PROCESS FOR PREPARING 3,3-DISUBSTITUTED OXINDOLES AND
THIO-OXINDOLES
The present invention relates to methods for preparing oxindole and thio-
oxindole compounds, particularly 5-pyrrole-3,3-oxindoles, which compounds are
useful as precursors to various pharmaceutical compounds.
BACKGROUND OF THE INVENTION
The synthetic routes to many useful compounds, including pharmaceutical
drugs, typically entail a large number steps. However, the presence of numerous
steps in the synthetic route to the desired product tends to result in lower yields of the
product even before purification.
Many useful compounds in the art have an oxindole backbone and
particularly a 3,3-disubstituted oxindole backbone. Of particular interest is 5-(7-
fluoro-3,3-dimemyl-2-oxo-23-dihydro-lH-indol-5-yl)-l-methyl-lH-pyrrole-2-
carbonitrile, which contains a 3,3-disubstituted oxindole backbone. In fact, the
current route to 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indol-5-yl)-l-
methyl-lH-pyrrole-2-carbonitrile involves at least 6 steps to give an overall yield of
6%.
What is needed in the art are alternate methods for preparing 3,3-disubstituted
oxindole compounds and the intermediates utilized in preparation thereof.
SUMMARY OF THE INVENTION
In one aspect, methods for preparing oxindole compounds and, desirably, 3,3-
disubstituted oxindole compounds are provided.
In. another aspect, methods for preparing 5-pyrrole-3,3-oxindole compounds
are provided.
In a further aspect, methods for preparing 5-(7-fluoro-3,3-dimethyl-2-oxo-
2,3-dihydro-1 H-indol-5-yl)-1 -methyl-1 H-pyrrole-2-carbomtrile are provided.
In yet another aspect, methods for preparing thio-oxindole compounds and,
desirably, 3,3-disubstituted thio-oxindole compounds are provided.
1

In a further aspect, methods for preparing iminobenzo[b]thiophene
compounds are provided.
In still another aspect, methods for preparing benzo[b]thiophenone
compounds are provided.
In yet a further aspect, methods for preparing compounds of the structure are
provided:

In another aspect, methods for selectively preparing a compound of the
structure are provided:

In still a further aspect, 2-(5-bromo-2-fluorophenyl)-2-methylpropionitrile; 2-
(3-chloropyridin-2-yl)-2-memylpropiomle;2-(3-chloroquinoxalin-2-yl)-2-
methylpropionitrile; 2-(2-fluorophenyl)-2-methylpropionitrile; 2-(2,3-
difluorophenyl)-2-memylpropionitrile;2-(2,6-difluorophenyl)-2-memylpropionitrile;
2-(2,3-difluorophenyl)isobutyramide;2-(2,6-difluorophenyl)isobutyramide; 2-(2-
fluorophenyl)isobutyramide; 2-(3-chloropyridin-2-yl)isobutyramide; l-(2,6-
difluorophenyl)cyclopropanecarboxylic acid amide; or a pharmaceutically acceptable
salt thereof are provided.
Other aspects and advantages of the invention will be readily apparent from
the following detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
A novel route to oxindole compounds and particularly 3,3-oxindole
compounds is provided. Advantageously, a shorter route to oxindole compounds is
2

also provided using 3 steps. The process includes converting a fluoroarene to a
secondary nitrile substituted arene, converting the nitrile substituent to an amide, and
cyclizing the amide to the oxindole compound.
Suitably, an oxindole prepared in the present method has the following
structure:

wherein, R1, R2, R3, and R4 are, independently, selected from among H, halogen, CN,
Cj to C6 alkyl, substituted C\ to C6 alkyl, C2 to C alkenyl, substituted C2 to Ce
alkenyl, C2 to Ce alkynyl, substituted C2 to Ce alkynyl, C3 to Cs cycloalkyl,
substituted C3 to Cg cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, N2+, OS02CF3, CF3, N02, SR5, OR5, N(R5)2, COOR5, CON(R5)2, and
S02N(R5)2; or R1 and R2; R2 and R3; R3 and R4; R1, R2, and R3; or R2, R3, and R4 are
fused to form (i) a 3 to 15 membered saturated or unsaturated carbon-containing ring;
or (ii) a 3 to 15 membered heterocyclic ring containing in its backbone from 1 to 3
heteroatoms selected from among 0, S, and NR11; R5 is selected from among Ci to
C$ alkyl and Q to C6 substituted alkyl; R6 and R7 are, independently, selected from
among Q to C6 alkyl, substituted Ci to C6 alkyl, C3 to C14 cycloalkyl, substituted C3
to Cu cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C2 to C6
alkenyl, substituted C2 to Cg alkenyl, C2 to C$ alkynyl, substituted C2 to C$ alkynyl,
N(R5)2, SR5, and OR5; or R6 and R7 are fused to form (iii) a 3 to 8 membered
saturated or unsaturated carbon-containing ring; or (iv) a 3 to 8 membered
heterocyclic ring containing in its backbone from 1 to 3 heteroatoms selected from
among O, S, and NR11; R8 is selected from among H, Ci to C6 alkyl, substituted Ci to
C6 alkyl, Ci to C6 alkoxy, substituted Ci to C6 alkoxy, Ci to C6 aminoalkyl,
substituted Ci to C6 aminoalkyl, Ci to C6 thioalkyl, substituted Ci to C6 thioalkyl,
CF3, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or R8 is fused with
R4 to form (v) a 5 to 8 membered saturated or unsaturated carbon-containing ring; or
(vi) a 5 to 8 membered heterocyclic ring containing in its backbone 1 to 3
3

heteroatoms selected from among 0, S, and MR11; wherein any of (i)-(vi) are
optionally substituted by Ci to C6 alkyl, substituted Ci to C6 alkyl, halogen, Ci to Cs
alkoxy, substituted d to C6 alkoxy, orN(R5)2; RU *s absent, H, Ci to C6 alkyl,
substituted Ci to C6 alkyl, aryl, or substituted aryl; A, D, E, and G are, independently,
selected from among C and N, wherein if any one of A, D, E, or G are N, the
corresponding R'-R4 is optionally absent; or a pharmaceutically acceptable salt
thereof. In one example, G is N. In another example, E and G are N. In a further
example, D and G are N. In yet another example, A and G are N. In still a further
example, R8 is H. In yet another example, Rs is cyclohexane. In a further example,
R6 and R7 are fused to form an adamantane ring.
In another embodiment, the following oxindoles are prepared:

In one embodiment, oxindoles of the following structure are prepared, where
R'-R4 and R6-R8 are defined above:

In a further embodiment, 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-lH-
indol-5-yl)-l-methyl-lH-pyrrole-2-carbonitrile is prepared.
4

In yet another embodiment, the following oxindoles are prepared:

In still a further embodiment, the following oxindole compounds, which are
covered by the compounds of US Patent Application Publication No. US 2005-
0222148-A1 hereby incorporated by reference, are prepared.

In yet another embodiment, the following oxindole compound, which is
described in US Patent Application Publication No. US 2006-0030717-A1 hereby
incorporated by reference, is prepared.

This oxindole compound is prepared using the following intermediates.

The term "alkyl" is used herein to refer to both straight- and branched-chain
saturated aliphatic hydrocarbon groups having 1 to about 10 carbon atoms, desirably
1 to about 8 carbon atoms, and more desirably 1 to about 6 carbon atoms. The term
"alkenyl" is used herein to refer to both straight- and branched-chain alkyl groups
having one or more carbon-carbon double bonds and containing about 2 to about 10
carbon atoms. Desirably, the term alkenyl refers to an alkyl group having 1 or 2
carbon-carbon double bonds and having 2 to about 6 carbon atoms. The term
"alkynyl" group is used herein to refer to both straight- and branched-chain alkyl
5

groups having one or more carbon-carbon triple bond and having 2 to about 8 carbon
atoms. Desirably, the term alkynyl refers to an alkyl group having 1 or 2 carbon-
carbon triple bonds and having 2 to about 6 carbon atoms.
The term "cycloalkyl" is used herein to refer to an alkyl group as previously
described that is cyclic in structure and has 3 to about 10 carbon atoms, and desirably
about 5 to about 8 carbon atoms.
The terms "substituted alkyl", "substituted alkenyl", "substituted alkynyl",
and "substituted cycloalkyl" refer to alkyl, alkenyl, alkynyl, and cycloalkyl groups,
respectively, having one or more substituents including, without limitation, halogen,
CN, OH, NO2, amino, aryl, heterocyclic, alkoxy, aryloxy, alkylcarbonyl,
alkylcarboxy, and arylthio which groups can be optionally substituted. These
substituents can be attached to any carbon of an alkyl, alkenyl, or alkynyl group
provided that the attachment constitutes a stable chemical moiety.
The term "aryl" as used herein refers to an aromatic system which can include
a single ring or multiple rings fused or linked together where at least one part of the
fused or linked rings forms the conjugated aromatic system. Desirably, the aromatic
system contains 6 to 14 carbon atoms. The aryl groups can include, but are not
limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, phenanthryl,
indene, benzonaphthyl, fluorenyl, and carbazolyl.
The term "substituted aryl" refers to an aryl group, desirably a C6-Q4 aryl
group, which is substituted with one or more substituents including halogen, CN,
OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, hydroxyalkyl,
alkylcarbonyl, alkylcarboxy, aminoalkyl, and arylthio, which groups can be
optionally substituted. Desirably, a substituted aryl group is substituted with 1 to
about 4 substituents.
The term "heteroaryl" as used herein refers to a stable 5- to 14-membered
monocyclic or multicyclic aromatic heterocyclic ring system. The heteroaryl ring has
carbon atoms and one or more heteroatoms including nitrogen, oxygen, and sulfur
atoms. Desirably, the heteroaryl ring has 1 to about 4 heteroatoms in the backbone of
the ring. When the heteroaryl ring contains nitrogen or sulfur atoms in the backbone
of the ring, the nitrogen or sulfur atoms can be oxidized.
6

The term "heterocyclic" refers to optionally saturated or partially saturated
heterocyclic rings having 3 to 15 ring atoms, desirably 3 to 8 ring atoms, and
desirably containing from 1 to 3 heteroatoms selected from among 0, S and N.
When the heterocyclic ring contains nitrogen or sulfur atoms in the backbone of the
ring, the nitrogen or sulfur atoms can be oxidized. The term "heterocyclic" also
refers to multicyclic rings in which a heterocyclic ring is fused to an aryl ring. The
heterocyclic ring can be attached to the aryl ring through a heteroatom or carbon
atom provided the resultant heterocyclic ring structure is chemically stable.
A variety of heterocyclic or heteroaryl groups are known in the art and
include, without limitation, oxygen-containing rings, nitrogen-containing rings,
sulfur-containing rings, mixed heteroatom-containing rings, fused heteroatom
containing rings, and combinations thereof. Oxygen-containing rings include, but are
not limited to, furyl, tetrahydrofuranyl, pyranyl, pyronyl, and dioxinyl rings.
Nitrogen-containing rings include, without limitation, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl, pyridyl, piperidinyl, 2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
piperazinyl, azepinyl, triazinyl, pyrrolidinyl, and azepinyl rings. Sulfiir-containing
rings include, without limitation, thienyl and dithiolyl rings. Mixed heteroatom
containing rings include, but are not limited to, oxathiolyl, oxazolyl, thiazolyl,
oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl,
morpholinyl, thiamorphohnyl, thiamorphohnyl sulfoxide, oxepinyl, thiepinyl, and
diazepinyl rings. Fused heteroatom-containing rings include, but are not limited to,
benzofuranyl, thionapthene, indolyl, benazazolyl, purindinyl, pyranopyrrolyl,
isoindazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzopyranyl, quinolinyl,
isoquinolinyl, benzodiazonyl, napthylridinyl, benzothienyl, pyridopyridinyl,
benzoxazinyl, xanthenyl, acridinyl, and purinyl rings.
The term "substituted heterocyclic" or "substituted heteroaryl" as used herein
refers to a heterocyclic group having one or more substituents including halogen,
CN, OH, N02, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy,
hydoxyalkyl, alkylcarbonyl, alkylcarboxy, aminoalkyl, and arylthio, which groups
can be optionally substituted. Desirably, a substituted heterocyclic group is
substituted with 1 to about 4 substituents.
7

The term "alkoxy" as used herein refers to the 0(alkyl) group, where the
point of attachment is through the oxygen-atom and the alkyl group is optionall]
substituted.
The term "aryloxy" as used herein refers to the O(aryl) group, where the poin
of attachment is through the oxygen-atom and the aryl group is optionall]
substituted.
The term "hydroxyalkyl" as used herein refers to the alkylOH group, when
the point of attachment is through the alkyl group.
The term "arylthio" as used herein refers to the S(aryl) group, where the poin
of attachment is through the sulfur-atom and the aryl group can be optionally
substituted.
The term "alkylcarbonyl" as used herein refers to the C(0)(alkyl) group
where the point of attachment is through the carbon-atom of the carbonyl moiety an<
the alkyl group is optionally substituted.
The term "alkylcarboxy" as used herein refers to the C(0)0(alkyl) group,
where the point of attachment is through the carbon-atom of the carboxy moiety and
the alkyl group is optionally substituted.
The term "aminoalkyl" as used herein refers to both secondary and tertiary
amines where the point of attachment is through the nitrogen-atom and the alkyl
groups are optionally substituted. The alkyl groups can be the same or different.
The term "thioalkoxy" or "thioalkyl" as used herein refers to the S(alkyl)
group, where the point of attachment is through the sulfur-atom and the alkyl group
is optionally substituted.
The term "halogen" as used herein refers to CI, Br, F, or I groups.
The oxindoles discussed herein also encompass tautomeric forms and salts
derived from pharmaceutically or physiologically acceptable acids, bases, alkali
metals and alkaline earth metals. Also included are oxindole derivatives, including,
but not limited to, esters, carbamates, sulfates, ethers, oximes, carbonates, and the
like.
Physiologically acceptable acids include those derived from inorganic and
organic acids. A number of inorganic acids are known in the art and include
8

hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, and phosphoric acids, among
others. Similarly, a variety of organic acids are known in the art and include, without
limitation, lactic, formic, acetic, fumaric, citric, propionic, oxalic, succinic, glycolic,
glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, tartaric, malonic,
mallic, phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic,
panthenoic, benzenesulfonic, toluenesulfonic, stearic, sulfanilic, alginic, and
galacturonic acids, among others.
Physiologically acceptable bases include those derived from inorganic and
organic bases. A number of inorganic bases are known in the art and include
aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc sulfate or
phosphate compounds, among others. A number of organic bases are known in the
art and include, without limitation, N,N,-dibenzylethylenediamine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine, and procaine, among others.
Physiologically acceptable alkali metal salts and alkaline earth metal salts can
include, without limitation, sodium, potassium, calcium and magnesium salts in the
form of esters, and carbamates.
These salts can be in the form of esters, carbamates and other conventional
"pro-drug" forms, which, when administered in such form, convert to the active
moiety in vivo. In one embodiment, the prodrugs are esters. See, e.g., B. Testa and
J. Caldwell, "Prodrugs Revisited: The "Ad Hoc" Approach as a Complement to
Ligand Design", Medicinal Research Reviews, 16(3):233-241, ed., John Wiley &
Sons (1996).
The oxindoles discussed herein also encompass "metabolites" which are
unique products formed by processing of the oxindole by the cell or patient.
Desirably, metabolites are formed in vivo.
Methods of preparing oxindole compounds, desirably 3,3-disubstituted-
oxindoles, are thereby provided. Oxindoles IV are prepared by substituting
fiuoroarene I with a secondary nitrile to form nitrile n, converting nitrile II to amide
HI, and cyclizing amide HI to form oxindole IV. Alternatively, nitrile II can first be
converted to acid V and thereby to amide JJI. See, Scheme 1, where R!-R4, R6, R7,
and R8 are defined above and X is defined below.
9


The method utilizes fluoroarene I as the starting material. Desirably, the
fluoroarene has the following structure and contains a halogen in the ortho position
(X).

wherein, R!-R4, A, D, E, and G are defined above. More desirably, X is fluorine.
10
In one embodiment, the fluoroarene is of the following structure, wherein R1-
R4andX are defined above:


In another embodiment, the fluoroarene is of the following structure:

wherein, X is F, CI, or Br; and R2 is Br, CI, I, or H.
In a further embodiment, the fluoroarene is selected from among:

The fluoroarene is subsequently reacted with a secondary nitrile to undergo a
nucleophilic aromatic substitution. See, for example the reagents utilized in the
substitution reaction described in US Patent No. 6,303,782; JACS 2000,122, 712;
Org. Synth. 2002, 79, 209; and European Patent No. 1,046,635, which are hereby
incorporated by reference. Typically, the secondary nitrile is R6R7CHCN, wherein
R6andR7 are defined above. This reaction is typically performed in the presence of
a base including silyl reagents such as sodium hexamethyldisilazide (NaHMDS),
potassium hexamethyldisilazide (KHMDS), lithium hexamethyldisilazide
(LiHMDS); lithium diisopropylamide (LDA); Grignard reagents such as isopropyl
magnesium halide including isopropyl magnesium chloride OPrMgCl), methyl
magnesium bromide (MeMgBr), vinyl magnesium bromide (vinylMgBr), o-tolyl
magnesium bromide, and dibutyl magnesium chloride; sodium hydride (NaH);
1,1,3,3-tetramethylguanidine (TMG); methyl lithium (MeLi); hexyl lithium (HexLi);
potassium t-butoxide (t-BuOK); potassium t-pentoxide (t-PentOK), among others.
Desirably, the base is a silyl reagent, a Grignard reagent, or LDA. More desirably,
the base is sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium
hexamethyldisilazide, Uthium diisopropylamide, isopropyl magnesium chloride,
methyl magnesium bromide, o-tolyl magnesium bromide, or dibutyl magnesium
chloride. More desirably, the base is a Grignard reagent including isopropyl
magnesium chloride, methyl magnesium bromide, o-tolyl magnesium bromide, or
dibutyl magnesium chloride.
11

The process described herein also permits selective conversion of fluoroarene
I to nitrile II by reducing the production of undesired by-products. By-products
include isomers of nitrile II formed by reaction of the secondary nitrile with
substituents other than the fluorine atom at the 1-position of fluoroarene I. In one
embodiment, the secondary nitrile reacts with one or more of the X or R'-R4
substituents of fluoroarene I to form by-product(s). By doing so, the process thereby
provides higher yields of the desired nitrile II product.
The inventors have found that when a Grignard reagent is utilized as the base
for conversion of fluoroarene I to nitrile II, fewer by-products were formed. Suitable
Grignard reagents include those described above. Further, use of a lower temperature
promoted conversion of fluoroarene I to nitrile II. The term "lower temperatures" as
used herein for this conversion includes temperatures of about -40 to 0°C. Most
desirably, the temperature is about -25°C. The inventors therefore found that the
combination of the Grignard reagent and lower temperature afforded nitrile II in good
yields with the least amount of by-products, particularly when X is a fluorine atom.
The inventors have also found that preparation of nitrile II from fluoroarene I
is desirable over the preparation of nitrile II via alkylation of the a-carbon of the
corresponding benzylnitrile compound as described in I. Fleming, et al, J. Chem.
Soc, Perkin Trans. 1,1986,349, which is hereby incorporated by reference.
Specifically, alkylation of the benzylnitrile as described by Fleming is difficult to
control and results in a mixture of by-products including mono- and di-alkylated
nitriles, as well as unreacted benzylnitrile starting material. Further, separation of
nitrile II from any by-product and/or unreacted benzylnitrile not only requires a
separate step, but the procedure for separation is difficult, thereby resulting in lower
yields of nitrile H However, the use of fluoroarene I to prepare nitrile II, as
described in the present application, eliminates the generation of the alkylated by-
products described by Fleming.
12

A nitrile of the following structure is thereby prepared.

wherein, R'-R4, A, D, E, G, X, R6, and R7 are defined above.
In one embodiment, a nitrile of the following structure is prepared:

In another embodiment, a nitrile of the following structure is prepared.

In a further embodiment, 2-(5-bromo-2-fluorophenyl)-2-methylpropionitrile;
2-(3-cMoropyridm-2-yl)-2-methylpropiomle;2-(3-chloroquinoxalin-2-yl)-2-
methylpropionitrile; 2-(2-fluorophenyl)-2-methylpropionitrile; 2-(2,3-
difluorophenyl)-2-methylpropionitrile; and 2-(2,6-difluorophenyl)-2-
methylpropionitrile are prepared.
The nitrile group of nitrile compound II is then converted to amide III of the
following structure using techniques known to those of skill in the art including,
without limitation, those transformations described in Larock, Comprehensive
Organic Transformations, John Wiley & Sons, New York, NY, (1999); US Patent
No. 6,482,983; Fleming, 1986, cited above; and Lebedev et al., Tet. Lett. 43:1397-
1399 (2002), which are hereby incorporated by reference.
13


wherein, R!-R4, R6, R7, and X are defined above and R8 is selected from among H, Q
to C6 alkyl, substituted C\ to Co alkyl, Ci to C$ alkoxy, substituted d to C6 alkoxy,
C\ to Q aminoalkyl, substituted Ci to Cg aminoalkyl, Ci to C thioalkyl, substituted
Ci to Co thioalkyl, CF3, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
In one embodiment, nitrile II is converted to amide III using basic or acidic
hydrolysis. In one example, nitrile II is converted to amide III using Ritter or Ritter-
type reactions as described in US Patent No. 6,482,983; and Lebedev cited above. In
another example, amide III is prepared by reacting nitrile II with an alcohol,
sulfonate, phosphate, ester, or boronic ester. In a further example, amide III is
prepared by reacting nitrile II with (R80)nZ, where R8 is selected from among H, Q
to C6 alkyl, substituted Q to Cg alkyl, Ci to C6 alkoxy, substituted Q to C6 alkoxy,
Ci to C6 aminoalkyl, substituted Ci to Q aminoalkyl, Ci to C6 thioalkyl, substituted
Ci to C6 thioalkyl, CF3, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, n
is 0 to 3, and Z is H when n is 1, SO2 when n is 2, P=0 when n is 3, C=0 when n is
2, B when n is 3, SOaalkyl when n is 1, (C=0)2 when n is 2, and acetyl when n is 1,
under acidic or basic conditions. One of skill in the art would readily be able to
select suitable reagents for either acidic or basic hydrolysis and include those
described in Larock cited above and incorporated by reference. Basic hydrolysis to
amide HI can be performed with hydrogen peroxide and a base readily selected by
one of skill in the art. Acidic hydrolysis to amide II can be performed using a strong
acid, such as sulfuric acid, methanesulfonic acid, or hydrochloric acid.
14

In one embodiment, amides of the following structure are prepared.

In another embodiment, amides of the following structures are prepared.

In a further embodiment, 2-(2,3-difluorophenyl)isobutyramide; 2-(2,6-
difluorophenyl)isobutyramide; 2-(2-fluorophenyl)isobutyramide; 2-(3 -chloropyridin-
2-yl)isobutyramide; l-(2,6-difluorophenyl)cyclopropanecarboxylic acid amide are
prepared.
Amide IE is alternatively prepared by first converting nitrile II to an acid V of
the following structure, where R*-R4, R6, R7, X, A, D, E, and G are defined above,
which is subsequently converted to the amide HI noted above.

Conversion of nitrile II to acid V to amide III can be performed using the
transformations set forth in Larock cited above or US Patent No. 6,482,983, which
are hereby incorporated by reference. In one example, nitrile II is hydrolyzed to acid
V, which is reacted with an amine, desirably at elevated temperatures in the presence
of p-toluenesulfonic acid, to prepare amide in. In another example, nitrile II is
hydrolyzed to acid V, acid V is converted to acid chloride VI, and acid VI is
converted to amide m using the transformations set forth in Larock; Fleming, 1986;
or US Patent No. 6,482,983 cited above.
15

Amide HI is then treated with a strong base that is capable of deprotonating
the hydrogen-atom of the amide functional group. Deprotonation of the amide
results in the formation of the amide anion, which reacts with the halo group in the
ortho position (X) to cyclize to the oxindole IV. One of skill in the art could readily
select a suitable strong base to cyclize the amide and includes those reagents set forth
in Fleming, Tetrahedron Lett., 1982,23,2053 and J. Chem. Soc, Perkin Trans. I,
1986,349, which are hereby incorporated by reference, among others. Desirably, the
strong base is lithium hydride, lithium diisopropylamide, alkyl lithium reagents, aryl
lithium reagents, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and
potassium hexamethyldisilazide, among others.
Also provided are methods for preparing 5-pyrrole-3,3-oxindole compounds
of the structure:

wherein, R1, R3, and R4 are, independently, selected from among H, chlorine, CN, Ci
to C6 alkyl, substituted Ci to Ce alkyl, C2 to C6 alkenyl, substituted C2 to C$ alkenyl,
C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to Cs cycloalkyl, substituted C3 to
Cs cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, OSO2CF3,
CF3, N02, SR5, OR5, N(R5)2, COOR5, CON(R5)2, and S02N(R5)2; or R1 and R2; R2
and R3; R3 and R4; R1, R2, and R3; or R2, R3, and R4 are fused to form (i) a 3 to 15
membered saturated or unsaturated carbon-containing ring; or (ii) a 3 to 15
membered heterocyclic ring containing in its backbone from 1 to 3 heteroatoms
selected from among O, S, and NRU; R5 is selected from among Ci to C6 alkyl and
Ci to C6 substituted alkyl; R6, R7, R8, A, D, E, and G are defined above; R9 is Ci to C6
alkyl, substituted Ci to C6 alkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, or CORA; RA is H, Ci to C6 alkyl, substituted Ci to C6 alkyl, Ci to C6
alkoxy, substituted Ci to C6 alkoxy, Ci to C6 arninoalkyl, or substituted Ci to C6
aminoalkyl; and R10 is H, OH, NH2, CN, halogen, Ci to C6 alkyl, substituted Ci to C6
16

alkyl, C2 to C6 alkenyl, substituted C2 to C& alkenyl, C2 to C6 alkynyl, substituted C2
to C6 alkynyl, Ci to C6 alkoxy, substituted Ci to C& alkoxy, Ci to C6 aminoalkyl,
substituted Ci to C$ aminoalkyl, or CORA. See, Scheme 2.

This method includes substituting a fluoroarene with a secondary nitrile to
form a nitrile compound II of the structure:

wherein, R2 is a leaving group such as halogen, OS02CF3, or N2+;
converting nitrile II to amide HI of the structure:
17

cyclizing amide III to oxindole IV of the following structure:

coupling oxindole IV with a pyrrole of the structure:

wherein, R-R4 and R6-R10 are defined above and Y is a leaving group. In one
example, the pyrrole is of the structure:

In another example, the pyrrole is a cyanopyrrole. In a further example, the pyrrole
is of the structure:

18

If R2 is a halogen other than bromine, or triflate, oxindole IV can first be
brominated at the 5-position to form the bromooxindole compound VH, which is
thereby reacted with the pyrrole noted above to form the pyrrole oxindole VHI.
The term "leaving group" as used herein refers to any substituent that is
displaced upon the reaction with another reagent. There are a large number of
leaving groups that can be utilized to form the 5-pyrrole-3,3-oxindole compounds
and include, without limitation, boron-containing leaving groups such as those
described in US Patent Application Publication No. US-2005-0272702-A1, which is
hereby incorporated by reference. Desirably, the leaving group is the following:

In one embodiment, the oxindole compound prepared is of the following
structure:

In a further embodiment, a method for preparing 5-(7-fluoro-3,3-dimethyl-2-
oxo-2,3-dmydro-lH-indol-5-yl)-l-memyl-lH-pyrrole-2-carbonitrile is provided and
includes substituting a fluoroarene with a secondary nitrile to form a compound of
the structure:



19
converting the nitrile to an amide of the structure:


cyclizing the amide to an oxindole of the following structure:
coupling the oxindole with a l-methyl-5-cyano-2-pyrrole compound.
In another embodiment, a method for preparing 5-(7-fmoro-3,3-dirnethyl-2-
oxo-2,3-dihydro-lH-indol-5-yl)-l-methyl-lH-pyrrole-2-carbonitrile is provided anc
includes substituting a fluoroarene with a secondary nitrile to form a compound of

converting the nitrile an amide of the structure:

cyclizing the amide to an oxindole of the following structure:

the structure:
coupling the oxindole with a l-methyl-5-cyano-2-pyrrole compound.
The l-methyl-5-cyano-2-pyrrole compound can be a boronate salt, borinate
salt, boronic ester, borinic ester, boronic acid, or borinic acid. Desirably, the 1-
methyl-5-cyano-2-pyrrole is a boronic acid. More desirably, the l-methyl-5-cyano-
2-pyrrole compound is 5-[l,3,6,2]dioxazaborocan-2-yl-l-methyl-lH-pyrrole-2-
carbonitrile, the preparation of which is described in US Patent Application
Publication No. US-2005-0272702-A1, which is hereby incorporated by reference.
20


converting the nitrile to an amide of the structure:

cyclizing the amide to an oxindole of the following structure:

brominating the oxindole to form a compound of the structure:

5-(7-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indol-5-yl)-l-methyl-lH-
pyrrole-2-carbonitrile can also be prepared by substituting a fluoroarene with a
secondary nitrile to form a compound of the structure:
coupling the brominated oxindole with a l-methyl-5-cyano-2-pyrrole compound as
described above.
In one embodiment, 5-(7-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-lH-indol-5-
yl)-l-methyl-lH-pyrrole-2-carbonitrile is prepared according to the sequence of steps
provided in Scheme 3.
21


In another embodiment, a method of preparing a compound of the structure is
also provided:

wherein said method includes:
substituting a fiuoroarene with a secondary nitrile to form a compound of the

converting the nitrile to an amide of the structure:

22
structure:

cyclizing the amide to an oxindole of the following structure:

brominating the oxindole to form a compound of the structure:

coupling the brominated oxindole with a l-methyl-5-cyano-2-pyrrole compound to
form the product described above. See, Scheme 4.

In still another embodiment, a method of preparing a compound of the
structure is provided:


23
wherein the method includes alkylating a benzylnitrile to form a compound of the
structure:





converting the nitrile to an amide of the structure:
cyclizing the amide to an oxindole of the following structure:
brominating the oxindole to form a compound of the structure:
coupling the brominated oxindole with a l-methyl-5-cyano-2-pyrrole compound to
form the product described above. See, Scheme 5.

In a further embodiment, methods of preparing thio-oxindole compounds are
provided. These thio-oxindole compounds can be prepared directly from the
oxindoles prepared as described above using thionating agents known in the art.
Suitable thionating agents include, without limitation, 2,4-bis(4-methoxyphenyl)-l,3-
dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) or phosphorus
pentasulfide.
24

In yet another embodiment, methods for preparing thio-oxindole compounds
are provided and include preparing nitrile II as described above; converting nitrile II
to amide HI; converting amide IE to thioamide DC; and cyclizing thioamide DC to
thio-oxindole X. See, Scheme 6.

In still a further embodiment, methods for preparing iminobenzo[b]thiophene
compounds are provided and include preparing nitrile II as described above;
converting nitrile II to amide HI; converting amide HI to thioamide DC; and cyclizing
thioamide DC to iminobenzo[b]thiophene XI. See, Scheme 6.
Several reagents can be utilized to cyclize the thioamide to the
iminobenzo[b]thiophene and include, without limitation, bases such as those
described above or weaker bases thereof which could readily be selected by one of
skill in the art.
25

In yet another embodiment, methods for preparing benzo[b]thiophenone
compounds are provided and include preparing nitrile II as described above;
converting nitrile II to amide HI; converting amide HI to thioamide DC; cyclizing
thioamide IX to iminobenzo[b]thiophene XI; and converting iminobenzo[b]thiophene
XI to benzo[b]thioophenone XII. See, Scheme 6.
Also provided is a method for preparing thio-oxindole compounds including
converting fluoroarene I to nitrile II; converting nitrile II to thioamide DC; and
cyclizing thioamide DC to thio-oxindole X. See, Scheme 7.

Further provided is a method for preparing iminobenzo[b]thiophene
compounds including converting fluoroarene I to nitrile II; converting nitrile II to
thioamide DC; and cyclizing thioamide DC to iminobenzo[b]thiophene XL See,
Scheme 7.
26

A method for preparing benzo[b]thiophenone compounds are also provided
and include converting fluoroarene I to nitrile II; converting nitrile II to thioamide
DC; cyclizing thioamide IX to iminobenzo[b]thiophene XI; and converting
iminobenzo[b]thiophene XI to benzo[b]thiophenone XH. See, Scheme 7.
The nitrile II can be converted to a thioamide using techniques described in
the art and as described in US Patent Application Publication No. US-2005-0227971-
Al, which is hereby incorporated by reference. Typically, the nitrile is converted to
a thioamide using a base and a sulfur-containing agent (See, R. Shabana, H. J.
Meyer, S.-O. Lawesson Phosphorus and Sulfur 1985, 25, 297). The sulfur-
containing agent includes, without limitation, a dialkyldithiophosphate, a
diaryldithiophosphate, hydrogen sulfide (H2S), 2,4-bis(4-methoxyphenyl)-l,3-dithia-
2,4-diphosphetane-2,4-disulfide (Lawesson's reagent), or phosphorus pentasulfide.
Desirably, the sulfur-containing agent is a dialkyldithiophosphate or
diaryldithiophosphate, and more desirably diethyldithiophosphate. The base is
typically an amine. Desirably, the amine is an alkylated amine including N,N-
diisopropylethylamine (Hunig's base), triethylamine, or pyridine, among others.
The iminobenzo[b]thiophene VI can then be converted to the corresponding
benzo[b]thiophenone XII using reagents known to those of skill in art. Specifically,
the imine moiety of the benzo[b]thiophene can be protonated and thereby hydrolyzed
to a carbonyl. In one example, when R8 is H, the imine moiety can be protonated
with a strong acid such as hydrochloric acid, hydrosulfuric acid, and triflic acid,
among others, and thereby hydrolyzed to a carbonyl group to provide a
benzo[b]thiophenone XII.
The following examples are provided to illustrate the invention and do not
limit the scope thereof. One skilled in the art will appreciate that although specific
reagents and conditions are outlined in the following examples, modifications can be
made which are meant to be encompassed by the spirit and scope of the invention.
27

EXAMPLES
Example 1. Product distribution in the reaction of 1,2,3-trifluorobenzene and
2-methylpropionitriIe in the presence of various bases.
The reaction tubes of Mettler Toledo MiniBlock™ were independently
charged with 1,2,3-trifluorobenzene (1.32 g, 0.01 mol). A solution of 2-
methylpropionitrile (14 g) in toluene (160 mL) was prepared and 8.5 mL (containing
0.01 mol of 2-methylpropionitrile) was dispensed to each tube. Equimolar amounts
of the bases in Table 1 were then added dropwise at ambient temperature. The
mixtures were heated to 65 °C over 3 hours, cooled to ambient temperature and
quenched with 5% hydrochloric acid (6 mL each). The organic phases were separated
and solvents evaporated. The residues were analyzed by GC/MS as solutions in
acetonitrile.
Table 1
Normalized (area %) product distribution

"The reaction mixture contained a number of side-products.
5 and 16% of the respective tert-pentoxyethers and minute amounts of the desired nitriles.
c66 and 22% of the respective tert-butoxyethers and minute amounts of the desired nitriles.
d33.5% isomer A, 5.2% isomer B, in addition to a number of side-products.
'5.5% isomer A, 0.7% isomer B, in addition to a number of side-products.
28

These data illustrate isomer A could be isolated as the major product,
particularly when using the Grignard bases.
Example 2. Product distribution in the reaction of 1,2,3-trifluorobenzene and
2-methylpropionitrile in the presence of isopropylmagnesium chloride in
various solvents.
This example was performed as described in Example 1, whereby seven
samples were prepared by dissolving 1,2,3-trifluorobenzene (1.32 g, 0.01 mol) and 2-
methylpropionitrile (0.9 mL, 0.69 g, 0.01 mol) in the solvent (8 mL each) noted in
Table 2. Isopropylmagnesium chloride (2M in THF, 5 mL each) was independently
added dropwise to these mixtures. The mixtures were then heated to 35 °C over 3
hours, cooled to ambient temperature and quenched with 5% HC1 (6 mL). The
reaction mixture containing triethylamine was additionally treated with concentrated
hydrochloric acid. The organic phases were separated and the solvents were
evaporated. The residues were analyzed by GC/MS as solutions in acetonitrile.
Table 2
Normalized (area %) product distribution

Solvent Isomer A Isomer B Isomer C
Tetrahydrofuran 83.0 16.5 0.4
Dioxane 83.7 16.3 0
1,2-Dimethoxyethane 85.9 14.1 0
Ethyl ether 84.8 15.2 0
Triethylamine 80.2 16.0 3.7
Dichloromethanea 85.8 14.2 0
Methyl tert-butyl ether 84.2 15.6 0.1
a The reaction mixture contained numerous side-products.
These data illustrate that the ether solvents were most useful in isolating the
isomer A compound as the major product.
29

Example 3. Product distribution in the reaction of 1,2,3-trifluorobenzene and
2-methylpropionitrile in the presence of isopropylmagnesium chloride at
various temperatures.
Three flasks were equipped with a thermocouple, condenser with a nitrogen
inlet, and amagnetic stirring bar. 1,2,3-trifluorobenzene (1.32 g, 0.01 mol) and 2-
methylpropionitrile (0.9 mL, 0.69 g, 0.01 mol) were added to each flask and thereby
dissolved in THF (8 mL). The contents of the first flask were cooled to -25 °C; the
contents of the second flask were cooled to 0 °C; and the contents of the third flask
were heated to 60 °C. Isopropylmagnesium chloride (2M in THF, 5 mL each) was
added dropwise to each solution maintaining the respective reaction temperatures.
After 2 hours, the reactions were quenched with 5% HC1 (6 mL each). The organic
phases were separated and the solvent was evaporated. The residues were analyzed
by GC/MS as solutions in acetonitrile. See, Table 3.
Table 3
Normalized (area %) product distribution

Reaction temperature
CO Isomer A Isomer B Isomer C
-25 88.0 12.0 0
0 85.5 14.5 0
60 82.2 17.2 0.14
These data illustrate that temperature has a minimal effect on the isomer
distribution. However, the use of a lower temperature provides a higher amount of
Isomer A.
Example 4. Reaction of haloarenes and 2-methylpropionitrile in the presence
of various bases in THF.
The reaction tubes of Mettler Toledo MiniBlock™ were independently
charged with the haloarenes (0.01 mol) identified below and a solution of 2-
methylpropionitrile in THF (8.5 mL, 0.01 mol) which was prepared from the nitrile
(14 g) and THF (160 mL). An equimolar amount of the base (0.01 mol) was
independently added to each tube dropwise at ambient temperature. The reaction
30

mixtures were heated to 65 °C over 1 hour, cooled to ambient temperature and
quenched with 5% HC1 (6 mL). The organic phases were separated and the solvents
were evaporated. The crude product mixtures were examined using gas
chromatography (GC)/mass spectroscopy (MS) and proton nuclear magnetic
resonance H-NMR).
A.

haloarene: 1 -bromo-3,4-difluorobenzene;
base: isopropylmagnesium chloride (2M in THF);
0.642 grams of products:
(i) 2-(5-bromo-2-fluorophenyl)-2-methylpropionitrile:
major, 73.1% by GC/MS;
!H-NMR (CDC13): 5 7.59 (H6, dd, 6.8,2.4 Hz), 7.44 (H4, ddd,
8.6, 4.4, 2.4), 7.01 (H3, dd, 11.2, 8.8), 1.785 (s, 6H, CH3);
(ii) 2-(4-bromo-2-fluorophenyl)-2-methylpropionitrile:
minor, 9.1% by GC/MS;
(iii) l-(3,4-difluorophenyl)-2-methylpropan-l-one:
minor, 15% by GC/MS.

haloarene: 2,3-dichloropyridine;
base: isopropylmagnesium chloride (2M in THF);
1.237 grams of:
(i) 2-(3-chloropyridin-2-yl)-2-methylpropionitrile
50% yield as evidenced by 'H-NMR;
31

Structure assignment was based on GC/MS and -NMR data
(CDCI3): 5 8.48 (H6, dd, 4.4,1.6 Hz), 7.76 (H4, dd, 8.0,1.6), 7.29 (H5, dd, 8.0,4.8),
1.87 (s, 6H, CH3); 13C-NMR data (CDC13): 8 154.20 ppm C2,147.05 C6,139.45 C4,
131.03 C3,124.37 C5,123.10 CN, 38.59 C, 26.59 CH3; and
(ii) residual haloarene: 50%.

haloarene: 2,3-dichloroquinoxaline;
base: potassium hexamethyldisilazide (0.5M in toluene);
0.988 grams of:
(i) 2-(3-chloroquinoxalin-2-yl)-2-methylpropionitrile: 95.9% yield as
evidenced by GC/MS);
'H-NMRCDMSO-dg): S 8.19-8.15 (m, 1H), 8.13-8.10 (m, 1H), 8.01-
7.96 (m, 2H), 1.94 (s, 6H);
(ii) residual haloarene: 2.82%; and
(iii) 2-[3-(cyanodimethylmethyl)-quinoxalin-2-yl]-2-methylpropionitrile:
1.32% yield.
D.

haloarene: 2,3-dichloroquinoxaline;
base: isopropylmagnesium chloride 1 (2M in TKF);
product: 2-(3-chloroquinoxalin-2-yl)-2-methylpropionitrile (38.1% by
GC/MS) and residual haloarene (61.1%).
32

haloarene: 1 -chloro-2-fluorobenzene;
base: o-tolylmagnesium chloride (1M in THF);
products: 2-(2-chlorophenyl)-2-methylpropionitrile (29.6% by GC/MS);
residual haloarene (47.9%); and 2'-methylisobutyrophenone (12.7%)
F.

haloarene: l-bromo-2-fluorobenzene;
base: sodium hexamethyldisilazide (1M in THF);
product: 2-(2-bromophenyl)-2-methylpropionitrile (5.2% by GC/MS) and
residual haloarene (76.8%)

substrate: 1,2-difluorobenzene;
base: dibutylmagnesium chloride (1M in heptane);
products: 2-(2-fluorophenyl)-2-methylpropionitrile (2.8% by GC/MS); 2-
methylheptan-3-one (29.0%); and its imine analog (57.8%)
Example 5. Reaction of 1,2-difluorobenzene with various secondary nitrites
in the presence of isopropylmagnesium chloride in THF.
Mettler Toledo MiniBlock™ reaction vessels were independently charged
with 1,2-difluorobenzene (0.01 mol), anitrile (0.01 mol) identified below, and THF
(8 mL). Isopropylmagnesium chloride (2M in THF, 5 mL each) was added dropwise
at ambient temperature to each vessel. The reaction mixtures were heated to 65 °C
33

over 4 hours, cooled to ambient temperature and quenched with 5% HC1 (6 mL). The
organic phases were separated and the solvents were evaporated. The crude product
mixtures were examined using GC/MS and 'H-NMR.
A.

nitrile: 2-methylpropionitrile;
0.637 grams of 2-(2-fluorophenyl)-2-methylpropionitrile (97.9% by GC/MS).
'H-NMR (DMSO-ds): 5 7.52-7.42 (m, 2H), 7.34-7.25 (m, 2H), 1.74 (s, 6H).

nitrile: 2-norbornanecarbonitrile;
1.570 grams of the following products:
(i) exo-2-(2-fluorophenyl)bicyclo[2.2.1]heptane-2-carbonitrile (95.1% by
GC/MS);
(ii) endo-2-(2-fluorophenyl)bicyclo[2.2. l]heptane-2-carbonitrile (0.73%);
and
(iii) 1 -bicyclo[2.2.1 ]hept-2-yl-2-methyl-propanone (1.65%).
The structure was assigned based on 'H-NMR and literature data (I. Fleming,
et al, /. Chem. Soc, Perkin Trans. 1,1986,349; S. Caron, et al, J. Am. Chem. Soc.
2000,122, 712).
34

nitrile: cyclohexanecarbonitrile;
products: l-(2-fluorophenyl)cyclohexanecarbonitrile (43.3% by GC/MS) and
1 -cyclohexyl-2-methylpropanone (33.2%)
Example 6. Preparation of 2-(2,3-difluorophenyl)-2-methylpropionitrile and 2-
(2,6-difluorophenyl)-2-methylpropionitrile.

1M sodium hexamethyldisilazide in tetrahydrofuran (40 mL) was added in
portions to a stirred solution of 1,2,3-trifluorobenzene (5.03 g) and 2-
methylpropionitrile (2.81 g) in toluene (30 mL). The reaction mixture was heated to
68 °C for 3 hours, additionally stirred at ambient temperature overnight, and
quenched into 5% HC1. The organic phase was separated and washed with water and
brine. Evaporation of the solvent gave an oil (5.99 g) containing a 76:24 ratio of
isomers: 2-(2,3-difluorophenyl)-2-methylpropionitrile (65.4% by GC/MS, RT 6.20
min.); 2-(2,6-difluorophenyl)-2-methylpropionitrile (20.3%, RT 6.78 min.); and 2-[3-
(cyanodimethylmethyl)-2-fluorophenyl]-2-methylpropionitrile (14.1%, RT 10.4
min.). -NMR (DMSO-de): major CH3 singlet at 1.76 ppm and a minor singlet at
1.83 ppm.
Example 7. Hydrolysis of a crude mixture of 2-(2,3-difluorophenyl)-2-
methylpropionitrileand2-(2,6-difluorophenyl)-2-methylpropionitrile.

35

A sample of crude 2-(2,3-difiuorophenyl)-2-memylpropiorntrile and 2-(2,6-
difluorophenyl)-2-methylpropionitrile (4.12 g) was dissolved in methanol (10 mL)
and water (3 mL). Tetrabutylammonium hydrogensulfate (25 mg) and sodium
percarbonate (1.20 g) were added to the methanol solution at ambient temperature,
followed by a dropwise addition of 50% hydrogen peroxide (3 mL) within 5 hours.
The stirring was continued for 40 hours, after which the reaction mixture was
extracted with ethyl acetate and water. The organic phase was dried over anhydrous
magnesium sulfate, filtered and evaporated to provide an oil, which solidified upon
evaporation with hexane to give a waxy solid (4.80 g).
GC/MS showed two m/z 199 isomers: 18.5 and 63.6% (23:77 ratio; RT 9.05
and 9.27 min., respectively). 'H-NMR (DMSO-de) showed a major singlet at 1.60
ppm (CH3) and two major CONH2 signals at 5.98 and 5.45 ppm. These resonances
were attributed to 2-(2,3-difluorophenyl)isobutyramide. Minor CONH2 signals at
6.43 and 5.73 ppm were attributed to 2-(2,6-difluorophenyl)isobutyramide.
Example 8. Thionation of a crude mixture of 2-(2,3-
difluorophenyl)isobutyramide
and 2-(2,6-difluorophenyl) isobutyramide.

A crude sample of 2-(2,3-difluorbphenyl)isobutyramide and 2-(2,6-
difluorophenyl)isobutyramide (1.86 g) was heated to 84 °C with Lawesson's reagent
(2.0 g) in 1,2-dimethoxyethane (30 mL) for 16 hours. The clear, light-orange solution
was cooled to ambient temperature and poured into water. The precipitated orange oil
was stirred overnight to form sticky, pale yellow oil. The pale yellow oil was
extracted with chloroform (3x), the organic extracts washed with water (2x), and
dried over anhydrous magnesium sulfate. Filtration followed by evaporation gave a
light-brown solid (2.37 g). GC/MS showed m/z 215 product (RT 11.31 min.) along
with threeother by-products.
36

Example 9. Cyclization of a mixture of 2-(2,3-difluorophenyl)isobutyramide
and 2-(2,6-difluorophenyl)isobutyramide to a mixture of 7-fluoro-3,3-dimethyl-
1,3-dihydroindol-2-one and 4-fluoro-3,3-dimethyl-1,3-dihydroindol-2-one,
respectively.

A crude sample of 2-(2,3-difluorophenyl)isobutyramide and 2-(2,6-
difluorophenyl)isobutyramide (0.548 g) was dissolved in dimethylformamide (DMF
- 3 mL), treated with a small portion of lithium hydride suspended in DMF (1 mL),
and heated gradually to 120 °C over 7 hours. Upon cooling, the mixture was
quenched with 5% HC1 and ethyl acetate. The quenched mixture was extracted twice
with ethyl acetate and the combined organic phases were back-extracted with brine
(3x). After drying over anhydrous magnesium sulfate, filtration and evaporation, an
oil (0.373 g) was obtained that solidified on standing.
Analysis by GC/MS showed two m/z 179 isomers in 81:19 ratio (8.23 and
8.98 min., respectively). -NMR (DMSO-d6): 1.34 and 1.27 ppm (s, CH3; minor
and major, respectively). The major isomer was identified as 7-fluoro-3,3-dimethyl-
l,3-dihydroindol-2-one based on GC/MS, LC and 'H-NMR data comparison with an
authentic sample, prepared by an independent route.
Example 10. Basis Hydrolysis of 2-(2-fluorophenyl)-2-methylpropionitrile.

2-(2-Fluorophenyl)-2-methylpropionitrile (0.211 g) was magnetically stirred
with aqueous solutions of 5N sodium hydroxide (2 mL), 55% tetrabutylammonium
hydrogensulfate (0.1 mL) and 30% hydrogen peroxide (3 mL) for 22 hours. The
reaction mixture was diluted with toluene and extracted. The aqueous phase was
neutralized with 5% hydrochloric acid and extracted twice with ethyl acetate. The
37

combined organic extracts were washed with water, then brine, and dried over
anhydrous magnesium sulfate. Filtration and evaporation gave 2-(2-
fluorophenyl)isobutyramide as a pale-green oil that solidified on standing (0.173 g).
GC/MS: m/z 181 (RT 9.80 min.). !H-NMR (DMSO-d6): 7.39-7.27 (m, 2H), 7.19-
7.07 (m, 2H), 6.83 and 6.78 (2 s, CONH2), 1.43 (s, 6H)
Example 11. Acidic Hydrolysis of 2-(3-chloropyridin-2-yl)-2-methylpropionitrile
with concomitant purification.

A crude mixture of 2-(3-chloropyridin-2-yl)-2-methylpropionitrile and 2,3-
dichloropyridine (0.171 g) was dissolved in concentrated hydrochloric acid (4 mL)
and the solution was heated to 90-95 °C for 5.5 hours. Upon cooling, it was diluted
with water and extracted twice with dichloromethane. The aqueous phase was
basified with sodium hydroxide (with cooling) to pH of 8 and extracted twice with
dichloromethane. The organic extracts were washed with water and dried over
anhydrous magnesium sulfate. Filtration and evaporation gave 2-(3-chloropyridin-2-
yl)isobutyramide (64 mg).
'H-NMR (DMSO-d6): 5 8.48 (dd, 4.6,1.5 Hz), 7.83 (dd, 7.95,1.5), 7.325 (dd, 7.95,
4.6), 6.97 and 6.93 (2 s, CONH2), 1.50 (s, 6H).
The reaction illustrated that acidic hydrolysis was the preferred method of
hydrolysis since the protonation solubilizes the mixture of pyridines in aqueous
medium.
Further, since the 'H-NMR spectrum showed minimal by-products, it was
hypothesized that the 2,3-dichloropyridine by-product (which was produced in
Example 4) was hydrolyzed to 2-hydroxy-3-chloropyridine which formed a water-
soluble salt (phenolate) upon treatment with NaOH. Thus, only the desired amide
product was extracted into the organic phase.
38

Example 12. Hydrolysis of exo-2-(2-fluorophenyl)bicyclo[2.2.1]heptane-2-
carbonitrile.

The crude nitrile (1.51 g) noted above was heated to 75 °C with concentrated
sulfuric acid (2 mL) and water (0.5 mL) for 17 hours. The reaction mixture was
diluted with water and extracted twice with ethyl acetate. The organic extracts were
washed twice with brine and the solvent evaporated to give a pale-brown solid (1.91
g), 2-(2-fluorophenyl)bicyclo[2.2.1]heptane-2-carboxylic acid aniide. -NMR
(DMSO-d6) showed amide protons at 6.81 and 6.42 ppm. GC/MS: m/z 233 (purity
4.9%, RT 12.54 min.).
Example 13. Preparation of 1-(2,6-difluorophenyl)cyclopropanecarboxylic
acid amide.

l-(2,6-Difluorophenyl)cyclopropanecarbonitrile was prepared as described in
US Patent No. 4,859,232 by alkylation of 2,6-difluorophenylacetonitrile with 1,2-
dibromoethane in 50% sodium hydroxide in the presence of catalytic amounts of
tetrabutylammonium bromide (quantitative yield; GC/MS: m/z 179, RT 8.24 min.;
*H-NMR (DMSO-de): 8 7.58-7.48 (m, 1H), 7.24-7.16 (m, 2H), 1.84-1.79 (m, 2H),
1.46-1.41 (m,2H)).
l-(2,6-Difluorophenyl)cyclopropanecarbonitrile was also prepared by
reacting 1,2,3-trifluorobenzene (2.64 g), cyclopropanecarbonitrile (1.65 g) and 0.5M
potassium hexamethyldisilazide in toluene (40 mL). The isolated solid (2.99 g)
contained a mixture of l-(2,6-difluorophenyl)cyclopropanecarbonitrile (39.6% by
GC/MS; RT 8.22 min.; authentic with the one prepared above), l-(2,3-
difluorophenyl)cyclopropanecarbonitrile (12.4%; RT 8.65 min.; m/z 179,100%), two
di-substituted products with m/z 226 (37.0 and 4.4%; RT 12.6 and 14.0 min., m/z
39

184 (100%) and 226 (100%), respectively), and a tri-substdtuted product with m/z
273 (6.6%; RT 16.4 min., m/z 190 (100%)).
l-(2,6-Difluorophenyl)cyclopropanecarbonitrile (5.42 g) was hydrolyzed at
ambient temperature with an aqueous solutions of 5N sodium hydroxide (20 mL),
55% tetrabutylammonium hydrogensulfate (0.5 mL) and 30% hydrogen peroxide (5
mL) in toluene (5 mL) for 39 hours. The prepared semi-solid reaction mixture was
diluted with ethyl acetate and the phases were separated. The aqueous phase was
neutralized with 5% hydrochloric acid and extracted twice with ethyl acetate. The
combined organic extracts were washed with 5% hydrochloric acid, then brine, and
dried over anhydrous sodium sulfate. Filtration and evaporation gave l-(2,6-
difluorophenyl)cyclopropanecarboxylic acid amide as light-brown solid (4.98 g, 84%
yield). M.p. 136.7-137.6 °C (from ethyl acetate). GC/MS: m/z 197 (purity 97.5%, RT
9.85 min.). !H-NMR (DMSO-d6): 8 7.43-7.34 (m, 1H), 7.10-7.01 (m, 2H), 6.96 (br s,
1H), 6.64 (br s, 1H), 1.50-1.46 (m, 2H), 1.00-0.97 (m, 2H). -NMR (CDC13): 8
7.61-7.26 (m, 1H), 6.98-6.90 (m, 2H), 5.44 (br s, 2H), 1.79-1.74 (m, 2H), 1.17-1.12
(m,2H). 13C-NMR(DMSO-d6): 173.4,164.2,160.9,130.3,116.5,112.1,19.05,
15.8.
Example 14. Preparation of 2-(2-fluorophenyl)isobutyramide via acidic
hydrolysis.

A 500-mL flask equipped with a nitrogen inlet, an addition funnel, magnetic
stirring bar, temperature controller, condenser, and a cooling bath was charged with
1,2-difluorobenzene (22.8 g, 0.20 mol), 2-methylpropiomtrile (13.8 g, 0.20 mol) and
tetrahydrofuran (160 mL). Isopropylmagnesium chloride (2M in THF, 100 mL 0.20
mol) was added from the addition funnel within 30 minutes. The solution was heated
to 65 °C for 6 hours. Upon cooling in an ice bath, 6N HC1 (100 mL) was added
dropwise so the temperature did not exceed 30 °C. The mixture was transferred into
a separatory funnel and the phases were separated. The aqueous phase was extracted
with ethyl acetate. The combined organic extracts were washed with 20% brine and
40

dried with anhydrous sodium sulfate. Filtration and evaporation yielded a light-
orange liquid (12.0 g) that was mixed with concentrated sulfuric acid (2 mL) and
water (1.25 mL) and the mixture was heated at 65 °C for 8 hours. Water (25 mL) was
added causing precipitation of an off-white solid. After cooling to ambient
temperature and slurring the solids in water, the suspension was filtered and the
solids washed with water. Drying under vacuum, followed by drying in a dry box,
gave 2-(2-fluorophenyl)isobutyramide (8.6 g).
Example 15. Scaled-up preparation of 2-(2,3-difluorophenyl)-2-
methylpropionitrile and 2-(2,6-difluorophenyl)-2-methylpropionitrile.

A 1-L, four-necked flask equipped with a nitrogen inlet, an addition funnel,
an overhead mechanical stirrer, temperature controller, condenser, and a cooling bath
was charged with 1,2,3-trifluorobenzene (33.7 g, 0.255 mol), 2-methylpropionitrile
(17.6 g, 0.255 mol) and tetrahydrofuran (200 mL). The solution was cooled with
ice/water. Isopropylmagnesium chloride (2M in THF, 128 mL, 0.256 mol) was added
from the addition funnel maintaining the temperature between 4.1 and 5.1 °C. After
50 minutes, the cooling bath was replaced with a heating mantle and the reaction
mixture was gradually heated to 65 °C and stirred at this temperature for 3 hours. The
solution was cooled in an ice bath and 5% HC1 (150 mL) was added dropwise from
the addition funnel. The two liquid phases were separated and the aqueous phase
was extracted with THF. The combined organic extracts were washed with brine
(3x50 mL) and dried over anhydrous sodium sulfate. Filtration and evaporation of the
filtrate gave an oil (28.3 g) that was distilled under reduced pressure (85-97 °C/3.3-
3.5 ton) to give 21.9 g of a 79/21 (by GC/MS; RT 7.23 and 7.80 min., respectively)
mixture of 2-(2,3-difluorophenyl)-2-methylpropionitrile and 2-(2,6-difluorophenyl)-
2-me%lpropionitrile, respectively. JH-NMR (DMSO-d6): 8 7.55-7.46 (m), 7.33-7.28
(m), 7.21-7.18 (m), 1.83 (m, minor CH3), 1.76 (s, major CH3) (16:84, respectively).
41

A sample of this mixture of isomers was subjected to chromatography on silica gel
with 0-4% ether in hexane to give
2-(2,3-difluorophenyl)-2-methylpropionitrile [!H-NMR (DMSO-d6): 8 7.52-7.46 (m,
1H), 7.33-7.29 (m, 2H), 1.76 (s, 3H)] and 2-(2,6-difluorophenyl)-2-
methylpropionitrile [!H-NMR (DMSO-ds): 8 7.55-7.46 (m, 1H), 7.21-7.18 (m, 2H),
1.84-1.82 (m,3H)].
Example 16. Hydrolysis of 2-(2,3-difluorophenyl)-2-methylpropionitrile.

Hydrolysis of 2-(2,3-difluorophenyl)-2-methylpropionitrile was performed
according to the procedure of Example 10 using sodium hydroxide in the presence of
hydrogen peroxide to provide 2-(2,3-difluorophenyl)isobutyramide ['H-NMR
(CDC13): 8 7.17-7.08 (m, 3H), 5.98 (br s, 1H), 5.45 (br s, 1H), 1.60 (s, 6H)].
Example 17. Hydrolysis of 2-(2,6-difluorophenyl)-2-methylpropionitrile.

Hydrolysis of 2-(2,6-difluorophenyl)-2-methylpropionitrile was performed
according to the procedure of Example 10 using sodium hydroxide in the presence of
hydrogen peroxide to provide 2-(2,6-difluorophenyl)isobutyramide [H-NMR
(CDCI3): 8 7.34-7.29 (m, 1H), 6.91-6.85 (m, 2H), 6.43 (br s, 1H), 5.73 (br s, 1H),
1.68-1.66 (m,6H)].
Example 18. Cyclization of 1-(2,6-difluorophenyl)cyclopropanecarboxylic acid
amide to 4'-fluorospiro[cyclopropane-1,3'-indol]-2'(1'H)-one.

42

Lithium hydride powder (0.054 g, 6.75 mmol) was placed in a 25-mL flask
equipped with a thermocouple, condenser with nitrogen inlet, septum and a magnetic
stirring bar. l-(2,6-Difluorophenyl)cyclopropanecarboxylic acid amide (0.443 g, 2.2
mmol) was dissolved in N,N-dimethylformamide (DMF - 4.5 mL) and the solution
was added into the flask via a syringe. The suspension was heated to 120 °C and kept
at this temperature for 4 hours. Upon cooling, the reaction mixture was transferred
into a separatory funnel, diluted with water (fizzing) and 5% hydrochloric acid
solution, and extracted with ethyl acetate (3x). The combined organic extracts were
extracted with 20% brine (3x) and dried over anhydrous magnesium sulfate.
Filtration and evaporation gave yellowish solid (0.327 g, 82% yield). M.p. 171.1-
172.2 °C (from ethyl acetate). GC/MS: m/z 177 (purity 98.6%, RT 10.30 min.). !H-
NMR (DMSO-d6): 5 10.8 (br s, 1H), 7.22-7.15 (m, 1H), 6.79-6.71 (m, 2H), 1.78-1.74
(m,2H), 1.47-1.42 (m,2H).
Example 19. Cyclization of 2-(2,3-difluorophenyl)isobutyramide to 7-fluoro-
3,3-dimethyl-1,3-dihydroindol-2-one.

2-(2,3-Difluorophenyl)isobutyramide was cyclized to 7-fiuoro-3,3-dimethyl-
l,3-dihydroindol-2-one using the LiH/DMF conditions set forth in Example 18 f1!!-
NMR (DMSO-dg): 5 10.85 (br s, 1H), 7.16-6.94 (m, 3H), 1.26 (s, 6H); GC/MS: m/z
179 (100%), RT 8.24 min.].
43
Example 20. Cyclization of 2-(2,6-difluorophenyl)isobutyramide to 4-fluoro-
3,3-dimethyl-1,3-dihydroindol-2-one.


2-(2,6-Difluorophenyl)isobutyramide was cyclized to give 4-fluoro-3,3-
dimethyl-l,3-dihydroindol-2-one using the LiH/DMF conditions set forth in Example
18 H-NMR (DMSO-dg): 6 10.60 (br s, 1H), 7.32-7.20 (m, 1H), 6.77-6.70 (m, 2H),
1.34 (s, 6H); GC/MS: m/z 179 (164,100%), RT 8.99 min.].
Example 21. Cyclization of 1-(2,6-difluorophenyl)cyclopropanecarboxylic acid
amide using various organic bases as solvents, at 90 and 120 °C.

The reaction tubes of Mettler Toledo MiniBlock™ were independently
charged with l-(2,6-difluorophenyl)cyclopropanecarboxylic acid amide (0.1 g) and
the following organic bases were independently added (1 mL each): diisopropylethyl
amine (Hiinig's base), 2,6-lutidine, N-methylmorpholine (NMM), 2,6-di-tert-butyl-4-
methylpyridine (1 g, low melting solid, mp 33-36 °C), l,8-diazabicyclo[5.4.0]undec-
7-ene (DBU), and 1,1,3,3-tetramethylguanidine (TMG). The vessels were heated at
90 °C for 3 hours and upon cooling, analytical samples were withdrawn and
subjected to GC/MS. The chromatograms revealed only the substrate and no product
formed. The vessels were re-heated to 120 °C and kept for 6 hours. Again, GC/MS
showed no product formed.
These data indicate that stronger bases than the listed above are necessary for
the cyclization to occur.
Example 22. Cyclization of 2-(2-fluorophenyl)isobutyramide under various
conditions (base, solvent, temperature).

The reaction tubes of Mettler Toledo MiniBlock™ were independently
charged with 2-(2-fluorophenyl)isobutyramide (0.1 g), a solvent identified in Table 4
(4 mL each), and two equivalents of a base selected from solid lithium hydride (LiH),
44

solid lithium hexamethyldisilazide (LiHMDS), and 2M lithium diisopropylamide
(LDA) in heptane/THF/ethylbenzene. The mixtures were heated to 110 °C and stirred
magnetically for 4 hours. Upon cooling to ambient temperature, samples (0.2 mL)
were withdrawn, quenched with 5% HC1 (1 mL), and extracted with ethyl acetate (1
mL). The organic phases were analyzed by GC/MS: m/z 161 (146,100%), RT 9.18
min.
Table 3
Normalized (area %) of the product distribution

Base Solvent Product
LiH N,N-dimethylformamide 97
LiH N-methylmorpholine 0
LiH toluene 0
LiHMDS N,N-dimethylformamide 76
LiHMDS N-methylmorpholine 4
LiHMDS toluene 65
LDA N,N-dimethylacetamide 15
LDA 1 -methyl-2-pyrrolidinone 44
LDA 2-methyl-3 -pentanone 0
LDA 2,4-dimethyl-3-pentanone 0
In a similar experiment, the bases identified in Table 4 were added in THF
and the reaction mixtures heated at 65 °C for 16 hours.
Table 4
Normalized (area %) of the product distribution

Base Product
LiH 0
LiHMDS 6
NaHMDS <1
iPrMgCl 0
These data suggest that the solvent, base, and temperature are important in
determining the optimal conditions for the cyclization.
45

Example 23. Cyclization of various halo amides and thioamides.
The reaction tubes of Mettler Toledo MiniBlock™ were independently
charged with the following an amide selected from 2-(3-chloropyridyn-2-
yl)isobutyramide, 2-(2-fluoro-phenyl)-bicyclo[2.2.1]heptane-2-carboxylicacid
amide, and a mixture of 2-(2,3-difluorophenyl)isobutyrthioamide and 2-(2,6-
difluorophenyl)isobutyrthioamide. N,N-Dimethylformamide (2 mL each) was added
to each tube, followed by lithium hydride (2 equiv.) and the vessels were heated to
120 °C for 2.5 hours. Upon cooling, the reaction mixtures were quenched with 5%
HC1, brine, and ethyl acetate. The organic phases were separated, dried over
anhydrous sodium sulfate and analyzed by GC/MS. The following products were
identified, respectively:
(i) 3,3-dimethyl-l,3-dihydropyrrolo[3,2-6]pyridine-2-one
(m/z 162,100%; RT 9.56 min.);
(ii) spiro[bicyclo[2.2.1]heptane-2,3'-[3H]indol]-2'(rH)-one
(m/z 213,146 (100%); RT 12.52 min.);
(iii) 4-fluoro-3,3-dimethyl-3H-benzo[b]thiophen-2-one and 7-fluoro-3,3-
dimethyl-3H-benzo[b]thiophen-2-one
(m/z 196,153 (100%); RT 7.68 and 8.19 min.).
All publications cited in this specification are incorporated herein by
reference herein. While the invention has been described with reference to a
particularly preferred embodiment, it will be appreciated that modifications can be
made without departing from the spirit of the invention. Such modifications are
intended to fall within the scope of the appended claims.
46

What is Claimed Is:
1. A method for preparing oxindole compounds comprising the steps of:
(a) substituting a fluoroarene of formula I with a secondary nitrile:

wherein:
X is halogen;
R1, R2, R3, and R4 are, independently, selected from the group
consisting of H, halogen, CN, Ci to C6 alkyl, substituted Ci to C6 alkyl, C2 to Q
alkenyl, substituted C2 to C6 alkenyl, C2 to C& alkynyl, substituted C2 to C6 alkynyl,
C3 to Cs cycloalkyl, substituted C3 to Cg cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, N2+, OSO2CF3, CF3, N02, SR5, OR5, N(R5)2, COOR5,
CON(R5)2, and S02N(R5)2; or
R1 and R2; R2 and R3; R3 and R4; R1, R2, and R3; or R2, R3, and R4 are
fused to form:
(i) a 3 to 15 membered saturated or unsaturated carbon-
containing ring; or
(ii) a 3 to 15 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of 0, S, and
NR";
wherein (i) or (ii) are optionally substituted by Ci to C6 alkyl,
substituted d to C6 alkyl, halogen, Ci to C6 alkoxy, substituted Ci to C6 alkoxy, or
N(R5)2;
R5 is selected from the group consisting of Ci to C6 alkyl and Ci to C6
substituted alkyl;
A, D, E, and G are, independently, selected from the group consisting
of C and N, wherein if any one of A, D, E, or G are N, the corresponding R*-R4 is
optionally absent;
47

Ru is absent, H, Ci to Ce alkyl, substituted Ci to Ce alkyl, aryl, or substituted
aryl;
or a pharmaceutically acceptable salt thereof;
(b) converting the nitrile substituent of the product of step (a) to an
amide; and
(c) cyclizing the product of step (b) to said oxindole.
2. The method according to claim 1, wherein said oxindole compound is
of the structure:

wherein:
R6 and R7 are independently selected from the group consisting of Ci to Ce
alkyl, substituted Ci to C6 alkyl, C3 to C14 cycloalkyl, substituted C3 to C14
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C2 to C6 alkenyl,
substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, N(R5)2,
SR5, and OR5; or
R6 and R7 are fused to form:
(iii) a 3 to 8 membered saturated or unsaturated carbon-containing
ring; or
(iv) a 3 to 8 membered heterocyclic ring containing in its backbone
from 1 to 3 heteroatoms selected from the group consisting of O, S, and NR11;
R8 is selected from the group consisting of H, Ci to C6 alkyl, substituted Ci to
C6 alkyl, Ci to C6 alkoxy, substituted d to C6 alkoxy, Ci to C$ aminoalkyl,
substituted C\ to Ce aminoalkyl, Ci to C6 thioalkyl, substituted Ci to C6 thioalkyl,
CF3, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or
R8 is fused with R4 to form:
(v) a 5 to 8 membered saturated or unsaturated carbon-containing
ring; or
48

(vi) a 5 to 8 membered heterocyclic ring containing in its backbone
1 to 3 heteroatoms selected from the group consisting of O, S, and MR11;
wherein any of (iii)-(vi) are optionally substituted by Q to C6 alkyl,
substituted d to C& alkyl, halogen, Ci to Ce alkoxy, substituted Ci to C6 alkoxy, or
N(R5)2;
or a pharmaceutically acceptable salt thereof.
3. The method according to claim 1 or claim 2, wherein said secondary
nitrile is R6R7CHCN, wherein:
R6 and R7 are, independently, selected from the group consisting of Ci to Ce
alkyl, substituted Ci to C6 alkyl, C3 to C14 cycloalkyl, substituted C3 to Q4
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C2 to C6 alkenyl,
substituted C2 to C6 alkenyl, C2 to C& alkynyl, substituted C2 to C6 alkynyl, N(R5)2,
SR5, and OR5; or
R6 and R7 are fused to form:
(iii) a 3 to 8 membered saturated or unsaturated carbon-containing
ring; or
(iv) a 3 to 8 membered heterocyclic ring containing in its backbone
from 1 to 3 heteroatoms selected from the group consisting of O, S, andNR11;
wherein (iii) or (iv) are optionally substituted by C\ to C6 alkyl, substituted d
to Ce alkyl, halogen, Ci to C6 alkoxy, substituted d to C6 alkoxy, orN(R5)2.
4. The method according to any one of claims 1 to 3, wherein the
product of step (a) is:

wherein:
R6 and R7 are independently selected from the group consisting of Ci to C6
alkyl, substituted Ci to C6 alkyl, C3 to C14 cycloalkyl, substituted C3 to C14
49

cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C2 to C6 alkenyl,
substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C$ alkynyl, N(R5)2,
SR5, and OR5; or
R6andR7 are fused to form:
(iii) a 3 to 8 membered saturated or unsaturated carbon-containing
ring; or
(iv) a 3 to 8 membered heterocyclic ring containing in its backbone
from 1 to 3 heteroatoms selected from the group consisting of 0, S, and NR!1;
wherein (iii) or (iv) are optionally substituted by C\ to Ce alkyl, substituted Q
to C(, alkyl, halogen, Ci to Ce alkoxy, substituted C\ to Q alkoxy, or N(R5)2.
5. The method according to any one of claims 1 to 4, wherein the
product of step (b) is:

wherein:
R6 and R7 are independently selected from the group consisting of Q to C6
alkyl, substituted Ci to C6 alkyl, C3 to C14 cycloalkyl, substituted C3 to C14
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C2 to C6 alkenyl,
substituted C2 to CQ alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, N(R5)2,
SR5, and OR5; or
R6andR7 are fused to form:
(iii) a 3 to 8 membered saturated or unsaturated carbon-containing
ring; or
(iv) a 3 to 8 membered heterocyclic ring containing in its backbone
from 1 to 3 heteroatoms selected from the group consisting of O, S, and NRn;
wherein (iii) or (iv) are optionally substituted by Ci to C6 alkyl, substituted Ci
to C6 alkyl, halogen, Ct to C6 alkoxy, substituted Ci to C6 alkoxy, orN(Rs)2.
50

R8 is selected from the group consisting of H, Ci to C& alkyl, substituted Ci to
C6 alkyl, Ci to C6 alkoxy, substituted Ci to C6 alkoxy, Ci to C6 aminoalkyl,
substituted Ci to Cg aminoalkyl, Ci to C6 thioalkyl, substituted Ci to C6 tbioalkyl,
CF3, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or
R8 is fused with R4 to form:
(v) a 5 to 8 membered saturated or unsaturated carbon-containing
ring; or
(vi) a 5 to 8 membered heterocyclic ring containing in its backbone
1 to 3 heteroatoms selected from the group consisting of O, S, and NR11;
wherein any of (iii)-(vi) are optionally substituted by Ci to C6 alkyl,
substituted Q to C6 alkyl, halogen, Ci to C6 alkoxy, substituted Ci to C6 alkoxy, or
N(R5)2.

comprising the steps of:
(a) substituting a fluoroarene of formula I:

6. A method for preparing an oxindole compound having the structure of
formula IV:
with a secondary nitrile having the formula RCHCN, to form a compound
of formula II:
51


wherein:
X is halogen;
R1, R2, R3, and R4 are, independently, selected from the group
consisting of H, halogen, CN, Ci to Ce alkyl, substituted Ci to C6 alkyl, C2 to C6
alkenyl, substituted C2 to Ce alkenyl, C2 to C6 alkynyl, substituted C2 to Ce alkynyl,
C3 to Cs cycloalkyl, substituted C3 to Cs cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, N2+, OS02CF3, CF3, N02, SR5, OR5, N(R5)2, COOR5,
CON(R5)2, and S02N(R5)2; or
R1 and R2; R2 and R3; R3 and R4; R1, R2, and R3; or R2, R3, and R4 are
fused to form:
(i) a 3 to 15 membered saturated or unsaturated carbon-
containing ring; or
(ii) a 3 to 15 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of O, S, and
NR11;
R5 is selected from the group consisting of Ci to C6 alkyl and Q to C6
substituted alkyl;
R6andR7 are independently selected from the group consisting of Ci
to C6 alkyl, substituted d to C6 alkyl, C3 to C14 cycloalkyl, substituted C3 to C14
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C2 to C6 alkenyl,
substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, N(R5)2,
SR5, and OR5; or
R6andR7 are fused to form:
(iii) a 3 to 8 membered saturated or unsaturated carbon-
containing ring; or
52

(iv) a 3 to 8 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of 0, S, and
NR11;
R8 is selected from the group consisting of H, Q to C& alkyl,
substituted Ci to C6 alkyl, Ci to C6 alkoxy, substituted Ci to C& alkoxy, Ci to C6
aminoalkyl, substituted Ci to C6 aminoalkyl, Ci to C6 thioalkyl, substituted Ci to C6
thioalkyl, CF3, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or
R8 is fused with R4 to form:
(v) a 5 to 8 membered saturated or unsaturated carbon-
containing ring; or
(vi) a 5 to 8 membered heterocyclic ring containing in its
backbone 1 to 3 heteroatoms selected from the group consisting of O, S, and NR11;
wherein any of (i)-(vi) are optionally substituted by d to C6 alkyl, substituted
Ci to C6 alkyl, halogen, Ci to Ce alkoxy, substituted Ci to C6 alkoxy, or N(R5)2;
A, D, E, and G are, independently, selected from the group consisting
of C and N, wherein if any one of A, D, E, or G are N, the corresponding R*-R4 is
optionally absent;
R11 is absent, H, Q to C6 alkyl, substituted Ci to C6 alkyl, aryl, or
substituted aryl;
or a pharmaceutically acceptable salt thereof;
(b) converting the nitrile substituent of compound II to an amide having
the structure of formula III:

(c) cyclizing the compound III to form said oxindole IV.
7. The method according to any one of claims 1 to 6, wherein step (a)
further comprises a base.
53

8. The method according to claim 7, wherein said base is sodium
hexamethyldisilazide or isopropyl magnesium halide.
9. The method according to any one of claims 1 to 8, wherein step (b) is
performed using hydrogen peroxide.
10. The method according to any one of claims 1 to 9, wherein step (c) is
performed in the presence of a strong base.
11. The method according to any one of claims 1 to 10, wherein said
fluoroarene is:

wherein:
X is F, CI, or Br; and
R2 is Br, CI, I, or H.
12. The method according to claim 11, wherein said fluoroarene is:

54
13. The method according to any one of claims 1 to 10, wherein the
product of step (a) is:


14. The method according to any one of claims 1 to 10, wherein the
product of step (b) is:

15. The method according to any one of claims 1 to 10, wherein said
oxindole is of the structure:

16. A method for preparing a 5-pyrrole-3,3-oxindole compound of the
structure:

wherein:
R1, R3, and R4 are independently selected from the group consisting of H,
chlorine, CN, d to C6 alkyl, substituted Q to C6 alkyl, C2 to C6 alkenyl, substituted
C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to Cg cycloalkyl,
substituted C3 to C& cycloalkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, CF3, N02, SR5, OR5, N(R5)2, COOR5, CON(R5)2, and S02N(R5)2; or
R3 and R4 are fused to form:
(i) a 3 to 15 membered saturated or unsaturated carbon-containing
ring; or
55

(ii) a 3 to 15 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of O, S, and
NR11;
R5 is selected from the group consisting of Ci to C6 alkyl and Q to C6
substituted alkyl;
R6 and R7 are, independently, selected from the group consisting of Ci to C&
alkyl, substituted Ci to C6 alkyl, C3 to Q4 cycloalkyl, substituted C3 to C14
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C2 to C$ alkenyl,
substituted C? to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, N(R5)2,
SR5, and OR5; or
R6 and R7 are fused to form:
(iii) a 3 to 8 membered saturated or unsaturated carbon-containing
ring; or
(iv) a 3 to 8 membered heterocyclic ring containing in its backbone
from 1 to 3 heteroatoms selected from the group consisting of O, S, and NR11;
R8 is selected from the group consisting of H, Ci to C6 alkyl, substituted d to
C6 alkyl, Ci to C6 alkoxy, substituted Q to Ce alkoxy, Ci to C$ aminoalkyl,
substituted Ci to Ce aminoalkyl, Ci to C thioalkyl, substituted Ci to C6 thioalkyl,
CF3, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or
R8 is fused with R4 to form:
(v) a 5 to 8 membered saturated or unsaturated carbon-containing
ring; or
(vi) a 5 to 8 membered heterocyclic ring containing in its backbone
1 to 3 heteroatoms selected from the group consisting of O, S, and NR11;
wherein any of (i)-(vi) are optionally substituted by Ci to C$ alkyl, substituted
Ci to C6 alkyl, halogen, Ci to C6 alkoxy, substituted Ci to Ce alkoxy, or N(R5)2;
R9 is Ci to C6 alkyl, substituted C\ to C6 alkyl, aryl, substituted aryl,
heteroaryl, substituted heteroaryl, or CORA;
RA is H, Ci to C6 alkyl, substituted Ci to C6 alkyl, Ci to Ce alkoxy, substituted
Ci to C6 alkoxy, Ci to C$ aminoalkyl, or substituted Ci to Ce aminoalkyl;
56

R10 is H, OH, NH2, CN, halogen, Q to C6 alkyl, substituted Ci to C6 alkyl, C2
to C6 alkenyl, substituted C2 to 0,$ alkenyl, C2 to Ce alkynyl, substituted C2 to Ce
alkynyl, Ci to Ce alkoxy, substituted Ci to C$ alkoxy, Ci to Cf, aminoalkyl,
substituted Ci to C6 aminoalkyl, or CORA;
R11 is absent, H, Q to C6 alkyl, substituted d to Ce alkyl, aryl, or substituted
aryl;
A, D, E, and G are, independently, selected from the group consisting of C
and N, wherein if any one if A, D, E, or G are N, the corresponding R!-R4 is
optionally absent;
said method comprising:
(a) substituting a fluoroarene with a secondary nitrile to form a compound
of the structure:

wherein, R is selected from the group consisting of halogen, N2+, and
OSO2CF3;
(b) converting the product of step (a) to an amide of the structure:

57
(c) cyclizing the product of step (b) to a compound of the following
structure:



(d) coupling the product of step (c) with a pyrrole of the structure:
17. The method according to claim 16, wherein Y is a boron-containing
leaving group.
18. A method for preparing 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-
lH-indol-5-yl)-l-methyl-lH-pyrrole-2-carbonitrile5 comprising:

(b) converting the product of step (a) to an amide of the structure:

(a) substituting a fluoroarene with a secondary nitrile to form a compound
of the structure:
(c) cyclizing the product of step (b) to a compound of the following
structure:

(d) coupling the product of step (c) with a 1 -methyl-5-cyano-2-pyrrole
compound.
58

19. A method of preparing a compound of the structure:

said method comprising:
(a) substituting a fluoroarene with a secondary nitrile to form a compound
of the structure:

(b) converting the product of step (a) to an amide of the structure:

(c) cyclizing the amide to an oxindole of the following structure:

(d) brominating the oxindole to form a compound of the structure:

(e) coupling the brominated oxindole with a l-methyl-5-cyano-2-pyrrole
compound.
20. A method for preparing 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-
lH-indol-5-yl)-l-methyl- lH-pyrrole-2-carbonitrile comprising:
59


(b) converting the product of step (a) to an amide of the structure:

(a) reacting 1,2,3-trifluorobenzene with isobutyronitrile or methylating 1-
cyanomethyl-2,3-difluorobenzene to form a compound of the structure:
(c) cyclizing the product of step (b) to a compound of the following
structure:

(d) brominating the product of step (c) to form a compound of the
structure:

(e) coupling the product of step (d) with a 1 -methyl-5-cyano-2-pyrrole
compound.
21. The method according to any one of claims 18 to 20, wherein said 1 -
methyl-5-cyano-2-pyrrole compound is aboronate salt, borinate salt, boronic ester,
borinic ester, boronic acid, or borinic acid.
60

22. A method for preparing 7-fluoro-3,3-dimethyl-indol-2-one,
comprising:

(b) converting the product of step (a) to an amide of the structure:

(a) reacting 1,2,3-trifluorobenzene with isobutyronitrile or methylating 1-
cyanomethyl-2,3-difluorobenzene to form a compound of the structure:
(c) cyclizing the product of step (b) to said 7-fluoro-3,3-dimethyl-indol-2-
one.
23. The method of claim 22 further comprising
(d) brominating the product of step (c) to form 5-bromo-7-fiuoro-3,3-
dimethyl-indol-2-one.
24. A method of preparing a compound of the structure:

said method comprising:
61
(a) alkylating a benzylnitrile to form a compound of the structure:

compound.
25. A method for preparing thio-oxindole compounds comprising the
steps of:
(a) substituting a fluoroarene of formula I with a secondary nitrile:

wherein:
X is halogen;
R1, R2, R3, and R4 are, independently, selected from the group
consisting of H, halogen, CN, d to C6 alkyl, substituted Ci to C6 alkyl, C2 to C<5
alkenyl, substituted C2 to C& alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl,
C3 to Cg cycloalkyl, substituted C3 to Cg cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, N2+, OS02CF3, CF3, N02, SR5, OR5, N(R5)2, COO(R5)2,
CON(R5)2, and S02N(R5)2; or
62

R1 and R2; R2 and R3; R3 and R4; R1, R2, and R3; or R2, R3, and R4 are
fused to form:
(i) a 3 to 15 membered saturated or unsaturated carbon-
containing ring; or
(ii) a 3 to 15 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of O, S, and
NR11;
wherein (i) or (ii) are optionally substituted by Ci to C6 alkyl,
substituted Ci to Ce alkyl, halogen, Cj to Q alkoxy, substituted Ci to Cg alkoxy, or
N(R5)2;
R5 is selected from the group consisting of Ci to Ce alkyl and Q to C&
substituted alkyl;
A, D, E, and G are, independently, selected from the group consisting
of C and N, wherein if any one if A, D, E, or G are N, the corresponding R*-R4 is
optionally absent;
Ru is absent, H, Ci to C$ alkyl, substituted Ci to C6 alkyl, aryl, or substituted
aryl;
(b) converting the nitrile substituent of step (a) to an amide;
(c) cyclizing the product of step (b) to an oxindole; and
(d) converting said oxindole to said thio-oxindole.
26. A method for preparing a nitrile compound of the structure:

wherein:
X is halogen;
R1,R2,R3,andR4 are, independently, selected from the group
consisting of H, halogen, CN, C\ to C6 alkyl, substituted Ci to Ce alkyl, C2 to C6
alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to Ce alkynyl,
63

C3 to Cg cycloalkyl, substituted C3 to Cg cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl,. N2+, OS02CF3, CF3, N02, SR5, OR5, N(R5)2, COO(R5)2,
CON(R5)2, and S02N(R5)2; or
R1 and R2; R2 and R3; R3 and R4; R1, R2, and R3; or R2, R3, and R4 are
fused to form:
(i) a 3 to 15 membered saturated or unsaturated carbon-
containing ring; or
(ii) a 3 to 15 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of 0, S, and
NRn;
wherein (i) or (ii) are optionally substituted by Q to Cg alkyl,
substituted Q to Ce alkyl, halogen, Q to Ce alkoxy, substituted Ci to Ct alkoxy, or
N(R5)2;
R5 is selected from the group consisting of Ci to C6 alkyl and Ci to C6
substituted alkyl;
A, D, E, and G are, independently, selected from the group consisting
of C and N, wherein if any one of A, D, E, or G are N, the corresponding R*-R4 is
optionally absent;
R11 is absent, H, Ci to C6 alkyl, substituted Ci to C6 alkyl, aryl, or
substituted aryl;
R°andR' are independently selected from the group consisting of Ci
to C6 alkyl, substituted G to Cg alkyl, C3 to Cu cycloalkyl, substituted C3 to C14
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C2 to Cg alkenyl,
substituted C2 to C$ alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, N(R5)2,
SR5, and OR5; or
R6andR7 are fused to form:
(iii) a 3 to 8 membered saturated or unsaturated carbon-
containing ring; or
(iv) a 3 to 8 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of O, S, and
NR11;
64

wherein (iii) or (iv) are optionally substituted by Ci to C6 alkyl,
substituted Q to C6 alkyl, halogen, Ci to C6 alkoxy, substituted Ci to C6 alkoxy, or
N(R5)2;
said method comprising substituting a fluoroarene of the structure

with a secondary nitrile of the formula R6R7CHCN in the presence of a
Grignard reagent.
27. The method according to claim 26, which is performed at a
temperature of about -40 to about 0°C.
28. The method according to claim 27, wherein said temperature is about
-25°C.
29. A method for selectively preparing a nitrile compound of the
structure:

wherein:
X is halogen;
RIandR4 are, independently, selected from the group
consisting of H, halogen, CN, Q to Ce alkyl, substituted d to C6 alkyl, C2 to C6
alkenyl, substituted C2 to C6 alkenyl, d to C$ alkynyl, substituted C2 to C6 alkynyl,
C3 to C8 cycloalkyl, substituted C3 to Cg cycloalkyl, aryl, substituted aryL heteroaryl,
65

substituted heteroaryl, N2+, OS02CF3, CF3, N02, SR5, OR5, N(R5)2, COO(R5)2,
CON(R5)2, and S02N(R5)2; or
R1 and R2; R2 and R3; R3 and R4; R1, R2, and R3; or R2, R3, and R4 are
fused to form:
(i) a 3 to 15 membered saturated or unsaturated carbon-
containing ring; or
(ii) a 3 to 15 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of O, S, and
NRn;
wherein (i) or (ii) are optionally substituted by Ci to Co alkyl,
substituted Ci to Cs alkyl, halogen, Cj to C6 alkoxy, substituted Q to C6 alkoxy, or
N(R5)2;
R5 is selected from the group consisting of Ci to Ce alkyl and C\ to C6
substituted alkyl;
A, D, E, and G are, independently, selected from the group consisting
of C and N, wherein if any one of A, D, E, or G are N, the corresponding R*-R4 is
optionally absent;
R11 is absent, H, Q to C6 alkyl, substituted Q to d alkyl, aryl, or
substituted aryl;
R andR are independently selected from the group consisting of Ci
to C6 alkyl, substituted Q to C6 alkyl, C3 to C14 cycloalkyl, substituted C3 to C14
cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C2 to C6 alkenyl,
substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, N(R5)2,
SR5, and OR5; or
R6andR7 are fused to form:
(iii) a 3 to 8 membered saturated or unsaturated carbon-
containing ring; or
(iv) a 3 to 8 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of O, S, and
NRn;
66

wherein (iii) or (iv) are optionally substituted by Ci to C6 alkyl,
substituted Ci to C6 alkyl, halogen, Ci to C6 alkoxy, substituted Ci to C6 alkoxy, or
N(R5)2;
said method comprising substituting a fluoroarene of the structure:

with a secondary nitrile of the formula R6R7CHCN in the presence of a
Grignard reagent at a temperature of about -25°C.
30. The method according to any one of claims 26 to 29, wherein said
Grignard reagent is selected from the group consisting of isopropyl magnesium
chloride, methyl magnesium bromide, vinyl magnesium bromide, o-tolyl magnesium
bromide, or dibutyl magnesium chloride.
31. A method for preparing iminobenzo[b]thiophene compounds,
comprising:
(a) substituting a fluoroarene of formula I with a secondary nitrile:

wherein:
X is halogen;
R1, R2, R3, and R4 are, independently, selected from the group
consisting of H, halogen, CN, Ci to Ce alkyl, substituted C\ to C6 alkyl, C2 to C6
67

alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl,
C3 to Cs cycloalkyl, substituted C3 to Cs cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, N2+, OS02CF3, CF3, NO2, SR5, OR5, N(R5)2, COO(R5)2,
CON(R5)2, and SOiNCR5; or
R1 and R2; R2 and R3; R3 and R4; R1, R2, and R3; or R2, R3, and R4 are
fused to form:
(i) a 3 to 15 membered saturated or unsaturated carbon-
containing ring: or
(ii) a 3 to 15 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of O, S, and
NR11;
wherein (i) or (ii) are optionally substituted by Ci to C6 alkyl,
substituted Q to Ce alkyl, halogen, Ci to C6 alkoxy, substituted d to C6 alkoxy, or
N(R5)2;
R5 is selected from the group consisting of Ci to C6 alkyl and Ci to C6
substituted alkyl;
A, D, E, and G are, independently, selected from the group consisting
of C and N, wherein if any one if A, D, E, or G are N, the corresponding R!-R4 is
optionally absent;
R11 is absent, H, Ci to C6 alkyl, substituted Ci to C6 alkyl, aryl, or substituted
aryl;
(b) converting the nitrile substituent of step (a) to an amide;
(c) converting said amide to a thioamide;
(d) cyclizing said thioamide to said iminobenzo[b]thiophene.
32. , A method for preparing iminobenzo[b]thiophene compounds,
comprising:
(a) substituting a fluoroarene of formula I with a secondary nitrile:
68


wherein:
X is halogen;
R1, R2, R3, and R4 are, independently, selected from the group
consisting of H. halogen, CN, Ci to Ca alkyl, substituted Ci to Ce alkyl, C2 to C6
alkenyl, substituted C2 to Ce alkenyl, C2 to Ce alkynyl, substituted C2 to C6 alkynyl,
C3 to Cg cycloalkyl, substituted C3 to Cg cycloalkyl, aryl, substituted aryl, heteroaryl,
substituted heteroaryl, N2+, OS02CF3, CF3, N02, SR5, OR5, N(R5)2, COO(R5)2,
CON(R5)2, and S02N(R5)2; or
R1 and R2; R2 and R3; R3 and R4; R1, R2, and R3; or R2, R3, and R4 are
fused to form:
(i) a 3 to 15 membered saturated or unsaturated carbon-
containing ring; or
(ii) a 3 to 15 membered heterocyclic ring containing in its
backbone from 1 to 3 heteroatoms selected from the group consisting of O, S, and
NR11;
wherein (i) or (ii) are optionally substituted by Ci to C6 alkyl,
substituted Ci to C6 alkyl, halogen, Ci to C& alkoxy, substituted Ci to C& alkoxy, or
N(R5)2;
R5 is selected from the group consisting of Ci to C6 alkyl and Ci to C6
substituted alkyl;
A, D, E, and G are, independently, selected from the group consisting
of C and N, wherein if any one if A, D, E, or G are N, the corresponding R!-R4 is
optionally absent;
Ru is absent, H, Q to C6 alkyl, substituted Ci to C6 alkyl, aryl, or substituted
aryl;
69

(b) converting the nitrile substituent of step (a) to a thioamide; and
(c) cyclizing said thioamide to said iminobenzo[b]thiophene.
33. The method according to claim 31 or claim 32, further comprising:
(e) hydrolyzing said hninobenzo[b]thiophene to a benzo[b]thiophenone.
34. A compound selected from the group consisting of 2-(5~bromo-2-
fluorophenyl)-2-memylpropionitrile; 2-(3-chloropyridin-2-yl)-2-methylpropionitrile;
2-(3-chloroquinoxalin-2-yl)-2-methylpropionitrile; 2-(2-fluorophenyl)-2-
methylpropiomtrile;2-(2,3-difluorophenyl)-2-methylpropionitrile; 2-(2,6-
difluorophenyl)-2-methylpropionitrile; 2-(2,3 -difluorophenyl)isobutyramide; 2-(2,6-
difluorophenyl)isobutyramide; 2-(2-fluorophenyl)isobutyramide; and 2-(3-
chloropyridin-2-yl)isobutyramide; l-(2,6-difluorophenyl)cyclopropanecarboxylic
acid amide; or a pharmaceutically acceptable salt thereof.
70

Methods for preparing oxindole and thio-oxindole compounds are provided, which compounds are useful as precursors to useful pharmaceutical compounds. Specifically provided are methods for preparing 5-pyrrole-3,3-oxindole compounds
and 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-l-methyl-1H-pyrrole-2-carbonitrile. Also provided are methods for
preparing iminobenzo[b]thiophene and benzo[b]thiophenone compounds.