FeBr3-Catalyzed Tandem Reaction of N -Propargylamides with Disulfides or Diselenides for the Synthesis of Oxazole Derivatives

Article abstract of DOI:10.1055/s-0035-1561202

A methodology of FeBr₃-catalyzed tandem reaction of N-propargylamides with disulfides or diselenides for the formation of oxazole derivatives has been developed. The strategy includes several steps in one pot. Series of N-propargylamides and disulfides were suitable as substrates in this transformation for synthesizing the corresponding oxazole derivatives in moderate to good yields.

Full text of DOI:10.1055/s-0035-1561202

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
X.-H. Gao et al.
Letter
Synlett
FeBr3-Catalyzed Tandem Reaction of N-Propargylamides with Di-
sulfides or Diselenides for the Synthesis of Oxazole Derivatives
Xu-Hong Gao
O
R2
FeBr3 (10 mol%)
I2 (4 equiv)
O
X
R1
Peng-Cheng Qian
Xing-Guo Zhang
Chen-Liang Deng*
X
R2
R1
N
+
R2
X
H
N
MeCN (anhydrous, 2 mL)
100 °C, air
21 examples
23–82% yield
R1, R2 = alkyl, aryl
X = S, Se
College of Chemistry and Materials Engineering,
Wenzhou University, Wenzhou 325035,
P. R. of China
dcl78@wzu.edu.cn
Received: 09.11.2015
Accepted after revision: 12.12.2015
Published online: 05.01.2016
reaction of N-(propargyl)benzamide with disulfides to pro-
duce oxazoles. It is worth noting that the protocol is suit-
able for the construction of selenium-containing oxazoles
(Scheme 1).
DOI: 10.1055/s-0035-1561202; Art ID: st-2015-w0881-l
Abstract A methodology of FeBr3-catalyzed tandem reaction of N-
propargylamides with disulfides or diselenides for the formation of ox-
azole derivatives has been developed. The strategy includes several
steps in one pot. Series of N-propargylamides and disulfides were suit-
able as substrates in this transformation for synthesizing the corre-
sponding oxazole derivatives in moderate to good yields.
FeBr3 (10 mol%)
I2 (4 equiv)
O
R2
O
X
R1
X
R2
+
R1
N
R2
X
H
N
MeCN
(anhydrous, 2 mL)
100 °C, air
X = S, Se
Key words FeBr3, tandem, N-propargylamides, disulfides, oxazole
Scheme 1 FeBr3-Catalyzed tandem reaction for the synthesis of oxaz-
ole derivatives
Oxazole are widely used N,O-containing heterocyclic
compounds,1 which represent an important structural skel-
eton found in numerous natural products with biological
and pharmaceutical activities such as antitumor, antibacte-
rial, antiviral, and antifungal agents.2 Methods for the direct
synthesis of oxazole rings with different starting materials
have been fully developed because of this widespread pres-
ence.3 Among these, transition-metal-catalyzed tandem re-
action of N-(propargyl)benzamide to oxazoles emerged as
an alternative strategy and has attracted much attention.
For example, gold-,4 palladium-,5 tin-,6 zinc-,7 tungsten-,8
and ruthenium9-catalyzed cyclization of propargylamides
for the formation of oxazoles has been reported. However,
some of the above-mentioned protocols suffer from one or
more limitations such as expensive catalysts, hazardous re-
agents, prolonged reaction time, or harsh reaction condi-
tions. The development of a mild, environmentally benign,
and cheaper method is still an immense work. Over the
past decades, the use of iron-based catalysts to promote a
range of organic reactions have widely been described for
their abundance, cheaper costs, and environmentally be-
nign characteristics.7a,10 However, iron-catalyzed transfor-
mation for the synthesis of oxazoles is rarely explored.7a
Herein, we report our research regarding the iron-catalyzed
The reaction of N-(prop-2-yn-1-yl)benzamide (1a) with
1,2-diphenyldisulfane (2a) was selected as a model reaction
to optimize reaction conditions, and the results are sum-
marized in Table 1. We initiated our studies of the treat-
ment of 1a with 2a in the presence of FeCl3 (10 mol%) and I2
(2 equiv) in MeCN (2 mL) at 80 °C for 12 hours under an N2
atmosphere. A 24% yield of 2-phenyl-5-[(phenylthio)meth-
yl]oxazole (3a) was isolated (Table 1, entry 1). In the ab-
sence of I2, only a trace amount of 3a was detected by GC–
MS analysis evidencing that I2 played a critical role in the
transformation (Table 1, entry 2). Consequently, several io-
dine sources such as NIS, Bu4NI, and IPy2BF4 were tested;
however, they were inferior to I2 in terms of yield (Table 1,
entries 3–5). Subsequently, a series of iron salts, including
FeF3, FeBr3, Fe(acac)3, and Fe(OTf)3, were examined. Screen-
ing revealed that all of the iron salts had reactivity for the
tandem reaction, and FeBr3 was more efficient than the
others (Table 1, entries 1 vs. 6–9). For example, the reaction
was carried out successfully when FeF3, FeBr3, Fe(acac)3,
and Fe(OTf)3 were used as catalysts, furnishing the target
product 3a in 39%, 50%, 49%, and 26% yield, respectively.
Various reaction solvents were also investigated (dioxane,
DMSO, toluene, EtOAc, and THF), with MeCN to determine
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
X.-H. Gao et al.
Letter
Synlett
which provided the best result (Table 1, entries 10–14). In-
terestingly, increasing the temperature and loading of I2 en-
hanced the yield of 3a. The reaction performed under three
equivalents of I2 increased the yield of 3a to 60% yield (Table
1, entry 15). The optimum conditions were determined to
be four equivalents of I2 at 100 °C (Table 1, entries 16–18).
tively (Table 2, entries 2–4). The bulky substrates 1f and 1g
reacted well with 2a to form target products in good yield
(Table 2, entries 5 and 6). The heterocyclic substrate 1h was
also suitable for the transformation, achieving the cycliza-
tion product 3h in 61% yield (Table 2, entry 7). It is note-
worthy that alkyl-substituted substrates 1i–k could also be
employed to produce the corresponding products in mod-
erate yields (Table 2, entries 8–10). The effects of disulfides
2b–h were also evaluated under standard conditions, and
they were all suitable substrates for the transformation. For
example, disulfide 2b, with the 2-chlorophenyl group pro-
viding steric hindrance, performed successfully to afford
product 3l in 75% yield (Table 2, entry 11). In addition to 2b,
disulfides 2c–e, which bearing electron-withdrawing
groups (Cl and F) on their phenyl rings, successfully reacted
with 1a to provide the desired product in 77%, 68%, and 62%
yield, respectively (Table 2, entries 12–14). In the case of di-
sulfide 2f, cyclization product 3p was separated in 68%
yield (Table 2, entry 15). Aliphatic disulfides 2g and 2h
were also good substrates for the reaction, leading to target
products in moderate yield (Table 2, entries 16 and 17). In-
terestingly, 1,2-diphenyldiselane 2i was also compatible
with the optimized conditions and reacted with 1a to yield
product 3s in 40% yield (Table 2, entry 18). Another two
diselenides 2j,k reacted with 1a also successfully, albeit in
lower yield (Table 2, entries 19 and 20).
To probe the mechanism of this transformation, a series
of control experiments was performed. First, the treatment
of 1a in the presence of I2 (2 equiv) in MeCN for two hours
was executed. An 85% yield of intermediate A was isolated
(Scheme 2, eq. 1), followed by a reaction with disulfide 2a
under standard reaction conditions to furnish the desired
product 3a in 83% yield (Scheme 2, eq. 2). Subsequently, we
conducted the reaction without the assistance of I2, but
only a trace amount of B was separated (Scheme 2, eq. 3).
Based on the above results and aforementioned litera-
ture,10,11 we proposed a mechanism for the reaction, as out-
lined in Scheme 3. First, iodine combined with the terminal
alkyne of substrate 1a to form complex B, followed by intra-
molecular keto–enol tautomerism. The hydroxyl group at-
tacked the iodinium ion to furnish intermediate A, which
reacted with PhSSPh to produce the target product 3a.
In summary, we have developed a FeBr3-catalyzed tan-
dem reaction of propargylamides with disulfides for the
synthesis of oxazoles.12 Various substrates proceeded well
under optimal reaction conditions to afford the desired
products in moderate to good yields. It is noteworthy that
the protocol successfully converted diselenides into the cor-
responding cyclization product, albeit in lower yield. Fur-
ther studies aimed at expanding the scope of this reaction
are currently under way in our lab.
Table 1 Optimization of Reaction Conditionsa
O
Ph
O
[Fe]/[I]
S
Ph
S
Ph
+
Ph
N
H
Ph
S
solvent
air, 100 °C
N
1a
2a
3a
Entry [Fe] (10 mol%) [I] (2 equiv) Solvent (2 mL) Temp (°C) Yield (%)b
1
2
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeF3
I2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
dioxane
DMSO
toluene
EtOAc
THF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
120
24
trace
20
nr
–
3
NIS
4
Bu4NI
5
IPy2BF4
trace
39
50
49
26
nr
6
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
7
FeBr3
Fe(acac)3
Fe(OTf)3
FeBr3
FeBr3
FeBr3
FeBr3
FeBr3
FeBr3
FeBr3
FeBr3
FeBr3
8
9
10
11
12
13
14
15c
16d
17d
18d
nr
9
29
41
60
68
75
57
MeCN
MeCN
MeCN
MeCN
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Fe] (10 mol%), [I] (2
equiv), solvent (anhydrous, 2 mL), stirring at 100 °C for 12 h.
b Isolated yield.
c I2 (3 equiv) was added.
d I2 (4 equiv) was added.
With the optimized reaction conditions in hand, the
scope of substrates 1 and 2 was explored, and the results
are illustrated in Table 2. Generally, propargylamides 1a–k,
which contain electron-donating groups or electron-with-
drawing groups, proceeded quickly in this cyclization to
give moderate to good yields of products. For example,
treatment of 1b with 2a under standard conditions led to a
78% yield of 3b (Table 2, entry 1). Substrates 1c–e, with
electron-withdrawing groups 4-F, 4-Br, and 4-CN on their
aromatic rings, performed well in the reaction to furnish
corresponding products in 78%, 71%, and 72% yield, respec-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
X.-H. Gao et al.
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Synlett
O
I2 (2 equiv)
O
I
eq 1
eq 2
Ph
Ph
N
Ph
H
MeCN (anhydrous, 2 mL)
100 °C, air
N
1a
A 85%
Ph
O
standard conditions
O
S
I
Ph
S
Ph
Ph
S
N
N
2a
3a 83%
A
O
O
FeBr3 (10 mol%)
O
N
Ph
Ph
N
+
Ph
eq 3
H
MeCN (anhydrous, 2 mL)
100 °C, air
N
1a
C
4a
trace
trace
Scheme 2 Control experiments
PhSSPh
I2
O
Ph
Ph
O
SPh
O
I2
I
O
PhSI
Ph
N
N
N
H
Ph
N
H
1a
+I
3a
A
Fe[II]
Fe[III]
B
I2
Scheme 3 Proposed mechanism
Table 2 FeBr3-Catalyzed Tandem Reaction of 1 with 2a
O
R2
FeBr3 (10 mol%)
I2 (4 equiv)
O
N
X
R1
X
R2
R1
N
H
+
R2
X
MeCN
(anhydrous, 2 mL)
100 °C, air
1
2
3
X = S, Se
Entry
1
R1
R2
X
Product
Yield (%)b
S
N
1b 4-MeC6H4
2a Ph
2a Ph
S
S
3b 78
3c 78
O
S
N
2
3
1c 4-FC6H4
O
F
S
N
1d 4-BrC6H4
2a Ph
S
3d 71
O
Br
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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Table 2 (continued)
Entry
R1
R2
X
Product
Yield (%)b
S
N
4
1e 4-NCC6H4
2a Ph
S
3e 72
3f 82
O
NC
S
S
N
N
O
O
5
1f 3-MeC6H4
2a Ph
S
6
7
1g 2-MeC6H4
2a Ph
2a Ph
S
S
3g 81
3h 61
S
O
1h 2-thiophene
S
N
O
8
9
1i Me
2a Ph
2a Ph
2a Ph
S
S
S
3i 36
3j 43
3k 48
N
S
Bn
O
1j Bn
N
S
O
O
11
10
1k Me(CH2)12
N
S
Cl
11
1a Ph
2b 2-ClC6H4
S
3l 75
N
N
N
S
Cl
O
O
12
13
1a Ph
1a Ph
2c 3-ClC6H4
S
S
3m 77
3n 68
S
S
2d 4-ClC6H4
Cl
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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X.-H. Gao et al.
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Table 2 (continued)
Entry
R1
R2
X
Product
Yield (%)b
14
1a Ph
2e 4-FC6H4
S
3o 62
3p 68
S
S
F
O
O
N
N
15
16
17
18
1a Ph
1a Ph
1a Ph
1a Ph
2f 4-MeC6H4
S
S
O
2g Me
S
3q 52
3r 64
3s 40
N
2h Et
S
S
O
N
Se
N
2i Ph
Se
O
O
O
Se
Se
N
N
Bn
19
20
1a Ph
1a Ph
2j Bn
Se
Se
3t 23
3u 29
2k Me
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), FeBr3 (10 mol%), I2 (4 equiv), MeCN (anhydrous, 2 mL), stirring at 100 °C for 12 h under air atmosphere.
b Isolated yield.
(2) (a) Lindquist, N.; Fenical, W. J. Am. Chem. Soc. 1991, 113, 2303.
Acknowledgment
(b) Garfunkle, J.; Ezzili, C.; Rayl, T. J.; Hochstatter, D. G.; Hwang,
We thank the National Natural Science Foundation of China (Nos.
21102104, 21272177), the Natural Science Foundation of Zhejiang
Province (Nos. LY14B020011), the Foundation of Zhejiang Province
Department of Education (No. Y201327597), and Wenzhou Universi-
ty for their financial support.
I.; Boger, D. L. J. Med. Chem. 2008, 51, 4392.
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Lett. 2014, 16, 5906. (b) Yu, J.; Yang, H.; Fu, H. Adv. Synth. Catal.
2014, 356, 3669. (c) Yu, X.; Xin, X.; Wan, B.; Li, X. J. Org. Chem.
2013, 78, 4895. (d) Hu, Y.; Yi, R.; Wang, C.; Xin, X.; Wu, F.; Wan,
B. J. Org. Chem. 2014, 79, 3052. (e) Bartoli, G.; Cimarelli, C.;
Cipolletti, R.; Diomedi, S.; Giovannini, R.; Mari, M.; Marsili, L.;
Marcantoni, E. Eur. J. Org. Chem. 2012, 630. (f) Kreisberg, J. D.;
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Rhee, Y. M.; Ahn, K. H. Angew. Chem. Int. Ed. 2011, 50, 11446.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561202.
S
u
p
p
ortiInfogrmoaitn
S
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p
ortioInfgrmoaitn
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(12) Typical Procedure
Under air atmosphere, a reaction tube was charged with N-
(prop-2-yn-1-yl)benzamide (1a, 0.2 mmol), diphenyldisulfane
(2a, 0.4 mmol), FeBr3 (10 mol%), I2 (0.8 mmol), and MeCN (2
mL). The vessel was sealed and heated at 100 °C (oil bath tem-
perature) for 12 h and then cooled to room temperature. The
reaction mixture was washed with sat. Na2S2O3 (2 × 15 mL) and
then brine (1 × 15 mL). After the aqueous layer was extracted
with EtOAc, the combined organic layers were dried over anhy-
drous Na2SO4, and evaporated under vacuum. The residue was
purified by flash column chromatography (hexane–EtOAc) to
afford the desired product 3a.
2-Phenyl-5-[(phenylthio)methyl]oxazole (3a)
Yellow solid (40.1 mg, 75% yield); mp 43–44 °C. 1H NMR (500
MHz, CDCl3): δ = 7.87 (dd, J = 5.9, 2.3 Hz, 2 H), 7.33–7.32 (m, 3
H), 7.30–7.28 (m, 2 H), 7.21–7.18 (m, 2 H), 7.16–7.13 (m, 1 H),
6.76 (s, 1 H), 4.03 (s, 2 H). 13C NMR (125 MHz, CDCl3): δ = 161.5,
148.4, 134.5, 131.3, 130.2, 129.0, 128.6, 127.3, 127.3, 126.1,
125.9, 29.7. LRMS (EI, 70 eV): m/z (%) = 267 (5) [M+], 158 (100),
130 (15), 104 (14), 77 (8). ESI-HRMS: m/z calcd for C16H14NOS+
[M + H]+: 268.0791; found: 286.0794.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F