LETTER
1577
Preparation and Reactions of Magnesiated Uracil Derivatives
Mohamed Abarbri, Paul Knochel*
Institut für Organische Chemie, Ludwig-Maximilians-Universität München, Butenandtstrasse 5-13, Building F, 81377 München, Germany
E-mail: Paul.Knochel@cup.uni-muenchen.de
Received 15 July 1999
Abstract: The I/Mg-exchange of 5-iodouracil derivatives affords
the corresponding polyfunctional Grignard reagents which were
found to react with various electrophiles in good yields.
Key words: uracil, magnesium, functionalized organometallics,
copper
Heterocycles are major molecular building blocks found
in many biologically active molecules and their function-
alization is an active field of research.1 Especially useful
in this respect are metalated heterocycles and among them
many useful lithiated heterocyclic reagents have been pre-
pared.2 However due to the highly reactive nature of the
carbon-lithium bond, only a few functional groups are tol-
erated in these heterocycles. Recently, we have shown
that a range of zincated polyfunctional heterocycles could
be prepared and reacted with electrophiles leading to
Scheme
polyfunctional heterocyclic derivatives.3 Although most
organic functional groups could be present on these zin-
cated heterocycles, their moderate reactivity did not allow
the reaction with electrophiles like aldehydes or ketones.
It was expected that the reactive Grignard reagents would
be more appropriate for such reactions combining a good
reactivity with a good functional group tolerance. Recent-
a transmetalation to the corresponding copper derivative
with CuCN·2LiCl,9 a benzoylation with PhCOCl gives the
ketone 3i-j in 73-75% yield. Finally the allylation with
ly, we have shown that the I/Mg-exchange allows a
ethyl (2-bromomethyl)acrylate10 leads to the desired allyl-
smooth preparation of polyfunctional aryl,4 alkenyl5 and
ated products 3k-l in 76-83 % yield (entries 11-12).
pyridyl6 magnesium species. Herein, we wish to report
In summary, we have prepared magnesiated uracils via an
iodine-magnesium exchange and have shown its excellent
reactivity with various electrophiles leading to uracil de-
rivatives having potential biological properties.11 Exten-
sion of these reactions is currently underway in our
laboratories.
that magnesiated uracil derivatives can be readily pre-
pared by this exchange reaction. Thus, the 5-iodouracils
1a-c respectively substituted at nitrogen with a benzyl
group, a ethyloxymethyl group and a 3,5-dimethoxyben-
zyl group7 react with i-PrMgBr at -40oC within 45 min af-
fording the corresponding Grignard reagents 2a-c which
are perfectly stable at this temperature for several hours.
The reaction of 2a-c with various electrophiles (aldehyde,
ketone, immonium salt or allylic bromide) proceeds
smoothly furnishing various new 5-substituted uracil de-
rivatives of type 3 (Scheme and Table 1).
Acknowledgement
We thank the Leibniz program for generous support. We thank De-
gussa-Hüls AG, BASF AG and Chemetall GmbH for the generous
gift of chemicals. M.A. thanks the University of Tours (France) for
leave.
Whereas aromatic and aliphatic aldehydes undergo a
smooth addition leading to the heterocyclic benzylic alco-
hols 3a-d (see entries 1-4 of Table 1), the addition of ke-
tones like cyclohexanone proved to be more sluggish
leading to the tertiary alcohol 3g in only 45 % yield (see
entry 7). The reaction with the immonium trifluoroacetate
References and Notes
(1) a) Newkome, G. R.; Pandler, W. W. Contemporary
Heterocyclic Chemistry, Wiley, New York, 1982; b) Gilchrist,
T. L. Heterocyclen-Chemie, VCH, Weinheim, 1995.
(2) a) Snieckus, V. Chem. Rev. 1990, 90, 879, b) Rocca, P.;
Marsais, F.; Godard, A.; Quéguiner, G. Tetrahedron 1993, 49,
49, c) Sakamoto, T.; Kondo, Y.; Murata, N.; Yamanaka, H.
Tetrahedron 1993, 49, 9713.
+
-
(CH2=N(Allyl)2 , CF3CO2 )8 furnishes the expected ami-
nomethyl derivatives 3e-f in excellent yields (see entries
5 and 6). The electrophilic cyanation reagent TolSO2CN
reacts with the magnesiated uracil 2a providing the 5-cy-
anouracil derivative 3h in 47 % yield (see entry 8). After
Synlett 1999, No. 10, 1577–1578 ISSN 0936-5214 © Thieme Stuttgart · New York