Thermal rearrangement of azido ketones into oxazoles via azirines: One-pot, metal-free heteroannulation to functionalized 1,3-oxazoles

Article abstract of DOI:10.1002/ejoc.201201269

α-Azidoacetophenones were converted into 2-aryl-1,3-oxazole-4- carbaldehydes through rearrangement of the carbon framework upon exposure to DMF/POCl₃. The unprecedented rearrangement occurs via alkenyl azides and 2H-azirines. A mechanism for this unusual reaction was proposed and evidenced.

Full text of DOI:10.1002/ejoc.201201269

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201269
Thermal Rearrangement of Azido Ketones into Oxazoles via Azirines:
One-Pot, Metal-Free Heteroannulation to Functionalized 1,3-Oxazoles
Shailesh R. Shah,*[a] Sudhanva S. Navathe,[a] Amol G. Dikundwar,[b] Tayur N. Guru Row,[b]
and Andrea T. Vasella[c]
Dedicated to Professor Goverdhan Mehta
Keywords: Rearrangement / Oxygen heterocycles / Nitrogen heterocycles / Ketones
α-Azidoacetophenones were converted into 2-aryl-1,3-ox-
azole-4-carbaldehydes through rearrangement of the carbon
framework upon exposure to DMF/POCl3. The unprece-
dented rearrangement occurs via alkenyl azides and 2H-azir-
ines. A mechanism for this unusual reaction was proposed
and evidenced.
ferent substitution patterns. There are several methods for
their synthesis, most of which require advanced starting
materials and many involve transition metal-catalyzed reac-
tions.[10]
Introduction
1,3-Oxazoles are prominent five-membered heterocyclic
compounds.[1] Recent interest in these heterocycles was
spurred by the isolation of a number of bioactive 1,3-ox-
azoles[2] and by their use as ligands in asymmetric synthe-
sis[3] and as protective groups.[4] We report an unusual syn-
thesis of 2-aryl-1,3-oxazole-4-carbaldehydes from α-azido-
acetophenones[5,6] and propose a mechanism to rationalize
the transformation that involves an unprecedented thermal
rearrangement of the carbon skeleton. 2-Substituted 4-for-
myloxazoles are biosynthetically formed by the action of
nonribosomal peptide synthetase (NRPS) and polyketide
synthase (PKS). They are intermediates in the biosynthesis
of many natural oxazoles.[7] Oxazoles possessing a func-
tional group are indeed versatile intermediates[8] for the
synthesis of differently substituted 1,3-oxazoles and for the
construction of other five- and six-membered heterocycles
of interest in medicinal chemistry.[8d]
Results and Discussion
The Vilsmeier reagent is one of the most versatile and
widely used reagents, not only for the formylation of acti-
vated aromatic and vinylic compounds but also in the syn-
thesis of various heterocycles.[11] While studying the reac-
tion of α-azido ketones 1a–e[12] under Vilsmeier conditions
(DMF/POCl3, 90–95 °C) that was reported to yield 5-aryl-
4-formyl-1,3-oxazoles,[10j] we observed the unexpected for-
mation of 2-aryl-4-formyl-1,3-oxazoles 2a–e in moderate
yields (Scheme 1; Table 1).
In the context of a medicinal chemistry project aimed at
designing new heterocyclic entities useful in the treatment
of metabolic disorders,[9] we required 1,3-oxazoles with dif-
[a] Department of Chemistry, Faculty of Science, The M. S.
University of Baroda
Vadodara 390002, India
Fax: +91-265-2793693
E-mail: shailesh-chem@msubaroda.ac.in
Homepage: http://www.msubaroda.ac.in//science/upload/
S_R_Shah_profile.pdf
[b] Solid State and Structural Chemistry Unit, Indian Institute of
Science,
Bangalore 560012, India
[c] Departement Chemie und Angewandte Biowissenschaften
Laboratorium für Organische Chemie
ETH Hönggerberg, HCI, 8093 Zürich, Switzerland
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201269.
Scheme 1. Rearrangement of α-azido ketones into 1,3-oxazoles via
azirines.
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Eur. J. Org. Chem. 2013, 264–267

Thermal Rearrangement of Azido Ketones into Oxazoles via Azirines
Table 1. 2-Aryl-1,3-oxazole-4-carbaldehydes 2a–e.
perature (350 °C). The azirine hypothesis was reasserted
when alkenyl azide 4d was smoothly transformed into cor-
responding azirine 5d under microwave conditions.[13,14c]
The synthesis of 2H-azirines by thermolysis of vinyl azides
is well precedented.[14] This preparative experiment helped
us to study the spectral characteristics[13] of the azirines.
The IR spectrum of 5d (liquid) shows sharp bands at 1759,
1735, 1587, and 1068 cm–1 and the absence of the azide
band at 2112 cm–1, which is observed for 4d. The 13C NMR
spectrum has typical signals at δ = 192.4 (CHO), 163.2
(C=N of azirine), and 60.8 (Csp3 of 2H-azirine) in addition
to the signals of the aromatic carbon atoms.
Hydrolysis of iminium cations 6 may have occurred dur-
ing isolation of intermediate 4 or in situ, as larger amounts
of benzoic acids and lower yields of 1,3-oxazoles were ob-
tained when the solvent was used as received without fur-
ther drying. Exposure of intermediate 4 to the original reac-
tion conditions (DMF/POCl3, 90–95 °C) resulted in the
same products in nearly the same proportion as that ob-
tained from 1, which is consistent with either (partial) hy-
drolysis and further transformation of 4 or the reversibility
of hydrolysis by the excess amount of the Vilsmeier reagent.
The rearrangement is thus rationalized by a mechanism
consistent with the above observations, as depicted in
Scheme 2. Initial Vilsmeier product 6 generates azirine 8,
presumably via nitrene 7 or via a triazine, or in a concerted
manner[5,15] by analogy to the Neber rearrangement. Ad-
dition of HCl to 8 affords aziridine 9, which undergoes ring
opening to give 10. Intermediate 10 reacts with a further
[17]
Compound
R
Yield[a] [%]
M.p.[b] [°C]
2a[17c]
H
42
31
29
52
48
94
90
121
135
130
2b[17b]
2c[17a]
CH3
OCH3
Br
2d[17b]
2e[17a,17b]
Cl
[a] Unoptimized, isolated yield from α-bromoketones. [b] Uncor-
rected in open capillary.
As byproducts, benzoic acids 3 (Scheme 1) were isolated.
Prompted by the difficulties in differentiating between the
formylated isomeric 1,3-oxazoles by NMR spectroscopy,
the structure of oxazole 2d was established by single-crystal
X-ray analysis[18] (Figure 1).
Figure 1. ORTEP diagram of oxazole 2d (R = Br). Only one of the
two symmetry-independent molecules is shown.
To rationalize the formation of 2 from the azido ketones,
we examined the unprecedented transformation more
closely. An intermediate was observed after the addition of
POCl3 and upon warming the reaction mixture from 0 °C
to room temperature. It was identified as 2-azido-3-chloro-
3-arylpropenal (4),[10j] which is the hydrolysis product of ex-
pected intermediate 6 of a typical Vilsmeier reaction. The
structure of 4 was confirmed by X-ray analysis[19] of needles
of 4d (Figure 2).
Figure 2. ORTEP diagram of alkenyl azide 4d (R = Br).
Intermediate 4a (liquid) was converted into azirine 5a
under the thermal conditions of GC, as evidenced by the
most abundant mass peak at m/z = 179 with the expected
isotopic peaks;[13] this suggests the transformation of inter-
mediate 4 into 5 when performing the Vilsmeier reaction of
1 at 90–95 °C. The same result was observed when 4d was
Scheme 2. Proposed mechanism depicting the rearrangement of
subjected to ESI mass analysis with a higher source tem- azido ketones into1,3-oxazoles via azirines.
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S. R. Shah et al.
SHORT COMMUNICATION
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11. Reductive dechlorination (by an X-philic reaction)[16]
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finally leads to oxazole 2.[17] The observed side products,
the benzoic acids, could be formed by hydrolysis of interme-
diates 10–14 before heterocyclization. Donor substituents
resulted in lower yields of the desired product, as seen by
comparing 2b and 2c to 2a, whereas halogen substituents
led to higher yields of products 2d and 2e (Table 1).
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Conclusions
In summary, a moderate yielding, one-pot synthesis of 2-
aryloxazole-4-carbaldehydes from readily available, inex-
pensive reagents involves an unprecedented rearrangement
occurring via 2H-azirines and constitutes a metal-free het-
eroannulation to functionalized 1,3-oxazoles.
[3]
[4]
[5]
Experimental Section
General Procedure for the Synthesis of 2-Aryloxazole-4-carb-
aldehydes 2a–e: In a 250-mL, two-necked, round-bottomed flask,
sodium azide (3.16 g, 55 mmol) was added in one portion to an
ice-cooled (10–15 °C), magnetically stirred solution of arylacyl
bromide (50 mmol) in DMF (50 mL). After stirring for 30 min, the
acyl bromide was completely converted into the phenacyl azide
(TLC 10% EtOAc in petroleum ether). Then, POCl3 (14 mL,
150 mmol) was added dropwise at 10–15 °C within 30–45 min. The
reaction mixture was allowed to attain room temperature (30 °C)
and was stirred for 3–4 h. After this time, the reaction mixture was
heated slowly to 90–95 °C and stirred for 2–3 h. The reaction mix-
ture was then cooled to room temperature and poured into an ice–
water mixture (500 mL). The mixture was stirred for 1 h and ex-
tracted with CHCl3 (3ϫ 100 mL). The organic layer was washed
with aqueous NaHCO3 solution to remove the formed benzoic acid
and with water and brine and then dried with anhydrous Na2SO4.
The solvent was removed, and the residue was chromatographed
(5% EtOAc/petroleum ether) to yield 2-aryloxazole-4-carbal-
dehydes 2a–e as crystalline products.
[6]
[7]
[8]
[9]
CCDC-817127 (for 2d) and -887930 (for 4d) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif
Supporting Information (see footnote on the first page of this arti-
cle): Representative experimental procedures and spectral analyti-
cal data for all the compounds.
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Acknowledgments
S. S. N. acknowledges an RFSMS fellowship from the University
Grants Commission New Delhi. Analytical support was extended
by the Zydus Research Centre, Ahmedabad and Sun Pharma Ad-
vanced Research Centre, Vadodara. Thanks are due to Mr. H. R.
Rawal (M. S. University) and Mr. V. Bhaskar Rao, (University of
Hyderabad) for elemental analyses.
[1] For reviews on oxazole chemistry, see: a) I. J. Turchi (Ed.), The
Chemistry of Heterocyclic Compounds Vol. 45: Oxazoles, John
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Thermal Rearrangement of Azido Ketones into Oxazoles via Azirines
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[12] α-Azidoacetophenones can be prepared from the correspond-
ing α-bromoacetophenones and may be used in the next step
without isolation.
[17] These oxazoles were reported earlier by multistep synthesis: a)
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[18] 2d: CCDC-817127; molecular formula: C10H6Br1N1O2; mono-
clinic; a = 3.9271(5) Å; b = 34.3676(40) Å; c = 7.0792(8) Å; β
= 95.169(2)°; V = 951.56(3) Å3; T = 295(1) K; space group,
P21, Z = 4; ρcalcd. = 1.76 gcm–3; μ(Mo-Kα) = 4.289 mm–1; reflns
measured, 10082; unique reflns, 3863; no. of parameters = 253;
Robs = 0.047; wR2obs = 0.108; Δρmin,max = –0.220, 0.416 eÅ–3;
gof = 1.031.
[13] See the Supporting Information.
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[19] 4d: CCDC-887930; molecular formula: C9H5Br1Cl1N3O1; mo-
noclinic;
a = 10.2287(33) Å; b = 4.0564(13) Å; c =
12.9024(43) Å; β = 100.314(5)°, V = 526.69(6) Å3; T =
295(1) K; space group, P21, Z = 2; ρcalcd. = 1.93 gcm–3; μ(Mo-
Kα) = 4.136 mm–1; reflns measured, 3666; unique reflns, 2005;
no. of parameters = 136; Robs = 0.041; wR2obs = 0.088;
Δρmin,max = –0.242, 0.572 eÅ–3; gof = 0.99.
Received: September 23, 2012
[16] N. S. Zefirov, D. I. Maknon’kov, Chem. Rev. 1982, 82, 615.
Published Online: November 26, 2012
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