A Lewis acid initiated intramolecular cyclization of benzylidene acetal with an azide functional group: Novel synthesis of oxazolines and oxazines

Article abstract of DOI:10.1039/c1cc14722f

Stereoselective synthesis of 2-phenyl-oxazolines and 2-phenyl-oxazines via Lewis acid initiated intramolecular cyclization of benzylidene acetal with an azide functional group is described. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc14722f

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COMMUNICATION
A Lewis acid initiated intramolecular cyclization of benzylidene acetal
with an azide functional group: novel synthesis of oxazolines and
oxazinesw
Amit Banerjee, Ponminor Senthil Kumar and Sundarababu Baskaran*
Received 31st July 2011, Accepted 4th October 2011
DOI: 10.1039/c1cc14722f
Stereoselective synthesis of 2-phenyl-oxazolines and 2-phenyl-
oxazines via Lewis acid initiated intramolecular cyclization of
benzylidene acetal with an azide functional group is described.
In recent years, oxazolines and oxazines have been considered
as a very interesting class of heterocycles with wide range of
applications in synthetic organic chemistry. Oxazolines are
Scheme 1 Synthesis of 2-phenyl-oxazoline via intramolecular cycliza-
tion of benzylidene acetal with an azide functional group.
frequently found in biologically active natural products and
pharmaceuticals exhibiting cytotoxic, neuroprotective, antibiotic
and antifungal properties.1 In addition, 2-oxazoline moieties
serve as hydrolysable precursors for carboxylic acids in prodrugs
and also as templates in organic synthesis.2 In recent years,
oxazoline ring systems, especially C2-symmetric bis-oxazolines
(box’s), have received a great deal of attention as chiral ligands in
coordination chemistry for inducing high enantioselectivity.3–5
As a consequence of their wide ranging applications, many
synthetic methods towards the synthesis of oxazolines have
been reported in the literature.6 Generally oxazolines are
prepared by the reaction of b-aminoalcohols with nitriles, acid
chlorides, esters, carboxylic acids, imino ethers, alkyl imidates
and acyl benzotriazoles.7 Other methods such as (i) reaction
between aldehyde and hydroxy azide and (ii) cyclization of
hydroxy amides using the Burgess-reagent, diethylaminosulfur
trifluoride (DAST), PPh3/DIAD, diisopropylcarbodiimide
(DIC)/Cu(OTf)2 and immobilised p-toluenesulfonyl chloride/
Et3N have also been reported.8
Scheme 2 Synthesis of benzylidene acetal 3 from D-glucose.
In this communication, we report a novel intramolecular
cyclization of benzylidene acetal with an azide functional
group11 which resulted in the stereoselective synthesis of
2-phenyl-oxazolines and 2-phenyl-oxazines in good yields.
Interestingly, compound (À)-3 on treatment with BF3ÁOEt2
(4 eq) in dry DCM underwent smooth Lewis acid initiated
intramolecular Schmidt type cyclization in a remarkable
manner to give the corresponding cyclized product (À)-4 in
good yield (Scheme 1). Compound (À)-3 was prepared starting
from D-glucose via intermediate (À)-112 as shown in Scheme 2.
Moreover the structure and stereochemistry of the cyclized
product (À)-4 were unambiguously confirmed by single crystal
X-ray analysis (Fig. 1).13
Recently, we developed a novel method for the direct
oxidation of benzylidene acetals to a- and b-benzoyloxy
carboxylic acids in one pot. This methodology was further
exploited in the enantioselective synthesis of a-benzoyloxy
carboxylic acids from terminal olefins.9 Our enduring interest in
exploring the synthetic potential of benzylidene acetals in organic
synthesis resulted in the development of highly chemo- and
regioselective methods for the cleavage of benzylidene acetals
under mild reaction conditions.10
This unusual transformation was further studied with
various benzylidene acetals having sensitive functional groups
and the results are summarized in Table 1. The benzylidene
acetals having the azido-methyl group at the alpha position
underwent smooth cyclization to give the corresponding
2-phenyl-oxazolines in good yields (Table 1, entries 1 and 2).
Similarly, benzylidene acetals having the azido-methyl group
at the beta position reacted readily under these conditions to
give the corresponding 2-phenyl-oxazines in good yields
(Table 1, entries 3–5). Moreover, under the reaction conditions,
Department of Chemistry, Indian Institute of Technology Madras,
Chennai 600 036, India. E-mail: sbhaskar@iitm.ac.in
w Electronic supplementary information (ESI) available: General pro-
cedure, experimental details and crystallographic data. CCDC 670499.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc14722f
c
12218 Chem. Commun., 2011, 47, 12218–12220
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Fig. 1 ORTEP diagram of 2-phenyl-oxazoline (À)-4.
Cyclization of benzylidene acetal with an azide
Table
functional group
1
Scheme 3 Plausible mechanism for the intramolecular cyclization of
benzylidene acetal with an azide functional group.
Entry Substrate
Time/h Product
Yield (%)a
initially coordinate with the less hindered oxygen atom (a) of
the benzylidene acetal (À)-5, thus creating a partial polarization
followed by intramolecular attack by the azide group at the
benzylic carbon leading to the amino-diazonium ion intermediate
(À)-5a. The resultant intermediate (À)-5a on 1,2-hydride shift
coupled with nitrogen expulsion8g and subsequent proton loss
would result in the formation of the corresponding 2-phenyl-
oxazoline (À)-6.
1
2
3.5
88
3
5
85
68
As expected, azido-benzylidene acetal 16 under the same
reaction conditions failed to give any cyclized product, which
further supports the proposed mechanism.
In conclusion, a mild and efficient method has been developed
for the synthesis of oxazolines and oxazines via BF3ÁOEt2
mediated intramolecular cyclization of benzylidene acetal with
an azide functional group. Salient features of this methodology
are mild reaction conditions and the reaction proceeds without
any racemization of the chiral center. We hope this novel
methodology will find wide application in organic synthesis.
We thank DST and CSIR, New Delhi, for financial support
and DST-FIST, New Delhi, for infrastructure facility. A.B.
and P.S.K. thank CSIR, New Delhi, for research fellowships.
The authors thank V. Ramkumar for single crystal X-ray
analysis.
3
4
5
4.5
65
69
5
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12220 Chem. Commun., 2011, 47, 12218–12220
This journal is The Royal Society of Chemistry 2011