.1

Synthesis of Aryl Ethers by Pd-Catalyzed Direct Nucleophilic Substitution Reactions

<img file="ES2200162T3_D0016.tif" />

^to for entries 1-9 and 7-9, reaction conditions: 1.5 mol% Pd2 (dba) 3. 3.6 mol% of Tol-BINAP, 1 equiv of aryl bromide, 1.2 equiv of alcohol and 2.0 equiv of NaH. For input 6: 5 mol% of Pd (OAc) 2. 6 mol% of Tol-BINAP, 1 equiv of aryl bromide and 2.0 equiv of NaO t-Bu.^b Yields refers to the average insulated yields for two cycles.

While only preliminary studies of the mechanism of this procedure have been carried out, it is most likely continued by a pathway similar to that of the Pd catalyzed intramolecular CO-binding formation reaction. ⁵ and the related aryl amination procedure (Scheme 22.1 a). ¹⁶ Oxidative addition of the Pd (0) Ln complex to the aryl bromide produces A. Substitution of the bromide with the alkoxide produces palladium (aryl) alkoxide B. Reductive elimination of B produces the aryl ether with regeneration of the active catalyst agent. ¹⁷ In the cases that continue in lower yields, a β-hydride elimination / reductive elimination sequence that produces the reduced arene by-product competes with the reductive elimination (Scheme 22.1 b). ^13c As observed in the aryl amination process, the effects of the ligand are key to favoring the reductive elimination process over the β-hydride elimination pathway. We think that the use of less electron donating and bulky ligands (although probably still chelating ligands) should favor the reductive elimination procedure.^{16b, 18c}

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Scheme 22.1 (a) Phosphine omitted for clarity purposes

<img file="ES2200162T3_D0017.tif" />

Under the conditions employed, the formation of aryl ether in toluene in the absence of catalyst was not observed for any of the substrates examined in Table 22.1. Because the rates of nucleophilic aromatic substitution processes are increased in aprotic polar solvents, we decided to investigate uncatalyzed reactions in more detail using DMF as the solvent for the substrate shown in Table 22.1.¹⁹In fact, under these conditions, aryl bromides containing electron-withdrawing substituents could be effectively converted to aryl ethers (entries 1-5). In previous reports of nucleophilic substitution reactions of aryl bromides with alcohols, either higher temperatures or the use of 4 or more equivalents of the alcohol were generally employed. For the substrates studied, we found that 1.2 equivalents of the alcohol were sufficient to achieve good yields of aryl ethers at 55-70 ° C.²⁰ In contrast, in reactions of electron-rich or neutral aryl bromides with alcohols in DMF, only small amounts (&lt;10%) of aryl ether products were observed. Furthermore, under these conditions, both meta- and para-isomers were observed in the reaction of 4-bromo-t-butylbenzene with NaOt-Bu, suggesting that there is a functional benzine pathway.²¹

In order to further contrast catalyzed and uncatalyzed processes, and to extend the synthetic utility of Pd catalyzed transformation, the reaction of 4-bromo-2-chlorobenzonitrile was examined under both conditions, the conditions catalyzed by Pd in ​​toluene and conditions not catalyzed in DM F (Table 22.2). The Pd catalyzed reaction of 4-bromo-2-chlorobenzonitrile with cyclohexanol, NaOt-Bu, or sec-phenethyl alcohol in toluene produced an aryl ether product that resulted from the unique substitution of the bromide. In the absence of a Pd catalyst agent, slow substitution of chloride in toluene for cyclohexanol and sec-phenethyl alcohol was observed, while reaction with NaOt Bu did not produce aryl ether products. In DMF, reaction not catalyzed by cyclohexanol or sec-phenethyl alcohol in DMF produced a mixture of aryl ether products, while no aryl ether products were observed with NaOt Bu.

(Table 22.2 goes to next page)

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TABLE 22.2

Comparison of Pd-catalyzed and non-catalyzed substitution of 4-bromo-2-chlorobenzonitrile

<img file="ES2200162T3_D0018.tif" />

^to Yields refers to the average isolated yield of C for two cycles. ^b The isolated product of the catalyzed reaction contains 5% 4-cyclohaxyloxybenzonitrile. Isolated yield for uncatalyzed reaction refers to a mixture of C and D. Isolated yield for uncatalyzed reaction refers to the sum of the isolated yield for C and D.

The results presented above provide proof of concept that our palladium catalyzed methodology is applicable for the formation of aryl ethers by intermolecular coupling of an aryl bromide and an alkoxide. Furthermore, our study is instructive of uncatalyzed substitutions both in toluene (under catalyzed process conditions) and in DMF. They indicate that the exact comparison of the efficiencies of catalyzed and uncatalyzed reactions requires the use of favorable reaction conditions for both cases. Experiment protocol for comparative example 11

General considerations

All reactions were carried out in oven or flame dried glassware. All manipulations involving air-sensitive materials were carried out in a glove box under vacuum atmosphere under purified nitrogen or using standard Schlenk techniques under argon atmosphere. All reactions were carried out under an argon atmosphere and were stirred with a magnetic stirrer. Toluene was distilled under nitrogen from molten sodium. Sodium tert-butoxide and sodium hydride (95%) were purchased from Aldrich Chemical Company and stored in vacuum atmosphere glove box. (S) - (-) - 2,2'-bis (di-p-tolylphosphino) -1,1'-binaphthyl) (Tol-BINAP), Pd2 (dba) 3, Pd (OAc) 2, were purchased from Strem Chemical Company and were used without further purification. Sodium hydride (in 60% dispersion in mineral oil), anhydrous methyl alcohol, cyclopentanol, 3-pentanol, (1R, 2S, 5R) - (-) menthol, 9-bromoanthracene, sec-phenethyl alcohol, Anhydrous 2-propanol, anhydrous benzyl alcohol, tetrahydro-4H-pyran-4-ol, menthol, 4-bromobenzonitrile, and 1-bromonaphthalene from Aldrich Chemical Company and were used without further purification. 4-Bromobenzotrifluoride and 4-bromo-2-chlorobenzonitrile were purchased from Lancaster Inc. and were used without further purification. Cyclohexanol was purchased from Mallinckrodt Inc. and distilled over CaH2 under reduced pressure. Anhydrous DMF was purchased from Aldrich Chemical Company or distilled over CaH2. Silica gel chromatography purifications were carried out by flash chromatography using silica EM Science Kieselgel 60 (230-400 mesh) packed in columns. Yields refer to isolated yields of compounds of purity greater than 95% as determined by capillary gas chromatography (GC) and proton Nuclear Magnetic Resonance (NMR) spectroscopy analysis. ¹ H). New compounds were also characterized by element analysis (E&amp;R Analytical Laboratory, Inc). The yields reported in this section refer to a single experiment while those reported in Table 1 are an average of two experiments.

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General Procedures for Pd Catalyzed Aryl Ether Formation

A Schlenk flask equipped with a Teflon-coated stir bar was loaded with NaH (1.0 mmol, in 60% dispersion in mineral oil), toluene (2 mL), and the alcohol (0.50 mmol). The mixture was heated to 70 ° C for 15 min under an argon atmosphere, cooled to room temperature, and Pd2 (dba) 3 (0.0075 mmol), Tol-BINAP (0.018 mmol), aryl bromide ( 0.50 mmol) and 1 mL of toluene.

The mixture was stirred at the indicated temperature until the starting material was consumed according to GC analysis. At this time, the solution was cooled to room temperature and diethyl ether (50 mL) and water (50 mL) were added. The aqueous layer was separated and extracted with diethyl ether (50 mL). The organic fractions were separated, washed in brine (50 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.

4-isopropoxybenzonitrile (Table 1, entry 1)

The general procedure was followed on a 0.50 mmol scale to yield 65 mg (80% yield) of a colorless oil. IR (sharp, cm^-1) Vmax: 2981, 2225, 1605, 1506, 1299, 1259; NMR¹H (CDCl3) δ 7.55 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 4.61 (septet, J = 6.0, 1H ), 1.34 (d, J = 6.0 Hz, 6H); ¹³C NMR (CDCl3) 161.4, 133.9, 126.3, 116.0, 70.4, 21.7; Anal Calcd. for C10H11 NO: C, 74.51; H, 6.88, found: C, 74.35; H, 7.08.

4-trifluoromethylphenyl 3- (Table 1, entry 2)

The general procedure was followed on a 0.75 mmol scale to yield 114 mg (54% yield) of a colorless oil. IR (sharp, cm^-1) vmax: 2970, 1615, 1518, 1329, 1257, 1161, 1116, 1068; NMR¹H (CDCl3) δ 7.53 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 4.19 (quintet, J = 5.8 Hz, IH), 1.65-1.77 (m, 4H) 0.97 (t, J = 7.4 Hz, 6H); ¹³C NMR (CDCl3) S 161.4, 126.9, 126.8, 126.7, 115.6, 80.5, 26.0, 9.5; Anal Calcd. for C12H15F3O: C, 62.31; H, 6.11, found: C, 62.04; H, 6.30.

4 - ((1R, 2S, 5R) -mentyloxy) benzonitrile (Table 1, entry 3)

The general procedure was followed on a 0.5 mmol scale to yield 96 mg (74% yield) as a white solid. mp 73 ° C; IR (sharp, cm^-1) vmax: 2959, 2220, 1602, 1504, 1252, 988; NMR¹H (CDCl3) δ 7.55 (d, J = 8.5 Hz, 2H), 9.92 (d, J = 8.5 Hz, 2H), 4.10 (dt, 1H, J = 3, 8, 10.4 Hz), 2.08-2.15 (m, 2H), 1.68-1.79 (m, 2H), 1.401.60 (m, 2H), 0.90-1.97 (m, 9H), 0.74 (d, J = 7.0Hz, 3H); ¹³C NMR (CDCl3) 161.8, 134.0, 119.4, 115.8, 103.2, 77.8,

47.7, 39.8, 34.3, 31.3, 26.1, 23.2, 22.0, 20.6,16.5; Anal Calcd. for C17H24NO: C, 70.33; H, 9.01, found: C, 79.50; H, 8.91.

4-Benzyloxybenzonitrile ²² (Table 1, entry 4)

The general procedure was followed on a 0.75 mmol scale to yield 113 mg (72% yield) of a white solid mp 89-90 ° C (litmp 91-93 ° C); IR (KBR, cm^-1) vmax: 2220, 1606, 1508, 1462, 1263, 1170, 1027, 837; NMR¹H (CDCl3) δ 7.57 (dd, J = 6.8, 1.9 Hz, 2H), 7.37-7.42 (m, 5H), 7.02 (dd, J = 6.8, 1.9 Hz, 2H), 5.11 (s, 2H); ¹³C NMR (CDCl3) δ 161.8, 135.6, 133.9, 128.6, 128.3, 127.3, 119.0, 115.5, 104.1, 70.2; Anal Calcd. for C14H11NO: C, 80.35; H, 5.30, found: C, 80.60; H, 5.27.

4-methoxybenzonitrile (Table 1, entry 5)

The general procedure was followed on a 0.75 mmol scale to yield 77 mg (77% yield) as a white solid. mp 56.0-56.8 ° C (lit²³ mp 57-59 ° C); NMR¹H (CDCl₃) δ 7.57 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); ¹³C NMR (CDCl3) δ 162.7, 133.8, 119.0, 114.6, 103.8, 55.4.

4-t-Butylphenyl t-butyl ether (Table 1, entry 6)

A Schlenk flask equipped with a Teflon-coated stir bar was loaded with Na (Ot-Bu) (97 mg, 1.00 mmol), Pd (OAc) 2 (5.6 mg, 0.025 mmol), and Tol-BINAP (20.4 mg, 0.030 mmol). The flask was emptied, refilled with argon, and charged with toluene (3 mL) and 4-t-butyl bromobenzene (87 µL, 0.50 mmol). The mixture was heated to 100 ° C for 40 h, cooled to room temperature and diethyl ether (20 mL) and water (20 mL) were added. The organic layer was separated, washed in brine (20 mL), dried over anhydrous MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (99/1 hexane / ethyl acetate) to yield 4-t-butylphenyl-t-butyl ether as a colorless oil (59 mg, 53% yield ). IR (sharp, cm^-1) Vmax: 2964, 1605, 1506, 1364, 1245, 1169; NMR¹H (CDCl3) δ 7.25 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 1.33 (s, 9H), 1.30 ( s, 9H); ¹³C NMR (CDCl3) δ 153.0, 145.9, 77.9, 34.2, 31.5, 28.9; Anal Calcd. for C14H22O: C, 81.50; H, 10.75, found: C, 81.59; H, 10.53.

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1-Naphthyl cyclohexyl ether (Table 1, entry 7)

A Schlenk flask equipped with a Teflon-coated stir bar was loaded with NaH (40 mg, 1.50 mmol), toluene (2 mL), and cyclohezanol (94 µL, 0.90 mmol). The mixture was heated at 70 ° C for 10 minutes under an argon atmosphere and then cooled to room temperature. To this was added 1-bromonaphthalene (104 μL, 0.75 mmol), Pd2 (dba) 3 (10.3 mg, 0.0125 mmol), (R) - (+) - 2.2 '- (di -p-tolylphosphino) -1,1'-binaphthyl (Tol-BINAP) (18.3 mg, 0.027 mmol), and 2 mL of toluene. The mixture was heated at 70 ° C for 20 h and at that time diethyl ether (60 mL) and water (60 mL) were added. The aqueous layer was separated and extracted with diethyl ether (60 mL). The organic fractions were combined, washed in brine (60 mL), dried over anhydrous MgSO4. The drying agent was removed by filtration and mother alcohol was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (50/1 hexanes / ethyl acetate) to yield 1-naphthyl cyclohexyl ether as a colorless oil (101 mg, 60% yield). IR (sharp, cm^-1) vmax: 3051, 2934, 2857, 1579, 1401, 1268, 1236, 1094; NMR¹H (CDCl3) δ 8.25-8.29 (m, 1H), 7.69-7.36 (m, 1H), 7.28-7.43 (m, 3H), 6.77 ( dd, J = 7.1, 1.3 Hz, 1H), 4.41 (quintet, J = 4.4 Hz, 1H), 1.93-1.97 (m, 2H), 1.32 -1.80 (m 8H); ¹³C NMR (CDCl3) δ 153.5, 134.8, 127.4,

126.7, 126.2, 125.8, 124.9, 122.4, 119.9, 75.3, 31.6, 25.8, 23.6; Anal Calcd. for C16H18O: C, 84.91; H, 8.02, found: C, 85.04; H, 7.88.

9-Antryl cyclopentyl ether (Table 1, entry 8)

The general procedure was followed on a 0.5 mmol scale with a reaction temperature of 100 ° C to yield 58 mg (49% yield) of a white solid mp 60-62 ° C; IR (sharp, cm^-1) V_max: 2960, 1337, 1084; NMR¹H (CDCl3) δ 8.29-8.32 (m, 2H), 8.19 (s, 1H), 7.95-7.99 (m, 2H), 7.41-7.48 (m , 4H), 4.90-4.96 (m, ¹H), 2.002.20 (m, 4H), 1.65-1.85 (m, 4H); ¹³C NMR (CDCl3) δ 150.9, 132.4, 130.9, 128.3, 125.3, 124.7, 123.1, 121.7, 88.3, ​​33.1, 23.1; Anal Calcd. for C19H18O: C, 86.99; H, 6.92, found: C, 87.2; H, 6.92

9-Antril 4-tetrahydro-4H-pyran ether (Table 1, entry 9)

The general procedure was followed on a 0.50 mmol scale with a reaction temperature of 100 ° C to yield 125 mg (90% yield) of a yellow solid at 99.9-100.8 ° C; IR (KBr, cm^-1) v_max: 3048, 2951, 2839, 1409, 1343, 1168, 1092, 1003, 737; NMR¹H (CDCl3) δ 8.27-8.30 (m, 2H), 8.18 (s, 1H), 7.92-7.97 (m, 2H), 7.39-7.48 (m , 4H), 4.38-4.46 (m, 1H), 3.98-4.06 (m, 2H), 3.27-3.37 (m, 2H), 1.95-2, 17 (m, 4H); ¹³C NMR (CDCl3) δ 149.4, 132.3, 128.3, 125.4, 125.3, 125.0, 122.8, 122.1, 106.5, 80.5, 66.2, 33.6; Anal Calcd. for C19H18O2: C, 81.99; H, 6.52, found: C, 81.75; H, 6.66.

4-Cyclohexyloxy-2-chlorobenzonitrile (Table 2, entry 1)

The general procedure was followed on a 0.50 mmol scale to yield 96 mg (81 yield) as a white solid mp 30-32 ° C. The isolated product had an impurity of 5% as determined by GC analysis which was identified by GC / MS as 4-cyclohexyloxybenzonitrile (GC / MS, m / z = 201) and NMR analysis. IR (sharp, cm^-1) vmax: 2935, 2228, 1599, 1491, 1044; NMR¹H (CDCl3) δ 7.52-7.57 (m, 1 H), 6.98 (d, J = 2.4 Hz, 11-1), 6.80-6.85 (m, 11-1 ), 4.31 (quintet, J = 3.8 Hz, 11-1), 1.90-2.01 (m, 2H), 1.74-1.89 (m, 2H), 1.50- 1.62 (m, 3H), 1.30-1.43 (m, 3H); ¹³C NMR (CDCl3) δ 161.8, 138.1, 134.9, 116.9, 116.4, 114.6, 104.3, 76.3, 31.3, 25.3, 23.4; GC / MS (m / z) 235, 237.

2-Chloro-4-sec-phenethyloxybenzonitrile (Table 2, entry 2)

The general procedure was followed on a 0.50 mmol scale to yield 107 mg (83% yield) of a colorless oil. IR (sharp, cm^-1) vmax: 3032, 2982, 2932, 2228, 1598, 1489, 1454, 1297, 1277, 1239, 1067; NMR¹H (CDCl3) δ 7.24-7.46 (m, 6H), 6.97 (d, J = 2.4 Hz, 1 H), 5.33 (q, J = 6.4 Hz, 1 H ), 1.65 (d, J = 6.4 Hz, 3H); ¹³C NMR (CDCl3) δ 161.8, 141.2, 137.9, 134.8, 128.9, 128.1, 125.3, 117.5, 116.2, 114.7, 104.8, 77.5, 24.1; Anal Calcd. for C15H12ClNO: C, 70.02; H, 4.70, found: C, 70.14; H, 4.68.

4-t Butyloxy-2-chlorobenzonitrile (Table 2, entry 3)

The general procedure was followed on a 0.50 mmol scale to yield 87 mg (83% yield) of a colorless oil. (Table 2, entry 3) IR (sharp, cm^-1) vmax: 2980, 2228, 1595, 1484, 1238, 1160, 1041; NMR¹H (CDCl3) δ 7.54-7.56 (m, 1H), 7.09-7.10 (m, 1H), 6.93-6.97 (m 1H), 1.44 ( s, 9H); ¹³C NMR (CDCl3) δ 160.6, 137.4, 134.4, 123.1, 120.5, 116.1, 106.4, 81.0, 28.7; Anal Calcd. for C11H12ClNO: C, 63.01; H, 5.77, found: C, 62.09; H, 5.56.

General procedure for uncatalyzed coupling reaction in DMF

A 25 mL resealable Schlenk flask was charged with NaH (0.60 mmol, in 60% dispersion in mineral oil), anhydrous DMF (2 mL), alcohol (0.60 mmol), and aryl halide. (0.50 mmol) under an argon atmosphere. The bottle was sealed and heated to the indicated temperature until the starting material was consumed according to GC analysis. At this time, the solution was cooled to room temperature and diethyl ether (50 mL) and water (50 mL) were added. The aqueous layer was separated and extracted with diethyl ether (50 mL). The organic layers were combined, washed in brine (50 mL), dried over anhydrous MgSO4,

ES 2 200 162 T3 filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel.

4-Bromo-2-sec-phenethyloxybenzonitrile (Table 2, entry 2)

The general procedure for the uncatalyzed coupling reaction in DMF was followed on a 0.50 mmol scale to yield 61 mg (40% yield) of the title compound as a white solid and 2-chloro-4-secphenethyl oxybenzonitrile ( 44 mg, 34% yield) as a colorless oil mp 101-102 ° C; IR (KBr, cm^-1) v_max: 2226, 1590, 1482, 1408, 1253, 1063, 943; NMR¹H (CDCl3) δ 7.29-7.39 (m, 6H), 7.07 (dd, J = 8.3, 1.6 Hz, 1 H), 6.99 (d, 1.6 Hz, 1H), 5.39 (q, J = 6.4Hz, 1H), 1.71 (d, J = 6.4Hz, 1H); ^{12 13}C NMR (CDCl3) δ 159.4, 140.4, 133.7, 128.3,

127.8, 127.6, 124.9, 123.7, 117.4, 115.2, 76.0, 23.6; Anal Calcd. for C15H12BrNO: C, 59.62; H, 4.00, found: C, 59.41; H, 3.84.

References for Comparative Example 10 (1) For a review of CO aryl and alkenyl binding reactions, see: (a) Chiuy, CK-F. In Comprehensive Organic Functional Group Transformations; Katritzky, AR; Meth-Cohn, O .; Rees, CW, Ed; Pergamon Press: New York, 1995; Vol. 2, Ch. 2.13. (b) Paradisi, C. In Comprehensive Organic Synthesis; Trost, BM; Fleming, L; Semmelhack, MF, Ed; Pergamon Press: New York, 1991; Vol 4, Ch 2.1.

(2) (a) Lu, T .; Hyunsook, KS; Zhang. H .; Bott, S .; Atwood, JL; Echegoyen, L .; Gokel, GWJ Org. Chem. 1990, 55, 2269. (b) Pluta, KJ Heterocyclic Chem. 1984, 31, 557 (c) Testaferri, L .; Tiecco, M .; Tingali, M .; Bartoli,

C.; Massoli, A. Tetrahedron 1985 ?, 41, 1373. (d) Testaferri, L .; Tiecco, M .; Tingoli, D .; Chianelli, D .; Montanucci, M. Tetrahedron 1983, 39, 193. (e) Shaw, JE; Kunerth, DC; Swanson, SBJ Org. Chem. 1978, 41, 732. (s) Bradshaw, JS; Hales, RHJ Org. Chem. 1971, 36, 318 (3) (a) Lee, S .; Frescas, S .; Nichols, DE Synthetic Comm. 1995, 25, 2775. (b) Capdevielle, P .; Maumy, M. Tetrahedron Lett. 1993, 34, 1007. (c) Keegstra, M. TO.; Peters, T H .; Brandsma, L. Tetrahedron 1992, 48, 3633. (d) Yeager, GW; Schissel, DN Synthesis 1991, 63. (e) Aalten, HL; Van Koten, G .; Grove, DM; Kuilman, T; Piekstra, OG; Hulshof, LA; Sheldon, RA Tetrahedron 1989, 45, 5565. Penta-valent organobismuth reagents were used in the synthesis of aryl ethers in the presence and absence of Cu salts, see: (d) Barton,

DHR; Finet, J.-P .; Khamsi. J .; Pichon, C. Tetrahedron LetL 1986, 27, 3619. (e) Barton, DHR; Finet, J.-P .; Motherwell, WB; Pichon, CJ Chem. Soc., Perkin Trans. / 1987, 251.

(4) A variety of electron-deficient transition metal complexes were used as activators for the synthesis of aryl ethers from the reaction of aryl fluorides and aryl chlorides with alcohols see: (a) Pearson, AJ; Bruhn, PR; Gouzoules, F .; Lee, SH. J. Chem. Soc., Chem. Commun. 1989, 659. Pearson, AJ; Gelormini, AMJ Org. Chem. 1994, 59, 4561. (c) Moriarty, RM; Ku, YY .; Gill, US Organometallics 1988, 7, 660. (d) Baldoli, C .; Buttero, P. D .; Maiorana, S .; Papagni, AJ Chem. Soc., Chem. Commun. 1985, 1181. (e) Percec, V .; Okita, SJ Polym. Sci. Part A: Polym. Chem. 1993, 31, 923.

(5) Palucki, M .; Wolfe, JP; Buchwald, S, LJ Am. Chem. Soc. 1996, 118, 10333. (6) Mann, G .; Hartwig, JFJ Am. Chem. Soc. 1996, 118, 13109.

(7) For examples of nickel catalyzed aryl ethers syntheses, see: (a) Cramer, R .; Coulson, DR JOrg. Chem. 1975, 40, 2267. (b) Cristau, H.-J .; Desmurs, J.-R. Ind. Chem. Libr. 1995, 7, 249.

(8) Treatment of trans- [PdBr (C6H5) (PPh3) 2] with a solution of NaOMe in toluene at 35 ° C has been reported to produce benzene (80% yield), HCHO (20% yield) and anisole (trace) see: Yoshida, T .; Okano, T .; Otsuka, SJ Chem. Soc., Dalton Trans. 1976, 993.

(9) Any of the enantiomers of Tol-BINAP as well as BINAP can be used. However, BINAP is approximately 2.6 times more expensive (Strem Chemicals) than Tol-BINAP.

(10) Reactions carried out at 100 ° C using Pd (OAc)₂ as a pre-catalyst they produced an aryl ether at a benzonitrile ratio of 6: 1, while the benzonitrile by-product was not observed using Pd2 (dba) 3 as a pre-catalyst agent.

(11) Because only one product was detected by GC and TLC analysis, and the stereochemistry of carbinol carbon was preserved in the Pd-catalyzed intramolecular coupling reaction (see reference 5), it is assumed that the stereochemistry of (1R, 2S, 5R) - (-) - menthol is preserved during the course of the reaction.

(12) The following is a representative procedure: A 25 mL oven-dried Schlenk flask was charged with NaH (1.00 mmol, 40 mg, in 60% dispersion in mineral oil), 2-propanol (46 μL 0, 60 mmol) and toluene (2 mL) under an argon atmosphere. The mixture was heated to 50 ° C for 15 min, cooled to room temperature, and 4-bromobenzonitrile (91 mg, 0.50 mmol), Pd2 (dba) 3 (6.9 mg, 0.0075 mmol) were added, (R) - (+) - 2,2'-bis (di-ptolylphosphino) -1,1'-binaphthyl (Tol-BINAP) (12.2 mg, 0.018 mmol), and 1 mL of toluene. The mixture was heated at 50 ° C for 22 h under an argon atmosphere and then cooled to room temperature. Water (50 mL) and

ES 2 200 162 T3 diethyl ether (50 mL) and the aqueous layer was separated and extracted with diethyl ether (50 mL). The organic layers were combined, washed in brine (50 mL), dried over anhydrous MgSO4. The drying agent was removed by filtration and mother alcohol was concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (19/1 hexanes / ethyl acetate) to yield 4-isopropoxybenzonitrile as a colorless oil (65 mg, 80% yield).

(13) Zask, A .; Helquist, PJ Org. Chem. 1978, 43, 1619.

(14) (a) With Pd (OAc) 2 as pre-catalyst agent, a ratio of 9.2: 1 aryl ether: t-butylbenzene was obtained; using Pd2 (dba) 3 this ratio was 4: 1 (GC analysis not corrected for response factors). This embodiment is contrary to that observed in the Pd-catalyzed coupling of 4-bromobenzonitrile with 2-propanol. (b) No meta product was observed in this procedure, as would be expected from the benzene formation. (c) Both t-butylbenzene and 4,4'-di-t-butylbiphenyl were by-products of the palladium-catalyzed reaction of 4-t-butylbromobenzene with NaOtBu. We are not sure about the mechanism of formation of t-butylbenzene in this reaction. (d) Contrary to the other substrates examined (Table 1), the use of t-BuOH and NaH instead of NaOtBu produced large amounts of arene by-products and only traces of the desired aryl ether product.

(15) GC analysis of the crude reaction mixture of 9-bromoanthracene with tetrahydro-4H-pyran-4-ol gave a 10: 1 ratio of aryl ether to anthracene, while GC analysis of the Crude reaction mixture of 9-bromoanthracene with cyclopentanol gave a 2.4: 1 ratio of aryl ether to anthracene. Clarification: these relationships are not corrected for response factors.

(16) (a) Wolfe, JP; Wagaw, S.; Buchwald, SLJ Am. Chem. Soc. 1996,118,7215. (b) Hartwig, JF; Richards, S .; Baranano, D .; Paul, F J. Am. Chem. Soc. 1996, 18, 3626. (c) Driver, MS; Hartwig, JFJ Am. Chem.Soc. 1996, 118.7217. (d) Widenhoefer, RA; Buchwald, S. L Organometallics 1996.15, 2755. (e) Louie, J .; Paul, F .; Hartwig, J. F Organometallics 1996, 15, 2794. (s) Paul, F .; Patt, J .; Hartwig. J. F Organometallics 1995, 14, 3030.

(17) Direct reductive elimination from [(R) -Tol-BINAP] Pd (p-C6H4CN) (OCH2CMe3) to produce the aryl ether product in 84% yield has recently been demonstrated in this laboratory.

(18) (a) Stille, JK The Chemistry of the Metal-Carbon Bond, Vol2, Hartley, FR; Patai, S. Eds., Wiley, New York, 1985, 625. (b) Gillie, A .; Stille, JKJ Am. Chem. Soc. 1980, 102, 4933. (c) The stearic effect of ligands on the rate of the reductive clearance process was first reported by Jones: Jones, WD; Kuykendall, VL Inorg. Chem. 1991, 30, 2615.

(19) Conditions for the nucleophilic substitution reaction generally require 4.0 alkoxide equivalents relative to aryl bromide at 80-120 ° C. See reference 2.

(20) Uncatalyzed reactions carried out in DMF that was not strictly anhydrous did not produce aryl ether products. (21) (a) Cram, DJ; Rickbom, R .; Knox, GRJ Am. Chem. Soc. 1960, 82, 6412. (b) Hales, RH; Bradshaw, JS; Pratt, DR; J. Org. Chem. 1971, 36, 314.

(22) Mauleon, D .; Granados, R .; Minguillon J. Org. Chem. Soc. 1983,48, 3105. (23) Aldrich Chemical Company