TITLE
SELECTIVE ACYLATION OF
4-SUBSTITUTED-1,3-PHENYLENEDIAMINE
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] This invention is directed to a method of selectively acylating the
1-amino group of 4-substituted-l,3-phenylenediamine.
DESCRIPTION OF RELATED ART
Related Background Art
[0002] Selective protection of functional groups can be a critical element in the
synthesis of a complex molecule. For example, 4-Nitro-1,3-phenylenediamine is
a useful inexpensive starting material for synthesizing larger molecules.
However, a one-step route to 2-amino-4-acylated nitrobenzene requires a
selective acylation of 4-nitro-l,3-phenylenediamine at the 1-amino position.
[0003] There are four isomcric nitrohsnylenediaminss with unsymmetrioal
amino substituents. A consideration of the relative electronic effects of induction
and resonance successfully predicts one specific amino substituent in each of
three of these isomers that is more nucleophilic in the presence of a variety of
electrophiles. See U.S. Patent No. 4,137,310; Shalaby et al., J. Org. Chem. 1996,
61, 9045-9048; Abasolo et al, J. Heterocyclic Chem. 1987, 24, 1771-1775;

Harvey et al., J. Chem. Soc. Perkin Trans. I1988, 694-696; and Rajuppa et al.,
Indian J. Chem. 1980,19B, 533-535. These electronic arguments, however, are
less clear in predicting the most nucleophilic amino substituent of 4-nitro-1,3-
phenylenediamine. Acylation of 4-nitro-1,3-phenylenediamine using a mixture
of acetic anhydride and acetic acid gave a 2:1 mixture of 2-amino-4-
acetimidonitrobenzene and the diacetyl derivative. See Phillips, J. Chem. Soc.
1930, 1910-1916. Japanese Patent No. 09255636 discloses that 2-amino-4-
acetimidonitrobenzene can be synthesized by selective cleavage of 1,3-
bisacetamide-4-nitrobenzene. There has been no report of reaction conditions
that selectively differentiate between the two amino substituents of 4-nitro-l,3-
phenylene diamine.
[0004] The present invention provides the necessary reaction conditions to
selectively acylate 4-substituted-l,3-phenylenediamine at the 1-amino position in
high yield.
BRIEF DESCRIPTION OF THE INVENTION
[0005] This invention is directed to a method of selectively acylating a
compound of formula (II):

wherein:
R1 is NO2, -N+R33, trihalomethyl, -CN, -SO3H, -CO2H, -CO2 R3, -CHO and
-COR3, wherein R3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-CI2 cycloalkyl, C6-C12 aryl,
C2-C9 heteroaryl, or C1-C9 heterocycloalkyl;
comprising the step of reacting the compound of formula (II) with an
acylating reagent to form a compound of formula (I):


wherein R2 is selected from C1-C12 alkyl, C1-C12 haloalkyl, C2-C7 alkenyl,
C2-C7 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, C1-C9 heterocycloalkyl, C2-C9
heteroaryl, C1-C12 alkoxy, C1-C12 haloalkoxy, C3-C12 cycloalkoxy, C1-C9
heterocycloalkoxy, C6-C12 aryloxy, and C2-C9 heteroaryloxy;
or salts thereof.
DETAILED DESCRIPTION
[0006] In the present invention compounds of formula (II) are selectively
acylated at the 1-amino position to form compounds of formula (I). Using the
conditions disclosed herein compounds of formula (I) can be produced in high
yield in one step using acylating reagents such as, for example, acetyl chloride,
acetic anhydride, ethyl chloroformate, benzoyl chloride and pivaloyl chloride.
[0007] The present method provides compounds of formula (I) in crude yields of
at least about 60%. In one embodiment of the present method the compound of
formula (I) is synthesized with a crude yield of at least about 70%. In another
embodiment of the present method the compound of formula (I) is synthesized
with a crude yield of at least about 80%. In the most preferred embodiment of
the present method the compound of formula (I) is produced in a crude yield of
about 90%.
[0008] For purposes of this invention the term "alkyl" includes straight chain
moieties with a length of up to 12 carbon atoms, but preferably 1 to S carbon
atoms, and more preferably 1 to 4 carbons. The term "alkyl" also includes
branched moieties of 3 to 12 carbon atoms. The term "alkenyl" refers to a radical

aliphatic hydrocarbon containing one double bond and includes both straight and
branched alkenyl moieties of 2 to 7 carbon atoms. Such alkenyl moieties may
exist in the E or Z configurations; the compounds of this invention include both
configurations. The term "alkynyl" includes both straight chain and branched
moieties containing 2 to 7 carbon atoms having at least one triple bond. The term
"cycloalkyl" refers to alicyclic hydrocarbon groups having 3 to 12 carbon atoms
and includes but is not limited to: cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, norbornyl, or adamantly. Most preferred is where the
cycloalkyl moiety contains 3 to 6 carbon atoms.
[0009] For purposes of this invention the term "aryl" is defined as an aromatic
hydrocarbon moiety and may be substituted or unsubstituted. An aryl may be
selected from but not limited to, the group: phenyl, a-naphthyl, p-naphthyl,
biphenyl, anthryl, tetrahydronaphthyl, phenanthryl, fluorenyl, indanyl,
biphenylenyl, acenaphthenyl, acenaphthylenyl, or phenanthrenyl. An aryl may be
optionally mono-, di-, tri- or terra-substituted with substituents selected from, but
not limited to, the group consisting of alkyl, acyl, alkoxycarbonyl, alkoxy,
alkoxyalkyl, alkoxyalkoxy, cyano, halogen, hydroxy, nitro, haloalkyl,
trifluoromethyl, trifluoromethoxy, trifluoropropyl, amino, alkylamino,
dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, alkylthio,
-SO3H, -SO2NH2, -SO2NHalkyl, -SO2N(alkyl)2 , -CO2H, CO2NH2, CO2NHalkyl,
and -CO2N(alkyl)2. Preferred substituents for aryl include: alkyl, halogen,
amino, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy, arylalkyl,
and alkylaryl. Preferably an aryl group consists of 6 to 12 carbon atoms.
[0010] For purposes of this invention the term "heteroaryl" is defined as an
aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl
moieties are five or six membered rings containing 1 to 4 heteroatoms selected
from the group consisting of S, N, and O, and include but is not limited to:
(1) furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole,
imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole,
N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole,
1 -methyl-1,2,4-triazole, lH-tetrazole, 1-methyltetrazole, benzoxazole,
benzothiazole, benzofuran, benzisoxazole, benzimidazole,

N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline,
pyrrolidinyl; (2) a bicyclic aromatic heterocycle where a phenyl, pyridine,
pyriraidine or pyridizine ling is: (i) fused to a 6-membered aromatic
(unsaturated) heterocyclic ring having one nitrogen atom; (ii) fused to a 5 or
6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms;
(iii) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one
nitrogen atom together with either one oxygen or one sulfur atom; or (iv) fused to
a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom
selected from O, N or S. Preferred substituents for heteroaryl include: alkyl,
halogen, amino, alkylamino, dialkylamino, trifluoromethyl, trifluoromethoxy,
arylalkyl, and alkylaryl. A preferred heteroaryl moiety contains 1 to 9 carbon
atoms.
[0011] For purposes of this invention the term "heterocycloalkyl" refers to a
substituted or unsubstituted alicyclic ring system (moncyclic or bicyclic) wherein
the heterocycloalkyl moieties are 3 to 12 membered rings containing 1 to 6
heteroatoms selected from the group consisting of S, N, and O. A preferred
heterocycloalkyl moiety contains 1 to 9 carbon atoms, and more preferably
contains 2 to 5 carbon atoms. Examples include, but are not limited to, pyrroline,
pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, dioxane,
morpholine, dithiane, and thiomorpholine.
[0012] For the purposes of this invention the term "alkoxy" is defined as
C1-C12-alkyl-O-, but preferably consists of 1 to 8 carbon atoms; the term
"aryloxy" is defined as aryl-O; the term "heteroaryloxy" is defined as
heteroaryl-O-; the term "cycloalkoxy" is defined as cycloalkyl-O; the term
"heterocycloalkoxy" is defined as heterocycloalkyl-O-; wherein alkyl, aryl,
cycloalkyl, heterocycloalkyl and heteroaryl are as defined above.
[0013] For the purpose of this invention the term."haloalkyl" refers to an alkyl
moiety substituted with one or more halogenoatoms. An example of haloalkyl
moiety is trifluoromethyl. The term "haloalkoxy" refers to an alkoxy moiety
substituted with one or more halogen atoms, such as trifluoromethoxy.
[0014] The term "substituent" is used herein to refer to an atom radical, a
functional group radical or a moiety radical that replaces a hydrogen radical on a

molecule. Unless expressly stated otherwise, it should be assumed that any of the
substituents may be optionally substituted with one or more groups selected from:
alkyl, halo, nitro, amino, hydroxyl, cyano, alkylamino, dialkylamino, alkoxy,
haloalkoxy, alkylthio, mercapto, haloalkylthio, aryl, aryloxy, arylthio, heteroaryl,
heteroaryloxy, heteroarylthio or acyl. This list is provided for illustrative
purposes and is not intended to be exhaustive.
[0015] For the purposes of this invention the term "substituted" refers to where a
hydrogen radical on a molecule has been replaced by another atom radical, a
functional group radical or a moiety radical; these radicals being generally
referred to as "substituents."
[0016] For the purposes of this invention the phrase "crude yield" refers to the
percentage of starting material converted to the final product as calculated prior
to purification by recrystalization.

[0018] Scheme I illustrates the selective acylation of the 1-amino group, wherein
R1 and R2 are as defined herein, of a 1,3-diamino phenyl compound of
[0017] Salts may be formed from addition of organic and inorganic acids. For
example salts can be formed from the addition of acids, including but not limited
to, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic,
mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,
methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,
camphorsulfonic, and similarly known acceptable acids. The most preferable
acids for forming salts are acetic acid and hydrochloric acid.

formula (II). The 1,3-diamino compound is reacted with an acylating agent, such
as, for example, acetic anhydride, acetyl chloride, benzoyl chloride, ethyl
chloroformate and pivaloyl chloride. Prefereably this reaction is conducted in the
presence of a base. One skilled in the art would know of appropriate bases for
use in this reaction, however, a tertiary amine base is preferable, such as
triethylamme and pyridine. Pyridine is the most preferred.
[0019] In a preferred embodiment of the method of the present invention R1 is
NO2.
[0020] This reaction can be conducted in an aprotic organic solvent. Commonly
used solvents include methylene chloride, chloroform, CH3CN, diethyl ether,
THF, and tolene, or combinations thereof. This is not an all inclusive list and one
skilled in the art would know of other useable solvents.

[0021] Scheme II shows the specific conversion of 4-nitro-l,3-phenylenediamine
to 2-amino-4-acetimidonitrobenzene by adding acetyl chloride to a cooled
solution of the starting material, 17% CH3CN/THF and pyridine. This reaction
was complete by the time the last of the acid chloride had been added. The
reaction was then quenched with water, forcing the product to precipitate. The
precipitate was collected by filtration and recrystallized using acetic acid to give
product in a 69% yield. Other solvents can be used for the recrystallization, such
as 23% v/v aqueous methoxyethanol and toluene. This is not an all inclusive list

and one skilled in the art would know of other possible recrystallizing solvents or
solutions.
Example 1
[0022] Preparation of 2-amino-4-acylimidonitrobenzene using an acid chloride.
[0023] A THF solution of the acid chloride (1.2 equivalents, 2.4 M) was added
to an ice/water-cooled solution of 4-nitro-l,3-phenylenediamine (0.3 M) and
pyridine (4.0 equivalents) in 17% v/v CH3CN/THF. The reaction mixture was
added to water after the starting material was consumed (as measured by TLC),
causing the product to precipitate. The product was collected by filtration. The
product formed using acetyl chloride was recrystallized from acetic acid
(8 mL/g), when benzoyl chloride was used the product was recrystalized from
23% v/v aqueous methoxyethanol (13 mL/g), and the products formed from ethyl
chlororformate and pivaloyl were recrystallized from toluene (14 mL/g). Yields
are shown in Table 1.
Example 2
[0024] Preparation of 2-amino-4-acetimidonirrobenzene using acetic anhydride.
[0025] This reaction was performed as in Example 1 except acetic anhydride was
used in place of an acid chloride. Under these conditions the reaction required 2
days to be completed. The product was recrystallized using acetic acid (8 mL/g).
Yields are shown in Table 1.
Example 3
[0026] Preparation of 2-amino-4-trifluoroacetimidonitrobenzene using
trifluoroacetic anhydride.
[0027] This reaction was performed as in Example 1 except trifluoroacetic
anhydride (1.0 equiv.) was used in place of an acid chloride and the reaction was
performed at -78°C. Under these conditions the reaction resulted in a 1:1:1
mixture of the mono-acylated products and the 1,3-bistrifluoroacetamide product
(as measured by GC/MS).


a Crude. b Recrystallized. c Determined by HPLC. e The products were not
isolated. GC/MS indicated that the crude reaction mixture contained a 1/1/1
mixture of starting material and the mono-and di-acylated compound.
[0028] Table 1 shows the results from reactions of 4-nitro-l.,3-phenylenediarnme
with various acylating agents.
[0029] lH and 13C NMR data for the compounds by the reaction of 4-nitro-1,3-
phenylenediamine with various acylating agents:
[0030] Compound No. 1 1HNMR(300 MHz, d6- DMSO) δ 2.70 (s, 3H), 6.65 (d, J
= 9.0 Hz, 1H), 7.48 (s, 2H), 7.54 (s, 1H), 7.91 (d, 7=9.0 Hz, 1H), 10.17 (s, 1H), 13C
NMR (75.5 MHz, d6- DMSO) 5 170.0,148.4, 146.1, 127.3, 126.7, 108.9,106.1,
24.93.
[0031] Compound No. 2 1H NMR (300 MHz, d6- DMSO) 5 6.94 (8, J= 9.0 Hz,
1H), 7.54-7.64 (m, 5H), 7.78 (s, 1H), 7.94-7.99 (m, 3H), 10.47 (s, 1H); 13CNMR (75.5
MHz, d6 -DMSO) δ 167.0,148.2,146.2,135.2,132.7, 129.1,128.6, 127.1,127.1,
110.0,107.5.
[0032] Compound No. 3 1H NMR (300 MHz, d6- DMSO) δ 1:25 (t, J= 7.0 Hz,
3H), 4.15 (q, J= 7.0 Hz, 2H), 6.62 (dd, J= 7.8 and 1.5 Hz), 7.32 (d, J= 1.5 Hz), 7.48
(s, 2H), 7.89 (d,J= 7.8 Hz), 10.0 (s, 1H); I3CNMR(75.5 MHz, d6- DMSO) δ
153.9, 148.4,146.5, 127.4, 126.5, 108.4,104.8, 61.4,15.0.

[0033] Compound No. 4 1H NMR (300 MHz, d6- DMSO) δ 1.22 (s, 9H), 6.82 (dd,
J= 7.6 and 1.8 Hz, 1H), 7.45 (s, 1H), 7.63 (d, J= 1.8 Hz, 1H), 7.91 (d, J=7.6Hz, 1H),
9.40 (s, 1H), 13CNMR (75.5 MHz, d6- DMSO) δ 177.9,148.2, 146.4,126.9,126.8,
109.9,107.2,27.6.
[0034] The examples disclosed in this application are for illustrative purposes so
that the subject matter may be more readily understood and should not be construed
to limit the scope of the invention as claimed herein.

WHAT IS CLAIMED IS:
1. A method of selectively acylating a compound of formula (II):

wherein:
R1 is NO2, -N+R33, trihalomethyl, -CN, -SO3H, -CO2H, -CO2 R3, -CHO and
-COR3, wherein R3 is C1-C6 alkyl, C1-C6 haloalkyl, C3-C12 cycloalkyl, C6-C12 aryl,
C2-C9 heteroaryl, or C1-C9 heterocycloalkyl;
comprising the step of reacting the compound of formula (II) with an
acylating reagent to form a compound of formula (I):

wherein R2 is selected from C1-C12 alkyl, C1- C12 haloalkyl, C2-C7 alkenyl,
C2-C7 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, C1-C9 heterocycloalkyl, C2-C9
heteroaryl, C1- C12 alkoxy, C1- C12 haloalkoxy, C3-C12 cycloalkoxy, C1-C9
heterocycloalkoxy, C6-C12 aryloxy, and C2-C9 heteroaryloxy;
or salts thereof.

2. The method of Claim 1, further comprising that the acylation occurs in the
presence of a base.
3. The method of Claim 2, wherein the base is a tertiary amine.
4. The method of Claim 3, wherein the base is pyridine.
5. The method of Claim 1, wherein the acylating reagent is selected from the
group consisting of acetic anhydride, acetyl chloride, benzoylchloride,
ethylchloroformate, and pivaloyl chloride.
6. The method of Claim 5, wherein the acylating reagent is acetyl chloride.
7. The method of Claim 1, wherein the crude yield of the compound of
formula (I) is at least about 60%.
8. The method of Claim 1, wherein the crude yield of the compound of
formula (I) is at least about 70%.
9. The method of Claim 8, wherein the crude yield of the compound of
formula (I) is at least about 80%.
10. The method of Claim 9, wherein the crude yield of the compound of
formula (I) is at least about 90%.
11. The method of Claim 1, further comprising the step of recrystallizing the
compound of formula (I).
12. The method of Claim 1, wherein the compound of formula (I) is
recrystallized in a solvent selected from the group consisting of acetic acid, an
aqueous methoxyethanol solution and toluene.
13. The method of Claim 1, wherein R1 is NO2.

This invention is directed to a
method of selectively acylating a compound of
formula (II): (II), wherein: R1 is NO2, -N+R33,
trihalomethyl, -CN, -SO3H, -CO2H, -CO2 R3,
-CHO and -COR3, wherein R3 is C1-C6, alkyl,
C1-C6 haloalkyl, C3-C12 cycloalkyl, C6-C12 aryl,
C2-C9 heteroaryl, or C1-C9 heterocycloalkyl;
comprising the step of reacting the compound
of formula (II) with an acylating reagent to form
a compound of formula (I): (I), wherein R2 is
selected from C1-C12 alkyl, C1-C12 haioaikyl,
C2-C7 alkenyl, C2-C7 alkynyl, C3-C12 cycloalkyl,
C6-C12 aryl, C1-C9 heterocycloalkyl, C2-C9
heteroaryl, C1-C12 alkoxy, C1- C12 haloalkoxy,
C3-C12 cycloalkoxy, C1-C9 heterocycloalkoxy,
C6-C12 aryloxy, and C2-C9 heteroaryloxy; or salts
thereof.