ACS Combinatorial Science
LETTER
Scheme 2. Possible Exploitations of the Azide Functionality
chromatographic purification without evaporation of the sol-
vents to dryness) in toluene, although in only 10% overall yield
from 6{1} (Scheme 3). Conversion was complete within two
hours but, again, many side products probably deriving from
intermolecular reactions were detected.
At this stage it was clear that the synthetic strategy could be
feasible, but that propiolic acid was probably not the ideal alkyne
to study the reactions more in detail.
To this purpose, we used trimethylsilyl propynoic acid 9{2}
instead and attempted to use it directly in a PasseriniꢀZhu
reaction. To our surprise the major compound was not the Passerini
product but cycloadduct 5{1,1,2}, isolated in 20% yield: indeed
under the microwave heating conditions the Passerini adduct
reacted further to give the dipolar cycloaddition. Moreover, also
compound 5{1,1,1} was isolated from the reaction mixture in 6%
yield, probably deriving from desilylation of the Passerini inter-
mediate (indeed desilylation of the cycloadduct was less likely,
since heating 5{1,1,2} under the same reaction conditions did
not afford 5{1,1,1}). Interestingly both 5{1,1,2} and 5{1,1,1}
were not obtained as nearly 1:1 mixtures of diasteroisomers,
as usually occurs because of the poor stereoselection of the
Passerini reaction, but with one of the two diasteroisomers
predominating (∼3:1).
Once more, preforming the aldehyde, filtering IBX side pro-
ducts and adding the isocyanide and the alkyne at room tem-
perature proved to be superior. In this case the Passerini
adduct could be isolated in 40% yield and subsequent intra-
molecular cycloaddition in refluxing toluene, although slower,
afforded solely 5{1,1,2} in 79% yield as an equimolar mixture of
diastereoisomers.
On the other hand, when we tried other propynoic acids, less
reactive than 9{2} toward cycloaddition, the Passerini adducts
could be isolated after a classic PasseriniꢀZhu protocol under
microwave heating, adding all the reagents at once. Indeed, when
an alkyl or aryl group was present onto the C-3 of the alkyne the
intramolecular cycloaddition was much slower and required 3ꢀ4
days in refluxing toluene to go to completion.
Compound 2{1,1,3} was then chosen for further optimiza-
tion of the cycloaddition reaction and the results are reported
in Table 1. Despite our expectations, the use of ionic liquids,11
with or without Cu(I) activation, under conventional or
microwave heating, proved to be ineffective and usually com-
plete decomposition of the starting material was observed. On
the other hand DMF (entry 3) proved to be superior to other
conventional solvents and the reaction under microwave
heating was complete within 20 min, affording the desired
cycloadduct in 70% isolated yield. Toluene, although being
the most common solvent employed for this kind of reactions
was not very efficient under microwave conditions because of
its low heating capacity: on the other hand, when a few drops
of DMSO were added, the reaction proceeded to completion
within one hour, although the yield was lower (57%) than
with DMF.
With these results in hand we then moved to prepare a small
library of triazoloxazinones to investigate the scope of the
reaction (Scheme 4 and Table 2). Both one-pot microwave
oxidation/Passerini condensation process and preliminary oxida-
tion of the azidoalcohol with subsequent MCR at room tem-
perature were exploited. Where possible, the one-pot procedure
was preferred for its operative simplicity, but in some cases the
latter approach turned out to be necessary because of the
instability of some alkynes and/or Passerini adducts under harsh
it would be possible to apply the same microwave-assisted
PasseriniꢀZhu protocol used for the synthesis of oxazolines,
since the reactivity of isocyanides with alkynes is well documen-
ted even at room temperature. In addition, while copper-
mediated dipolar cycloadditions of terminal alkynes with azides
proceed smoothly at room temperature, the thermal cycloaddi-
tion of internal alkynes is often troublesome and requires harsher
conditions.
In view of these considerations, we first decided to prepare
compound 2{1,1,1} to study the cycloaddition reaction
(Scheme 3). However, we feared that propiolic acid 9{1} could
be instable in the presence of IBX, thus we reacted, under the
standard PasseriniꢀZhu conditions, azidoalcohol 6{1} and
t-butyl isocyanide 7{1} with trifluoroacetic acid,10 planning to
isolate R-hydroxyamide 8 to be subsequently esterified with
propiolic acid 9{1}. Unfortunately trifluoroacetic acid was found
to be not compatible with the reaction conditions, product 8
being isolated only in traces. On the other hand, when we
preliminary oxidized the azidoalcohol 6{1} to the corresponding
aldehyde under microwave heating, filtered the reaction mixture,
added isocyanide and TFA and finally performed the MCR at
room temperature, the final R-hydroxyamide 8 was obtained in
satisfactory 58% isolated yield. With the deacylated Passerini
adduct in hand we then reacted it with 9{1} in the presence of
DCC and catalytic DMAP at ꢀ78 °C to afford ester 2{1,1,1},
although in only 32% yield. Moreover, compound 2{1,1,1} was
found to be unstable in the dry state, giving many side products
probably deriving from intermolecular cycloaddition reactions.
Having demonstrated that the PasseriniꢀZhu protocol could
be performed in two steps without isolating the aldehyde, we
then attempted the same strategy employing propiolic acid 9{1}
itself instead of TFA. Although crude compound 2{1,1,1} was
contaminated by several side products, the overall 30% isolated
yield was an improvement compared to the previous methodol-
ogy. In addition, cycloadduct 5{1,1,1} could be isolated by
refluxing a concentrated solution of 2{1,1,1} (deriving from
454
dx.doi.org/10.1021/co200072z |ACS Comb. Sci. 2011, 13, 453–457