COMMUNICATION
The pyridinone-methide elimination†
Rotem Perry-Feigenbaum,a Phil S. Baranb and Doron Shabat*a
Received 27th July 2009, Accepted 17th September 2009
First published as an Advance Article on the web 5th October 2009
DOI: 10.1039/b915265b
The quinone-methide elimination is a common, efficient
methodology used in linkers designed to undergo self-
fragmentation. Here, for the first time, we demonstrate this
elimination in a pyridine ring system. Under physiological
conditions, a compound constructed of a pyridine core, a
reporter, and an enzymatic trigger underwent significantly
faster 1,4-elimination than its parent compound with a
benzene core. In addition, an AB2 self-immolative dendron
based on a pyridine core released its two reporter units upon
activation through 1,6- and 1,4 pyridinone-methide elimi-
nation reactions, again faster than the analogous benzene
system. Increased aqueous solubility was observed with com-
pounds based on pyridine relative to those based on benzene.
The pyridinone-methide elimination could be applied as an
alternative tool in designing self-immolative linkers for release
of active target molecules in an aqueous environment.
of compounds 1 or 2 generates phenolate 1a or 2a, respectively.
Phenolate 1a undergoes 1,6-elimination to release a reporter group
(R) and p-quinone-methide 1c, whereas phenolate 2a undergoes
1,4-elimination to release the reporter and o-quinone-methide 2c.
When the reaction is performed under aqueous conditions, the
majority of the released quinone-methide is trapped by water to
generate the corresponding hydroxy-benzylalcohol. This linking
technique is usually applied to activate a prodrug or to release a
reporter unit for diagnostic purposes.
The 1,6- and 1,4-quinone-methide eliminations have been used
to achieve multiple-release of end groups in dendritic molecules.6,7
These eliminations are an effective powerful tool in the ac-
tivation of self-immolative dendrimers8–12 and self-immolative
polymers.13–15 Very recently we demonstrated a novel dendritic
chain reaction that takes advantage of the quinone-methide
eliminations to accomplish unique exponential amplification for
diagnostic purposes.16
Although there have been numerous reports of quinone-methide
eliminations in benzene ring systems, there are no examples of
this elimination in a pyridine ring. Pyridine is a water-soluble
compound whereas benzene is completely insoluble in aqueous
media. Thus, use of linkers with a pyridine moiety for applications
to be performed under aqueous conditions should increase the
compounds’ water solubility. Here we report the first evaluation
of the quinone-methide type elimination in a pyridine ring system.
Initially, we decided to explore the disassembly of pyridine
system 3 (Fig. 2). This molecule has a phenylacetamide triggering
group that, upon cleavage by penicillin-G-amidase17 (PGA), gener-
ates amine 3a. This amine undergoes spontaneous 1,6-elimination
and decarboxylation to release amine 3b, which then releases 3c by
cyclisation of the side chain to form an N,N¢-dimethylurea. This
intermediate should then undergo 1,4-elimination to release the
reporter and the o-pyridinone-methide.
The quinone-methide elimination is a powerful and efficient reac-
tion used in the design of linkers with self-immolative capabilities.
There are numerous examples in the scientific literature of its
use in the synthesis of prodrugs and molecular probes.1–5 It was
shown that 4-hydroxy-benzylalcohol or 2-hydroxy-benzylalcohol
can be applied as self-immolative spacers to link a reporter
molecule and a triggering unit (Fig. 1). Cleavage of the trigger
aDepartment of Organic Chemistry, School of Chemistry, Raymond and
Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel Aviv
69978, Israel. E-mail: chdoron@post.tau.ac.il; Fax: +972 (0) 3 640 9293;
Tel: +972 (0) 3 640 8340
bDepartment of Chemistry, The Scripps Research Institute, 10550 North
Torrey Pines Road, La Jolla, CA 92037, U. S. A.
† Electronic supplementary information (ESI) available: Experimental
details, synthetic schemes and copies of NMR spectra. See DOI:
10.1039/b915265b
Fig. 1 The 1,6- and 1,4-quinone-methide elimination pathways. R could be a reporter unit used for diagnostic purposes or a drug molecule.
This journal is The Royal Society of Chemistry 2009 Org. Biomol. Chem., 2009, 7, 4825–4828 | 4825
©