(2014) Hantzsch pyrrole synthesis.
Hantzsch pyrrole synthesis - Wikipedia
Hantzsch pyridine synthesis - Wikipedia
The Hantzsch pyrrole synthesis involves the reaction of β-ketoesters with ammonia (or primary amines) and α-haloketones. Although the Hantzsch method produces N-substituted pyrroles, the yields are often low and this may be why the procedure has been somewhat under utilized historically., Furthermore, the “one-pot” synthesis of pyrrole-3-carboxylic acids has not been reported and thus stepwise, in-flask (batch) protocols are necessary. Herein, we describe the first direct continuous flow synthesis of pyrrole-3-carboxylic acids. In addition, we have applied the method to the synthesis of pyrrole-3-carboxamide derivatives in an uninterrupted sequence.
Several aspects of this new continuous flow process are noteworthy. For example, this is the first instance of the synthesis of pyrrole-3-carboxylic acids and pyrrole-3-carboxamides directly from inexpensive commercially available starting materials in a single continuous process without isolating intermediates. As noted previously, the standard in-flask synthesis of these compounds involves multiple reaction steps requiring workup and purification of several intermediates. Second, the HBr generated as a byproduct in the Hantzsch reaction is employed in the flow method to saponify the t-butyl esters in situ to provide the corresponding acids in a one-chip reaction. By way of comparison, we performed the in-flask (batch) synthesis of 1-benzyl-2-methyl-5-phenyl-1H-pyrrole-3-carboxylic acid (, Entry 1) using the optimized conditions we developed for our continuous flow method (see for experimental details). Interestingly, the reaction proceeded as expected to provide the product but in significantly lower yield (40%) than the flow process (65%). Finally, the products can be further manipulated in the final step by coupling diverse amines to generate a variety of amides allowing the introduction of additional structural complexity. To demonstrate the utility of the flow method to generate useful quantities of material for further synthetic manipulation, we scaled up the flow synthesis of 1-benzyl-2-methyl-5-phenyl-1H-pyrrole-3-carboxylic acid (, Entry 1) by approximately 17-fold. Gratifyingly, using the flow method, 850 mg (63% yield) of the compound was efficiently produced in 2.5 h flow time.
Hantzsch Dihydropyridine (Pyridine) Synthesis
Tert-butyl esters are versatile protecting groups for carboxylic acids which are stable under basic conditions but can be removed using acid. Typically strong protic acids, such as HCl, H2SO4, HNO3, or TFA, are employed for tert-butyl ester hydrolysis in aqueous or organic solvents. During the Hantzsch pyrrole synthesis HBr is generated as a side product and in our procedure DIPEA is used as a neutralizing agent. We hypothesized that we could take advantage of the strong acid generated in the Hantzsch reaction to saponify the tert-butyl ester formed in the initial product. With this in mind we varied the reaction conditions using different equivalents of DIPEA () and found that the use of 0.5 equiv of DIPEA was optimal to efficiently convert the tert-butyl ester pyrroles to the corresponding acids in situ (, Entry 2).
The pyrrole framework is a ubiquitous structural motif found in a wide range of biologically active natural products and pharmaceutically active agents. Members of this important class of heterocyclic compounds display a variety of pharmacological properties including antibacterial, antiviral, anti-inflammatory, anticancer, and antioxidant activity. A prime example is atorvastatin calcium (Lipitor), the world’s leading cholesterol-lowering drug. Consequently, there is significant interest in the development of efficient methods for the synthesis of pyrrole derivatives bearing diverse substitution patterns. There are several classical methods for the synthesis of pyrroles, including the Hantzsch, Paal–Knorr, and Knorr, in addition to a variety of cycloadditions and transition metal-catalyzed cyclization reactions. Although these methods have proven effective for the preparation of pyrrole derivatives, they involve multistep in-flask (batch) syntheses that limit scope and efficiency, especially with respect to analogue library synthesis.
The Hantzsch pyrrole synthesis - Canadian Journal of Chemistry
Automated microreactor-based (microfluidic chip) continuous flow chemistry is emerging as a powerful technology for the synthesis of small molecule compounds. The application of continuous flow methods to the production of libraries of drug-like structures (primarily heterocycles) has the potential to greatly accelerate the drug discovery process. Continuous flow synthetic methods have the advantage of being highly efficient, atom economical, environmentally friendly (reduction of waste streams), and cost effective. Moreover, the potential to run multistep reactions in a single, uninterrupted microreactor sequence using continuous flow chemistry is particularly beneficial for the rapid and efficient generation of large numbers of compounds with high purity and minimal byproducts. Our research is focused on developing flow chemistry methods for multistep transformations that are either not possible or highly inefficient using in-flask chemistry. We have previously reported general methods for the preparation of 1,2,4-oxadiazoles and imidazo[1,2-a]pyridine-2-carboxamides in uninterrupted continuous flow sequences. We now report an efficient continuous flow procedure for the synthesis of functionalized, highly diverse derivatives of the pyrrole-3-carboxylic acid scaffold.
The first one-step, continuous flow synthesis of pyrrole-3-carboxylic acids directly from tert-butyl acetoacetates, amines and 2-bromoketones is reported. The HBr generated as a by-product in the Hantzsch reaction was utilized in the flow method to saponify the t-butyl esters in situ to provide the corresponding acids in a single microreactor. The protocol was used in the multistep synthesis of pyrrole-3-carboxamides, including two CB1 inverse agonists, directly from commercially available starting materials in a single continuous process.
Hantzsch pyrrole synthesis on solid support - …
Hantzsch pyrrole synthesis | SpringerLink
Hantzsch pyrrole synthesis;
Hantzsch pyridine synthesis - overview - ChemTube3D
Hantzsch pyridine synthesis
Hantzsch pyrrole synthesis on solid support.
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