United States Patent (19) 11 4,347,379 Lai 45) Aug. 31, 1982

54 SYNTHESIS OF 57 ABSTRACT ALPHA-ALKOXYCARBOXYLIC ACDS Numerous alpha-carboxylic are prepared in a 75 Inventor; John T. Lai, Broadview Heights, liquid medium by the reaction of an Ohio having at least one reactive hydroxyl or thiol group, with a monoketone, and a haloform, in the presence of 73 Assignee: The B. F. Goodrich Company, Akron, a phase transfer catalyst and an alkali metal . Ohio The term "alpha-alkoxycarboxylic acids' includes al pha-phenoxycarboxylic acids, alpha-thioalkoxycar (21) Appl. No.: 129,000 boxylic acids and alpha-thiophenoxycarboxylic acids. 22 Filed: Mar. 10, 1980 Specific on the beta atom of an 51 int. C...... C07C 51/00 alpha-alkoxycarboxylic (or "2-alkoxycarboxylic') 52 U.S. C...... 562/495; 564/189; reaction product formed in this novel synthesis, are 564/201; 260/399; 564/202; 564/205; introduced by appropriate choice of the reac 260/405.5; 564/209;564/210; 260/413; tant; alkoxy and phenoxy substituents on the alpha car 260/465 D; 260/465.4; 562/426; 562/431; bon atom of a 2-alkoxycarboxylic acid are introduced 562/468; 562/470,562/471; 562/472; 562/500; by appropriate choice of the organic compound having 562/504:562/505; 562/507; 562/508; 562/510; a hydroxyl or thiol group. De-alkoxylation of the 2 562/581; 562/586; 562/587; 562/588; 562/599; alkoxycarboxylic acid yields alpha-beta monoolefini 564/123; 564/161; 564/162; 564/171; 564/174; cally unsaturated carboxylic acids which are necessarily 564/175; 564/181; 564/188: 564/191 alpha substituted, and may also be beta-substituted. It is 58) Field of Search ...... 562/470,588, 471, 431, now possible to produce, simply and conveniently, 562/508, 512, 426, 472, 468, 505, 507,581,586, numerous substituted alpha-beta monolefinically unsat 587, 602,495, 500, 504,510,599; 260/399, 413, urated carboxylic acids with a variety of substituents on 465.4, 465 D, 405.5 the alpha carbon atom, and, optionally on the beta car bon atom of these substituted carboxylic acids. Esters 56) References Cited may also be conventionally derived from both the 2 U.S. PATENT DOCUMENTS alkoxycarboxylic acids, and the unsaturated carboxylic acids. 2,490, 109 12/1949 Weizmann ...... 562/588 2,525,249 10/1950 Weizmann ...... 562/588 During the phase transfer catalyzed synthesis of this 3,038,002 6/1962 Reeve...... 562/470 invention, an intermediate acyl halide derivative is 3,368,943 2/1968 Gilbert et al...... 562/588 formed prior to the formation of the 2-alkoxycarboxylic 3,992,432 11/1976 Napier et al...... 260/465.1 acid reaction product. The formation of the acyl halide 4,167,512 9/1979 Lai ...... 260/239.3 B derivative allows the subsequent direct formation, in a modification of the same reaction, of 2-alkoxycarboxy OTHER PUBLICATIONS lic acid amides (or "2-alkoxycarbamides'), simply by Weizmann et al., J.A.C.S. 70, pp. 1153-1157, (1948). adding a primary or secondary amine to the reaction Starks, Chemtech, Feb. 1980, pp. 110-117, (1980). mass. By dealkoxylation of the 2-alkoxycarbamides, Weygand, Preparative Organic Chemistry, pp. 868-871, specific, necessarily alpha-substituted and optionally (1972). beta-substituted acrylamides are synthesized which pre Primary Examiner-Michael L. Shippen viously could be prepared, if at all, only with difficulty. Attorney, Agent, or Firm-Alfred D. Lobo: Nestor W. Shust 7 Claims, No Drawings 4,347,379 2 monoxide, phosgene and formic acid. It is the difficulty SYNTHESIS OF ALPHA-ALKOXYCARBOXYLC of preparing alpha-trichloromethyl alkanol which limits ACDS the applicability of the disclosed Weizmann et al reac tion to alpha-isobutyric acid. Yet the preparation of the BACKGROUND OF THE INVENTION s TCMA is critical because the disclosed reaction will not This invention is related to a novel synthesis of alpha proceed if acetone and chloroform are substituted for alkoxycarboxylic acids which, with known technology, the TCMA. It is the difficulty of making and using could otherwise only be made in the laboratory, usually TCMA which limits its use in the disclosed synthesis to with considerable difficulty. By the term "alpha-alkox the laboratory. ycarboxylic acids' I refer also to alpha-phenoxycar- O A phase transfer catalyzed reaction known as the boxylic acids, alpha-thioalkoxycarboxylic acids, and "ketoform reaction' is disclosed in my U.S. Pat. No. alpha-thiophenoxycarboxylic acids. This invention is 4,167,512, and illustrated in one particular example by more particularly related to the preparation of beta-sub the reaction of a N,N'-alkyl substituted ethylene di stituted alpha-alkoxycarboxylic acids from which can amine with acetone and chloroform; and, in another be derived a wide variety of (a) substituted acrylic acids example, with o-phenylene diamine reacted with cyclo which are both alpha and beta substituted, and (b) sub hexanone and chloroform. The reaction product in each stituted acrylamides which are both alpha and beta example is a 2-keto-1,4-diazacycloalkane. The patented substituted. The alpha-alkoxycarboxylic (or "2-alkoxycarboxy synthesis also proceeds by virtue of a phase transfer lic") acids and their esters have been highly regarded 20. catalyzed reaction mechanism in which an amine, a for their utility in perfumes and other cosmetics; paints, haloform and a ketone are separate reactants, but the coatings and impregnants; texties; and, in the paper patented synthesis does not envision the use, as yet industry. The acids and esters have also been used on a another reactant, of an organic compound having at laboratory scale, as a starting material for the prepara least one reactive hydroxyl or thiol group. tion of various acrylates some of which, if they were 25 SUMMARY OF THE INVENTION commercially available, could provide polymers with a wide range of physical and chemical properties not It has been discovered that an organic compound readily available in available acrylates and methacry having at least one reactive hydroxyl or thiol group, lates. As is well known, the physical and chemical prop such as alcohols and thioalcohols, phenols and thio erties of polymers of acrylic acid esters and methacrylic 30 phenols will react in a phase transfer catalyzed reaction acid esters depend to a large degree on the type of with a haloform, and a ketone, to yield alpha-alkoxycar alcohol from which the esters are prepared, and, the boxylic acids. More particularly, the alpha-alkoxycar length of the sidechain. Little is known about the prop boxylic acids may be produced with a wide variety of erties of acrylates with substituents on the beta carbon, substituents, both on the alpha and the beta carbon simply because making compounds with such substitu- 35 atoms, under controlled easily obtained conditions, ents was impractical. Still less is known about polymers usually without requiring heating of the reaction mix which may be formed from substituted acrylic acids ture. having substituents on both the alpha and beta carbon Accordingly, it is a general object of this invention to atOS. provide a simple and convenient synthesis of alpha Thus, despite the ability of acrylate and methacrylate 40 alkoxycarboxylic acids including alpha-phenoxycar esters to copolymerize with nearly all types of mono boxylic acids, and corresponding thioalkoxy carboxylic mers, which ability has resulted in extensive industrial acids, utilizing commercially available raw materials, use of the esters, the fact remains that, because of the unavailability of all but a few acrylate and methacrylate which react in the presence of a phase transfer catalyst, esters, only the few are presently in wide use. This is so 45 and provide excellent yields with a remarkable freedom despite the knowledge that some polymers which have from undesirable byproducts. more desirable properties for specific applications than It is also a general object of this invention to provide poly(methyl methacrylate) ("PMMA') or copolymers alpha-alkoxycarboxylic acids which may thereafter be of methyl methacrylate and other esters may even be de-alkoxylated to alpha-beta monoolefinically unsatu more economical than PMMA. It is undisputed that the 50 rated carboxylic acids which are necessarily alpha-sub bulk availability of only a few substituted acrylates has stituted and optionally, also beta-substituted, and which precluded the commercial exploitation of many novel acids would otherwise be impractical to synthesize. acrylate-containing polymers, particularly those acryl It is a specific object of this invention to provide a ates with substituents on both the alpha and beta carbon novel synthesis, wherein a preselected primary or sec atoms. 55 ondary alcohol or thioalcohol, phenol or thiophenol, is In an article titled "The Synthesis of alpha-Alkox reacted with a saturated acyclic or cyclic monoketone, yisobutyric Acids and Alkyl Methacrylates from and, a haloform, in the presence of (i) a phase transfer Acetonechloroform', by Ch. Weizmann, M. Sulz catalyst (ii) an organic solvent, and (iii) solid or aqueous bacher and E. Bergman, J.A.C.S. Vol 70, p. 1153-1157, alkali. The phase transfer catalyst is selected from the there is disclosed a preparation starting with alpha-tri- 60 group consisting of a tertiary or quaternary compound chloromethyl alkanol (referred to in the article as of an element selected from Groups VA and VIA of the "acetonechloroform', and hereinafter, for brevity, as Periodic Table, and, a polyether. An intermediate acyl "TCMA), which must first be prepared, and the prepa halide derivative is formed which then results in an ration of which usually entails considerable difficulty. alpha-alkoxycarboxylic acid reaction product. This Though once the TCMA is prepared, it readily reacts 65 product is particularly suited for de-alkoxylation to vigorously with a solution of potassium hydroxide in yield an alpha-substituted alpha-beta monoolefinically alkanol, it is acknowledged in the reference that TCMA unsaturated which may also optionally suffers undefined decomposition to acetone, carbon be beta-substituted. 4,347,379 3 4. It is also a specific object of this invention to provide 2-cyclohexylmercapto-isobutyric acid; a novel and convenient synthesis, directly, for an alpha 2-isobutoxy-methylethyl acetic acid; alkoxycarboxylic acid amide (or "2-alkoxycarbamide") 2-isobutoxycyclohexane carboxylic acid; by adding a primary or secondary amine to the reac 2-isobutoxy-2-ethyl heptoic acid; tants which, without the amine, would yield a 2-alkox 2-ethoxy-isobutyric acid; and, ycarboxylic acid. Because of the formation of an acyl 2-dodecoxyisobutyric acid. halide intermediate, the amide is formed. In this modifi The more preferred substituted alpha-alkoxycarboxy cation of the phase transfer catalyzed synthesis of this lic acids are those wherein: R1 and/or R2 and/or R3 is invention, substituents may be introduced on both the each selected from the group consisting of alkyl having 10 from 1 to 18 carbon atoms, benzyl, cyclohexylmethyl, alpha and the beta of the substituted acrylam and polymethylene having from 2 to 6 carbon atoms ides formed. which are cyclizable. DETAILED DESCRIPTION OF PREFERRED Examples of the aforespecified more preferred substi EMBODIMENTS tuted compounds are: 15 2-methoxyisobutyric acid; The basic structure of the compounds prepared by 2-methoxycyclohexane carboxylic acid; the synthesis described herein, is a substituted alpha 2-methoxy-2-methylpentanoic acid; alkoxymonocarboxylic acid, formed by reaction of a 2-phenoxy isobutyric acid; and, primary or secondary alcohol or thioalcohol, a phenol 2-thiophenoxy isobutyric acid. or a thiophenol, with a haloform selected from chloro 20 According to the synthesis of this invention is has form, bromoform and iodoform, and a cyclic or acyclic been found that phenols, thiophenols, alcohols, and monoketone in the presence of a phase transfer catalyst thioalcohols may be reacted with a saturated or unsatu and an alkali, preferably an alkali metal hydroxide. The rated monoketone and a haloform reactant, in an or reaction may be represented as follows: ganic solvent for the reactants, in the presence of aque 25 ous or solid alkali, provided there is also supplied a R3 phase transfer catalyst selected from the group consist . . . ing of a polyether and an onium salt including a quater RXH + CHY + R2-CO-R ->R--cooh nary or tertiary organic compound of a Group VA or VIA element of the Periodic Table, and salts thereof. 30 More preferred are the tertiary amines, quaternary wherein, X represents or sulfur; amines, and salts thereof. The reaction may be carried Y represents halogen selected from the group consist out at any temperature within a wide range from about ing of chlorine, bromine and iodine; i the freezing point of the reaction mass to about the R, R2 and R3 are independently alkyl having from 1 reflux temperature of the solvent, provided it is lower to about 24 carbon atoms, phenyl, hydroxyphenyl, halo 35 than a temperature which is deleterious to the alpha alkyl having from 1 to about 12 carbon atoms, hydroxy alkoxycarboxylic acid formed. The reaction is of partic alkyl having from 1 to about 12 carbon atoms, cyanoal ular interest because it generally proceeds at room ten kyl having from 2 to about 12 carbon atoms, alkoxyal perature or below, at satisfactory speed, and with excel kyl having from 1 to about 24 carbon atoms, cycloalkyl lent yields. The reaction may also be carried out at any having from 4 to about 7 carbon atoms, or aralkyl hav 40 desired pressure from subatmospheric to superatmos ing from 7 to about 14 carbon atoms; and, pheric, but atmospheric pressure is preferably employed R2 and R3 each additionally represent alkylene hav for convenience, and because there appears to be no ing from 2 to about 7 carbon atoms some of which in substantial advantage to be gained from operating at combination, one with another, represent cycloalkyl higher pressures. having from 5 to about 14 carbon atoms at least four of 45 By "onium salts' I more particularly refer to tertiary which are cyclized. or quaternary amines and salts such as are generally Though the foregoing reaction proceeds with a ter used in the phase transfer catalysis of heterogeneous tiary alcohol or tertiary thioalcohol, the results are not reactions in immiscible liquids. The general requirement attractive from a practical point of view. The reaction for the onium salt chosen is that it be soluble in both the also proceeds with diols and dithiols, for example 1,2- 50 organic and aqueous phases, when these two liquid butanediol and 1,2-benzene diol. Illustrative of particu phases are present, and usually a little more soluble in lar substituents that may be introduced into the struc the organic phase than the aqueous phase. The reaction ture of the above-identified alpha-carboxyllic acid are: will also proceed with a phase transfer catalyst when where R and/or R2 and/or R3 is alkyl, examples are there is only a single organic liquid phase present, but methyl, ethyl, n-propyl, n-butyl, t-butyl, n-hexyl, n 55 such a reaction is less preferable than one in which both octyl, 2-ethylhexyl, n-decyl, n-tetradecyl, n-octyldecyl, aqueous and organic liquid phases are present. A wide and the like; variety of onium salts is effective in this synthesis. where R is aralkyl, examples are benzyl, and 2 . . The onium salts include the well-known salts, tertiary phenylethyl; amines and quaternary compounds of Group VA ele where R2 and R3 are combined to form cycloalkyl, 60 ments of the Periodic Table, and some Group VIA examples are tetramethylene, pentamethylene. elements such as are disclosed in U.S. Pat. No. 3,992,432 Examples of specific substituted alpha-alkox and in a review in Angewandte Chemie, International ymonocarboxylic acids derived from readily available Edition in English, 16 493-558 (August 1977). Dis starting materials, and prepared by the synthesis of this cussed therein are various anion transfer reactions invention, are: 65 where the phase transfer catalyst exchanges its original 2-methoxy-2-phenyl propionic acid; ion for other ions in the aqueous phase, making it possi 2-ethoxy-2-isobutylpropionic acid; * . . ble to carry out chemistry there with the transported 2-methoxy-2-isobutoxy-4-methyl pentanoic acid; anion, including OH ions. 4,347,379 5 6 The onium salts used in this synthesis include one or (mol wt about 5000); poly(ethylene glycol methyl more groups having the formula (RY) X, wherein Y ether); 1,2-dimethoxyethane; diethyl ether, and the like. is either a pentavalent ion derived from an element of The organic solvent is preferably one of the reactants Group VA, or a tetravalent ion derived from an ele but may also be any solvent in which the reactants are ment of Group VIA; R is an organic moiety of the salt soluble. Most preferred are primary alcohols which are molecule bonded to Y by four covalent linkages when also reactants. Other solvents which do not take part in Y is pentavalent, and three covalent linkages when Y is the reaction include hydrohalomethylenes, particularly tetravalent; X is an anion which will dissociate from hydrochloromethylenes, sulfolane, dibutyl ether, di the cation (RY) in an aqueous environment. The methyl sulfone, diisopropyl ether, di-n-propyl ether, group (RY)-X may be repeated as in the case of O 1,4-dioxane, tetrahydrofuran, benzene, toluene, hexane, dibasic quaternary salts having two pentavalent Group carbon tetrachloride and the like. Most preferred soi VA ions substituted in the manner described. vents are primary alcohols which enter into the reac The preferred onium salts for use in the invention tion, and, hydrochloromethylenes. have the formula The presence of a haloform, such as chloroform, 15 iodoform or bromoform is essential for the reaction to proceed. Most preferred is chloroform as a necessary reagent, but in combination with the phase transfer wherein M is N or P, and R1-R4 are nonovalent hydro catalyst the chloroform may also have a catalytic effect. carbon radials preferably selected from the group con The precise mechanism or the manner in which the sisting of alkyl, alkenyl, aryl, alkaryl, aralkyl, and cyclo 20 haloform affects the reaction, is not understood. The amount of haloform used does not appear to be critical, alkyl moieties or radicals, optionally substituted with at least to initiate the reaction, but it is essential that at suitable heteroatom-containing functional groups. The least a stoichiometric amount of haloform be used if no onium salts are generally selected to be preferentially ketone is to be left unreacted. Though a small amount of less soluble in the less polar of the two distinct liquid 25 unreacted ketone is not deleterious, it is desirable to phases. Any of the salts disclosed in U.S. Pat. No. employ a slight excess of haloform over the stoichio 3,992,432 will be found effective, but most preferred are metric amount indicated, to avoid unreacted ketone. those in which the total number of carbon atoms in R, Though an excess, up to about a 50% excess of halo R2, R3, and R4 cumulatively range from about 13 to form over stoichiometric may provide acceptable re about 57, and preferably range from about 16 to about sults, more than 50% over stoichiometric is to be 30. Most preferred onium salts have M-N, and hydro avoided because of the formation of undesirable side carbon radicals where R1 is CH3, and R2, R3, and Rare products. A preferred amount of chloroform is in excess each selected from the group consisting of n-C4H5; of 20 percent by weight of the reaction mass, and is the n-C5H11; mixed C5H11; n-C6H13; mixed C6H13; haloform most preferred. C6H5; C6H5CH2; n-C8H17; n-C12H25; n-C18H37; 35 Alternatively, a stoichiometric amount of chloroform mixed Cs-Coalkyl; and the like. However, R1 may also may be used, and an excess of ketone, generally a large be selected from C2H5, n-C3H7 and n-C4H9. excess. If an alcohol such as methyl alcohol is chosen as Various counterions may be used, including Cl-, a reactant, an excess of the alcohol is used because it Br, I-, NO3, SO4, HSO4 and CH2CO2 . Most also serves as the solvent for the reaction. preferred is Cl. 40 If however, instead of a primary alcohol which is a The tertiary amines or trianines useful as phase trans solvent for the other reactants, another organic com fer catalysts in this synthesis include the alkyl amines pound having at least one reactive hydroxyl group is and the aryldialkylamines, exemplified by tributylamine used, and such compound did not function as a solvent and phenyldibutylamine respectively, which are com for the reactants, at least a stoichiometric amount of the monly available, wherein each alkyl may have from 1 to 45 compound is required. Under such circumstances, an about 16 carbon atoms. inert solvent for the reactants, which solvent does not The polyethers useful as catalysts in this synthesis enter into the reaction, would be used. It will be evident include cyclic polyethers such as the crown ethers, to one skilled in the art that the goal of obtaining the disclosed in Agen wandte Chennie, supra, and ayclic poly highest yield of the desired reaction product with the ethers having the formula 50 minimum amount of undesired byproducts and the greatest economy of raw materials, will require a little trial and error. This reaction being a phase transfer catalyzed reaction, it is difficult to predict with any wherein R and R' are independently alkyl having from degree of certainty, precisely how well a reaction will 1 to about 16 carbon atoms, or alkyl containing substi 55 proceed even when it is known that it will certainly tuted functional groups such as hydroxy, sulfur, amine, proceed. ether, etc. Most preferred acyclic polyethers have the When an amide is desired, at least a stoichiometric formula amount of the primary or secondary amine is added, at least a 20% excess being preferred. Preferred substitu 60 ents for the primary and secondary amines are set forth hereinafter, and the primary amines are most preferred. wherein R is alkyl having from 1 to about 16 carbon Unreacted amine does not interfere with the reaction, atons but too large an excess may give rise to problems in R" is alkyl having from 1 to about 16 carbon atoms, separating the reaction product from the reaction mass. or H, and 65 Though the amount of phase transfer catalyst used is r is an integer in the range from 0 to about 300. Most not critical, its catalytic function is unique in this modi preferred are commonly available polyethers such as: fied ketoform reaction which yields a 2-alkoxycarba tetraethylene glycol dimethyl ether; polyethylene oxide mide. In general, it is sufficient to use no more onium 4,347,379 7 8 salt catalyst than about 2 percent by weight of the reac perature rose to 16 C. Stirring of the reaction mass was tion mass, and it is preferred to use in the range from continued overnight, and thereafter the reaction mass about 0.1 to about 1 percent by weight. was filtered. Solid NaCl precipitated out and was The temperature for carrying out both the modified washed with MeOH to free it from desired reaction ketoform reactions described hereinabove spans a wide product, and the 2-methoxyisobutyric acid formed dur range, whether the reaction, in one form, results in the ing the reaction is recovered after acidification of the formation of a 2-alphaalkoxycarboxylic acid, or, in an sodium salt, by evaporation of the methanol. other modified form, results in the formation of a 2 The structure of the compound is confirmed and alphaalkoxycarbamide. Best results are obtained at a supported by IR, NMR, GC and mass spectrometer temperature above the freezing point of the reaction O analysis. mass and below room temperature (20° C.), melting ice temperature being most preferred. In an analogous manner, by choosing the alcohol and De-alkoxylation of the 2-alphacarboxylic acids and the ketone with appropriate substituents, the 2-alkox 2-alphacarbamides obtained may be carried out by heat ycarboxylic acids identified hereinbelow are synthe ing with an equivalent amount of phosphorus pentox 15 sized. Melting points and boiling points are given. ide, or with oxalic acid, zinc chloride or alcoholic sulfu ric acid. Alkoxyacids containing secondary alkyl radi Compound B. pt. or m. pt. cals are especially easily converted into unsaturated 2-methoxycyclohexane carboxylic acid b. pt. 104-6' C/1.5 mm compounds, so that obtaining a wide variety of substitu 2-methoxy-2-methylpentanoic acid b. pt. 89-92 C./1.5 mm ents on the alpha carbon, and also, on the beta carbon 20 2-phenoxyisobutyric acid m. pt. 97-9 C. may now be conveniently accomplished. Conditions for 2-thiophenoxyisobutyric acid m. pt. 63-5 C. de-alkoxylation are well known in the art and require no further detailed description. The mono-ketone is preferably saturated and may be According to a modification of the synthesis of this cyclic or acyclic. Useful cyclic are those which 25 invention it has also been found that phenols, thiophen cyclize forming a cycloalkyl ring. Other ketones are ols, alcohols, and thioalcohols may be reacted with a chosen to provide a desired in the alpha primary or secondary amine, a saturated or unsaturated alkoxycarboxylic acid. Most preferred ketones are cy monoketone and a haloform reactant, in an organic cloalkanones, dialkylketones, and aralkylketones. solvent for the reactants, in the presence of aqueous or The preferred alkali is an aqueous alkali metal hy 30 solid alkali, provided there is also supplied a phase droxide solution such as aqueous sodium hydroxide, or transfer catalyst identified hereinabove. The reaction potassium hydroxide, preferably in the range from product is a 2-alkoxycarbamide which may be repre about 20 percent to about 70 percent solutions. If the sented by the formula alkali metal hydroxide is used in solid form, it is prefera bly in finely divided powder form typically less than 80 35 U.S. Standard mesh in size. The amount used is prefera bly at least three equivalents of alkali metal hydroxide for good progress of the desired reaction. It is preferred to use sufficient aqueous alkali solution to form a visu ally distinct aqueous phase in the presence of the or 40 wherein, X represents oxygen or sulfur; ganic Solvent phase. In general, the amount of aqueous R, R2, R3, Rand R5 are independently alkyl having alkali used is preferably at least 5 percent by weight of from 1 to about 24 carbon atoms, phenyl, hydroxy the reaction mass. There is no advantage to using more phenyl, haloalkyl having from 1 to about 12 carbon aqueous alkali than about 75 percent by weight of the atoms, hydroxyalkyl having from 1 to about 12 carbon reaction mass. It will be appreciated that, if solid alkali 45 is used, it will be a reactant which is soluble in another atoms, cyanoalkyl having from 2 to about 12 carbon reactant, or in a solvent for the reactants, only to the atoms, alkoxyalkyl having from 1 to about 24 carbon extent that it provides necessary OH- ions for carrying atoms, cycloalkyl having from 4 to about 7 carbon out the phase transfer synthesis. atoms, or aralkyl having from 7 to about 14 carbon The following examples serve to illustrate the inven 50 atoms; and, tion. Where not otherwise stated, parts are given as R2 and Reach additionally represent alkylene hav parts by weight and the temperatures in degrees centi ing from 2 to about 7 carbon atoms which in combina grade. tion, one with another, represent cycloalkyl having from 5 to about 14 carbon atoms at least four of which EXAMPLE 1 are cyclized. Preparation of 2-methoxyisobutyric acid 55 The formation of the above-identified carbamide is Methanol (MeOH), chloroform (CHCl3), acetone presumed to result from a precursor acyl halide which, and benzytriethylammonium chloride (hereafter but for the presence of the amine, would result in the "BTAC" for brevity), are placed in a large three formation of a 2-alkoxycarboxylic acid. The 2-alkox necked flask and cooled in an ice bath. The proportions 60 ycarbamide formed is easily de-alkoxylated by acid of MeOH, CHCl3, acetone and BTAC were 32, 23.9, elimination of the alkoxy group, as is conventional, to 17.43 and 2.28 parts by weight respectively. While the yield a beta-substituted alpha-beta monoolefinically mixture was being stirred on the ice bath, 56 parts 50% unsaturated carbamide which is also necessarily alpha NaOH was added dropwise. About 80% of the NaOH substituted. The importance of this synthesis stems from was added over a period of 30 min and the temperature 65 the fact that it is not practical to convert a 2-alkoxycar was kept below 9 C., after which the temperature re boxylic acid, once it is formed, into a carbamide. mained at 9 C. for about 20 min. The remainder of the The preparation of a 2-alkoxycarbamide and its de NaOH was added over a period of 10 min and the tem alkoxylation is illustrated by Example 2 hereinbelow: 4,347,379 9 10 carboxylic acid which optionally is also beta-sub EXAMPLE 2 stituted. Preparation of 2-methoxy-N,N'-diethyl-isobutyramide 3. The method of claim 1 wherein said alpha-alkox The reactants used in Example 1 hereinabove are ycarboxylic acid or alpha-thioalkoxycarboxylic acid is again placed in a 250 ml three-necked flask and one represented by the structural formula equivalent of diethylamine is added to the flask. The flask is cooled on an ice bath, as before, and the 50% R3 NaOH solution added dropwise. The reaction which occurs may be represented as follows: R2-C-COOH O

CH3OH -- CHC13 -- CH3COCH3 -- C2H5NHC2H5 -Ge. wherein, X represents oxygen or sulfur; CH3 R, R2 and R3 are independently alkyl having from 1 to about 24 carbon atoms, phenyl, hydroxyphenyl, CH-i- N(CH5)2 15 haloalkyl having from 1 to about 12 carbon atoms, OCH3 hydroxyalkyl having from 1 to about 12 carbon atoms, cyanoalkyl having from 2 to about 12 car After the reaction is complete, sufficient water is added bon atoms, alkoxyalkyl having from 1 to about 24 to dissolve the NaCl crystals formed, and to leave two carbon atoms, cycloalkyl having from 4 to about 7 distinct layers, one aqueous and the other organic. The carbon atoms, or aralkyl having from 7 to about 14 organic layer is recovered and the 2-methoxy-N,N'-die carbon atoms; and, thylisobutyramide obtained by evaporation of the alco R2 and R3 each additionally represent alkylene hav hol. ing from 2 to about 7 carbon atoms which in com The structure of the compound is confirmed and 25 bination, one with another, represent cycloalkyl supported by IR, NMR, GC and mass spectrometer analysis. having from 5 to about 14 carbon atoms at least In an analogous manner, by an appropriate choice of four of which are cyclized. a ketone, any of the substituents identified hereinabove 4. The method of claim 3 including maintaining a may be introduced on the beta carbon atom. The choice temperature above the freezing point of the reaction of the organic compound having at least one hydroxyl 30 mass but below the reflux temperature of the solvent, or thiol group is of lesser importance if the alkoxy and, adding said haloform in a slight excess over the group on the alpha carbon of the 2-alkoxycarbamide is stoichiometric amount required to react essentially all to be eliminated to produce an alpha- and beta-sub of said monoketone. stituted alpha-beta monoolefinically unsaturated carb 5. The method of claim 4 wherein X is oxygen, and amide. This dealkoxylation is effected by simple acidic 35 R, R2 and R3 are independently selected from said elimination, by acidifying with sulfuric acid or hydro alkyl, cycloalkyl, aralkyl and phenyl. chloric acid, as is conventional. 6. A method for preparing an alpha-alkoxycarboxylic As will now be evident, a primary amine will not acid, or alpha-thioalkoxycarboxylic acid, represented serve to provide two substituents on the nitrogen atom, by the structural formula therefore secondary amines are most preferred. The following carbamides are prepared by the foregoing procedure: R3 2-thiophenoxy-N,N'-diethylisobutyramide; R2-C-COOH 2-thioethoxy-N,N'-dipropylisobutyramide; 2-ethoxy-N,N'-dibutylcyclohexane carbamide; 45 2-methoxy-2-phenoxy-N,N'-diethylpropionamide; and, 2-methyl-2-phenoxy-N-methyl,N'-phenyl-butyramide. wherein, X represents oxygen or sulfur; I claim: R1,R2 and R3 are independently alkyl having from 1 1. A method for preparing an alpha-alkoxycarboxylic to about 24 carbon atoms, hydroxyphenyl, haloal acid, or alpha-thioalkoxycarboxylic acid, comprising 50 kyl having from 1 to about 12 carbon atoms, hy reacting an organic compound selected from the group droxyalkyl having from 1 to about 12 carbon consisting of alcohols, thioalcohols, phenols and thio atoms, cyanoalkyl having from 2 to about 12 car phenols with a cycloalkanone, dialkylketone or aralk bon atoms, alkoxyalkyl having from 1 to about 24 yiketone in the presence of (i) a haloform, (ii) alkali carbon atoms, cycloalkyl having from 4 to about 7 metal hydroxide, and (iii) a phase transfer catalyst se 55 carbon atoms, or aralkyl having from 7 to about 14 lected from the group consisting of tertiary and quater carbon atoms; and, nary compounds of Group VA and Group VIA ele R2 and R3 each additionally represent alkylene hav ments, and, a polyether, said phase transfer catalyst ing from 2 to about 7 carbon atoms which in com being present in an amount sufficient to form a salt of bination, one with another, represent cycloalkyl said alpha-alkoxycarboxylic acid or alpha-thioalkox 60 having from 5 to about 14 carbon atoms at least ycarboxylic acid; forming said alpha-alkoxycarboxylic four of which are cyclized, comprising, acid or alpha-thioalkoxycarboxylic acid by acidifying reacting an organic compound having at least one said salt; and, recovering said alpha-alkoxycarboxylic reactive hydroxyl or thiol group with a monoke acid or alpha-thioalkoxycarboxylic acid. tone in the presence of (i) a haloform, (ii) alkali, and 2. The method of claim 1 including, in addition, de 65 (iii) a phase transfer catalyst selected from the alkoxylating said alpha-alkoxycarboxylic acid or alpha group consisting of tertiary and quaternary con thioalkoxycarboxylic acid; and, recovering an alpha pounds of Group VA and Group VIA elements, substituted alpha-beta monoolefinically unsaturated and, a polyether, said phase transfer catalyst being 4,347,379 11 12 ." , , , forming an alpha-beta monoolefinically unsaturated present in an amount sufficient to form said alpha- carboxylic acid which is alpha-substituted, and alkoxycarboxylic acid or alpha-thioalkoxycarboxy- represented by the structural formula lic acid; 5 R3 recovering said alpha-alkoxycarboxylic acid or al- R=l-cooh pha-thioalkoxycarboxylic acid; 7. The method of claim 6 wherein R2 and R3 are 10 independently selected from said alkyl, aralkyl, and dealkoxylating said alpha-alkoxycarboxylic acid or cycloalkyl. alpha-thiocarboxylic acid; and, sk k is k :

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