General Synthesis of Potentially Antiviral a-Adamantyl Carbonyl Compounds[**] By Manfred 7: Reetz, Wilhelm F. Muier, Komad Schwrllnus, and Ioarinis Clzatiiiosifitlis[*] Recently, it was discovered['] that certain a-adamantyl carbony1 compounds are considerably more active as antiviral agents and a great deal less toxic than 1 -aminoadamantane[2'. The multistep syntheses which were described in are based on phenols as starting materials, and are therefore restricted to the cyclohexanone framework. We wish to report that our method of a-tert-alkylation of carbonyl compounds can be applied generally to the introduction of 1 -adamantyl Silylenol ethers (2a)-(2k), which are easily obtained from ketones (1 a)-(1 I I ) [ ~ ~react , smoothly with 1 -bromoadamantane in the presence of titanium tetrachloride at -40°C to - 50°C to afford the desired a-adamantyl ketones (3) in good yields (Table 1). Table 1 shows that structurally

According to Dubois et a/.['] it is possible to convert bulky carboxylic acid esters into ketones ria the corresponding acid chlorides on using Grignard reagents in the presence of copper salts. Combination of the methods allows the synthesis of ketones having adamantyi groups in specific positions. Concerning the antiviral activity of the compounds ( 3 ) , in ritro tests with viruses of the Newcastle disease show that for example 2-(1 -adamantyl)-4-methylcyclohexanone (3 e ) is about three times more active and half as toxic as l-aminoadamantane"]. Experinzental:

Synthesis of 2-( 1 -adamantyl)cyclohexanone (3 b ) : A cooled solution (- 50°C) of 3.8 g (20mmol) titanium tetrachloride in 10ml dry methylene chloride is added within two minutes to a cooled mixture (- 50°C) of 3.5 g (20 mmol) l-trimethylsiloxycyclohexene and 4.5 g (20.9 mmol) 1-bromoadamantane in 60 ml of dry methylene chloride. The reaction mixture is stirred for 30 minutes, hydrolyzed, and the solvent of the organic phase evaporated off. Recrystallization of the residue from methanol affords 3.5 g of pure 2-(1-adamantyl)cyclohexanone as well as 1.Og from the mother liquor: yield 8 9 % ; m.p. 86°C; 'H-NMR (CCI,): b=l.72 (s, ISH), 1.42-2.4 (m, 9H); IR (KBr): 2960, 2930. 2895, 2840, 1695, 1445, 1345, 1310, 1205, 1130, 1120, 1110, 1065cm-'. Received: June 19. 1978 [ Z 114 IE] Publication delayed at authors' request German version: Angew. Chem. 91, 7X (1979)

Table 1 . a-Adamantylation of ketones ( / o ) - ( / h ) (A: triethylamine; 8 : TiCI4: -40 to -50°C) and carboxylic esters ( I i ) - ( / I ) ( A : lithium diisopropylamide: B: catalytic amounts of ZnC1,: room temperature). R1

R2

R3

Yield

[ y , ][a]

[I]

[2]

k

66 (78) x9 (95) 73 (90) 62 (75) 72 (80) 75 (80) 8 1 (89) 70 (XO) 80 47 77

I

70

U

h c

[I