Preparation of cyclic-keto-acids

Cyclic-keto-acids of the general formula: ##STR1## wherein R is hydrogen or a monovalent alkyl radical which can be either straight chain or branched having from 1 to about 20 carbon atoms and X=1, 3, or 4, are prepared by reacting a functionalized 1-bromoalkane of the formula: ##STR2## wherein R and X are as defined above and Y is a leaving group, preferably the halogens, in a liquid solvent medium with carbon monoxide at elevated temperature and pressure in the presence of a catalytic amount of a metal carbonyl compound and an alkali or an alkaline earth metal inorganic base.

TECHNICAL FIELD 
The present invention relates to a process for the carbonylation of a 
functionalized 1-bromoalkane to form a cyclic-keto-carboxylic acid as the 
predominant product. 
The practical value of such acids and their esters is that they can be used 
in the synthesis of pharmaceuticals, such as steroids, and for preparing 
herbicides. 
BACKGROUND 
The preparation of .alpha.-keto-carboxylic acids and their derivatives has 
been the subject of a large number of investigations. According to Rodd, 
The Chemistry of Carbon Compounds (1952 edition), Vol. 1, pages 227-229, 
the following methods of preparation are available: 
gentle oxidation of .alpha.-hydroxyacids containing a secondary hydroxyl 
group, or by the enzymatic deamination of .alpha.-amino-acids; 
hydrolysis of an acyl cyanide; 
hydrolysis of .alpha.-oximino-esters; 
from glycidic acid esters on treatment with benzene saturated with boron 
trifluoride; 
from .alpha.,.beta.-dibromocarboxylic acids by forming a piperidine 
addition compound followed by hydrolysis; 
from .alpha.-keto-acetals by ultraviolet irradiation in the presence of 
N--bromosuccinimide; 
from .alpha.-bromomethylketones by boiling with selenium dioxide in 
absolute methanol or ethanol; 
from carboxylic acid esters by oxidation with selenium dioxide; 
permanganate oxidation of vinyl ketones; 
from carboxylic acid esters by condensation with oxalic ester followed by 
decarboxylation; 
from aldehydes via 5-alkylidene-2-thio-oxazolid-4-ones or by reaction with 
methyl methoxyacetate; hydrolysis of azlactones or acetamido-acrylic 
acids; hydrolysis of the reaction product of Grignard reagents on 
diethyl-oxamic ester; 
oxidation of .alpha.-hydroxyacid esters containing two .beta.-hydrogen 
atoms by N--boromosuccinimide in carbon tetrachloride to 
.beta.-bromo-.alpha.-keto-acid esters; and by the action of alkali on the 
dimethanesulphonates and ditoluene-p-sulphonates of 
.alpha.,.beta.-dihydroxy-carboxylic acids. 
Methods for preparing arylpyruvic acids also are known. For example, U.S. 
Pat. No. 4,152,352 discloses the preparation of an arylpyruvic acid by 
reacting an arylmethyl halide in a liquid solvent medium with carbon 
monoxide at pressures 5 to 200 bars in the presence of a catalytic amount 
of a metal carbonyl compound and an alkaline earth metal inorganic base. 
Further, U. K. patent application No. 2,026,478A discloses that alkali 
metal salts of an arylpyruvic acid can be prepared by reacting an 
arylmethyl halide, carbon monoxide and an alkali metal base in the 
presence of a metal carbonyl compound as catalyst and in the presence of 
an alcohol or cyclic ether as solvent. 
In co-pending U.S. application Ser. No. 353,440, entitled "PROCESS FOR 
PREING ARYLALKYPYRUVIC ACIDS," filed Mar. 1, 1982, there is disclosed a 
method of preparing certain arylalkypyruvic acids by carbonylating a 
suitable arylalky halide in a liquid solvent medium with carbon monoxide 
at elevated temperature and pressure in the presence of a metal carbonyl 
compound and an alkali or an alkaline earth metal inorganic base. Further, 
in co-pending U.S. Application Serial No. 353,473, entitled "PROCESS FOR 
PREING ALKYL ALPHA-KETO-CARBOXYLIC ACIDS FROM ALKYL HALIDES," filed 
Mar. 1, 1982, the preparation of alkyl-.alpha.-keto-carboxylic acids by 
reacting a primary alkyl halide in a liquid solvent medium with carbon 
monoxide in the presence of a catalytic amount of a metal carbonyl and an 
inorganic base is disclosed. Still further, in co-pending U.S. Application 
Serial No. U.S. Ser. No. 405,817, entitled "PROCESS FOR PREING 
.beta.-SUBSTITUTED-.alpha.-KETO-CARBOXYLIC ACIDS," filed Aug. 6, 1982, 
there is disclosed the preparation of 
.beta.-substituted-.alpha.-keto-carboxylic acids by reacting a secondary 
halide with carbon monoxide in the presence of a metal carbonyl catalyst 
and an inorganic base. 
The cobalt-catalyzed carbonylation of secondary benzyl halides to give 
either monocarbonyl or double carbonyl insertion or coupling of organic 
halides is reported by E. Francalanci et. al., Journal of 
Electroanalytical Chemistry, 1982, pp. 59-70. 
THE INVENTION 
It has now been found that cyclic-keto-acids of the general formula: 
##STR3## 
in which R represents hydrogen or a monovalent alkyl radical which can be 
either straight chain or branched containing from 1 to about 20 carbon 
atoms, and X=1, 3, or 4 can be prepared by carbonylating a functionalized 
1-bromoalkane of the general formula: where R and X are as defined above 
and Y is a leaving group, preferably a halogen, in a liquid solvent 
medium, with carbon monoxide at a pressure of from about 300 to 3000 psig 
in the presence of a catalytic amount of a metal carbonyl compound and an 
alkali or alkaline earth metal inorganic base. 
The functionalized 1-bromoalkane reactants suitable for use in the present 
process are well known in the art as are methods for their preparation 
and, as defined above, are of the general formula: 
##STR4## 
when R is hydrogen or a monovalent alkyl radical which can be either 
straight chain or branched containing from 1 to about 20 carbon atoms, 
X=1, 3, or 4 and Y is a suitable leaving group, preferably the halogens 
viz., iodine, bromine, and most preferably chlorine. Other suitable 
leaving groups, such as, for example, nitrates, sulfonates and acetates 
also may be used with the proviso that under the reaction conditions of 
the instant process, hydrolysis does not become a major competing reaction 
with the resultant production of unwanted alcohols as the major product. A 
few exemplary materials of this type include 1-bromo-3-chloro-or 
3-bromopropane, butane, pentane, hexane, heptane, octane, nonane, decane, 
undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, 
heptadecane, octadecane, nonadecane, eicosane, and the like; 
1-bromo-5-chloro- or 5-bromopentane, hexane, heptane, octane, nonane, 
decane, undecane, dodecane, tridecane, tetradecane, pentadecane, 
hexadecane, heptadecane, octadecane, nonadecane, eicosane, and the like; 
1-bromo-6-chloro- or 6-bromohexane, heptane, octane, nonane, decane, 
undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, 
heptadecane, octadecane, nonadecane, eicosane and the like; the nitrate, 
sulfonate and acetate esters of 1-bromo-3-hydroxypropane, butane, pentane, 
hexane, heptane, octane, nonane, decane, undecane, dodecane, tridecane, 
tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, 
eicosane and the like; the nitrate, sulfonate and acetate esters of 
1-bromo-5-hydroxypentane, hexane, heptane, octane, nonane, decane, 
undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, 
heptadecane, octadecane, nonadecane, eicosane and so forth. A particularly 
useful reactant is 1-bromo-3-chloropropane from which cyclopropylglyoxylic 
acid (a precursor for the synthesis of steroids) is produced by the 
process of the present invention. 
The reaction is carried out in the presence of a mixture of water and 
alcohol as a reaction medium. Preferably, the alcohols employed for the 
reaction may be straight-chain, branched or cyclic, and preferably contain 
up to 6 carbon atoms. Methanol, ethanol, propanol, isopropanol, n-butanol, 
isobutanol, tert-butanol, and tert-amyl alcohol may be mentioned as 
examples. Cyclic ethers, such as tetrahydrofuran, also may be used. A 
particularly preferred solvent alcohol is tert-butanol. Mixtures 
containing about 10% to 90% by weight of water and about 90% to 10% by 
weight of alcohol generally are used. Preferred mixtures contain about 30% 
to 80% by weight water and about 70% to 20% by weight alcohol. 
The reaction takes place in the presence of a basic substance suitably an 
alkali or an allkaline earth metal hydroxide employing a metal carbonyl 
compound. During the reaction, the 1-bromoalkane undergoes reaction with 
the carbon monoxide and basic substance whereby the salt of the desired 
cyclic-keto-carboxylic acid is formed from which the 
cyclic-keto-carboxylic acid is isolated after acidification in a known 
manner. It is believed that the salt of the keto acid is formed first 
followed by intramolecular nucleophilic displacement under the alkaline 
conditions of the reaction medium to form the cyclic keto acid. 
Specific examples of suitable basic agents which can be used in the 
practice of the process include; LiOH, NaOH, KOH, RbOH, Ca(OH).sub.2, 
Ba(OH).sub.2 and Mg(OH).sub.2. LiOH and Ca(OH).sub.2 are particularly 
preferred. Yields of cyclic-keto-carboxylic acids of up to approximately 
62% can be obtained using Ca(OH).sub.2 as the basic substance and a 
solvent medium of tert-butanol and water. 
The amount of basic agent used can vary within wide limits. In general, the 
molar ratio of the alkali metal or alkaline earth metal base to 
1-bromoalkane reactant is preferably 10:1 to 1:1. 
In the process described herein, it is preferred to use metal carbonyl 
compounds as carbonylation catalysts. These catalysts include particularly 
metal carbonyls such as iron pentacarbonyl, dicobalt-octacarbonyl and 
nickel-tetracarbonyl, of their salts such as, for example, the calcium, 
potassium or sodium salts thereof. Dicobalt-octacarbonyl is very 
particularly suited. These catalysts can be added to the medium in the 
solid state or in the form of solutions in the solvent used for the 
carbonylation reaction. The molar percentage of the metal carbonyl 
compound to the 1-bromoalkane reactant is preferably from about 0.1 to 
about 25%. 
The concentration of the 1-bromoalkane used in the reaction solvent is not 
critical and can vary within wide limits. Thus, it can be between about 1 
to 30% by weight, based on the weight of the solvent, however, it is 
possible to go outside of these limits without disadvantage. 
The present process is advantageously carried out by bringing the mixture 
consisting of the 1-bromoalkane reactant, the metal carbonyl catalyst and 
the alkali or alkaline earth metal base, suspended in the mixture of water 
and alcohol, into contact, under nitrogen, in a suitable 
pressure-resistant reactor equipped with a stirrer, with a large excess of 
carbon monoxide (amount greater than 2 moles of carbon monoxide per mole 
of the starting 1-bromoalkane reactant) introduced at the desired pressure 
and temperature, in accordance with techniques suitable for bringing about 
the reaction between a liquid phase and a gas phase. 
The carbonylation reaction is carried out at a temperature in the range of 
from about 30.degree. C. to about 150.degree. C., preferably from about 
50.degree. C. to 100.degree. C., over a period of time of from about 3 to 
60 hours, typically 3 to 20 hours. 
In general, the reaction takes place at elevated carbon monoxide pressures 
which may range from about 300 psig to about 3000 psig. Preferably, the 
reaction takes place at a pressure in the range of about 500 psig to 1000 
psig. The carbon monoxide may contain or be mixed with an inert gas, such 
as nitrogen. 
On completion of the reaction, the product mixture is filtered, resulting 
in the alkali metal or alkaline earth metal salt of the 
cyclic-keto-carboxylic acid being separated from the liquid reaction 
components as the main solid component. The filtrate contains the 
remainder of the alkali or alkaline earth metal salt of the 
cylic-keto-carboxylic acid, and, where unbranched alcohols are used, also 
esters in addition to unreacted 1-bromoalkane as well as acid and alcohol 
products from the starting 1-bromoalkane. 
In a further process step, the metal salt of the cylic-keto-carboxylic acid 
is acidified with a dilute acid, such as hydrochloric acid, so as to 
displace the cyclic-keto-carboxylic acid from its alkali or alkaline earth 
metal salt. 
If desired, lower alkyl esters of the cyclic-keto-carboxylic acid products 
of the present invention can be prepared by esterifying the 
cyclic-keto-carboxylic acid product according to conventional 
esterification techniques employing lower aliphatic alkanol and acid 
catalysts such as, for example, BF.sub.3, BF.sub.3.HCl, or BF.sub.3.MeOH, 
BF.sub.3.Et.sub.2 O or diazomethane at suitable reaction conditions.

The following example illustrates the invention. 
EXAMPLE 1 
Into a 300 ml autoclave were charged 7.87 g (50 mmoles) of 
1-chloro-3-bromopropane and 70 ml of t-BuOH. Next, 0.682 g (2 mmoles) of 
Co.sub.2 (CO).sub.8 were added under CO, and then a mixture of 7.4 g (100 
mmoles) of lime and 30 ml of H.sub.2 O were added. After 850 psi CO was 
charged to the autoclave, the reaction mixture was heated to 80.degree. C. 
over a period of time of approximately 1 hour and held at that temperature 
for 15 hours. The CO uptake stopped after 11 hours. After centrifugation, 
the solid was rinsed once with a 20 ml portion of a 50:50 t-butanol/water 
solution and then acidified with 150 ml of HCl solution containing 
.about.100 mmoles of HCl. The free acid was extracted from the aqueous 
solution with diethyl ehter (2.times.120 ml) to give a 62% yield of 
cyclopropylglyoxylic acid based on proton NMR data with internal standard. 
Having described the process which Applicants regard as their invention, it 
should be recognized that changes and variations within the scope and 
spirit of the invention can be made by one skilled in the art and it is 
accordingly to be understood that the present description of the invention 
is illustrative only. It is desired that the invention be limited only by 
the lawful scope of the following claims.