D. J. BEAVER, D. P. ROMAN AND P. J. STOFFEL
1236
hydrogen peroxide (10 ml.) were added, and the solution was then refluxed for 3 hours. After refluxing, the solution was cooled and extracted several times with ether. The ether extracts were washed with a 10% bicarbonate solution, leaving some yellow neutral material in the ether layer. The bicarbonate washings were strongly acidified and extracted with ether. The ether was evaporated down leaving a yellow, oily residue of acidic material. Chloroform was added t o the residue; the precipitate which formed was filtered off and washed with chloroform, leaving 0.401 g. (28.6%) of acid, m.p. 130-135'. Two recrystallizations from ether-petroleum ether raised the m.p. t o 134.5135.5' (0.35 g., 2 5 % ) . An authentic sample of p(2-carboxybenzoy1)-propionic acid16melted a t 135-136.8'. The mixed melting point was 134.5-135.5'. The neutral material from the first ether extraction, amounting t o 81 mg., was identified as the dilactone of the above acid. Norcarenone (XX).-The tosylate of 5-hydroxymethyl-2cyclohexenone (9.2 g., 0.0328 mole), was dissolved in 450 ml. of 95y0 ethanol and cooled t o 0'. Barium hydroxide (0.0892 N , 330 ml., 0.0295 equivalent) was added dropwise and with stirring over a period of 40 min. The base was added a t such a rate as t o maintain an average PH of 7.6-7.8. At no time was the pH allowed to go above pH 8. After all the base had been added, the solution was stirred until the PH of the solution fell to 6. The ethanol was then removed under reduced pressure. The aqueous solution was extracted three times with ether and the combined ether extracts washed with saturated salt solution. The ether was dried over sodium sulfate, which was removed by filtration, after which the ether was distilled off under reduced pressure. The residue was transferred to a small distillation flask with the aid of a small amount of benzene and distilled, giving the following fractions. Fraction
1 2 3 4 5 6
B.p. hlm.
Wz6D
Wt., g.
44
0 25
44
25 2.5 25 .25
1 5150 1 5148 1 5130 1 5130 1 5150 1.5110
0.1693 ,3379 ,3384 .4224 .2060 .2703
O C .
44-46
46-45 46-45 Forced over
The ultraviolet showed A,,. 292, log e 2.79; Amax 218, log e 4.94. These values indicate 10% of the 2,4-dienone and therefore the true value for pure norcarenone is log e 4.98 (e . 9,530). . . Anal. Calcd. for C7H80: C, 77.75; H , 7.46. Found: C, 78.03; H, 7.47.
Rearrangement of XX to Cyc1oheptadienone.-Norcarenone containing about 26% of the dienone (2.0 g., 0.0185 mole) was dissolved in ether; sodium hydroxide (0.8 g., 0.02 mole), dissolved in 25 ml. of water, was then added and the solution stirred. The aqueous layer turned redbrown almost immediately, while the ether layer became orange-yellow. The mixture was stirred for 5.5 hours, after which time the peak a t 218 mp had disappeared and the value for the peak a t 292 mp had increased markedly. The aqueous layer was then separated, acidified t o PH 2 with dilute hydrochloric acid, and extracted three times with ether. The ether extracts were combined with the original ether layer and washed with saturated boric acid solution, followed by saturated salt solution. The ether solution was dried over sodium sulfate, the sodium sulfate removed by filtration, and the ether distilled under reduced pressure. The residue was transferred with the aid of a little ether and distilled into a Dry Ice-acetone cooled receiver. The material distilled a t 34-36' a t 0.8 mm., and amounted to 1.16 g. (58y0), @D 1.5305. The ultraviolet spectrum showed a peak a t 292 mp (log e 3.81), indicating essentially complete purity. Isolation of a Eucarvone Intermediate from Basic Treatment of Carvone Hydrobromide.-The carvone hydrobromide was treated under the conditions used for the conversion of tosplate XVIII to norcarenone. Nineteen grams (0.088 mole) of hydrobromide was dissolved in 200 ml. of 95% ethanol, and a 0.2 N solution of barium hydroxide was added a t such a rate that the PH remained below 8.5 and above 8. The temperature of the reaction was maintained a t about 20". After evaporating the alcohol, washing and extracting the aqueous layer with three 75-m1. portions of ether, 9.5 g. of crude material was obtained. After solvent evaporation, the material was distilled a t 0.18-0.2 mm. Redistillation of the first fraction afforded 750 mg. of product, b.p. 52-54'' (0.03 mm.), which was analyzed. Fraction
B.P., ' C .
Wt., g.
1 2 3
63-73 75-125 Residue
0.98 4.36 2.50
Anal. Calcd. for CloHldO: C, 79.94; H , 9.41. Found: C, 79.45; H, 8.97. 235 mfi, E 7200) Treatment of the first fraction (A,, with potassium hydroxide in methanol (1 M ) gave a 36% spectral yield of eucarvone in 30 minutes (Amax 303 mp, e 1880). I t was found that eucarvone undergoes 45% deterioration in 2.5 hours under the same conditions, whereas carvone undergoes virtually no change. MADISON, WISCONSIN
(16) W.Roser, B e y . , 17, 2770 (1881).
[CONTRIBUTION FROM
VOl. 79
THE
RESEARCH LABORATORIES OF MONSANTO CHEMICAL COMPANY]
The Preparation and Bacteriostatic Activity of Substituted Ureas BY DAVIDJ. BEAVER, DANIELP. ROMAN AND PAULJ. STOFFEL RECEIVED AUGUST 23, 1956 The preparation and in vitro bacteriostatic activity of some ureas, carbanilides and related compounds against dlicvococcus pyogenes var. U U ~ P U Sare described and the physical data of the compounds are tabulated. A discussion of the relation of antimicrobial action to structure is included.
Introduction The present paper is a continuation of work described previously1s2on the relationship of chemical structure to bacteriostatic properties. The search for compounds more stable to light and less soluble in alkaline soap solutions than the pre(1) D. J. Beaver and P . J. Stoffel, THISJOURNAL, 14, 3410 (1952). (2) D. J. Beaver, R . S. Shumard and P. J. Stoffel, i b i d . , 76, 5579
(1053).
viously described bis- and tris-phenols prompted the present study and it was found that certain substituted ureas overcame these limitations of the phenols. The parent compound urea3 was first mentioned as a bacteriostat in 1906 and reviewed4 in 1944 and the anthelmintics and bac(3) G.Peju and J. Rajat, Compl. reird. soc. bid., 61,477 (1906) (4) L. Weinstein and A. McDonald, Scieiice, 101, 44 (1044). (5) M.Shimotani, J . Pharm. SOC.J a p a n , 14, 440 (1952).
March 5, 1957
PREPARATION AND BACTERIOSTATIC ACTIVITYOF SUBSTITUTED UREAS
teriostatics properties of thioureas were reviewed recently. Outstanding antimicrobial activity is reported for specific tri- and tetrachlorocarbanilides, some of which completely inhibit the growth of Micrococcus pyogenes var. aureus (MPA) in dilutions of 1 to 10-30 million. They are compatible with and stable in the alkaline media normally found in soap stocks, are non-toxic to higher order animals, are retained on the skin and show no tendency toward discoloration or staining.
Discussion I n the course of screening the compounds covered in this paper, i t was soon apparent that the bacteriostatic properties of ureas as a group were remarkably specific in that activity was greatly enhanced or lost completely with slight changes in chemical structure. The physical data on these compounds are shown in Tables I1 to IX and are numbered consecutively for cross reference with their bacteriostatic activities which are summarized in Table I.
1237
GROUPA R-@coNH@BJ
R
R’
Max. diln. against M P A
H H 4-Chloro 4-Chloro 4-Chloro 2,4-Dichloro 3,4-Dichloro 3,4-Dichloro 3,4-Dichloro 3,4-Dichloro 3,4-Dichloro 3,CDichloro 3,4-Dichloro
H 4-Chloro 4-Chloro 2,4-Dichloro 2,5-Dichloro 2,4-Dichloro H 2-Chloro 2,4-Dichloro 3-Chloro 4-Chloro 3.4-Dichloro 3,4,5-Trichloro
None 1-10 thousand 1-1 thousand 1-10 thousand 1-10 thousand 1- 10 thousand 1-10 thousand 1-10 thousand 1-10 thousand 1-30 million 1-30 million 1-10 million 1-10 million
No.
.. 67 79 80 81 83 115 124 127 125 126 129 130
GROUPB
TABLE I Max. diln. a t which growth of M P A is inhibited
Thirty million Ten million One million One hundred thousand
No.
R’
Max. diln. against M P A
Compound
126
125.126 54,129,130,166,167,205 20, 55, 82, 93, 103, 110, 111, 133, 158,169,171,199 91,109,118,137, 150,160,161,164, 170, 173, 175
118
Chloro Methoxy Sulfamyl Hydrogen Methyl Phenyl Nitro Hydroxy Ani1ino Dimethylamino Amino
1-30 million 1-100 thousand 1-100 thousand 1-10 thousand 1-10 thousand 1-10 thousand 1-10 thousand 1-10 thousand 1-1 0 thousand 1-10 thousand 1-1 thousand
All other compounds were less active than one part in 100,000. The ureas reported in Tables 11, I11 and IV do not inhibit bacterial growth of MPA in dilutions greater than one to one thousand until chlorine is introduced into the molecule. A superior order of activity is found in the phenylureas and carbanilides, reaching a maximum in 3,3’,4-trichlorocarbanilide (125) and 3,4,4’-trichlorocarbanilide(126). The remarkable specificity of these compounds when compared to numerous analogs and homologs suggests a “lock and key” combination as one of the essential properties to successful inhibition of bacterial growth. No appreciable effectiveness is found among the carbanilides, Group A, until both phenyl rings are chlorinated and that effectiveness is a t a maximum when chlorine is present in the 3- and 4-positions of one ring and the 3- or 4position of the second ring (125 and 126). Effectiveness is reduced to a minimum with the introduction of chlorine in any ortho position (126 vs. 124, 127). With compound 126 selected as a standard, the 3,4-dichlorophenyl moiety was retained and analogs and isosteric derivatives were studied. Group B illustrates the effect of replacing the 4’-chlorine with other groups. A similar trend is observed for substitution of chlorine in the meta position. Since the introduction of an ortho chlorine reduces activity to a minimum, it is desirable to determine the effect of a similarly substituted posi(6) D. C. Shroeder, Chcm. Rcrs., 66, 186 (1955).
137
115 116 123 136 135 134 119 120
tive group. I n group C, i t is shown again that activity is drastically reduced by ortho substitution regardless of the electronic character of the substituting group. GROUPC R I
c1 NO.
124
115 122 117
R
M a x . diln. against M P A
Chloro Hydrogen Phenyl Methoxy
1-10 thousand 1-10 thousand 1-10 thousand 1-1 thousand
The marked lowering of activity by both electronegative and positive groups would again suggest a unique and specific “lock and key” relationship as one of the essential factors for bacterial inhibition. Again retaining the 3,4-dichlorophenyl moiety, the compounds shown in groups D and E, and reported in Tables V and VI, were prepared to determine the effect of replacing the second phenyl ring with other aryl and alkyl groups. None of these compounds were active at dilutions higher than one part in ten thousand against MPA.
D. J. BEAVER,D. P. ROMAN AND P. J. STOFFEL
1235
Vol. 79
TABLE I1 X
11
TYPE,R.NHCISHR' R
?io.
X
R
Procedure
Yield,
%
Analysis Calcd.
M.P., o c .
r0 nitrogen Found
1 H 0 2-Kaphthyl C 9 6 . 8 212 dec." 15.05 15.05 2 H 0 4-Biphenylyl C 97.0 209 dec.b 13.18 12.64 3 I-Naphthyl 0 1-Saphthyl D 9.00 9.16 4 9 . 8 295-296' 4 2-Naphthyl 0 2-Naphthyl D 9.00 9.29 86.7 305306' 5 2-Naphthyl 0 3-Methoxypropj 1 A 80.0 142.5-143.0 10.84 10.57 6 1-Naphthyl 0 Cyclohexyl A 100.0 237.0-238.0 10.43 10.30 7 2-Naphthyl 0 Dicyclohex yl A 99.3 177.3-177.8 8.02 8.02 8 Cyclohexyl 0 Cyclohexyl E 30.2 226.0-227. Od 12.58 12.77 9 Dicyclohexyl 0 Ethyl A 11.10 11.11 8 7 . 4 146.8-147.5 10 Dicyclohexyl 0 Dicyclohexyl E 7.23 7.20 3 6 . 5 81.O-81.7 11 Cyclohexyl S Phenyl 91.5 l50,1-150.9' 11.93 11.97 A5 12 Cyclohexyl S 4-Ethoxyphenyl B 74.5 122.2-123.0 10.05 9.88 13 Cyclohexyl S 4-Dimethylaminoplienyl B 15.15 1 5 . 2 0 91.0 127.0-127.8 14 Cyclohexyl B 0.86 9.72 S 1-Naphthyl 74.2 141.8-142.5 15 Cyclohexyl B 8.68 S.TO S Dicyclohexyl 49.2 103.2-103.6 16 Phenyl s 4-Dimethylaminoplieriyl B 15.50 15.70 84.2 154.4-154.8 17 Phenyl S 2-Kaphthyl B 10.07 10.05 83.6 158.2-159.0' 18 Phenyl B 8.85 8.76 S Dicyclohexyl 63.7 86.5-87.3' 19 Phenyl 10.30 10.36 S 4-Ethoxyphenyl A5 8 9 . 8 133.9-134, 3h 20 3,4-Dibromophenyl S 4-Bromophenyl 51, 5 j i 51.58' A7 4 7 . 5 125.0-126.1 NOTE:Tables I1 and VI1 headed X, 0 = oxygen, S = sulfur. a W. Wlodkowsky and 2. Darst, {. prakt. Chem., [2] 59, 277 (1899), gives m.p. 213'. M. J. \'an Gelderen, Rec. trav. chim., 52, 977 (1933), gives m.p. 210 . T. L. Davis and H. W. Underwood, Jr., THIS JOURNAL, 44, 2601 (1922), give m.p. 2%' for 1-naphthyl, 296" for 2-naphthyl. K. N. A . Skita and H. Rolfes, Ber., 53, 1248 (1920), give m.p. 229-230". Campbell, B. K. Campbell and S. J. Patelski, Proc. Indiana Acad. Sci., 53, 119 (1943), give m.p. 148". f K. Mainzer, Her., 15, 1417 (1882), gives m.p. 156". 0 Reference e gives m.p. 88-89'. R . F. Hunter and J. W. Jones, J . C h e m SOL.,133, 2206 (1930), give m.p. 148". i Analysis is yo bromine.
*
GROUPD
0
C1 \NHCONHR
c1 / R
Max. diln. against MPA
4-Chlorophenyl Phenyl Hydrogen Ethyl t-Octyl 1-Naphthy1 2-Kaphthyl 2-Hydroxyprop) 1 Tetrahydrofurfuryl Cyclohexyl
1-30 million 1-10 thousand 1-10 thousand 1-10 thousand 1-10 thousand 1-10 thousand 1-10 thousand 1-1 thousand 1-1 thousand 1-1 thousand
No.
126 115 84
85 86 88 89 90 92 87
GROUPE
NO.
a4 96 94 97 100 108 107 104 102
R
R'
Max. diln. against MPA
H 2-Hydroxyethyl Allyl 2-Chloroallyl 3-Chloroallyl Cyclohcxyl Phenyl Butyl 2-Chloroallyl
H 2-Hydroxyethyl Allyl 2-Chloroallyl 3-Chloroallyl Cyclohexyl Phenyl Ph en y 1 Phenyl
1-10 thousand 1-10 thousand 1-1 thousand 1-1 thousand 1-1 thousand 1-1 thousand 1-1 thousand 1-1 thousand 1-1 thousand
Table VI1 describes the heterocyclic carboxaiiilides in which one nitrogen of the urea moiety is
bound in the hetero group. Varying degrees of activity were found, but a review of 25 derivatives fails to disclose any group equivalent to 3,4,4'trichlorocarbanilide. Compounds 150, 160, 161 and 164 were the most active but they were effective a t a maximum dilution of 1:100,000. I n group F is shown a comparison of substituted ureas with similarly substituted thioureas. The thio derivatives are invariably less effective. GROUPI.'
x
No.
X
R
Max. diln. against MPA
126 166 129 170 115 168 150 151 158 159
0
4-Chlorophenylamino 4-Chlorophenylamino 3,4-Dichlorophenylamino 3,4-Dichlorophenylamino Anilino Anilino 4-Morpholin yl 4-Morpholinyl 1-Pyrrolidine-2-thione 1-Pyrrolidine-2-thione
1-30 million 1-10 million 1-10 million 1-100 thousand 1-10 thousand 1-1 thousand 1-100 thousant1 1-1 thousand 1-1 million 1-1 thousand
S 0
S 0
S 0
s 0 s
Several brottlocarbanilides prepared for dirccl comparison with the chloro derivatives show a decreasing order of activity in both the urea and thio urea series as shown in group G. With the liiaximuni order of activity apparently attained in compound 126, a series of 33 isosteric
March 5 , 1057
PREPARATION AND BACTERIOSTATIC ACTIVITYOF SUBSTITUTED UREAS
1239
TABLE I11
R
NO.
21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49
80 51 52 53 54 55 56
Procedure H H C H A6 3-Diethylaminopropyl H 42 3. Isopropylaminopropyl H A7 3-Methoxypropyl H A7 Cyclohexyl H A5 2-Naphthyl Cyclohexyl A Cyclohexyl Allyl A2 Allyl CsHsNHCOIiHCHzCHtCHr CsHrNHCONHCHzCHzCHi- A6 Butyl Butyl AG Heptyl A Heptyl 2-Ethylhexyl 2-Ethylhexyl A7 Phenyl A7 Phenyl H A Cyclohexyl Cyclohexyl Cyclohexyl A H Cyclohexyl A Cyclohexyl Cyclohexyl A Cyclohexyl Cyclohexyl A H A6 3-Methoxypropyl H 2-Naphthyl A Cyclohexyl A Cyclohexyl H Ethyl A H 1-Naphthyl A H A 2-Naphthyl H A Cyclohexyl Cyclohexyl A Cyclohexyl Cyclohexyl A2 Cyclohexyl
R'
H
H H H H
H H H H H H H H 2-Methyl 2-Methyl 4-Methyl 4..Methyl 2-Methoxy 2-Ethoxy 2-Ethoxy 2-Ethoxy 4-Ethoxy 4-Ethoxy 4-Ethoxy 4-Ethoxy 4-Ethoxy Dodecyl 4-Dimethylamino 4-Dimethylamino 2-Phenyl ?-Phenyl %Phenyl 4-Chloro 4-Chloro 4-Chloro 2-Methoxy
R"
1-Naphthyl
H
A
2-Naphthyl H H Cyclohexyl Formyl Formyl Allyl Formyl
€1 Ethyl 3-Diethylaminopropy1 Cyclohexyl 2,4-Dichlorophenyl 3,4-Dichlorophenyl 3,4-Dichlorophenyl 2,5-Dichlorophenyl
A A A0 A A7 A? A2 A7
*
136.0-136 . G d 196.1-196.5 142.2-142.8 205.2-205.8 173.4-173.7 155.3-156.0 86.6-87.2 177.5-178.2 99.8-100.4 151.9-152.48 238.0-239.0 237.4-238.0 182.6-183.0 149.6-150.2 . .,. ,. ,. .
Analysis % nitrogen Calcd. Found 20.58 20.38 16.85 16.62 17.87 17.73 13.45 13.20 12.83 12.86 10.73 10.57 9.37 9 47 12.92 12.83 17.10 16.84 13.00 12.90 8 42 8.32 7.77 7.88 9.73 9.75 12.03 11.91 8.93 9.21 12.03 11.92 8.93 9.07 8.49 8.43 11.10 11.11 9.15 9.04 8.13 8.02 13.45 13.49 9.14 9.00 9.14 8.98 10.70 10.5G 8.15 8.18 6.13 6.20
96.0
227.5-228.5
13.79
81.3 88.0 100.0 100.0 85.3 63.0 87.2 71.0
252-253 114.6-113.Zi 76.4-77.0 110.0-110.7 118.5-119.1 122.5-123.5 151.2-152.0 152.5-153.0
Yield.
%
61.5 100 0 58.0 100.0 97.3 73.3 79.4 100.0 100.0 98.6 76.0 93.7 86.8 95.1 86.0 100.0 91.5 100.0 78.0 71.0 65.2 85.3 97.6 99.3 95.6 91.8 100.0
M.P., "C. 148.5-149.0a 69.5-70.0 143.7-144.2 87.5-88.2 186.3-187. I* 233.0-234.0 180.3-181.3c 65.5-66.0 132 decomp. 82.7-83.0
. ........ . . .. .. . . .
13.79 11.67 12.90 7.43 8.16 CirHoClaNzOi 8.16 ClrHClaNzOz CisHiaClaNzO 30.00° CisHizClzN~03 8 . 2 6
13.89 13.9; 11.59 12.60 7.39 7.99 8.00 30.09' 8.19
A. Skita and H. RoLfes, ibid., 53, 1248 (1920), give 1n.p. 182". P. a A. Steiner, Ber., 8 , 518 ( H i s ) , gives m.p. 149'. W. Michler, Ber., 9, 398 (1876), gives 1n.p. Sabatier and J. B. Senderens, Ann. chim., [8]4, 379 (1905), give m.p. 169 , 136'. H. F. J . Lorang, Rec. trav. chim., 46,635 (1927), gives m.p. 152". f M. H. Werther, ibid., 52,670 (1933),gives m.p. 118'. 0 Analysis is % chlorine. GROUPG
GROUPH
K
No.
x
R
R'
Max. diln. against M P A
125 133 82 167 169
0 0 0
3,4-Dichloro 3,4-Dichloro 3,4-Dibromo 3,4-Dichloro 3,4-Dichloro
3-Chloro 3-Bromo 3-Chloro 3-Chloro 3-Bromo
1-30 million 1-1 million 1-1 million 1-10 milion 1-1 million
S S
derivatives were screened to determine the overall effect of the urea linkage connecting both the 3,4-dichlorophenyl (group H) and 4-chlorophenyl (group J) moieties. None of these conipounds approach the activity of 129 or 126 except the symmetrical carbanilate 205. No explanation is offered except to point out this frequently recurring phenomenon wherein a slight change in structure has resulted in enormous variations in activity and reversals of trends when chang-
No.
129 174 180 185 186 192 195 203 205
R
-KHCONH--NHCO---h7~CH-hTHCOCONH-NHC=KH,XH-NHCOKHCHz-SHSOKH--SH C H z S -XHCOO-
Max. diln. against MPA
1-10 million 1-10 thousand 1-1 thousand 1-10 thousand 1-10 thousand 1-1 thousand 1-10 thousand 1-10 thousand 1-10 million
ing from one series to another no niatter how closely related. A similar investigation of the carbanilates will be reported in a forthcoming paper. Experimental The compounds described in Tables 11-IX have been prepared following one of the procedures A-E as noted. Thr reactants, when commercially available, were used as received without further purification. \%'hen unavailable,
D. J. BEAVER,D. P. ROMAN AND P. J. STOFFEL
1240
Vol. 79
T U L I~V
R
NU.
R
R'
Prucedure
R'
Yield.
%
M.p., OC.
Analysis % ' nitrogen Calcd. Found
H 2-Methoxy 146.2-146.8" A 84.3 11.57 11.47 H 2-Ethoxy 94.4 10.94 173.8-174.2' A 10.69 H 4-Ethoxy A 10.94 100.0 188.2-188.8" 10.85 H A 11.66 "Ethyl 61.2 184.9-185.5 11.43 H 4-Dimethylamino 94.0 208.0-208. 8d A 16.46 16.32 H 4-Diethylamino A 88.8 178.7-179.3 14.83 14.71 H A 9.73 9.67 95.7 173.0-173.6 2-Phenyl H 9.73 0.48 85.5 240-241" 4-Phenyl A >400f 18.43 18.10 H 4-Amino A 78.5 212.8-213.8' 4-Anilino H 13.88 13.85 98.2 A 11.35 H 11.33 25O-25lh 95.0 4-Chloro A 22. 7BP 2-Methoxy 2:j. 13'' 222.3-223.0 2,4-Dichloro -4 99.5 22. 7gP 23. 6 j p 4-Methoxy 230.0-230.5 58.0 2,4-Dichloro A 2-Ethoxy 9.35 9.16 146.4-147.0' 4-Ethoxy A 65.2 4-Ethoxy 202.0-202.4' 2-Methyl 10.33 10.37 A 84.0 4-Ethoxy 220.4-221. Ok 10.33 10.14 4-Methyl A 100.0 4-Ethoxy 211.8-212.2 14.07 14.05 4-Dimethylanlino A 91.1 4-Ethoxy . . ....... 6.60 6.81 A2 100.0 Dodecyl 8.44 8.44 4-Ethox~. 194.8-195.4 2-Phenyl A 95.8 11.06 11.01 2-Phenyl 155.8-156.2 86.8 4-Anilino A 7.69 7.85 2-Phenyl 182.2-182.8 74.0 2-Phenyl A .. .. 4-Phenyl 4-Phenyl A 312 dec 76.6 .. .. 79 A 3 15-3 19" 4-Chloro 98.0 4-Chloro 33. 7OP 33. 20n 80 253.0- 253.8" 4-Chloro 98.0 2,4-Dichloro A 33. 7OP 81 33.40" 261.5-262.5 4-Chloro A 83.0 2,5-Dichloro 6.93 6.99 82 208.5-209.0 3-Chloro 94.0 3,4-Dibromo A 83 261-263" 2,4-Dichloro 2,4-Dichloro A 97.5 "J. 11. Ransom, Am. Chem. J., 23, 40 (1900)' gives m.p. 144O. R. Leuckart, J . prakt. Chem., [2] 41, 327 (1890), gives H. Staudinger and R. Endle, Ber., 50, m.p. 170'. G. Abati and P. Gallo, Chenz. Z e n f r . ,I, 246 (1907), give m.p. 178". 1045 (1917), give m.p. 208'. e M. J. Van Gelderen, Rec. trav. chim., 52,977 (1933), reports m.p. 240". f E. Lellmann and E. Wurthner, Ann., 228, 225 (1885), give no data. 0 A. Krammer, J . prakt. Chem., [2]86, 361 (1912), gives m.p. 213.5'. H. Goldschmidt, Ber., 25, 1364 (1892), gives m.p. 238'. i A. F. McKap, Can. J . Chern., 30, 227 (1952), gives m.p. 148'. Reference e k A. F. McKay, ibid.,30,227 (1952), gives m.p. 217". j A. F. McKay, ibid.,30, 227 (1952)' gives m.p. 210". F. D. Chattaway and K. P. Orton, Ber., 34, 1074 (1901), give m.p. 310". " I?. D. Chattaway and K. P. gives m.p. 312O. Ort:n, ibid., 34, 1074 (1901), give n1.p. 273". 0 G. Young and A. E. Dunstan, J . Chein. Soc , 93, 1058 (1908), give m.p. 262 . p Analysis is % chlorinc. Procedure A? 3,4-Dichlorocarbanilide (1 15).--A soluGROUPJ tion of 11.9 g. (0.1 mole) of phenyl isocyallate in 50 1111. of ether was added dropwise, with constant stirring to 16.2 g. (0.1 mole) of 3,4-dichloroaniline in 50 ml. of ether. T l ~ c product separated during addition as fine white plates. The slurry was held for 2 hours, filtered, washed with 20 nil. of ether and dried; yield theoretical. (In several cases, M a x , diln. R against MPA EO. the reaction is sufficiently exothermic to evaporate the ether and additional ether was added to maintain a stirrable -XIlCONl31-30 million 126 slurry.) One recrystallization from ethanol gave fine, color1-100 thousand -CONH175 less needles. 1-10 thousand -CSNH176 An unexpected result was obtained on preparing the carbanilide from 3,4-dichlorophenyl isocyanate and p-phenyl1-1 thousand 177 -CHzXHenediamine. Irrespective of molar ratios, when reacting 1-1 thousand -SHCHt178 in ether the disubstituted derivative was obtained (191); 1-10 thousand -KHCO179 but when run in benzene only the mono-substituted deriva-N=CH1-1 thousand 181 tive could be formed (120). The reduction of 3,4-dichloro4'4trocarbanilide (136) gave a product identical with 1-1 thousand -NH.CHzCO182 (120). 1-1 thousand -CHzhTHCONH193 Sub-procedures A were carried out exactly as described 1-1 thousand 204 -KHCOOin A substituting the reactant solvent as A2 Skellysolve "D" (heptane fraction) they were prepared in this Laboratory as described under A3 Benzene "Preparation of Intermediates." A4 Acetone Compounds described under procedures A-A7 and B A5 Abs. ethanol were prepared by treating the appropriate isocyanate or No solvent A6 isothiocyanate with amine in a suitable solvent. The solNo solvent OO", 4 hr. A7 . . _ vents and amines were anhydrous to prevent reaction of the , , 231 (1840). (7) P. P. Sah, Rcc. lrav ~ h i ~ n69, isocyanates to form the symmetrical carbanilides. 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78
'
March 5 , 1957
PREPARATION AND BACTERIOSTSTIC
ACTIVITY OF
SUBSTITUTED U R E A S
1241
TABLE V
NO.
R
R'
Procedure
C H H A Ethyl H A t-Octyl H A Cyclohexyl H A 1-Naphthyl H A 2-Naphthyl 89 H A 2-Hydroxypropyl H 90 A 3-Hydroxypropyl H 91 A Tetrahydrofurfuryl H 92 A 4-Chlorophenyl Ethyl 93 A2 Allyl Allyl 94 A Isopropyl Allyl 95 A 2-Hydroxyethyl 2-H ydroxyeth yl 96 A 2-Chloroallyl 2-Chloroallyl 97 A Isopropyl 2-Chloroallyl 98 A &Butyl 2-Chloroallyl 99 A 3-Chloroallyl 3-Chloroallyl 100 A2 3-Methoxypropyl 101 2-Chloroallyl A7 Phenyl 2-Chloroallyl 102 A 2.3-Dichloroallgl H 103 A Phenyl Butyl 104 A Phenyl 2-Cyanoethyl 105 A 2-Propynyl Isopropyl 106 A Phenyl Phenyl 107 A Cyclohexyl Cyclohexyl 108 A 3-Chloro-2-butenyl Cyclohexyl 109 A 4-Ethoxyphenyl Allyl 110 A2 3,4-Dichlorophenyl Allyl 111 A 2-Propynyl 3,4-Dichlorophenyl 112 A Phenyl 113 Butyl A4 2-Thiazolyl H 114 a C. W. Todd, U. S. Patent 2,655,447, no data given. 84 85 86 87 88
Yield.
M . p . , oc.
%
155.6-156.3 93.7 17!3.5-180.1' 100.0 145.8-146.6 100.0 188.0-188.7 100.0 97.0 265-266 267-268 97.2 152.0-152.8 100.0 98.8 126.5-128.0 144.1-144.9 100.0 77.0 116.0-116.8 62.5-63.5 100.0 84.0-84.5 93.4 156.8-157.6 65.0 100.7-101.4 100.0 84.7-85.2 100.0 100.0 93.9-95.0 100.0 156.0-156.6 ....... . . 100.0 118.7-119.4 92.9 105.1-105.9 61.2 98.5-99.4 96.5 114.7-115.5 89.3 84.4-85.1 71.1 148.3-149.1 39.5 177.6-178.4 98.0 160.4-160.8 88.7 . .. .. .. 100.0 116.8-117.5 87.3 145.2-146.0 69.0 98.5-99.4 96.5 225 dec. 99.0 Analysis is % nitrogen.
Procedure B.* 3,3',4,4'-Tetrachlorothiocarbanilide (170). -A solution of 20.4 g. (0.1 mole) of 3,4-dichlorophenyl isothiocyanate and 16.2 g. (0.1 mole) of 3,4-dichloroaniline in 75 ml. of absolute ethanol was held a t reflux for 1 hour. On cooling, the product separated in a white granular mass which was filtered, washed with 30 ml. of ethanol and dried. One recrystallization from ethanol gave fine, white granules. Procedure C.9 Phenylurea (21).-A solution of 11.9 g. (0.1 mole) of phenyl isocyanate in 400 ml. of ether was held at 20' while passing anhydrous ammonia through the solution until precipitation was complete. The crude product was filtered and recrystallized from ethanol to give small, white plates. Procedure D.10 1,3-Di-2-naphthylurea (4).-A dry mixture of 60.0 g. (0.42 mole) of 2-naphthylamine and 24.0 g. (0.2 mole) of urea was heated gradually to 160" and held for 3 hours until the evolution of ammonia was complete. The crude mass was pulverized and extracted with three 200-ml. portions of boiling alcohol, discarding the filtrates. The extracted cake was recrystallized from glacial acetic acid to give a white microcrystalline powder. Procedure E." 1,3-Dicyclohexylurea (8).-A solution of 60.0 g. (0.6 mole) of cyclohexylamine and 800 ml. of toluene was held at 100' while passing in phosgene until no more solids formed. The heavy slurry of cyclohexamine HC1 salt was filtered and discarded. The filtrate was evapo(8)T. Otterhacher and F. C. Whitmore, THIS JOURNAL, 51, I909 (1929). (9) P. P. Sah and K. S. Chang, Bcr., 69, 2762 (1936). (10) T. L. Davis and H. W. Underwood, Jr., THISJOURNAL, 44, 2601 (1922). (11) A. W. Hofmann, Ann., 70, 140 (1849).
.
.
Analysis % chlorine Calcd. Found
34.58 12,10* 22.37 24.70 21.41 21.41 26.92 26.92 24.50 31.00 24.83 24.70 24.20 40.00 33.13 31.70 40.00 30.30 29.92 45.20 21.03 21.20 24.50 19.85 7. 6O6 28.31 19.41 36.25 36.58 21.03 24.60
34.45 12.32b 22.70 24.85 21.17 21.34 26.73 26.80 24.28 31.02 25.01 24.70 24.15 40.00 32.90 31.91 39.96 29.85 29.90 44.90 21.34 21.12 24.61 20.30 7.49b 28.37 19.40 36.43 36.44 21.34 24.62
rated under vacuum and the crude residue was recrystallized from ethanol to give small colorless needles. Preparation of Intermediates.-The preparations of only those compounds which are new are described. The number in parentheses following the compounds corresponds to the product in Tables 11-IX for which it was used. N-Formyl-3,4-dichloroanilinel~ (54).-A solution of 32.4 g. (0.2 mole) of 3,4-dichloroaniline and 18.4 g. (0.4 mole) of 95y0 formic acid was refluxed for 6 hours. On cooling, the product separated and was filtered. One recrystallization from benzene gave fine, colorless plates. N-(2-Propyny1)-3,4-di~hloroaniline1~ (1 12).-A 162.1-gd (1 .O mole) charge of 3,4-dichloroaniline was held a t 75-80 with vigorous stirring while adding dropwise 60.0 g. (0.5 mole) of propargyl bromide. After addition was completed, the resultant slurry was held a t 85' for 3 hours. The reaction mix was cooled and held a t 20' using an icesalt-bath while neutralizing with a solution of 30 g. (0.75 mole) of sodium hydroxide in 500 ml. of water. The oil which separated was extracted with two 300-ml. portions of ether and dried over calcium chloride. The ether was removed under light vacuum and the remaining oil was distilled. After removal of the 3,4dichloroaniline, the product was obtained as a mobile yellow oil b.p. 152.7-153.4' (7 mm.), ~ % S1.5991. D N-AUy1-3,4-dichloroaniline1*(11 1).-Prepared as above using allyl chloride and held 18 hours a t 80-85'. Lemon (12) F. D. Chattaway, K . J. Orton and W. H. Hurtley, Bcr., 32, 3636 (1899). (13) T.J. Nolan and H. W. Clapham, J . Soc. Chcm. I n d . , London, 44,
220T (lQ25).
n.J. BEAVER,D . P. ROMANAND P. J
1242
STOFFEL
Vol. 79
TABLE VI R
CIA.NHCOSH? I).
TYPE
R
NO.
a
115 H 4-Methyl 116 117 2-blethoxy 118 4-Methoxy 119 4-Dimethylamino 120 +Amino 121 Dodecyl 122 2-Phenyl 123 4-Phenyl 124 2-Chloro 125 3-Chloro 126 4-Chloro 127 2,4-Dichloro 128 2,5-Dichloro 129 3,4-Dichloro 130 3,4,5-Trichloro 131 3-Chloro-4-hydroxy 132 3,5-Dichloro-4-hydroxy 3-Bromo 133 134 4-Anilino 135 4-Hydroxy 136 4-Sitro 137 4-Sulfamyl 138 4-(2-Thiazolesulfamvl) . , 139 4-(2-Pprimidiiiesulfamyl) Analysis is yo nitrogen
Yield. I'rocednre
A A
A A A A3 A7 A A A A A A A
-4 *4 A A A A A3 A A4 A4 A4
c/o
100.0 100.0 95.2 93.5 95.0 96.0 98.0 91.6 84.5 87.0 91.5 88.0 97.3 94.2 100.0 100.0 95.4 92.4 300.0 100.0 82.5 95,3 83.6 82 S 79.0
yellow oil, darkening rapidly, b.p. 159.0~-161.0°(7.5 nun.),
n2% 1.5895.
3,4-Dichlorophenyl Iso~yanate.~4--0neliter of ethyl acetate was saturated with phosgene and held a t reflux while adding a solution of 324 g. (2.0 mole) of 3,4-dichloroaniline in 1.5 1. of ethyl acetate in a fine stream over 2-3 hours. Phosgene was passed into the reaction flask throughout t h e reaction so as to maintain an excess of phosgene a t all times. n'hen all the amine was added, the phosgene was cut off and the solution held a t reflux for 1 hour. Approximately 1.5 1. of ethyl acetate was distilled a t atmospheric pressure, removing practically all dissolved phosgene. The remaining solvent was removed under vacuum gradually dropping the pressure during the distillation. Following a small precut, the product was obtained as a mobile colorless liquid b.p. 116.7-118.1° (10.5 mm.) which gradually set t o a hard crystalline mass, c.p. 40-41' (90.5%). A n d . Calcd. for C7H8CI?KO: N, 7.45. Found: N, 7.45. 3,4-Dichlorophenyl Isothiocyanate.l6-A solution of 58.0 rnl. of 38% hydrochloric acid and 350 ml. of water was held a t 10-15" with vigorous agitation while adding 80.0 g. (0.7 mole) of thiophosgene during '/2 hour. The cooling bath was removed, and a solution of 128.0 g. (0.7 mole) of 3,4dichloroaniline in 400 ml. of toluene was added in a fine stream allowing the temperature to rise t o 40-45' over '/z to 1 hour. The flask was then gradually heated to 85" and held for 3 hours. A small amount of solid material was filtered and discarded. The toluene layer was separated. The aqueous layer was twice extracted with 30-ml. aliquots of toluene, and the extracts combined. The toluene phase was twice washed with 50-ml. aliquots of water, separated and distilled. The solvent, water and low-boiling material was removed gradually reducing the pressure t o 20 mm. a t 180". Following a small precut the product was obtained ais a yellow mobile oil, b.p. 134.8-135.9' (7.0 mm.); .~~ ____ (14) 1%'.
€I. Iirirne and R . L. Shriner, THISJOURNAL, 63, 3180
(1931). (15) G. M. Dyson and (19%).
H. J. George, J . Chem. Soc., 126, 1702
M.P., =c.
217.2-217.7 258.0-259.0 173.8-174.3 233.1-234.0 229.6-230.4 >360
. .. . . ... . 183.3-184.1 233.0-234.0 220.0-220.6 210.7-211.3 255.2-256.0 238.5-239.2 242.2-242.6 -381-282 308-3 10 237.4-238.0 272-273 208.5-209.2 208.8-209.5 213.8-214.5 294-295 258.5-259.5 271-272 290 dec.
Analysis % chlorine Found Calcd.
25.11 23.96 22.78 82.78 21.83 23.92 15.78 19.85 19.85 33. 70 33.70 33.70 40.57 -40.57 40.37 46.09
8,46" 7.66" 7.78" 19.04 23.86 21.72 11.68" 15.8
