Synthesis of 5-carboxamide-oxazolines with a passerini-zhu/staudinger-aza- wittig two-step protocol

Full text of DOI:10.1021/cc100122n

J. Comb. Chem. 2010, 12, 613–616
613
Scheme 1. PADAM Strategy
Synthesis of 5-Carboxamide-oxazolines with a
Passerini-Zhu/Staudinger-Aza-Wittig
Two-Step Protocol
Fabio De Moliner,† Stefano Crosignani,‡ Luca Banfi,†
Renata Riva,† and Andrea Basso*,†
UniVersita` degli Studi di GenoVa, Dipartimento di
Chimica e Chimica Industriale, GenoVa, Italy, and Merck
Serono S. A., GeneVa, Switzerland
ReceiVed June 22, 2010
Our research group has been active during the past decade
to discover novel applications of isocyanide-based multi-
component reactions (I-MCRs), such as the Passerini1 and
Ugi2 condensations. Specifically, we have reported the
PADAM (Passerini reaction-amine deprotection-acyl mi-
gration) strategy that, starting from N-protected R-aminoal-
dehydes, employs a Passerini reaction to straighforwardly
generate ꢀ-acylamino-R-hydroxyamides (Scheme 1).3 This
strategy has been employed by us and by others to assemble
biologically active peptidomimetic compounds.4
During the search for variations of this methodology, we
attempted to replace the N-Boc- or N-Fmoc-protected ami-
noaldehyde with the corresponding R-azidoaldehyde, having
in mind to employ the azido group as a surrogate of a
protected amine. R-Azidoaldehydes have been very rarely
reported in the literature, the only examples being related to
sugar chemistry5 and would be very precious and versatile
building blocks in I-MCRs; we, therefore, decided to
investigate their synthesis.
and it has been used in a limited number of cases to prepare
selected oxazolines.8
Scheme 2. Outcome of the PADAM Strategy Applied to
R-Azidoaldehydesa
Our first attempts started from R-azidoacid 1, prepared
according to a known procedure;6 this was converted into
the corresponding Weinreb amide and reduced to aldehyde
2 with lithium aluminum hydride. Although the crude
aldehyde was far to be pure, we attempted a Passerini
reaction with benzylisocyanide and benzoic acid, obtaining
adduct 3{1,1,1} in 18% yield as a mixture of two diastere-
oisomers. To prove whether compound 3{1,1,1} could be
transformed into ꢀ-benzoylamino-R-hydroxyamide 4 accord-
ing to the PADAM protocol, it was reacted with triph-
enylphosphine, known to reduce azides to amines via
phosphazene formation and subsequent hydrolysis. The
reaction proceeded smoothly in dichloromethane and water
but, instead of 4 furnished oxazoline 5{1,1,1} according to
a Staudinger-Aza-Wittig (SAW) reaction (Scheme 2).
The SAW reaction is a very common strategy to assemble
medium-size heterocycles.7 However, this strategy is typi-
cally carried out using carbonyl compounds and leading to
imines; on the contrary, there are fewer examples of
intramolecular SAW with the less reactive esters or amides,
a Reagents and conditions: (i) N,O-dimethylhydroxylamine hydrochloride,
DCC, HOBt, Et3N, DCM, rt, 76%; (ii) LAH, Et2O, 0 °C, for the yield see
text; (iii) benzoic acid, benzyl isocyanide, DCM, rt, 18%; (iv) triph-
enylphosphine, DCM, H2O, rt, 99%.
* To whom correspondence should be addressed. Phone: +39 010
3536110. Fax: +39 010 3536118. E-mail: andrea.basso@unige.it.
† Università degli Studi di Genova.
‡ Merck Serono S. A.
10.1021/cc100122n  2010 American Chemical Society
Published on Web 07/27/2010

614 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Scheme 3. Passerini-Zhu/Staudinger-Aza-Wittig Protocola
Reports
a Reagents and conditions: (i) IBX, THF, MW (150 W), 100 °C; (ii)
polymer supported triphenylphosphine, DCM, MW (150 W), 100 °C.
Oxazolines are privileged structures in medicinal chem-
istry; they have found applications as anti-inflammatory
drugs,9 dopaminergic agonists,10 antibacterials,11 cytotoxic,12
and neuroprotective agents.13 Different synthetic protocols
are available to assemble the oxazoline ring, mainly based
on cyclodehydration of amido alcohols,14 haloamidation of
alkenes,15 and condensation of imidate hydrochlorides,16
carboxylic acids,17 esters,18 imino ether hydrochlorides,19
aminoacids,20 nitriles,21 and aldehydes22 with amino alcohols.
Some approaches involving multicomponent reactions have
recently been reported.23 These protocols allow for the
introduction of various functional groups at the 2, 4, and 5
position of the oxazoline core; however, they mainly use
starting materials where the substituents in positions 4 and
5 are already displayed by the starting aminoalcohol deriva-
tive, thus limiting the number of available building blocks;
moreover, reports about the introduction of a carboxamide
onto the 5 position are very rare, require multistep synthesis
and are not amenable to combinatorial applications.24 On
the other hand, such compounds have found interesting
biological properties as glucokinase activators or antibacteri-
als.25 A synthetic strategy able to assemble 2,4-substituted-
5-carboxamideoxazolines in a very straightforward manner
and, in a combinatorial fashion,26 could open up the scenario
to a novel class of molecules with specific biological
properties.
Having this interesting strategy in hand, we moved to
explore more efficient ways to prepare the R-azidoaldehyde
building blocks, but we had to face with the intrinsic
instability of such compounds, having heavily marked
tendency to generate autocondensation adducts. On the other
hand we were pleased to find that the azido group was rather
stable, both under oxidative and reductive conditions, as
judged by IR analysis of the products. This prompted us to
investigate the synthesis of the corresponding R-azidoalco-
hols 6 with known procedures27 and their in situ oxidation
during the Passerini reaction, modifying a protocol recently
introduced by Zhu28 with different alcohols. With our delight
this method afforded the desired adducts 3 in good yields
(Scheme 3); after careful optimization of the reaction
conditions, it was found that use of THF or EtOAc as the
solvent under microwave heating (100 °C) with a slight
Figure 1. Chemsets employed in the Passerini-Zhu/
Staudinger-Aza-Wittig Protocol.
Table 1. Investigation of the Scope of the Synthetic Protocol
compound
yielda (%)
compound
yield (%)
3{1,1,1}
3{2,4,2}
3{2,5,1}
3{3,2,3}
3{3,6,2}
3{1,2,2}
3{3,3,2}
3{1,3,4}
3{1,7,1}
3{1,3,3}
3{3,4,4}
3{3,2,1}
3{4,2,1}
75b
35
42
5{1,1,1}
5{2,4,2}
5{2,5,1}
5{3,2,3}
5{3,6,2}
5{1,2,2}
5{3,3,2}
5{1,3,4}
5{1,7,1}
5{1,3,3}
5{3,4,4}
5{3,2,1}
5{4,2,1}
99b
84
93
49b
57b
65b
65b
74b
50b
66b
81b
74b
77b
96b
96b
quantitativeb
98b
93b
91b
96b
97b
97b
98b
a Yields are referred to products purified by flash chromatography.
b Yields are referred to the mixture of diastereoisomers.
excess of IBX as oxidating agent (1.3 equiv) resulted superior
compared to the original conditions reported by Zhu. All
Passerini adducts were then smoothly converted into the
corresponding oxazolines 5. We investigated the scope of
the reaction employing three chemsets of azidoalcohols
6{1-4}, carboxylic acids 7{1-7}, and isocyanides
8{1-4 } (Figure 1), and the results are reported in Table 1.
The final compounds, apart from entries b and c, were always
obtained as a nearly 1:1 mixture of two diastereoisomers,

Reports
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 615
which could be separated by standard chromatographic
purification. This has to be ascribed to the well-known poor
selectivity of the Passerini reaction when chiral aldehydes
are employed; remarkably the diastereomeric Passerini
adducts did not show difference in reactivity during the
cyclization step and the diastereomeric ratio was conserved
also in the oxazoline adducts. Identification of syn and anti
diastereoisomers was made on the basis of J coupling
constants between H-4 and H-5, being in the range 10-11
Hz in the case of the syn adduct and in the range 5-7 Hz in
the case of anti adduct, in accordance with the Karplus
equation and the geometry of the diastereomeric oxazolines.
Furthermore, the correct configuration was confirmed also
by NOE experiments.
°C in a sealed NMR tube or in an open vessel left for one
month on the bench.
Furthermore, we conducted DSC analysis on azidoalcohols
6{1} and 6{4} to check their stability under microwave
heating, finding a degradation temperature of 161 and 166
°C, respectively, with energy liberation of 1642 and 1906
J/g. This demonstrates that our synthetic protocol, requiring
heating at 100 °C, is sufficiently safe on a multimilligram
scale for automatized library production.
In conclusion, we have demonstrated that a novel class of
oxazolines can be efficiently assembled in two steps from
readily available building blocks using a Passerini-Zhu/SAW
protocol. We are currently applying this methodology to the
preparation of a 1000-member library that will be subjected
to primary screening to determine the biological properties
of such compounds. The results will be reported in due
course.
To make this procedure amenable for large library
production, we conducted parallel studies on model
compound 5{1,2,2}, finding that extractive work up and
chromatographic purification after the Passerini step could
be suppressed without significant decrease (<10%) of the
final yield: simple filtration of IBX side products was
sufficient to afford a crude material that could effectively
undergo the cyclization to oxazolines; moreover, use of
polymer supported triphenylphosphine in the SAW reac-
tion facilitated the final purification, suppressing the
formation of free triphenylphosphinoxide that often con-
taminated products 5.
Acknowledgment. The authors thank Valeria Rocca for
HPLC analyses, Veronique Colovray e Julien Steffanelli for
stability studies, and Luke Harris for DSC analyses. A.B.
acknowledge Merck Serono and Fondazione San Paolo for
financial support.
Supporting Information Available. General experimental
1
procedures, full characterization and copies of H and 13C
NMR spectra for compounds 3 and 5. This information is
available free of charge via the Internet at http://pubs.acs.org/
The obvious slower conversions observed with this sup-
ported reagent were overcome by performing this step under
microwave heating, able to quantitatively transform Passerini
adducts 3 into oxazolines 5 within 75 min (20 min were
sufficient in most of the cases). Also use of polymer
supported IBX was attempted; however, this was found to
be not compatible with the reaction conditions required by
the Passerini-Zhu step.
One concern was relative to the optical stability of the
in situ generated R-azidoaldehydes under the rather harsh
conditions required by the Passerini-Zhu protocol. Partial
or total racemisation of this building block would indeed
be a major drawback in view of the preparation of
optically pure products. Compounds 5{3,6,2} and
5{1,7,1}, prepared with optically pure carboxylic acids,
did not show any trace of epimerization and this seems
to confirm that racemization did not occur. In order to
rule out completely this side event, enantiomeric oxazo-
lines 5{3,2,1} and 5{4,2,1} were analyzed by chiral HPLC
analysis and absence of cross-contamination peaks (purity
>99%) confirmed that racemization did not occur through-
out the whole synthetic process.
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