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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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In contrast to aromatic aldehydes, aliphatic aldehydes invariably afforded complex mixtures of products when submitted to the above conditions. Based on their molecular weights, a few products could tentatively be identified as dialkylated, as well as dehydrodialkylated, compounds, such as 24. These perhaps were derived from tautomerization of the initially formed imine 19 to the thermodynamically more stable enamine 20 followed by reaction with a second aldehyde molecule and subsequent reduction (Scheme 3).
3.2. FORMATION OF [6,7]- AND [6,8]-FUSED SYSTEMS 87
R
NH2 RCHO
18
BtH = N
H
Bt
NH
21
NH
23
Scheme 3.
R
N.
24
To suppress enamine-derived side products, we explored addition of benzotriazole (BtH) to the reaction mixture. The premise behind these experiments was the ability of BtH to form stable adducts with imines,23,24 thereby blocking tautomerization of 19 to 20 through in situ formation of the benzotriazolyl derivative 21. It was hoped that subsequent hydride displacement of the Bt moiety would afford the desired mono alkylated products 23. Indeed, analytical high-performance liquid chromatography (HPLC) revealed a remarkable improvement in terms of product purity, especially for reactions carried out at room temperature, with the desired secondary anilines 23 being essentially the only products detected. In
88 BENZOFUSED HETEROCYCLES VIA SOLID-PHASE Sa/AR REACTIONS
further studies, the benzotriazole-mediated suppression of enamine-derived side-product formation was shown to be of broad scope. However, enamine-derived side products were still observed for reactions with phenylacetal-dehyde or, more markedly, with diphenylacetyldehyde, where the driving force for tautomerization is particularly strong. Figure 3.1 displays a representative selection of aldehydes that were successfully employed in the reductive alkylation step using the optimized conditions outlined above.
With a variety of secondary anilines 14 in hand, formation of the seven-membered thiazepine ring was attempted using a selection of common coupling reagents, including HATU/DIEA, DIC/HOBt, DIC/DMAP, and EDC, as well as some non-carbodiimide-type reagents, such as DECP and Mukaiyama’s reagent. It was found that only DIC solutions in solvents of low polarity, such as benzene and/or CH2C12, and devoid of additives like HOBt or DMAP were able to furnish the desired A^(5)-alkylated ben-zothiazepinones 16 (Scheme 2). Use of polar solvents like DMF or NMP resulted in formation of considerable amounts (20-50%) of the corresponding TV-acylureas 15 as side products.25,26 Moreover, it was imperative that the resin 14 resulting from reductive alkylation be subjected to a wash with aqueous acetic acid (2% v/v) prior to cyclization. Omitting this washing step completely inhibited cyclization of the secondary anilines 14; under the reductive alkylation conditions, the carboxyl function in 14 had been converted into its sodium salt, which was unreactive toward carbodiimide-type reagents. Gratifyingly, the newly established cyclization conditions proved to be of wide generality, allowing essentially all secondary anilines 14 to be smoothly converted to the corresponding A'( 5 (-substituted 1,5-ben-zothiazepinones 16.
The remaining steps completing the synthetic sequence featured manipulation of the exocyclic amino group of the 1,5-benzothiazepinone template. This included Fmoc removal from 16 and treatment of the resulting primary amines 17 with aldehydes, carboxylic acids, sulfonyl chlorides, and/or isocyanates to generate, upon cleavage from resin, the corresponding secondary amines 2A, amides 2B, sulfonamides 2C, and/or ureas 2D, respectively (Scheme 2). These four transformations reliably afforded the desired
3,5-disubstituted l,5-benzothiazepin-4-ones in high purities and yields, showing full compatibility with all types of functional groups examined. In subsequent studies, we demonstrated that the solid-phase assembly of benzothiazepinones according to Scheme 2 proceeded without racemiza-tion at the a-carbon atom.4
3.2. FORMATION OF [6,7]- AND [6,8]-FUSED SYSTEMS 89
We have previously described how chemical-encoding strategies can facilitate identification of bioactive compounds from large combinatorial libraries.27,28 Compatibility of our dialkylamine encoding method with the
1,5-benzothiazepinone synthesis has been established through model studies. The extra steps devoted to the introduction of the chemical codes were shown not to adversely affect the purity of the 1,5-benzothiazepinone compounds.4 We have used this chemistry to generate a number of large encoded 1,5-benzothiazepinone libraries for high-throughput screening.
In an attempt to extend the scope and the diversity of the benzothiazepi-none chemistry on solid support, we explored the possibility of alkylating N(5) after formation of the seven-membered ring (Scheme 4). This sequence is known in solution-phase chemistry, albeit with a different protecting group strategy for the a-amino group.29 In contrast to the secondary anilines 14 derived from reductive alkylation of 12, the cyclization of the primary aniline 12 was found to proceed smoothly under a variety of common amide-bond-forming conditions. After cyclization of the primary aniline 12 using DIC in DMF, the resulting 7V(5)-unsubstituted ben-zothiazepinone 25 was subjected twice to phase-transfer alkylation conditions using allyl-bromoacetate, Bu4NBr, and KOH powder in THF, to afford the orthogonally protected intermediate 26 (Scheme 4). We were surprised to find that the Fmoc-protecting group was stable under the phase-transfer alkylation conditions. Fmoc deprotection, followed by acylation of the primary amino group and Pd(0)-catalyzed cleavage of the allyl ester function furnished acids 29, which were reacted with primary and/or secondary amines in the presence of DECP in DMF to afford the corresponding amides 30 upon cleavage from the resin. Again, the high optical purity of these compounds was established by HPLC analysis.
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