5580
A. J. SPEZIALE AND P. C. HAMM
Kodak Co. White Label product which had been recrystallized several times from absolute alcohol and dried in a vacuum desiccator over potassium hydroxide and phosphorus pentoxide. T h e material melted a t 145.2-146.7' in a sealed tube. Taylor and Grants reported a melting point of 143.4'. The pyridinium chloride was stored as a standard solution in acetonitrile. Titration of aliquots with either standard base or silver nitrate showed no change in acid or chloride concentration over a period of many weeks. Pyridinium perchlorate prepared from aqueous perchloric acid and pyridine melted a t 298.6-299.6O.Q T h e neutral equivalent of this material was 179.2. The calculated value is 179.6'. N-Methylpyridinium chloride was prepared by passing methyl chloride into pyridine a t a temperature of 55-60'. T h e hygroscopic salt after recrystallization froin acetonitrile and dryingina vacuum desiccntor over phosphorus pentoxide melted a t 139.7-140.8". A Volhard titration showed the presence of 27.3% chlorine. T h e calculated value is 27.4%. T h e salt was stored in acetonitrile solution. Tetraethylammonium chloride was prepared from the bromide and decomposed without melting.'o A Volhard determination showed the presence of 21 .2y0 halogen (calculated 21.47&). Tetraethylammonium perchlorate was prepared from silver perchlorate and tetraet1iyl:nmniotiium bromide. I1 After several recrystallizations from 9554 ethanol, the product gave no precipitate with either hydrochloric acid or acidified silver nitrate. The material, after drying a t 57' ( 1 mm.), decomposed in the range 310-330' without melting. (Healey and Martell reported a melting point with decomposition of 345'.) A Dumas nitrogen analysis showed the presence of 6.459G nitrogen (calculated S.llC7,). Kinetic Procedures.-The reaction was studied by following the rate of disappearance of the absorption band of acetyl cyanide which falls near 304 mp in acetonitrile solution. The ultraviolet measurements were made with a Beckman quartz spectrophotometer model DU, in which the 10-crn. cell compartment had been replaced with a water-tight coin(8) M. D. Taylor and L. P. Grant, J . Chern. E L , 32, 93 (1955). (9) F. Arndt and P. Nachtung, Ber., 69B,448 (1926). (IO) W. E. Thompson a n d C. A. Krause, TEXIS J O U R N A L , 69, 1010 (1947).
VOl. 78
partmetit provided with quartz windows and two outlets for circulating water from a thermostat.lZ Long-necked 1-cm. Beckinan silica cells sealed with ground-glass stoppers were used for reaction vessels. Distilled water was circulated in a closed system from a copper coil placed in a thermostat t o the compartment by means of a n Eastern centrifugxl pump, model 131. The speed of the pump was regulated with a Variac. Because of small particles and bubbles in the water, more reproducible optical density values could be obtained by turning off the circulating pump duririg the short time the reading was being taken. It was established that the temperature of the water in the compartment did not vdry by more than 3~0.03' under these conditions. T h e thermostat wvas set a t 25.0" with a Precision thermometer which had been checked against three different Anschiitz thermometers. Time was measured with a Presion timer. I n preparing solutions all liquids wcrc transfcrrcd by pipet i n a n attempt to minimize the amount of water in the systcrri. In a typical run the appropriate amount of pyridine was weighed into 2 volumetric flask. Stand:nrd pyridiniurn chloride and standard neutral salt solution werc pipetted in, the flask was three-quarters filled with acetonitrile and weighed. Approximately the desired amount of hydrogen cyanide was added from the ice-jacketed buret (which was protected from atmospheric moisture with a cnlcium chloride tube and a ground-glass joint a t the tip which fitted the volumetric flask). The flask was again weighed and filled t o the mark with solrent. This solution W:LS diluted by pipetting aliquots into two other volumetric flasks which were filled nearly to volume and thermostated. The contents of one was used for the solvent cell, and to the other was added the acetyl cyanide by pipet. T h e solutions were immediately transferred into the Beckmiti cells and measurements were begun.
Acknowledgment.-We gratefully acknowledge the support of this research by the B. F. Goodrich c o. ( l a ) We wish to thank M r . Gideon Fraenkel who designed this water-tight cell compartment.
CAMBRIDGE, MASSACHUSETTS
(11) F. A. Healey and A. E. Martell, ibid., 73,3190 (1051).
[CONTRIUUTION FROM THE ORGANIC CHEMICALS DIVISION,S r . LOUIS RESEARCIIDEPARTMENT, MONSANTO CI-IEMICAL COMPANY]
Preparation of 2-Substituted Acetamides BY A. J. SPEZIALE A N D P. C. HAMM RECEIVED MAY4, 1956
A variety of 2-substitutcd acctaiiidcs were prepxed for tlie most part froin the p:Lreiit 2-cliliiroacetaiiiidcs by displacement reactions.
I t has been shown that a wide varicty of N-substituted and N,N-disubstituted 2-chloroacetamides possess outstanding activity as pre-emergence, grass-specific herbicides' and that the related chloropropionamides and butyramides are almost completely devoid of this type of action.2 It was of interest, therefore, to determine the variations in activity by replacing the a-chlorine and hydrogen atoms in the 2-chloroacetamides by other functional groups. This paper deals with the synthesis of compounds of this type. Among the groups introduced are other halogen atoms, hydroxy, alkoxy, amino, phthalimido, nitrile, thiocyanate, alkylthio, thiosulfate and isothiouronium. Since the N-substituted 2-chloroacetamides ( 1 ) P. C. H a m m and A. J. Speziale, J . A g j i . Food Chcm
, 4, 518
( 1!150).
(2) P. C . Iianirn a n d A . J . Speziale. i b i d . , 4, in press (1036).
were available from previous work, mcthods of synthesis for many of the 2-substituted acetamides were designed to use these available compounds. Several different N-substituents which had previously been shown to be highly active as Z-chloroacetamides were chosen to determine the scope of phytotoxicity. The herbicidal activity of these compounds and the correlation of their activities with those of the 2-chloroacetamides is reported elsewhere The 2-haloacetamides which were prepared during the course of this investigation and not reported previously are listed in Table I. Other 2-substituted acetamides which were synthesized, for the most part, from the parent 2-chloro- or 2-iodoacetamides are given in Table 11. The preparation (3) A J Speziale and 1' C. Ilamm, Tars
JOURNAL,
78, 2550 (IOSCi)
Nov. 5, 19%
P R E P A R A T I O N OF 2-SUBSTITUTED
ACETAMIDES
55S1
TABLE I 0 2-HALOACETAMIDES
R' Yield, KO.
I1 111 IV V VI VI1 VI11 IX X
Y FCH2" BrCHz ICHz ICH2
R
R'
Allyl Allyl Allyl Allyl H Cyclohexyl H Furfuryl I C H ~ ~Pentametliylene ICHs H p-Methoxyphenyl CI,CH Allyl Allyl CldC H Propyl C13C Propyl Propyl XI c13c Allyl Allyl XI1 c13c H Dodecyl a Fluoroacetyl chloride prepared accurding tilled under reduced pressure.
M.p.,
70 OC. 73 ..... 85 . . .. . 82 123-124 90 94-95 89 . ... . 96 147-148 93 . . ... 89 43-44
B.p., Mm.
nZ5D
O C .
Formula
1.0 . . . . CsHizFNO 1 . 2 1.5131 CsHlzBrKO . . . . . . . . CsHiaISO ,. . . . . . . CrHsIIC02 . . . . 1.5765 CiHiJKO . . . . . . . . CsHloIX02 93 1 . 2 1.5021 CsHilClzNO 92 1 . 7 . . . . C6HBC13NO 81 . . . . . 95 1 . 0 1.4850 C~HiaC13N0 75 . . . . . 83 1 . 0 1.5082 CsHioClaNO 95 48-49 . . . . . . . . CiaHzeC13N@ to W. E. Truce, THISJOURNAL, 70, 2828 (1948). 99 99
Halogen, Yo Calcd. Found
...
...
36.64 36.73
...
...
47.78
47.73
... ...
... ...
Nitrogen, 7 Calcd. F o u n d
8.90
9.00
5.24
5.13
.. ..
.. ..
5.54 5.66 4 . 8 1 4.78 34.08 34.32 6.73 6.54 52.02 51.70 .. .. 43.16 43.48 .. .. 43.88 44.12 .. .. 32.16 31.77 ,. .. * Product could iiot be dis-
-
0 HC1 of a representative member of each type of com/I .SH pound is given. ( CsH;)2TCCH:SC< In the preparation of 2-amino-N-substituted0 rDMF SH2 II acetamides (XXXII), following the procedures of XXVIII ( c ~ H ~ ) ~ s C C H __ ~ C ~ Haworth et al.,4 and Sheehan,j the melting points XXXIX and physical characteristics of the amine hydroId CnHnOH . c chlorides XXXIa,c did not agree with those re--+ (C3H,):NH HC1 + p~rted.~ The intermediate N-(substituted)-phthalll KH2CNH2 CHs-S imides XXX were synthesized from potassium I I phthalimide and the appropriate 2-chloroacetamide @=C C=SH in dimethylformamide. With the availability of \NH/ the N-substituted-2-chloroacetamides, 3 this method XXXIX appeared more feasible than that which employed phthaloyl glycine4sj in the preparation of conipounds of type XXX. Treatment of X X X with ethanol, it is probably not an intermediate to chloro~ hydrazine hydrate and hydrochloric acidj gave the XXXIX. While ethyl c h l ~ r o a c e t a t e , ~ 2-aminoacetamide hydrochlorides (XXXI) which acetamide,6bchloroacetic acid6c and dichloroacetic were converted to the free bases by the use of Am- acid6dreact with thiourea to give XXXIX, this appears to be the first reported instance in which this berlite IRA 400 (OH) ion-exchange resin. T o illustrate further the sequences of reactions reaction occurs with N-substituted-2-chloroacetfor XXXIa,c, N,N-diallyl-l,3-dioxo-2-isoindoline-amides Id. In the preparation3 of 4-(chloroacety1)-morphoacetamide (XXXb) was prepared in 92% yield. The amine hydrochloride X X X I b was obtained as line (IC)from chloroacetyl chloride and morpholine an oil which on treatment with alkali gave the free a t -10 to -20°, there was isolated 4,4-bisbase XXXIIb which formed a picrate. 2-Amino- (4-morpholinocarbonylmethyl)-morpholiniumchloN,N-diallylacetamide (XXXIIb) was further charb- ride (XLIc) in 57, yield from crude IC by filtration acterized by chloroacetylation to N-(diallylcar- prior to distillation. The morpholinium chloride amoylmethyl)-2-chloroacetamide (XXXIII) which, XLIc was synthesized according to scheme (Icon reaction with potassium phthalimide in di- XLIc) and shown to be identical with the material methylformamide, gave N-(diallylcarbamoylmeth- isolated from crude IC. It is postulated that XLIc was also formed in this manner during the preparayl)-1,3-dioxo-2-isoindolineacetamide(XXXIV). In the reaction of 2-chloro-N,N-dipropylacetam- tion and isolation of IC. The isolation of XLIIe from the distillation resiide (Id) with thiourea, i t was found that the use of dimethylformamide (DMF) or alcohol as sol- due in the preparation of XXXVe from Ie and XLe vents gave strikingly different results. When is further evidence that the series of reactions equivalent amounts of Id and thiourea were re- (I-XLII) occur in the preparation of I and XXfluxed in 957, ethanol, only dipropylamine hydro- XV. In this instance, however, the quaternary chloride and X X X I X were obtained in 74 and 86% halide XLIe was not isolated but rather eliminated yields, respectively. However, in dimethylform- ethyl chloride during the distillation of XXXVe amide a t 30°,a 21% yield of pseudothiohydantoin to give the tertiary amine XLII. The 2-haloacetamides showed, in general, the (XXXIX) and 75Y0 yield of the desired isothioexpected reactivity toward nucleophilic reagents uronium salt XXVIII were isolated. Since the isothiouronium salt XXVIII was re- in the replacement of the halogen atom. These covered unchanged when a sample was refluxed in reactions, performed with a variety of such reagents, should provide a simple synthetic method for (4) R. D. Haworth, D. H. Peacock, W. R. Smith a n d R. Mac-
+
+
LY
Oillivray, J. Chem. S O L . 2972 , (1952). (R) J. C. Sheehan a n d V. S. Frank, THISJOURNAL, 71, 1856 (1949); J. C. Sheehan and W. L. Richardson, ibid.. 76, 6329 (1954).
(6) (a) C F H Allen a n d J. A. VanAllan, Ovg Synlheser, 27, 71 (1947), (b) E Mulder, Ber., 8 , 264 (1875); ( c ) R. Andieasch, Monalsh., 8, 421 (1887), (d) A E. Dixon, J. Chcm. Soc., 6S, 815 (1893).
35S2
.%
-
t.
'7 0.1
m
hl
. J . .
=i..
1 0
m .0.1
N
,c.
Y '
. N
C
. . . . . .. . . .. ... ... ... ... .. . .ccc.a-I
.t.CJp=
Y
0
z
'
Nov. 5 , 1956
~ K E P A K A T I O NOF 2-SUI3STITUTED ACETAMIDES
5553
The solid residue, after concentration of the filtrate under reduced pressure, was extracted with fivc 100-nil. portions of boiling ethanol. Evaporation of the alcohol to dryness gave 23.3 g. (88y0)of the Bunte salt as the monohydrate. R' .i sample for analysis was recrystallized twice from ethanol I XL containing a few ml. of water. n 2-(Amidinothio)-N,N-dipropylacetamide Hydrochloride (XXVIII).--A solution of 11.2 g. of thiourea in 100 ml. of R > S C I1C H 2 K ( r " R'l}NH.HCl dimethylformamide was treated with 26.6 g. of 2-chloroI l l R"' R' S,K-dipropylacetamide in 25 ml. of dimethylformamide at 30" with cooling. The mixture was stirred overnight during XXXV which solid material precipitated out. An aliquot of the reaction mixture was titrated with silver nitrate solution and the theoretical amount of chloride ion was shown to be present. The mixture was diluted with 200 ml. of dry acetone and the isothiouronium salt X X Y I I I was collected (c) R , R ' = R",R"' = 3XLI on a filter; yield 20 g. (539;); m.p. 136-138'. An addioxdpentamethylene tional 8.5 g. of material was obtained by dilution of the ( e ) R = H; R ' = c)-c!ohexyl acetone filtrate with 500 ml. of ether; total yield 28.5 g. R 1 ' = R"' = ethyl (75(,-;,). A portion of this material mas recrystallized from dimcthylformamide-acetone mixture. On further dilution of acetone-ether mother liquor, a 0 21 L;( yield of crude pseudotliiohydalitoin ( X X X I X ) was isolated. X purer product was obtained by filtering the alcohol insoluble portion; 1n.p. 200-205". Anal. Calcd. for CSH4XzOS: S, 24.12; S, 27.60. the preparation of diverse 2-substituted acetFound: X,23.98; S, 27.50. amides. In attempting to prepare the isothiouronium salt in 95';< Experimental' ethanol, only pseudothiohydantoin ( X X X I X ) and dipropyl2-Ha1oacetamides.-These compounds are listed in amine hydrochloride were isolated. . 1 solution of 11.2 g. Table I. T h e 2-iodoacetamides were prepared from the of thiourea in 50 ml. of 95(;6 ethanol was heated to reflux 2-chloroactamides3 in the usual manner with potassium and 26.6 g. of 2-chloro-N,X-dipropylacetdmiae in 10 ml. of iodide in acetone. The other haloacetamides were synalcohol was added in 5 minutes. Refluxing was continued for thesized from the appropriate amine and acyl chloride as 1.5 hr. during which time crystals formed. .ifter cooling to described p r e v i ~ u s l y . ~ room temperature, there was collected 15.0 g. (867,) of N,N-Diallylglycolic Amide (XIII).--A mixture of 15.2 g. XXXIX. The filtrate was concentrated to a small volume (0.2 mole) of glycolic acid and 45 g. (0.47 mole) of diallyl and diluted with 500 ml. of dry acetone. There was obtained amine was heated at reflux (111-150') for 34 hr. during in this manner lb.2 g. ('745;;) of pearly plates which were idenwhich time amine-water azeotrope was distilled slowly a t tified as dipropylamine hydrochloride; m.p. 268-272" dec. 86-93'. Excess amine was then distilled under reduced Triethyl-(furfurylcarbamoylmethy1)-ammonium Iodide pressure, and the liquid residue was dissolved in ether, (XXXVII) .-.I solution of 5.3 g. of N-furfuryl-2-iodoacetdried and distilled. The infrared spectrum showed characamide in 50 ml. of dry benzene was treated with 3.0 g. of teristic absorption in hydroxyl and amide regions. triethylamine in 30 ml. of dry benzene at 50-6U". After Attempts to prepare XI11 from h7,N-diallyl-2-chloroheating at 60-65" for about 4 hr., 10 xnl. of benzene was acctamide by replacement of the chlorine atom in alkaline removed by distillation t o ensure dryness. The white media failed. With a n equivalent of 570 sodium hydroxide crystalline iodide was collected on a filter and recrystallized solution at room temperature, a mixture of products (infra- from ethyl acetate-ethanol mixture. red) in low yield resulted. When a n excess of 10% sodium X X X Y I I I was prepared similarly from the 2-iodoacetcarbonate solution was used a t 62-63' for 37 hr., the replace- amide and tributylamine, and XXXVI was prepared from ment reaction took place, but only to about 85y0completion XXXYe and methyl iodide in the usual manner. (infrared and analysis of product j. 4,4-Bis-(morpholinocarbonylmethyl)-morpholiniumChloN ,N-Diallvl-2-ethoxvacetamide (XIV).-To a sodium ride (XLIc).-In the preparation of 4-(chloroacetyl)ethoxide solition prepared from 4.6 g. of sodium and 200 morpholine (IC)a small amount of white solid (m.p. 204nil. of absolute ethanol, 34.7 g. of S,N-diallyl-2-chloro205') was isolated from the crude material prior to the acetamide was added at 0-5' during 20 minutes. The final d i ~ t i l l a t i o n . ~This solid was shown to be the morphomixture was stirred for 4 hr., allowed t o warm to room linium chloride (XLIe) and a sample was synthesized as temperature and sodium chloride removed by filtration. follows. T o a solution of 16.3 g. (0.1 mole) of 4-(chloroExcess alcohol was removed under reduced pressure, and acetyl)-niorpholine in 50 ml. of 1,2-dichloroethane, there was the residue dissolved in ether. The ether solution was added 17.5 g. (0.2 mole) of morpholine. .ifter refluxing washed with dilute hydrochloric acid, sodium bicarbonate for 2 hr., the hydrochloride was recovered in quantitative solution and water and dried over magnesium sulfate. yield. T o the filtrate containing the intermediate 4Removal of the ether left a light yellow oil which distilled (morpholinoacety1)-morpholine (XXXYc), 16.3 g. (0.1 at 75" (0.6 mm.). mole) of 4-(chloroacety1)-morpholine was added, and the T h e alkylthioacetamides were prepared similarly and resulting solution refluxed for 3 hr. The solvent was their sulfones by oxidation with 30y0 hydrogen peroxide in removed under reduced pressure and the residue treated glacial acetic acid. with 100 ml. of acetone and filtered. There mas obtained 1 -(Cyanoacety1)-piperidine (XV).--A mixture consisting 3.8 g. of white Crystalline material, m . p . 203-205'. of 32.3 g. of 1-(chloroacety1)-piperidine,15.6 g. of potassium The acetone solution was treated with a n additional cyanide and 100 ml. of ethanol was held a t 75-80' for 2 16.3 g. (0.1 mole) of 4-(chloroacety1)-morpholine. +After hr. T h e potassium salts were removed by filtration and refluxing for 4 hr., the solvent was distilled and 200 ml. of washed with ethanol. The combined filtrates were evapobenzene added. Removal of the benzene by distillation rated to dryness and the residue recrystallized from water. to ensure dryness left an oily residue which solidified immediSodium 4-(Hydroxyacety1)-morpholine Thiosulfate Monoately. .An acetone suspension upon filtration gave 19.2 g. hydrate (XXVII) .-This was prepared by a modification of of product, m.p. 201-203'. -In additional 5.3 g. was the procedure for sodium glycolanilide thiosulfate.8 -1 obtained from the mother liquors. The total yield was solution consisting of 16.4 g. of 4-(chloroacety1)-morpholine, 28.3 g. (747,). A . portion recrystallized froin absolute 24.8 g . of sodium thiosulfate pentahydrate and 200 ml. methanol melted a t 203-204', and the melting point w a s of 50% ethanol was heated under reflux for 4 hr., cooled and not depressed on admixture with the material (n1.p. 201filtered t o remove a small amount of suspended impurities. 205') obtained in the preparation of 4-(chloroacety1)morpholine. (7) Melting points are uncorrected. Analyses b y M r . A. Bybell and infrared spectra b y Mr. 0. Kinast. Anal. Calcd. for C16H&lN30:: C1, 9.36; K, 11.18. Found: C1, 9.43; N , 11.18. fR) LJ. Weiss and S . Sokol, ' I r r I s SOIJRNAL, '74,IfiR7 (1950). 0
v
+
55S4
J. W. CRARY,0. I
