September 1969
783
R-~-c--A~ R
R'
1r
H H H H H H
H H H
3-Chloro-2-thieiiyl 2-Thien yl 2,4-C12CsH, p-Br CsHc O-ClCsH, p -C1C6 H 4
H
H H H H H H H
H CH3 H II H
H C H:,
H H
H
cr-I,
I
II
Rj
0
Method
Yield, 'ic
-4 B B B B -4
69 2 :3 71 46 69
B A A B B B B
58 62 80
n
prompted an expansion of our synthetic efforts, encompassing a large number of derivatives of A in order to investigate the structure-activity relationships goveriiing thi\ clas, of compounds. Moreover, during the course of thii \vorI\- it wai found that many cyclic ketals derived from 2-(l-iniidnzolyl)acetophenotie. 2.e.) type H, showed significant hiological activity. In the present paper we wiih to report the synthe~isand antimycotic and antibnctcrial propertie? of compoiindY derived from and related to A arid B. Chemistry.-The 2- (1-i midazolyl)acetophenones (compounds 1-14, Table I), required as starting materials, were prepared by the reaction of the aryl bromoalkyl ketones \I ith excess imidazole in J l e C S or DAIF a t room tempernture (method A). The literatuie method3 for preparing 8 in alcohol ~ 1 x 5tried but was unsatisfactory a. it led primarily to quaternary salts ubseyuently simplified by brominating the prerequisite acetophenone followed by treatment of the crude reaction mixture with a fivefold excess of imidazole (method B). The reaction of a-broinopropiopheiione with imidazole furniihed 9 iri 6Sy0 yield. It* iiuthenticity \viis established hy it* identity to the methylntiori product of the ariion ( J f 8 [hemmcth) 1phoiphor:imidc (HA1I'*4) S a H 1. Compound 14 \vas prepared by succe>+tve treatment of isobutyrophenone with Br2 and imidazole. a-Arylimidazole-1-ethanols, ihown in Table 11, were obtained by three methods. Compound A (X = OH) was produced convenientl- and directl? by the baiecatalyzed reaction of imidazole and styrene oxide, but. commercial inaccessibility of subhtituted aromatic epoxides made exteriGon of this met hod unpractical. S:iBFT I rcdiiction of fhc 1,rtoneh gavc thc h i r c t l id~ o h o i - iir exelleiit yield^ (method C'). Prevlo~i, experieim4 had shown that the imidazole anion ivah most advantageously alkylated in a dipolar aprotic wlvriit iiicli :I. D l l F Therefore *odium imidazole ( 3 ) German Patent 488,681 (lY.54); F. I\-. Ueilbtein, "Handbrlch der Organisclien Ciiemie," Vol. 23 ( I I ) , p 3T. (4) E. E. Godefroi, J . 078. Chem.. 33, 860 (1968).
r-
l i
5s 59 49 "V
ii
45
lip,
oc
160- 162
136- 138 16;)-170 167-168 179-180 160-161 228-229 154-lL56 117-118 139-140 167-168 13 0- 138 220-221 171-172 167-1 68
h a l , ses
C, H C, H, N C, H, K C, H, Tu' C, H
C, H, N C, H, S
C, H, S
c, H C, H c, €1 C, H, S C, H, N C, H, N
was treated with a-bromonieth: 1-p-chlorobenzyl alcohol in DAIT, giving 19 in S3% yield (method D). This method also allowed for the preparation of tertiary alcohol, 22 and 24, *iiice the prerequt,ite chlorohydrins are acce4ble from the reaction of chloroacetone and Grignard reagent\. When the oxime of 8 IW* 11) drogenated in the presence of liane\- Si.compound -4 (X = S H J was obtained. Scheme, involving catalytic reductions precluded preparation of ha1ogeii:ited derivatives, so that attention was focused on treatment of the ketones with a variety of amines to yield the corre*ponding imines. Reductiori of the latter by SiiBFI, gave amines 28-54 (see Table 111). I'erforming the reduction at 5-25' n a i found to be e,.ential. as even at the.e temperatures the reaction ~ v n at \ time. accompanied by formation of dibenq 1:tminei. Cle\ nted temperature5 promoted this side reacl ion. The sodium salts of alcohol< 15-27 reacted smoothly with benzyl chlorides in DAIF, THF, or HAIPA, most favorable iewlts being obtained with the latter a t 5-2.;". The resultant ether5 are listed in Table IT. Sitrophen)l ether\ 56 :itid 57 ere obtained b! treatment of the :~ppropri:itealcohol :inion5 with p-nitrofluo robeI IZ(>I o i* 2,4-d ii ii t rochloro bel ize 1le. Che mica1 reduetioil (1;e-aqueoui SH,Cl) furni,hed amine 58. Initial efforts to ketalize 8 by coriveIitioiia1 procedures were unsatisfactory, due to unacceptably low conversions. Attention was therefore turned to the direct alkylation of sodium imidazole with 2-bromomethyl-2aryldioxolaneq and the corresponding 1,3-dioxanes ill DAH'. Some of the dioxolanes had already been prepared by I'atel and Oneto.6 Our o ~ v napproach ~ v a *prompted hy ~v-orkof Garbish,' :uid cori,i\tcd of 1)roniiiiat iiig :iwtoplietioiie~ i i i the appropriate 1,2- or 1,3-diol. This gave 96-114 in fair to good yields. Oftentimes ketalization had to be ( 5 ) 11. H. 1Ialinovskii and .\, G . 1-ridasins, Z h . ( l i i s i i c i i . Khim., 3 0 , 15:11 (lY60); Cliem. A b s t r . , 55, 7341 (1Y61). (6) A. R. Patel and J. E. Oneto. J . Pharm. Sci., 63, 588 (1963). ( 7 ) E. IT. Garbisii, Jr., J . 01.8, Chem., 30, 2109 (1965).
ii
1 0
0 I 1 I
I I
I I
>
I 1 I
2 I I I
2 I
2 I
I-IIll-CIH--
787
Scptcmbcr 1969
Jlp,
oc
125-1 26 167-168 169-170 95-96 184-183 182-1 8: 120-12 1 139-140 147-148 1.51-152 144-145 164-165 119-120 127-12s 124-123 160-161 122-12.j 95-96 161-16' 12,-?126 129-1x0 1.54-1.5.5 1.6137 90-9 1 167-168 129-1 30 138- 130 187-1 88 1i2-17:2 124-12.7 1:31-1:32 114-1 15 149-1;i0 135-136 125-126 166-167 172-173 125-126 122-123 160-161 131) 190-200 (0.4 m n )
driven to completion by axeotropic removal of HLO with C6Ha (method E), but this was unnecessary for 101, 103, 104, and 105, which crystallized out of the crude bromination mixture (method F). All bromides were then treated with sodium imidazole in DJIF to furnish ketals 115-134 which were best isolated ab nitrate salts. A compilation of ketals is offered in Table V. Biological Results.-All conipourids described ere tested against an array of microorganisms according to the method described earlier.2 The in vitro assays were conducted primarily on Aspergillus fumigatus, on the yeast Candida albicans, the dermatophytes Microsporum caiiis, Trichophyton rubrum, and Trichophytori meiitagrophytes, the gram-positive bacteria E'ryso-
inslq bes
C, H C, H c, H C, H, S C, H, 1; C, H , S C, H, N C, H, S C, H , S C, rI, s C, H, S C, H, S C, H C, H C, H , S C, H, K C, H, S (', H, S C, H, S Cy, H, N H, S (*,H, N (', H, K (', H, S ( < ,1-1, s (', H, S
(", H (', H (', 11,
x
(', H (',
H, N
(', H, N C', H (3,
r-1,
C', H,
s s
