tert-Butyl Carbamate (BOC) deprotection
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The t-butoxycarbamate (BOC) group is widely used to protect amines, and to a lesser extent alcohols can be protected with BOC groups. Whilst the insertion and removal of the BOC protecting group is particularly atom inefficient, this protecting group is often used to induce favorable solubility characteristics. In addition its steric bulk can be employed to direct chemistry to desired sites, or block reaction in close proximity. Also, removal of BOC under mild conditions makes it useful where orthogonal protecting group strategy is required. Many amine / amino acid /peptide synthons supplied to the pharma industry are sold BOC protected. The reagents used for deprotection are listed below - mainly acidic reagents, although thermal/enzymic methods can be used:
Heterogeneous catalysts & Acid resins
The BOC group is generally one of the most sensitive to acids, so often selective deprotection in the presence of other acid sensitive groups is possible.
Strong acids – organic or inorganic
The use of acids or Lewis acidic reagents leads to the generation of the t-Butyl cation as an intermediate. This can fragment to isobutylene or react with halides/sulfonates to generate potential genotoxic impurities. Generation of actual PGI by-products, especially if non-volatile, may require tracking and analysis of levels in the API, especially if generated towards the end of the synthetic sequence thus such operations if absolutely required should be placed early on in the synthesis if feasible.
Org. Process Res. Dev. 2013, 17, 221−230 Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies To Demonstrate Control
A further potential issue with BOC deprotection is that nuclophilic sites on the substrate/product can be alkylated by t-Bu+ leading to the formation of undesirable by-products. Amidines, guanidines, thiols and electron-rich aromatic rings are particularly prone to alkylation with t-Bu+. A number of different scavengers can be added to suppress alkylation.
Green Criteria for BOC deprotection
- Reagents have no major toxicity or safety issues acids like TFA should be avoided. Large molar excesses of acids should be avoided if possible.
- Process has no major safety issues and the generation of hazardous waste is minimised and controlled.
- Adequate consideration has been given to the impact of undesirable volatiles and PGI’s.
- Solvents should be chosen to minimise any potential impact. Many BOC deprotections are carried out in chlorinated solvents like dichloromethane, or 1,4-dioxan which should be minimised or replaced wherever possible.
General reviews on BOC deprotection
Greene's Protective Groups in Organic Synthesis, 4th Edition
Protecting Groups. By Philip J. Kocieński
J. Org. Chem. 2010, 75, 8117–8125 - Kinetics and Mechanism of N-Boc Cleavage: Evidence of a Second-Order Dependence upon Acid Concentration
J. Org. Chem. 1994, 59, 3216-3218 - Selective Removal of an N-BOC Protecting Group in the Presence of Other Acid-Sensitive Groups