CZ20001413A3 - Process for preparing aromatic compounds substituted with tertiary nitrile group - Google Patents

Abstract

A process for preparing an aromatic compound is described substituted by a tertiary nitrile group of the formula 1.0.0, which is to react aromatic a compound of formula 2.0.0 with a secondary nitrile of formula (3.0.0) in the presence of a base having a numerical value a pKa value of from about 17 to about 30, provided that the difference between the numerical values of pKa base and the corresponding the secondary nitrile of formula 3.0.0 is not greater than about 6, in an aprotic solvent having a dielectric constant (ε) less than about 20, and at a temperature in the range of about 0 ° C to about 120 ° C to give the final aromatic compound substituted with a tertiary nitrile group of the formula 1.0.0, where W1, W2, W3, W4, and W5, and R1, R 2, R 3, R 4, R 5, R 6 and R 7 in said formulas 1.0.0, 2.0.0 and 3.0.0 are selected from known organic groups and residues as described in detail in the description.

Description

A process for the preparation of aromatic tertiary nitrile groups

Links to related pending applications

Reference is made to US Patent Application No. 09/153762, filed September 15, 1998, which is a continuation-in-part of US Application No. 60/064211, filed November 4, 1997, and is now referred to, and to the corresponding European Patent Application No. 09/15376. 98308961.6 based on said continuation-in-part application, filed November 2, 1998 and published as EP-A-0 915 089 12.05.1999. The above applications are incorporated herein by reference in their entirety and priority is claimed from the filing date first of the above applications.

of substituted compounds

Field of the invention

The invention relates to a novel process for the preparation of aromatic compounds substituted with a tertiary nitrile group, which is applicable to a number of compounds of this type. These aromatic compounds substituted with a tertiary nitrile group include compounds of Formula (1.0.0)

wherein W ¹ , W ² , W ³ , W ⁴ and W ⁵ and the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹ have the meanings given below. The process according to the invention can be illustrated by the following reaction scheme:

• · • ·

-2 9 9 9 99 99 9 9 9 9 9 9 9 9 9 9 9 99

R ' ^R \ W

V, R

R ¹

F (2.0.0)

(1.0.0)

The process of the present invention is simple and provides acceptable yields of the final product. The process according to the invention differs from the prior art processes by its wide applicability and the discovered suitability in terms of chemical processing and reaction conditions for the base used as the reaction promoter as well as the tertiary structure of the nitrile group in the final product, which will be described below.

The nature of the base used in the process of the invention is critical in order to achieve acceptable yields of the final tertiary nitrile-substituted aromatic compounds, which distinguishes the present process from the prior art. The conjugated base acid to be used must have a pK _and in the range of about 17 to about 30. An example of a base that meets these critical requirements is potassium, sodium or lithium salt of bis (trimethylsilyl) amide (KHMDS).

It has also been found in the present invention that the type of solvent used in the reaction between the secondary nitrile and the substituted aromatic compound is an option that is critical to obtain acceptable yields of the final product. The solvent selected should be aprotic and have a dielectric constant (ε) of less than about 20. Examples of suitable solvents for use in the process of the invention include toluene and tetrahydrofuran (THF). The dielectric constant of THF is 7.6 and the dielectric constant of toluene is 2.4 (Handbook of Chemistry and Physics).

• ·

Suitably, the nitrile reactant in the process of the invention is secondary to the degree of substitution of the carbon atom to which the nitrile moiety is attached. Of course, in the final products prepared by the process of the invention, the carbon atom to which the nitrile moiety is attached is tertiary because it is not attached to any hydrogen atom.

The choice of the temperature at which the reaction mixture containing the secondary nitrile and the aromatic compound is maintained is less critical than the choice of the above base or solvent. However, to obtain acceptable yields of the final product in the process of the invention, a temperature range is characteristic and should be in the range of about 0 ° C to about 120 ° C.

The final tertiary nitrile-substituted aromatic compounds prepared by the process of the present invention are characterized by a wide range of chemical structures and a wide variety of practical uses, including both therapeutic and non-therapeutic applications of these end products.

Preferred final tertiary nitrile substituted aromatic compounds are those useful as therapeutic agents, particularly as type IV phosphodiesterase (PDE4) inhibitors. PDE4 inhibitors are useful in therapeutic methods for the treatment of many conditions, which are allergic or particularly asthma, chronic obstructive bronchitis, rheumatoid arthritis and osteoarthritis, dermatitis, psoriasis and allergic rhinitis, in humans and animals.

Of these PDE4 inhibitors containing the final tertiary nitrile substituted aromatic compounds, the selective PDE4 inhibitors disclosed in US Application No. 08/963904, filed April 1, 1997, which is a continuation of disorders, diseases and inflammatory origin, lung disease, are preferred.

(contiuation-in-part) US Application No. 60/016861, filed May 3, 1996, now revoked and International Application No. PCT / IB97 / 00323 based on application filed April 1, 1997, intended for the United States and published as WO 97 / 42174 13.11.1997.

The above preferred group of selective PDE4 inhibitors can be represented by formula 4.0.0

wherein R _a is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or alkylphenyl, wherein the alkyl moiety contains 1 to 3 carbon atoms, wherein the phenyl groups are optionally substituted with one or two alkyl groups of 1 to 4 carbon atoms, -O-alkyl, wherein the alkyl moiety contains 1 to 3 carbon atoms, bromine or chlorine atoms, R is hydrogen, alkyl of 1 to 6 carbon atoms, (CH ₂ ) n -cycloalkyl, wherein n is 0 to 2 and the cycloalkyl moiety contains 3 to 7 carbon atoms, or - (Z) _b -aryl, wherein b is 0 or 1, the aryl moiety contains 6 to 10 carbon atoms, and Z 'is an alkylene group having 1 to 6 carbon atoms or an alkenylene group C 2 -C 6 alkyl wherein the alkyl and aryl moieties of the R groups are optionally substituted with one or more halogen atoms, preferably fluorine or chlorine atoms, hydroxy groups, C 1 -C 5 alkyl groups, C 1 -C 5 alkoxy groups and R ¹ is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl or cycloalkyl of 3 to 7 carbon atoms, wherein the alkyl and phenyl groups of R ¹ are optionally substituted with up to 3 methyl groups, ethyl groups , trifluoromethyl groups or halogen atoms.

This preferred class of selective PDE4 inhibitors can be further illustrated by preferred specific compounds of formulas 4.0.1 and 4.0.2.

A method of preparing the above-described group of selective PDE4 inhibitors is described in US Application No. 09/153762, filed September 15, 1998, which is a continuation-in-part of US Application No. 60/064211, filed November 4, 1997 and now revoked and in the corresponding European application on the basis of that continuation-in-part application filed .......... and published as

EP-A-0 .......... on .......... In particular, the above-mentioned applications describe a synthetic process for the reaction of indazole 2.1.0 with cyclohexane-1,4- dicarbonitrile of formula 3.1.0 to form the final aromatic compound substituted with a tertiary nitrile group of formula 4.0.3

CN (2.1.0)

CN (3.1.0)

This synthetic process described above is carried out in the presence of a base such as lithium bis (trimethylsilyl) amide, natriumbis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide

(KHMDS), lithium diisopropylamide or lithium-2,2,6,6-tetramethylpiperidine. The above bases are described to be selective and allow the addition of very high amounts of cyclohexane-1,4-carbonitrile of formula 2.0.1 to the R- and R ^x -substituted indazole of formula 2.0.0 by displacing the fluorine atom from the indazole in preservation of carbonitrile functionalities. It is further mentioned that it is preferred to use potassium bis (trimethylsilyl) amide (KHMDS) as a promoter base, in a solvent such as tetrahydrofuran, toluene or xylene or xylenes, preferably toluene, at a temperature between about 25 ° C and about 125 ° C, preferably at about 100 ° C, for 1 hour to 15 hours, preferably for about 5 hours, to yield acceptable yields of the final tertiary nitrile-substituted aromatic compound of Formula (1.0.0).

g.Qsayadni ..... st.av techniques

Loupy et al., Synth. Comm., 1990, 20, 2855-2864, disclose the use of a solvent-free solid-phase transfer catalyst to carry out the S _N Ar reaction of di- or mono-nitrohalogenated compounds and unactivated aryl halides. The reaction is carried out with a nucleophile such as Ph ₂ CHCN in the presence of a base such as a stoichiometric amount of powdered solid KOH and a catalyst such as a tetraalkylammonium salt such as Aliquat 336 or TDA-1 as illustrated by the following reaction scheme:

NO ₂

PhPh CN

KOH

Aliquat 336

-7 ► ► 9 9 9 9 9 · 9 · · · 9 · 9 9 9 9

In contrast to the process of the present invention, the process described by Loupy et al. It is performed with a chlorine, bromine or fluorine substituted arene core, which is due to the electron deficiency of the arene core caused by the further presence of the nitro group.

Makosza et al., J. Org. Chem., 1994, 59, 6796-6799, also disclose nucleophilic halogen substitution in p-halonitrobenzenes and describe in particular the reaction according to the following reaction scheme:

The method described by Makosza et al. Uses ethyl cyanoacetate and can be carried out with either a chlorine or fluorine substituted arene core. However, none of these features of the Makoszy et al. Process can be used in the process of the invention.

Rose-Munch et al., J. Organomet. Chem., 1990, 385 (1), C1-C3, describe the synthesis of α-substituted aryliminonitriles by addition of α-iminonitrile to (fluorarene) tricarbonylchromium complexes in the presence of a base, e.g. This reaction is illustrated in particular by the following reaction scheme:

Ph

Cr (CO) ₃ h ₂ C _x

-N = C. CN

Ph //

Ph

N = <

Ph

THF

HMPT n-BuLi

CN

Cr (CO) ₃

9 9 9 9 9 9 «99 9900 9

999 99 99 99 99 99 99. · 9999

-8- ··· ·· ··. ·· ..

The method described by Rose-Munch et al. induces an electron deficient state in the fluorine-substituted arene nucleus by complexing it with tricarbonylchrome, which in turn allows displacement of the lithium anion of the fluorine substituent on the arene nucleus. However, the synthetic approach of the Rose-Munch et al. is substantially different from the process of the present invention in which lithiation is impracticable.

Plevey and Sampson, J. Chem. Soc., 1987, 2129-2136 describe the synthesis of 4-amino-2,3,5,6-tetrafluorglutethimide, and as part of the preparation, describe the reaction of hexafluorobenzene with ethyl cyanoacetate in the presence of potassium carbonate, as shown in the following scheme:

^H 3 ^C ° in the _Y-CN

O

K ₂ CO ₃

DMF

115 ° C

The method described by Plevey and Sampson also uses an arena core that is in an electron deficient state, as is the case with the above-described methods that characterize the prior art. The Plevey and Sampson process is substantially different from the process of the present invention.

Sommer et al., J. Org. Chem., 1990, 55, 4817-4821, disclose a process allowing displacement of halogen from 2-halo-substituted benzonitrile present as stabilized carbanion to prepare (2-cyanaryl) arylacetonitriles. The process is carried out using two equivalents of a strong base, for example potassium t-butoxide, and is described to be sensitive to the nature of the base, a solvent, for example dimethylformamide (DMF), a leaving group, ring substituents and ring type. This method is also indicated to be applicable to heteroaromatic compounds substituted

-9 • XX XX χ · χ χ χχ

ΧΧΧ X X ΧΧΧ X X χ χχχ

ΧΧΧ XX XX · χ χ XX XX X XX 9 XX X

X XX X

XX XX X

X χ χχ X • XX XX in ortho position by halogen and cyano groups. The method of Sommer et al. Is illustrated by the following reaction scheme:

The method of Sommer et al. Is substantially different from the method of the present invention in that both the chlorine and fluorine substituents on the arene nucleus are displaced and a secondary nitrile substituent is used which induces an electron deficient state in the substituted arene nucleus, thereby facilitating subsequent displacement.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a novel process for preparing aromatic compounds substituted with a tertiary nitrile group by reacting an aromatic compound of Formula (2.0.0).

wherein W ¹ , W ² , W ³ , W ⁴ and W ⁵ and the substituents R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings given below, with the secondary nitrile of formula 3.0.0

H

CN (3.0.0) •

-10 9 9 9 9 9 9 9 9 9 9

99 wherein R ⁶ and R ⁷ have the meanings given below, in the presence of a base having a numerical pK _and in the range of about 17 to about 30, provided that the difference in numerical values of pK _and base and the corresponding secondary nitrile of Formula 3.0.0 is not greater than about 6, in an aprotic solvent having a dielectric constant (ε) of less than about 20, and at a temperature in the range of about 0 ° C to about 120 ° C to provide a final aromatic compound substituted with a tertiary nitrile group of Formula 1.0.0

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ and W ¹ , W ² , W ³ , W ⁴ and W ⁵ have the meanings indicated herein.

The present invention relates to a novel process for preparing aromatic compounds substituted with a tertiary nitrile group. In a preferred embodiment of the method, the starting aromatic compound used has the general formula 2.0.0

wherein (I) each of the dashed lines is independently absent or represents a bond such that single or double bonds are formed at

4> 4

444 4

4

4 4

449 «

-114 4 4 4

4 4 4

4 4 4

4 4 4

44 of the respective positions of the aromatic compound of formula 1.0.0 or 2.0.0, provided that at least one of these dashed lines is a bond, (II) W ¹ , W ² , W ³ , W ⁴ and W ⁵ are each independently members selected from the group consisting of:

(A) C (carbon) and the dashed line attached to it is a bond, (B) N (nitrogen) and the dashed line attached to it is either absent or a bond, (C) O and the dashed line is absent, (D) S (= 0) _k , where k is an integer of 0, 1 or 2 and the dashed line is absent, and (E) in the absence of a five-membered ring, provided that each W ¹ to W ⁵ is selected so that no more than one is absent, no more than one is O or s (= O) _k optionally together with one N in each case, and no more than four are N where present only N (III) R ¹ R ² , R ³ , R ⁴ and R ⁵ are each independently selected such that:

(A) when the corresponding W ^{1 '5} is O or S (= O) _k R ^{1 5} is not present, (B) when the corresponding W ^{1 5} carbon atom, R ^{1 5} is a member independently selected from the group consisting of hydrogen, a halogen atom selected from chlorine, bromine and iodine, -N (R ¹² ) ₂ , -SR ¹² , -OR ¹² , an alkyl group having 1 to 6 carbon atoms substituted with 0 to 3 substituents R ⁹ , -N (R ¹² ) ₂ , -SR ^12, -OR ^12, alkenyl having 2 to 6 carbon atoms substituted with 0-3 R ^9, alkynyl having 3 to 6 carbon atoms substituted with 0-3 R ^9, carbocyclic ring system having 3 to 14 carbon atoms substituted by 0 to 3 substituents R ⁹ or 0 to 3 substituents R ¹⁰ , a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroiso-12; · · ** · · φ φ · · Quinolinyl, benzotriazolyl and thiazolyl, said heterocyclic ring system being substituted with 0 to 2 substituents R ¹⁰ , and any two R 10 ^{The 1} ' ⁵ attached to the adjacent carbon atoms together together form a three or four carbon chain forming a fused five or six membered ring, which ring is optionally substituted on any of its aliphatic carbon atoms with a substituent selected from the group consisting of a halogen atom selected from chlorine, bromine and iodine. (C 1 -C 4), (C 1 -C 4) alkoxy and -NR ¹⁵ R ¹¹ , wherein (1) R ⁹ is independently selected from hydrogen, cyano, -CH ₂ NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ , -R ¹⁵ , -OR ¹⁵

-S-alkoxyalkyl of 2 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 6 carbon atoms in the cycloalkyl moiety , phenyl, benzyl, phenethyl, phenoxy, benzyloxy, C 3 -C 6 cycloalkoxy, C 1 -C 4 alkyl substituted with a substituent selected from the group consisting of methylenedioxy, ethylenedioxy, C 1 -C 3 phenylalkyl and carbocyclic a C 5 -C 14 radical, and a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, substituted with 0 to 3 substituents R ¹⁵ , wherein (a) R ¹⁵ is a member selected from phenyl substituted with 0 to 3 substituents R ¹¹ , benzyl substituted with 0 to 3 substituents R ¹¹ , alkyl yne with 1 to 6 carbon atoms substituted with 0 to 3 substituents R ^11, alkenyl having 2-4 carbon atoms substituted with 0 to 3 substituents R ^11, alkoxyalkyl with 3-6 carbon atoms substituted with 0 to 3 substituents R ¹¹ »φ φ φ · · • • φ φ φ φ φ φ φ φ φ φ

Where R ^{X 1} is a member independently selected from the group consisting of cyano, -CH ₂ NR ¹⁸ R ¹⁹ , -NR ¹⁸ R ¹⁹ , alkoxyalkyl of 3 to 6 atoms C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 -C 10 cycloalkyl, C 3 -C 6 cycloalkylmethyl, benzyl, phenethyl, phenoxy, benzyloxy, arylalkyl C 7 -C 10 cycloalkoxy, C 3 -C 6 cycloalkoxy, methylendixoyl, ethylenedioxy, C 5 -C 14 carbocyclic and 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein R ¹⁸ and R ¹⁹ are each independently selected from the group consisting of C 1-6 alkyl and phenyl substituted with 0-3 R ¹¹ , (b) R ¹⁶ is a member selected from the group consisting of C 1 -C 4 alkyl substituted with 0 to 3 groups selected from C 1 -C 4 alkoxy, C 2 -C 6 alkoxy, C 2 -C 6 alkenyl, phenyl and benzyl, (2) when R ^{10 is a} substituent on a carbon atom, is a member independently selected from phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, cyano, (C 1 -C 4) alkyl, (C 3 -C 3) alkyl (C-C cyk) cycloalkylmethyl, (C v-C 6) cycloalkyl, (C,-C až) alkoxy, (C až-C alko) alkoxyalkyl (C až-C as), (C až-C cyk) cycloalkoxy (C 1 -C 6) alkylthio, (C 1 -C 4) alkylthioalkyl, (C 1 -C 3) alkylthioalkyl group to alkyl, -OR ^15, -NR ¹⁵ R ^1S, alkyl having 1 to 4 carbon atoms substituvoanou -NR ¹⁵ R ^16, alkoxyalkylene group having 2-6 carbon

9 9 • · ·

998 9 9

-14 • ··

9999 · ·

9 9

99

9 9 9

9 9 9

9 9 9

99 carbon optionally substituted by Si (alkyl) ₃ , wherein the alkyl group has 1 to 3 carbon atoms, methylenedioxy, ethylenedioxy, -S (O) _m R ¹⁵ , -SO ² NR ¹⁵ R ¹⁶ , -OCH ₂ CO ₂ R ¹⁵ ,

-C (R ¹⁶ ) = N (OR ¹⁶ ) and a 5- or 6-membered heterocyclic ring system containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, or when R ^{10 is a} substituent on a nitrogen atom, is a member independently selected from the group consisting of phenyl, benzyl, phenethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl, C 2 -C 6 alkoxyalkyl carbon atoms, -CH ₂ NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ and -C (R ¹⁶ ) = N (OR ¹⁶ ), wherein R ¹⁵ and R ¹⁶ are as defined above, (3) R ¹² is a member selected from a group comprising an alkyl group having 1 to 6 carbon atoms substituted with 0 to 3 substituents R ⁹ and an alkoxyalkyl group having 3 to 6 carbon atoms substituted with 0 to 3 substituents R ⁹ , wherein R ¹⁰ is as defined above, and (C) if appropriate W ^{1 '5} nitrogen atom, then R ^1' is ⁵ members than optionally selected from phenyl, benzyl, phenethyl, phenoxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl in the cycloalkyl moiety -CH ₂ NR ¹⁵ R ^16, -NR ¹⁵ R ^16, alkoxyalkyl of 2 to 6 carbon atoms and -C (R ¹⁶⁾ = N ^(OR16), wherein R ^1S and R ¹⁶ are as defined above.

The above starting compound of formula (2.0.0) is reacted with a secondary nitrile of formula (3.0.0) (3.0.0)

H

CN • • · CN • • • • • •

Wherein R ⁶ and R ⁷ have the meanings given below, in the presence of a base whose pK _and conjugated acids range from about 17 to about 30, provided that the difference in the numerical values of pK _and between the base and the corresponding secondary nitrile of formula 3.0.0 are not more than about 6, and preferably not more than about 4, and in an aprotic solvent having a dielectric constant (ε) of less than about 20, and at a temperature in the range of from about 0 ° C to about 120 ° C to form an aromatic compound substituted with a tertiary nitrile group of Formula (1.0.0)

Rl ₂ ^r2 s I 1, (1.0.0) R

-CN

R

R ⁷ wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ and W ¹ , W ² , W ³ , W ⁴ and W ⁵ have the meanings indicated herein.

One of the key features of the process of the present invention is that the nitrile moiety in the final product of Formula (1.0.0) is tertiary and therefore the reactant must be secondary as shown in Formula (3.0.0).

H

R \\ .CN

R ⁷ (3.0.0) wherein R ⁶ and R ⁷ cannot be hydrogen atoms. The process of the present invention provides good results although R ⁶ and R ⁷ have a large number of different meanings. Thus, in the secondary nitrile reactant of Formula 3.0.0:

R ⁶ and R ⁷ are independently selected from the group consisting of -N (R ¹² ) 2, (C 1 -C 6) alkyl substituted with 0 to 3 R ⁹ , -N (R ¹² ) 2, -SR ¹² , -OR ¹² , C 2 -C 6 alkenyl substituted with 0 to C

-16- substituents R ⁹ , alkynyl group having 3 to 6 carbon atoms substituted with 0 to 3 substituents R ⁹ , carbocyclic a ring system of 3 to 14 carbon atoms substituted with 0 to 3 R ⁹ or 0 to 3 R ¹⁰ substituents, and a heterocyclic ring system independently selected from furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl and thiazolyl, said heterocyclic ring system being substituted with 0-2 R ¹⁰ substituents, or

R ⁶ and R ⁷ taken together form a carbocyclic ring system of 3 to 14 carbon atoms substituted with 0 to 3 substituents R ⁹ or 0 to 3 substituents R ¹⁰ , phenyl, 1- or 2-naphthyl substituted with 0 to 3 substituents R ⁹ or 0 to 3 substituents or a heterocyclic ring system independently selected from imidazolyl, pyrazolyl, indolyl, furanyl, thienyl, pyrrolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl and thiazolyl groups; 0 to 2 R ¹⁰ substituents wherein

R and R have the meanings given above for the definitions

1-5

The process of the present invention, i.e., reacting an aromatic compound of formula 2.0.0 with a secondary nitrile of formula 3.0.0, must be carried out in the presence of a base having a pK _and in the range of about 17 to about 30, provided the difference between the numerical values The pK _and base and the corresponding secondary nitrile of Formula 3.0.0 are not more than about 6 and preferably not more than about 4, and in an aprotic solvent having a dielectric constant (ε) of less than about 20, and at a temperature in the range of about 0 ° C to about 120 ° C.

The nature of the base used in the process of the present invention is critical to obtain acceptable yields of the final tertiary nitrile-substituted aromatic compound, which serves to distinguish the process of the invention from the prior art methods. The relative base strength used in the process of the present invention should preferably be as close as possible to the relative base strength of the secondary nitrile component of Formula 3.0.0 used in the process. Next, the strength of the base used should be quantified. This quantification allows for greater selectivity of the selected base as well as allows for a precise comparison of the relative strength of the base with the corresponding relative strength of the secondary nitrile reactant.

To quantify the relative strength of the base for use in the method of the invention, the dissociation constant K _and base and the corresponding secondary nitrile of Formula 3.0.0 are used herein. The dissociation constant is defined as the equilibrium constant for the transfer of proton from HA to water and is calculated according to the following equation:

K = [H ₃ O ⁺ ] [A: η [HA] where the values in parentheses are the molar concentrations at equilibrium for the acid and its dissociated components. Suitably, the dissociation constants are expressed as the negative logarithm, abbreviated p. Tak pK _a = -log K _a . Stronger acids have larger dissociation constants, but have a correspondingly smaller _pKa values. The value that can be used to quantify the comparative difference between the base strength and the corresponding secondary nitrile used in the process of the invention demonstrates their usefulness in carrying out the process.

Thus, the relative potency of the base A: 'and the corresponding secondary nitrile under consideration is suitably expressed as pK _{and the} conjugated acid HA. Where a base is characterized as a strong base, the opposite is also in its essence. .....

the truth is that its conjugated acid is a weak acid. And numerical values for the pK _a of the conjugate acid of two or more bases make it easy to compare the base and quickly determine which base is stronger and who is weaker bases. The stronger base has conjugated acid with a higher numerical value of pK _a . According to the invention, for a given based directly or indirectly provides the numerical value of _pKa, which means that said numerical value is the _pK value of the conjugate acid of said base.

The base used in the process of the invention preferably has a numerical pK value _and as close as possible to the value of the secondary nitrile 3.0.0 used in the process. Consequently, based on the numerical pK values _and secondary nitriles of formula 3.0.0 suitable for use in the process of the present invention, the requirement that the base used has a pK value _and in the range of about 17 to about 30 is considered necessary. . A further requirement is that the difference in the numerical values of pK _and between the base and the corresponding secondary nitrile of formula 3.0.0 is not greater than about 6 and preferably not greater than about 4. The secondary nitrile of formula 3.0.0 used in the process of the present invention has the general the chemical structure represented by the following general formula (3.0.1)

R ¹ = CC = N

Ø ² where the acidic proton is indicated by a distinctive letter.

A preferred base for use in the process of the invention that meets the above critical requirements is the potassium, sodium or lithium salt of bis (trimethylsilyl) amide, also referred to as hexamethyldisilazane (HMDS). The HMDS potassium salt is more preferred over the sodium or lithium salt, and the HMDS sodium salt is more preferred over the lithium salt. At a bargain

-19999 9 9 99 9 99 9

999 9900 9 9 9 9

999 99 99 99 99 99 ·

9,999,999

999 99 99 9 99 99 Only the potassium or sodium salts of HMDS are used in the process according to the invention. A preferred base of KHMDS is represented by Formula 5.0.0

H, h ₃ c.

h ₃ c

Si — μΘ K \

-Si —- CH

H ₃ C '

5.0.0)

CH,

Other bases of this type may also be used, for example bases of the following general formula 5.0.1

R ^ 23 / ^Si ~~ N

R ² y

22 ^

5.0.1)

T

R ²¹ wherein R ²⁰ , R ²¹ , R ²² , R ²³ , R ²⁴ and R ²⁵ are independently selected from the group consisting of C 1 -C 5 alkyl and phenyl and X * is a suitable cation, preferably selected from the group consisting of potassium, sodium and lithium. A preferred base is a compound wherein each of R ²⁰ to R ²⁵ is methyl, which corresponds to the KHMDS of Formula 5.0.0 above. Another preferred base is a compound wherein one R group on each Si atom is tert-butyl, while the remaining R groups are all methyl, for example R ²¹ and R ²⁴ are both tert-butyl and R ²⁰ , R ²² , R ²³ and R ²⁵ are all methyls. Another preferred base is a compound wherein two R groups on each Si atom are tert-butyls, while the other two R groups are phenyls, for example R ²⁰ , R ²² , R ²³ and R ²⁵ are all tert-butyls and R ²¹ and R ²⁴ are both methyls.

In the process of the invention, the type of solvent used to carry out the reaction of the secondary nitrile is aromatic

4 4 4

4 ·

4 ·

4 4

4 4

44

443 4 4 4

4 4 4 4 4

4 4 4 4

445 44 44 4

The compound, also critical, to obtain acceptable yields of the final product. The solvent selected should be aprotic and have a dielectric constant (ε) of less than about 20. As is known, solvents can be classified according to whether or not they are capable of acting as hydrogen bond donors. Solvents that may be hydrogen bond donors such as water and alcohols are referred to as protic solvents. Solvents that cannot be hydrogen bond donors such as hexane and carbon tetrachloride are referred to as aprotic solvents. To be suitable for use in the process of the invention, the solvent must be aprotic. Thus, toluene and tetrahydrofuran, the two preferred solvents used in the process of the invention, are both aprotic solvents.

Another criterion that a solvent must meet to be suitable for carrying out the process of the invention is that it must have a dielectric constant (ε) of less than about 20. The dielectric constant (e) of the solvent is a quantitative measure of its ion-exchange ability. This property is related approximately when the solvent is polar or non-polar. Solvents with relatively low dielectric constants (ε) are usually non-polar solvents, and solvents with relatively high dielectric constants (ε) are usually polar solvents. An example of a solvent having a high dielectric constant (ε) suitable for use in the process of the present invention is Ν-methyl-α-pyrrolidone (NMP), whose ε is 32.2. As mentioned above, the dielectric constants (ε) of toluene and tetrahydrofuran (THF), the two preferred solvents for use in the process of the present invention, are 2.4 and 7.6.

As mentioned above, toluene and tetrahydrofuran are examples of suitable solvents in the process of the invention. Other suitable solvents meeting the above criteria are, but are not limited to, hexane, benzene, o-, m- and p-xylene, diethyl ether, diisopropyl ether, methyl.

-21φφφ · φ φ «

Φ ΦΦΦ Φ Φ Φ <

Φ Φ Φ Φ Φ Φ Φ Φ «

Φ Φ φ Φ Φ 1

Č uty ΦΦ ΦΦ tert-butyl ether and 1,2-dimethoxyethane. It is also contemplated that the use of a mixture of two or more suitable solvents as described above is within the scope of the present invention. It is preferable to use a single solvent alone, but different conditions may occur, or it may be advantageous to use a solvent mixture rather than a single solvent alone. These conditions include, but are not limited to, solubility problems with respect to the reactants, desired temperature adjustments at which the process of the invention is carried out, availability and cost of the solvents used, and separation of the final product from the reaction mixture and subsequent purification.

The critical nature of the choice of base and solvent envisaged for operation in the base / solvent system in the process of the invention is justified by the determination that many such combinations either fail to produce a final tertiary nitrile substituted aromatic compound or produce the final product unacceptably. low yields. For example, it has been found that using a base / solvent system containing potassium bis (trimethylsilyl) amide (KHMDS) as the base and either toluene or tetrahydrofuran (THF) as the solvent, the final aromatic compound substituted with the tertiary nitrile group of the present invention can be prepared in 85% yields or greater, typically 90% or greater by weight and often 95% or greater by weight based on the weight of the reactants.

The term unacceptably low yields is used herein as a contrast to the unexpectedly excellent results obtained by the process of the present invention to the poor results obtained by the prior art methods. It goes without saying that the surprising improvement in yields obtained by the use of the process of the invention may not always show only in very high percentage yields as such. Thus, it may be the case that for a given final product of formula 1.0.0, φφ φφ »φ φ«

I Φ Φ <

»Φ φ«

I Φ Φ «φφ φφ

The methods of the prior art are inefficient to give a yield of 0%, or the yields of the final product are extremely low. -22- φ I φ φ φ φ · · φφ Thus, it can be assumed that the yield of 25% obtained using the process of the invention may represent an unexpected improvement over the yields obtained by prior art processes, where the yields of the final product are for example 0% or> 1%.

The percent yields obtained using the process of the present invention are described in detail herein.

Cases of these defects in the yields of the final product in the prior art processes are very common. For example, if the base used is lithium diisopropylamide (LDA), although the solvent used is tetrahyrofuran (THF), which is otherwise suitable, the original reaction mixture may decompose. Similarly, when the base / solvent system used is potassium t-butoxide (t-BuOK) in tetrahydrofuran (THF), the original reaction mixture decomposes. When cesium, sodium or potassium carbonate (Cs ₂ CO ₃ , Na ₂ CO ₃ or K ₂ CO ₃ ) is used as the base and the solvent is tetrahydrofuran (THF), the reaction does not proceed at all.

The solvent component of the base / solvent system is also critical to obtain acceptable results. For example, if the selected base is potassium bis (trimethylsilyl) amide (KHMDS), which is otherwise suitable, and the selected solvent is dimethylsulfoxide (DMSO), no reaction takes place. Further, when the base is potassium (trimethylsilyl) amide (KHMDS) and the solvent is

-pyrrolidone (NMP), a process for preparing the final compound substituted with a tertiary nitrile group, proceeds at unacceptably low yields of about 5% by weight or less, based on the reactants.

Selection of the temperature at which the secondary nitrile and substituted aromatic reaction mixture is maintained

The N-methyl-aromatic containing compound in the process of importance than the choice of the above invention is less critical of said base and solvent system. However, to obtain acceptable yields of the final tertiary nitrile substituted aromatic compound

-23 · · · · · · · · ·

99> 4 · I> 4

I · · 4

With the group of the invention, the reaction temperature is necessary and should be in the range of about 0 ° C to about 120 ° C, preferably in the range of about 20 ° C to about 110 ° C, even more preferably in the range of about 30 ° C to about 100 ° C. about 105 ° C, and most preferably in the range of about 40 ° C to about 100 ° C. The choice of the temperature at which the reaction of the process according to the invention is carried out influences, among other factors, the time required to carry out the reaction to a sufficient degree of completeness.

In general, it has been found that the process in the aforementioned preferred, while still operating temperatures within the ranges, and in particular in the more preferred and most preferred ranges, the process of the invention is sufficiently completed in the range of about 0.1 hour to about 50 hours. more preferably in the range of about 0.5 hours to about 30 hours, and most likely in the range of about 1 hour to about 18 hours.

The process according to the invention can be illustrated by the following reaction scheme:

-R * W

5

H

CN

R ⁷ base

R ^R w ³ , - ^{r 2} <yv

R ¹ solvent temperature ₅ / ^vvx S> ^{¥ V} -R ¹ (2.0.0) (3.0.0) (1.0.0)

In the above reaction scheme, starting material 2.0.0 is reacted with secondary nitrile 3.0.0 in the presence of a base such as potassium bis (trimethylsilyl) amide (KHMDS) in a solvent such as toluene, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane or a mixture thereof, preferably toluene or tetrahydrofuran, at a temperature between 0 ° C and 120 ° C, preferably between 40 ° C and 100 ° C, to give the final product of formula 1.0. 0. These preferred embodiments of the process of the present invention are further elucidated in the working examples below. However, these examples are given

94

4 4

4 4

4 4

4 4

49

-244 ·· 49 8 · 4 4 4 4

4 4 4 4 4 ·

444 44 44444

4 4 4 4

444 44 44 4 as an illustrative and limiting scope of the present invention to the present disclosure.

it is not intended to be construed as an invention. For the scope of the claims appended

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a solution of arylfluoride 2.0.0 in toluene (10 volumes) is added nitrile 3.0.0, the number of equivalents of which is shown in Table 1 below, and a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene, the number of equivalents is shown in Table 1 below. Each reaction mixture was stirred at the temperature and for the time also shown in Table 1 below, after which each reaction mixture was cooled to room temperature, poured into 1 N HCl and then extracted with toluene. The organic extracts were washed with water, dried over magnesium sulphate, filtered and concentrated. The crude product is purified by silica gel chromatography to give the desired product of Formula 1.0.0 in the yield shown in Table 1 below.

Examples 2 to 19

To a solution of arylfluoride 2.0.0 in tetrahydrofuran (10 volumes) is added nitrile 3.0.0, the number of equivalents of which is shown in Table 1 below, and potassium bis (trimethylsilyl) amide, the number of equivalents of which is given in Table 1 below. Each reaction mixture was stirred at the temperature and for the time indicated in Table 1 below, after which each reaction mixture was cooled to room temperature, poured into 1 N HCl and then extracted with methyl tert-butyl ether. The organic extracts were washed with water, dried over magnesium sulphate, filtered and concentrated. The raw product is this to it this to it it to it to this it to this · This

Purification by silica gel chromatography affords the desired product of Formula (1.0.0) in the yield shown in Table 1 below.

Table 1

in pr. C. product formulas solvent- body T (° C) time KHMDS (eq.) R ⁶ R ⁷ CHCN (eq.) yield (%) 2 (1.0.0) toluene 60 4 0 min 1.5 3.3 94 3 (1.1.1) toluene 60 4 0 min 1.5 4 93 4 (1.1.2) toluene 100 ALIGN! 3 h 1.5 4.1 69 5 (1.1.3) toluene 60 4 5 min 1.5 4 77 6 (1.1.4) toluene 70 48 h 1.5 4 85 7 (1.1.5) toluene 70 10 min 1.5 3.9 72 8 (1.1.6) THF 60 50 h 1.5 4 66 9 (1.1.7) toluene 60 16 h 1.5 4 95 10 (1.1.8) toluene t.m. 5 h 1.5 2 24 11 (1.1.9) THF 75 2 h 1.5 4 72 12 (1.1.10) THF 75 13 h 1.5 4 71 13 (1.1.11) THF 75 13 h 1.5 4 69 14 (1.1.12) toluene 75 48 h 1.5 4 47 15 Dec (1.1.13) THF 75 24 h 1.5 4 67 16 (1.1.14) THF 75 30 h 1.5 4 35 17 (1.1.15) THF 75 28 h 1.5 4 30 18 (1.1.16) THF 75 15 min 1.5 4 70 19 Dec (1.1.17) THF 80 4 h 1.5 4 28

t.m. = room temperature

Example 2

2-Methyl-2- (4-trifluoromethyl-phenyl) -propionitrile (1.1.0)

-26CF,

ΦΦ »» »» »» »» »» »» φ φ φ φ φ φ φ φ φ φ φ φ φ;;;;;

H ₃ C '

ΌΝ

CH,

Purification by silica gel chromatography (ethyl acetate / hexanes 15:85).

¹ H NMR (400 MHz, CDCl 3) δ 1.73 (s, 6), 7.59 (d, 2, J = 9.0), 7.64 (d, 2, J = 9.0). ¹³ C NMR (100 MHz, CDCl 3) δ 28.90, 37.25, 123.12 (q, J = 272.7), 123.75, 125.64, 125.93, 130.15 (q, J) = 33.2),

145.38.

IR 2988, 2239, 1622, 1415, 1330, 1170, 1128, 1069, 842 cm ^-1 . H, 4.73; N, 6.57. Found: C, 61.91; H, 4.96; N, 6.61.

Example 3

4- (cyanomethyl-methyl) -benzonitrile (1.1.1)

CN

(1.1.1)

H ₃ C 1 CN

CH,

Purification by filtration on a silica gel column eluting with ethyl acetate, mp 88-89 ° C.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.78 (s, 6), 7.64 (d, 2, J = 8.1), 7.74 (d, 2, J = 8.3). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 28.87, 37.49, 112.06,

118.19, 123.32, 126.08, 132.85, 146.48.

IR (CHCl3) 2989, 2233, 1611, 1505, 1463, 1408, 1371, 1100, 838 cm @ ^-1 .

• 9

9999

-27 «99 99 * · · · · 9 9

989 99 9

9 9 9

999 99 99 9 9 9 9 9 9

9

99 99

Analysis for C _n H ₁₀ N ₂ Calculated: C, 77.62; Found: C 77.26, H 5.90, N 16.52.

H 5.92,

N 16.46,

Example 4

2- (3-methoxyphenyl) -2-methylpropionitrile (1.1.2)

Purified by silica gel chromatography (ethyl acetate / hexanes 10:90).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.75 (s, 6), 3.86 (s, 3), 6.88 (dd, 1, J = 2.5, 8.3), 7, 04-7.06 (m, 1), 7.07-7.11 (m, 1), 7.34 (t,

1, J = 8.3. ¹³ C NMR (100 MHz, CDCl ₃ ) δ 29.02, 37.09, 55.24, 111.40, 112.60, 117.23, 124.41, 129.91, 142.93, 159.83 .

IR 2983, 2940, 2236, 1602, 1586, 1489, 1463, 1434, 1294, 1268, 1048, 782 cm ^-1 .

Analysis for C _n H ₁₃ NO: Calculated: C 75.40, H 7.48, N 7.99 Found: C 75.61, H 7.67, N 7.86.

Example 5

2- (2-chlorophenyl) -2-methylpropionitrile (1.1.3)

1.1.3) •

Purified by silica gel chromatography (ethyl acetate / hexanes: 90).

¹ H NMR (300 MHz, CDCl 3) δ 1.91 (s, 6), 7.29-7.34 (m, 2), 7.46-7.53 (m, 2). ¹³ C NMR (100 MHz, CDCl 3) δ 27.19, 36.24, 123.50, 127.00, 127.33, 129.41, 131.92, 133.31, 136.95.

IR 2984, 2236, 1473, 1432, 1234, 1043, 759 cm ^-1 .

Analysis for C ₁₀ H ₁₀ C1N: Calculated: C 66.86, H 5.61, N 7.80 Found: C 67.22, H 5.64, N 7.63.

Example 6

2- (3,5-dimethoxyphenyl) -2-methylpropionitrile (1.1.4)

Purified by silica gel chromatography (ethyl acetate / hexanes 15:85).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.74 (s, 6), 3.85 (s, 6), 6.43 (t, 1,

J = 2.2), 6.64 (d, 2, J = 2.2). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 29.06,

37.34, 55.44, 99.12, 103.63, 124.44, 143.81, 161.10.

IR 2982, 2939, 2236, 1598, 1459, 1427, 1207, 1159, 1067, 1052, 696 cm ^-1 .

Anal _. Calcd for C ₁₂ H ₁₅ NO ₂ : C 70.22, H 7.37, N 6.82. Found: C 70.17, H 7.65, N 6.96.

Example 7

2-Methyl-2- (4-methylpyridin-2-yl) -propionitrile (1.1.5) •

-29 • · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

CN

Purified by silica gel chromatography (ethyl acetate / hexanes 20:80).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.77 (s, 6), 2.41 (s, 3), 7.08 (dd,

1, J = 0.8, 5.0), 7.43 (d, 1, J = 0.8), 8.47 (d, 1, J = 5.0). ¹³ C NMR (75 MHz, CDCl ₃ ) δ 22.39, 29.06, 40.54, 121.98, 124.89, 125.66,

149.79, 150.48, 160.55.

IR 2982, 2238, 1605, 1478, 1130, 995, 830 cm ^-1 .

Analysis for C ₁₀ H ₁₂ N ₂ Calculated: C 74.97, H 7.55, N 17.48 Found: C 74.96, H 7.85, N 17.45.

Example 8

2- (4-Methoxyphenyl) -2-methylpropionitrile (1.1.6)

Purified by silica gel chromatography (ethyl acetate / hexanes 20:80).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.74 (s, 6), 3.85 (s, 3), 6.94 (d, 2,

J = 8.9), 7.42 (d, 2, J = 8.9). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 29.25,

36.44, 55.34, 114.19, 124.82, 126.25, 133.50, 159.02.

IR 2982, 2235, 1513, 1256, 1186, 1033, 831 cm ^-1 .

-30Analysa for C ₁₃ N0 Calculated: C, 75.40,

H, 7.48; N, 7.99. Found: C, 75.48; H, 7.55; N, 8.10.

Example 9

2- (2-methoxyphenyl) -2-methylpropionitrile (1.1.7)

Purified by silica gel chromatography (ethyl acetate / hexanes 20:80).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.80 (s, 6), 3.96 (s, 3), 6.97-7.02 (m, 2), 7.29-7.39 ( m, 2). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 27.00,

34.43, 55.51, 112.02, 120.76, 124.80, 125.92, 128.62, 129.39,

157.30.

IR 2980, 2235, 1493, 1462, 1437, 1253, 1027, 756 cm ^-1 .

Analysis for C _n H ₁₃ NO: Calculated: C 75.40, H 7.48, N 7.99 Found: C 75.29, H 7.30, N 8.25.

Example 10

1- (2-chlorophenyl) -cyclopropanecarbonitrile (1.1.8)

(1.1.8)

Purified by silica gel chromatography (ethyl acetate / hexanes 20:80).

-31 1 H NMR (300 MHz, CDCl ₃ ) δ 1.28-1.38 (m, 2), 1.71 -1.75 (m,

2), 7.21-7.43 (m, 4). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 13.17, 16.27,

121.78, 127.16, 130.07, 131.16, 133.60, 136.54.

IR 3063, 3020, 2235, 1477, 1435, 1051, 1033, 759 cm ^-1 .

Anal. Calcd for C ₁₀ H ₈ ClN: C 67.62, H 4.54, N 7.89. Found: C 67.35, H 4.58, N 7.88.

Example 11

- (4-chlorophenyl) -2-methylpropionitrile (1.1.9)

Cl h ₃ c

CH ₃ (1.1.8)

Purified by silica gel chromatography (ethyl acetate / hexanes 10:90).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.75 (s, 6), 7.39 (d, 2, J = 9.0), 7.45 (d, 2, J = 8.9). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 30.34, 38.06, 125.34,

127.80, 130.33, 135.03, 141.22.

IR 2984, 2237, 1495, 1106, 1013, 828 cm ^-1 .

Analysis for C ₁₀ H ₁₀ ClN: Calculated: C 66.86, H 5.61, N 7.80 Found: C 66.51, H 5.83, N 7.74.

Example 12

2-Methyl-2-m-tolylpropionitrile (1.1.10)

(1.1.10) • · • φ

-32 • ·· φ · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

Purified by silica gel chromatography (ethyl acetate / hexanes 10:90).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.75 (s, 3), 2.42 (s, 3), 7.14-7.18 (m, 1), 7.27-7.18 ( m, 3). ¹³ C NMR (75 MHz, CDCl ₃ ) δ 22.81,

30.42, 38.35, 123.26, 125.95, 127.13, 129.80, 130.09, 139.94,

142.61.

IR 2983, 2237, 1607, 1490, 1461, 1368, 1198, 1090, 787 cm ^-1 . Analysis for C _U H ₁₃ N: Calculated: C 82.97, H 8.23, N 8.80 Found: C 82.97, H 8.23, N 8.80.

Example 13

2-Methyl-2-phenylpropionitrile (1.1.11)

(1.1.11)

Purified by silica gel chromatography (ethyl acetate / hexanes 10:90).

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.76 (s, 3), 7.35, -7.53 (m, 5). ¹³ C

NMR (100 MHz, CDCl ₃ ) δ 29.15, 37.16, 124.55, 125.05, 127.79,

128.94, 141.42.

IR 2983, 2237, 1495, 1448, 764 cm ^-1 .

Analysis for C ₁₀ HNN requires: C 82.72, H 7.64, N 9.65 Found: C 82.76, H 7.90, N 9.88.

Example 14

1- (2-methoxyphenyl) -cyclopropanecarbonitrile (1.1.12)

CN (1/1/12) to ·

-33 • to · it

Purified by silica gel chromatography (ethyl acetate / hexanes 10:90 to give an oil which crystallizes on standing), mp 49-59 ° C.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.26-1.30 (m, 2), 1.61-1.66 (m, 2),

3.97 (s, 3), 6.92-6.97 (m, 2), 7.24 (dd, 1, J = 7.9, 1.7), 7.29-7.37 (m , 1). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 10.18, 15.24, 55.61, 110.89, 120.38, 123.08, 124.07, 129.82, 129.92, 158.97 . IR 2234, 1496, 1465, 1248, 1026, 756 cm ^-1 .

Analysis for C H _{U U} NO: Calculated: C 76.28, H 6.40, N 8.09 Found: C, 76.28; H, 6.40; N, 8.09.

Example 15

2S) -2- (2-methoxyphenyl) bicyclo (2,2,1] hept-5-ene-2-carbonitrile (1.1.13)

Purified by silica gel filtration (ethyl acetate / hexanes 35:65 to give an oil which crystallizes from ethanol), m.p. 135-137 ° C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.52 (d, 1, J = 9.0), 1.61-1.64 (m, 1),

2.02 (dd, 1, J = 12.6, 3.4), 2.21 (dd, 1, J = 11.8, 2.8), 2.99 (broad s, 1), 3, 62 (broad s, 1), 3.91 (s, 3), 6.40 (dd, 1,

J = 5.8, 3.0), 6.67 (dd, 1, J = 5.8, 3.0), 6.91-6.96 (m, 2), 7.24-7.30 (m, 2). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 41.42, 43.13, 43.68, 46.90, 48.41, 55.60, 111.66, 120.41, 124.51, 125.36 , 129.02, 129.38, 134.44, 140.87, 158.08.

IR (KBr) 2992 2977 2226 1597 1489, 1439, 1248, 1023, 764 723 cm ^-1 . Analysis for C ₁₅ H ₁₅ NO calculated: C 79, 97, H 6.71, N 6.22, found : C 79.97, H 6.71, N 6.22

• 4 · «44

4444 444 · 4 *

444 4444 44 ··· · 4 · 4444444 4 · 4

4,444 4 4 · 4

444 44 44

-34Example 16

2- (4'-Bromobiphenyl-4-yl) -2-methylpropionitrile (1.1.14)

Purified by silica gel chromatography (ethyl acetate / hexanes 10:90), mp 111-112 ° C.

1 H NMR (400 MHz, CDCl ₃ ) δ 1.76 (s, 6), 7.44 (dd, 2, J = 6.6, 1.9), 7.52-7.57 (m, 6 ). ⁿ C NMR (100 MHz, CDC1 ₃₎ δ 29.13, 39.98, 121.90, 124.38, 125.68, 127.40, 128.64, 131.98, 139.13, 139.57 , 140.86.

IR (KBr) 2986, 2235, 1483, 1461, 1105, 815 cm ^-1 .

Analysis for C ₁₆ H ₁₄ BrN: Calculated: C 64.02 H 4.70 N 4.67 Found: C 64.27, H 4.70, N 4.58.

Example 17

1- (4-Bromobiphenyl-4-yl) -cyclohexane-1,4-dicarbonitrile (1.1.15)

(1.1.15)

9 9

9

9

-3599 99 ► 9 9 «► 9 9 <

ft 9 9 4 9 9 4

99

Purified by silica gel chromatography (IPE / CH ₂ Cl ₂ / hexanes 25:25:50) to give the product as a 1: 1 mixture of diastereoisomers, mp 211 ° C.

¹ H NMR (400 MHz, CDCl 3) δ 1.84-2.62 (m, 8), 3.15 (broad s, 1), 7.41-7.62 (m, 8). ¹³ C NMR (100 MHz, CDCl 3) δ 25.82, 25.92, 26.41, 27.24, 33.12, 35.74, 42.79, 43.52,

122.05, 122.11, 126.00,

138.82 138.91

121,20,

128,62,

140.25.

121,47,

128,65,

132,02,

120.88,

126,10,

139,00,

121.11, 127.63, 140.17,

IR (KBr) 2945, 2235, 1484, 1455, 1388, 1081, 1003, 812 cm ^-1 . Analysis for C ₂₀ H ₁₇ BrN ₂ requires: C 65.76, H 4.69, N 7.67 Found: C 65.76, H 4.65, N 7.67.

Example 18 (2S) -2- (2-methoxyphenyl) bicyclo [2.2.1] heptane-2-carbonitrile (1.1.16)

Purified by silica gel chromatography (ethyl acetate / hexanes 5:95), mp 87-88 ° C.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.30-1.48 (m, 2), 1.52 (d, 1,

J = 10.0), 1.60-1.80 (m, 2), 1.98 (dt, 1, J = 13.5, 3.5),

2.12-2.18 (m, 1), 2.23 (dd, 1, J = 13.5, 2.4), 2.33 (s, 1), 2.97 (d, 1, J) = 3.6), 3.91 (s, 3), 6.89-6.94 (m, 2), 7.24-7.28 (m,

2). ¹³ C NMR (100 MHz, CDCl ₃ ) δ 25.99, 28.64, 37.02, 37.09,

37.41, 42.97, 46.67, 55.58, 111.99, 120.14, 124.16, 125.26, 128.86, 129.68, 157.48.

IR (KBr) 2971, 2225, 1597, 1491, 1251, 1026, 764 cm ^-1 .

Analysis for C ₁₅ H ₁₇ NO: Calculated: C 79.26, H 7.54, N 6.16 Found: C 79.08, H 7.58, N 6.19.

X X

X X

-36xx χχ

XX XX XX · · χ χ.

X XX XX

XX X

ΧΧΧΧ X X

Example 19

2- (3,4-dimethoxyphenyl) -2-methylpropionitrile (1.

.17)

(1.1.17)

Purified by high pressure liquid chromatography panel 95: 5 using a Chiracel OJ column (5 cm ³ H NMR (300 MHz, CDCl ₃ ) δ 1.75 (s, 6), 3.92 (s

3), 8.89 (d, 1, J = 8.1), 7.01 (s, 1), 7.03 (d,

NMR (100 MHz, CDCl ₃ ) δ 29.24, 36.73, 55.95,

111.16, 117.06, 124.73, 133.94, 148.52, 149.06.

(hexanes / 2-prox 25 cm).

Claims (10)

A process for the preparation of an aromatic compound substituted with a tertiary nitrile group of formula 1.0.0, characterized in that an aromatic compound of formula 2.0.0 (2.0.0) is reacted with a secondary nitrile of formula 3.0.0 H (3.0.0) in the presence of a base having a numerical value of pK _and in the range of about 17 to about 30, provided that the difference of the numerical values of pK _and base and the corresponding secondary nitrile of formula 3.0.0 is not greater than about 6 in aprotic a solvent having a dielectric constant (ε) of less than about 20, and at a temperature in the range of about 0 ° C to about 120 ° C to provide a final -38 • 44 44 · 44 44 44 4 4 4 4 4 · 4 · 4 4 4 4 4444 4,444 4 4 4,444 4 4 4 4 4 4 4444 4444 An aromatic compound substituted with a tertiary nitrile group of formula 1.0.0, wherein the dashed lines, W ¹ , W ² , W ³ , W ⁴ and W ⁵ and the substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ occurring in said compounds of formulas 1.0.0, 2.0.0 and 3.0.0 have the following meanings: (I) each of the dashed lines is independently absent or represents a bond, such that single or double bonds are formed at the respective positions of the aromatic compound of formula 1.0.0 or 2.0.0, provided that at least one of these dashed lines is a bond, (II) ) W ¹ , W ² , W ³ , W ⁴ and W ⁵ are each independently a member selected from the group consisting of: (A) C (carbon) and the dashed line attached to it is a bond, (Β) N (nitrogen) and the dashed line attached to it is either absent or a bond, (C) 0 and the dashed line is absent, (D) S (= 0) _k , where k is an integer of 0, 1 or 2 and the dashed line is absent, and (E) in the absence of a five-membered ring, provided that each W ¹ to W ⁵ is selected so that no more than one is absent, no more than one is O or s (= O) _k optionally together with one N in each case, and no more than four are N where present only N (III) R ¹ R ² , R ³ , R ⁴ and R ⁵ are each independently selected as in that: (A) when the corresponding W ¹ ' ⁵ is O or S (= O) _k , R ¹ ' ⁵ is absent, (B) when the corresponding W ¹ ' ⁵ is a carbon atom, R ¹ ' ⁵ is a member independently selected from the group consisting of a hydrogen atom, a halogen atom selected from chlorine, bromine and iodine, -N (R ¹² ) ₂ , -SR ¹² , -OR ¹² , an alkyl group having 1 to 6 carbon atoms substituted with 0 to 3 substituents R ⁹ , -N (R ¹²⁾ ) _2, -SR ^12, -OR ^12, alkenyl having 2 ΦΦ ΦΦ Φ Φ Φ • Φ Φ Φ Φ Φ Φ Φ Φ Φ ΦΦ ΦΦ ΦΦ Φ Φ Φ Φ Φ ΦΦΦ Φ ΦΦΦΦΦ ΦΦΦ ΦΦ Φ -39 • φφ 99 9 9 9 9 9 9 ΦΦΦ «« ΦΦ ΦΦ to 6 carbon atoms substituted with 0 to 3 R ⁹ substituents, alkynyl of 3 to 6 carbon atoms substituted with 0 to 3 R ⁹ substituents, carbocyclic ring system of 3 to 14 carbon atoms substituted with 0 to 3 R ⁹ substituents or 0 to 3 R ¹⁰ , a heterocyclic ring system independently selected from furanyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl and thiazolyl, the heterocyclic to 2 ring system being substituted with 0 R ¹⁰ , and any two R ¹⁵ ' ⁵ ' attached to adjacent carbon atoms together together form a three or four carbon chain forming a fused five or six membered ring, which ring is optionally substituted on any of its aliphatic carbon atoms with a substituent selected from the group consisting of and a halogen selected from chlorine, bromine and iodine, a (C 1 -C 4) alkyl group, a (C 1 -C 4) alkoxy group, and -NR ¹⁵ R ¹⁶ , wherein (1) R ⁹ is a member independently selected from hydrogen, cyano , -CH ₂ NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ , -R ¹⁵ , -OR ¹⁵ , -S-alkoxyalkyl of 2 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkylmethyl of 3 to 6 carbon atoms in the cycloalkyl moiety, phenyl, benzyl, phenethyl, phenoxy, benzyloxy, cycloalkoxy of 3 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms substituted with a substituent selected from the group consisting of methylenedioxy, ethylenedioxy, C 1 -C 3 phenylalkyl, and C 5 -C 14 carbocyclic radical, and a 5- to 10-membered heterocyclic ring system containing containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, substituted with 0 to 3 substituents R ¹⁵ , where φφ • φφ «« ««φφφφφφφφφφφφφφφφφφ -40Φ · · · Φ · • · • · · φ φ φ φ φ φφ φφ φ · • · φ φ · φ φ φ φφ (a) ^R15 is a member selected from the group consisting of phenyl substituted by 0 to 3 substituents R ^u, benzyl substituted with 0-3 R ^11, C 1 -C 6 carbon atoms substituted with 0 to 3 substituents R ¹¹ , alkenyl of 2 to 4 carbon atoms substituted with 0 to 3 substituents R ¹¹ , alkoxyalkyl of 3 to 6 carbon atoms substituted with 0 to 3 substituents R ¹¹ , wherein R ¹¹ is a member independently selected cyano, -CH ₂ NR ¹⁸ R ¹⁹ , -NR ¹⁸ R ¹⁹ , C 3 -C 6 alkoxyalkyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 3 cycloalkyl up to 10 carbon atoms, cycloalkylmethyl of 3 to 6 carbon atoms in the cycloalkyl moiety, benzyl, phenethyl, phenoxy, benzyloxy, arylalkyl of 7 to 10 carbon atoms, cycloalkoxy of 3 to 6 carbon atoms, methylene dixoyl, ethylenedioxy, C 5 -C 14 carbocyclic and a 5- to 10-membered heterocyclic ring system containing 1 to 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein R ¹⁸ and R ¹⁹ are each independently selected from the group consisting of C 1 alkyl to 6 carbon atoms and phenyl substituted with 0-3 R ^11, (b) ^R16 is a member selected from the group consisting of alkyl of 1-4 carbon atoms substituted with 0 to 3 groups selected from the group consisting of alkoxy having 1 to 4 carbon atoms, (C 2 -C 6) alkoxyalkyl, (C 2 -C 6) alkenyl, phenyl and benzyl; (2) when R ^{10 is a} substituent on carbon, it is a member independently selected from phenyl, benzyl, phenethyl, phenoxy, benzyloxy, halogen, cyano, (C 1 -C 4) alkyl, (C 3 -C 7) cycloalkyl, cycloalkyl (C 3 -C 6) methyl group in the cycloalkyl moiety, (C 1 -C 6) alkoxy, alkoxyalkyl 49 · 4 · 4 4 9,444 4 4 4 44 4 ·· -4144 4 4 4 4 444 4 • ·· 4 4 4 4 • · · · 9 9 4 4 4 4 4 C 1 -C 4 alkoxy and C 1 -C 3 alkyl, C 1 -C 6 cycloalkoxy, C 1 -C 6 alkylthio, C 1 -C 4 alkylthioalkyl and C 1 up to 3 carbon atoms in the alkyl moiety, -OR ^{1 S} , -NR ¹⁵ R ¹⁶ , alkyl of 1 to 4 carbon atoms substituted with -NR ¹⁵ R ¹⁶ , alkoxyalkylene of 2 to 6 carbon atoms, optionally substituted with Si (alkyl) 3, wherein the alkyl group has 1 to 3 carbon atoms, methylenedioxy, ethylenedioxy, -S (O) mR ¹⁵ , -SO ² NR ¹⁵ R ¹⁶ , -OCH ₂ CO ₂ R ¹⁵ , -C (R ¹⁶ ) = N (OR ¹⁶ ) and a 5- or 6-membered heterocyclic ring system containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur, or when R ^{10 is a} substituent on a nitrogen atom is a member independently selected from the group consisting of phenyl, benzyl, phenethyl, (C1-C4) alkyl, (C1-C4) alkoxy, (C3-C6) cycloalkyl, (C3-C6) cycloalkylmethyl, cycloalkyl moieties, (C 2 -C 6) alkoxyalkyl, -CH ₂ NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ^16, and -C (R ¹⁶ ) = N (OR ¹⁶ ), wherein R ¹⁵ and R ¹⁶ are as defined above, ( 3) R ¹² is a member selected from the group consisting of C 1 -C 6 alkyl substituted with 0 to 3 R ⁹ substituents and C 3 -C 6 alkoxyalkyl substituted with 0 to 3 R ⁹ substituents, wherein R ¹⁰ is as defined above, and (C) when the corresponding W ^{1 '5} N, then R ¹ ' ⁵ is independently selected from phenyl, benzyl, phenethyl, phenoxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl carbon atoms in the cycloalkyl moiety, -CH ₂ NR ¹⁵ R ¹⁶ , -NR ¹⁵ R ¹⁶ , alkoxyalkyl of 2 to 6 carbon atoms and -C (R ¹⁶ ) = N (OR ¹⁶ ); -42 · 4 «4 45 4« 44 444 4444 4 4 4 4 4 4 4 4 · 1 444 4 4 4 4444 4 4 4 4 5 4 4 4 4 4 Wherein R ¹⁵ and R ¹⁶ are as defined above, (IV) R ⁶ and R ⁷ are independently selected from the group consisting of: -N (R ¹² ) ₂ , alkyl of 1 to 6 carbon atoms substituted with 0 to 3 substituents R ⁹ , -N (R ¹² ) ₂ , -SR -OR alkenyl having 2 to 6 carbon atoms substituted with 0-3 R ^9, alkynyl having 3 to 6 carbon atoms substituted with 0-3 R ^9, carbocyclic ring system having 3 to 14 carbon atoms substituted with 0 to 3 substituents R ⁹ or 0 to 3 R ¹⁰ substituents, and a heterocyclic ring system independently selected from furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrazolyl, pyrimidinyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl and thiazolyl, this heterocyclic ring system is substituted with 0-2 R ¹⁰ substituents, or R ⁶ and R ⁷ taken together form a carbocyclic ring system of 3 to 14 carbon atoms substituted with 0 to 3 substituents R ⁹ or 0 to 3 substituents R ¹⁰ , phenyl, 1- or 2-naphthyl substituted with 0 to 3 substituents R ⁹ or 0 to 3 substituents R ¹⁰ , or a heterocyclic ring system independently selected from the group consisting of furanyl, thienyl, pyrrolyl, imidazolyl, tetrahydropyranyl, pyridyl, piperidinyl, pyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl, tetrahydroisoquinolinyl, benzotriazolyl and thiazolyl, said heterocyclic ring system being up to 2 R ¹⁰ substituents wherein pyrazolyl, indolyl, R ⁹ , R ¹⁰ R ¹⁵ and R have the meanings given above for the definitions 1-5 ^{2 * * *} The method of claim 1, wherein the difference in numerical pKa values between the base and the corresponding secondary nitrile of Formula 3.0.0 is not greater than about 4. • * φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ 3. A process according to claim 1, wherein the base is a compound of formula (5.0.1,23). R Si — kjO \. ₂₂ ^ Si-R (5.0.1) where R ^20, R ^21, R ^22, R ^23, R ²⁴ and R ²⁵ are independently selected from the group consisting of alkyl of 1-5 carbon atoms and phenyl, and X ⁺ is a suitable cation. 4. The process of claim 3 wherein the suitable cation is a member selected from the group consisting of potassium, sodium and lithium. The process of claim 3, wherein said base is a compound of formula 5.0.1 wherein one R group on each silicon atom is tert-butyl, while the remaining R groups are all methyl. The process of claim 3, wherein said base is a compound of formula 5.0.1 wherein two R groups on each silicon atom are tert-butyls, while the remaining R group on each silicon atom is phenyl. 7. The process of claim 1 wherein said base is potassium, sodium or lithium salt of bis (trimethylsilyl) amide (HMDS). The method of claim 7, wherein said base is a HMDS potassium salt of Formula 5.0.0 · 9 «. -44 • 9 9 9 9 9 3 '3 (5.0.1) The method of claim 1, wherein said solvent is a solvent selected from the group consisting of toluene, tetrahydrofuran, hexane, benzene, o-, m- and p-xylene, diethyl ether, diisopropyl ether, methyl tert. butyl ether, 1,2-dimethoxyethane; and mixtures containing one or more of said solvents. The process according to claim 1, wherein a base / solvent system is used which comprises the bis (trimethylsilyl) amide potassium salt (KHMDS) as the base and toluene or tetrahydrofuran (THF) as the solvent.