Troc Protecting group Mechanism & (De)Protection

What is the Troc Protecting Group?

Troc (2,2,2-trichloroethoxycarbonyl) can convert amines or alcohols into stable carbamate or carbonate derivatives. This leads to a similar effect that we see in groups like Fmoc or Boc: the previously nucleophilic amine or alcohols loses its reactivity (driven by delocalization of electrons into the carbonyl system).

The nice thing is that Troc is orthogonal as the deprotection conditions for Fmoc (base), Boc (acid) or silyl groups like TBS (fluoride) do not remove it. Instead, it has a unique mechanism of reductive beta-elimination to release the free group.

Did you know: The Troc group was introduced by the legendary Robert Burns Woodward in the 1960s? (see below)

Troc Protection Mechanism

The Troc protecting group is introduced by reacting the free amine or alcohol with 2,2,2-trichloroethyl chloroformate (Troc-Cl) with addition of a base.

Most common protection conditions are Troc-Cl with pyridine in CH₂Cl₂ or THF. If the starting material is very polar, Troc-Cl with NaOH or NaHCO₃ in water.

Troc Deprotection Mechanism

The Troc protecting group can be removed with certain reductive methods which all function via beta-elimination. Most common is use of zinc or other single-electron reductants that reduce the terminal carbon. The beta-elimination gives a free carbamate – an intermediate seen in mechanisms of many other protecting groups – that rapidly decarboxylates to the deprotected amine (or alcohol).

Most common deprotection conditions are Zn powder in THF/H₂O or so-called couples/alloys consisting of mixtures of Zn-Pb or Cd-Pb. More rarely used, reduction with electrolysis also removes the Troc group.

Always remember protecting group stability or lability are always general (e.g., here: removal by reduction). Nothing in chemistry (or life) is black and white 🙂
Here is a neutral method (not reductive) using trimethyltin hydroxide. [1]

A fascinating point is that under the right conditions, Me₃SnOH actually deprotects Troc selectively in the presence of methyl esters (you would expect that the methyl ester is quite labile to hydrolysis with hydroxide).

Troc PRotecting grouP in total synthesis

The very first introduction of the Troc protecting group was already… very advanced! Woodward and co-workers used the starting material below in the synthesis of cephalosporin C, an antibiotic natural product. [2]

What is the product after treating this molecule with Zn in aqueous AcOH?

This is a cool example where one of the three Troc groups does not decarboxylate (the one on the right). This is because it was not attached to a free alcohol, but rather, only the trichloroethoxy was masking the free acid. Because this is not a free carbamate or carbonate, we do not see a decarboxylation.

Thanks for checking out this article – feel free to read about other protecting groups!
Below you can find typical Troc protection and deprotection conditions.

Troc Protection conditions [3]

To a solution of the alcohol (0.80 g, 1.48 mmol) in methylene chloride (30 ml) at 0 °C was added pyridine (0.96 ml, 11.84 mmol, 8 equiv) followed by 2,2,2-trichloroethyl chloroformate (0.8 ml, 5.92 mmol, 4 equiv), and the reaction mixture was stirred at 0 °C for 1 h. Saturated aqueous sodium bicarbonate (50 ml) was added and the organic layer was separated. The aqueous layer was extracted with methylene chloride (3 x 50 ml), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (2% EtOAc/hexanes) afforded protected product (0.98 g, 93%) as a colorless oil.

Troc deprotection conditions [4]

To a solution of protected Troc-amine (40 mg, 57 µmol) in 4 mL of MeOH was added activated zinc (400 mg). The mixture was stirred at 25 °C for 5 min, and glacial HOAc (4 mL) was added. The mixture was heated at 60 °C for 30 min, cooled and concentrated under reduced pressure. The residue was treated with 5 mL of 5% aqueous NaOH, and the solution was extracted with EtOAc (5 × 5 mL). The combined extracts were washed with brine, dried over anhydrous K₂CO₃, and concentrated under reduced pressure. Flash chromatography on silica gel (100:1 CH₂Cl₂/MeOH) gave 25 mg (86%) of the free amine as a viscous oil.

TROC Protecting Group References

• P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
• [1] Highly Chemoselective Deprotection of the 2,2,2 Trichloroethoxycarbonyl (Troc) Protecting Group | Barry M. Trost, Christopher A. Kalnmals, Jacob S. Tracy, and Wen-Ju Bai | Org. Lett. 2018, 20, 8043−8046
• [2] The Total Synthesis of Cephalosporin C. | Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbruggen, H. | J. Am. Chem. Soc. 1966, 88, 852− 853
• [3] Patent WO2007/15929, 2007, A2
• [4] Total Synthesis of (±)-Symbioimine | Yefen Zou, Qinglin Che, Barry B. Snider | Org. Lett. 2006, 8, 24, 5605–5608