Parallel fluorous biphasic synthesis of 3H-quinazolin-4-ones by an Aza-Wittig reaction employing perfluoroalkyl-tagged triphenylphosphine

Article abstract of DOI:10.1016/S0040-4039(01)02279-1

A perfluoroalkyl-tagged triphenylphosphine was applied in a fluorous biphasic system for the efficient parallel synthesis of 3H-quinazolin-4-ones via an Aza-Wittig reaction. The products were isolated by solid-phase extraction on fluorous reversed-phase silica gel. A new solid-phase bound phosphine derivative was used for comparison and yielded similar results.

Full text of DOI:10.1016/S0040-4039(01)02279-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 807–810
Parallel fluorous biphasic synthesis of 3H-quinazolin-4-ones by
an Aza-Wittig reaction employing perfluoroalkyl-tagged
triphenylphosphine
Sophie Barthe´le´my,† Siegfried Schneider‡ and Willi Bannwarth*
Institut fu¨r Organische Chemie und Biochemie, Universita¨t Freiburg, Albertstraße 21, D-79104 Freiburg, Germany
Received 10 September 2001; accepted 26 November 2001
Abstract—A perfluoroalkyl-tagged triphenylphosphine was applied in a fluorous biphasic system for the efficient parallel synthesis
of 3H-quinazolin-4-ones via an Aza-Wittig reaction. The products were isolated by solid-phase extraction on fluorous reversed-
phase silica gel. A new solid-phase bound phosphine derivative was used for comparison and yielded similar results. © 2002
Elsevier Science Ltd. All rights reserved.
Combinatorial chemistry has emerged during the last
decade as an important tool for the rapid synthesis of
compound libraries. Solid-phase chemistry, originally
only applied to the synthesis of oligonucleotides and
peptides, has been extended to the synthesis of libraries
of small molecules with huge structural diversity. Nev-
ertheless, a few problems with solid-phase synthesis
have been encountered. Adaptation of solution chem-
istry to a solid-phase strategy is not always straightfor-
ward. In addition, synthesis on solid support is difficult
to follow and characterization of solid-phase bound
compounds is not simple. Furthermore, appropriate
linker entities are needed for the attachment of starting
materials, intermediates and final products to the solid
phase. However, after synthesis, it should be possible to
cleave the desired compounds from the support mate-
rial in high yields.
Synthesis in fluorous biphasic systems was first reported
by Horva´th and Ra´bai for the recycling of catalysts3
and was developed later, mainly by Curran, for combi-
natorial approaches.4–7
Fluorous techniques allow for the separation of
perfluoro-tagged compounds from standard organic
compounds by simple work-up procedures, such as
liquid–liquid extraction between perfluorinated solvents
and organic solvents. Alternatively, solid-phase extrac-
tion protocols using fluorous reversed phase silica gels
can be applied.8 In both procedures, time-consuming
chromatographic separations can be omitted. These
facts make the FBS strategy especially suitable for the
preparation of combinatorial libraries by parallel syn-
thesis in solution and for the recycling of perfluoro-
tagged catalysts.
Thus, alternative techniques, based on solution chem-
istry, are becoming more prominent for the synthesis of
compound libraries. These alternative methods com-
prise, in essence, polymer-supported reagents,1 poly-
mer-based scavenger entities2 and synthesis in fluorous
biphasic systems (FBS).
Recently, we have reported on the synthesis of
perfluoroalkyl-tagged triphenylphosphines. We have
used these phosphines as ligands for Pd complexes,
which we have applied to Stille and Suzuki CC-cou-
plings.9,10 High coupling yields were obtained and, due
to the perfluoro-tags, the catalysts could be recycled
several times by liquid–liquid extraction without signifi-
cant loss of activity.
Keywords: fluorous biphasic system; Aza-Wittig; perfluoro-tagged
phosphine; 3H-quinazolin-4-ones.
Herein we report for the first time on the use of a
perfluoroalkyl-tagged phosphine as a fluorous reagent.
Phosphine 1 was applied to an intramolecular Aza-Wit-
tig reaction generating a quinazoline core. Quinazolines
are important pharmacophores present in a great num-
ber of biologically active compounds.11–14
* Corresponding
+49(0)7612038705;
uni-freiburg.de
author.
e-mail:
Tel.:
+49(0)7612036063;
fax:
willi.bannwarth@organik.chemie.
† Present address: Calbiochem-Novabiochem AG, Weidenmattweg 4,
CH-4448 La¨ufelfingen, Switzerland.
‡ Present address: EvotecOAI, 111 Milton Park, Abingdon, England.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02279-1

808
S. Barthe´le´my et al. / Tetrahedron Letters 43 (2002) 807–810
compound 6 is easy to prepare and represents a cheap
alternative to the commercially available solid-phase
bound triphenylphosphine. After the cyclization step
shown in Scheme 1, which was carried out with the
solid-phase bound phosphine 6 instead of 1, a simple
filtration step was performed to separate the desired
Generally, due to the formation of CN-double bonds,
Aza-Wittig reactions have attracted a great deal of
interest, since they allow to access different types of
heterocyclic structures.15 Thus, the strategy presented
here is not limited to quinazolines and can be extended
to other types of heterocycles as well.
quinazolin-4-ones
4 from the solid-phase bound
triphenylphosphine oxide and any possibly unreacted
solid-phase bound iminophosphorane. As shown in
Table 1, the yields obtained with the solid-phase bound
phosphine 6 were comparable with the ones obtained
with 1.20 In this way, we have established two alterna-
tive ways of synthesizing pure products without the use
of time-consuming chromatographic steps.
The actual synthesis is outlined in Scheme 1.
In a Staudinger reaction the starting materials of type 2
reacted quantitatively with the perfluoro-tagged phos-
phine 1 leading to the iminophosphoranes 3.16 These
intermediates were not isolated but converted directly
by an intramolecular Aza-Wittig reaction to the desired
quinazoline derivatives. The reactions were carried out
in toluene with C6H5CF3 as the co-solvent. After the
reaction, separation and isolation of the products of
type 4 was achieved by solid-phase extraction on
fluorous reversed phase silica gel.17 Since the unreacted
iminophosphoranes 3 and the phosphane oxide 5 are
equipped with the perfluoro-tag, they are retained on
this material, whereas the products can be washed off
efficiently. In this way, easy isolation of quinazolin-4-
ones 4 is possible even if the cyclization does not
proceed quantitatively.
For further comparison, we have carried out the
cyclization step with P(Ph)3 (compounds 4a–d). In con-
trast to the straightforward isolations mentioned above,
the desired compounds were obtained in pure form only
after a tedious silica gel chromatography.
The starting materials for the Aza-Wittig reactions were
prepared according to Scheme 3. The anthranilic acid
derivatives 7 were transformed with NaNO2/HCl fol-
lowed by NaN3 into the corresponding o-azido benzoic
acid derivatives 8 which were isolated in yields of
30–84%. Reaction with SOCl2 yielded the correspond-
ing acid chlorides 8, which reacted with the anions of
the amides, obtained from 9, and LDA. The desired
starting materials 2a–j for the Aza-Wittig reactions
were obtained in isolated yields of 19–54%.
To demonstrate the feasibility of this approach we have
synthesized a small library of representative quinazolin-
4-ones by parallel synthesis (Table 1). The desired
target molecules 4a–j were obtained in good yields and
high purity.18 All compounds were characterized unam-
biguously by spectroscopic means.
The perfluoro-tagged triphenylphosphine oxide 5,
formed as a side product of the reaction shown in
Scheme 1 could be reduced with Cl3SiH to the phoshine
1 and, thus, we were able to recycle it for further
reactions in an isolated yield of 88.5%.21
For comparison, we have also employed the solid-phase
bound triphenylphosphine 6, which was prepared
according to Scheme 2.19 As can be seen in Scheme 2,
O
N
O
O
O
P
Rf
R1
R2
R1
R2
3
N
R5
N
R5
(1)
Toluene, Trifluorotoluene
R4
R4
N3
P
R3
R3
2a-j
Rf
3
3
Rf = -CH2-CH2-C8F17
intramolecular
cyclization
O
R4
R5
R1
R2
N
+
O
P
Rf
3
N
R3
5
4a-j
Scheme 1.

S. Barthe´le´my et al. / Tetrahedron Letters 43 (2002) 807–810
809
Table 1.
Scheme 2.
outlined above are of general value for the parallel
synthesis of heterocycles by intramolecular Aza-Wittig
reactions.
In summary, we have demonstrated that the application
of a perfluoroalkyl-tagged phosphine 1 in intramolecu-
lar Aza-Wittig reactions leads to a simple work-up
procedure for the isolation of the products, which has
been demonstrated for a small library of quinazolin-4-
ones. We have also applied a solid-phase bound phos-
phine 6, which is easy to prepare and yields the desired
products after a filtration step, therefore omitting time-
consuming chromatographic procedures. The methods
Acknowledgements
S.B. and S.S. would like to thank Byk Gulden, Kon-
stanz and Fluka AG, Buchs, CH for financial support.

810
S. Barthe´le´my et al. / Tetrahedron Letters 43 (2002) 807–810
1. NaNO2/HCl
R1
R2
COOH
NH2
R1
R2
-
COCl
N3
R4NH
LDA
R5
R4N
R5
2. NaN3
+
3. SOCl2
O
O
R3
R3
9
7
8
O
O
R1
R2
N
R5
R4
N3
R3
2a-j
(19-54%)
Scheme 3.
T.; Hamel, E.; Lee, K. H. Bioorg. Chem. Med. Lett. 2001,
11, 1193–1196.
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