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102 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE Sa/AR REACTIONS
Some 30 benzyl bromides, allyl bromide, and different esters of bro-moacetic acid were found to work well in the /V(4)-alkylation reaction. Benzyl chlorides, oc-bromo acetophenones, as well as unactivated alkyl bromides, however, did not give satisfactory results.
For the final step involving functionalization at N( 1) of 62, anilide deprotonation with lithiated 4-benzyl-2-oxazolidinone as a base and alkylation with benzyl bromides again proved effective. Compared to the results obtained in the benzodiazepine series, the 7V(l)-alkylation reaction was generally found to proceed less smoothly with the 3,4-disubstituted quinoxalinones 62. Good results were obtained only if the resin batches were submitted twice to the alkylation conditions. Figure 3.4 displays a selection of structures (63-65) accessible from this first synthetic approach. In no case was there any evidence for racemization at the a-carbon atom of the amino acid.
In the synthetic approach reported by Lee and colleagues,8 resin-bound 4-fluoro-3-nitrobenzoic acid la was treated with methyl and/or ethyl esters of a-amino acids 66 in DMF using DIEA as a base (Scheme 10). The resulting o-nitro anilines 67 were then subjected to nitro-group reduction with the intermediate di-anilines undergoing spontaneous cyclization to quinoxalinones 68. Subsequent alkylation at N(4) using benzyl bromides in refluxing acetone with K2C03 as base followed by cleavage from the resin ultimately afforded the 3,4-disubstituted quinoxalinones 69 in good purities and yields.
An interesting side reaction was observed upon cleavage of the Af(4)-un-derivatized quinoxalinones 68 (Scheme 11). A significant fraction of the
63 64 65
Figure 3.4. Selection of quinoxalin-2-ones synthesized from 1a and a-amino acids 60.
3.3. FORMATION OF [6,6]-FUSED SYSTEMS 103
DIEA, DMF, 25 °Ñ
(R = Me, Et)
(i) X-CH2-R , K2C03
(ii) TFA, CH2CI2
104 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE S/vAR REACTIONS
cleaved material had undergone oxidation to the 3,4-dehydroquinoxali-nones 70. This oxidation could be suppressed by prior functionalization at ÓÓ(4), as in the preparation of 69 above.
A second side reaction suffered by yV(4)-unfunctionalized quinoxali-nones leading to racemization at the a-carbon was revealed in the closely related studies of Morales and co-workers, who assembled the [6,6] ring system from 4-fluoro-3-nitrobenzoic acid coupled as an ester to Wang resin (lb) (Scheme 12).9 This undesirable side reaction could also be prevented by functionalization of N(4) prior to cleavage, which in this instance was accomplished by acylation with chloroformates and thiochloroformates. Derivatization at N( 1) was again effected using the Ellman alkylation protocol and provided optically pure samples of the quinoxalinones (72).
To summarize this section, several research groups have effectively exploited parallels between S^Ar strategies leading to [6,7]- and [6,6]-ben-zofused heterocycles and have described complementary reaction protocols suitable for generating diverse combinatorial libraries of benzothiazin-3-ones and quinoxalin-2-ones.
DIEA, DMF, 25 °Ñ
(R = Me, Et)
(i) SnCI2*2H20, DMF î
(ii) CIC(X)OR2, NaHC03,
(iii) lithiated 4-benzyl-2-oxazolidinone, THF
(iv) benzyl bromide, 65 °Ñ (v) TFA, DCM
3.4. FORMATION OF [6,5J-FUSED SYSTEMS 105
3.4. FORMATION OF [6,5]-FUSED SYSTEMS
Benzimidazoles and their derivatives possess varied pharmacological activities59,60 and have therefore been targets of intense synthetic efforts using both solution- and solid-phase methods. In one of the pioneering studies on the assembly of benzofused heterocycles via S^Ar reactions of ofluoro-ni-troarenes, Phillips and Wei reported a solid-phase synthesis of benzimidazoles from 3-fluoro-4-nitrophenol, amines, and ethyl benzimidates (Scheme 13).61
The o-fluoro-nitroarene was attached to TentaGel resin as a phenolic ether 73 via a modified Wang-type linker. Following aminolysis of 73, reduction of the intermediate nitroaniline to di-aniline 74 proceeded poorly
(ii) Cu(acac)2, NaBH4, ÅÞÍ