CA1137115A - Process for the preparation of aminoarylhydroxy substituted acetylenes - Google Patents

Abstract

PROCESS FOR THE PREPARATION OF
AMINOARYLHYDROXY SUBSTITUTED ACETYLENES

Abstract Aminoarylhydroxy substituted acetylenes are prepared by reacting a bromoarylhydroxy substituted acetylene at a temperature of less than 150°C. with ammonia in the contact presence of a copper salt such as copper chloride.

Description

~137115 This invention relates to a process for producing an aminoarylhydroxy substituted acetylene and in particular for producing 2-methyl-4-(3-aminophenyl)-3-butyn--2-ol, which can then be converted to meta-aminophenylacetylene.

One technique to prepare aminophenylacetylene is first to prepare nitrophenylacetylene and then to selectively hydrogenate the nitro group to produce the desired aminopheny-lacetylene. Techn;aues for achieving this are described, for example, in U.S. patent number 4,139,561 filed February 27, 1978 in the names of Anatoli Onopchenko et al and entitled, "Novel Substituted Amino-Aromatic Acetylenes and Their Method of Preparation". The techniques of Onopchenko et al depend, however, on the use of certain nitroaromatic compounds as the initial charge stocks. It is also desirable to develop proce-dures for the preparation of amino aromatic acetylenes from dihalogenated aromatics such as dibromobenzene, since these charge stocks may be more plentiful in the marketplace and may be less expensive to employ. The dibromobenzene can be converted to the monobromohydroxy substituted phenyl acetylene by appropriate techniques described by the applicants in their d~

U.S. patent No. 4,223,]72 filed December 7, 1978, entitled "Process for the Preparation of Bxomoarylacetylene and Aryl-diacetylene Precursors". Such bromophenylhydroxy substituted acetylenes are new compositions of matter. It is the object of this invention to convert the bromophenylhydroxy substituted acetylene to the corresponding aminophenylhydroxy substituted acetylene.
In accordance with the invention, an aminophenylhydroxy substituted acetylene is prepared by a process which comprises contacting a brc~.ophenylhydrQxy substituted acetylene having the formula: -R OH
Br ~ C = C - C - Rl where Ar can be phenyl, naphthyl or biphenyl; R can be H, alkyl having from 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, phenyl, and cycloalkyl having from 5 to 6 carbon atoms; and Rl and R2 can be the same or different and are selected from the group consisting of hydrogen, lower alkyl groups having from 1 to 4 carbon atoms, phenyl, substituted phenyl; or where Rl and R2 can form a saturated 5- or 6-membered ring a.t a temperature of less than 150C.
with ammonia in the contact presence of a copper salt.
The bromoarylhydroxy substituted acetylenes useful as a charge stock for the process of this in~ention can be prepared by contacting an aryl dibromide with a substituted terminal acetylene compound containing at least three-carbon atoms and a hydroxy group on the carbon atom adjacent to the acetylene group under mild conditions and wherein the molar ratio of the.acetylene compound to the aryl dibromide is 30 from about 0~4:1 to about 1.5:1. The reaction suitably occurs in the presence of an amine-type solvent which serves-.
not only as a solvent but also as a complexing agent with the by-product HBr which is produced during the reaction.

11371iS

The substitution reaction is catalyzed by a complex palladium salt containing two halogen moieties and two substituted phosphine moieties where the substituents on the phosphorus are phenyl, lower alkyl groups, and substituted phenyl groups.
The catalytic activity of the palladium complex salt is promoted with a small amount of cuprous iodide.
Any aryl dibromide can suitably be employed to prepare the bromoarylhydroxy substituted acetylene charge stock, and the source of the aryl dibromide is not critical.
Preferred are aryldibromides having the formula:

Br ~ Br >~
R

where R can be H, alkyl having from 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, phenyl, and cycloalkyl having from 5 to 6 carbon atoms.
Suitable non-limiting examples of aryldibromides useful in the pxocess of this invention are:
m-, o- and p-dibromobenzene

2,4-dibromotoluene 2,6-dibromotoluene 2,4-dibromoethylbenzene 2,6-dibromoethylbenzene 2,4-dibromocyclohexylbenzene 2,6-dibromocyclohexylbenzene 2,4-dibromobiphenyl 2,6-dibromobiphenyl 2,3-dibromonaphthalene 1,8-dibromonaphthalene 2,4-dibromopropylbenzene 2,6-dibromohexylbenzene 2,6-dibromononylbenzene 2,4-dibromoisobutylbenzene 2,4-dibro~o-6-chlorotoluene The aryldibromide is reacted with a substituted terminal acetylene compound containing at least 3 carbon atoms and a hydroxv group on the carbon atom adjacent to the acetylene group. The preferred substituted terminal acetylene compounds are those having the formula:

1~ OH
HC - C - C - R
R2 ,, where Rl and R2 can be the same or different and are selected from the group consistlng of hydrogen, lower alkyl groups having from 1 to 4 carbon atoms, phenyl, substituted phenyl;
or where Rl and R2 can form a saturated 5- or 6-membered ring. The preparation of these compounds is well known in the art and forms no part of the subject invention. For example, acetylene can be reacted with acetone to form 2-methyl-3-butyn-2-ol, which is the preferred substituted terminated acetylenic charge stock for use in the process of this invention. Other suitable acetylenic compounds include the following:

3-methyl-1-pentyn-3-ol;
3-ethyl-1-pentyn-3-ol;
2-phenyl-3-butyn-2-ol;
l-ethynylcyclohexanol; and l-ethynylcyclopentanol.

-1~37115 The reaction of the aryldibromide with the terminal acetylenic compounds defined above occurs in the presence of a dialkyl ox trialkyl amine solvent and a complex catalyst system. ~he amine solvent can suitably have the formula:

where R3, R4 and R5 can be the sa~e ox different and are selected fro~ the group consisting of hydrogen and lower alkyl groups having from 1 to 4 carbon atoms, with the proviso that no more than one of said R groups can be hydrogen.
Suitable solYents include but axe not limited to dimethvl-amine, trimethylamine, diethylamine, triethylamine, ethyl-propylamine, ethylbutylamine and dibutylamine.
The catalyst employed is a complex palladium salt containing two halogen moieties, where the halogen is selected from the gxoup consisting of bromine, iodine and -chlorine, and two trisubstituted phosphine moieties where the constituents are selected from pheny~, alkyl groups having from 1 to 4 carbon atoms, and substituted phenyl groups. A suitable palladium co~plex would have the formula:
¦R6 P ¦ Pd tX) 2 where x is bromine, iodine or chlorine, and R6,R' and R" are the same or different and are selected from the group consist-ing of phenyl, alkyl groups having from 1 to 4 carbon aioms and substituted phenyl groups. The substituents on the phenyl groups can include alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, and halogen. A suitable list of representative palladium complex ~1371~5 salts which can be employed in the process of this inven-tion include:
bis(txiphenylphosphine)palladiu~ dibxomide;
bis(tri-n-butylphosphine)palladium dichloride;
bis(tri-t-butyl-phosphine)palladium dichloride;
bis(tri-i-butylphosphine)palladium dichloride;
bis(triethylphosphine)palladium dichloride;
bis(tripropylphosphine)palladium dichloride;
bis(tritolylphosphine)palladium dichloride;
bis~trianisylphosphine)palladium dichloride;
bis(tri(chlorophenylphosphine)palladium dichloride;
and bis(tri(bromophenyl)phosphine)palladium dichloride.
The palladlùm catalyst can be added to the reaction mixture as such or can be formed in situ in the reaction mixture by the separate addition of a palladium salt having the formula Pd(x)2 where x is as defined, and a trisubsti-tuted phosphine compound having the formula:

,R6 R"
where R6,R' and R" are as defined and wherein the molar ratio of the trisubstituted phosphine to the palladium is about 2:1. If desired, the reaction can occur in the presence of excess trisubstituted phosphine, e.g. triphenyl-phosphine, over and above that necessary to form the pal-ladium catalyst.
Whether the palladium catalyst is formed in situ or whether the palladium catalyst is formed separately and added to the reaction system, the mo~ar ratio of the tri-substituted phosphine compound to palladium in the reactionsystem is above 2:1, and can suitably be from 2.5:1 to 50:1.

1~37~15 Usually the aryl dibromide is reacted with the terminal acetylene compounds in a molar ratio of about 1:1 to avoid the production of aryldiacetylenes. But suitable molar ratios include those from 0.4:1 to 1.5:1, but are more preferably from 0.95:1 to 1.05:1.
The bromoarylhydroxy substituted acetylenes, made as described above, have the formula:

R OH
B A C - C C R

where Ar can be phenyl, naphthyl or biphenyl; R can be H, alkyl having from 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms, phenyl, and cycloalkyl having from 5 to 6 carbon atoms; and Rl and R2 can be the same or different and are selected from the group consisting of hydrogen, lower alkyl groups having from 1 to 4 carbon atoms, phenyl, substituted phenyl; or where Rl and R2 can form a saturated 5- or 6-membered ring at a temperature of less than 150C.
with ammonia in the contact presence of a copper salt.
Preferably in the above formula Ar is phenyl so that the preferred acetylenes have the formula:

~ OH
Br ~ C - C - C - R

where R can be H, alkyl ha~ing from 1 to 10 carboniatoms, preferably 1 to 4 carbon atoms, phenyl, and cycloalkyl having from 5 to 6 carbon atoms, and Rl and R2 can be the same or different and are selected from the group consisting of hydrogen, lower alkyl groups ha~ing from 1 to 4 carbon atoms, phenyl, substituted phenyl; or where Rl and R2 can form a saturated 5- or ~-membered ring.

~137115 More preferably in the above formula, R is hydrogen and bromo is meta to the acetylene group, and Rl and R2 are methyl. The bromoaryl hydroxy substituted acetylene is reacted in accordance with the invention with ammonia to produce the corresponding amine as shown in Equation 1 below, which utilizes certain specific charge stocks which fall within the scope of the charge stocks defined above.
Equation 1 Br ~ C - C - C - CH3 + NH3 ' copper salt ~ OH
NH2C - C - C - CH + HBr The ammonia is usually aqueous concentrated 28%
ammonia,and contacting between the ammonia and the bromo-arylhydroxy substituted acetylenes occurs by vigorous mixing of the materials.
The molar ratio of the NH3 to the bromo charg~
stock is at least sufficient to satisfy the stoichiometric requirements of the process, and usually the molar ratio of NH3 to Br is from 10:1 to 1000:1.
The reaction occurs suitably under autogenous pressure developed at a reaction temperature from about 25C.
to 150C., usually from 75 to 120C. Temperatures above 150C~ should be avoided since the desired product decomposes while temperatures below 25C. are expen~ive and the reaction is too slow.
The reaction is catalyzed by the presence of a copper salt, which is soluble in water and will ionize in water. Suitable copper salts include copper chloride, copper nitrate, copper acetate, copper bromide and copper sulfate.

1~37115 g Copper oxide is covalent and is not a salt within the definition of this invention since it will not ionize in water.
The invention will be further described with S reference to the following experimental work.

Example 1 A 5~0 ml carbon steel autoclave equipped with a Magna-drive stirrer was charged with 15.2 grams 2-methyl-4-(3-bro~ophenyl)-3-butyn-2-ol, 4 grams of cuprous chloride, 120 ml 28% aqueous ammonia and several grams of copper metal.
After purging with nitrogen, the temperature was raised to 100C. and held for 4 hours. VigorQuS stirring was main-tained throughout the reaction period. The maximum auto-genous pressure attained during the run was 125 psig. The reaction was allowed to cool to room temperature. The reaction mixture was discharged and extracted with methylene chloride. The methylene chloride extract was dried over magnesium sulfate and stripped to give the product which was analyzed by gas chromatography to show a conversion of 81%
and a selectivity to 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol of 87%.
The results are shown on Table 1 below.
Additional runs were made similar to Example 1 above, and these are also summarized on Table 1 below.

11371~S

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X O _ N ~) ~~n ~ I~ a~ j ,~ ~ ~ _o ___ _ _ l il371~5 Referring to Table 1, Examples 5 and 6 show too high a temperature gives poor results, while Examples 7 and 8 show the chloro analogue will not convert to the amino derivative.
Example 9 2 grams of 2-methyl-4-(3-aminophenyl)-3-butyn-2-ol were dissolved in 15 ml of toluene containing one pellet (0.1 gram) of sodium hydroxide which had been crushed to a powder.
The mixture was charged to a 100 ml, round-bottom flask 10 equipped with a Dean-Stark trap and condenser. The mixture was refluxed for one hour, and the acetone by-product was removed periodically through the Dean-Stark trap. The reaction product was then cooled, and the mixture filtered to remove particles of caustic. After the solvent was 15 stripped, a quantitative yield of 3-aminophenylacetylene (1.4 grams) of greater than 98% purity as analy~ed by gas chromatography was obtained.

Resort may be had to such variations and modifica-tions as fall within the spirit of the invention and the 20 scope of the appended claims.

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of an aminophenylhydroxy substituted acetylene which comprises:
contacting a bromophenylhydroxy substituted acetylene having the formula:
where R can be H, alkyl having from 1 to 10 carbon atoms, phenyl, and cycloalkyl having from 5 to 6 carbon atoms, and R1 and R2 can be the same or different and are selected from the group consisting of hydrogen, lower alkyl groups having from 1 to 4 carbon atoms, phenyl, or where R1 and R2 can form a saturated 5- or 6-membered ring at a temperature of less than 150°C with ammonia in the contact presence of a copper salt.

2. A process in accordance with claim 1 wherein aqueous NH3 is employed.

3. A process in accordance with claim 2 wherein the copper salt is copper chloride.

4. A process in accordance with claim 3 wherein the reaction temperature is from 75° to 120°C.

5. A process in accordance with claim 4 wherein the bromoarylhydroxy substituted acetylene is 2-methyl-4-(bromophenyl)-3-butyn-2-ol.

6. A process in accordance with claim 1 wherein said aminophenylhydroxy substituted acetylene is coverted to an aminophenyl acetylene by reacting said aminophenylhydroxy substituted acetylene with an alkali metal hydroxide in the presence of a solvent for said acetylene compounds.