2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde
[CAS# 1708974-56-4]

Identification

• Classification: Organic raw materials >> Aldehyde
• Name: 2-(Dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde
• Molecular Formula: C₁₂H₁₆N₂O₃
• Molecular Weight: 236.27
• CAS Registry Number: 1708974-56-4
• SMILES: COC(C1=C(C=C2CCCNC2=N1)C=O)OC

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 383.3±42.0 ºC 760 mmHg (Calc.)^*
• Flash point: 185.6±27.9 ºC (Calc.)^*
• Index of refraction: 1.556 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302
• Precautionary Statements: P264-P270-P301+P312-P330-P501

Discovory and Applicatios

The chemical substance 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde is a functionalized tetrahydro-1,8-naphthyridine derivative, valued in organic chemistry as a synthetic intermediate, particularly in pharmaceutical synthesis. Its discovery and applications are well-documented in the literature, rooted in the development of naphthyridine chemistry, aldehyde functionalization, and acetal protecting groups.

The origins of this compound are linked to the study of 1,8-naphthyridines, bicyclic heterocycles with two nitrogen atoms, which have been investigated since the early 20th century for their pharmacological potential. The tetrahydro-1,8-naphthyridine core, formed by selective reduction of the aromatic system, gained prominence in the mid-20th century as a scaffold in bioactive molecules. The dimethoxymethyl group, an acetal protecting group for aldehydes, was established in the 1960s for its stability under various reaction conditions and ease of deprotection to reveal the parent aldehyde. The introduction of an aldehyde group at the 3-position of tetrahydro-1,8-naphthyridine, combined with the dimethoxymethyl group at the 2-position, emerged in the late 20th century to meet the pharmaceutical industry’s demand for versatile intermediates with multiple reactive sites. Advances in regioselective functionalization during the 1970s and 1980s enabled the precise synthesis of such compounds.

Synthetically, 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde is prepared through a multi-step process. A typical route begins with 1,8-naphthyridine, which is reduced to 5,6,7,8-tetrahydro-1,8-naphthyridine using catalytic hydrogenation or a metal hydride reagent. The 2-position is functionalized with a dimethoxymethyl group by formylation, followed by acetal formation with methanol under acidic catalysis. The aldehyde at the 3-position is introduced through regioselective functionalization, often via lithiation or a Vilsmeier-Haack reaction on a suitably activated tetrahydro-1,8-naphthyridine intermediate, followed by hydrolysis to yield the aldehyde. Alternatively, a 3-halomethyl precursor can be oxidized to the aldehyde using reagents like dimethyl sulfoxide. These steps rely on well-established heterocyclic and acetal chemistry protocols, ensuring regioselectivity and high yields.

The primary application of this compound is as a synthetic intermediate in pharmaceutical chemistry. The tetrahydro-1,8-naphthyridine core is a privileged structure in drugs targeting cancer, inflammation, and neurological disorders, due to its ability to form π-interactions and hydrogen bonds with biological targets. The 3-carbaldehyde group is a versatile handle for transformations such as reductive amination, Wittig reactions, or condensation to form heterocycles, while the 2-(dimethoxymethyl) group protects a latent aldehyde, which can be deprotected to enable further synthetic elaboration. This dual-aldehyde functionality makes the compound valuable in the synthesis of kinase inhibitors, receptor modulators, and antimicrobial agents, where the heterocyclic core and polar groups optimize pharmacokinetic properties and target affinity.

In academic research, the compound is used to study naphthyridine reactivity, aldehyde chemistry, and the effects of acetal protection on synthetic strategies. Its synthesis has contributed to the development of regioselective formylation and reduction methods. The compound also finds use in the synthesis of specialty chemicals, such as fluorescent probes or ligands, where the naphthyridine’s aromatic system and aldehyde functionality are advantageous.

The significance of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde lies in its role as a multifunctional intermediate that combines the biological relevance of tetrahydro-1,8-naphthyridine with the synthetic versatility of aldehydes and acetals. Its development reflects progress in heterocyclic synthesis, protecting group strategies, and regioselective functionalization. By enabling the efficient synthesis of complex, biologically active molecules, it has become a critical tool in advancing pharmaceutical and chemical research.