A mild and efficient synthesis of 2-oxazolines via transamidation- cyclodehydrosulfurisation of thioamides with 2-aminoethanol

Article abstract of DOI:10.1055/s-0032-1317341

Transamidation of thioamides with 2-aminoethanol, followed by cyclodehydrosulfurisation of the resultant N-(β-hydroxyethyl)thioamides, has been utilised for the mild and efficient synthesis of 2-oxazolines. The developed protocol was found to be of general applicability. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317341

3678▌
PAPER
paper
A Mild and Efficient Synthesis of 2-Oxazolines via Transamidation–
Cyclodehydrosulfurisation of Thioamides with 2-Aminoethanol
Synthesis of 2-Oxazolines from Thioamides and 2-Aminoethanol
D. Raghavender Goud, Uma Pathak*
Synthetic Chemistry Division, Defence R & D Establishment, Jhansi Road, Gwalior 474002 (M.P.), India
Fax +91(751)2341148; E-mail: sc_drde@rediffmail.com
Received: 17.07.2012; Accepted after revision: 10.09.2012
carboxylic acids with amino alcohols at high temperature
(150–200 °C), and their cyclisation to 2-oxazolines also
occurs under forcing conditions, particularly when the
carbon adjacent to the nitrogen is unsubstituted.
Abstract: Transamidation of thioamides with 2-aminoethanol, fol-
lowed by cyclodehydrosulfurisation of the resultant N-(β-hydroxy-
ethyl)thioamides, has been utilised for the mild and efficient
synthesis of 2-oxazolines. The developed protocol was found to be
of general applicability.
A possible explanation for the observed difference in be-
haviour of thiobenzamide and benzamide toward 2-ami-
noethanol may be the decreased amide bond resonance in
thioamides compared to their oxy analogues. We assume
that the formation of 2-phenyl-2-oxazoline from thioben-
zamide may be proceeding through a tetrahedral mecha-
nism (Scheme 1). The decreased amide bond resonance in
thioamides renders the carbon–nitrogen bond weak, and
electron density at the thiocarbonyl carbon is also deplet-
ed. Nucleophilic attack by the amino group onto the thio-
carbonyl carbon (leading to the formation of tetrahedral
intermediate C) is facilitated; C is further stabilised due to
better charge delocalisation by sulfur. Transamidated
product D, formed through deaminative collapse of tetra-
hedral structure C, would then undergo a second nucleo-
philic attack by the alcohol onto the thiocarbonyl carbon,
followed by elimination of hydrogen sulfide, resulting in
the formation of 2-oxazoline F.
Key words: 2-oxazolines, thioamides, 2-aminoethanol, transami-
dation, cyclodehydrosulfurisation
The synthesis of 2-oxazolines1 is of great interest due to
the pharmaceutical and synthetic importance of such oxa-
zolines. Thus, the oxazoline moiety exists in a variety of
natural products and biologically active compounds,2–7
while synthetic applications of 2-oxazolines include their
use as intermediates,8,9 protecting groups10 and chiral aux-
iliaries.11,12 In addition, oxazolines have been employed as
hydrolysable precursors for carboxylic acids in pro-
drugs.13 The reaction of carboxylic acids with amino alco-
hols is the most common method for the synthesis of
oxazolines.14–18 Other substrates which can be employed
for their preparation are imidate hydrochlorides,19 ortho
esters,20 imino ether hydrochlorides,21 aldehydes22,23 and
nitriles.24–27 Despite potential applications of the reported
procedures, there are limitations associated with them, in-
cluding the utilisation of complex reagents, harsh reaction
conditions, the lack of general applicability and the use of
costly Lewis acids.14–16,24–29 The limitations imposed by
the currently available methods have led to calls for the
development of improved, more versatile methods. In a
continuation of our studies on thioamides,30 we herein re-
port a new, mild and efficient method for the synthesis of
2-oxazolines from primary thioamides and 2-aminoeth-
anol.
H
B
H
–S
HO
OH
N+
S
S
– NH3
H2N
OH
R
NH2
R
R
NH2
N
H
D
A
C
O
HS
O
– H2S
N
H
N
During the course of our studies on the reaction of thio-
amides, we attempted the synthesis of N-(2-hydroxyeth-
yl)thiobenzamide via transamidation of thiobenzamide
with 2-aminoethanol; in addition to the desired product,
the formation of 2-phenyl-2-oxazoline was also observed.
The reaction occurred under very mild conditions upon
stirring 2-aminoethanol and thiobenzamide in benzene at
60–70 °C. When the same reaction was attempted with
benzamide to form the corresponding β-hydroxy amide
analogue, no transamidation was found to occur. General-
ly, β-hydroxy amides are prepared by the condensation of
R
R
F
E
Scheme 1 A plausible mechanism for the formation of 2-oxazolines
from thioamides and 2-aminoethanol
These observations indicated a possibility for the develop-
ment of a synthetically useful protocol for the preparation
of 2-oxazolines. A survey of the literature revealed that a
method for accessing oxazolines from thioamides and 2-
aminoethanol was still unexplored. Hence, our efforts
were applied toward the development of a mild and sim-
ple method for the formation of 2-oxazolines from thio-
amides and 2-aminoethanol.
SYNTHESIS 2012, 44, 3678–3682
Advanced online publication: 02.10.2012
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1
1
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DOI: 10.1055/s-0032-1317341; Art ID: SS-2012-Z0598-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2-Oxazolines from Thioamides and 2-Aminoethanol
3679
For optimisation studies we selected thiobenzamide as a until complete cyclodehydrosulfurisation of N-(2-hy-
model compound. Reaction was carried out by heating an droxyethyl)thiobenzamide along with formation of 2-phe-
equimolar amount of thiobenzamide and 2-aminoethanol nyl-2-oxazoline was achieved.
in different solvents, such as toluene, benzene, tetrahydro-
furan, N,N-dimethylformamide, ethanol, acetonitrile and
water, and also under solventless conditions, at various
temperatures.
To examine the scope and limitations of the developed
protocol, it was applied to a variety of substrates. Thio-
benzamides containing electron-withdrawing or electron-
donating groups, such as hydroxy, methoxy and halo, per-
In ethanol, N,N-dimethylformamide and acetonitrile, the formed well under the applied reaction conditions. Substi-
reaction proceeded with the formation of the correspond- tution at the para or meta position did not affect the
ing oxazoline along with benzonitrile, in approximately outcome of the reaction; however, with ortho-substituted
equal amounts, as major products. In toluene and benzene, substrates, transamidation became sluggish, indicating
in addition to the oxazoline (54%) and benzonitrile (17%), that ortho substitution results in steric hindrance. To con-
uncyclised N-(2-hydroxyethyl)thiobenzamide (29%) was firm this, an equimolar amount of thiobenzamide, 2-chlo-
also obtained. In tetrahydrofuran, neither the oxazoline rothiobenzamide and 2-aminoethanol was reacted. As
nor N-(2-hydroxyethyl)thiobenzamide was obtained. expected, thiobenzamide reacted preferentially, with a
With water, as well as under solventless reaction condi- conversion of 82% into the corresponding oxazoline,
tions, good results were obtained for the first step, i.e. while only 14% of 2-(2-chlorophenyl)-2-oxazoline was
transamidation; however, the reaction progressed com- formed from 2-chlorothiobenzamide. When both of the
paratively faster under solventless conditions. To achieve ortho positions are occupied (e.g., 2,6-dichlorothiobenz-
the complete cyclodehydrosulfurisation of N-(2-hydroxy- amide), reaction failed to occur. Additionally, it was ob-
ethyl)thiobenzamide, the reaction was continued further served that substrates with steric hindrance and electron-
under solventless conditions; however, extended reaction donating groups require two mole equivalents of 2-amino-
time did not lead to completion of the reaction, and a mix- ethanol for complete conversion. Heterocyclic thioamides
ture of N-(2-hydroxyethyl)thiobenzamide (38%), oxazo- were also successfully converted into their corresponding
line (55%), benzonitrile (4%) and benzamide (3%) was 2-oxazolines (Table 1, entries 7 and 8). Substrates with an
obtained after four hours.
acidic proton, such as 4-hydroxythiobenzamide (Table 1,
entry 4), led to protonation of 2-aminoethanol as soon as
both were mixed. The problem was resolved by the addi-
tion of aqueous potassium carbonate at the commence-
ment of the reaction; nonetheless, a considerable amount
(25%) of nitrile formation was observed. Alkylthio-
amides, such 4-methoxybenzylthioamide, amylthioamide
and thioacetamide, also turned out to be adaptable to this
protocol. For n-alkyl substrates, cyclodehydrosulfurisa-
tion of the corresponding N-(2-hydroxyethyl)thioamides
in aqueous potassium carbonate was found to be more dif-
ficult than the conversion with aromatic thioamides. This
may be attributed to the combined outcome of the elec-
tron-donating effect of the alkyl group and hydrogen
bonding of the hydroxy group with water, which in turn
increases the electron density at the thiocarbonyl carbon
and reduces the nucleophilicity of the hydroxy group, re-
spectively. In such cases, utilisation of ethanolic potassi-
um carbonate restored the useful outcome of the protocol
(Table 1, entries 11 and 12). Although a good conversion
occurred in the case of 2-methyl-2-oxazoline (Table 1, en-
try 12), a low yield was obtained due to losses during
workup. For cyclohexanecarbothioamide (Table 1, entry
9), the transamidation and cyclodehydrosulfurisation
steps occurred slowly, and also a higher amount of potas-
sium carbonate was required for completion of the reac-
tion.
Next, for completion of the cyclodehydrosulfurisation of
N-(2-hydroxyethyl)thiobenzamide, simple organic and in-
organic bases, such as triethylamine, pyridine, DBU, po-
tassium carbonate and sodium hydroxide, were
investigated. Among them, best results were obtained
with aqueous potassium carbonate.
Potassium carbonate may be assisting in the deproton-
ation of intermediate E, and it may also help in the scav-
enging of hydrogen sulfide, leading to clean product
formation (Scheme 2). With other reagents, desulfurisa-
tion of N-(2-hydroxyethyl)thiobenzamide also occurred
along with cyclisation. In aqueous potassium carbonate,
complete conversion into the desired product was ob-
served after 8 hours at 80 °C, and the corresponding hy-
droxy amide formation was also reduced to trace amounts.
O
HO
HS
S
O
K2CO3
– KSH
N
H
N
R
R
R
N
H
D
F
E
Scheme 2
An optimised procedure developed after extensive exper-
imentation is as follows: thiobenzamide and 2-aminoeth-
anol were heated at 80 °C under solventless conditions
until the thiobenzamide completely disappeared from the
reaction mixture. This was followed by the addition of
aqueous potassium carbonate, and the mixture was stirred
In conclusion, we have demonstrated a general, simple
and mild protocol for the synthesis of 2-oxazolines. This
convenient and practical approach may find wide applica-
bility in both synthetic and medicinal chemistry.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 3678–3682

3680
D. R. Goud, U. Pathak
PAPER
Table 1 Formation of 2-Oxazolines from Thioamides and 2-Aminoethanol
S
aq K2CO3
B
Δ
O
OH
+
H2N
A
R
NH2
N
R
Entry
R
2-Aminoethanol/K2CO3 Step A
Temp (°C)
Step B
Yielda (%)
Time (h)
Temp (°C) Time (h)
1
2
Ph
1.1:2
1.1:2
1.5:2
2.5:2
2:2
80
1.25
3.5
3
80
90
90
90
90
90
80
90
80
80
70
70
8
4
85
4-BrC6H4
90
90
–
87
3
4-MeOC6H4
4-HOC6H4
2,4-Cl2C6H3
2,5-Cl2C6H3
3-pyridyl
2-thienyl
Cy
5
81
4
–
6
60
5
90
90
80
90
–
1.75
1.5
0.75
1.5
–
5
85
6
2:2
6
80
7
1.1:2
1.1:2
1.5:3
1.1:2
1.1:2
1.1:2
6
87
8
8
83
9
16
6
81
10
11
12
4-MeOC6H4CH2
n-Bu
80
70
70
0.9
0.5
0.25
87
3.5
70
Me
4
35 (80b)
a Isolated yield.
b Conversion as determined by GC.
MS (EI): m/z = 147 [M+], 117, 105, 91, 77, 63, 51.
Reagents were obtained from a commercial supplier and used with-
out further purification. Thioamides for entries 2–6 and 8–11 (Table
1) were prepared by thionation of the corresponding amides using a
reported method.31 Melting points were measured on a Scientific
MP-DS melting point apparatus. Column chromatographic purifi-
cation of products was performed on silica gel (60–120 mesh). 1H
and 13C NMR spectra were recorded on a Bruker AVANCE II 400
MHz instrument. Chemical shifts are expressed in parts per million
(δ) downfield from the internal standard tetramethylsilane and are
reported as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet
of doublet), td (triplet of doublet), br s (broad singlet) and m (mul-
tiplet). Mass spectra were obtained with an Agilent 5975C GC-MS
system and elemental analyses were performed on an Elementar
vario MICRO cube CHNS analyser.
Anal. Calcd for C9H9NO: C, 73.45; H, 6.16; N, 9.52. Found: C,
73.48; H, 6.19; N, 9.43.
2-(4-Bromophenyl)-2-oxazoline (Entry 2)23
Light yellow solid; yield: 196 mg (87%); mp 94–96 °C.
1H NMR (400 MHz, CDCl3): δ = 4.05 (t, J = 9.6 Hz, 2 H), 4.44 (t,
J = 9.6 Hz, 2 H), 7.55 (d, J = 8.8 Hz, 2 H), 7.80 (d, J = 8.8 Hz, 2 H).
MS (EI): m/z = 227 [M+ + 2], 225 [M+], 197, 195, 185, 183, 171,
169, 157, 155, 146, 129, 116, 102, 89, 76, 75, 63, 50.
Anal. Calcd for C9H8BrNO: C, 47.82; H, 3.57; N, 6.20. Found: C,
47.85; H, 3.62; N, 6.22.
2-(4-Methoxyphenyl)-2-oxazoline (Entry 3)23
Colourless solid; yield: 143 mg (81%); mp 60–62 °C.
2-Substituted 2-Oxazolines; General Procedure
A mixture of a thioamide (1 mmol) and 2-aminoethanol (1.1 mmol)
was heated at 80 °C with stirring. Progress of the reaction was mon-
itored by TLC and GC-MS. Upon complete disappearance of the
thioamide, K2CO3 (2 mmol) in H2O (0.5 mL) was added and the re-
action was further continued until complete formation of the corre-
sponding 2-oxazoline occurred. After completion of the reaction,
the reaction mixture was cooled to r.t. and extracted with Et2O
(5 × 2 mL). The extracts were dried (anhyd Na2SO4) and the solvent
was removed to afford pure product (>95% purity). To remove the
excess 2-aminoethanol after solvent removal in the case of entries
4, 5 and 6, the contents were passed through a short plug of silica
gel. For detailed experimental procedures, see the Supporting Infor-
mation.
1H NMR (400 MHz, CDCl3): δ = 3.85 (s, 3 H), 4.03 (t, J = 9.4 Hz,
2 H), 4.41 (t, J = 9.6 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 7.89 (d, J =
8.8 Hz, 2 H).
MS (EI): m/z = 177 [M+], 162, 147, 135, 132, 121, 114, 107, 92, 77,
63, 51.
Anal. Calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C,
67.81; H, 6.29; N, 7.81.
2-(4-Hydroxyphenyl)-2-oxazoline (Entry 4)32
Colourless solid; yield: 98 mg (60%); mp 215–217 °C.
1H NMR (400 MHz, DMSO-d6): δ = 3.88 (t, J = 9.4 Hz, 2 H), 4.33
(t, J = 9.4 Hz, 2 H), 6.80 (d, J = 8.4 Hz, 2 H), 7.69 (d, J = 8.4 Hz, 2
H), 9.85 (br s, 1 H).
2-Phenyl-2-oxazoline (Entry 1)23
Colourless oil; yield: 125 mg (85%).
MS (EI): m/z = 163 [M+], 133, 121, 107, 93, 77, 65, 51.
1H NMR (400 MHz, CDCl3): δ = 4.07 (t, J = 9.6 Hz, 2 H), 4.44 (t,
J = 9.6 Hz, 2 H), 7.41 (t, J = 8.0 Hz, 2 H), 7.46 (t, J = 4.2 Hz, 1 H),
7.94 (d, J = 8.4 Hz, 2 H).
Anal. Calcd for C9H9NO2: C, 66.25; H, 5.56; N, 8.58. Found: C,
66.26; H, 5.61; N, 8.47.
Synthesis 2012, 44, 3678–3682
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2-Oxazolines from Thioamides and 2-Aminoethanol
3681
2-(2,4-Dichlorophenyl)-2-oxazoline (Entry 5)33
1H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.4 Hz, 3 H), 1.35–1.40
(m, 2 H), 1.58–1.65 (m, 2 H), 2.27 (t, J = 7.6 Hz, 2 H), 3.82 (t, J =
9.6 Hz, 2 H), 4.22 (t, J = 9.4 Hz, 2 H).
Light yellow oil; yield: 183 mg (85%).
1H NMR (400 MHz, CDCl3): δ = 4.12 (t, J = 9.6 Hz, 2 H), 4.44 (t,
J = 9.6 Hz, 2 H), 7.28 (dd, J = 2.0, 2.0 Hz, 1 H), 7.48 (d, J = 2.0 Hz,
1 H), 7.49 (d, J = 8.4 Hz, 1 H).
MS (EI): m/z = 127 [M+], 112, 98, 85, 69, 55.
Anal. Calcd for C7H13NO: C, 66.10; H, 10.30; N, 11.01. Found: C,
66.13; H, 10.35; N, 10.90.
MS (EI): m/z = 219 [M+, 37Cl2], 217 [M+, 35Cl, 37Cl], 215 [M+,
35Cl2], 185, 173, 159, 150, 136, 123, 109, 100, 87, 76, 75, 61, 50.
2-Methyl-2-oxazoline (Entry 12)34
Light yellow oil; yield: 30 mg (35%).
1H NMR (400 MHz, CDCl3): δ = 1.98 (s, 3 H), 3.83 (t, J = 9.4 Hz,
2 H), 4.25 (t, J = 9.4 Hz, 2 H).
MS (EI): m/z = 85 [M+], 56, 55, 54, 43.
Anal. Calcd for C9H7Cl2NO: C, 50.03; H, 3.27; N, 6.48. Found: C,
50.07; H, 3.32; N, 6.49.
2-(2,5-Dichlorophenyl)-2-oxazoline (Entry 6)33
Light yellow oil; yield: 172 mg (80%).
1H NMR (400 MHz, CDCl3): δ = 4.19 (t, J = 9.6 Hz, 2 H), 4.50 (t,
J = 9.6 Hz, 2 H), 7.40 (dd, J = 2.6, 2.6 Hz, 1 H), 7.44 (d, J = 8.8 Hz,
1 H), 7.85 (d, J = 2.4 Hz, 1 H).
Anal. Calcd for C4H7NO: C, 56.45; H, 8.29; N, 16.46. Found: C,
56.47; H, 8.33; N, 16.36.
MS (EI): m/z = 219 [M+, 37Cl2], 217 [M+, 35Cl, 37Cl], 215 [M+,
35Cl2], 185, 173, 159, 150, 136, 123, 109, 100, 93, 87, 76, 75, 61, 50.
Acknowledgment
Anal. Calcd for C9H7Cl2NO: C, 50.03; H, 3.27; N, 6.48. Found: C,
50.06; H, 3.34; N, 6.50.
The authors are thankful to Dr. M. P. Kaushik, Director, DRDE,
Gwalior for his keen interest and encouragement.
2-(3-Pyridyl)-2-oxazoline (Entry 7)34
Light yellow solid; yield: 129 mg (87%); mp 65–67 °C.
Supporting Information for this article is available online at
1H NMR (400 MHz, CD3OD): δ = 3.87 (t, J = 12.0 Hz, 2 H), 3.94
(t, J = 11.6 Hz, 2 H), 7.46 (dd, J = 4.8, 4.8 Hz, 1 H), 8.17 (td, J =
2.0, 2.0 Hz, 1 H), 8.59 (dd, J = 1.4, 1.4 Hz, 1 H), 8.89 (d, J = 2.4 Hz,
1 H).
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References
MS (EI): m/z = 148 [M+], 118, 106, 92, 78, 65, 51.
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2-(2-Thienyl)-2-oxazoline (Entry 8)23
Light yellow solid; yield: 127 mg (83%); mp 58–60 °C.
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J = 9.4 Hz, 2 H), 7.08 (dd, J = 4.0, 4.0 Hz, 1 H), 7.45 (dd, J = 0.8,
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MS (EI): m/z = 153 [M+], 123, 111, 96, 83, 76, 70, 64, 57, 51.
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2-Cyclohexyl-2-oxazoline (Entry 9)23
Colourless oil; yield: 124 mg (81%).
1H NMR (400 MHz, CDCl3): δ = 1.20–1.34 (m, 3 H), 1.37–1.47 (m,
2 H), 1.75–1.79 (m, 2 H), 1.91–1.94 (m, 3 H), 2.25–2.32 (m, 1 H),
3.81 (t, J = 9.6 Hz, 2 H), 4.20 (t, J = 9.4 Hz, 2 H).
MS (EI): m/z = 153 [M+], 152, 125, 124, 112, 111, 106, 99, 98, 91,
85, 79, 73, 67, 55.
Anal. Calcd for C9H15NO: C, 70.55; H, 9.87; N, 9.14. Found: C,
70.59; H, 9.91; N, 9.03.
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2-(4-Methoxybenzyl)-2-oxazoline (Entry 10)
Light yellow oil; yield: 166 mg (87%).
1H NMR (400 MHz, CDCl3): δ = 3.55 (s, 2 H), 3.80 (s, 3 H), 3.83
(t, J = 9.6 Hz, 2 H), 4.23 (t, J = 9.6 Hz, 2 H), 6.85 (d, J = 8.4 Hz, 2
H), 7.23 (d, J = 8.4 Hz, 2 H).
13C NMR (100.6 MHz, CDCl3): δ = 33.82, 54.39, 55.22, 67.60,
114.01, 127.19, 129.99, 158.61, 167.34.
MS (EI): m/z = 191 [M+], 176, 162, 148, 133, 121, 105, 91, 77, 65.
Anal. Calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C,
69.11; H, 6.89; N, 7.23.
2-n-Butyl-2-oxazoline (Entry 11)35
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