Willgerodt–Kindler reaction-driven one pot solventless entry to 2-oxazolines

Article abstract of DOI:10.1080/10426507.2015.1135151

We report an efficient and green protocol for the synthesis of 2-oxazolines by the reaction of aromatic nitriles with β-aminoalcohols using sulfur under solvent-free conditions. The reaction occurs via the Willgerodt-Kindler mechanism followed by transami

Full text of DOI:10.1080/10426507.2015.1135151

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Willgerodt-Kindler Reaction Driven One pot
Solventless Entry to 2-Oxazolines
Shivani Bansal, Poonam Gupta & A. K. Halve
To cite this article: Shivani Bansal, Poonam Gupta & A. K. Halve (2016): Willgerodt-Kindler
Reaction Driven One pot Solventless Entry to 2-Oxazolines, Phosphorus, Sulfur, and Silicon and
the Related Elements, DOI: 10.1080/10426507.2015.1135151
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1135151
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Date: 11 February 2016, At: 09:27

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Willgerodt-Kindler Reaction Driven One pot Solventless Entry to 2-Oxazolines
Shivani Bansal*, Poonam Gupta and A. K. Halve
SOS in Chemistry, Jiwaji University, Gwalior-474011 (India)
Corresponding author Email: shivani2987@gmail.com
ABSTRACT
We report an efficient and green protocol for the synthesis of 2-oxazolines by the reaction of
aromatic nitriles with β-aminoalcohols using sulphur under solvent free conditions. The reaction
occurs via Willgerodt--Kindler mechanism followed by transamidation and dehydrosulfuration.
This methodology offers several advantages such as good yields, mild and practical reaction
conditions, simple work-up procedure and broad substrate scope, which makes the process
simple, convenient and environmentally friendly.
Keywords
β-aminoalcohol, Oxazoline, Sulphur, Solvent free condition, Willgerodt-Kindler Reaction
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Introduction
The oxazoline ring is an important moiety of bioactive natural products [1,2] and pharmaceuticals
including siderophores and post synthetically modified non ribosomal polypeptides[3-5]. Amongst
the oxazolines, 2- oxazolines have received great attention because of their wide range of
therapeutic and biological activities such as antidiabetic[6], antihypertensive[7], antidepressive[8],
anticancer[9], antiHIV[10], antitumor[11], antialzheimer[12], antimalarial[13], antibacterial[14] and
many other clinical applications[15,16]. Apart from that, 2-oxazolines also serve as auxiliaries and
ligands in asymmetric synthesis and protecting groups for carboxylic acids[17,18] and
hydroxylamines[19]. Derivatives of 2-oxazolines have also been used as precursors and
intermediates in synthetic transformations [20-21]
.
Therefore, a number of methods have been reported for the preparation of 2-oxazolines from
carboxylic acids [22-24], aldehydes [25], nitriles [26-29], carboxylic esters [30], amides [31], azides [32]
[33]
and olefins
with amino alcohols. Apart from these methods, 2-oxazolines can also be
prepared by the transamidation rearrangement reaction of thiomides [34]. However, most of the
procedures have several drawbacks such as use of expensive and complex reagents, toxic organic
solvents, long reaction time, strong acidic conditions and low product yields. Therefore,
development of a better and efficient methodology with high activity, short reaction time and
simple workup procedure with mild and practical reaction conditions is highly desirable.
The present study is an extension of the Willgerodt-Kindler reaction. This reaction is a well
known method for the preparation of thioamides [35]. In the traditional Willgerodt--Kindler
reaction, carbonyl compounds react with elemental sulphur and an amine like morpholine to give
thioamide, which is formed as a result of consecutive oxidation and rearrangement reactions[36-
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37]. Here, we have explored the Willgerodt--Kindler reaction of nitrile derivatives which, to best
of our knowledge, have not been studied yet for the synthesis of oxazolines.
In continuation of our interest towards development of a synthetically useful methodology for
the formation of 2-oxazolines, a simple, efficient and high-yielding method by the reaction of
aromatic nitriles with 2-aminoalcohols using sulphur under solvent free condition is reported
here (Scheme 1).
In the classical route of Willgerodt-Kindler reaction, aryl alkyl ketones are converted into
thioamides[38-39]. However, this strategy has already been extended to a wider range of substrates
including aromatic and aliphatic aldehydes, acetals, nitriles, alkenes, alkynes, cinnamic acids,
thiols, imines, amines and benzyl halides[40-41]. Considering this fact, we reasoned that the
reaction of 2-aminoethanol with aromatic nitrile in presence of sulphur may result in formation
of 2-oxazolines via Willgerodt-Kindler reaction, transamidation and subsequent
dehydrosulfuration. However, the reaction of nitrile with aminoalcohol is very well explored for
the formation of 2-oxazolines. Several catalysts like ZnCl2, cellulose sulfuric acid, silica sulfuric
acid, Fe(NO3)3.9H2O, Dowex50-W, InCl3, ZrOCl2·8H2O, Cu complexes, Pd/Fe3O4 and many
more have been used for the activation of the nitriles towards nucleophilic addition by
[48]
aminoalcohols[42-47]. Milton and co-workers
had attempted a good reaction for the formation
of 2-oxazolines using nitrile and aminoalcohol under metal and catalyst free conditions,
however, the methodology employs an environmentally unfriendly solvent, methanol. Here, we
have overcome this demerit by performing the reaction under solvent free conditions without
using any metal or catalyst.
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Furthermore, to explore the possibility of formation of oxazoline from nitrile and aminoethanol,
we have attempted the reaction of benzonitrile, aminoethanol and triethylamine in various
solvents, whereby, the expected product 2-Phenyl-4,5-dihydrooxazole was formed along with
untreated benzonitrile, aminoethanol and thioamide. Therefore, we attempted the next reaction
without triethylamine. In solvents like chloroform, ethyl acetate, toluene, benzene, and
tetrahydrofuran, no reaction occurred mainly due to the insolubility of the salt in non-polar
solvents. Therefore, we attempted the reaction in polar solvents viz. acetonitrile, ethanol,
methanol and dimethylsulfoxide. However, the solubility of the reactants and long reaction hours
did not improve the product formation. Next, we attempted the reaction in solvent free conditions
using sulphur afforded the expected product, 2-Phenyl-4,5-dihydrooxazole, in good yield. Next,
we varied the amount of sulphur used in the reaction of benzonitrile (1.0 mmol) with 2-
aminoethenol (1.0 mmol) to afford 2-phenyloxazoline under solvent free conditions at 80 ºC. The
best results were obtained using 1.0 mmol of sulphur which furnished the expected product in
86% isolated yield.
Sulphur activates the condensation reaction of 2-aminoalcohols with derivatives of benzonitriles
under solvent free condition at 80 ºC and gave a wide range of 2-oxazolines in good to high yield
within 1-3 h. Table 1.
After optimising the reaction conditions, we examined the scope of this transformation and our
results are compiled in Table 1. Diverse nitriles bearing different functional groups were reacted
with 2-aminoethanol. The reaction of different nitriles with aminoethanol yielded 2-substituted
oxazolines in similar fashion, at same reaction temperature but in different time period.
Benzonitrile having electron withdrawing groups furnished high yields of corresponding 2-
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oxazolines in short reaction time (entry 3-6, 10-11). Introduction of nitro group in benzonitrile
consumed more time while affording lower yield as compared to any other electron deficient
nitrile because the nitro group interferes in the dehydrosulfuration process (entry 7). However,
the reaction of naphthalen-2-yl-acetonitrile with 2-aminoethanol led to significant product
formation at high temperature (entry 12).
Conclusion
In summary, we have described a very simple and efficient synthetic methodology for the
preparation of 2-oxazolines with aromatic nitriles and amino alcohol using sulphur via
Willgerodt-Kindler Reaction. The notable features of this procedure are reduced reaction time,
easy and clean workup procedure, mild reaction conditions, use of non-toxic reagents and good
to excellent yields, which makes this protocol superior to other previously reported methods.
Experimental Section
Instruments and Characterization:
All materials were commercial reagent grade and purchased from Sigma-Aldrich and were used
without purification, unless otherwise indicated. Melting points were measured in open glass
1
13
capillary and are uncorrected. H and C NMR spectra were recorded on a Bruker AV II 129
400 NMR spectrometer (Bruker Bio Spin, Switzerland) using TMS as internal standard at 400
and 100 MHz respectively. IR spectra were recorded on a Perkin Elmer FTIR spectrophotometer
using KBr optics. All reactions were monitored by TLC and all yields refer to isolated products.
1
The Supplemental Materials file contains sample IR, H NMR and 13C NMR for the reported
products
GENERAL PROCEDURE FOR THE PREPARATION OF 2-OXAZOLINES FROM NITRILES:
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An equimolar mixture of 2-aminoethanol (1.0 mmol) and sulphur (1.0 mmol) were heated under
solvent free condition at 50 ºC. Nitrile (1.0 mmol) was then added in reaction mixture and
refluxed at 80 ºC. The progress of the reaction was monitored through TLC (n-hexane: EtOAc,
8:2). After completion of reaction excess of water is added and product has been filtered (for
solid). Further chromatographic purification afforded pure product. All the compounds were
characterised by IR and 1H and 13C NMR spectroscopic data as well as by comparison with data
of reported compounds.
1
Data for 1; 2-Phenyl-4,5-dihydrooxazole: Yield (0.126 g, 86%); Oil; H NMR (400 MHz,
CDCl3): δ = 7.94 (t, J = 3.6 Hz, 2H), 7.49--7.39 (m, 3H), 4.43 (t, J = 9.6 Hz, 2H), 4.06 (t, J = 9.4
13
Hz, 2H) ppm. C NMR (100 MHz, CDCl3): δ = 164.6, 131.3, 128.3, 128.1, 127.7, 67.6, 54.9
ppm. IR (KBr): νmax/cm1 = 2936, 1649, 1603, 1496, 1360, 1260, 1079, 944, 779, 694; MS (EI):
m/z = 147 [M]+; Found C, 73.56; H, 6.34; N, 9.18; O, 10.92 C9H9NO requires C, 73.45; H, 6.16;
N, 9.52; O, 10.87%
Acknowledgements
We are thankful to the Head, School of studies in Chemistry and Central Library of Jiwaji
University, Gwalior, India for providing necessary facility and support of this work.
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Table 1. Synthesis of 2-oxazolines using sulphur
Time
(h)
Entry Nitrile Producta
Yieldb(%) M.P.(ºC) Ref.
1
2
3
4
5
6
7
8
1
1.5
1
1.5
1
1.5
3
0.5
86 Oil
50
82 59-61
87 80-81
86 40-42
87 Oil
84 98-99
71 180-181
85 68-69
50
50
51
51
51
9
1.5
80 206-208
10
11
12
13
2
1.5
2.5
1.5
84 85-87
81 Oil
86 153-155
84 58-60
50
50
[a]All the product gave satisfactory spectral data [b] Yield refers to isolated products.
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Scheme 1. Preparation of 2-oxazolines using sulphur
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Scheme 2. Reaction protocol for oxazoline
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