Oxa-6-aza-adamantanes

2-Oxa-6-aza-adamantanes have been prepared by all five pathways A—E. 

By treatment of N(9)-methyl-7-ethoxy-granat-3a-ol (38) with hydrogen bromide Stetter Mehren obtained in 1967 unsubstituted N(6)-methyl-2-oxa-6-aza-ada-mantane (40). This was the first synthesis of a 2-oxa-6-aza-adamantane. 

Kashman and Benaiy reported the successful ring closure of the hicyclic alcohol S9 by lead tetraacetate (without or with iodine added) to the N(6)-acetyl-2-oxa-6-aza-adamantane (41). 

N(9)-Phenylsu]fonyl-9-azabicycloi3,3.1 ] nona-2,6-diene (44) is another suitable starting material for the synthesis of C(4),C(8)-disubstituted 2-oxa-6-aza-adamantanes, the two substituents being equal The configurations at C(4) and C(8) may either 

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Ring closures to 2-oxa-6-aza-adamantanes starting from bicyclic dienes were also accomplished by hydroxybromination of the 9-aza-diene 62 with N-bromo-succinimide (-> 63 53%) and by reaction of the 9-oxa-diene 1 with N -dibromo-p-tolylsulfonamide (- 64 25%). Both dibromides were converted to 63 (raney-nickel/Hj), which itself by treatment with sodium in liquid ammonia, yielded unsubstituted 2-oxa-6-aza-adamantane (5S), also characterized as its hydrochloride 38 HCl and N-benzoyl-derivative 66. 

Heating a solution of the syn-exo-diepoxide 74 in 0.5N HCl yielded 61% of N(6)-phenylsulfonyl4 8 -dihydroxy-2 -oxa-6-aza-adamantane (76) as the sole tricyclic compound, which was also characterized as its diacetate 49. Analogous treatment of the anti-epoxide 75 led to a mixture of adamantane-diol 76 (48%) and the isomeric N(7)-phenylsulfonyl-4 l0 -dihydroxy-2-oxa-7-aza-isotwistane (77) (22%). Both diols were also converted to the corresponding diacetates 49 and 78 K... 

Reaction of the syn-exo-diepoxide 20 (9-oxa) with methylamine under pressure gave 61%of N(6)-methyl-4 8 -dihydroxy-2-oxa-6-aza-adamantane (79), which by subsequent acetylation yielded the diacetate 80. 

A special case is the observed substitution with retention as the result of the reaction of N(6)-phenylsulfonyl-4° 8° -diiodo-2-oxa-6-aza-adamantane 54) with silver acetate in acetic acid during 9 hrs at 60°, which yielded 4° -acetoxy-8 -iodo-adamantane 55 (20% relative to reacted 54) and 4° 8° l-diacetoxy-ada-mantane 56 (66% relative to reacted 54). Because of the reduced basicity of N(6) by the sulfone group this reaction will not be classified as one involving normal neighboring group participation (2.1.5.2.) . 

In both cases studied using G 56-adamantanes as starting materials rearranged products were observed where oxonium ions occurred as intermediates, namely on treatment of 4°l l,8°l l-diiodo-2,6-dioxa-adamantane (J 2.1.2.1.) and N(6)-phenylsulfonyl-4N(6)8N(S),diiodo.2 -oxa-6-aza-adamantane (47 2.1.5.2.) with silver acetate in acetic acid, see G 36 - G 38 (oxonium ion) - G 39 (adamantane) + G 40 (isotwistane) ... 

A further example was the reaction of N(6)-phenylsulfonyl-4 8° -diiodo-2-oxa-6-aza-adamantane (50) with silver acetate (Table 6). The d -acetoxy-S U... 

In this section several characteristic NMR-data of 2-oxa-6-aza-adamantanes [X(2) = O, Y(6) = NR] diall be discussed standing as typical examples for the rather large number of 4,8-disubstituted 2,6-dihetero-adamantanes known so far. 

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