Sovember 1969 3-HALO-2-PHEXYLGLYCIDAnlIDE HTPSOTICS 989

3-Halo-2-phenylglycidamide Hypnotics
J. B. CARR,G. R. HAYNES,
Department of Organzc Chemzstry

AND J . R. ALBERT
J. I<,I<ODAUA,
Department of Pharmacology, Shell Development Company, Bzologzcal Sciences Research Center, JIodesto, Califo, nzu 92352
Recezved June 16, 1969

A serie. of 3-hal0-2-pheiiylglycidamidea has been sq nthesiied and evaluated as hypnotici in mice. 3-Chloro-
2-(2,4-dichlorophenyl)glycidamide(54) was found to he equal in hypnotic potency to sodium pentobarbital and
to have a fourfold greater therapeiitic ratio.

Some glycidamindes are known to be central nervous
system depressants. Several 2,j-dialkyl- and 3,3-di-
alkylglycidamides have been reported in a review by
Wheeler’ on nonbarbiturate hypnotici. The 2-ethyl-3-
propylglycidamide, oxanamide, i b marketed as a minor
tranquilizer. Although a few 2-phenyl-3-alliylgly-
cidamides are kn01~11,*3~
they have not been reported to
posess hypnotic activity. This paper deals with the
synthesis and pharmacology of the 3-halo-2-phenylgly-
cidamides, a heretofore unreported class of compoundc.
Chemistry.-Isomer mixtures of the 3-halo-2-phenyl-
glycidamides (IV and V) I\ ere prepared in good over-all
yield from 2,2-dihaloacetophenones (I) as shon n in
Scheme I. T n o methods itere employed to obtain the
to afford isomeric mixtures in M hich the isomer resulting
from acylation para to the most electronegative halogen
predominates. Acylation of In-chlorofluorobenzene
with dichloroacetyl chloride afforded a mixture con-
iisting of approximately 607, of 2,2,2’-trichloro-4’-
fluoroacetophenone. From this mixture 2,2,2’-tri-
chloro-4’-fluoroacetophenone was isolated in 10% yield.
Similarly, acylation of m-chlorotoluene gave a crude mix-
ture consisting of approximately 40yG of 2,2,4’-tri-
chloro-2’-methylacetophenorie, 50% of 2,2,2’-trichloro-
4’-methylacetophenone, and 107, of unidentified mate-
rial as determined by glpc. The two major components
were isolated in 1.5% yields by distillation.
Chlorination a t the 2 position of the appropriately
ring-substituted acetophenone was effected in 90-100%

-
I
SCHEVE
yields by the method of Falbe and Schulze-Steinen.5
(KCX)
D C O C H X , + HCN 2,2-Dibromo-2’.4’-dichloroacetophenonewas obtained
by this method using Brz a t 65-70’. I n ring-deacti-
R
vated acetophenones the reaction proceeds smoothly to
I afford 2,Z-dihaloacetophenones;however, in activated
QH acetophenones ring chlorination can occur. With 3
moles of chlorine, mole of 4’-methoxyacetophenorie the
product was 2,2,3’-trichloro-4’-methoxyacetophenone.
HCK reacts readily with I to afford the corresponding
mandelonitriles (11). The mandelonitriles prepared,
I1
their method of synthesis and yields are summarized in
Table I. I n general, better yields of 11, G5-100%, were
SaOCH obtained when liquid HCK was ured as a solvent to
CH OH afford a homogeneous reaction mixture.6 Difficulty
R was encountered in obtaining analytically pure samples
CONH,
of I1 due to the tendency of the cyanohydrin formation
I11 to reverse. Therefore, most of the mandelonitriles
were converted t o the corresponding mandelamides
(111) (Table 11) without extensive purification.
I n general, the mandelamides containing halogens on
the a-methyl group and electron-withdrawing substit-
uents on the phenyl ring were obtained in better than
Iv v 50yc yield without exhaustive work-up. The low yield
of 30 (4270) and of 32 (18%) might be explained on the
starting 2-haloacetophenones. Friedel-Crafts acylation basis of steric hindrance to hydroly4s of the C S group
of the appropriately substituted benzene with chloro- or by the bulky a-trichloromethyl and a-dibromomethyl
dichloroacetyl chloride afforded GO-90Yo yields of the groups. Soticeably lower yields were also obtained
corresponding 2-chlorinated acetophenones. Acyla- from mandelonitriles containing electron-donating
tion of mixed halogenated benzenes has been reported4 groups on the phenyl ring, 27 and 41. I n the prepara-
(1) Ii. W. Wheeler, “Medicinal Chemistry,” Vol. VI, E. E. Campaigne
and SV. H. Hartunp, Ed., John Killey and Sons, Inc.. New York, iX. P., ( 5 ) .I Falbe and M J bchulae-Steinen, German Patent 1223.284 (1886)
1963, p 110. (0) ( ‘ u u t i m should lie rvrrcised \I hen cairling out t l i i s reaction on a large
(2) E. C. Iinonles and J. 13. Cloke, J. z4m.Clrem. Soc., 64, 2028 (1932). wale in Ilil~iiil 115 d r o g m c\ anide 17 it11 2-~111oro-or 2 2-~licliloroacetopIlenone*.
(3) 3 . 1.Murray and J. B. Cloke, zbzd., 66,2749 (1934). The i e a c t i u n proceeds instaneonsl~ upon addition of the catal! s t The
(4) 13 IC. Diep, N. P. Buu-Hoi, and N. D. Xuong, J . Chem. Soc., 2784 evolution of large amount, of heat causes \igorous I)oiling of the 11>drogen
(19b3). clanide.
!)!JO
Sovcniber 1969 991

No. s n AIp, oc .\nalyaea

43 H C1 67-7i N, CI
44 1-I CI 113-114 N, CI
4 .i 2-Cl CI 101-10.2 ?i; Ck
46 2-CI C1 16.i-168, .i N; Cld
47 4-CI C1 Y O , .i-U4 5 ; Cle
4\ 4-C1 c1 112,*i-11:3 N ; Cl1
49 4-Br C1 1OS-1 09 .i , so
*io 4-Br CI 102 .i-104 sh
.1i 4-F CI 11:3-117 N,Cl
.i2 4-CH3 C1 1.i7-1.5S . .i s,C I ,
.x3 4-CH3S0, CI I i6-l.iS. .-) s ;CIk
4i
. 2,4-CI2 C1 122. .i-l24 N, C1
--
.).I 2,4-CI3 CI 170-171 .i N , CI
.-)6 2$-Cl, H 12L-127 N , C1
--
.)i "4-Clz Bl 1:5-140 3 Si
.4i 2,,.j-Clj CI 160-1 62 s, e1
.iS 2,,i-C1, e1 17.5 .?-I77 ?;; Clm
60 2,.i-Cla H 1%. . i - l R O s;C1n
61 2,4,-i-C13 C1 1:31 .i-1;3.5 s,c1
62 2,4,.i-C13 e1 162. .i-166 ?;; C1.
63 2,,5,4-C13 c1 141 *-IF143 5 , c1
64 2,3,4-C13 C1 192 x, c1
6.i 2-C1, 4-F CI 96-102 N, e1
66 ? T I , 4-F C1 164-1 7 0 N,C1
67 2-C1, 4-CHs C1 %S.,5-100. .i s,CI
6s 2-C1, 4-CH3 CI 140-141, .5 N :C1p
61) 2-CH3, 4 C l C1 96-99 s,CI
70 24x3, 4 x 1 CI 112. !i-114.3 ?:
TI 2,4F:! CI 98-99 s,Cl
72 3-KOz H 109. .i-l12. 3 N
iS 2,4-CI? CdH, 161-162 S , H;Cr

i4 16 106-1U6 .i N, CI

a * Decomposed upon stailding. c CI: calcd, :30.3; found, ;<1.0. d Cl: calctl, i30.5: foulid,
8.5(,; B isomer, 159; A isomer by nmr.
31.0. C1: calcd, 30.5; found, 31.8. f c1: calcd, 30.5; found, 31.8. 0 Halogen eqiiiv: calcd, 138: found, 134.
e Halogen equiv:
calcd, 138; found, 134. Pure A isomer was not, isolated. j X: calcd, 6.6; found, 7.3. C1: calcd, 16.8; foiind, 19.0. k C1: calcd,
12.9; found, 13.5. 'Halogen equiv: calcd, 103; found, 103. C1: calcd, 39.9: found, 40.6. flC1: calcd, 30.6; foruld, 29.1.
0 C1: calcd, 47.2; found, 48.1. p K : calcd, 5 . i ; found, 5.0. C1: calcd, 28.8; foiind, 32.0. q Isomer form iuicertain, see text.
r C: calcd, 52.5; found, 53.4.

with the phenyl ring and the other to eclipsing of C1 was prepared in 7370 yield by the alkaline peroxide oxi-
with the phenyl ring. Since the steric requirement of dation* of 2-(2,4-dichlorophenyl)-2-hexenenitrile(VI)
C1 exceeds that of H, less steric hindrance to eclipsing, as shown in Scheme 11. VI was obtained by the hase-
and, therefore, a lower transition-state energy would be
SCHEVE
I1
expected to occur in the conformation leading to the
product in which the phenyl ring and a-H are cis. On
this basis the predominant B isomer has been assigned
configuration IT.', that having the phenyl and the C1
trans on the epoxide ring. This a+nment ir sup- CI
ported by the higher B/A isomer ratio obtained with CHC H- ,o,
glycidamides having greater steric requirements due to
a n ortho substituent 011 the phenyl ring as compared to
those lacking an ortho substituent. The a-dichloro- I acetone
methylmandelamides with an 0 1 tho substituent on the CI
phenyl ring give isomeric mixtures consisting of 8593% VI 73
B isomer and 5-15yo A isomer. I n contrast, mixtures of
catalyzed condensationg of 2,4-dichlorobenzyl cyanide
approximately GOYc B and 40% A mere formed from
and butyraldehyde. The configuration of 73 cannot be
the a-dichloromethylmandelamideslacking an ortho sub-
stituent on the phenyl ring. assigned urieyuivocallp since the stereocheniical course
2-(2,4-Dichlorophenyl)-3-propylglycidamide(73) (Y) -1.Vigier and J. Ureux. Bull. Suc. C h i n . F r u j t c c , HTT ~ILl63).
Sovember 1969 3-HALO-2-PHEXYLGLTCIDAMIDEHYPXOTICS
The following are representative of the methods iised to pre-
pare t,he compounds discussed in this paper.
Halogenated Acetophenones.-The follon-ing k i i o w i halo-
genated acetophenoiies, not commercially available, were pre-
pared by literatrue methods:b,15 2,2,2',4'-tetrachloroacetophe-
none15 2,2,4'-tri~hloroacetophetiorie,~~'~ 4'-bronio-2,2-dichloro-
acetophenolie; 2,,2-dich~oro-4'-fliior~iacetop~ieii(~tie,~~ 2,2-di-
chloro-4'-met hylacetophei~otie,~~ 2,2-dichloro-4'-niel hylciilfotiyl-
a c e t o p h e ~ i o t i e , ~2,2,2',5'-tetrachloroncetophenotie,~~20
s~~~ 2,2,2",-
4',5 '-pet itac.hloroacetopheiioiie, l6 2,2 ',5 '-t richlorc meet ophe-
iiotie,6.*o and %,2,2',:3',4'-pe1itarhlol.ouc.eto~~heii~itie.~~ 2,ZIli-
chloroacetopheiioiie atrd %,2-dichloro-4'-tiitroacetophe1iotiewere
purchased from Fritilon Labol,atories and ;\Intheson Coleman
atid Bell Co., respectively.
2,2,2'-Trichloroacetophenone \vas prepat,ed bj- the met hod of
Falbe and Schi~lze-Sleinen.~CI, was bubbled into a stirred
wiliitioit of 08 g (0.44 mole) of ~"-chloroacetopheii(~ite iii 240 ml of
glacial 11C02H a t :30° iwiitaiiiitig a miall amoiitit of HC1 gas.
The reactioti temperatitre slowly rose to 51)'. After 4 hr no
start,itig material was detectable b y glpc. After atanditig over-
night the reaction mixtiire was poiired into H20 and the proditct
was extracsted with CH2C1,. The extracts were warhed with 5yc
K a H C 0 3 solution and with H 2 0 attd dried (MgSO?): Solvent
removal afforded 86 g (987;) of slightly yellow liqiud. A n d .
(CxH;CLO) CI.
2,2-Dibromo-2',4'-dichloroacetophenonewas pt,epat,ed by a
slight modifiratioii of the previous proceditre.6 To a stirred
soliitioii of i X . 5 g (0.415 mole) of 2",~'-dichloroacetopheiioiie in
500 ml of glacial HCO?H at 40' was added a fen- drops of Br2.
The soliition was wamied sloxly t o G8' at which time the Br,
color disappeared. At 6%" the remiiinder of 133 g (0.83 mole, 43
rnl) of Rr, was added dropwke. .ifter the addition wah complete,
two layers separated from the cooled reactioii mixtiire. The
lower layer was separated atid the upper layer was poured itito
H,O aitd extracted with CHUCly. The combined extracts and
lower layer were washed (H&, 5 ( 2 SaHCOa solution, HsO) atid
dried (JlgS04). Solvent removal atforded 142 g ((387;) of
slightly yellow liquid. :lna/. (CsH4Br2C120) Br, C1, halogen
equiv.
4'-Methoxy-2,2,3'-trichloroacetophenone was prepared i n
X4(!'; yield, nip 90-'J%D,by the prev . described procediire5
ritilizing 3 moles of CI, mole of 4'-me acetophetione. -lna/.
(CgH?Cl,O,) CI.
2,2-DichIoro-2',4'-difluoroacetophenonewas prepared iii 85%
yield, bp 70-84" (0.5-0.8 mm), by the procediire of Whetstone,
rt ai.,15 from ni-difliioroberi&etie arid dichloroaret)-1 chloride.
. h a / . (CsH,ClyF,O) C1.
4'-Fluoro-2,2,2'-trichloroacetophenone was preparedlj from
Iri-chlolofliiorobetizeiie and dichloroacetyl chloride. Iliatilla-
tion of the crirde prodiirt afforded a mixture of isomers, bp 1%-
136" (9.8-10.2 mm), from which the product, was isolated in a 105;
yield, nip 210' by repeated 1 I e O H ret
(CEHICI~FO)C, H, C1.
2'-MethyI-2,2,4'-trichloroacetophenone was pi.epared15 from
tu-chlorotoliieiie atid dichloroacetyl chloride. T'ariium distilla-
tion through a 20-plate bitbble-cap columti iixing a 20:l refliix
ratio afforded the prodrict in 15% yield, bp 155-158" (11-12 mm),
of !IOc'; isomeric purity as evidenced by glpc. Ilrie to the diffi-
ciilt y in separating the pitre isomer, elemental analyses were not
obtained. The ir 3pectrum was conrktent with the assigned
s t i w t u r e . This product was cotiverted to the mandelamide
(39,Table 11), for which acceptahle elemental analyses were ob-
tained.
4'-Methyl-2,2,2'-trichloroacetophenone war obtained in a
I j r ; yield of 955; isomeric pii . (glpc) by hexane extractioii
of the pot residiie from the tillation of %'-met,hyl-2,2,4'-
ti.ichloroacetophenorie. Elemeiital analyses were not obtained,
biit the ir spectrum was consistent with the asbiglied atriletiire.
This product was converted to the mandelamide (38, Table II),
993
for which acceptable elemental aiialyses were obtained. The
atriictiire assignment of 2'-methy1-2,2,4'-trichloroacetophe1ione
arid 4'-methy1-2,2,2'-trichloroacetopheiione was made 011 the
basis of oxidation of the latter by alkaline KMn04- 22 t o the
kiiowti 2-chl~11~otrr~~hthnlic acid, nip SOT," from H?O 316-
318 ) .
2,2,2,2',4'-Penta~hloroacetophenone.~-Cl~ was added slowly
over 30 h r with stiuitig to 307 g (1.19 moles) of %.2,3',.1'-tetra-
c~hloroncetop,hetiotie iindergoing iiv irradiation. The reaclioli
temperat tire was maintai~ied at 153-160°. The prodiict was
sti,ipped iitidei. high vaciiiini to give 347 g (lOO", ) o f yellow liqiiid
of 95:; piirity a3 itidicaled by glpc atid ir. .Inai. (C811,C1,0)
C1: i>alrd,60.7; foiuid, 61.2.
2,4-Dichloro-a-idichloromethyl)mandelonitrile (8).-T11 a
rtit,red soliitioti of "0.' g (O.T8:3 mole) of ",L',2',4'-tetrachlol.oaceto-
phenone iii 80 ml (2.0 moles) of H C S at 15" was added 15 drops
of freshly prepared satiii,ated aqiieoiis K C S soliitioti. Aivigoroiih
exothermic i~e:icticiii cicwrred raiisiiig i'efliixitig of the HCN.
After 15 m i t i of refliixitig, 100 nil of I<:trO 'ivas added aiid the excess
H C S was i.emovrt1 b y distillatioti iiito a S a O H wliitioii. Re-
tallizatioti of the i'esidtitlit erodiict from hexatie-beiizetie
2-Chloro-a-(dichloromethyl)-4-fluoromandelonitrile(16).-
To a vigoroiihly .tii,red, heterogetieoris mixtiire of 40.0 g (0.165
mole) of 2,2~2'-ti,ic~hl~~t~~i-4'-flric,l.oac.etophetiotie atid 21 g (0.4:3
mole) of S a C K i t i :3T, nil of I.:t,O aiid 55 in1 of H2O at 3-7" was
added over 1.5 miti :3:3.:3 nil (0.40 mole) of c.oiic'eiitt,ated HC1.
After 30 miti at 3' the vigoroitrly biirred hciliitioti was dlowed t o
warm slowly t o 2 3 " over a pei,iotl of 1.5 111,. Ciiticeiitrated HC1
(10 ml) was added, the 15trO layer separated, aitd the aqiieoiis
layer was extracted with Et&. The combitied Et& fl,actioti.:
were dried (AIgSO,). Filtration, solvetit removal, atid re(
lizatiori finm Et,O gave :;6.9 g (X35;) of rolot~lessprodrict, mp
96-98".
2,4-Dichloro-a-(dichloromethyl)mandelamide (29).-Ai stirred
siispensioii of 300 g (1.05 moles) of 8 iti 1 1. of 80'; H,SO, was
heated on a steam bath for 16 hr, cooled, atid poiired over ire.
The re.iriltant grimmy d i d was d i w l v e d i i i CHyClU, dried
(lIgSO?),and rooled t'o afford 258 g i81r-i)of 29,nip 135-13io.
~-(Chloromethyl)-2,5-dichloromandelamide (34).-A siispeii-
sion of 25.0 g (0.10 mole) of a-~chl~ir~iniethyl)-0.',5-dichlc~romatidel-
onitrile in 125 nil of 007; H~SC)Iwar stii.i,ed at i'ootn temperatiire
for 16 hr and poiired over ice, aiid the resiiltaiit white
were filtered to afford 26 g ( 9 i r i )of 34,nip 151.3-156".
3-Chloro-2-(2,4-dichlorophenyl)glycidamide 154 and 5 5 ) .
Method A.-To a stiwed ritspenrioii of 2.1 g (0.05 mole of S a H )
of hexane-washed 5 0 5 SaH-miiieral oil siispeiisioti i t i 50 ml of
aiihydroiis T H F n'as added all a t oiice a soliitioii of 15 g (0.05
mole) of 29 iii 100 nil of aiihydmiis T H F . A i 1 exothermic reac-
tion occiirred with H U evoliitioii atid the formation of a white
precipitate. The i,eactioii mixtiire was stirred for G hr, poiired
into H,O, aird extracted with Et,O. The Et20 extracts were
washed with I1,O and dried (3IgSOd) and the solveiit was re-
moved to afford a yellow, vibcoiis liqiiid. Ilecrystallizatioti from
CH,C1,-CsHlr gave G g of white
iug 835; of 54 atid 1src of 55 k)
matography throrigh silica gel G iisiiig Et,O as the eliietit afforded
600 mg of critde 55 atid 4.2 g of criide 54. I~ecr\-.tallizatioii from
CH2C1,-C6Hlr gave 400 mg (.is;)of 55,mp 1i0-lTI.5°, and 3.1 g
(235;) of 54,mp 122-123'.
Method B.-To a stimed soliition of 60.6 g (0.20 mole) of 29
in I75 nil of aiihj-droit- 1IeOH was added drop\yi-i.ea solution of
10.8 g (0.20 mole) of NaO;\Ie in 100 ml of anhydroiis LIeOH.
The resiilting soliitioii was stirred at room temperatiire for 6 hr
aiid allowed to statid overnight. The reactioii mixtiire Tyaq
poured into H2O and extracted with CH,CI?. The extract> were
washed with HYO and di,ied (lIgSO,), and the solvent was re-
moved t o afford a criide mixtiire of 54 aiid 55. Eliition chro-
thmiigh silica gel G iising EtaO as the eliient gave,
itllizatioti from C I 1 2 C l ~ - C ~:34.:3
I ~ ~g~ (64'
, ,; ) of 54,nip
122 -124", : t i i d 1.7 g ( 3 ' , ; )of 55, nip l(iU.6 ~ 1 7 0 ' .
2-(2,4-L)ichlorophenyl)-2-hexenenitrile (VI): TG :I itiiretl
niixture [if 3 . 3 g (0.W niole) of 2,4-dichlurobei1~~.1 q u i d e aud
L'c) g (0.40 tiide) 1,f LutyralcleL~~de\ \ U S added \\it11 i,oilliilg :I
(22) C . F. Iioelacli. "Organic Syntlieseh." Coil. Val. 111. 1:. C', Ilornini
Ed.. J o h n Wiley and Sons, I n c . , X e v l - o r k , X. T.,l%:, 1) 791.
(23) .\. Benning, H. Fruhbaas. and 0. Grosskinskig. German P a t e n t
1,006,411 (1957).
 K Of1

1V. K = H O('H o r OH
K and R- = H or ('H
K =alkylamtno 01 dialkyl,imino
I. R = H,C(;H->.C,,HjC'HI.
ri-C;H,,
Rl=H.OCH,
R = H, alkyl. alkeiiyl o r acyl

L' R = ( ' H H I1-C H

'l'lic 1.2,.4.l-tc~trdi? cti~o-i-cliiiiioliiiol~('l'ublc 1) I\ ( ' I
prepared from the correqmiding hetone by S:iBI-I IT-
duction (method A) or 1)) the addition of :iGrigrinrtl
reagent (method B). While we were unable to c.terif>
the tertiary alcoholh, ti\ CJ of the hecoridary alcoholh were
fully by C'H2C0 to the corresporidiiig
-diliydro-4-cjuiiiolo~ie having :L p> r-
rolidinoprop~1 group I I I the :< positiori \\ ah prepared b j
aluminum r*opr opoxide ouidatiori of the previouhl!
reported 3- 13- (l--p\ iwlidinoprop> 1) ]-12,8,4trtr a h j -
< 1ru-4-c [ulnollrlol.