Spirocyclic amides

Similar oxidations are achieved in bicyclie amides [1082], spirocyclic amides [1084], and acylated 1-adamantamines [1083]. A -Acetyladaman-tamine is hydroxylated on the tertiary as well as the secondary carbons to yield A-acetyl-l-adamantamine-4a-ol and A-aeetyl-l-adamantamine-3-ol [1083]. The yields of all hydroxylated products are not very high (equations 517 and 518). 

Thus, oxidation of oxazoline derivatives of phenolic compounds 33 with IBD in trifluoroethanol leads to spirocyclic amides 34 [26]. The low yield of compound 34b is attributable to the carbamate carbonyl of 33b competing effectively with the oxazoline nitrogen to capture the electrophilic intermediate obtained by activation of the phenol (Scheme 14). 

In some instances the attack of the arene on the nitrilium salt occurs at the ipso carbon rather than the ortho carbon. For example, the Bischler-Napieralski cyclization of phenethyl amide 10 affords a 2 1 mixture of regioisomeric products 11 and 12. The formation of 12 presumably results from attack of the ipso aromatic carbon on the nitrilium salt 13 followed by rearrangement of the spirocyclic carbocation 14 to afford 15, which upon loss of a proton vields product 12. ... 

Phenyl-[l,3]dioxane 32 has been reported to bind the 0X2 receptor with a pX of 8.3 and a pXb of 7.9, and is 600-fold selective for 0X2 over 0X1 [85,86]. JNJ-10268752 (no specific structure has been disclosed) has been described as a selective 0X2 receptor antagonist (X, 0X1 /OX2 = 18/2, 500 nM, respectively) [87]. Compounds exemplified by 33 have been reported as 0X2 receptor antagonists (IC5o = 9nM) selective versus 0X1 (IC50 = 1870 nM) [88]. Recently, open chain amide 34, sulfonamide compound 35 [89,82], and spirocyclic sulfonamide 36 [90]... 

Nair et al. (87,88) achieved a synthesis of spirooxindole-containing molecules by adding isatins to various carbonyl ylides (Scheme 4.46). There has been relatively little research regarding the efficiency of C=0 of 1,2-dicarbonyl compounds as dipolarophiles relative to their olefinic counterparts. As anticipated, Nair found that the more electrophilic carbonyl of the isatin 187 (non-amide carbonyl) reacted smoothly with the carbonyl ylide formed from diazoketone 186 to give the spirocyclic adduct 188. Nair s yields were moderate to good (44—83%), but were based on recovered isatin. 

Imperial Chemical Industries (ICI) chemists " prepared a novel series of spirocyclic 2,4-oxazolidinediones 243 derived from 7-substituted isatins (Scheme 6.54). The key intermediate a-acyloxy amides 242 were readily prepared from 241 in three steps. Base-catalyzed cyclization of 242 then afforded the target compounds that were reported to be potent inhibitors of aldose reductase. Pfizer chemists approached 5-substituted isatin spirocyclic analogues 243 via a-hydroxy esters 244 that were converted to the corresponding a-carbamyloxy esters 245 in good yield using chlorosulfonyl isocyanate. Cyclization of 245 with potassium ferf-butoxide then produced 243 in acceptable yield (Scheme 6.54 Table 6.10, Fig. 6.20). 

Treatment of bicyclic lactone 24 with benzylamine in dioxane afforded an open chain triflate amide, which was stirred in THF in the presence of potassium carbonate to cyclizate to the spirocyclic p-lactam 25 (Scheme 9) [58]. 

The silanediol 21 has been prepared for use as a potential protease inhibitor by treatment of arylsilane 22 with CF3SO3H. This is a convenient method for the preparation of silyl triflates (which are readily hydrolysable, see below) but in this case it is thought that the amide carbonyl intercepts the protonated species 23 (loss of the t-Bu ester group also occurring) to give the spirocyclic silyl ether 24, which is then hydrolysed to give the diol, (Scheme 5)94. 

MC2. Spirocycle 38 is formed in good yield under nearly identical conditions. This suggests that the lack of reactivity in the case of the acrylamide is probably due to disruption of the RCM catalytic cycle by disadvantageous complexation of a Ru-intermediate by the amide oxygen. 

If the -position is blocked as in the case of cyclic enaminones, the acylation proceeds on nitrogen. The corresponding amide is isolable, and the spirocyclization to 2-indolone derivatives can be later accomplished in good yield (equation 40). 

In the synthesis of the Nevirapine ring system [161], q clization of chloro-amine 392 (Scheme 127) afforded diazepinone derivatives 395 and 397 along with chloro-amide 396. Products 396 and 397 were formed via spirocyclic intermediate 393. The relative amounts of 395, 396 and 397 could be subjected... 

A suitable entry into the chemistry of Ti and Zr complexes is the use of highly reactive metal amides. In fact, by treatment of M(NEt2)4 (M = Ti, Zr) with two equiv of the (Me3Si)2HOSi-SiMe2-SiOH(SiMe3)2 (1), spirocyclic metal disiloxides of type 2 (M = Ti, Zr) can be obtained as moisture... 

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