An operationally simple protocol
for a palladium-catalyzed 13CO and 14CO exchange
with activated aliphatic
and benzoic carbonyls is presented. Several 13C and 14C building blocks, natural product derivatives, and pharmaceuticals
have been prepared to showcase the method for late-stage carbon isotope
incorporation and its functional group compatibility.
Unique reactivity is shown by the fluorotitanium complex obtained from TiF4 and 1,1′‐bi‐2‐naphthol. It is more reactive than the chloro‐, bromo‐, and alkoxytitanium complexes previously employed and catalyzes the enantioselective additions of allyltrimethylsilane to aldehydes [Eq. (a)], providing an alternative to known methods involving the corresponding organotin reagents.
A simple and efficient method for converting methyl sulfones to sulfinic acids is described. The process involves alkylation with a benzylic halide, followed by in situ elimination of the resulting styrene in the presence of excess base to yield a sulfinic acid in a single reaction process. The usefulness of the alkylation-elimination sequence is demonstrated by generating a variety of sulfinic acids from methyl sulfones. Late stage functionalization and C-labeling of several biologically active methyl sulfones were accessed via sulfinate intermediates.
The preparation of 3,4,5-substituted 8-carboxamido-1,5-benzodiazepin-2-ones using a solid-phase synthetic method is described. 4-Fluoro-3-nitrobenzoic acid is tethered to a solid support via the acid group. Aromatic substitution of the aryl fluoride with either an alpha- or beta-substituted beta-amino ester is carried out in the presence of DIEA in DMF. The reduction of the aryl nitro group is accomplished in the presence of SnCl(2).H(2)O. Hydrolysis of the ester is carried out in the presence of a heterogeneous mixture of 1 N NaOH/THF (1:1). The resulting aniline acid is cyclized to form the benzodiazepinone skeleton with DIC and HOBt. Selective alkylation at the N-5 position of the benzodiazepinone is accomplished with alkyl halides in the presence of K(2)CO(3) in acetone. The desired products are cleaved from solid supports and obtained in 46-98% isolated yields.
[reaction: see text] A regioselective method for the preparation of 1,5-trisubstituted 1H-1,2,3-triazoles via a 1,3-dipolar cycloaddition of 1-trimethylsilylacetylenes with organoazides is described. Immobilization of the azide on REM resin and subsequent cycloaddition afforded a 2 x 2 x 4 x 3 membered 1,5-disubstituted 1H-1,2,3-triazole library with an average purified yield of 68%.
We investigated the formation of macrocycles from alpha,omega-diynes in cobalt-mediated co-cyclotrimerization reactions. Long-chain alpha,omega-diynes underwent metal-mediated [2 + 2 + 2] cycloadditions with nitriles, cyanamides, or isocyanates in the presence of CpCo(CO)2 (Cp = cyclopentadienide) to yield pyridine-containing macrocycles, i.e., meta- and para-pyridinophanes, such as 5m/5p, 35m/35p, and 41m/41p. The regioselectivity of these reactions was affected by the length and type of linker unit between the alkyne groups, as well as by certain stereoelectronic factors. An analogous alpha,omega-cyano-alkyne, 28, combined with an alkyne to yield two isomeric meta-pyridinophanes, such as 5m and 29m, and an ortho cycloadduct (benzannulation product), such as 29o. We developed a reaction protocol for these cobalt-based [2 + 2 + 2] cycloadditions that involves markedly improved conditions such that this process offers a convenient, flexible synthetic approach to macrocyclic pyridine-containing compounds. For example, diyne 6 reacted with p-tolunitrile in 1,4-dioxane to give 7p and 7m (7:1 ratio) in 87% yield at a moderate temperature of ca. 100 degrees C in 24 h without photoirradiation or syringe-pump addition. Isocyanates were also effective reactants, as exemplified by the formation of 44p almost exclusively (44p:44m > 50:1) in 64% yield from diyne 8 and 2-phenylethylisocyanate. By using this improved protocol we were able to co-cyclotrimerize long-chain alpha,omega-diynes with alkynes in certain cases to demonstrate a successful macrocyclic variant of the Vollhardt reaction. For instance, diyne 6 reacted with dipropylacetylene to give paracyclophane 57p and benzannulene 57o (2:1 ratio) in 29% yield.
A convergent, practical, and efficient synthesis of 2',6-difluoro-5'-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABA(A) alpha(2/3)-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilogram scale and utilized biaryl bromide 6 and imidazotriazine 22 as key intermediates. Biaryl bromide 6 was prepared via a highly selective aromatic bromination. The regioselective condensation of aminotriazine 15 with chloroacetaldehyde provided the desired imidazotriazine intermediate 22. A highly regioselective palladium-catalyzed arylation in the final step highlights the efficiency of the route.
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