tert-Butyl 5-Cyano-3-Iodo-1H-Indole-1-Carboxylate: Properties & Uses
tert-Butyl 5-Cyano-3-Iodo-1H-Indole-1-Carboxylate: Properties & Uses
tert-Butyl 5-cyano-3-iodo-1H-indole-1-carboxylate is a Boc-protected, C-3 iodinated indole bearing a C-5 cyano group, making it a highly versatile bifunctional building block for palladium-catalyzed cross-coupling reactions and downstream pharmaceutical synthesis.
- CAS Number
- To be confirmed — see review flag
- Molecular Formula
- C14H13IN2O2
- Key Functional Groups
- Boc carbamate (N-1), C-3 iodo, C-5 cyano
- Primary Synthetic Role
- Electrophilic partner in Pd-catalyzed cross-coupling (Suzuki, Sonogashira, Negishi)
- N-1 Protection
- tert-Butoxycarbonyl (Boc), removable under mild acidic conditions
- Storage Recommendation
- Cool, dry, well-ventilated storage away from light and moisture; see SDS for full details
- SKU
- T195404
Chemical Identity and Structural Features
tert-Butyl 5-cyano-3-iodo-1H-indole-1-carboxylate (SKU T195404) is a halogenated, nitrogen-protected indole derivative. The compound features three strategically positioned functional handles on the indole scaffold:
- N-1 Boc group: The tert-butoxycarbonyl (Boc) protecting group on nitrogen prevents undesired N-alkylation or N-metalation during downstream transformations and is readily removed under mild acidic conditions (e.g., TFA in DCM or HCl in dioxane).
- C-3 Iodo substituent: The carbon–iodine bond at the C-3 position is the most reactive site toward oxidative addition by palladium(0) catalysts, enabling efficient cross-coupling reactions. Aryl iodides are generally superior to the corresponding bromides or chlorides in terms of reactivity.
- C-5 Cyano group: The nitrile at C-5 serves as an electron-withdrawing group that modulates the electronic density of the indole ring. Importantly, the cyano group is itself a versatile handle that can be converted to carboxylic acids, amines (via reduction), tetrazoles, or amidines, greatly expanding structural diversity achievable from this single starting material.
The combination of these three features — a removable N-protecting group, a highly reactive aryl iodide, and a transformable nitrile — makes this compound a particularly efficient scaffold for the construction of complex indole-containing molecules.
Applications in Synthetic Chemistry
The C-3 aryl iodide functionality of tert-Butyl 5-cyano-3-iodo-1H-indole-1-carboxylate renders it an excellent electrophilic coupling partner in a broad range of transition-metal-catalyzed reactions:
- Suzuki–Miyaura coupling: Reaction with arylboronic acids or esters under Pd(0)/Pd(II) catalysis furnishes C-3 arylated indoles useful in medicinal chemistry campaigns targeting kinases and GPCRs.
- Sonogashira coupling: Coupling with terminal alkynes (Cu/Pd co-catalysis) provides 3-alkynylindole motifs that serve as precursors to heterocyclic ring systems via subsequent cyclization.
- Negishi and Kumada coupling: Organozinc or Grignard reagents can be employed to install alkyl or alkenyl groups at C-3.
- Buchwald–Hartwig amination: Introduction of amine partners at C-3 via Pd-catalyzed C–N bond formation.
Beyond cross-coupling, the cyano group at C-5 participates in cycloaddition reactions (e.g., [3+2] cycloaddition with azides to form tetrazoles), nucleophilic additions, and reductions. Sequential, chemoselective manipulation of the iodo, cyano, and Boc groups allows access to highly elaborated indole pharmacophores from a single precursor, reducing synthetic step counts and improving efficiency.
Role in Pharmaceutical and Drug Discovery Research
The indole nucleus is among the most prevalent heterocyclic frameworks in approved pharmaceuticals and drug candidates. Substituted indoles appear in a wide range of therapeutic areas including oncology, neurology, anti-infective, and cardiovascular medicine. tert-Butyl 5-cyano-3-iodo-1H-indole-1-carboxylate is specifically valuable in drug discovery because:
- The Boc group enables safe handling during automated parallel synthesis and solid-phase workflows, and can be removed in the final deprotection step to reveal the free NH indole.
- The C-5 cyano group is a bioisostere for carboxylic acids and can improve membrane permeability relative to polar protic groups, a relevant consideration during lead optimization.
- The C-3 position of indoles is a recognized pharmacophoric vector; C-3 substituted indoles are present in the structures of compounds active at serotonin receptors (5-HT), and in numerous kinase inhibitor scaffolds.
- The molecular complexity achievable from this single building block — via parallel coupling and subsequent cyano-group manipulation — is consistent with fragment-based drug discovery (FBDD) and diversity-oriented synthesis (DOS) strategies.
Researchers engaged in medicinal chemistry library synthesis will find T195404 a cost-effective entry point to a structurally diverse set of 3,5-disubstituted indoles with tunable physicochemical properties.
Handling, Storage, and Safety Considerations
As with all synthetic reagents containing halogen and nitrile functionality, appropriate laboratory safety practices must be followed when using tert-Butyl 5-cyano-3-iodo-1H-indole-1-carboxylate:
- Storage: Store in a cool, dry, well-ventilated location, protected from light and moisture. Ensure container is tightly sealed when not in use. Recommended storage temperature and specific stability data should be confirmed from the product SDS and Certificate of Analysis (CoA) provided by Aladdin Scientific.
- Personal Protective Equipment (PPE): Use appropriate gloves, lab coat, and eye protection. Handle in a fume hood when weighing or dissolving the compound.
- Nitrile group awareness: Although aryl nitriles are considerably less toxic than HCN, good laboratory practice dictates avoiding prolonged inhalation of dust or vapors.
- Waste disposal: Dispose of waste in accordance with local institutional and governmental regulations governing halogenated organic waste.
- First aid: In case of skin or eye contact, wash thoroughly with water. Refer to the full SDS for emergency procedures.
Researchers should always consult the current Safety Data Sheet (SDS) supplied with the product before use. The SDS is available on request from Aladdin Scientific customer service or via the product page.
Frequently asked questions
What cross-coupling reactions is tert-Butyl 5-cyano-3-iodo-1H-indole-1-carboxylate best suited for?
The C-3 aryl iodide is an excellent electrophilic partner for Pd-catalyzed Suzuki–Miyaura, Sonogashira, Negishi, and Buchwald–Hartwig reactions. Aryl iodides are among the most reactive aryl halides toward oxidative addition, making this compound highly efficient in these transformations under standard catalytic conditions.
How is the Boc protecting group removed from this compound?
The N-1 Boc group can be cleaved under standard mild acidic conditions. Commonly used deprotection protocols include treatment with trifluoroacetic acid (TFA) in dichloromethane (DCM), typically at 0 °C to room temperature, or hydrogen chloride (HCl) in 1,4-dioxane. These conditions selectively remove the Boc group without affecting the aryl iodide or cyano functionality under typical reaction times.
Can the cyano group at C-5 be further functionalized?
Yes, the C-5 cyano group is a versatile handle for further transformation. It can be hydrolyzed to a carboxylic acid under acidic or basic aqueous conditions, reduced to a primary amine using LiAlH4 or catalytic hydrogenation, reacted with azides to form tetrazoles via [3+2] cycloaddition, or converted to amidines using appropriate nitrogen nucleophiles. These transformations substantially expand the chemical space accessible from T195404.
What solvents are recommended for dissolving this compound?
Common polar aprotic solvents such as DMF, DMSO, THF, and acetonitrile are generally suitable for dissolving Boc-protected aryl iodoindoles. The specific solubility and recommended solvents should be confirmed from the product CoA or technical documentation available from Aladdin Scientific, as solubility can vary by lot and purity.
Is T195404 suitable for use in fragment-based drug discovery (FBDD)?
tert-Butyl 5-cyano-3-iodo-1H-indole-1-carboxylate is well-suited as a synthetic building block in FBDD workflows. Its multiple orthogonal reactive sites allow rapid generation of structural diversity around the indole core, and the Boc group enables compatibility with automated parallel synthesis platforms commonly used in FBDD and diversity-oriented synthesis programs.
References
- Joule, J.A.; Mills, K. Heterocyclic Chemistry, 5th ed.; Wiley-Blackwell: Oxford, 2010. General reference for indole chemistry and reactivity.
- Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. doi:10.1021/cr00039a007
- Sonogashira, K. Development of Pd–Cu catalyzed cross-coupling of terminal acetylenes with sp2-carbon halides. J. Organomet. Chem. 2002, 653, 46–49. doi:10.1016/S0022-328X(02)01158-0
- Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 4th ed.; Wiley: New York, 2006. Reference for Boc deprotection conditions.
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