Novel application of α-azido aldehydes in multicomponent reactions: Synthesis of triazolo-fused dihydrooxazinones via a passerini reaction-dipolar cycloaddition strategy

Article abstract of DOI:10.1021/co200072z

α-Azido aldehydes can be employed in Passerini reactions with isocyanides and various propiolic acids to afford the three-component adducts in moderate to good yields. These compounds undergo a straightforward azide-alkyne dipolar cycloaddition to furnish triazolo-fused dihydrooxazinones.

Full text of DOI:10.1021/co200072z

LETTER
pubs.acs.org/acscombsci
Novel Application of r-Azido Aldehydes in Multicomponent
Reactions: Synthesis of Triazolo-Fused Dihydrooxazinones via a
Passerini ReactionꢀDipolar Cycloaddition Strategy
Fabio De Moliner,† Stefano Crosignani,‡ Andrea Galatini,† Renata Riva,† and Andrea Basso*,†
†Universitꢀa degli Studi di Genova, Dipartimento di Chimica e Chimica Industriale, Genova, Italy
‡Merck Serono S. A., Geneva, Switzerland
S Supporting Information
b
ABSTRACT: R-Azido aldehydes can be employed in Passerini reactions with
isocyanides and various propiolic acids to afford the three-component adducts in
moderate to good yields. These compounds undergo a straightforward azide-alkyne
dipolar cycloaddition to furnish triazolo-fused dihydrooxazinones.
KEYWORDS: R-azido aldehydes, multicomponent reactions, triazolo-fused dihy-
drooxazinones, Passerini reaction
Scheme 1. Passerini Reaction Applied to the Synthesis of
Oxazolines
socyanides play a dual role as both a nucleophile and electro-
phile, allowing interesting multicomponent reactions to be
I
carried out, including the classic Passerini1 and Ugi2 condensa-
tions and the more recent transformations involving the use of
alkynes.3 While the Ugi reaction has been widely exploited in
pharmaceutical chemistry to prepare biologically relevant mol-
ecules and libraries, the Passerini condensation has encountered
less success, that can be ascribed to two main factors. The first
being that only three diversity inputs can be introduced, thus
limiting for example the application of intramolecular versions to
prepare heterocycles, while the second relates to the formation,
during the reaction, of an ester functionality that is usually not
very appealing in pharmaceutical chemistry due to its lability in
physiological media.
In the past, we have tried to overcome this limitation by
introducing the so-called PADAM strategy4 that, starting from a
classic Passerini adduct, affords a β-acylaminoamide by acyl
migration, thus transforming the ester group into a more valuable
amide functionality. This strategy has been applied by us5 and
others6 to prepare acyclic peptidomimetics in a very straightfor-
ward manner. More recently we have also applied the same
approach to prepare pyrazinone derivatives,7 through a cycliza-
tion/aromatization step following the PADAM protocol. With
the same intent of preparing heterocyclic structures, we have also
replaced the amine deprotection and acyl migration steps with a
StaudingerꢀAza Wittig (SAW) cyclization to oxazolines 3
(Scheme 1).8 This latter strategy has been made possible by
employing an innovative class of building blocks in the Passerini
reaction, namely R-azidoaldehydes 1. The intrinsic instability of
these compounds has been overcome by generating them in situ
modifying the PasseriniꢀZhu protocol.9
great success as substrates for click reactions, however in our
opinion compounds of general formula 4, deriving from cycload-
dition of 2 with a terminal alkyne (Scheme 2), would suffer from
the same limitations of the Passerini adducts, due to the presence
of an ester functionality. On the other hand, by installing the
alkyne functionality onto the acid component of the multi-
component reaction, would have produced, after the cycloaddi-
tion, a more precious lactone 5 and moreover a unique 6,
7-dihydro-4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-4-one, never re-
ported before in the literature.
Although from a theoretical point of view the approach
seemed simple and straightforward, we were aware of possible
limitations and difficulties. More precisely, we questioned whether
Having gained a straightforward access to compounds of
general formula 2, we questioned whether the azido group could
be exploited in postcondensations transformations other than
the SAW reaction. Organic azides have recently encountered
Received: April 21, 2011
Revised:
May 29, 2011
Published: May 31, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/co200072z ACS Comb. Sci. 2011, 13, 453–457
|

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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
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LETTER
Scheme 3a
a Reagents and conditions: (i) IBX, THF, 100 °C (MW, 150 W); (ii) 7{1}, TFA, THF, rt, 58%; (iii) 9{1}, DCC, DMAP, DCM, ꢀ78 °C to rt, 32%;
(iv) 7{1}, 9{1}, THF, rt, 30%; (v) toluene, reflux, 10%.
Table 1
entry
solvent
PhMe an.
reaction conditions
time
yield
1
reflux
3 days
48%
43%
70%
62%
43%
57%
/
2
Dioxane an.
MW (120 °C, 200 W)
MW (150 °C, 200 W)
MW (200 °C, 200 W)
MW (130 °C, 100 W)
MW (140 °C, 200 W)
110 °C
2 h
3
DMF an.
20 min
1 min
4
DMF an.
5
tBuOH/H2O
PhMe an./DMSO
C8DABCOþN(CN)2
AMMOENG 110
PhMe an.
1 h
6
1 h
ꢀ
7
overnight
overnight
overnight
overnight
overnight
overnight
overnight
overnight
7 h
8
80 °C
/
9
CuI, DIPEA, r.t.
/
10
11
12
13
14
15
PhMe an.
CuI, DIPEA, 80 °C
CuI, DIPEA, r.t.
19%
/
C8DABCOþN(CN)2ꢀ
C8DABCOþN(CN)2
AMMOENG 110
AMMOENG 110
tBuOH/H2O
ꢀ
CuI, DIPEA, 80 °C
CuI, DIPEA, r.t.
/
/
CuI, DIPEA, 80 °C
CuSO4 5H2O, Na ascorbate, 80 °C
/
/
3
conditions. In particular, trimethylsilylpropynoic acid 9{2} and
3-nitrophenylpropynoic acid 9{5} were not compatible with the
one-pot protocol (entries 2 and 9), the latter furnishing a
plethora of side products and no trace of the desired Passerini
adduct. It must be noted that the presence of the alkyne
moiety in the carboxylic acid seems to worsen the yields
compared to classic Passerini reactions, ranging from 23 to
53%. Furthermore adducts 2, although showing a single TLC
spot, were in some cases not very pure according to NMR
spectra.
Nevertheless, we were pleased to find that impurities did not
interfere with the following cyclization step, nor generated side
products contaminating the final triazoles. Yields ranged from
moderate to good (43ꢀ79%), and this strategy was particularly
suitable for the synthesis of a larger library in a combinatorial
format. In fact, reactions were in most of the cases quite clean and
their extractive workup and chromatographic purification experi-
mentally easy. Moreover, completion times remained short even
upon variation of the substituents present on the starting
materials. To our great delight, finally, separation of the two
diastereoisomers (always in nearly 1:1 ratio) was possible upon
column chromatography. Assignment of the absolute configura-
tion was made on the basis of the J coupling constant between
H-6 and H-7, consistently around 3.5 Hz in the case of the cis, less
polar, diastereoisomer and around 1.5 Hz in the case of the trans,
more polar, diastereoisomer. These coupling constants were
in accordance with those theoretically determined on model
compounds.
In conclusion, we have demonstrated that a novel class of
triazolo-fused oxazinones can be efficiently assembled in two
steps from readily available building blocks using a Passeri-
niꢀZhu/cycloaddition protocol. These results, together with
the previously reported synthesis of oxazolines, demonstrate the
utility of novel R-azidoaldehyde building blocks and the versa-
tility of the Passerini multicomponent reaction to assemble
heterocyclic compounds. We are currently investigating the
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LETTER
Scheme 4a
a Reagents and Conditions: (i) IBX, THF, 100 °C (MW, 150 W), then 7, 9, THF, rt; (ii) 7, 9, IBX, THF, 100 °C (MW, 150 W); (iii) DMF, 150 °C
(MW, 150 W). Chemsets are shown in the bottom part.
’ ACKNOWLEDGMENT
Table 2
The authors thank Prof. Cinzia Chiappe for helpful discussion
on the use of ionic liquids in cycloaddition reactions.
entry
6
7
9
yield 2
preformed aldehyde
yield 5
1
1
1
1
1
1
2
2
2
2
2
2
3
3
3
1
1
1
1
1
1
1
1
1
2
2
1
1
1
2
2
3
4
5
3
4
5
5
2
5
2
3
4
40%
yes
no
no
no
yes
no
no
yes
no
yes
yes
yes
no
no
79%
20%
70%
70%
44%
63%
35%
60%
2
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53%
38%
49%
36%
38%
35%
4
5
(2) Doemling, A.; Ugi, I. Multicomponent reactions with isocya-
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7
8
9
10
11
12
13
14
37%
47%
31%
43%
24%
57%
29%
43%
77%
58%
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’ ASSOCIATED CONTENT
S
Supporting Information. General procedures and full
b
1
characterization of compounds 2 and 5. Copies of H NMR
and 13C NMR spectra for compounds 5.This material is available
free of charge via the Internet at http://pubs.acs.org.
Funding Sources
A.B. thanks Merck Serono for financial support (PhD stu-
dentship for F.D.M.) and Fondazione San Paolo for NMR
equipment.
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