Oct. 5 , 1959
AMINOSUBSTITUTED DIPHENYLACETONES [CONTRIBUTION FROM
THE
5103
RESEARCH LABORATORIES OF THEUPJOHN Co.]
Analogs of Amphenone. The Synthesis of Aminosubstituted Diphenylacetones and Related Compounds BY JOHN B. WRIGHT AND ERWINS. GUTSELL] RECEIVED MARCH9, 1959
A number of compounds chemically related to Amphenone ( I ) were prepared. Most of these compounds differed from Amphenone in possessing a hydrogen atom in place of the methyl group attached t o the tertiary carbon atom. The general method of synthesis for these compounds involved reaction of an aminophenyllithium derivative with a-ethoxy esters t o give 4,4’-diamino-( 1-a-ethoxyethy1)-benzhydrols( I V ) which on treatment with dilute acid yielded the desired compounds 11. The latter compounds were readily reduced to the carbinols and formed oximes which could be reduced readily to amines. Reaction of an aminophenyllithium derivative (or a Grignard reagent) with a-alkoxyketones followed by hydrolysis gave similar compounds (VI1 and IX). The preparation of related compounds based upon the reaction of aminophenyllithium derivatives with other esters and lactones is discussed also. Preliminary biological data indicate that several of these derivatives possess a high order of Amphenone-like activity.
3,3-Bis-(@-aminophenyl)-butanone-2 dihydrochloride (Amphenone) (I) is a substance possessing NH,-@+ -
CHB 0 /I -C-CH~
interesting biological activity. Its most noteworthy action is its effect upon the adrenal glands, producing inhibition of adrenocortical activity in animals and in man.2s3 However, its undesirable side effects have prompted the search for other corn pound^^^^ which would possess the adrenal inhibitory activity of Amphenone. Amphenone was first prepared by Allen and C ~ r w i n . ~The J structure of the product that they obtained was later shown to be that indicated by I n our search for other compounds that would possess the biological properties shown by Amphenone we decided to investigate compounds of the type 11. These compounds would differ from I.*sg
h R’
‘R’ IIa, R = R’ = CH, R ” = CH3 b, R = R’ = CH8 R” ‘&Hs c, R = R ’ = CHa R ” = C&
d, R = R‘ = H R ” = CH, e, R = H, R’ = CHI R” = CHs f, R = R’ = benzyl R ” = CH,
H O
The p-bromoaniline I11 was converted to the corresponding lithio derivative in the usual way by reaction with lithium ribbonlo in ether solution. 11, R = H , lower alkyl Addition of an a-ethoxy ester to this ethereal R’ = H, lower alkyl R ” = CHI, lower alkyl, aryl solution gave the tertiary carbinol IV in yields I averaging 65-70%. Conversion of IV to I1 was N brought about by refluxing in dilute hydrochloric R’ ?R’ acid. I n the preparation of I1 where R and/or R’ is ilmphenone mainly in the fact that they do not possess the methyl group on the tertiary carbon H, the reaction sequence was carried through with atom. Furthermore, i t was hoped that it would be the corresponding benzyl compounds and the benzyl possible to synthesize these compounds by strictly groups were removed ultimately in the final comchemical means thus avoiding an electrolytic re- pound by hydrogenolysis with hydrogen and duction used in the synthesis of A m p h e n ~ n e . ~ , ~ palladium catalyst. Compounds of the type I1 The general method of synthesis that was used is that were prepared are listed in Table I. Compounds of this type in which the two aryl (1) Ott Chemical Co., Muskegon, Mich. groupings were different were prepared by reaction (2) H. Kless, Airrncimiffcl-Forsch..8, 83 (1958). of the requisite lithium derivative with a-alkoxy(3) Lancer, 237 (1956). (4) W.L. Bencze, L. I. Barsley, M. J. Allen and E. Schlittler, Hclu. ketones or a-phenoxyketones (V, R ” = CzH6, Chim. Acta, 41, 882 (1958). (5) J. J. Chart, el al., Erpcricnfia, 14, 151 (1958). (6) M.J. Allen and A. H. Corwin, THIS JOURNAL, 72, 117 (1950). (7) M . J. Allen, U. S. Patent 2,539,388. (8) W. L. Bencze and M . J. Allen, J . Org. Chcm., 22, 352 (1957). (9) J. Korman and E. C. Olson, ibid., 22, 870 (1957).
(10) Several grades of lithium ribbon were tried in these reactions. I n our hands, the most successful was a grade obtained from the Lithium Corporation of America containing approximately 0.6% sodium. Experiments with the newer low-sodium (0.02-0.005%) grades were less successful.
5194
JOHN
B. WRIGHTAND ERWIN S. GUTSELL
Vol. 81
TABLE I
N R’ R
Pro- Yield, cedure % A 98 CHI A 98 C2Ha A 86 CsHa
R”
R’ CH: CHa CHs
CHa CHs CHs
B C B H ~ C H ZCsHiCHa CHs C CHs H H CHI C~H~CC HH ~ ~ BO
22j
40 60.‘
M.p.
‘R‘ Analyses,
Molecular Calcd. formula C H CilHzJGzO 76.99 8 . 1 6 CwHzaNzO 77.38 8 . 4 4 CZ~HI~Z 80.41 O 7.31
OC.’ Recrystn. solvent Ethanol ti5-6Ga Ethanol 71.5-72.5‘ 1G6-167C~d3e Benzene-cyclohexane (1:l) 189-192.5 Benzene Isopropanol 143.5-114 IOj-107 Acetune-methanol (1 : 3 )
CisHsoNzO 85 91 6 . 7 1 CiaHisKzO 74.97 6 . 7 1 CaiHszKzO 83.00 7.19
$4
Found C H 77.20 8 . 2 3 77.58 8.09 80.43 7.72
N 9.34 9.29 7.76
4.66 85.94 6.75 11.66 74.77 7.06 6.25 83.15 7.40
4.72 11.70 6.46
N 9.45 9.03 7.82
The dihydrochloride after recrystallization from anhydrous ethanol melted a t 212” dec. Anal. Calcd. for CI&IN@. The dihydrochloride 2HC1: C, 61.78; H, 7.10; N, 7.59; C1, 19.20. Found: C, 61.71; H, 7.12; N, 7.68; C1, 19.11. after recrystallization from anhydrous ethanol melted a t 215” dec. Anal. Calcd. for C20Hz6N20.2HCl:C, 62.66; H, This compound was prepared by a different method by F. Krohnke 7.36; N, 7.31. Found: C, 62.82; H, 7.25; K, 7 53. [ C h e m . Ber., 72, 1731 (1939)], who reports a melting point of 168’. The monohydrochloride was prepared by dissolving the free base in acetone and adding an excess of an ethereal hydrogen chloride solution, m.p. 224” dec., after recrystallizaC,~72.99; : H, 6.89; N,7.09. Found: C, 72.64; tion from ethanol and drying a t 100”. A n d . Calcd. for C ? ~ H M S Z O , H C H, 7.01; hT,7.43. The reason for the isolation of the monohydrochloride rather than the dihydrochloride here is not clear. The second molecule of HC1 may have been lost during the drying at 100’. e The reaction mixture was extracted with This is the over-all yield for two steps. 0 One-fifth of the amount of ether was emchloroform rather than with ether. ployed. The product was extracted with benzene instead of chloroform.
’
C6H5). The crude intermediate tertiary carbinol VI was found usually to melt over a wide range, probably due to the presence of a mixture of diastereoisomers. In these cases the crude product was treated directly with dilute hydrochloric acid to give the desired ketone VII.
,
&&//I H+ -4
H
O
1 /I P-RR‘NCeHdC-CR’’ I VIIa, R = R’ = CH? R ” = CHI b , R = R’ = H R” CHj C, R = H, R ’ = CH3
+ R”’0H
C6H5 R ” = CHI d, R = R’ = benzyl R ” = CH, e, R = CH?, R’ = benzyl R ” = CHI
-4n alternate method of synthesis that was employed involved first the preparation of an a-ethoxy-p-aminopropiophenone (VIII) . CHjCH
I
*>cH~ CHlCHz
t
Br
r
0
I1
CHaMgBr
CHs OGHs
]--
CH&HCBr
0
1
0
I H+ II ~~-RR‘NC~HIC--CHCH~--+ ~ J - R R ’ N C ~ H I C H C C H ~ I I 1
I 1 dil. HC1 CsHb OR”’ VI p-RR’NC6HaC”CR’’ H+ CBHS I OR”’ I dil. HC1
HS
