889

TABLE I D-thTeO-l-(p-ACYLPHENYL)-1,3-PROP.INEDIOLS AKD DERIVATIVES

OH H

Compd 1 I1 111

I V

Inh 11, IC

R1 CHaCO (CHdlCIICO CeHsCO

Oco C H C O C H I C 0 CHaCO

N N H C S N H?

R2 CHCllCO CHC12CO CIICI,CO

CHCIzCO

CHC12CO ClIaCO

1i

Ra H H I1

I1

€I I1 I1

CHClzCO H I 1

Id CHIC Ie CHICO CHCICO CO(CH?)COIH If CHICO C H C l C O CHa(CH,)iaCO Ig ~ - C B H I C O C H ~ C H C l C O H

I CH=CHCO

I h CeHsCH=CHCO CHClOCO H I I a (CHI)?CHCO CHaCO H IIb (CHa)?CHCO H H I I I a CeHsC(=XH) CHaCO H I I I b C6HsCO C H K O H I I I c CeHsCHOH CHCI-CO H

IVa ~ C O CHICO H

IVb 0- CHCIXO H

a Concentration in methanol. DL form. At softening but no definite melting up to 320".

mum inhibitory concentrations are as

blp, 'C [ a I 2 5 ~ , deg ( c j a Formula 125-127 +13.4 (1.25) CnHd2hNO4 97-99 +14 ( 0 . 8 ) CisHisClnSOa 160-161 + 7 . 8 (0.9) CisHiiCI?SO4

163-164 + 10.5 (1.05) CisH?1ChS04

130 166-167 +7 (0.5) 139-140 -24.5 (1,551

17V 123-124 81-82 187-189 f9.5 (0.45)

155-156 + 5 . 5 ( 0 . 6 5 ) 138-139 + 2 (1.15) 108-109 -22 (1.05) 186-187 f3.2 (0.95) 139-140 + 5 . 6 (0.95) 129-130 +5.F) (1.1)

184-185 +3 (1)

112-113

--Calcd, %---- C H N C I

48.76 4.72 4.38 22.15 51.73 5.50 4.02 20.36 56.55 4.48 3.66 18.55

55.68 5.97 3.61 18.26

48.76 4.72 4.38 22.15 62.13 6.82 5.57 63.14 7.23 6.69

---Found, %- C H N C I

48.48 4.86 4.25 22.35 51.73 5.50 4.26 20.38 56.84 4.55 3.81 18.74

55,il 5.86 3.66 18.40

48.70 4.82 4.48 22.04 61.85 6.95 5.55 63.03 7.45 6.46

Ci4HisChN403S 42.75 4.62 14.25 18.03 42.74 4.83 14.46 17.89 CiIHiYCl??iOi 48.59 4.56 3.33 16.87 48.55 4.60 3.35 16.91 CnsHdsC12NOs 62.36 8.12 2.50 12.69 62.10 8.17 2.64 12.77 C?2HziCI?NOs 58.68 4. io 16.75 58.89 4.93 18.62

CmHisClrNOa 58.84 4.69 li.37 58.71 4.80 17.22 CiaHziN01 64.49 7.58 5.01 64.20 7.58 5.01 Cl3H19~03 65.80 8.07 5.90 66.01 7.96 5.66 C I ~ H ~ N ~ O I 69.21 6.43 8.97 68 93 6.31 8.74 CisHisNOn 68.99 6.11 4.47 69.16 5.98 4.53 CisHieCI?NOa 56.26 4.98 18.46 56.17 5.12 18.25

CiaHzsNOa D7.68 7.89 4.38 67.88 8.01 4.60

C?oH?iChNOs 55.56 6.29 16.40 55.59 6.52 16.43

176" there is a sharp change in color to orange followed by gradual darkening and

follows (in ug/ml): 11, S.. aweug (WLRI-25), 31; E . coli, 62; P. vulgayis, 125; 111, IV, Ib , and IIa, X. auwus (WTARI- X ) , >12-5; E. coli, >125.

Experimental Section

Physical constants and arialyt,ical values are reported in Table I. Melting points were determined using the Thomas-Hoover capillary melting point apparatus which was calibrated against known standards. The ultraviolet and infrared spectra were obtained, respectively, with a Beckman DK-1 spect'rophot,ometer and a Baird Model 455 double-beam instrument. Unlers other- wise stated, the former were determined as solutions in 95% ethanol and the lat'ter as Sujol mulls.

Tetrahydrofuran (THF) used was purified and dried by dis- tillation from LiAlH,. Prior to evaporation or concentration, the nonaqueons organic solut,ions were dried over Na2S04. The evaporations and concentrations were carried out in vacuo with a rot8ary flash evaporator at, temperatures not exceeding 30".

~-threo-2-Acetamido-l-(~-cyanophenyl)-l,3-propanediol was prepared as describedl for the corresponding DL compound: mp 122.5; [ a I z 5 ~ +4.1" (e 3, CILOH); vmaL (cm-I) 2300 (CsX) , 1645 (amide C=O).

Anal. Calcd for Cl2Hl4X2O3: C, 61.53; H, 6.02; IL', 11.96. Found: C, 61.65; H, 6.17; N, 11.82.

D-threo-l-( p-Acetylphenyl)-2-( 2,2-dichloroacetamido)-1,3-pro- panediol (I).-Ethereal CHILi (300 ml, 0.8 LV) was added at 40" over a period of 4 hr to a stirred solution of 8 g of D-threo-1-(p- cyanophenyl)-2-acetamido-1,3-propanediol in 600 ml of THF. After 2 hr of additional stirring, a solution of 100 g of (NH4)2 SO4 in 100 ml of water was added over a period of 1 hr. The organic layer was separated; the aqueous phase was extracted four times with 200-ml portions of ethyl acetate-THF (1: 1). The extracts were combined with the organic layer, dried (Na2SOa), and evapo- rated. The residiie was heated on a steam bath with 300 ml of 10% I T 8 0 4 for 3 hr. The sollition was cooled, washed twice with 25-ml portions of ethyl acletat>e, made basic with 20% KOIl a t 0-3', and estixcated eight times with 400-ml portions of ethyl

acetate. The combined extracts were dried and evaporated. The residue was refluxed for 4 hr with 13 ml of methyl dichloro- acetate in 50 ml of methanol. hfter evaporation, the oily residue was passed through 100 g of an activated magnesium silicate column (Florisil) which was eluted with ethyl acetate. The crys- talline fractions were combined and recrystallized from ethyl acetate-hexane ( 1 : l ) to give 2.8 g of product: Xmnx [mfi ( e ) ] 252.5 (15,7c50). vmax (em-') 1672 (amide C=O), 1693 (ketone C=O); v:::c"(cm-l) 1685 (ketone C=O), 1708 (amide C=O).6

In an alternate procedure, the solution of 1.5 g of o-threo-l- (p-cyanophenyl)-2-acetamido-1,3-propanediol in T H F (400 ml) was treated with 1.50 ml of 1 S ethereal C H J I g I over a period of 23 hr a t reflux temperature. The reaction mixture was worked up as above to give 0.46 g of product.

DL-threo-l-( p-Acetylphenyl)-2-( 2,2-dichloroacetamido)-1,3- propanediol (Ia) was prepared from o~-threo-l-( p-cyanophenyl)-2- acetamido-1,3-propanediol by the above procedure.

~-threo-l-(p-Acetylphenyl)-2-acetamido-l,3-propanediol ( Ib ) was prepared by the above procedure omit,ting the hydrolysis and dichloroacetylation steps; vmar (cm-1) 1634 (amide C=O) and 1676 (ketone C=O).

~-threo-l-(p-Acetylphenyl)-2-am~no-1,3-propaned~ol (IC).-A suspension of 2.5 g of I in 25 ml of 107, H?SOI was heated on a steam bath for 3 hr. After cooling, the solution was washed with 50 ml of ethyl acetate, made basic with NH40H a t 0-5', aiid extracted five times with 150-ml portions of ethyl acetate. The combined extracts were dried and concentrated to ca. 25 ml to give on cooling 1.05 g of off-white crystals which were recrystallized from ethyl acetate: vmgX (cm-l) 1678 (ketone C=O), v~~~~~ (cm-1) 1682 (ketone C=O).

D-threo-1 -( p-Acetylpheny1)-2-( 2,2-dichloroacetamido)-1,3-pro- panediol Thiosemicarbazone (Id).-A solution of 0.132 g of I and 0.037 g of thiosemicarbazide in 25 ml methanol was refluxed for

(6) The dicliloracetamido carhonyl band undergoes a 25-35-em-' shift to liigher frequency on passage from mull t o solution (see example 1110). The hand of the ketone function shifts only slightly or remains a t the same posi- tion (see examples IC and IIh). A s a result, the absorption frequency of tlie dicliloroacetyl carhonyl is believed to be below tha t of tlie ketone carbunhl wllen determined as a mull and above it when determined in soliition.