COMMUNICATION
a-Lithio quinuclidine N-oxide (Li-QNO): A new base for synthetic
chemistry{
Ian A. O’Neil,* Inder Bhamra and Peter D. Gibbons
Received (in Cambridge, UK) 21st July 2006, Accepted 17th August 2006
First published as an Advance Article on the web 19th September 2006
DOI: 10.1039/b610533e
1 equivalent of tert-butyllithium to generate 1 equivalent of
Li-QNO with the remaining QNO 1 present as an additive, to
enhance the reactivity of the carbanion. In the cases we have
studied this reagent system is as effective or superior to the use of
alkyllithiums or LDA in conjunction with the mutagenic HMPA
as an additive.
a-Lithio quinuclidine N-oxide (Li-QNO) behaves as a strong
non-nucleophilic base and an HMPA mimetic in a tandem
process, in a range of synthetically useful reactions
Numerous reactions in organic synthesis require the additive
hexamethylphosphoric triamide (HMPA) to render them viable.1
HMPA is a dipolar aprotic solvent that is able to form strong
ligand–cation complexes. As a result of this it enhances the rates of
a wide variety of main group organometallic reactions. It also has
an influence on regio- and stereochemistry of key reactions such as
enolate formation. HMPA can also enhance the formation and
reactivity of carbanions, ylide reactivity and carbanion regioselec-
tivity (1,2 versus 1,4 addition). HMPA is thought to act as a metal
binding agent that disrupts the aggregation states that enolates
normally exist in.2 HMPA is a listed mutagen and as such its use is
limited in both industry and academia. Several other substances
Central to the success of this reagent is a reliable method for the
synthesis of anhydrous QNO. We have found that this is
conveniently carried out by the reaction of ozone with quinuclidine
in either diethyl ether or hexane at 278 uC.6–8 The QNO
precipitates out of solution and the solvent can be removed under
vacuum. The reaction solvent, usually THF can then be added.
Anhydrous QNO is only sparingly soluble in THF at room
temperature. We have also found that ultrasonic agitation of QNO
in THF for 10 min prior to the addition of tert-butyllithium
facilitates the formation of the Li-QNO anion. Presumably the
sonication aids the dispersion of the QNO, and after sonication we
can dissolve ca. 0.3 g of QNO in 30 ml of THF at room
temperature. We have examined the use of Li-QNO as a base in a
number of synthetically useful transformations.
including
1,3-dimethyl-3,4,5,6-tetrahydropyrimidin-2(1H)-one
(DMPU) have been employed as replacements for HMPA but
all have limitations.3 We have previously reported the successful
use of quinuclidine N-oxide (QNO) 1 as a replacement for HMPA
in several key reactions including the benzylation of the dianion of
methyl 3-nitropropionate, the nitroaldol reaction between nitro-
propane and benzaldehyde, the Michael addition of 1,3-dithiane to
cyclohexenone and the SiCl4 mediated cleavage of cyclohexene
oxide.4 Most importantly QNO is non-mutagenic.4
Initially, we studied the benzylation of the dianion of methyl
nitropropionate 3.5 Treatment of methylnitropropionate 3 with
2 equivalents of Li-QNO followed by addition of benzyl bromide
gave the product 4 in 34% yield. Significantly, no addition of the
quinuclidine N-oxide anion into the ester was observed. This was
comparable to when LDA was used as the base in the presence of
2 equivalents of HMPA. We took this as evidence that Li-QNO
removes the two acidic protons in the substrate 3 regenerating
2 equivalents of QNO, which serves to promote the alkylation
step. Furthermore, when an additional 3 equivalents of QNO were
present as an additive, benzylation occurred in almost quantitative
yield, superior to the case when 5 equivalents of HMPA were used
(Scheme 2).
In this communication we wish to report the use of a-lithiated
QNO (Li-QNO) 2 as a new base, which combines high basicity
with low nucleophilicity. In a tandem process, QNO 1 is lithiated
with tert-butyllithium to generate Li-QNO 2. The Li-QNO 2 then
acts as a powerful base and deprotonates a substrate molecule
added to the system. This generates an equivalent of QNO 1,
which then acts as an HMPA mimetic, enhancing the reactivity of
the carbanion that has been formed (Scheme 1). The reagent
system is flexible so that an excess of QNO 1 can be treated with
We then turned our attention to the Wittig olefination
of 3-phenylpropyltriphenylphosphonium bromide
5
with
Scheme 1
Robert Robinson Laboratories, Department of Chemistry, University of
Liverpool, Crown St, Liverpool, UK L69 7ZD. E-mail: ion@liv.ac.uk;
Fax: +44 (0)151 794 3588; Tel: +44 (0)151 794 3485
{ Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b610533e
Scheme 2
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 4545–4547 | 4545