3-Bromo-1-(triisopropylsilyl)indole: Handling & Synthetic Use Guide
3-Bromo-1-(triisopropylsilyl)indole: Handling & Synthetic Use Guide
3-Bromo-1-(triisopropylsilyl)indole is a versatile, bench-stable indole building block in which the nitrogen is protected by a bulky triisopropylsilyl (TIPS) group and the C3 position carries a bromine atom primed for metal-catalysed cross-coupling or directed metalation reactions.
- CAS Number
- To be confirmed — see SDS (review flag)
- Molecular Formula
- C17H26BrNSi
- Molecular Weight
- 368.38 g/mol (calculated; needs verification)
- Key Functional Handles
- C3-Br (electrophilic handle for coupling); N1-TIPS (nitrogen protection)
- Recommended Storage
- Cool, dry, inert atmosphere; store under argon or nitrogen, 2–8 °C recommended
- Typical Purity
- ≥95% (verify with CoA supplied with lot)
- SKU
- B152783
Chemical Identity and Properties
3-Bromo-1-(triisopropylsilyl)indole (SKU B152783) belongs to the class of N-silyl-protected haloindoles. The triisopropylsilyl (TIPS) group on nitrogen is significantly larger than trimethylsilyl (TMS) or tert-butyldimethylsilyl (TBS), imparting enhanced hydrolytic stability under mildly basic conditions and excellent compatibility with organolithium and Grignard reagents. The C3-bromine substituent renders this compound an electrophilic partner in palladium- or nickel-catalysed cross-coupling reactions (Suzuki–Miyaura, Negishi, Kumada, Sonogashira) as well as a substrate for halogen–metal exchange.
The compound is typically a crystalline or waxy solid. Its lipophilicity, conferred by the three isopropyl groups, results in good solubility in common anhydrous organic solvents such as THF, diethyl ether, DCM, toluene, and DMF, while it is essentially insoluble in water. Verify exact melting point and spectral data against the certificate of analysis (CoA) provided with each lot.
Synthetic Applications and Reaction Protocols
Palladium-catalysed cross-coupling: The C3–Br bond undergoes efficient oxidative addition to Pd(0) species. Standard Suzuki–Miyaura conditions (Pd(PPh3)4 or Pd(dppf)Cl2, arylboronic acid, aqueous base, THF or dioxane, 60–80 °C) install aryl or heteroaryl groups at C3. Negishi coupling with organozinc reagents and Sonogashira coupling with terminal alkynes are also well-precedented for analogous 3-haloindoles protected at nitrogen.
Halogen–metal exchange: Treatment with n-BuLi or iPrMgCl·LiCl (Turbo Grignard) at –78 °C in anhydrous THF effects clean lithiation or magnesiation at C3. The resulting organometallic intermediate can be quenched with electrophiles (aldehydes, ketones, acyl chlorides, disulfides, TMSCl) to afford 3-substituted TIPS-indoles. Conduct all metalation steps under strict inert-atmosphere (Schlenk or glovebox) conditions.
TIPS removal after functionalisation: The TIPS group is cleaved under mild fluoride conditions (TBAF, 1.0–1.2 equiv, THF, RT, 1–2 h) or with HF·pyridine to reveal the free NH indole. Protodesilylation under acidic aqueous conditions (dilute HCl or AcOH/H2O) is also effective. Verify deprotection completeness by TLC or LC-MS before workup.
General protocol note: All reactions should be performed under an anhydrous inert atmosphere. Weigh the solid reagent in a glovebox or use a Schlenk flask backfilled with argon. Use freshly dried and degassed solvents for metalation steps.
Storage, Handling, and Safety Guidelines
Storage: Store B152783 in a tightly sealed container under an inert gas (argon or nitrogen) at 2–8 °C, away from moisture, light, and oxidising agents. Silyl groups are susceptible to protodesilylation by adventitious water; prolonged exposure to humid air should be avoided. Check the product SDS for full hazard classification and confirm storage class with your institutional chemical-safety officer.
Handling: Use standard laboratory PPE: nitrile gloves, safety glasses, and a laboratory coat. Work in a well-ventilated fume hood. Avoid inhalation of dust or vapours. Because the compound contains an aryl bromide moiety, treat it as a potential irritant until full toxicological data are confirmed via the SDS.
Waste disposal: Dispose of all residues and solutions as halogenated organic waste in accordance with local, national, and institutional regulations. Do not pour down the drain.
First aid (general): In case of skin or eye contact, flush with copious water for at least 15 minutes and seek medical attention. Consult the product SDS for comprehensive first-aid measures and emergency contact information.
Quality, Purity, and Verification
Each lot of B152783 supplied by Aladdin Scientific is accompanied by a Certificate of Analysis (CoA) documenting purity (typically ≥95% by GC or HPLC), identity confirmation by 1H NMR, and, where applicable, 13C NMR or mass spectrometric data. Researchers should verify the CoA before use, particularly confirming:
- Purity ≥95% (or as specified for the intended application)
- Absence of residual free indole (NH stretch in IR, ~3400 cm-1)
- Correct molecular ion by ESI-MS or APCI-MS
For sensitive metalation reactions, additional KF assay (to detect fluoride contamination from silica) or water content determination by Karl Fischer titration may be advisable. Contact Aladdin Scientific technical support for lot-specific spectral data or custom purity specifications.
Frequently Asked Questions
See the FAQ section below for answers to the most common questions from researchers working with 3-Bromo-1-(triisopropylsilyl)indole.
Frequently asked questions
Why choose TIPS over TMS or TBS for N-protection of indole?
The TIPS group is substantially bulkier than TMS or TBS, providing greater steric protection around the indole nitrogen. This translates to superior hydrolytic stability under mildly basic or acidic aqueous workup conditions compared with TMS-indoles, and better tolerance of strong nucleophiles and organolithium reagents than TBS. TIPS is therefore preferred when multiple sequential transformations are required before deprotection.
Can 3-Bromo-1-(triisopropylsilyl)indole be used directly in Suzuki–Miyaura coupling without pre-activation?
Yes. The C3–Br bond undergoes oxidative addition to Pd(0) under standard Suzuki–Miyaura conditions without any pre-activation step. Typical conditions include Pd(PPh3)4 or Pd(dppf)Cl2 as catalyst, an arylboronic acid coupling partner, an aqueous inorganic base (K2CO3 or Cs2CO3), and a mixed THF/water or dioxane/water solvent system at 60–80 °C. The TIPS group is generally stable under these conditions, allowing selective C3 arylation while nitrogen remains protected.
How should I remove the TIPS group after completing C3 functionalisation?
TIPS deprotection is most conveniently achieved with tetrabutylammonium fluoride (TBAF, 1.0–1.2 equiv) in THF at room temperature for 1–2 hours; the reaction can be monitored by TLC. For acid-sensitive substrates, HF·pyridine or buffered HF systems offer a milder alternative. Aqueous acidic conditions (dilute HCl or dilute acetic acid in water/THF) also effect desilylation but may require longer reaction times and are less suitable for base-sensitive functionality.
What inert atmosphere technique is recommended for halogen–metal exchange at C3?
Halogen–metal exchange with n-BuLi or Turbo Grignard reagents is highly moisture- and oxygen-sensitive. Use a Schlenk line with high-vacuum/argon dual manifold, or perform reagent transfers and weighing inside a nitrogen- or argon-filled glovebox. Cool the reaction flask to –78 °C (dry ice/acetone bath) before addition of the organolithium reagent, and add reagents via syringe through a rubber septum. All glassware should be flame-dried under vacuum before use.
References
- Kaur, T. et al. N-Silylated indoles in heterocyclic synthesis: a review of protective group strategies and reactivity. (General textbook/review — specific citation to be verified.)
- Knochel, P. et al. Functionalization of arenes and heteroarenes via directed metalation using polyfunctional Grignard reagents. Angew. Chem. Int. Ed. 2003, 42, 4302–4320. (Representative precedent for haloindole metalation — specific applicability to this substrate needs confirmation.) doi:10.1002/anie.200300579
- Miyaura, N.; Suzuki, A. Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds. Chem. Rev. 1995, 95, 2457–2483. doi:10.1021/cr00039a007
Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.
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