3033
NOTES
June 20, 1953
Crystallization from ethyl alcohol gave 36 g., m.p. 166-167'. The bromide IV was converted successively to V, VI and VI11 by procedures that require no further description.' The xanthoethyl derivative VI1 was also made by an unmodified procedure.' (6) G. S. Skinner and J. B. Bicking, THISJOURNAL,79, 1140 (1950).
DEPARTMENT OF CHEMISTRY UNIVERSITY OF DELAWARE NEWARK, DELAWARE
degree of steric hindrance about the nitrogen atoms in the order: dimethyl (1 mg. per kg.), diethyl (2 mg. per kg.) and cyclohexamethylene (10 mg. per kg.). Tests for autonomic activity (in anesthetized dogs) revealed that all of the compounds markedly reduced blood pressure, but for only from five to thirty minutes after intravenous administration of 2 mg. per kg. Mechanism of action varied within the series.'
Experimental6 2-thenylamines were preSalts' pared by the Leuckart reaction from 2-thienylaldehyde' (0.1 mole), formic acid (0.25 mole) and appropriate secondary BY D. RICHARD SMITH*^ AND CHESTER J. CAVALLITO~~amine (0.2 mole). The procedure was similar to that of Smith and Macdonald'; refluxing was for ten hours or with RECEIVED JANUARY 24, 1952 volatile amines, heating was carried out in a pressure bomb. During the past few years, bis-quaternary- From dimethylamine, N,N-dimethyl-2-thenylamines was ammonium salts of a wide variety of types have obtained in better than 70% yield and its physical properties agreed with those published. Treatment with methyl been prepared and studied for curarimimetic and iodide yielded a crystalline methiodide, m.p. 167-168'. autonomic drug activity. Peak curarimimetic Anal. Calcd. for CsHdNS: C, 33.93; H, 4.98; I, activity usually is associated with bis-quaternary 44.82. Found: C, 34.09; H, 5.09; I, 44.20. salts in which ten carbon atoms or equivalent disN,N-Diethylthenylamine was prepared in similar manner tance separates the quaternary nitrogen atoms and in 65% yield; b.p. 40' a t 1.5mm., n% 1.5095. Anal. Calcd. for GH16NS: N, 8.27. Found: N, 8.18. autonomic blockade is maximal in homologs with a Methiodide, m.p. 156'. Anal. Calcd. for C1OHIBINS: five or six carbon atom separation. In the present series of compounds, 2-thenyl substituted quater- C, 38.59; H, 5.79. Found: C, 38.64; H, 5.89. From hexamethyleneimine there was obtained a 4 4 3 nary salts of various size were prepared for compari- yield of N-(2-thenyl)-hexamethyleneimine, b.p., 72-73 son with one another and with some corresponding a t 1.5 mm., n% 1.5375. isosteric phenyl substituted analogs. Anal. Calcd. for CIIHI~NS:N, 7.17. Found: N, 6.77.
Alkylene Bis-(2-thenylquaternaryammonium)
a,w-ALKYLENE
2-Thenylamines.-Tertiary
TABLE I BIS-QUATERNARYAMMONIUM SALTS R' R'
R-CHrk-(
+A'
I
I
R
R'
2-C,H,S CH, 2-CIHsS CHI 2-CdHaS CHI 2-CdIsS CHI 2-ChHsS CHa 2-CdHaS CHI 2-CdHsS C2Hs 2-CdHsS Cyclo(-CHr)s6 Ca6 CHs C6Hs CHa CaHI CHz a 90 lb. pressure in bomb.
X
M.P., "C. (cor.)
Reflux, Yield, hr. %
Carbon
Analyses. % Calcd. Hydrogen Bromine Carbon
3 219 23 60 42.15 5.83 4 223 8 85 43.37 6.07 5 111-114 8 75 44.53 5.70 6 218-220 3" 70 S, 12.18 9 226 35 50 48.59 7.09 10 200 7" 60 49.47 7.26 10 176-180 50 40 52.65 7.87 10 201-204 24 45 55.64 7.88 5 218-220 8 85 55.20 7.25 6 226 8 90 56.03 7.45 10 208 8 70 58.94 8.14 Hexamethyleneimonium derivative.
Muscle paralytic activity, as measured in mice according to published procedures, 3 followed the expected sequence* In the bis-thenyldimethylammonium series, activity increased in the following sequence with ED50 values of approximately 8 mg. per kg. for the Ce,2 for C9and 1 for the C,,, ; corresponding bis-benzyldimethylammonium derivatives were of the same order of activity as the thenyl analogs. In the Clo bisthenylammonium series, activity decreased with (1) Contribution from the Department of Chemistry, James Millikin University, and from the Research Laboratories of Irwin, Neisler & Company. ( 9 ) (a) Phillips Petroleum Co., Waco, Texas; (b) Irwin, Neisler & Compaoy. ( 8 ) C . J. Cavdlfto, A. E.k r l a and J. 0. W o p p e , T y x n JQURIUL, TP, 2081 (1960).
-
CHI),N-CH~R.~B~ RI ?
33.33 32.07 31.19 30.36 28.11 27.47 25.03 23.14 31.94 31.07 28.01
Found Hydrogen
42.42 5.98 43.71 6.28 44.65 6.26 S, 11.75 48.40 7.14 49.56 7.23 52.85 8.04 55.76 8.08 55.27 7.26 56.20 7.43 59.08 8.08
Bromine
32.75 31.65 30.65 29.90 28.29 26.96 24.45 23.36 31.64 30.72 27.75
Reaction of Thenylamines with Alkylene Dibromides.The bis-WatmmYammonium bromide salts were Prepared by heating the reagents in n-propanol solution in the proportions: 0.05 mole of a,o-alkylene dibromide, 0.15 mole of tertiary thenylamine, 50 d.of propanol. Heating time, yields and analyses are summarized in Table 1. The bisquaternary salts were recrystallized from n-ProPanol. Reaction of Benzyldimethylamine with Alkylene Dibromides.-Benzyldimethylamine (15 g. or 0.11 mole) was re(4) Curarimimetic tests by Dr. T. B. O'Dell, autonomic activity measurements by Dr. F. J. Macri, of Irwin, Neisler & Company. ( 5 ) Halogen analyses by Mr. C. F. Duewer of Irwin, Neisler & Company. Microanalyses by Clark Microanalytical Laboratory, Urbana, Illinois. (6)W. J. King and F. P. Nord, J . Or#.Chem., 18, 635 (1948). (7) P. A. S. Smith and A. J. Macdonald, Tms JOVRNAL, 78, 1087 (1960). (8) L. P. Kyrides, F. C. Meyer, F. B. Zianty, J. Bandater, Ibld., 7% 745 (1950).
Harvey
and
L. W.
VOl. 75
NOTES
3034
TABLE I REPLACEMENT O F AMINO GROUP BY HYDROGEN
__
-__.___---pro& Structure
Compound deaminated
ct
B . P . , OC.
n250
d'%
--Yield, using CaHiOH
7$H?& 47.4 67
3-HzN-CeH4CFa CeHeCFa 98-101 37 3-HzX-4-Br-CeH3CF3 4-Br-CBHdCF3 154-155 1.4705 1.607 40 5-HzN2-Br-CeHaCF3 2-Br-CeH4CFa 165-168 60 ~ - H z N - ~ , ~ - B ~ - C ~orH Z C F ~ 2,4-Rr-C&CF; 97-102. 6b 1.5279 2.006 53 ~-HzN-~,~-B~-C~H?CF~ Unfractionated reaction mixture ............ 49.3 65.7 a Calcd. for C7HzBr2FJ: Br, 52.56. Found: Br, 52.51. At 20.5 mm. The products consisted of benzotrifluoride, p-bromo-, o-bromo- and 2,4-dibromobenzotrifluoride. They were obtained in 4.8, 21, 12 and 11.5% yield, respectively, using ethanol; in 12.5, 20, 22 and 11.2% yield using HsPO?. fluxed for 8 hours in 100 ml. of n-propanol with 0.04 mole of alkylene dibromide. The solution was cooled, diluted with ethyl ether, the precipitate filtered off and recrystallized from hot n-propanol-benzene solution,
dibromobenzotrifluoride was formed. When the brominations were conducted a t 50" or when macetaminobenzotrifluoride served as the starting material, a considerable amount of unidentified IRWIN NEISLERAND Co. high boiling material resulted. DECATUR, ILLINOIS The structure of the 3-amino-4-bromobenzotrifluoride was established by deamination to a The Formation and Deamination of Brominated bromobenzotrifluoride which, when hydrolyzed m-Aminobenzotrifluoridesl with sulfuric acid, was converted to p-bromobenzoic acid. The amine was also diazotized and treated BY PAULTARRANT AND MARVIN R. LILYQUIST with hydrobromic acid to give the known 3,4JANUARY 26, 1953 RECEIVED dibromobenzotrifluoride. The 5-amino-2-bromom-Bromobenzotrifluoride is a useful starting benzotrifluoride was diazotized and reduced to material for the synthesis of a number of com- o-bromobenzotrifluoride thus establishing the posipounds since it readily forms a Grignard reagent.2 tion of the bromine as being adjacent to the triAlthough m-broniobenzotrifluoride can be made in a fluoromethyl group. Final confirmation resulted straightforward reaction from benzotrifluoride, when the replacement of the amino group by chlothe ortho and para isomers must be made indirectly. rine gave the known 2-bromo-5-chlorobenzotriJones3 has prepared p-bromobenzotrifluoride in an fluoride The aminodibromobenzotrifluoride was deaminover-all yield of about 40% from $-nitrotoluene; however, the process required the use of two brom- ated and hydrolyzed to 2,4-dibromobenzoic acid ination steps, a fluorination, a reduction and, fi- indicating that its structure was either 3-aminonally, the replacement of the amino group by bro- 2,4-dibromo- or 5-amino-2,4-dibromobenzotrimine. Jones was also able to prepare o-bromobenzo- fluonde. Since no 3-amino-2-bromobenzotrifl~otrifluoride, but again a lengthy procedure was ride was ever isolated, it seems likely that 5-aminoused. Since the completion of this research, 2,4-dibromobenzotrifluoride was iormed. Deaminations were carried out using either Benkeser and Severson4 have described a two-step syntheis of o-bromobenzotrifluoride involving the hypophosphorus acid or ethanol as the reducing metallation and subsequent bromination of benzo- agent. Better yields were obtained with hypophosphorus acid as indicated in Table I. trifluoride with 28% yields. Since m-arninobenzotrifluoride is commercially Experimental available, it seemed probable that it might serve as The Bromination of m-Amiiobenzotrifluoride.-The a starting point for a convenient synthesis of o- bromination of m-aminobenzotrifluoride and the correand p-bromobenzotrifluoride. This paper reports sponding acetamino compound were carried out under a a study of the bromination of m-aminobenzotri- variety of conditions. The latter compound was treated fluoride and the deamination of the resulting with bromine a t 100' without catalyst and a t 50' with a small amount of iron powder but most of the starting mateaminobromo compounds to form various bromo- rial was recovered. Essentially these same results have rebenzotrifluorides. cently been reported .E The bromination of m-aminobenzom-Aminobenzotrifluoride was brominated under a trifluoride at 10' without catalyst produced 21% convervariety of conditions. The best yields of mono- sions each of 3-amino-4-bromo- and 5-amino-2-bromobenzotrifluoride. At 5-10' using iron a 40% conversion to 3-aminobromobenzotrifluorides resulted when the reaction 4-bromobenzotrifluoride obtained but no other isomeric was carried out a t 5-10" in an excess of the amine products were isolated; was at 50", a 31y0 yield was obtained when no catalyst was employed. Both 3-amino-4- with no other monobromo compound isolated. A ty ical procedure follows. m-Aminobenzotrifluoride bromo- and 5-amino-2-bromobenzotrifluoride were (1 moleywas added to 300 ml. of glacial acetic acid in a oneobtained under these conditions but no 3-amino-2- liter flask equipped with stirrer, addition funnel and therbromobenzotrifluoride was isolated during any mometer. The contents were cooled to 10' and bromine experiments. When larger amounts of bromine (1 mole) added dropwise; about 2.5 hours were required for were used, a Compound believed to be 5-amino-2,4- the addition. After another hour of stirring, 500 ml. of '1) Presented at the 118th Meeting of the Amerlran Chemical So-
Ci@ly,Chicago, 1950. (8) f H. Simons and E. 0. Ramler, Trrxs J o W R N A t , 66, 389 (1943).
(8) R.0.Jonw, rbid., 80, 2346 (1947). (4) 8 % & tjbtthWDW and N. 0. B l r u n D n ,
i@id,h)$L
18&a (iorils
concentrated ammonia solution was added slowly and the
(5) E. T. McBce, R. A. Sanford and P. J. Graham, dbid., 72, 1891 ( 1950).
(6) E. T.McBar, @0+DQDP C10111).
Ch
R,Pictrm R, Dt h o W Y #-*d B, Rapkia, O 4 d , ,
