Alloc Protecting Group: Alloc Protection & Deprotection Mechanism

What is the Alloc Protecting Group?

The Alloc protecting group is related to the Allyl protecting group and orthogonal to almost every other protecting group out there.

It might seem complicated, but it’s just a fancy version of a carbamate protecting group based on two structures:
1) A carbamate which if present in its free form (-OH), can decarboxylate to release the original amino group. Other carbamate protecting groups we’ve seen like Boc, Cbz or Fmoc work this way. They just have a different “trigger” group.
2) An O-allyl group that is activated towards nucleophilic attack of palladium(0) to form of allyl-palladium complexes. Instead of e.g., a tBu group present in Boc which gets “triggered” by acid, this one is triggered by Pd(0)!

Due to the mild deprotection conditions, the group has seen significant application in the synthesis of complex peptides and carbohydrates as a solid alternative to e.g., Boc.

Alloc Protection Mechanism

Alloc protection is trivial and follows the same logic like other carbamates: Nucleophilic attack of the amine to some sort of activated Alloc reagent, typically AllocCl (allyl chloroformate – so like CbzCl for Cbz) or Alloc₂O (diallyl dicarbonate – like Boc₂O!).

Exemplary conditions are i) AllocCl, pyridine in THF; ii) AllocCl, DMAP, NEt₃ in CH₃CN; iii) Alloc₂O in dioxane, H₂O or in CH₂Cl₂; iv) Alloc-OSu, NEt₃, CH₂Cl₂

Alloc deprotection mechanism

As already alluded to, the magic of this group is in the activated allyl group (given it’s connected to the oxygen of the carbamate). The deprotection is a catalytic cycle, initiated by coordination of Pd(0) and oxidative addition to form an allyl-palladium(II) complex.

The carbamate ligand can dissociate from the complex and decarboxylate to give our desired deprotected amine (again, the same logic as we saw with Boc, Cbz and Fmoc).

But how do we regenerate our catalyst Pd(0) and get rid of the allyl group? There are two options:
1) Nucleophiles can attack the complex and transfer the allyl group, reducing Pd(II) to give Pd(0). Morpholine is one of the key allyl transfer reagent in the text books, but other amines (Me₂NH•BH₃), C-H acids (e.g., dimedone, barbituric acid)… can be used.
2) Hydride donors can reduce the allyl group via reductive elimination, giving butene. Silanes (such as PhSiH₃ / phenylsilane) are common but other hydride donors such as formic acid, SnBu₃H (tributylstannane) or sodium borohydride (NaBH₄) exist.

If no additional allyl transfer reagent / scavenger would be added, the cycle would not be closed and we would see undesired allylation of our deprotected amine (because it’s a nucleophile).

If you are crazy but want some of that OG E. J. Corey chemistry swag [1], you can also use Ni(CO)₄. This compound is extremely toxic and highly volatile… but why would you if you can use palladium?!
Fun fact: The name of Corey’s co-worker in the paper [1] is “Suggs” – so yeah, working with nickel carbonyl suggs!

Pd(0) is unstable. To not prepare it fresh, it can be formed from Pd(II) precursor catalysts like Pd(PPh₃)₂Cl₂ and reductants such as silanes. Not all Pd(0) reactions start with Pd(0)!

Examples of Alloc PROTECTION in Organic Synthesis

This first example [2] shows the orthogonality of Alloc – here, with Fmoc and a methyl ester. In this case, the borane-dimethylamine complex is used as a nucleophilic allyl transfer reagent.

Our second example [3] is from the total synthesis of antillatoxin. This marine natural product was isolated from some exotic cyanobacteria and, in addition to being toxic to shrimp (lol), might have interesting bioactivity (antiproliferation of cells via inhibition of tubulin polymerization).

You’ll see that two allyl groups were deprotected in one step – one from an amino group, and one from an ester. This set up the final intramolecular cyclization step to form the lactam (cyclic amide) in the product.

That’s All(oc) for this article! (ok, bad pun…) Feel free to check out my other articles on protecting groups, my page or my videos!

Alloc Protection experimental procedure [4]

“A mixture of amine (0.0842 mmol), NaHCO₃(44 mg, 0.53 mmol, 6 equiv), THF (3 mL), and H₂O (3 mL) at room temperature was treated with allyl chloroformate (28 μL, 0.26 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 12 h, extracted with EtOAc (200 mL, 100 mL), and the combined organic layers were washed with saturated aqueous NaCl (200 mL), dried over Na₂SO₄, and concentrated in vacuo. Column chromatography provided 38 (48.8 mg, 87% over 2 steps) as a white foam.”

Alloc deprotection experimental procedure [4]

“A stirred solution of 40 (8.61 g, 8.2 mmol, 1.0 equiv) in CH₂Cl₂ (82 mL) at 0 ̊C under Ar was treated with PhSiH₃ (7.1 ml, 57 mmol, 7.0 equiv) followed by Pd(PPh₃)₄ (0.95 g, 0.82 mmol, 10 mol %). The reaction mixture was stirred at 0 °C for 1 h and concentrated under reduced pressure. Column chromatography provided the semi-pure amine (7.79 g) as a yellow solid.”

Alloc Protecting Group References

• General: P. G. M. Wuts, T. W. Greene: Greene’s Protective in Organic Synthesis (Wiley)
• [1] Cleavage of allyloxycarbonyl protecting group from oxygen and nitrogen under mild conditions by nickel carbonyl | E. J. Corey, J. William Suggs | J. Org. Chem. 1973, 38, 3223
• [2] P. J. Kocienski: Protecting Groups (Thieme)
• [3] Total Synthesis and Revision of Absolute Stereochemistry of Antillatoxin, an Ichthyotoxic Cyclic Lipopeptide from Marine Cyanobacterium Lyngbya majuscula | Fumiaki Yokokawa, Hideyasu Fujiwara, Takayuki Shioiri | Tetrahedron 2000, 56, 1759
• [4] Next-Generation Total Synthesis of Vancomycin | Maxwell J. Moore, Shiwei Qu, Ceheng Tan, Yu Cai, Yuzo Mogi, D. Jamin Keith, Dale L. Boger | J. Am. Chem. Soc. 2020, 142, 16039