Solid-phase functionalization of heterocycles by direct lithiation

Article abstract of DOI:10.1055/s-1998-1684

Lithiation of polymer-bound 3-furanmethanol and 3-thiophenemethanol followed by the addition of electrophiles and resin cleavage afforded 2,4-disubsituted furans and thiophenes respectively in good yield. The 2,4-substituted thiophene can also be further lithiated on solid-phase at C-5 to give 2,3,5-substituted thiophenes.

Full text of DOI:10.1055/s-1998-1684

April 1998
SYNLETT
405
Solid-phase Functionalization of Heterocycles by Direct Lithiation
Zhengong Li and A. Ganesan*
Institute of Molecular and Cell Biology, National University of Singapore, 30 Medical Drive, Singapore 117609
Fax (65)7791117; E-mail: mcbgane@imcb.nus.edu.sg
Received 2 February 1998
Abstract: Lithiation of polymer-bound 3-furanmethanol and 3-
thiophenemethanol followed by the addition of electrophiles and resin
cleavage afforded 2,4-disubsituted furans and thiophenes respectively in
good yield. The 2,4-substituted thiophene can also be further lithiated
on solid-phase at C-5 to give 2,3,5-substituted thiophenes.
In recent years, combinatorial chemistry has emerged as an important
1
tool for drug discovery and medicinal chemistry. The consequent need
to produce large numbers of compounds in good yield and purity has
2
caused an explosion of interest in Solid-Phase Organic Synthesis
(SPOS). Expansion of the synthetic repertoire compatible with solid
supports depends on the successful adaptation of a variety of classical
and modern organic reactions previously performed in solution.
3
Polystyrene can be directly lithiated on the aromatic ring, as reported
by Fyles and Leznoff more than two decades ago (the benzylic carbon,
In solution, lithiation of the t-butyldimethylsilyl ether of 3-furan or
13
thiophene methanol occurs at C-2. It is likely that the steric bulk of the
4
11
another potential site for deprotonation, is not lithiated ). This implies
trityl group in our examples outweighs the beta-directing effect,
14
that a polystyrene-based matrix may be unsuitable for solid-phase
reactions involving strongly basic organometallic reagents.
cleanly promoting C-5 lithiation. The resulting 2,4-disubstitution
pattern is difficult to obtain synthetically, and previous methods have
13a,15
5
often temporarily blocked C-2.
Nevertheless, conditions for polystyrene lithiation are solvent-
dependent and require elevated temperatures, suggesting that kinetically
controlled reactions of resin-bound substrates can still be selectively
accomplished. In recent examples, n-butyllithium was used in solid-
We have also investigated the feasibility of sequential lithiations. Resin
2 was lithiated and reacted with an electrophile, followed by extensive
washing (THF, MeOH). The dried resin was resubjected to lithiation,
which now takes place adjacent to the alkoxymethyl group (Scheme 2).
The preparation of 5 and 6 illustrates the potential of this method to
build up 2,3,5-trisubstituted thiophenes from simple precursors.
6
7
8
phase nucleophilic additions, transmetalation, deprotonation, and
9
10
lithium-halogen exchange, and t-butyllithium
for formamidine
deprotonation. Here, we report the first solid-phase investigation into C-
lithiation of heteroaromatic compounds,
a well-established and
11
important synthetic procedure in solution.
Initially, we attached 3-furanmethanol and 3-thiophenemethanol to
polystyrene-trityl resin (Novabiochem, loading capacity of 0.67 mmol/
g). The loading of 3-thiophenemethanol was determined to be 0.4
mmol/g by resin cleavage and recovery of the alcohol. In the case of 3-
furanmethanol, instability to the acidic cleavage conditions prevented
direct determination of loading efficiency, and it was assumed to be
similar to that of the thiophene. Direct lithiation of the resins 1 and 2
(Scheme 1) generated orange-colored beads. Quenching with
electrophiles followed by resin cleavage gave the corresponding 2,4-
disubstituted furan (3) or thiophene (4) derivatives in good yields
12
(Table 1).
Scheme 2
In conclusion, C-lithiation represents a powerful method for the solid-
phase functionalization of furans and thiophenes. We are presently
extending these studies to other carbocyclic and heterocyclic aromatic
ring systems.
Acknowledgement. This work was funded by grants from the National
Science and Technology Board of Singapore.
Scheme 1

406
LETTERS
SYNLETT
References and Notes
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o
C. n-Butyllithium (0.2 mmol, 1.2 M in hexanes) was added
o
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