Transition metal and base free synthesis of 2-aryl-2-oxazolines from aldehydes and β-amino alcohols catalysed by potassium iodide

Article abstract of DOI:10.1039/c4ra08578g

Synthesis of 2-aryl-2-oxazolines from β-amino alcohols and aldehydes was achieved in good to excellent yield by employing a potassium iodide (KI)-tert-butyl hydroperoxide (TBHP) catalytic system. This protocol is very mild, metal and base free and can be performed under ambient reaction conditions. This oxidative cyclization strategy was further extended for the synthesis of optically active 2-oxazolines, which can act as very useful chiral auxiliaries and as ligands. This journal is

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DOI: 10.1039/C4RA08578G
GRAPHICAL ABSTRACT
Transition metal and base free synthesis of .
2ꢀarylꢀ2ꢀoxazolines from aldehydes and βꢀ
amino alcohols catalyzed by Potassium
Iodide
C. Uma Maheswari,*[1] G. Sathish Kumar, [2]
and M. Venkateshwar.[2]
[1] Department of Chemistry, Center for
Nanotechnology
and
advanced
Biomaterials
(CeNTAB), School of Chemical and Biotechnology,
SASTRA University, Thanjavur-613401, India
[2] Inorganic and Physical Chemistry Division, Indian
Institute of Chemical Technology, Tarnaka,
Hyderabad 500607, India

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COMMUNICATION
Transition metal and base free synthesis of 2ꢀArylꢀ2ꢀ
oxazolines from aldehydes and βꢀamino alcohols
catalysed by Potassium Iodide
Cite this: DOI: 10.1039/x0xx00000x
C. Uma Maheswari,* a G. Sathish Kumar b and M. Venkateshwar. b
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Synthesis of 2ꢀarylꢀ2ꢀoxazolines from βꢀamino alcohols and
aldehydes was achieved in good to excellent yields by
employing Potassium Iodide (KI)ꢀtertꢀ Butyl hydroperoxide
(TBHP) catalytic system. This protocol is very mild, metal
and base free and can be performed under ambient reaction
conditions. This oxidative cyclization strategy was further
extended for the synthesis of optically active 2ꢀoxazolines,
which can act as very useful chiral auxiliaries and as ligands.
Construction of nitrogen containing fiveꢀmember heterocycles
is an important synthetic strategy for organic chemists due to their
wide range of applicability in synthesis of various biologically
active compounds and their scope as ligands in homogeneous
asymmetric catalysis. Among them, 2ꢀoxazolines (4,5ꢀ
dihydrooxazoles) exist in a variety of natural products, bioꢀactive
compounds and also as enzyme inhibitors.1 Oxazoline derivatives
exhibit various pharmaceutical activities such as antiꢀdiabetic,2
antihypertensive,3 antiꢀdepressive,4 anticancer,5 antiꢀHIVꢀ16 and
antitumor7 activities to name a few. Chiral monoꢀand bisꢀoxazolines
are used as chiral auxiliaries and as ligands in asymmetric
synthesis.8 Achiral oxazolines finds their use as an important
protecting group and as a valuable intermediate in organic
synthesis.9 Numerous methods for the construction of 2ꢀoxazolines
have been reported (Scheme 1), from carboxylic acids,10 esters,11
nitriles,12 aldehydes,13 and olefins.14
Despite certain degree of success in the above mentioned
methods, they have several limitations like multiꢀstep synthesis and
significant amount of byꢀproduct formation. Moreover, some of
these methods require elaborate purification process and harsh
reaction conditions. Oxidative methods for the formation of
heterocyclic compounds are quite attractive and several methods
were already reported for the formation of benzoxazoles,
benzimidazoles and imidazolines from aldehydes.15
Scheme 1: Common routes for the construction of 2ꢀoxazolines.
However, synthesis of oxazolines by oxidative strategy from
aldehydes was little explored and was performed using pyridinium
hydrobromide perbromide (PHPB),16 NꢀBromosuccinimide
(NBS),17 and 1,3ꢀDiiodoꢀ5,5ꢀdimethylhydantoin (DIH).18 The main
drawbacks of these procedures are: they use stoichiometric amount
of reagents to facilitate the conversion in the presence of excess
base. This in turn leads to excess amount of inorganic salts as byꢀ
product. To circumvent this problem associated with stoichiometric
process, they can be replaced by environmentally friendly catalytic
oxidative methods which comes under the wellꢀknown term “green
chemistry” as proposed by Anastas and Warner.19 In catalytic
oxidation, the stoichiometric oxidants used for synthesis of fine
chemicals are molecular oxygen, hydrogen peroxide, alkyl
hydroperoxides especially tertꢀ Butyl hydroperoxide (TBHP),
persulfate, percarbonate, hypochlorite and hypochlorates to name a
few.20 In similar lines, there are few reports on TBHP mediated
oxidative cyclization for the synthesis of heterocycles. For eg. for
the synthesis of benzothiazoles,21 pyrazoles,22 oxazoles,23 2ꢀ
phenylquinazolines,24 in the presence of iodine or transition metals
like Cu or Fe. But there are no reported literatures for the synthesis
of 2ꢀoxazolines. Thus formation of 2ꢀarylꢀ2ꢀoxazolines by oxidative
cyclization starting from readily available aldehydes and βꢀamino
alcohols prove to be an important strategy (Scheme 2).
a
Department of Chemistry, School of Chemical and Biotechnology,
SASTRA University, Thanjavurꢀ613401, India, Tel.: +91 ꢀ(4362) 304346;
Fax: +91ꢀ(4362)ꢀ264111.
b
Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Tarnaka, Hyderabad 500607, India.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
Scheme 2: Formation of 2ꢀarylꢀ2ꢀoxazolines by Oxidative
Cyclization.
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The general applicability of this reaction was evaluated with
structurally diverse aldehydes and amino alcohols (Table 2). In
general the yields are moderate to good with different amino
alcohols and aldehydes. However, there was a slight variation in the
product yields depending on the position of the substitution on the
amino alcohol as well as aldehydes. For example, in case of 1ꢀ
aminoꢀ2ꢀpropanol, electron withdrawing groups on aldehydes gave
better yields compared to the electron donating substrates (entries 1ꢀ
5). In case of 2ꢀaminoꢀ1ꢀpropanol, yields are better with electron
donating substrates (entries 6ꢀ10). No such trend was observed
when 2ꢀaminoꢀ1ꢀbutanol was taken as the amino alcohol variant.
The yields are generally good with both electron withdrawing and
electron donating aldehydes (entries 11ꢀ15). When we employed
aliphatic aldehyde, butyraldehyde as aldehyde source with 1a for
this reaction, the yield decreased considerably (<20%). Thus this
methodology was best suited for the synthesis of 2ꢀarylꢀ2ꢀ
oxazolines.
We have successfully demonstrated the catalytic oxidative
transformations viz., synthesis of 3HꢀQuinazolinꢀ4ꢀones and 4Hꢀ
3,1ꢀBenzoxazinꢀ4ꢀones,25 amidation of aldehydes and alcohols,26
27
selective oxidation of aromatic amines to nitro compounds using
catalytic amount potassium iodide in the presence of TBHP as the
external oxidant. As part of our ongoing study on iodine/iodide
mediated catalytic oxidative functionalization, herein, we would
like to present a mild and selective synthesis of 2ꢀarylꢀ2ꢀoxazolines
using KIꢀTBHP catalytic system.
Table 1: Optimization of reaction conditions a,b
S.No Catalyst
(mmol)
[O]
Solvent
Conversion
Selectivityb
Table 2 Synthesis of 2ꢀoxazolines from aldehydes catalyzed by KIꢀTBHP.a,b
(%)b
58
60
64
95
93
67
63
48
92
75
84
64
89
1a
1b
100
83
100
ꢀꢀ
1c
ꢀꢀ
1.
2.
ꢀꢀ
ꢀꢀ
ꢀꢀ
AcOH
AcOH
AcOH
AcOH
H2O
ꢀꢀ
TBHP
ꢀꢀ
06
ꢀꢀ
ꢀꢀ
3.
KI
ꢀꢀ
4.
KI
TBHP
TBHP
TBHP
45
42
54
40
05
88
55
03
55
86
27
19
16
ꢀꢀ
5.
KI
ꢀꢀ
6.
KI
CH3CN
18
16
85
ꢀꢀ
7.
KI
TBHP CH3CNc,d
8.
KI
TBHP
TBHP
TBHP
THF
ꢀꢀ
9.
KI
CH2Cl2
ꢀꢀ
10.
11.
12.
13
KI
Toluene
06
46
33
ꢀꢀ
ꢀꢀ
d
KI
NaOCl CH2Cl2
ꢀꢀ
KI (0.1)
KI (0.1)
TBHP
TBHP
CH2Cl2
CH2Cl2
ꢀꢀ
a
Reaction Conditions: KI (0.1 mmol), 70% aq. TBHP (3.0 mmol), βꢀaminoꢀ
e
ꢀꢀ
b
alcohol (1.2 mmol), aldehyde (1 mmol), CH2Cl2 (3 mL), 12 h. Isolated
a
yield.
Reaction conditions: 1ꢀaminoꢀ2ꢀpropanol (1.2 mmol), benzaldehyde (1
mmol), KI (0.2 mmol), 70% aq. TBHP (3.0 mmol), Solvent (3ml), rt, 6h.
This oxidative cyclization strategy was applied for the
synthesis of optically active 2ꢀoxazolines, which are very useful as
chiral auxiliaries and as ligands (Table 3). The reaction with
benzaldehyde and various chiral amino alcohols (>98% ee)
provided the product with good yields and good optical purity
(entries 16ꢀ20). There is no improvement in optical purity of the
product, even when the reactions were carried out at lower
temperature (0 oC). The slight drop in optical purity may be
explained on the basis of imineꢀenamine tautomerism, which
accounts for partial racemization.
b
c
o
d
Conversion and selectivity based on GC. Reaction at 80 C. Simple
amide (Nꢀ(2ꢀhydroxypropyl)benzamide) was observed as the major product.
e Reaction time = 12h
For our initial optimization studies, benzaldehyde and 1ꢀ
aminoꢀ2ꢀpropanol was taken as the model substrates (Table 1).
Blank reactions without oxidant and catalyst (KI or I2) proved to be
futile and yielded only oxazolidine (1b) as the major product
(entries 1ꢀ3). When KI in combination with TBHP in dil. AcOH
was taken, the required 2ꢀoxazoline (1a) was formed along with an
amide (1c) (entry 4). Similar observation was made using water as
the solvent (entry 5). However, drastic improvement in product
selectivity was observed shifting from aqueous to organic solvents.
Among different organic solvents screened, CH2Cl2 proved to be the
best solvent in terms of conversion and selectivity (entry 8). Either
the change of oxidant (from TBHP to NaOCl) or decrease in
catalyst loading (from 20 mol% to 10 mol%) could not improve the
product conversion or selectivity (entries 10ꢀ12). But when 10
mol% of KI was used and the reaction time was prolonged for 12 h,
we could observe comparable yields as 20 mol% catalyst loading
with 6 h reaction time (entry 13). Thus KI in conjunction with
TBHP as the oxidant in CH2Cl2 at room temperature was taken as
the optimized reaction condition for oxidative cyclization (entry
13).
Since chiral Oxazolines are very useful chiral auxiliaries and
important class of ligands, the feasibility of the present catalytic
system on multiꢀgram scale was examined for the synthesis of 3p
[(S)ꢀ4ꢀisopropylꢀ2ꢀphenylꢀ4,5ꢀdihydrooxazole].
Reaction
of
commercially available chiral amino alcohol, LꢀValinol (5g, 48.5
mmol, 1.2 equiv.) with benzaldehyde (1 equiv.), KI (0.1 equiv.) and
3.0 equiv. of TBHP at room temperature in 40 mL of CH2Cl2
provided 3p in 80% (6.12 g) isolated yield after 12h with good ee
of 90.6%.
2 | J. Name., 2012, 00, 1-3
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Table 3. Synthesis of chiral 2ꢀphenylꢀ2ꢀoxazolines from
Moreover, the reaction was carried out at ambient conditions
and no other side products are obtained. The present
methodology was also extended to chiral amino alcohol
derivatives to yield chiral oxazolines, which are important as
ligands and auxiliaries. In addition, the present nonꢀtransition
metalꢀoxidant catalytic system also provides an easy scaleꢀup
and separation protocol.
benzaldehyde with chiral aminoꢀalcohols.a
Acknowledgements: CUM thanks SASTRA University’s in house
T.R. Rajagopalan funding program. She thanks Dr. K. Rajender
Reddy, Senior Scientist, I&PC Division, Indian Institute of
Chemical Technology (IICT), Hyderabad, India for his constant
motivation and Suggestions.
Notes and references
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a Reaction Conditions: aminoꢀalcohol (1.2 mmol), aldehyde (1 mmol),
CH2Cl2 (3 mL), KI (0.1 mmol), TBHP (3.0 mmol), 10 h. b Isolated yield. c
Optical purity based on optical rotation. d TBHP in decane was used.
A
plausible mechanism for the formation of 2ꢀarylꢀ2ꢀ
oxazolines was described as in Scheme 3. The initial step could be
the formation of imine 3’. Iodine acts as a mild lewis acid, thus
facilitating the intraꢀmolecular cyclization of 3’ to give oxazolidine
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In summary, we have developed a simple and straightforward
method for the synthesis of the 2ꢀarylꢀ2ꢀoxazolines by
oxidative cyclization of aldehydes and an aminoꢀalcohol using
KIꢀTBHP. This method eliminates the use of transition metal,
stoichiometric reagents and base for the formation of 2ꢀarylꢀ2ꢀ
oxazolines, a biologically active heterocyclic compound.
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