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Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
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nh2
73
74
DMF, n-BuOH, 90 °Ń
75
R
76
Scheme 13.
106 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE SwAR REACTIONS
under the standard SnCl2 conditions, but satisfactory results were obtained with Cu(acac)2-NaBH4. Treatment of 74 with a substituted benzimidate at elevated temperatures afforded benzimidazole 75, which upon cleavage provided the phenol product 76 in isolated yields of -50-90%.
3.4.2. Benzimidazolones (7)
The same authors have also reported on the solid-phase synthesis of benzimidazolones 7 from resin-bound 4-fluoro-3-nitrobenzoic acid lb, amines, disuccinimidocarbonate (DSC), and alkyl halides (Scheme 14).10
Treatment of lb with different amines at ambient temperature, followed by Sn(II)-mediated reduction of the nitro group under standard conditions afforded the corresponding di-anilines 78 in good yields and purities. Among a variety of phosgene-type reagents evaluated (e.g., phosgene, triphosgene, CDI, DSC), only DSC was found to give reliably high yields of monosubstituted benzimidazolones. Alkylation of the second nitrogen was effected with alkyl halides and NaH as a base, to afford, upon cleavage from the resin, the desired 1,3-disubstituted benzimidazolones (7) in excellent isolated yields.
3.4.3. 2-Alkylthio-benzimidazoles (8)
Lee et al. explored another variant of the benzimidazole theme (Scheme 14) by showing that it is possible to generate 1-substituted 2-alkylthiobenzimi-dazoles 8 from la, amines, 1,1 '-thiocarbonyldiimidazole (TCD), and ben-zylic halides.11 The title compounds and their corresponding sulfoxides have been reported to have a variety of potentially valuable pharmacological properties.62'64 The di-anilines 78 (X = NH) were prepared following standard methods and treated with TCD to yield the corresponding benzimi-dazole-2-thiones. Subsequent ^-alkylation using benzylic halides in the presence of DIEA in DMF at ambient temperature followed by TFA cleavage furnished the title compounds 8 in high purities and yields.
3.4.4. 2-Alkylaminomethyl- and 2-Thiomethyl-benzimidazoles (9)
Tumelty in our group pursued yet another benzimidazole idea, whereby substituted l-aryl-2-aminomethyl-benzimidazoles 9 were assembled from
3.4. FORMATION OF [6,5]-FUSED SYSTEMS 107
1a(X=NH) 1b (X=0)
(i) H2NR1, DMSO, 25 °Ń ^
(ii) 1M SnCI2e2H20, DMF
77 (R,R' = 0)
78 (R,R‘ = H) (X = O, NH)
(Y = NH, NR3, S)
Scheme 14.
la, anilines, bromoacetic anhydride, and amines (Scheme 14).12 The use of thiols in place of amines provided the corresponding substituted l-aryl-2-thiomethyl-benzimidazoles. Both compound classes have proven to be important as leads in several drug discovery programs and have utility as anti-arrhythmic and antiviral agents.65-67 As in the two prior examples, di-anilines 78 (R = NH) constitute key intermediates. However, in contrast
108 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE S/vAR REACTIONS
to the two previous reports, R1 was exclusively derived from anilines rather than alkyl- or aralkyl primary amines, thereby generating benzimidazoles containing the pharmacologically important diphenylamine motif. Elevated temperatures and the use of an auxiliary base (DIEA) were required for the SyyAr reaction to go to completion, particularly for anilines with deactivating electron-withdrawing substituents. Reaction of 78 with bromoacetic anhydride furnished exclusively monobromoacetylated intermediates. It is assumed that the acylation occurs on the primary aniline rather than on the deactivated secondary diphenylamine nitrogen. This issue is academic with respect to the structures of the final benzimidazoles, since both bromoace-tylated intermediates would afford the same products upon cyclodehydra-tion. Displacement of bromide by primary and/or secondary amines and by thiols is then possible, as illustrated in Scheme 14. The final step involved treatment of the resin-bound intermediates with TFA for 16 h to release the products with concomitant cyclodehydration forming the benzimidazoles 9.
3.5. CONCLUSIONS AND OUTLOOK
The goal of this review was to present a highly versatile synthetic strategy enabling solid-phase syntheses of a variety of pharmacologically relevant, “privileged” templates, such as benzodiazepines, benzothiazepines, and benzimidazoles. Starting from a common intermediate, resin-bound 4-fluoro-3-nitrobenzoic acid la,b, eight different benzofused heterocyclic core structures were assembled using the same basic series of synthetic transformations in conjunction with the appropriate core building blocks (Scheme 1). The general synthetic sequence consisted of nucleophilic aromatic displacement of fluorine by sulfur and/or nitrogen nucleophiles, subsequent reduction of the r;-nitro group, and cyclization, followed (and/or preceded) by introduction of further functionality at suitable positions.
As mentioned in the introduction, typically one of the most time-consuming steps in the synthesis of a combinatorial library by solid-phase methods is demonstrating the feasibility and generality of the synthesis of a particular core structure on resin. Hence a strategy wherein the synthetic transformations, once developed and optimized, can subsequently be reused in different contexts to produce an array of different compound classes has considerable merit. Having initially invested a considerable amount of time in establishing the practicability of the first scaffold chemistry (the ben-
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