July, 1031
PHENOXYAND BENZYLOXYALKYL THIOCYANATES [CONTRIBUTION FROM
THE
3159
WARNERINSTITUTE FOR THERAPEUTIC RESEARCH 1
Phenoxy- and Benzyloxyalkyl Thiocyanates1 BY JEROME D. GENZER,CHARLESP. HUTTRERAND G. C. VAN WESSEM A series of phenoxy- and benzyloxyalkyl thiocyanates has been prepared for pharmacological evaluation as fungicides against pa thogenic fungi associated with dermatophytosis.
The reaction of the halides with KSCN proCompounds of the type herein described have been studied in the past almost exclusively with ceeded quite readily when bromides were used, respect to their insecticidal and only whereas chlorides proved considerably less satisin isolated cases has any mention been made of their factory. In many cases, copper or K I was used anti-fungal activity.6 In contrast, the activity of to catalyze the latter reaction. The structural configuration of the thiocyanates alkyl and aryl thiocyanates and isothiocyanates as fungicides as well as insecticides is fairly well has not been intensively studied and the possibility known6,’and this was further verified by the testing exists that some of these compounds rearrange to of certain known as well as new aryl isothiocyanates the isothiocyanate during distillation. It has been prepared in this Laboratory.8 A consideration of shown that thiocyanates yield disulfides when the aforementioned facts, coupled with the results hydrolyzed with acids or bases,’O or when heated obtained from the fungicidal screening of certain with tertiary amines in acetic acid.“ ~ - ( p alkoxyalkyl thiocyanates previously described in Bromophenoxy)-propyl thiocyanate, when subthe literature, prompted the present investigation. jected to alkaline hydrolysis, was shown to yield The thiocyanates (Tables IV and V) were s C H 3 0 0 C o O__ (CH2)3Brprepared, by metathesis with KSCN, from the corresDondina halides. The halides in the 11 phenoiy seriis (Table I) were prepared from H O O C ~ O ~ C H 2 ) J B r C H ~ O O C D O ( C H Z ) ~ S C N the appropriately substituted phenol either by reaction of the latter with an alkylene halide in the presence of sodium hydroxide in an aqueous m e d i ~ m or , ~ bv the action of the alkvlene H O O C ~ O ( C H ~ ) ~ S C N H O O C ~ O ( C H Z ) 2% Z] halide on the sodi;m salt of the phenol in an 111 IV anhydrous alcoholic medium. The low yields of (I) are attributed to the formation of the diether. the corresponding disulfide, thereby establishing the thiocyanate structure. Similarly, a study of aq. NaOH the preparation of p-( y-thiocyanopropoxy)-benzoic a O H 4- X(CHdnX or NaOEt acid (111) from methyl p-(7-bromopropoxy)-benzoi ate (11) indicated the necessity of saponification R of the carbomethoxy group with alcoholic KOH previous to reaction with KSCN. The reverse procedure led to the formation of the disulfide R (IV) thereby establishing (111) as a thiocyanate (1) and not an isothiocyanate. In the benzyloxy series, the halides (Table 111) The yields reported in a majority of the preparawere prepared from the corresponding alcohols by tions are on the basis of single experiments and do not treatment with thionyl chloride in the presence of a necessarily constitute the maximum yield obtaintertiary amine and chloroform. The alcohols able. (Table 11) were easily obtained by refluxing the The pharmacological evaluation of the comappropriate benzyl halides with sodium and a pounds herein described will be reported elsewhere polymethylene glycol in the presence of xylene. by other workers.12
4
J
~
[
.1
____f
CH~CI
+ E a + HO(CH~),OH +
Experimental
1
The following examples are illustrative of the method of R preparation of the compounds listed in the tables. All (cH~) .OH melting and boiling points are uncorrected. Procedure I , y-( dsopropylphenoxy )-propyl Bromide (Table I, Compound 25).-Twenty-three grams (1 mole) of R metallic sodium was dissolved in 450 ml. of absolute alcohol (1) Presented before the Division of Medicinal Chemistry at the with stirring. To this solution was added 136 g. (1 mole) 119th meeting of the A.C.S., Cleveland. Ohio, April, 1951. o-isopropylphenol and then 250 g. (25% excess) of trimethyl(2) G. H. Coleman, U. S. Patents 2,185,183,2,185,184,2,185,185 ene bromide a t a moderate rate. Inorganic salt started (Jan.2, 1940). separating a few minutes after addition of the bromide. (3) J. E. Livak, U. S. Patents 2,185,207and 2,185,208(Jan. 2,1940). The mixture was refluxed for 5 hours, cooled and filtered. (4) A. Hartzell and F. Wilcoxon, Confrib. Boycc Thompson Ins!., 6 , There was a quantitative recovery of sodium bromide. 269 (1934). The alcohol was distilled and the unreacted bromide re(5) E.K.Harvill and J. M. Arthur, ibid., 18, 79 (1943). moved a t 12-15 mm. Then the residue was fractionated (6) F. Wilcoxon and S. A. E. McCallen, ibid., 7,333 (1935). (7) W.H . Davies and W. A. Sexton, Biochcm. J.,40,331 (1946). (10) C.Rabaut, Bull. SOC. chim., 27, 690 (1902).
C\CH~O =\I’
71,4323 (1950). (8) F.H. McMillan and J. A. King, THISJOURNAL, (9) C. S. Marvel and A. L. Tanenbaum, “Organic Syntheses,” Coll. Vol. 1, John Wiley and Sons,Inc.,New York, N. Y., 1944,p. 435.
(11) E.Hoggarth and W. A. Sexton, J . Chcm. SOC.,815 (1947). (12) L. Landis, D.Kley and N. Ercoli. J. Am. Phorm. Assoc., Scr. Ed., scheduled for publication, June, 1951.
3160
JEROME
n. C E N Z E R , C I I A R L E S P. HUTTRERAND G. c. VAN WESSEhl TABLE I PHENOXYALKYL HALIDES ,$--?,-o-c /\Cl
CHI,,X ,
R
r
R
NO.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 21 25
'C. 150 116 116
X 4 C1 5 C1 2 Br 2 Br 2 Br 2 Br 2 Br 2 Br 2 Br 2 Br 3 Br 3 Br 3 Br 3 Br 3 Br 4 c1 4 C1 4 C1 4 CI 4 CI 4 c1 3 Br 2 Br 2 Br 3 nr
n
2-Br 4-Br 2-CI 3-CI 4 4 2-CH: 3-CH3 4-CHs 4-Br 2x1 3-C1 4-C1 3-CHa 4-Br 2-C1 3-C1 2-CH3 3-CHa 4-CHa 4-NO% 4-OCHs 2-CH(CHn)z Z-CH(CHa)?
B.p.
Mm. 0.2 1.3 0 2
1.5215 1.5144
5 0.1
1.569 1.5680
ALP., OC.
Carbon Formula Calcd. Found CiaHirOCl CiiHisOCl CaHaOBrs CaHaOBrz CaHiOClBr CtHaOClBr 40.76 40.78 CsHaOClBr 40.76 41.10 CsHilOBr C,HltOBr CoHiiOBr CoHioOBrl CoHiaOClBr 43.29 43.55 CaHioOCIBr 43.29 43.39 CoHioOClBr 43.29 43.28 CioHlrOBr 52.40 52.60 CaHirOCIBr 45.54 45.66 CioHirOCla 54.79 55.02 CiaHirOCIz 54.79 54.54 66.50 66.82 CiiHisOCl CIiHirOC1 66.50 66 53 66 50 60 43 CiiHisOCl CeHia01NBr CioHuOzBr ChHirOBr
57 136 85 108 100 80 110 150 120 108
68
1
0 6 I 1
1 5478 I 5472 49 50
I
0 7 0.5 1
1.5792 1.5590 1.5580
37 120 2 128 0.03 2 130 0.4 114 1.5 114 0.1 93 97 .% 15.5 I 95-lO4 .Y
1.5422 1.5548 1.5350 1.5345 1.5189 1.5199 J 5180
80 81
.1
CirH170Hr
CllHi6OP.r
.04
26 34)CH(CHs)z
2
Br
90
.:3
27 28 29 30 31 32 33 34
3 3 3 3 3 3 3 3
Br 150-156 Br 164 Cl 140 C1 163 Br Br CI CI
1.4 1.6 1.2 3.2
2-COOCHs 4-COOCHs 2-COOCHs 4-COOCHs 2-COOH 4-COOH 2-COOH 4-COOH
naOD
I .532M'
CiiHi~OaBr CiiHiaOzBr CiiHiaOsCl CiiHisOsCI CioHiiOaBr CioHiiOsBr CioHiiOaCl CioHiiOaCl
71 161 75 156-157
.%, 32
55.32
-I
-
Analyses, % Hydrogen Halogen Yield, 40Calcd. Found Calcd. Found % cedure 215 1 16b 1 63' 2 44d 2 2 40' 3.40 3.12 49.04 48.83 23 2 3 . 4 0 3.73 49.04 48.60 26 2 2 52j 2 548 2 33; 53% 2 4.00 4.07 46.29 45.71 44 2 4.00 3 . 9 7 46.29 45.60 31 2 4.00 4.18 46.29 46.33 J 2 5.68 5.51 34.90 34.99 10 2 4.55 4.61 43.83 44.06 38 2 5.47 5.50 32.42 32.11 59 2 5.47 5.57 32.42 32.40 48 2 7.56 7.42 17.88 17.55 26 1 7.56 7.60 17.88 17.79 45 1 7 . 5 6 7.3fi 17.88 17.73 20 3 35k 3 14' 1 2 197'' 0.17 6.22
3 57'
1
21
2
37" 290 3 70 40' 46.33 46.59 46.33 47.29 55.94 56.58 55.94 55.52
4.25 4.25 5.13 5,13
4.35 30.89 31 .OO 4.68 30.89 30.95 5.43 16.55 16.74 5.03 16.55 16.73
PA
P P,? P,S
1
1 1 1 4 4 4 4
a J. v. Braun and E. Beschke, Ber., 39, 4357 (1906), report the preparation and analysis of this compound, b.p. 147' (12 mm.). * J. v. Braun and A. SteindorE, ibid., 38,962 (19O5), report preparation and analysis, b.p. 155" (15 mm.). Reported and analyzed by R. Stoermer and M. Schaffer, &id., 36,2874 (1903), b.p. 160-162' (16 mm.). d B. Jones, J . Chem. Soc., 1831 (1935), reports m.p. 58'. * R. Stoermer and M. Schaffer, reference c , prepared and analyzed this compound, b.p. 140-142'' (13 mm.). f R. Rmdfusz, P. M. Ginnings and V. Harnack, THIS JOURNAL, 42,157 (1920), prepared and analyzed this compound and reported b.p. 133-134' (20 mm.), ltnD 1.544. 9 W. A. Jacobs and M. Heidelberger, J . Biol. Chem., 21,440 (1915), prepared and analyzed this compound, b.p. 136-137" (14 mm.). L. Gattermann, Ann., 357, 356 (1907), prepared and analyzed,this compound, b.p. 254-255', m.p. 40". ' B. Jones, J. Chem. SOC.,1831(1935), reports b.p. 169' (12 mm.), m.p. 49.5'. Recrystallized from ethanol; poor yield. Solidifies a t room temperature; used crude in reaction with KSCN; unreacted phenol was washed out with NaOH solution before distilling; decomposition occurs if distilled through a column. E. Kahane and J. Levy, Bull. sot. chim. biol., 27, 562 (1945), b.p. 154" (11 mm.). Worked up in same manner as -N& compound. W. S. Gump and E. Nikawitz, THISJOURNAL, 72,3847 (1950), b.p. 123-127' ( 5 mm.), n*On.1.535 Distilled through I-foot glass helices packed column; no analytical sample; used slightly impure in reaction with KSCN. Distilled through 1-foot glass helices packed column: used slightly impure in subsequent saponification. p Yields from corresponding esters are quantitative. Recrystallized from Skellysolve B-ether mixture. Recrystallized from methanol-water (2:l). a Recrystallized from 80% ethanol. t TZ.Da t 25'.
TABLE I1
2 2-CIi,O-(
BENZYLOXYALKANOLS (--\
R
,
No.
R
n
'C.
B.p.
Mm.
n%
Formula
Carbon Calcd. Found
CHz),-OH Analyses % Hydro& Calcd. Found
Chlorine Calcd. Found
Yield,
%
Procedure
1 2 95 0.25 1,5209 CeH1202 81"s" 5 2 3 114 .9 1.5184 CioHi402 60b 3 3 5 140 .4 1.5099 Ci2Hi802 74.22 74.36 9 27 9 05 35 5 4 2-C1 2 84 .03 1 5348 CISH1IOzCl 57.90 58.05 5 89 5.87 19.00 18.95 84 5 5 2-C1 3 94 .5 1.5245 CIOH~ZO~CI 59.85 59 82 6 53 6.80 17 70 17.55 28 5 6 2-C1 5 139 .5 1.5202 Cl2HlrOzCl 63.02 63.16 7.44 7 74 15.54 15.65 54 5 G. Bennett, J. Chem. Soc., 127,1277 (1925) prepared and analyzed this compound, b.p. 138" (15 mm.). G. Bennett The correand A. L. Hock, ibid., 472 (1927) prepared and analyzed this compound b.p. 155' (23 mni.), 172' (43 mm.). sponding thenoxy compound was also prepared, b.p. 70-73" (0.05 mm ). Anal Calcd. for C7HloO2S: C , 53.16; H, 6 . 3 3 ; S, 20.25. Found: C, 52.95; H, 6.63; S, 20.41. (I
in vacuo. (This material was not absolutely pure but was used as such In reaction with KSCN.) Methyl p-(r-f3romopropoxy)-benzoate (Table I, Compound 28).-Forty-six grams (2 moles) of metallic sodium
was dissolved in 700 ml. of absolute ethanol. To this was added with stirring 305 g. (2 moles) of methyl p-hydroxybenzoate in 500 ml. of absolute ethanol. There was then added 500 g. (25% excess) of trimethylene bromide and the
3161
PHENOXYAND BENZYLOXYALKYL THIOCYANATES
July, 1951
TABLE I11 BENZYLOXYALKYL HALIDES$>-cH~-o-(cH~).cI
K
NO.
R
n
OC.
B.p. Mm.
naoD
Formula
Carbon Calcd. Found
Analyses. % H drogen Found
C a d
Chlorine Calcd. Found
Yield,
%
Procedure
2 75 0 . 2 1.5181 CpHiiOCl 77"s' 6 3 88 .5 1.5113 CloHliOCl 65* 6 d 4 75 .07 1.5109 CliHlsOCl 13' 4 5 86 .01 1,5079 Ci2H170Cl 67.76 67.86 8.00 7.82 16.70 16.57 75 6 5 2-C1 2 72 .01 1.5339 CsHloOC12 52.69 52.47 4.88 5.15 34.63 34.83 77 6 6 2-C1 3 120 .I 1.5268 CioHizOClz 54.79 54.83 5.47 5.38 32.42 32.35 48 6 7 2-C1 5 If4 1.6 1.5193 CizH160Cl? 58.30 58.34 6.48 7.62 28.74 28.99 7 6 G. Bennett, J . Chem. Soc., 127, 1277 (1925), prepared and analyzed this compound, b.p. 124' (20 mm.), ~ O 1.5204. D G. Bennett and A. Hock, ibid., 472 (1927), prepared and analyzed this compound, b.p. 129' (16 mm.). Idem., report Prepared from benzyl alcohol, metallic sodi,urn and 1,4-dichlorobutane by refluxing for 30 minutes, b.p. 1 3 5 O (12 mm.). filtering and fractionally distilling. e The corresponding thenoxy compound was also prepared, b.p. 69-70' (0.1 mm.). A n d . Calcd. for CIHgOClS: C, 47.59; H , 5.14. Found: C, 47.66; H, 5.09. 1 2 3
TABLE IV PHENOXYALKYL THIOCYANATES d--O-(
CH2),-SCN
R/-
-Analyses, %Hydrogen Carbon Calcd. Found Calcd. Found
c
SO.
R
n
F.P., C.
Nitrogen Calcd. Found
Yield,
Procedure 7 7 7b 7 7 7 7 7 7 7 7, 7a 7 7 7 7 7b 7b 7b 7b 7 7 7 7 7, 7a
141 0 . 4 123 . 3 1.5402j
Formula CoHoONS CioHiiONS CiiHisONS CoHaONRrS CsH8ONClS CiHsONClS CBH~ONCIS CioHiiONS CioHiiONS CioHiiONS CioHioONBrS CioHioONClS CioHioONClS CioHioONClS CiiHisONS CiiHinONBrS CiiHizONClS CizHiaONS CiaHiiONS CiiHiiOaNS CiiHiiOaNS CioHioOaNzS CmHiiOzNS CizHisONS
2
130
CI z H i L 0N S
65.16
65.32
6.79
6.77
6.33
6.39
51
7
3 2 4
140 .1 1.5363k 162 1 . 7 1.5920 164 0 . 5 1.5544
CisHirONS CiHsONBrS CiiHizONClS
66.34 41.87 54.65
66.13 41.62 54.87
7.28 3.10 4.97
7.18 3.34 4.98
5.97 5.42 5.80
6.00 5.33 5.64
60 51 40
7,7a 7
1
2
2
3 4
:I 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
4-Br 2-Cl 3-CI 4-C1 2-CHs 3-CHa 4-CH3 4-Br 2-c1 3-C1 4-C1 3-CH1 4-Br 3-C1 2-CHa 4-CHs 2-COOH 4-COOH 4-NO2 4-OCHa 2-CH (CHa),
2 2 2 2 2 3 3 3 3 3 4 4 4 4 3 3 3 2 2
25
:>CH(CHa)z
26 2-CH(CHa)? 27 2-Br 28 2-CI
B.p. naOD OC. Mm. 152 0.4 1.5599 125 . 4 1.5518 158 , 1 1 ,5480
2 2
180 126 137 132 1.58 130
3.0 0.1 , I 1.5710 .3 4 . 0 1.5534 0 . 5 1.5530
165 164 50 138 180 186 138 193
1.3 1.2 0.5 .6 .5 1.9 0.1 5.0
38-39 62-63 37-39
48-49 1.5644 1.5624 1.5471 1.5410 1.5543 1.5533 1.5410 69-70 159 53-54
.3
63.77 41.87 50.59 50.59 50.59 62.17 62.17 62.17 44.11 52.75 52.75 52.75 63.77 46.15 54.65 65.16, 65.16 55.69 55.69 50.42 57.42 65.16
63.82 42.17 50.48 50.42 50.77 62.03 62.19 61.88 44.49 52.90 52.67 52.43 63.73 45.95 54.62 65.15 65.35 55.73 56.65 50.51 57.42 65.30
6.28 3.10 3.75 3.75 3.75 6.70 5.70 5.70 3.68 4.39 4.39 4.39 6.28 4.20 4.97 6.79 6.79 4.64 4.64 4.20 5.31 6.79
6.07 3.08 3.47 3.68 3.92 5.54 5.89 6.02 3.68 4.52 4.13 4.37 6.31 4.07 5.02 6.37 6.88 4.64 4.71 4.02 5.03 7.16
6.76 5.42 6.56 6.56 6.66 7.25 7.25 7.25 5.15 6.15 6.15 6.15 6.76 4.89 5.80 6.33 6.33 5.94 5.94 11.76 6.69 6.33
6.79 5.17 6.67 6.33 6.44 7.09 7.42 7.24 5.21 6.22 6.12 5.84 6.89 4.97 5.72 6.21 6.07 6.05 5.92 11.78 6.81 6.45
% 81" 83' 37C'O 51d,e 83 33 17 60'20 63" 66lJ' 53 52 9gh 40 42 66l 55V' 15n 27Q 35' 35 44 43 47
8
Reference 4, m.p. 21'. Reference 4, b.p. 188-19l0 (14 mm.). Recrystallized from methanol. Recrystallized from methanol. e Anal. Calcd. for CeHsONBrS: Br, 30.96. Found: Br, 31.29. f These compounds were used by Harvill and Arthur, reference 5, in testing as insecticides but their method of preparation is only generically mentioned. S o analyses Anal. Calcd. for CloHloONClS: C1, 15.58. or physical constants were mentioned. 0 Solidifies a t room temperature. Found: C1, 15.65. Recrystallized from benzene-Skellysolve B-ether. i T Z D a t 27'. =D a t 27'. Refluxed 24 hours without KI. Refluxed 18.5 hours without KI. Refluxed 12 hours without KI. Refluxed 75 hours without KI. p Von H. P. Vogelsang, Th. Wagner-Jauregg and R. Rebling, Ann., 569, 187 (1950), report b.p. 181-184' (0.9 mm.), ?Z1'.'D 1.5615. q Idem., b.p. 190-193" (0.15 mm.), n i 7 1.5491. ~ mixture worked up the same as above (used as such in subsequent saponification). Procedure 11. 6-(p-To1oxy)-butyl Chloride (Table I , Compound 21).-Prepared according to reference 9 from p cresol, I ,4-dichlorobutane and aqueous sodium hydroxide. -&-Bromophenoxy)-propyl Bromide (Table I, Compound ll).-Prepared according to reference 9. The material solidified and was recrystallized from ethanol. In reactions carried out by this method it was found that the rate of addition of the sodium hydroxide did not appreciably affect the yield. Procedure 111. -p(p-Nitrophenoxy )-propyl Bromide (Table I, Compound 2'2).-Twenty-three grams (1 mole) of metallic sodium was dissolved in 300 ml. of absolute ethanol (stirring and slight heat were used to effect solution). To
this was added 139 g. (1 mole) of P-nitrophenol in 250 ml. of absolute ethanol and 250 g. (25y0 excess) of trimethylene bromide. The mixture was refluxed for 5 hours, cooled and filtered. The alcohol was removed in vacuo and the residue dissolved in ether (last bit of inorganic salt separated here and was removed). The ethereal solution was extracted twice with 3 N sodium hydroxide and twice with water to remove unreacted phenol. The ether layer was dried over calcium chloride, filtered and the ether evaporated. Unreacted halide was distilled and the residue fractionated using only a still head. The product solidified a t room temperature. Procedure IV. p-( 7-Bromopropoxy)-benzoic Acid (Table I, Compound 31).-Two grams of the corresponding ester (see procedure I ) was heated with a slight excess of alco-
:: 1 (it!
Vol. i 3 TABLE V
