4-Picolyl Chloride Hydrochloride

[1822-51-1]  · C6H7Cl2N  · 4-Picolyl Chloride Hydrochloride  · (MW 164.04)

(protection of alcohols,1,2 phenols,3 thiols,3,4 and carboxylic acids5)

Alternate Name: 4-(chloromethyl)pyridine hydrochloride.

Physical Data: mp 160-163 °C.

Solubility: sol H2O, EtOH; insol CH2Cl2, acetone.

Form Supplied in: white or off-white crystalline solid; available from several commercial sources.

Handling, Storage, and Precautions: the free base is reported to be unstable,1 and should be generated shortly before use.

Protection Reagent.

Alcohols (eq 1)1,2 (including hydroxy-containing amino acid derivatives),2 phenols,3 carboxylic acids (eq 2),5 and thiols (eq 3)3,4 have all been alkylated by this reagent (1). Esters (2) are also available from the respective acids by 1,3-Dicyclohexylcarbodiimide coupling with 4-pyridylmethanol in CH2Cl25 in comparable yield.

Dihydric alcohols such as (3) are preferentially alkylated on the primary OH, but (4) yields a mixture of dialkylated and both monoalkylated products.1

The protected materials have been of particular value in peptide chemistry. Cleavage5 of esters (2) takes place not only under the more obvious aqueous alkali or catalytic hydrogenation conditions, but also with Sodium-Ammonia or by electrolytic reduction at a mercury cathode. The protected alcohols,1,2 phenols,3 and thiols3,4 are similarly deprotectable by electrolysis.

The use of 2-1 and 3-picolyl2 ethers in such cases has also been investigated, and an N-protecting group, (4-picolyloxy)carbonyl,6 has also been described. The increased polarity of these picolyl-containing materials, relative to the more typical benzylic protecting groups, can appreciably assist in their purification.2 Nevertheless, these protecting groups remain outside the mainstream of peptide chemistry, probably due to the greater familiarity and availability of, for example, the benzyl- or t-butyl-based groups, and the fact that the Na/NH3 or electrolytic deprotection of the 4-picolyl group is likely to be incompatible with these. In this regard, the use of 2-(2- or 4-pyridyl)ethyl protecting groups7 (Pyoc carbamates,7a Pet esters,7b,7c), likely to impart similar polarity, but deprotectable cleanly in the presence of these other common functionalities, appears distinctly advantageous.

1. Wieditz, S.; Schäfer, H. J. ACS 1983, B37, 475.
2. Rizo, J.; Albericio, F.; Romero, G.; Garcia-Echeverria, C.; Claret, J.; Muller, C.; Giralt, E.; Pedroso, E. JOC 1988, 53, 5386.
3. Gosden, A.; Stevenson, D.; Young, G. T. CC 1972, 1123.
4. Gosden, A.; Macrae, R.; Young, G. T. JCR(S) 1977, 22.
5. Camble, R.; Garner, R.; Young, G. T. JCS(C) 1969, 1911.
6. Veber, D. F.; Paleveda, W. J.; Lee, Y. C.; Hirschmann, R. JOC 1977, 42, 3286.
7. (a) Kunz, H.; Barthels, R. AG(E) 1983, 22, 783. (b) Katritzky, A. R.; Khan, G. R.; Schwarz, O. A. TL 1984, 25, 1223. (c) Kessler, H.; Becker, G.; Kogler, H.; Wolff, M. TL 1984, 25, 3971.

Peter Ham

SmithKline Beecham Pharmaceuticals, Harlow, UK

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