CA1147742A - Process for the production of tertiary 2- haloacetamides - Google Patents

Abstract

Abstract of the Disclosure The disclosure herein relates to a novel process for producing tertiary 2-haloacetamides by reacting primary or secondary 2-haloacetamides with an agent capable of generating an anion of the primary or secondary 2-halo-acetamide under base conditions and alkylating the anion of the 2-haloamide with an alkylating agent; said anion is generated, for example, by electrolysis or by alkali metal hydrides, fluorides, oxides, hydroxides, carbonates, phosphates, or alkoxides.

Description

1~4 ~ f '~:2 -l- AG-1298 PROCESS FOR THE PRODUCTION OF

Bac~ground_of the Invention Field of the Invention The invention herein relates to the field of chemical processes for the preparation of 2-haloacetamides, p~rticularly those having a~ one nitrogen substituent an alkyl, alkenyl, alkynyl, alkoxyaIkyl or heterocycyl group and, additionally, an alkenyl or cycloalkenyl radical or a phenyl group substituted with various radicals.
Summasy of the In~ention The process of the present in~ention involves alkylating primary or secondary 2-haloacetamides under anion-forming conditions to produce tertiary 2-haloacet-amides. As used herein, the term~ "alkylation" or "alkylat-ing" are used generically to include reactions which give rise to ~arious ~ubstituents (not just al~yl groups) on the nitrogen atom of the primary or secondary amide anion.
The present invention relates to a process for the preparation of tertiary 2-haloacetamides having the formula .' R6 R
I XC-C-N~

which comprises reacting an anion of a compound of Formula II
: R6 O ~H
II X~C - C-~

' ~, ,.

~'7'~4.~

-2- AG-1298 preferably in situ, with a compound of the formula III RlXl or a Michael (1,4-) addition reagent such as ~ satur-ated acid or car~onyl derivatives having up to 8 carbon ato~s exemplified by acrylonitrile, ethyl acrylate, diethylmaleate, acetylenedicarboxylate, acrolein, etc., wherein in the above formulae:
X is chlorine, bromine or iodine;
xl is chlorine, bromine, iodine or a halogen equiva-lent such as p-toluenesulfonate, methyl sulfate(CH30S03~)j or other ; moiety recognized for its lability (but otherwise inertness);
R is hydrogen, Cl_l8 alkyl, C2_1g alXenyl, alkynyl or alkoxyalkyl, polyalkoxyalkyl, C3_7 cycloalkyl or cycloalkyl-alkyl, Cs_7 cycloalkenyl or cycloalkadienyl which may be : 15 3ubstituted with C1_6 alkyl groups; sat~rated or unsaturated heterocyclic radicals having up to 6 ring atoms containing 0~ S()a and/or N(Rs~b groups or a radical of the formula IV ~ (CH2tn tR4)m wherein a is 0-2 inclusive;
~ and n are 0 or 1;
m is 0-3 inclu5ive when R2 and R3 are other than hyd~oge~d, nr~5 Q~h~ se: , R2, R3, R4 and R5 are independently hydrogen, Cl_6 alkyl, alkoxy, polyalkoxy, or alkoxyalkyl, C2_6 alkenyl, alkenyloxy, alkynyl or alkynyloxy, C6_10 aryl, aryloxy, aralkyl or aralkyloxy, N02, halogen, CF3-, (C~3)3Si-, saturated or unsaturated heterocyclic radical having up to 6 ring atoms contianing 0, S()a and/or N(R5)b groups or R2, R~, R4 when

-3- AG-1298 combined with the p~enyl radical to which attached may form a C6_10 aryl radical; or, when not a hydrogen atom, the R
group may be substituted with an R2-Rs group;
Rl is Cl_lg alkyl, C3_1g alkenyl or alkynyl, C2_Lg alkoxyalkyl, C3_7 cycloalkyl or cycloalkylalkyl, C6_1Q
aral~yl, alkylthiomethyl cyanomethyl, loweracyloxymethyl, loweralkylthiocarbomethyl, substituted or unsubstituted carbamoylmethyl, benzothiazolinonylmethyl, phthalimidomethyl, mono- or di-loweracylamidomethyl or Cl_10 hvdrocarbylsulfon-ylamidomethYl ~groups or said Rl mem~er substituted withan R2-Rs member which is inert under reaction conditions, provided that when Rl is an alkenyl radical it cannot have an olefinic bond on the carbon atom attached to the nitrogen atom and R6 and R7 are independently hydrogen or alkyl, cycloal~yl, cycloalkenyl, alkenyl or aromatic hydrocarbon each ha~ing up to 12 carbon atoms.
A subgenus of compounds of particular interest which may be pri~pared by the process of this invention are tertiary 2-haloacet~m~des which are substit~ted on the amide nitrogen simultaneou~ly with l-cycloalken-l-yl and alkoxymethyl radicals which may further be substituted with groups which are non-reactlve in the process.
Another subgenus of compounds of special interest which are prepared by the process of this invention are tertiary 2~s-acetanilides substituted on the amide nitrogen with hydrogen, Cl_lo alkyl or alkoxyalkyl radicals, such as alkoxymethyl and alkoxyethyl ~herein the anilide r~ng may be unsubstituted or which may be substituted with non-interfering groups such : 30 as Cl_g alkyl, alkoxy, alkoxyalkyl,nitro, halogen, e.g., chlorine, bromine, iodine or fluorine, trifluoromethyl and the li~e.
Yet another preferred subgenus of compounds prepared by t~e pnx~ss of this in~ention are tertiary 2-haloaceta~;~Ps which are 35 substituted on the amide nitrogen atom simultaneously with .

-4- AG-1298 alkoxyalkyl radicals, e.g., alkoxymethyl, alkoxyethyl or alkoxyprop-2-yl radicals and alken-l-yl radicals which also may be substituted with non-interfering radicals.
The requisite anions of the 2-haloacetamides of Formula I$ ha~e a negative charge on the nitrogen atom and are qenerated in either stoichi etric or incremental amounts under basic conditions by means of electrolysis or by reaction with alkali metal fluorides, hydrides, oxides, hydroxides, carbonates or alkoxides. The corresponding alkaline earth compounds may also be used to form said anions. Preferred secondary 2-haloacetamide starting materials are those required to produce the above-mentioned tertiary 2-haloacetamides of particular interest in the pro-cess of this invention.
Preferred "alkylating agents", e.g., compounds of Formula III above, are tho~e compounds which donate the non-haloacyl substituent on the subgenera of compounds mentioned above. Compounds suitable for alkylating agents include the haloalkyl alkyl ethers, e.g., chloromethyl methyl ether, 2-bromoethyl methyl ether, halomethylthioethers, etc., but certain other ethers, e.g., 2-chloroethyl ethyl ether may be too sluggish for practical use. Other suitable alkylating agents include Cl_4 alkyl sulfates, e.g., dimethylsulfate, diethylsulfate, and Cl_l0 alkyl toluene sulfonate esters, e.g., methyl ~-toluenesulfonate, etc. Other alkylators include the halides of aliphatic and arylalkyl aromatic compounds, e.g., alkyl, alkenyl, alkynyl, and benzyl halides, such as methyl iodide, benzyl bromide, ethyl bromide, allyl chloride, bromide or iodide and propargyl bromide or iodide (the chloride i9 too sluggish). ~lso suitable alkylating agents are N-(halomethyl)-substituted acylamides and acetanilides or the 2-haloanaloqs thereof, e.g., N-(chloromethyl) acetamides, 2',6'-dialkyl-N-(chloromethyl)-2-chloro~acylanilide and hetero-cyclics, e.g., halomethyl-substituted benzo-, thieno- or pysidoheterocycles, e.g., 3-(chloromethyl)-2-benzothiazolinone.
Other reactive alkylating agents within the pur~iew of this invention include O-(halomethyl) esters of aliphatic or aromatic acids such as chloromethyl acetate or bromomethyl ' 7~

-5- AG-1298 benzoate and aliphatic and aromatic esters of~-haloalkanoic acid such as ethyl bromoacetate, benzyl chloroacetate, methyl-2-bromopropionate, etc. Specific examples of other alkylating agents include N-(bromomethyl) phthalimide, chloromethyl pivaloate, chloroacetonitrile.
The process of this invention is preferably conducted in the presence of a phase transfer catalyst such as poly-ethers or quaternary ammonium halide salts as described in more detail below.
Detailed Description of the Invention The process of the present inventisn may be practiced in any of the embodiments described herein.
(A) A preferred embodlment of the present process utilizes a multiphase system employing a base sufficiently strong enough to react with the starting sec-amide, option-ally dissolved in an organic solvent, mainly at the in~2r~ace, to produce incremental concentrations of amide anion. The presence of a phase transfer catalyst permits the so-formed amide anion to be transported via ion pair into the organic portion wherein most of the alkylating agent (i.e., compound of Formula III above) or activated olefin resides, and so react. The reaction will proceed without said catalyst, although yields are usually decreased, reaction times increased, and imidate by-product increased.
It will be un~erstood that the weaker the acidity of the amide of Form a II, the stronger must be the base. Thus, e.g., w3~1y acidic ~mideg s~ as the st~ng m2Iterials for prepa~ng a~lor (E~ple 13) or N-(2,6~methyl-1-cyclohexen-1-yl)iN-(me~ methyl)-2-chloroaoet3mide (E~m~le 1), ~y, 2',6'-die~hyl-2~ x~ce~ and 30 N-(2,6~methyl-1-cycloh~-1-yl)-2~oroaoetamide nK~re Ln this emkodi-m#nt, strong bases such as aq~s or solid sodium hyd~nd~e or p~ssium h~xKide. F~her, it is prefeD~ when aq~æ~s caustic is used that the solution be con~entrated; (i.e., 20-50%) Cn the other hand, Ln the alkylation of sLL~ ~ly acidic 35 materials such as 2-chloro-2',6'-dinitrnacetaniliae, it can be demonstrated that a weaker base such as solid or aqueous sodium carbonate can be used ~o success~ully generate amide an1an and consequEntly effect alkylation (EX~mple 17).
It will be appreciated that the amide anion in this embodiTent A will form an icn pair wqth the catiQn of the phase transfer catalyst.

'f 1 ~

-6- AG-1298 merefore, useful catalysts are ~e conta ~ ng organic-soluble cations such as amm~um, phosphcnium and sulfonium salts. EXemplary pAase ~nsfer catalysts include quaternary ~n~nium salts, e.g., aryl or ar~X~l trial~yl ammonium halide salts such as benzyl triethyl S ammonium bromide or chloride. Other phase transfer catalysts include the acyclic and cyclic poly ethers which complex with the base cation and then pair with amide anion as counter ion or transport to the organic phase for alkylation. Exemplary of such catalysts would include "18-crown-6" cyclic ether 10 in combination with potassium hydroxide or fl~oride as base.
Other bases in this embodiment A, dependent, how-ever, on sec-amide acidity are alkali metal hydroxides, carbonates, and phosphates and alkaline earth hydroxides, e.g., calcium oxide or hydroxide, trisodium phosphate, 15 potassium carbonate.
Inert solvents for use in this embodiment A in-clude, e.g., e~ters of alkanoic acids and alkanols such as ethyl acetate, etc., dichloromethane, benzene, chlorobenzene, tetrahydrouran, dimethyl sulfoxide, dimethy?formamfde, 2~ toluene, diethyl ether, except that when a~ueous bases are used, the solvent should be appreciably water insoluble.
(B) A second embodiment of the present invention utilizes two differe~ct modifications to overcome by-product imidate formation (formed via O-alkylation). In the first, when small amounts of starting amide are used, i.e., up to about 50 g, phase transfer catalyst i9 increased to about 20-5~ by weight o~ the amide charged, mixed with alkylating agent and the base added last. A second method, particularly useful for preparing large amounts of tertiary amide is to wash the reaction mixture (minus the base or aqueous phase) with dilute acid, preferably S%-10~ ~Cl solution, wherein the imidate, but not the tertiary amide product, is converted to starting sec-amide. This mixture of amides can then be treated with fresh alkylatinq agent, catalyst and base to effect conversion of remaining sec-amide to tert amide. It will be appreciated that such transformation of imidate to desired amide product can be effected in a recycling process either through a stepwise procedure, or by use of suitably designed e~uipment, as in a continuous or cascade process.

'7'7 - ? - ~G-129 (C) Anotner embodiment of the present 2rocess employs a reactive metal, metal hydride or organometallic base to effect stoichiometric conversion of starting amide to amide anion. Exemplary is the addition of a dry ether or tetrahydrofuran solution of a secondary 2-chloroacetamide to an excess of potassium hydride, slurried in the same sol-vent. Liberation of hydrogen occurs immediately, and in theory amount. The amide anion salt can then be reacted by addition of excess alkylating aqent. Excess hydride is destroyed with water, and the tert-amide isolated as des-cribed in examples ~elow. This embodiment has the advan-tages of minimizing imidate and diketopiperazine formation while preserving the alkylating agent which otherwise may be sensitive to a~ueous base.
; 15 In considering embodiments of A, B and C, the ratios of reactants in these processes are not critical, but are dictated primarily be economic considerations and avoid-ance of unwanted by-products. Kence, large excesses or de-ficiencies of any expensive component relative to another component should be avoided. Embodiment A is best conducted with an excess o NaO~.
The process of this invention may be carried out at temperatures ranging from subzero to ambient or higher, e.g., from -20 to +100C, but usually ~oom temperatures are sufficient, and desirable.
~ D) Another embodiment of this invention involves the generation of the secondary amide anion by electrolytic means. In electrolytic processes, the amide anion is gen-erated directly at a suitable cathode. The resulting anion 30 i3 alkylated with an appropriate compound of Formula III
above, e.g., haloalkyl alkyl ethers such as chloromethyl methyl ether.
The above embodiments are exemplified in the spe-cific working examples which follow.
Example 1 This example exemplifies preferred embodiments (A) and ~B) of the present process utilizing a multiphase system to generate a stable 2-haloacetamide anion and "alkylation"
of~same with a compound according to Formula III above in J ~

the presence of a phase-transfer catalyst to produce the corresponding stable tertiary 2-haloacetamide. Part (a) describes the preparation of the secondary 2-haloacetamide starting material and Part (b) describes the generation of ; 5 the amide anion and alkylation thereof.
(a) A reaction vessel is charged with 11.3 parts of chloroacetyl chloride, 150 parts of chlorobenzene and 25 parts of N-2,6-dimethylcyclohexylidene amine. The reaction mixture is refluxed for several hours, cooled and filtered to obtain 13.5 parts of solid product, M.P. 114-115C.
Calc'd for CloH17ONCl (percent); CL 17-55; N, 6-93 Found: Cl, 17.86; N, 7.02 The product was identified as N-(2,6-dimethyl-1-cyclohexen-l-yl)-2-chloroacetamide.
(b) A mixture of 400 g. of the sec-amide produced above in 760 ml methylene chloride and 300 ml chloromethyl methyl ether were mixed with 2 g. benzyl triethyl ammonium bromide. ~he mixture was cooled to 10~ then added in a thin stream over 0.5 hour to a vigorously stirred mixture of 1100 ml of 50% sodium hydroxide, 300 ml methylene chloride and 9 g. benzyl triethyl ammonium bromide contained in a 5-liter 4-necked round bottomed flask. Exterior cooling with an ice/acetone bath was necessary to maintain the temperature under 25C. The mixture was stirred for an additional one hour. GLC showed 78% tertiary amide produced and 22% of corresponding O-alkylated by-product, O-(methoxymethyl)-N-(2,6-dimethyl-1-cyclohexen-1-yl)-2-chloroacetimidate. The reaction mixture was separated, and the organic layer given a simple wash with 5% HCl solution to convert the imidate to starting secondary amide. To the washed mixture in methylene chloride was added an additional 120 ml of chloromethyl methyl ether and 5.0 g of the quaternary ammonium phase-transfer catalyst, followed by 350 ml of 50% NaO~ with stirring.
After separation of layers and additional water washing, the product was filtered through clay; methylene chloride solvent was evaporated and the residue heated to 85C (0.55 mm), then filtered through clay to purify the product. The product was recovered in about 99% yield and had a boiling point of

7 7 ~Z

127 (0.15 mm).
Calc'd for C12H20ClNO2 (percent): C, 5~.65; H, 8.20; N, 5.70;
Found: C, 58.48; H, 8.22; N, 5.62.
The product was identified as N-(2,6-dimethyl-1-cyclohexen-S l-yl)-N-(methoxymethyl)-2-chloroacetamide.
The above process in Part (b) may be performed with-out imidate formation thus obviating acid-catalyzed reforma-tion of sec-amide when lesser quantities, i.e., up to 50 g. of the sec-amide are used, the catalyst concentration is in-creased up to 20-50~ of the amount of sec-amide used and the base, NaOH, is added all at once.
Structure proof of the products obtained in this and ,;
the following examples was afforded by mass spectroscopy, gas liquid chromatography, nuclear magnetic resonance and elemental analysis.
Example 2 In this example, a different alkylating agent is used to alkylate the anion of a sec-amide.
Ten (10) grams (0.05 mol) of N-(2,6-dimethyl-1-~yclohexen-1-yl)-2-chloroacetamide, 16 g of chloroacetonitrile, 2 g of benzyl triethyl ammonium bromide and 200 ml of methyl-ene dichloride (C~2C12) were charged to a 500 ml 4-neck flask and cooled to 10C. To this mixture was added all at once about 100 ml of 50% aqueous NaOH and allowed to exotherm to 30C, then stirred over~ight. Water was added and the mixture filtered through clay. The CH2C12 layer was separated, dried over MgSO4 and filtered. GLC analysis showed 29% starting amide and 71% alkylated tertiary amide product. Evaporation left a black oily material which was passed through 115 g Florsil with chloroform; evaporation of the latter left 9.9 g of light yellow oil which was filtered through silica gel (150 g) with a 3:2 hexane/ether mixture. Evaporation of the solvent left 6 g light yellow oil which was disti~led to give 5.1 g of light yellow oil, b.p. 150C at 0.05 mm; this oil solidified iil the bottle. Yield 42%.

Calc d for C12H17ClN2ol (percent): C, 59.84; H, 7.14; N 11 65 Found: C, 59.87; H, 7.12; N, 11.64 The product was identified as N-(2,6-dimethyl-1-cyclohexen-l-yl)-N-(cyanomethyl)-2-chloroacetamide.
Example 3 In this example, the sec-amide anion was alkylated with O-~chloromethyl) pivalate.
Ten (10) grams (0.25 mol) of N-~2,6-dimethyl-1-cyclohexen-l-yl)-2-chloroacetamide, lS g pivaloyloxymethyl-chloride, 2,0 ml of CH2C12 were charged to a 500 ml flask.About 100 ml of 50% NaOH was added all at once with good stirring, with exotherm to 32C. After stirring 5 hours the contents clouded and salt precipitated. Water was added to dissolve the salt and the layers separated. The organic CH2C12 layer was dried over MgSO4, filtered and solvent re-moved, in vacuo, leaving an amber oil. After filtering through silica gel with 3:2 hexane/ether and evaporation of solvent, an oil was obtained which upon distillation gave 2.1 g of product having b.p. 140 at 0.0~ mm. Yield 13%.
Calc d for C16H26ClNO3 (Percent): C, 60.85; H, 8 30; N 4 43 Found: C, 60.73; H, 8.33; N, 4.42 The product was identified as N-(2,6-dimethyl-1-cyclohexen-1-yl)-N-(pivaloyloxymethyl)-2-chloroacetamide.
Example 4 Following generally the same procedure described in the preceding example, but substituting 3-(chloromerhyl)-2-benzothiazolinone as the alkylating agent, 2.9 g of product m.p. 142-144C. Yield 40%.
Calc'd for ClgH21ClN2O2S ~Percent): C, 59.25; H, 5-80; N, 7-69 Found: C, 59.11; H, 5.82; ~, 7.69 The product was identified as N-(2,6-dimethyl-1-cyclohexen-l-yl)-N-[3-(2-benzothiazolinone) methyl]-2-chloroacetamide.
Example 5 The above procedure was followed in general, but using N-~bromomethyl)phthalimide as the al~ylating agent. A
-7~2 ~ AG-1298 white solid, m.p. 167-169C, was recovered in an amount of 2.0 g. Yield 22~.
Calc'd for ClgH21ClN2O3 (percent): C, 63.24; H, 5.87; N, 7.76 Found: C, 62.70; H, 5.83; N, 7.71 S The product was identified as N-(phthalimidomethyl)-N-(2,6-dimethyl-l-cyclohexen-l-yl)-2-chloroacetamide.
Example 6 The general procedure above was followed, but using acrylonitrile as the alkylating agent. Four and one-half (4.5) grams of light yellow oil product was obtained, b.p.
169-173C at 0.05 mm. Yield 35%.
Calc'd for C13HlgClN2O (percent): C, 61.29: H, 7.52; N, 11.00 Found: C, 61.97; H, 7.60; N, 11.26 The product was identified as N-(2-cyanoethyl)-N-(2,6-dimethyl-1-cyclohexen-1-yl)-2-chloracetamide.
Example 7 In this example, the 2-halo sec-amide anion is alkylated with ethyl bromoacetate to produce the corresponding tertiary 2-halo acetamide.
N-(2,6-dimethylcyclohexen-1-yl)-2-chloroacetamide, 4.03 gm9 (0.02 mol) and 3.34 gms (0.02 mol) of ethyl bromo-acetate, together with 2.0 gms of triethyl benzyl ammonium chloride, were dissolved in 100 ml CH2C12 and the temperature lowered in an ice/acetone bath. Fifty (50) ml of 50% NaOH
were then added all at once. After about 5 minutes the re-action was indicated by GLC to be 90% completed. Ice water was added and the layers separated. The organic layer was washed with 2.5% NaCl, dried, filtered and stripped; at 'his stage the reaction was 95% completed. The mixture was allowed to stand at room temperature for about two days, but did not crystalize. iThe mixture was distilled to give a main fraction, b.p. 150C at 0.1 mm ~g. The product, 3.6 gms of a clear yellow oil, was obtained in 63% ~ield.
Calc'd for C14H22ClNO3 (~): C, 58.43; H, 7.71; N, 4.87 Found: C, 58.19; H, 7.71; N, 4.86 ~ ', 7 ~2 The product was identified as N-(l-ethoxycarbonylmethyl)-N-(2,6-dimethyl-1-cyclohexen-l~yl) 2-chloroacetamide.
Examples 1-7 have exemplified embodiments of the process of this invention to prepare tertiary 2-haloacetamides substituted on the amide nitrogen atom with an N-(l-cyclo-hexen-l-yl) and another radical. In Ex~mples 8 et seq., em-bodiments of this process will be described for the prepar-ation of 2-haloacetanilide compounds substituted with various radicals on the amide nitrogen atom.
Example 8 This example describes the preparation of an N,2'6'-trimethyl substituted acetanilide from the corresponding sec-amide anion formed by use of a solid base dissolved in a solvent, which anion is then alkylated with an ester o~ p-toluene 9ul fonic ~cid.
Two (2) gms (0.01 mol) of N-(2,6-dimethyl)-2-chloro-acetanilide, 3.7 gms (0.02) of methyl p-toluenesUl~Q~te and 2.26 gms (0.02) of potassium carbonate (K2CO3) were mixed in about 25 ml of dimethylformamide and stirred at room temp-erature until the reaction was complete as indicated by glc.After 16.5 hours, the product was recovered as a colorless solid, m.p. 61-62C, in 58% yield.
Calc'd for CllHl4clwo (%): C, 62.4; H, 6.7; Cl, 16.8 Found: C, 62.6; H, 6.8; Cl, 16.6 The product was identified as N-methyl-N-(2',6'-dimethyl)-2-chloracetanilide.
Example 9 This example describes the use of dimethyl sulfate as the alkylating agent to prepare an N-al~yl-2-chloroace-tanilide from the corresponding sec-amide anion.
2'-n-butoxy-6'-methyl-2-chloracetanilide, 4.9 gms (0.02 mol), dimethyl sulfate, 2.6 gms (0.02 mol) and 2.0 gms of triethyl benzyl ammonium bromide were mixed in 250 ml of CH2C12 under cooling. Fifty ~50) ml of 50% NaOH were then added all at once at 15C and the mixture stirred for two hours. Water (100 ml) was added and the resultant layers ; separated. The organic layer was washed with water, dried over MgSO4 and evaporated by Kugelrohr. A clear liquid, b.p.

'7~

135C at 0.07 mm Hg was obtained in 78% yield (4~2 gms) and recrystallized upon standin~ to a colorless solid, m.p. 41-42.5C.
Calc d for C14H20ClN2 (~); C, 62.33; H, 7.47; Cl, 13.14 Foundi C, ~2.34; H, 7.49; Cl, 13.16 The product was identified as 2'-n-butoxy-6'-methyl-N-methyl-2-chloroacetanilide Example 10 This example describes the preparation of an N-al~yl-2-haloacetanilide using an alkenyl halide as the alkylating agent.
2'-methoxy-6'-methyl-2-chloracetanilide, 4.7 gms t0.022 mol), 5.25 gms (0.044 mol) of 3-bromopropene and 2.0 gms of triethyl benzyl ammonium bromide were mixed in 2S0 ml of CH2C12 under cooling to 0C. Fifty ~50) ml of 50% NaOH
were added all at once maintaining the temperature below 15C
and stirred for 4.5 hours. Cold water (100 ml) was added and the layers separated. The organic layer was washed with water, dried over MgSO4 and evaporated to leave a beige-colored solid product, m.p. 94.5-96C.
20 Calc~d for C13H16ClNO2 (%): C, 61.54; H, 6-36; Cl, 13-97 Found: C, 61.66; H, 6.38; Cl, 13.24 The product was identified as 2'-methoxy-6'-methyl-N-allyl-2-chloroacetanilide.
Example 11 Following the same general procedure described in Example 10, but substituting 2,3-dichloropropene, 5.6 gms (0.05 mol),as the alkylating agent for the anion of 2'-methoxy-6'-methyl-2-chloracetanilide, 5.3 gms (0.025 mol), 2.0 gm (27.8~ yield) of an amber oil, b.p. 136C at 0.03 mm Hg (Xugelrohr), was obtained.
- Calc'd for C13HlsC12NO2 (~): C, 54.18; H, 5.25; Cl, 24.61 Found: C, 54.36; H, 5.30: Cl, 24.45 The product was identified as 2'-methoxy-6'-methyl-N-(2-chlorallyl)-2-chloroacetanilide.
Example 12 2 t -methyl-6'-methoxy-2 chloroacetanilide ~4.3 g, 0.02 mol), propargyl bromide (4.8 g., 0.04 mol), 2.0 g benzyl triethyl ammonium bromide and 50 ml CH2C12 were mixed in a 500 ml 4-neck flask. 20 ml of 50% a~ueous NaOH is added with 7'f ~Z

stirring and cooling at 20C~ The mixture was stirred for 7 ho~rs, water added and the formed organic layer separated and washed with a saturated NaCl solution, then dried over MgSO4 and the CH2C12 evaporated. The residual solid was crystal-lized from methanol and filtered to give 4.9 g of crystallineprisms m.p. 124-126C. Yield 97.3~.
Calc'd for C13H14ClNO2 (%): C, 62.03; H, 5.61; N, 5.56;
Cl, 14.08 Found: C, 61.99; H, 5.65; N, 5.54;
Cl, 14.10 The product was identified as 2'-methyl-6'-methoxy-N-(pro-pargyl)-2-chloroacetanilide.
Example 13 2-chloro-2',6'-diethylacetanilide (11.2 g, 0.05 mol) is dissolved in 200 ml methylene chloride with 3 g triethyl benzyl ammonium bromide and 10 ml chloromethyl methyl ether.
To the rapidly-stirred solution at room temperature is added all at once, 70 ml 50~ aqueous sodium hydroxide, with exterior cooling to prevent reaction temperatures exceeding 32C.
After addition, the mixture is stirred for ninety minutes, then a mixture of ice and water (ca 300 ml) added. The layers are separated, and the organic phase washed once again with 300 ml water. The methylene chloride is removed under vacuum to leave 13.1 g (97.4~ yield) of oily residue as product, assaying by glc at 92.4~. Eight grams of this material was distilled under vacuum (b.p. 120-130C at 0.05 mm) to give 7.9 g near colorless oil, assay 92.5% 2-chloro-N-(methoxy-methyl)-2',6'-diethylacetanilide (alachlor).
; Calc'd for C14H20clNo2 (~): C, 62.33; H, 7.47; Cl, 13.31;
N, 5.19 Found: C, 62.20; H, 7.50; Cl, 13.31;
N, 5.19 ~477~

,, - Example 14 The process of Example 13 was repeated, but using 2'-tert-butyl-2-chloroacetanilide as the sec-amide. The residual oil remaining after evaporation of the ~olvent solidified on standing to give 5.8 g of product m.p. 68-70~C.
The product was identified as 2'-tert-butyl-N-(methoxymethyl)-2-chloroacetanilide.
Example 15 Following the above procedure, but using 2'-(methoxy-methyl)-2-chloroacetanilide as the sec-amide starting material and chloromethyl methyl ether as the alkylating agent, the product 2'-(methoxymethyl)-N-(methoxymethyl)-2-chloroacetanilide was obtained.
Example 16 2',6'-Dimethyl-2-chloroacetanilide (1.0 g, 5.1 mmol), dimethylsulfate 11.33 g, 10.6 mmol), potassium fluoride (0.58 g, 10.0 mmol) and "18-crown-6" cyclic ether (0.26 g, 1.0 mmol) were magnetically stirred in 20 ml acetonitrile at room temperature for 15 hours.
Acetonitrile was removed under reduced pres~ure.
The residue was treated with ethyl ether and water. Ether layer was washed again with water and saturated sodium chloride, dried ovsr magnesium sulfate and ether removed under reduced pressure leaving white solid.
Nmr and glc analysis indicates 15% conver~ion to 2',6'-dimethyl-N-(methyl)-2-chloroacetanilide.
Example 17 2',6'-Dinitro-2-chloroacetanilide (2.4 g, 0.009 mol), 150 ml CH2C12, 1.1 g benzyl triethyl ammonium bromide and 3 ml chloromethyl propyl ether were first mixed, then 100 ml of saturated Na2CO3 added. On work-up, a dark oil wa~ obtained and eluted through Florsil with CH2C12 to give 3.1 g of a ye}low oil.
Calc'd for C12H14ClN3O~ C, 43.4~; H, 4.25; N, 12.67 Found; C, 43.41; H, 4.29; N, 12.20 The product was identified as 2~,6'-dinitro-N-In-propoxymethyl)-2-chloroacetanilide, ~7'7~:

Example 18 In this example, 2'-methyl-6'-nitro-2-chloro-acetanilide wa~ used as the sec-amide and chloromethyl ethyl ether as the alkylating agent and 509~ NaOH as the base. The 5 product was 3.5 g of a white solid m.p. 96-98C, identified aR 2'-methyl-6'-nitro-N-(ethoxymethyl)-2-chloroacetanilide.
Example 19 The procedure described in Example 1 was repeated, but ~Ising 2',6'-dimethoxy-2-chloroacetanilide as the sec-amide.
10 After work-up as before and evaporation of the solvent, 12.9 g of white solid was obtained which was recrystallized in isopropanol to give 11.8 g of white crystals, m.p. 104-106C, in 909e~ yield.
Calc~d for C12H16ClNo4 (%): C, 52.66; EI, s.as; N, 5.12 Found: C, 52.58; H, 5.99; ~7, 5.10 The product was identified as 2',6'-dimethoxy-N-(methoxymethyl)-2-chloroacetani}ide.
Example 20 2,2',6'-trichloroacetanilide (7 g, 0.029 1), 20 chloromethyl ethyl ether (5.5 g, 0.058 mol), benzyl triethy1 ammonium bromide (1.5 g) and 100 ml CH2C12 were charged to a 250 flask. 32 ml of 50% NaOH was added all at once, with exotherm to 36C and stirred for ~.S hour. Water was added and after washing the C~I2C12 layer separated, dried over 25 IqgS04, filtered and the solvent evaporated in vacuo leaving a white solid which was recrystallized from hexane to give 5.6 g of white solid, m.p. 80-83C. Yield 65%.
Calc'd for CllH12C13N2 (9~): C, 44.56; H, 4.08; N, 4.72;
Found: C, 44.56; H, 4.11; ~, 4.73 30 The product was identified as 2',6'-dichloro~ (ethoxymethyl)-2-chloroacetanilide.
Example 21 Following the above general procedure, 2 ~, 3l,4l,5l, 6'-pentafluoroacetanilide was alkylated with chloromethyl 35 methyl ether to obtain 3.4 g of a light yellow oi}, b.p.
123-125C at 0.05 mm; yield 56%.

77'~
-1~- AG-1298 Calc'd for CllHgClFsNO2 (%); C, 41.59; H, 2.86; N, 4.41 Found: C, 41.81; H, 2.71; N, 4.41 The product was identified as 2',3',4',5',6'-pentafluoro-N-(ethoxymethyl~-2-chloroacetanilide.
Example 22 This example illustrates the preparation of a tertiary N-heterocyclic-2-haloacetamide from the sec-amide anion there-of.
Two ~2.0) g of N-furfuryl-2-chloroacetamide were dis-10 solved in benzene with 2 ml chloromethyl methyl ether in 150 ml of C~2C12 and O.4 g benzyl triethyl ammonium bromide. Then 3 g of powdered NaOH were added. The mixture was stirred for ca 2 hours, allowed to settle, and the organic solution decanted, then washed with water. O~ evaporation, the residue 15 was distilled and 1.3 g of product recovered, b.p. 130-150C
at 0.3 mm; yield 52~.
Calc'd for CgH12ClNO3 (%): C, 49.67; H, 5.56; N, 6.44 Found: C, 49.10; H, 5.45; N, 6.18 The product was identified as N-(methoxymethyl)-N-(furfuryl)-20 2-chloroacetanilide.
Example 23 In this example, a tertia~y-2-haloacetamide having N-substituted alkenyl and alkoxyalkyl radicals is prepared using a halomethyl al~yl ether as the al~ylating agent.
Three (3) g of N-(3-methyl-2-buten-2-yl)-2-chloro-acetamide, 3 ml of chloromethyl ethyl ether and 1.5 gm of triethyl benzyl ammonium chloride were mixed in 100 ml of C~2Cl~ and cooled to 10C. Forty (40) ml of 50% NaOH were added all at once, and the temperature permitted to rise to 30 room temperature, i.e., 10-25C, with stirring. After 30-45 minutes, glc indicated that imidate was present together with the desired tert-amide. The mixture was then treated with HCl to regenerate the ~o~e sec-amide and recycled with ; reduced charge of reactants, i.e., 1.5 ml of chloromethyl 35 ethyl ether, 20 ml caustic soda and 1.0 gm of triethyl benzyl ammonium chloride. On workup (Kugelrohr) 2.7 gm of near colorless oil, b.p. 85-120~C at (0.06 mm ~g) having good glc assay was obtained.

'7'f'~

Calc'd for CloHlgClNO2 (~); C, 54.67; H, 8.26; N, 6.38 Fo~nd: C, 54.41; H, 8.45; N, 6.13 The product was identified as N-(3-methyl-2-buten-2-yl)-N-(ethoxymethyl)-2-chloroacetamide.
Example 24 Following essentially the same procedure in Example 23, but su~stituting 3.0 gm (0.0185 mol) of N~3-methyl-2-buten-2-yl)-2-chloroacetamide as the sec-amide and 3.3 gm (0.028 mol) of propargyl bromide as the alkylating agent, 2.15 gm (60% yield) of yellow oil, b.p. 109C at 0.8 nm Hg (Kugelrohr) was obtained.
Calc'd for CloH14ClNO (~): C, 60.15; H, 7.07; Cl, 17.75 Found: C, 59.96; H, 7.12; Cl, 17.69 The product was identified as N-(3-methyl-2-buten-2-yl)-N-2-propynyl-2-chloroacetanide Example 25 This example illustrates the use of the present pro-cess to prepare 2-haloacetamides substituted with multiple aliphatic groups on the amide nitrogen atom.
2-Chloroacetamide (4.0 g, 0.042 mol), chloromethyl isobutyl ether (11.0 g, 0.094 mol), benzyl triethyl ammonium chloride (0.6 g) and 100 ml CH2C12 were charged to a 500 ml flask with stirrer. 40 g 50% aqueous NaOH was added all at once, with exotherm to S2C. After stirring for 0.5 hour, water was added and after separation of layers, the CH2C12 wa. removed, dried over MgSO4, filtered and solvent removed in vacuo. The residue was taken up in ether and washed with water. The ether layer was dried over MgSO4, filtered and solvent removed in vacuo. The residue was vac~lum distilled to give 1.0 g of product, 'o.p. 138-140C at 0.05 mm; yield 9.0~..
Calc'd for C12H24ClNO3 (~): C, 54.23; H, 9.10; N, 5.27 Found: C, 54.03; H, 9.09; N, 5.22 l~he product was identified as N,N-bis (isobutoxymethyl)-2-chloroacetamide.

.~ ., l~t~742 Example 26 This example illustrates embodiment C of the inven-tion utilizing a metal hydride as the sec-amide anion genera-tor to produce the same t-amide product produced in Example 1.
Potassium hydride (KH) (0.056 mol, 10.2 g.) in mineral oil was washed 3 times with petroleum ether; after each wash most of the solvent was removed through a flexible needle under nitrogen pressure. N-(2,6-dimethyl-1-cyclohexen-l-yl)-2-chloroacetamide (0.05 mol, 11.3 g) in 300 ml ether was added dropwise rapidly with stirring over 0.5 hour, with the theory hydrogen evolved measured by a wet test meter.
Freshly-distilled chloromethyl methyl ether (0.18 mol, 15 g) in 200 ml ether was added dropwise and stirred for 50 minutes to insure full precipitation of potassium chloride. Wet ether added cautiously. When all excess KH had reacted, 300 ml of water were added. The ether -~as extracted, dried over MgSO4, filtered and removed under vacuum leaving 6.3 g of oil which was vacuum distilled to give 4.2 g of oil, b.p. 127C
(0.15 mm).
Example 27 Following the same general procedure described in Example 26, but substituting chloromethyl methyl thioether (ClC~2SCH3) as the alkylating agent, an oil was obtained in 11% yield.
Calc'd for C12H20ClNOS (%): C, 55.05; H, 7.70; N, 5.35;
Found: C, 54.88; H, 7.75; N, 5.29.
The product was identified as N-(methylthiomethyl)-N-(2,6-dimethyl-l-cyclohexen-l-yl)-2-chloroacetamide.
In 8 imilar manner, when chloromethyl phenyl thio-ether is used as the alkylating agent, one obtains the corresponding tertiary amide, N-(phenylthiomethyl)-N-(2,6-dimethyl-l-cyclohexen-l-yl)-2-chloroacetamide, Example 28 Following the procedure of the preceding example, 0.05 mol of 2'6'diethyl-2-chloroacetanilide was reacted with potassium hydride in diethyl ether. The reaction was slow, hence, an ether solution of the anilide, X~ and ClCH2SCH3 was 1~ 7~ `

stirred overnight. After completion of the reaction, a water and sodium bicarbonate solution was added. Upon work-up, 4.2 g (29% yield) of product, m.p. 42-4~, was obtained.
Calc'd for Cl4H2oClNOS (%): C, 58.83; H, 7~05; N, 4.90;
Found: C, 58.95; H, 7.09; N, 4.87.
The product was identified as N-(methylthiomethyl)-2'6'-diethyl-2-chloroacetanilide.
In s~milar manner, whe~ chloromethyl phenyl thio-ether i9 used as the al~ylating agent, one obtains the corresponding tertiary amide, N-(phenylthiomethyl)-2-chloro-2',6'-diethyl acetanilide.
Example 29 In similar manner as described in Example 26, 8.0 gm9 of (0.04 mol) of 20% KH was reacted with 4.03 gm (0.02 mol) of N-(2,6-dimethyl-l-cyclohexen-l-yl)-2-chloracetamide in diethyl ether solvent to generate the amide anion of the amide, which was then reacted with 6.68 gms (0.04 mol) of methyl 2-bromopropionate. On workup, a white solid, m.p.
~5-95C representing amixture of diasteromers was obtained in 38% yield.
Calc'd for Cl4H22ClNO3 (%): C, 58.43; H, 7.71; N, 4.87 Found: C, 58.42; H, 7.75; N, 4.93 The product was identified as N-(l-methoxycarbonyl-l-ethyl)-N-(2,6-dimethyl-l-cyclohexen-1-yl)-2-chloroacetamide.
ExamPle 30 Following the general procedure described in Example 26, but substituting ethyl 2-bromopropionate as the alkylating agent, a white solid, m.p. 50-60C, representing a mixture of diastereomers, was obtained in 28% yield.
Calc'd for ClsH2~ClNO3 (~): C, 59.69; H, 8.02; N, 4.64 Found: C, 59.85; H, 8.06; N, 4.62 The product was identified as N-(l-ethox~carbonyl-l-ethyl)-N-(2,6-dimethyl-l-cyclohexen-l-yl)-2-chloroacetamide.
ExamPle 31 In this example 2'6'-dimethyl-2-chloroacetanilide (0.05 mol) was dissolved in tetrahydrofuran (T~F) and reacted with ~H, the reaction in this solvent was ~uite rapid.
CH3SCH2Cl was then added as above and stirred for about two hours at 35-40C. The product was washed with NaHCO3 and 717~

identified as N-(methylthiomethyl)e2',6'-dimethyl-2-chloro-acetanilide.
Example 32 Potassium hydride (0.056 mol) in petroleum ether and N-(2,6-dimethyl-1-cyclohexen-l-yl)-2-chloroacetamide (0.05 mol) dissolved in 300 ml of ether were mixed and re-1uxed at 30 with evolution of about 2-2.5 1 of gas 0.085 lol of freshly prepared l-chloroethyl methyl ether (CH3-CHOCH3) was ad~ed with stirring (strong exo~nerm) over a 15 minute period with precipitation of a white solid. On workup, a solid was obtained in 23% yield, m.p. 76-79C.
Calc'd for Cl3H22ClNO2 (%): C, 60.11; H, 8.54; N, 5.39;
Found: C, 59.96; H, 8.57; N, 5.44.
The product was identified as N-(l-methoxy-l-ethyl)-N-(2,6-dimethyl-1-cyclohexen-1-yl)-2-chloroacetamide.
Example 33 The same general procedure of Example 32 was follow-ed, except here the sec-amide, 2'-methyl-6'-ethyl-2-chloro-acetanilide, 21.1 g (0.1 mol), was solubilized with a small amount of T~F in 400-500 ml diethyl ether. Reaction went well, but gasevolved when chloroethyl methyl ether was added. However, at final addition (about 2.5 x theory) the added ether didn't react although some KH was still present.
Upon workup, the product, N-(l-methoxy-l-ethyl)-2'-methyl-6'-ethyl-2-chloroacetanilide, was obtained in 86% yield, b.p.
130C at`0.05 mm ~g.
Calc'd for C14H20clNo2 (%): C, 62.33; H, 7.47; N, ~.19;
Found: C, 62.37; H, 7.47; N, 5.19.
Example 34 Following the procedure of Example 33 except uRing the sec-amide 2'6'diethyl-2-chloroacetanilide, the corres-ponding tertiary amide, N-(l-methoxy-l-ethyl)-2',6'-diethyl-2-chloroacetanilide, was prepared. The product,b.p. 153/
0.05,was obtained in 41% yield.
Calc'd for Cl5E22ClNO2 (%): C, 63.48; H, 7.81; N, 4.94;
Found: C, 63.46; H, 7.84; N, 4.91.

77~

Example 35 Twenty (20) ml of 20-25% KH slurry (ca. 0.05 mol) washed 4 times with ca 3Q0 ml petroleum ether each time. Last was permitted to stand overnight, then diethyl ether added, S stirring started and 10 g of N-(2,6-dimethyl-1-cyclohexen-1-yl)-2-chloroacetamide dissolved in 400 ml ether added thereto with continued stirring. Hydrogen allowed to exit through wet test meter (1.5 1 evolved); then 10 g. (0.072 mol) 2-bromoethylmethyl ether was added. Mixture refluxed for 4 hours, then stirred overnight at room temperature. Upon work-up 3.5 g distilled yield was obtained; b.p. 160-190/
0.04 mm.
Calc'd for C13H22ClNO2 (%): N, 5.39; Cl, 13.65 Found: ~, 5.71; Cl, 13.95 Product verified by GLC was identified as N-(2-methoxyethyl)-N-(2,6-dimethyl-1-cyclohexen-1-yl)-2-chloroacetanilide.
Example 36 This example illustrates sec-amide anion formation by direct electrochemical reduction and alkylation of the anion (Embodiment D).
The electrolyses were performed in an all-glass ~-cell of conventional design with a medium porosity sintered glass frit separating the anode and cathode compartments.
The volume of the cathode compartment was approximately 70 ml and that of the anode compartment was approximately 30 ml.
The cathode was a 45-mesh platinum gauze rectangle with a geometrical area of approximately 12 cm2. The anode was a graphite rod with a diameter of ~ mm. IA silver wire reference electrode extended into the cathode compartment and was contained and separated from the catholyte by a fritted compartment.
The solvent may be acetonitrile, N,N-dimethylforma-mide or other aprotic dipolar solvents suitable for electro-chemical reductions which contain a sufficient concentratîon of a supporting electrolyte salt to render it sufficiently conducting. The supporting electrolytes include, but are not limited to, alkali metal perchlorates, fluoborates and 7'~

halides and tetraalkylammonium perchlorates, fluoborates and halides.
The solvent-supporting electrolyte mixture was charged into both the cathode and anode compartments, and the catholyte was purged with an inert gas such as nitrogen or argon to remove dissolved oxygen. To the catholyte was added the secondary ~-chloroacetamide and the electrolysis was initiated. The electrolysis was carried out in a con-trolled potential mode using a Princeton Applied Research Model 173 potentiostat. The cathode potential relative to the silver reference electrode was maintained sufficiently negative to reduce the amide, as evidenced by hydrogen evolution at the cathode. Upon completion of the electroly-sis, a chloromethyl alkyl ether was added to alkylate the amide anion generated during the electrolysis. The chloro-methyl ether may not ~e present in significant concentrations during the electrolysis since it is reduced in preference to ; the amide. In cases where alkylation of the amide anion by neutral ~-chloroacetamide is a problem, the yield o' desired product may be improved by adding the al~ylating agent during the electrolysis in proportion to the amount of current passed.
As a specific example, 0.40 gram of N-(2,6-dimethyl-l-cyclohexen-l-yl)-2-chloroacetamide (the product of Example l(a)) was electrolyzed in acetonitrile which was 0.1 M in sodium perchlorate. The cathode potential was maintained at -2.0 V vs. the Ag reference electrode. After passing 193 coulombs, 0.21 g. of chloromethyl ethyl ether was added to the catholyte and allowed to stir for one-half (1/2) hour.
The catholyte was separated, and most of the aceto-nitrile was removed under reduced pressure. Water was addedto the residue, and the aqueous solution was extracted with 150 ml of e*hyl ether. The ether solution was washed with water and saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The mixture was filtered and ether was removed from the filtrate under reduced pressure to yield a clear oil. Gas chromatographic analysis of the reaction mixture indicates 16% secondary amide, 36.5% desired tertiary amide, N-(2',6'-dimethyl-1-cyclohexen-1-yl)-N-f'7~

(ethoxymethyl)-2-chloroacetamide! and 44% N! N'-bis(2,6-dimethyl-l-cyclohexenyl! piperazine-2,5-dione, the product resulting from self-alkylation. Optimization of this pro-cedure would increase yield of tert-amide product and decrease undesired by-products.
Examples 37-176 Following the same general processes described in Examples 1-36, but substituting the appropriate starting materials and reaction conditions, other exemplary tertiary 2-haloacetamide compounds according to Formula I above are prepared from the corresponding sec-amide and the same or equivalent anion generators, alkylating agents, solvents and/or phase-transfer catalysts. Typical of such compounds which are prepared according to the process of this invention are ~hown in the following table together with certain of their physical properties.

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The process according to this invention is of wide applicability as indicated in the preparation of the com-pounds in the above examples. Still further, the process of this invention may be suitabLy used to prepare a variety of other tertiary 2-haloacetamides from the anion of primary or sec-amides thereof. For example, the present ~rocess may be used ~o prepare know~ ~
N-(alkoxyalkyl)-N-(l-alken-l-yl)-Z-haloacetamides such as N-(methoxyethyl)-~-(l-isopropyl-2-methyl-1-propen-1-yl)-2-chloroacetamide; N-(methoxyethyl)-N-(l-isopropyl-l-propen-l-yl)-2-chlor~oacetamide; N-(methoxyethyl)-N~ methylpropen l-yl)-2-chloroacetamide; N-(methoxyethyl)-N-(l-ethylbuten-l-yl)-2-chloroacetamide; N-(methoxyethyl)-N-(l-isopropyl-vinyl)-2-chloroacetamide and N-(methoxyethyl~-N-(l-n-propyl-propen-l-yl)-2-chloroacetamide. The process of the present in~ention also permits the production of novel N-(alkoxy-methyl)-N-(l-alken-l-yl)-2-haloacetamides for the first time, as well as the above N-(C2-c6-alkoxyethyl)-haloacetamides.
Exemplary of such N-(al~oxymethyl) acetamide compounds (in addition to those shown in Examples 23, 149, 150 and 151 of Table I) are the methoxymethyl, ethoxymethyl, n- and iso-propoxymethyl and n-, iso- and t-butoxymethyl and pentoxymethyl homologs of the above alkoxyethyl compounds and other homologs having still other alkenyl radicals attached to the N atom;
said alkenyl radicals can be substituted with alkyl, cyclo-alkyl, alkenyl, a~c~nyl, aryl, aralkyl or heterocyclic radicals. Similarly, the process oi the present invention i9 amenable to the preparation of novel N-(alkoxymethyl)-N-(l-cycloalken-l-yl)-2-haloacetamides for the first time, as .~
.~

1~4~'7'~2 well as the N-(C2-C8-alkoxyalkyl)-N-(l-cycloalken-l-yl)-; 2-haloacetamides of the prior art.
In like manner the process of this invention may also be used to prepare N-heterocyclylmethyl-2-haloacetani-lides such as N-~2,4-dioxothiazolidin-3-ylmethyl)-2-haloacet-anilides, exemplified specifically by 2-chloro-N-(2,4-dioxo-thiazolidin-3-ylmethyl)-N-(2-methylphenyl) acetanilide and 2-chloro-N-(2,4-dioxothiazolidin-3-ylmethyl)-N-(2-methoxy-phenyl) acetanilide.
Within the carbon atom chain length limitations defined above for the various R members, i.e., R-R7, in-clusive, in Formulae I-IV, representative groups include as alkyls, methyl, ethyl, the various isomeric forms of propyls, butyls, pentyls, hexyls, heptyls, octyls, nonyls, 15 aecyls, undecyls, dodecyls, tridecyls~pentadecyls~ octa-decyls, etc., as alkenyls, e.g., vinyl, allyl, crotyl, ; methallyl, butenyls,~entenyls, hexenyls, heptenyls, octenyls, nonenyls, decenyls, etc., as alkynyls, e.g., ethynyl, prop-ynyls, butynyls, pentynyls, hexynyls, etc; the alkoxy, polyalkoxy, alkoxyalkyl and polyalkoxylalkyl analogs of the foregoing alkyl groups; cycloalkyls and cycloalkylalkyls having up to 7 cyclic carbons, e.g., cyclopropyl, cyclo-butyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropyl-methyl, cyclobutylmethyl, cyclopentylmethyl, etc.; cyclo-alkenyls and cycloalkadienyls having up to 7 cyclic carbons,e.g., cyclopentenes, cyclohexenes and cycloheptenes having mono- and di-unsaturation; C6_10 aryl and aralkyl and alkaryl groupa, e.g., phenyl, tolyls, xylyls, benzyl, naphthyl, etc., and said R members substituted with radicals which are non-reactive under reaction conditions, e.g., hydrogen, other R members, cyano, nitro, amino, trifluoro-methyl, alkylthio, etc. Preferred aliphatic members are those having up to 12 carbon atoms.
. .

'7~4~

The X member in Formulae I and II above comprises the halogen members chlorine, bromine and iodine, whereas the xl member comprises chlorine, bromine, iodine or a halogen equivalent derived from alkylating agents exemplified hereinabove.
The process of this invention is particularly amenable to the production of the subgenera o~ 2-haloaceta-mides described above as of particular interest.
Although many of the compounds defined by Formula I above are known compounds, certain of the 2-haloacetamides described herein are novel compounds and separately claimed by other inventors employed by the assignee herein.
It will be appreciated by those skilled in the art that the procsss of this invention may be modified in a lS manner within the skill of this art as to nature and concen-tration of reactants, reaction and separation conditions of temperature, pressure, residence times, etc., to produce other species of compounds not specifically named herein, but within the generic scope of this invention and its obvious equivalents.

Claims (86)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows

1. Process for the preparation of 2-haloacet-amides of Formula I

which comprises reacting an anion of a compound of Formula II

II with a compound of Formula III

or a (1,4-) Michael addition reagent wherein in the above formulae:
X is chlorine, bromine or iodine;
X1 is chlorine, bromine, iodine or a halogen equivalent;
R is hydrogen, C1-18 alkyl, C2-18 alkenyl, alkynyl or alkoxyalkyl, polyalkoxyalkyl C3-7 cycloalkyl or cycloalkylalkyl, C5-7 cycloalkenyl or cycloalkadienyl which may be substituted with C1-6 alkyl groups; or a radical of the formula IV wherein a is 0-2 inclusive;
b and n are 0 or 1;
m is 0-3 inclusive when R2 and R3 are other than hydrogen and 0-5 otherwise.
R2, R3, R4 and R5 are independently hydrogen, C1-6 alkyl, alkoxy, polyalkoxy or alkoxyalkyl, C2-6 alkenyl, alkenyloxy, alkynyl or alkynyloxy, C6-10 aryl, aryloxy, aralkyl or aralkyloxy, NO2, halogen, CF3, (CH3)3-Si-, saturated or unsaturated heterocyclic radical having up to 6 ring atoms containing O, S(O)a and/or N(R5)b groups or R2, R3 or R4 when combined with the phenyl radical to which attached may form a C6-10 aryl radical; or, when not a hydrogen atom, the R group may be substituted with an R2-R5 group;
R1 is C1-18 alkyl, C3-18 alkenyl or alkynyl, C2-18 alkoxyalkyl, C3-7 cycloalkyl or cycloalkylalkyl, C6-10 aralkyl, alkylthiomethyl, cyanomethyl, loweracyl-oxymethyl, loweralkylthiocarbomethyl, substituted or un-substituted carbamoylmethyl, benzothiazolinonylmethyl, phthalimidomethyl, mono- or di-loweracylamidomethyl, or C1-10 hydrocarbylsulfonylamidomethyl groups or said R1 member substituted with an R2-R5 member which is inert under reaction conditions, provided that when R1 is an alkenyl radical it cannot have an olefinic bond on the carbon atom attached to the nitrogen atom and R6 and R7 are independently hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, or aromatic hydrocarbon each having up to 12 carbon atoms.

2. Process according to Claim 1 wherein said compound of Formula II is converted to said anion thereof under basic conditions by electrolysis or reaction with alkali metal hydrides, fluorides, oxides, hydroxides, carbonates, phosphates or alkoxides.

3. Process according to Claim 2 wherein R1 is an alkoxyalkyl radical having up to 12 carbon atoms.

4. Process according to Claim 3 wherein R1 is an alkoxymethyl radical and X and X1 are independently chlorine or bromine.

5. Process according to Claim 4 wherein R1 is an alkoxymethyl radical and R is a radical having the formula wherein m, n, R2, R3 and R4 have the above meanings.

6. Process according to Claim 5 wherein m and n are zero and R2 and R3 are independently hydrogen or C1-6 alkyl radicals.

7. Process according to Claim 6 wherein said 2-haloacetamide is N-(methoxymethyl)-2',6'-diethyl-2-chloroacetanilide.

8. Process according to Claim 6 wherein said 2-haloacetamide is N-(n-butoxymethyl)-2',6'-diethyl-2-chloroacetanilide.

9 Process according to Claim 6 wherein said 2-haloacetamide is N-(ethoxymethyl)-2'-methyl-6'-ethyl-2-chloroacetanilide.

10. Process according to Claim 5 wherein R2 is alkoxy, polyalkoxy oralkenyloxy having up to 6 carbon atoms, nitro or trifluoromethyl and R3 and R4 are independently hydrogen, alkyl, or an R2 member.

11. Process according to Claim 10 wherein said 2-haloacetamide is N-(isopropoxymethyl)-2'-methoxy-6'-methyl-2-chloroacetanilide.

12. Process according to Claim 10 wherein said 2-haloacetamide is N-(ethoxymethyl)-2'-isopropoxy-6'-methyl 2-chloroacetanilide.

13. Process according to Claim 10 wherein said 2-haloacetamide is N-(ethoxymethyl)-2'-n-propoxy-6'-methyl-2-chloroacetanilide.

14. Process according to Claim 10 wherein said 2-haloacetamide is N-(n-propoxymethyl)-2'-methoxy-6'-methyl-2-chloroacetanilide.

15. Process according to Claim 10 wherein said 2-haloacetamide is N-(isopropoxymethyl)-2'-methoxy-3',6'- di-methyl-2-chloroacetanilide.

16. Process according to Claim 10 wherein said 2-haloacetamide is N-(allyloxymethyl)-2'-allyloxy-6'-methyl-2-chlororacetanilide.

17. Process according to Claim 10 wherein said 2-haloacetamide is N-(1-methylpropoxymethyl)-2'-allyloxy-6'-methyl-2-chloroacetanilide.

18. Process according to Claim 10 wherein said 2-haloacetamide is N-(n-propoxymethyl)-2'-isobutoxy-6'-methyl-2-chloroacetanilide.

19. Process according to Claim 10 wherein said 2-haloacetamide is N-(isopropoxymethyl)-2'-trifluoromethyl-2-chloroacetanilide.

20. Process according to Claim 10 wherein said 2-haloacetamide is N-(ethoxymethyl)-2'-trifluoromethyl-6'-methyl-2-chloroacetanilide.

21. Process according to Claim 10 wherein said 2-haloacetamide is N-(n-propoxymethyl)-2'-(2-methoxyethoxy)-6'-methyl-2-chloroacetanilide.

22. Process according to Claim 10 wherein said 2-haloacetamide is N-(isopropoxymethyl)-2'-(2-methoxyethoxy)-6'-methyl-2-chloroacetanilide.

23. Process according to Claim 4 wherein R is a cycloalkenyl or cycloalkadienyl radical having up to 7 carbon atoms or such radicals substituted with one or more C1-6 alkyl radicals.

24. Process according to Claim 23 wherein R is a 1-cyclohexen-1-yl radical or such radical substituted with one or more C1-6 alkyl radicals.

25. Process according to Claim 24 wherein R is a 2,6-dimethyl-1-cyclohexen-1-yl radical.

26. Process according to Claim 25 wherein said 2-haloacetamide is N-(isobutoxymethyl)-N-(2,6-dimethyl-1-cyclohexen-1-yl)-2-chloroacetamide.

27. Process according to Claim 24 wherein said 2-haloacetamide is N-(n-butoxymethyl)-N-(2,6-diethyl-1-cyclohexen-1-yl)-2-chloroacetamide.

28. Process according to Claim 24 wherein said 2-haloacetamide is an isomeric mixture of N-(ethoxymethyl)-N-(2-methyl-6-ethyl-1-cyclohexen-1-yl)-2-chloroacetamide and N-(ethoxymethyl)-N-(6-methyl-2-ethyl-1-cyclohexen-1-yl)-2-chloroacetamide.

29. Process according to Claim 4 wherein R is an alkenyl radical having up to 18 carbon atoms.

30. Process according to Claim 29 wherein said alkenyl radical has an olefinic bond on the carbon atom attached to the nitrogen atom.

31. Process according to Claim 30 wherein said 2-haloacetamide is N-(ethoxymethyl)-N-(2,4-dimethyl-2-penten-3-yl)-2-chloroacetamide.

32. Process according to Claim 30 wherein said 2-haloacetamide is N-(isopropoxymethyl)-N-(3-methyl-2-buten-2-yl)-2-chloroacetamide.

33. Process according to Claim 30 wherein said 2-haloacetamide is N-(n-butoxymethyl)-N-(3-methyl-2-buten-2-yl)-2-chloroacetamide.

34. Process according to Claim 3 wherein said alkoxyalkyl radical is an alkoxyethyl radical which may be substituted with one or more C1-4 alkyl groups on said ethyl moiety and X and X1 are independently chlorine or bromine.

35. Process according to Claim 34 wherein R is a C2-12 alkenyl radical which may be substituted with one or more C1-6 alkyl, C3-6 cycloalkyl or cycloalkylmethyl groups.

36. Process according to Claim 35 wherein said alkenyl or substituted-alkenyl radical has an olefinic bond on the carbon atom attached to the nitrogen atom.

37. Process according to Claim 36 wherein said 2-haloacetamide is N-(3-methyl-2-buten-2-yl)-N-(n-propoxy-ethyl)-2-chloroacetamide.

38. Process according to Claim 36 wherein said 2-haloacetamide is N-(2,4-dimethyl-2-penten-3-yl)-N-(2-methoxyethyl)-2-chloroacetamide.

39. Process according to Claim 34 wherein R is a radical having the formula wherein m, n, R2, R3 and R4 have the above meanings.

40. Process according to Claim 39 wherein m and n are zero and R2, R3 and R4 are independently hydrogen or C1-6 alkyl radicals.

41. Process according to Claim 39 wherein m and n are zero, R2 is alkoxy, polyalkoxy or alkenyloxy having up to 6 carbon atoms, nitro or trifluoromethyl and R3 and R4 are independently hydrogen, alkyl or an R2 member.

42. Process according to Claim 34 wherein R is a cycloalkenyl, or cycloalkadienyl radical having up to 7 carbon atoms which may be substituted with C1-6 alkyl radicals.

43. Process according to Claim 2 wherein R1 is a C1-18 alkyl radical.

44. Process according to Claim 43 wherein R is a radical having the formula wherein m, n, R2, R3 and R4 have the above meanings.

45. Process according to Claim 44 wherein m and n are zero and R2, R3 and R4 are independently hydrogen or C1-6 alkyl radicals.

46. Process according to Claim 44 wherein m and n are zero, R2 is alkoxy, polyalkoxy or alkenyloxy having up to 6 carbon atoms, nitro or trifluoromethyl and R3 and R4 are independently hydrogen, alkyl or an R2 member.

47. Process according to Claim 46 wherein said 2-haloacetamide is N-methyl-2'-butoxy-6'-methyl-2-chloro-acetanilide.

48. Process according to Claim 46 wherein said 2-haloacetamide is N-methyl-2'-isobutoxy-6'-methyl-2-choroacetanilide.

49. Process according to Claim 46 wherein said 2-haloacetamide is N-methyl-2'-n-propoxy-6'-methyl-2-chloroacetanilide.

50. Process according to Claim 46 wherein said 2-haloacetamide is N-methyl-2'-n-butoxy-6'-ethyl-2-chloro-acetanilide.

51. Process according to Claim 2 wherein R1 is an alkenyl or haloalkenyl radical having up to 12 carbon atoms.

52. Process according to Claim 51 wherein R is a radical of Formula IV.

53. Process according to Claim 2 wherein R1 is an alkynyl radical having up to 12 carbon atoms.

54. Process according to Claim 53 wherein R is a radical of Formula IV.

55. Process according to Claim 53 wherein R is an alkenyl radical having up to 12 carbon atoms.

56. Process according to Claim 2 wherein R1 is a heterocyclyl or heterocyclylmethyl radical having up to 6 ring atoms containing 0, S and/or N atoms.

57. Process according to Claim 56 wherein R is a radical of Formula IV.

58. Process according to Claim 56 wherein R
is a cycloalkenyl or cycloalkadienyl radical having up to 7 carbon atoms.

59. Process according to Claim 58 wherein said 2-haloacetamide is N-(2,6-dimethyl-1-cyclohexen-1-yl)-N-[3-(2-benzothiazolinone) methyl]-2-chloroacetamide.

60. Process according to Claim 2 wherein the initial product mixture is recycled after an acid wash to regenerate starting sec-amide from by-product imidate, and then reacted with additional compound of Formula III

61. Process according to Claim 2 wherein said amide anion is generated by an alkali metal hydride.

62. Process according to Claim 61 wherein said alkali metal hydride is potassium hydride.

63. Process according to Claim 2 wherein said amide anion is generated by an alkali metal hydroxide or alkaline earth hydroxide.

64. Process according to Claim 63 wherein said alkali metal hydroxide is aqueous sodium hydroxide.

65. Process according to Claim 63 wherein said alkali metal hydroxide is solid potassium hydroxide.

66. Process according to Claim 1 wherein said alkali metal carbonate is solid potassium carbonate.

67. Process according to Claim 1 wherein said amide anion is generated by an alkali metal fluoride.

68. Process according to Claim 67 wherein said alkali metal fluoride is potassium fluoride.

69. Process according to Claim 61, 62 or 63, wherein said reaction is conducted in the presence of a phase transfer catalyst.

70. Process according to Claim 64, 65 or 66, wherein said reaction is conducted in the presence of a phase transfer catalyst.

71. Process according to Claim 67 or 68, wherein said reaction is conducted in the presence of a phase transfer catalyst.

72. Process according to Claim 61, 62 or 63, wherein said reaction is conducted in the presence of a catalyst of a quaternary ammonium halide salt.

73. Process according to Claim 64, 65 or 66, wherein said reaction is conducted in the presence of a catalyst of a quaternary ammonium halide salt.

74. Process according to claim 67 or 68, wherein said reaction is conducted in the presence of a catalyst of a quaternary ammonium halide salt.

75. Process according to Claim 61, 62 or 63, wherein said reaction is conducted in the presence of a catalyst of a benzyl trialkyl ammonium halide salt.

76. Process according to Claim 64, 65 or 66, wherein said reaction is conducted in the presence of a catalyst of a benzyl trialkyl ammonium halide salt.

77. Process according to Claim 67 or 68, wherein said reaction is conducted in the presence of a catalyst of a benzyl trialkyl ammonium halide salt.

78. Process according to claim 61, 62 or 63, wherein said reaction is conducted in the presence of a catalyst of a polyether.

79. Process according to Claim 64, 65 or 66, wherein said reaction is conducted in the presence of a catalyst of a polyether.

80. Process according to claim 67 or 68, wherein said reaction is conducted in the presence of a catalyst of a polyether.

81. Process according to Claim 61, 62 or 63, wherein said reaction is conducted in the presence of a catalyst of a cyclic polyether.

82. Process according to Claim 64, 65 or 66, wherein said reaction is conducted in the presence of a catalyst of a cyclic polyether.

83. Process according to Claim 67 or 6g, wherein said reaction is conducted in the presence of a catalyst of a cyclic polyether.

84. Process according to Claim 1 wherein said anion is generated by electrolysis.

85. Process according to Claim 10 wherein said 2-haloacetamide is N-(-1-methylpropoxymethyl)-2'-n-butoxy-2-chloroacetanilide.

86. Process according to Claim 46 wherein said 2-haloacetamide is N-methyl-2'-isopropoxy-6'-methyl-2-chloroacetanilide.