Researchers Identify Advances for Heterocyclic Chemistry

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PTSM: Pharmaceutical Technology Sourcing and Management

PTSM: Pharmaceutical Technology Sourcing and Management-12-02-2015, Volume 11, Issue 12

Multi-component coupling reactions for the generation of heterocycles in fewer steps reduced processing times, cost, and waste are attracting interest.

The structural complexity of newer small-molecule drug candidates is increasing, with many containing several different heterocyclic substructures and numerous stereogenic centers. Preparing single isomers of these compounds can be quite challenging and requires the use of atom-efficient, low-waste, regio- and stereoselective reactions, according to Dave Green, vice-president of R&D with ANGUS Chemical Company. “A considerable amount of effort is being consumed to expand the utility of classic synthetic methods, often focusing on enantioselective catalysis or combining steps into what are now being called multi-component reactions (MCRs),” he observes.

In particular, multi-component coupling reactions for the generation of heterocycles in fewer steps with high regioselectivity and reduced processing times, cost, and waste are attracting significant interest. A new cross-dehydrogenative, heteroaromatic carbon–hydrogen (C–H) silylation reaction catalyzed by the simple base potassium tert-butoxide (KOtBu) is also a potentially useful reaction for API synthesis.

Cascade reactions

Older methods for the synthesis of heterocycles typically relied on the stepwise construction of linear frameworks followed by final cyclizations. “Today,” says Green, “reaction conditions and catalytic methods are being developed such that three or even four reactive components can be simultaneously combined, resulting in a cascade that leads to a highly functionalized product.” Nitroalkanes are often one of the building blocks used for the synthesis of nitrogen-containing heterocycles.

Nitroalkane MCRs

In one example published by Maiti et al. in 2010 (1), fully substituted pyrroles were prepared with five independently selected substituents (four-component reaction) in a completely regioselective manner. “It is also notable that all of the starting materials used in the reaction are readily accessible monofunctional reagents,” Green notes. For reactions using nitromethane, isolated yields were often in the 70 to 80% range, and typically higher than those using nitroethane (1). The 3-ketopyrroles obtained from the reaction are highly versatile intermediates and can be used for a variety of synthetic applications, according to Green.

Dehaen and co-workers reported a three-component coupling reaction between nitroalkanes, alkyl azides, and aldehydes that affords tri-substituted triazoles, again in a regioselective manner (2). This reaction proceeds via 1,3-dipolar cycloaddition of the azide with a nitroalkene formed in-situ. Tazobactam is one example of a current API that contains a 1,2,3-triazole moiety.

Heterocycles as in situ intermediates

ANGUS utilized MCR technology to synthesize 3-(N-methyl)-1-phenyl-1-propanol via a heterocyclic intermediate. The three-component reaction of formaldehyde and styrene with N-methyl hydroxylamine, which was readily prepared by selectively reducing nitromethane, proceeded through an isoxazolidine intermediate that was ring-opened to give only the desired regioisomer in nearly quantitative yield. This direct route to 3-(N-methyl)-1-phenyl-1-propanol is an important development, because this compound is the key intermediate in the manufacture of fluoxetine, according to Green. “By using the MCR technique, isolation of the methyl nitrone intermediate was avoided, preventing the issues associated with its propensity to oligomerize,” he explains.

Handling energetic materials


One of the challenges when preparing nitrogen-containing heterocycles via multi-component reactions that require the use of nitromethane or compounds like N-methylhydroxylamine (MHA) is the reactivity of these substances. Nitromethane, azides, and to a lesser extent MHA are energetic materials, and special handling requirements must be considered. “Minimization of the quantities of in-process and/or isolated materials is an excellent way to also minimize the potential energy release at any given point in the process,” Green says. He points to the recent development of commercially available micro-flow reactors as providing both laboratory- and production-scale options. “At the lab scale, a variety of process conditions and stoichiometries can be evaluated in order to define the safe operating limits for reagent concentrations/ temperature/pressure with essentially no potential energy release risk. In turn, scaling the best operating conditions in an analogous configuration greatly minimizes the risk associated with handling the larger volumes needed for commercial production,” he observes. 

Interest in heteroarylsilanes

The substitution of carbon for fluorine is recognized as an attractive method for preparing drug candidates with improved lipophilicity and other attractive properties. More recently, compounds containing silicon-carbon bonds have attracted interest, because such derivatives are also often more stable and have improved solubilities and pharmacokinetic properties.

To date, heteroaromatic organosilanes have been prepared using two rather limited methods: stoichiometric reaction of a heteroaromatic organometallic intermediate generated via a Grignard reaction with a silicon electrophile and catalytic C–H silylation mediated by a rhodium or iridium catalyst in the presence of an excess of a hydrogen acceptor. The functional group tolerance of these methods is minimal. In addition, they require the use of large quantities of reactive and/or expensive reagents. As a consequence, there is a desire for more general routes to organosilanes that are not only more cost-effective and practical on an industrial scale, but also provide access to novel compounds.

Fortuitous discovery

Students in the Grubbs and Stoltz groups at the California Institute of Technology recently stumbled on an interesting reaction catalyzed by KOtBu. They were investigating the conversion of biomass to chemicals via the breakage of carbon-oxygen bonds using an iron catalyst, potassium tert-butoxide, and a hydrosilane as a hydride equivalent and observed that a control reaction with just KOtBu and the hydrosilane gave silylated heteroaromatics as byproducts (4).

Using 1-methylindole as a model substrate, the reaction conditions were optimized for the selective production of a single organosilane in high yield. A catalytic amount (1-20 mol%) of KOtBu was found to be most effective, and cross dehydrogenative heteroaromatic C–H silylation occurs without the need for an acceptor, resulting in the generation of hydrogen gas as the only byproduct. Extensive studies were also performed to confirm that the KOtBu was indeed the catalyst (3).

The reaction is noteworthy not only because it is novel, but also because of its scope, scalability, and the fact that it is catalyzed by an inexpensive, commercially available substance based on potassium, which is an abundant alkali metal and not a rare and expensive precious metal. Furthermore, the reaction proceeds under mild conditions, has no complicated byproducts, the product is readily isolated, and in many cases no solvent is required.

With respect to the scope of the reaction, indoles with a variety of substituents on the nitrogen (N) molecule and at various positions on the arene ring, and many different electron-neutral and electron-rich N-, oxygen- and sulfur-containing heterocyclic compounds are tolerated, although carbonyl groups generally are not unless protected as acetals. In addition, bromide, iodide, cyano, and nitro substituents inhibit the reaction, while fluoride, chloride, trifluoromethyl, epoxide, N-alkyl aziridine, pyridine, and tertiary amine and phosphine groups do not (3).

Simple arenes also undergo the dehydrogenative heteroaromatic C–H silylation reaction, but the reactivity depends on the substituents. Anisole affords the ortho-substituted silylated product, while toluene and similar compounds undergo directing-group-free C(sp3)–H silylation to generate silylated benzyl derivatives. The electronic nature of any oxygen substituents also determines the regioselectivity (on the ring or the substituent) of the silylation (3).

Importantly for pharmaceutical applications, the reaction appears to be readily scalable; the neat reaction of N-methyl indole with 1.5 equivalents of triethylsilane at 45 °C was performed on a 100-gram scale followed by simple filtration and distillation, affording the desired C2 silylated product in 76% yield with high regioselectivity (> 20:1) (3).

In addition, the facile silylation of APIs was achieved to demonstrate the potential for application of the reaction for late-stage modification of pharmaceutically relevant compounds. The antihistamine thenalidine and the antiplatelet drug ticlopidine were successfully subjected to the regioselective C–H silylation reaction (58–68% yield with high chemo- and regioselectivity) (3). Therefore, this method should be useful for the rapid synthesis of compound libraries. Different heteroarylsilanes obtained using the KOtBu chemistry were also converted to more complex molecules via silicon-directed Suzuki–Miyaura cross-coupling and Hiyama–Denmark cross-coupling reactions to demonstrate their synthetic utility (3).


S. Maiti et. al., J. Org. Chem. 75(5), 1674-1683 (2010).

W. Dehaen et al., Angew. Chem. Int. Ed. 53(38), 10155–10159 (2014).

A. A. Toutov et al., Nature 518(7537), 80-84 (2015).