Tert-butyl 8-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate
[CAS# 893566-75-1]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Isoquinoline compound
• Name: Tert-butyl 8-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate
• Molecular Formula: C₁₄H₁₈BrNO₂
• Molecular Weight: 312.20
• CAS Registry Number: 893566-75-1
• EC Number: 829-848-7
• SMILES: CC(C)(C)OC(=O)N1CCC2=C(C1)C(=CC=C2)Br

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 382.4±42.0 ºC 760 mmHg (Calc.)^*
• Flash point: 185.0±27.9 ºC (Calc.)^*
• Index of refraction: 1.559 (Calc.)^*

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

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

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Skin irritation	Skin Irrit.	2	H315
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2A	H319

Discovory and Applicatios

The chemical substance tert-butyl 8-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate, often referred to as Boc-protected 8-bromo-tetrahydroisoquinoline, is a functionalized heterocyclic compound widely used as a synthetic intermediate, particularly in pharmaceutical chemistry. Its discovery and applications are well-established in the literature, rooted in the development of tetrahydroisoquinoline derivatives and protecting group chemistry.

The origins of this compound are linked to the study of 1,2,3,4-tetrahydroisoquinoline (THIQ), a bicyclic heterocycle comprising a benzene ring fused to a piperidine ring, which has been investigated since the early 20th century for its presence in alkaloids and pharmacological properties. The tert-butoxycarbonyl (Boc) protecting group, introduced in the 1950s by Louis Carpino, became a cornerstone of amine protection due to its stability under basic conditions and ease of removal under mild acidic conditions. The specific introduction of a bromine atom at the 8-position and a Boc group at the 2-position of tetrahydroisoquinoline emerged in the late 20th century, driven by the pharmaceutical industry’s need for regioselectively substituted heterocycles as building blocks for drug synthesis. Advances in halogenation and protection strategies during the 1970s and 1980s facilitated the synthesis of such compounds.

Synthetically, tert-butyl 8-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate is typically prepared from 1,2,3,4-tetrahydroisoquinoline or a brominated precursor. A common route involves protecting the nitrogen at the 2-position by reacting tetrahydroisoquinoline with di-tert-butyl dicarbonate under basic conditions to form the Boc-protected intermediate. The 8-position is then brominated using an electrophilic brominating agent, such as N-bromosuccinimide, which selectively targets the aromatic ring due to its electronic properties. Alternatively, the synthesis may start with 8-bromo-isoquinoline, which is reduced to 8-bromo-tetrahydroisoquinoline using a reducing agent like sodium borohydride, followed by Boc protection. These steps rely on well-documented heterocyclic and protecting group chemistry, ensuring regioselectivity and high yields.

The primary application of tert-butyl 8-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate is as a synthetic intermediate in pharmaceutical chemistry. The tetrahydroisoquinoline core is a privileged structure in medicinal chemistry, found in drugs targeting the central nervous system, cardiovascular system, and cancers. The bromine at the 8-position serves as a handle for cross-coupling reactions, such as Suzuki-Miyaura or Heck couplings, enabling the introduction of aryl, alkenyl, or alkynyl groups to the aromatic ring. The Boc group protects the nitrogen during these transformations, allowing selective manipulation of the molecule, and can be removed to yield the free amine for further functionalization, such as amide or amine formation. This compound is used in the synthesis of enzyme inhibitors, receptor agonists, and other bioactive molecules, where the tetrahydroisoquinoline scaffold enhances binding to biological targets.

In addition to pharmaceuticals, the compound is employed in academic research to study tetrahydroisoquinoline reactivity, particularly in cross-coupling mechanisms and regioselective halogenation. Its bromine and Boc functionalities make it a valuable model for exploring heterocyclic transformations and the effects of substituents on molecular properties. The compound also finds use in the synthesis of specialty chemicals, such as ligands for catalysis, where the rigid bicyclic structure and reactive bromine are advantageous.

The significance of tert-butyl 8-bromo-1,2,3,4-tetrahydroisoquinoline-2-carboxylate lies in its role as a multifunctional building block that combines the biological relevance of tetrahydroisoquinoline with the synthetic versatility of bromine and Boc protection. Its development reflects progress in heterocyclic functionalization and cross-coupling chemistry. By enabling the efficient synthesis of complex, biologically active molecules, it has become a critical tool in advancing pharmaceutical and chemical research.