Dimethyl 4-aminothiophene-2,3-dicarboxylate hydrochloride
[CAS# 121071-71-4]

Identification

• Classification: Organic raw materials >> Carboxylic compounds and derivatives >> Carboxylic esters and their derivatives
• Name: Dimethyl 4-aminothiophene-2,3-dicarboxylate hydrochloride
• Synonyms: 4-Aminothiophene-2,3-dicarboxylic acid dimethyl ester hydrochloride
• Molecular Formula: C₈H₉NO₄S^.HCl
• Molecular Weight: 251.69
• CAS Registry Number: 121071-71-4
• EC Number: 681-165-1
• SMILES: COC(=O)C1=C(SC=C1N)C(=O)OC.Cl

Properties

• Melting point: 166 - 169 ºC (Expl.)

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H315-H319-H335
• Precautionary Statements: P261-P264-P264+P265-P271-P280-P302+P352-P304+P340-P305+P351+P338-P319-P321-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Discovory and Applicatios

Dimethyl 4-aminothiophene-2,3-dicarboxylate hydrochloride is a substituted thiophene derivative in which a 4-amino group and two ester functions occupy the 2- and 3-positions of the thiophene ring; the hydrochloride salt form stabilises the amino substituent for handling and storage. The dialkyl thiophene-2,3-dicarboxylate motif has a well-established synthetic pedigree: classical approaches build the thiophene core by cycloaddition or multicomponent condensations (for example variants of the Gewald reaction or cycloadditions of activated alkynes with sulfur-containing nucleophiles), and subsequent functional-group transformations introduce amino and ester functionality or convert pre-installed ester groups into the corresponding 2,3-dicarboxylate pattern. The dimethyl ester / amine salt derivative is widely available from commercial suppliers and is used as a bench-stable synthetic intermediate for further elaboration into heterocycles and substituted thiophenes.

The historical development of thiophene chemistry originates from 19th-century studies of coal-tar constituents, but methods that specifically access 2,3-dicarboxylate substitution patterns and 4-aminothiophene derivatives were systematically expanded in the 20th century through both pericyclic/cycloaddition strategies and multicomponent condensations. The Gewald multicomponent reaction and its modern variants have been especially important for assembling 2-aminothiophene cores from readily available carbonyl compounds, activated nitriles and elemental sulfur; modifications and catalysed versions of this sequence have broadened substrate scope and improved yields, enabling access to diverse substitution patterns including the 2,3-dicarboxylate family. Alternative routes exploit additions to activated acetylenic esters followed by ring closure to install the thiophene ring with ester substituents already present at the 2- and 3-positions. These convergent strategies provide straightforward access to dimethyl 4-aminothiophene-2,3-dicarboxylate and related building blocks.

Applications of dimethyl 4-aminothiophene-2,3-dicarboxylate hydrochloride arise principally from its role as a synthetic synthon for medicinal chemistry, heterocycle construction and materials-related research. The combination of two ester groups and an amino group on the thiophene ring makes it a versatile precursor for condensation, amidation, cyclisation and annulation reactions that create fused heterocycles or install diverse substituents. In drug-discovery settings, 4-aminothiophene derivatives serve as scaffolds for compound libraries because the amino group can be derivatised to amides, ureas, sulfonamides or heterocycles, and the diester motif can be transformed into carboxylic acids, acid chlorides or used in further carbon–carbon bond-forming reactions. Such downstream conversions have been employed to generate thiophene-containing carboxamides, thieno[3,4-c]pyridines, thieno[2,3-b]pyrroles and related fused systems that appear in reports of biological screening and lead optimisation.

Beyond small-molecule medicinal chemistry, thiophene-2,3-dicarboxylates are also incorporated into materials and dye chemistry. The electron-rich thiophene core, when suitably functionalised, participates in conjugation and charge-transport frameworks; ester-to-amide or ester-to-aldehyde conversions provide handles for polymerisation or for installation of chromophoric groups. In several synthetic studies the 2,3-dicarboxylate derivatives have been used as key intermediates in the preparation of more elaborate heterocyclic systems and as precursors to compounds tested for antimicrobial, anti-inflammatory or enzyme-inhibitory activities. The commercial availability of the dimethyl ester hydrochloride salt has facilitated its adoption as a standard reagent for library synthesis and for exploratory chemistry in both academic and industrial laboratories.

Practical handling and synthetic considerations reflect the multifunctional nature of the molecule. The ester groups tolerate many common organic transformations but are susceptible to strong bases or prolonged acidic hydrolysis; selection of protecting-group strategies and chemoselective activation is therefore routine when using the compound in multistep sequences. The amino function as a hydrochloride salt is typically liberated under mild base when the free amine is required for coupling or cyclisation steps. Analytical characterisation of intermediates derived from dimethyl 4-aminothiophene-2,3-dicarboxylate routinely employs NMR, mass spectrometry and chromatography to confirm substitution patterns and to monitor transformations.

References

Puterová Z, Krutošíková A & Végh D (2010) Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes. ARKIVOC 2010 (i) 209–246. DOI: 10.3998/ark.5550190.0011.105

Shah R & Verma P K (2018) Therapeutic importance of synthetic thiophene. BMC Chemistry 12 137. DOI: 10.1186/s13065-018-0511-5

McKibben M R, Cartwright K A, et al. (2019) Synthesis of tetrasubstituted thiophenes via direct metalation. Journal of Organic Chemistry 84 24 16036–16052. DOI: 10.1021/acs.joc.9b02803