Facile, selective, and regiocontrolled synthesis of oxazolines and oxazoles mediated by ZnI2 and FeCl3

Article abstract of DOI:10.1021/ol301980g

An expedient method for a direct approach to the selective and regiocontrolled synthesis of 2-oxazolines and 2-oxazoles mediated by ZnI ₂ and FeCl₃ is described. A Lewis acid promoted cyclization of acetylenic amide with various func

Full text of DOI:10.1021/ol301980g

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4478–4481
Facile, Selective, and Regiocontrolled
Synthesis of Oxazolines and Oxazoles
Mediated by ZnI2 and FeCl3
Gopal Chandru Senadi,† Wan-Ping Hu,‡ Jia-Shing Hsiao,† Jaya Kishore Vandavasi,†
Chung-Yu Chen,§ and Jeh-Jeng Wang*,†
Departments of Medicinal and Applied Chemistry, Biotechnology, and Pharmacy,
Kaohsiung Medical University, Kaohsiung, Taiwan
jjwang@kmu.edu.tw
Received July 17, 2012
ABSTRACT
An expedient method for a direct approach to the selective and regiocontrolled synthesis of 2-oxazolines and 2-oxazoles mediated by ZnI2 and
FeCl3 is described. A Lewis acid promoted cyclization of acetylenic amide with various functionalities was well tolerated to give 2-oxazolines and
2-oxazoles in good to excellent yields under mild reaction conditions.
Oxazolines and oxazoles have great importance due to
their presence in a number of biologically active com-
pounds,1,2 such as antifungal, antiviral, antibacterial, and
antiproliferative activities.3 The potent biological activity
and the prevalence of oxazoles in both natural products
and pharmaceuticals has created significant interest in the
synthesis of these heterocycles.4
Oxazolines and oxazoles are also utilized for other appli-
cations such as useful reagent/intermediates in organic
synthesis.5,6 In addition 2-oxazolines are excellent catalyst
ligands7 and protecting groups,8 providing a continuing
stimulus for the development of more common and ver-
satile synthetic methodology to access these classes of
compounds.
† Department of Medicinal and Applied Chemistry.
‡ Department of Biotechnology.
§ Department of Pharmacy.
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In recent years, the cyclization of acetylenic amides 1 to the
corresponding methyleneoxazolines 2 and oxazoles 3 has
been a focus of interest (Scheme 1). These transformations
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r
10.1021/ol301980g
Published on Web 08/09/2012
2012 American Chemical Society

have been reported with transition metals9a such as Pd,9
Cu,10 Ag,11 W,12 Mo,12 Au,13 and Ru13b as well as with
Ce,16 Bronsted acids,14 and strong bases.15
Table 1. Optimization of Lewis Acid Mediated Cyclization to
Oxaza Heterocyclesa,b
Scheme 1. Synthetic Approach to Oxazolines and Oxazoles
time temp 5a yield 6a yield
entry reagent
solvent
(h)
(°C)
(%)
(%)
1
CuI
CH2Cl2
CH2Cl2
CH2Cl2
DMF
24
24
24
16
12
12
4
rt
À
À
However, some of the above-reported methods suffer
from one or more limitations such as low yield, poor regio-
selectivity, prolonged reaction time, and expensive cata-
lysts in most cases. Therefore development of mild, econom-
ical, and complementary approaches to oxaza heterocycle
derivatives is still highly desired due to their extreme
significance.
In recent decades, Zn17 and Fe18 based catalysts have
risen significantly in popularity to promote a broad range
of organic transformations, owing to their abundance,
affordability, and environmental friendliness. We herein
report a novel ZnI2 and FeCl3 promoted cyclization via a
CÀO bond formation for selective synthesis of substituted
oxazoline and oxazole heterocycles from acetylenic amide.
It is important to note that this is an inexpensive, regiose-
lective, alternative, and efficient approach in a 5-exo-dig
cyclization mode.
The construction of oxaza heterocycles was initiated
with N-Prop-2-ynyl-benzamide 4a as the substrate. We
first examinedthe ability of variousLewisacids topromote
the formation of oxaza heterocycles. When 4a was treated
with stoichiometric CuI, CuCl2, and CuSO4 in CH2Cl2,
there was no significant change in the reaction after 24 h at rt
(Table 1, entries 1À3). To our delight, 4a gave a dimerized
2
CuCl2
CuSO4
CuI
rt
À
À
3
rt
À
À
4c,d
5
rt
À
À
ZnCl2
ZnBr2
ZnI2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
1,2-DCE
1,2-DCE
CH3CN
toluene
THF
rt
75
72
93
À
traceh
traceh
À
6
rt
7
rt
8
FeCl3
À
24
24
24
16
24
16
24
16
24
24
2
rt
40
À
9
130
80
rt
traces
À
10
11
12
13
14
15e
16f
17
18
19
20
21
22
23e
24f
25g
26c
À
À
ZnI2
84
traces
85
68
85
68
À
À
ZnI2
rt
À
ZnI2
rt
À
ZnI2
rt
À
ZnI2
CH2Cl2
CH2Cl2
CH2Cl2
1,2-DCE
THF
rt
À
ZnI2
rt
À
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
45
80
65
80
80
80
80
80
80
80
64
90
À
À
2
À
toluene
CH3CN
1,2-DME
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
2
À
86
66
70
96
87
81
78
24
20
2
À
À
À
3
À
12
12
À
À
a All reactions were carried out in 1 mmol of 4a, 1 equiv of reagent,
and 2 mL of solvent unless otherwise noted. b For optimization, 4a was
isolated and studied. c 10 mol % of reagent. d Dimer of 4a. e 50 mol % of
reagent. f 30 mol % of reagent. g 20 mol % of reagent. h By 1H NMR.
(11) Harmata, M.; Huang, C. Synlett 2008, 1399–1401.
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11446–11450.
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630–636.
product in quantitative yield using 10 mol % of CuI and
DMF as a solvent (entry 4). Further reaction of 4a with
stoichiometric ZnCl2 and ZnBr2 produced the required
compound 5a in 75% and 72% yields respectively at rt
after 12 h (entries 5 and 6). Interestingly, the best yield of
5a was obtained when 1 equiv of ZnI2 was used, and the
reaction was complete within 4 h at rt to give a 93% yield
(entry 7). Surprisingly, we found that 4a on reaction with
stoichiometric anhyd. FeCl3 gave exclusively 6a in 40%
yield after 24 h at rt using CH2Cl2 (entry 8). Various
solvents were screened to examine the feasibilty of the
reaction with ZnI2 (entries 7, 11À14), and we observed
that the reaction proceeded well in CH2Cl2 as solvent
(entry 7). We also examined the reaction with 0.5 and
0.3 equiv of ZnI2 and observed that 0.5 equiv of ZnI2 gave
an 85% yield after 16 h (entries 15 and 16).
(17) (a) Malosh, C. F.; Ready, J. M. J. Am. Chem. Soc. 2004, 126,
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The promising result obtained from FeCl3 (Table 1,
entry 8) inspired us to further investigate the reaction
conditions for a complete conversion of compound 4a.
Org. Lett., Vol. 14, No. 17, 2012
4479

heterocyclic derivatives of oxazolines were obtained in
62%À94% yields (Scheme 2, 5iÀ5p) including derivatives
such as furan, benzofuran, benzothiophene, indole, and
isoxazoles. The reaction of mono- and di-R- substituted
propargyl amides with 0.5 equiv of ZnI2 afforded the
corresponding multisubstituted oxazolines and spirocyclic
compounds in 80%À97% yields (5qÀ5w). The structure of
compound 5m was confirmed by ORTEP (Figure 1).
Scheme 2. ZnI2 Promoted Cyclization Reaction of Propargyl
Amides for the Synthesis of Oxazolinesa
Scheme 3. FeCl3 Promoted Cyclization Reaction of Propargyl
Amides for the Synthesis of Oxazolesa
a All reactions were carried out in 1 mmol of acid chlorides, amine
(1.2 equiv), Et3N (2.0 equiv), and CH2Cl2 (5 mL), 2À12 h at rt, and then
ZnI2 (1 equiv) in CH2Cl2 (5 mL) unless otherwise noted. b Reactions
were carried out using 50 mol % of ZnI2. c Procedure for compound 5c
in the Supporting Information.d Reaction performed at 45 °C.
a All reactions were carried out in 1 mmol of acid chlorides, amine
(1.2 equiv), Et3N (2.0 equiv), and CH2Cl2 (5 mL), 2À12 h at rt, and then
FeCl3(50 mol %) in 1,2-DCE (5 mL) at 80 °C, 3À8 h, unless otherwise
noted. b Reactions were carried out with 30 mol % of FeCl3. c Procedure for
compound 8i in the Supporting Information. d Reaction conversion by GC.
The reaction of 4a with FeCl3 under various solvent
conditions such as CH2Cl2, 1,2-DCE, THF, toluene, ace-
tonitrile, and 1,2-DME (entries 17À22) revealed 1,2-DCE
tobe the best solvent (entry 18). Then, the amount of FeCl3
was varied (Table 1, entries 23À26). The results showed
0.5 equiv in 1,2-DCE at 80 °C (entry 23) to be the optimum
conditions.
Under the optimized reaction conditions, the reaction
scope of various propargyl amides with a variety of sub-
stituents were investigated for the formation of oxazolines.
As shown in Scheme 2, a series of substituents on N-Prop-
2-ynyl-benzamide including p-Me, o-NH2, m-MeO, o-Br,
p-F, and p-CF3 were tolerated and the corresponding
oxazolines were obtained in 81%À90% yields (Scheme 2,
5bÀg). Propargyl amides with an electron-donating group
on the ortho-, meta-, or para-position (5bÀd) gave slightly
higher yields than those of an electron-withdrawing group
on the corresponding positions (5eÀ5g). The reaction
worked well with a multisubstituted alkynyl amide to give
a 90% yield (5h). In contrast, a variety of aliphatic and
From the optimized conditions for oxazole, the reaction
scopes of various propargyl amides with a variety of
substituents were investigated. As shown in Scheme 3, a
series of substituents on N-Prop-2-ynyl-benzamide (4a)
including p-Me, o-Br, and p-CF3 were tolerated and
corresponding oxazoles were obtained in excellent yields
(Scheme 3, 6b, 6e, and 6g). The reaction of a mono-, di-,
and trimethoxy derivative gave the required compound in
good yields (6d, 8a, and 8b). The presence of a nitro group
at the meta- position gave a higher yield than at the para-
position (8c and 8d). The reaction of acryl amide deriva-
tives gave the desired compounds 6j and 8e in 88% and
90% yields. Multisubstituents such as 2-Cl-4-NO2 and
3-MeO-4-OH also produced the corresponding oxazole
derivatives with good yields of 87% and 90% (8g and 8h).
The reaction of o-NHMe gave the required compound,
albeit in low yield (8i). The reaction of aliphatic propargyl
4480
Org. Lett., Vol. 14, No. 17, 2012

amides underwent smooth conversion to produce oxa-
zoles in excellent yields (Scheme 3, 6i, 8f, and 8j). Attempts
were made on various heterocyclic derivatives such as
furan, benzofuran, benzothiophene, indole, and isoxazoles,
which delightfully gave the desired compounds with good
yields of 70%À90%. Finally, to explore the formation of a
2,4,5-trisubstituted oxazole derivative, R-substituted pro-
pargyl amides were employed under the standard condi-
tions and the reaction gave the required oxazoles in good
yields (Scheme 3, 6w, 8k). In general, the electron-donating
and -withdrawing groups do not effect product formation
under these conditions. The UV absorption of some
oxazole compounds was in the 300À400 nm region de-
pending on the conjugation ability. Compound 6j in SI
Table 1, entry 1 (see Supporting Information) showed a
maximum absorption at 312 nm, excitation at 340 nm, and
emission at 374 nm. The emission spectra of bis hetero-
cyclic compounds (6l, 6m, and 6n) were in the 345À360 nm
range. The structure of compound 6n was confirmed by
ORTEP19 (Figure 1).
Scheme 5. One Pot Synthesis of Oxazolines and Oxazoles
Scheme 4. A Plausible Reaction Mechanism for the Formation
of Oxazoline (A) and Oxazoles (B)
Figure 1. ORTEP for compounds 5m and 6n.
the addition of ZnI2 and FeCl3 producing the target
compounds 5a and 6a in moderate yields (Scheme 5).
In conclusion, we have developed the first example of a
ZnI2 and FeCl3 promoted cyclization of acetylenic amides
to selectively achieve oxazolines and oxazoles via a CÀO
bond formation. The present Lewis acid promoted cycliza-
tion is a practical route for oxazaheterocycles. On the basis
ofthe results obtained, several featuresshould benoted: (1)
an inexpensive, regioselective, alternative, and efficient
approach in a 5-exo-dig cyclization mode is used; (2) the
feasibility of reaction was studied with a wide range of
functionality in good to excellent yields; (3) the feasibility
of one pot synthesis via sequential addition gave the
desired oxazolines and oxazoles in moderate yield; (4) no
special precautions were required such as N2 or argon to
carry out the reaction, and this approach could find
applicability in further cyclization leading to the formation
of new heterocycles; and (5) the Lewis acid used here is
abundant, affordable, and environmentally benign.
A plausible mechanism as outlined in Scheme 4 was
proposed for the formation of oxazolines (A) and oxazoles
(B) on the basis of the results obtained. Initial coordination
of ZnI2 to the triple bond of 4 enhances the electrophilicity
of alkyne I. The amido-imido tautomerization of inter-
mediate I followed by regioselective intramolecular 5-exo-
dig cyclization via II gave the vinyl zinc intermediate III
which, on hydrolysis with HI generated in situ, resulted in
desired compound 5. In mechanism B, presumably, iron
acts as a Lewis acid that promotes the tautomerization of
compound 4 via IV followed by 5-exo-dig cyclization to
produce intermediate V. An internal proton transfer from
intermediate V resulted in the formation of the required
oxazole derivative 6.
Acknowledgment. We gratefully acknowledge funding
from the National Science Council of the Republic of
China and the KMU Center of Excellence for Environ-
mental Medicine.
To check the feasibility of the reaction in a one pot
sequential addition, we examined substrate 2a with pro-
pargyl amine in CH2Cl2 and 1,2-DCE as the solvent with
Et3N as the base to obtain the intermediate 4a, followed by
Supporting Information Available. Experimental pro-
cedures, compound characterization, and crystallographic
information. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) CCDC number for compounds 5m, 6n, and 8b are CCDC
890290, CCDC 890289, and CCDC 890288.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
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