Synthesis of 2,5-Disubstituted Oxazoles from Arylacetylenes and α-Amino Acids through an i 2 /Cu(NO 3) 2 ?3H 2 O-Assisted Domino Sequence

Article abstract of DOI:10.1055/s-0037-1612087

A new strategy has been developed for the synthesis of 2,5-disubstituted oxazoles from easily available arylacetylenes and α-amino acids in the presence of Cu(NO ₃) ₂ ?3H ₂ O and iodine. This reaction process involves the I ₂ /Cu(NO ₃) ₂ ?3H ₂ O-assisted transformation of arylacetylene to α-iodo acetophenone, Kornblum oxidation to phenylglyoxal, condensation to imine, decarboxylation/annulation/oxidation reaction sequence to approach 2,5-disubstituted oxazoles.

Full text of DOI:10.1055/s-0037-1612087

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
J. Wang et al.
Letter
Synlett
Synthesis of 2,5-Disubstituted Oxazoles from Arylacetylenes and
α-Amino Acids through an I2/Cu(NO3)2•3H2O-Assisted Domino
Sequence
Jungang Wanga
Yan Chengb
Jiachen Xiangb
Anxin Wu*b
N
HOOC
Cu(NO3)2•3H2O
I2, O2
Ar
R
+
R
O
Ar
H2N
R = alkyl or aryl
20 examples
66–83% yield
natural a-amino acids
a School of Chemical Engineering, Guizhou Minzu University,
Guiyang 550025, P. R. of China
b Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal Uni-
versity, Wuhan 430079, P. R. of China
chwuax@mail.ccnu.edu.cn
Received: 17.12.2018
Accepted after revision: 07.01.2019
Published online: 07.02.2019
attention (Scheme 1). More recently, amino acids acting as
a sort of environmentally friendly starting materials
aroused the interest of many chemists, because a very effi-
cient synthetic method for heterocycles was provided.21 To
the best of our knowledge, currently not a single method
has been reported for the synthesis of oxazoles from
DOI: 10.1055/s-0037-1612087; Art ID: st-2018-u0814-l
Abstract A new strategy has been developed for the synthesis of 2,5-
disubstituted oxazoles from easily available arylacetylenes and α-amino
acids in the presence of Cu(NO3)2•3H2O and iodine. This reaction
process involves the I2/Cu(NO3)2•3H2O-assisted transformation of
arylacetylene to α-iodo acetophenone, Kornblum oxidation to phenyl-
glyoxal, condensation to imine, decarboxylation/annulation/oxidation
reaction sequence to approach 2,5-disubstituted oxazoles.
Previous work
O
R
Ar
cat. [Cu], O2
(a)
(b)
(c)
R
R
Ar
+
H2N
N
R
Key words oxazoles, α-amino acids, copper catalysis, cascade reac-
tions, alkynes
O
O
R1
R3
HO
PTSA
H2N
R2
+
+
N
R3
R1
R2
Substituted oxazoles have wide applications in many
pharmacologically active synthetic molecules and natural
products,1 such as tumor-inhibitor peptide laboradorin
1-2,2 alkaloid (–)-muscoride A,3 antibacterial inhibitor pim-
prinols A–C,4 antidiabetic agent AD-5061,5 anti-inflamma-
tory drugs aristoxazole,6 oxaprozin,7 and JTE-522.8 They are
also widely used as synthetic intermediates in organic syn-
thesis and important ligands for transition-metal catalysis.9
Therefore, substantial effort has been devoted to the devel-
opment of methodologies for the synthesis of these privi-
leged structural motifs. A variety of methods have been
reported, including metal/halogen-promoted intramolecu-
lar10 or intermolecular11 cyclization of acyclic precursors,
transition-metal-catalyzed bimolecular annulation,12 oxi-
dation of oxazolines,13 the C–C coupling of prefunctional-
ized oxazoles with various organometallic reagents,14 and
other elegant protocols recently reported.15 Among them,
the cyclization of alkynes and nitrogenous compounds such
as the heterocyclization of alkynes with benzyl amine,16
amides,17 nitrides,18 acyl azide,19 nitrides and intramolecu-
lar cyclization of alkynyl amides20 attracted the chemists’
cat. [ArI]
mCPBA
O
R1
R3
R1
R2/H
N
R3
N
R2/H
R2
R2
O
[Cu]
R1
O
+
N
O
N
+
N3
(d)
(e)
R2
R1
R1
R1
R
O
PhIO, I2
N
HN
R
I
O
This work
Ar
N
HOOC
H2N
Cu(NO3)2•3H2O
I2, O2
R
R
+
O
Ar
Scheme 1 Synthesis of substituted oxazoles from alkynes and nitro-
genous compounds
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

B
J. Wang et al.
Letter
Synlett
alkynes and amino acids. Enlightened by the reported
results, we tried to synthesize 2,5-disubstituted oxazoles
from arylacetylene and α-amino acids.
Table 1 Reaction Optimizationa
Cu(NO3)2•3H2O
I2, DMSO
COOH
+
N
Initially, our investigation focused on the favorable con-
ditions of the reaction to synthesize the oxazole derivatives
from phenylacetylene and leucine (2-amino-4-methyl-
pentanoic acid). To our delight, a 2,5-disubstituted oxazole
product 3ac was obtained in 58% yield when phenylacety-
lene (1.0 mmol) and 2-amino-4-methylpentanoic acid (1.0
mmol) were mixed with Cu(NO3)2•3H2O (1.0 mmol) and I2
(1.0 equiv) in DMSO at 60 °C (Table 1, entry 1). Increasing or
reducing the amount of iodine could not raise the yield, and
the reaction could not be carried out without iodine (Table
1, entries 2–4). Different copper salts such as CuSO4, CuBr,
CuO and typical Lewis acids such as ZnCl2, AlCl3 were also
used to analyze the effects of these additives (Table 1,
entries 5–11). The results show that Cu(NO3)2•3H2O was
best for the reaction.
After screening varying amounts of Cu(NO3)2•3H2O, we
found that the yield was highest when the amount was 0.5
equivalents and dropped significantly to 16% in the absence
of Cu(NO3)2•3H2O (Table 1, entries 12, 13, 15, 16). Other
solvents, such as DMF, NMP, DMA, were also tried, but no
better results were obtained (Table 1, entries 17–19). The
effect of the temperature was also considered to optimize
the reaction conditions; it was difficult to perform the reac-
tion at room temperature, whereas a lower yield (relative to
Table 1, entry 13) was obtained at higher temperatures
(Table 1, entries 20–22). After the above experimental opti-
mizations, we found that 1a (1 mmol) could react with 2c
(1 mmol) in the presence of Cu(NO3)2•3H2O (0.5 mmol) and
I2 (1.0 mmol) in DMSO at 60 °C to afford the desired product
in 79% yield after 5 h.
Relying on the successful synthesis of the oxazole 3ac,
we investigated a range of other phenylacetylenes and α-
amino acids as shown in Scheme 2. For example, aromatic
amino acids such as phenylglycine, phenylalanine and ali-
phatic amino acids such as leucine, isoleucine, and valine
reacted smoothly with phenylacetylene to afford the corre-
sponding products in moderate to good yields (Scheme 2,
3aa–ae, 71–79%). Meanwhile, the derivatives of ethyl
phenylacetylene substituted with electron-withdrawing or
electron-donating groups on the phenyl ring also exhibited
good reactivity (Scheme 2, 3ba–fc, 66–83%). Encouraged by
the results of arylacetylenes, we further focused on hetero-
aryl acetylenes. Fortunately, the reactions of substrates
suchas2-ethynylthiophene, 3-ethynylthiophene, 4-ethynyl-
pyridine, and 1-ethynylnaphthalene also took place
smoothly to furnish the desired products in moderate to
good yields (Scheme 2, 3ka–lc, 69–77%).
NH2
O
3ac
1a
2c
Entry Additive
(equiv)
I2
Solvent
Temp
(°C)
Yield
(%)b
(equiv)
1
2
Cu(NO3)2•3H2O (1.0)
Cu(NO3)2•3H2O (1.0)
Cu(NO3)2•3H2O (1.0)
Cu(NO3)2•3H2O (1.0)
CuSO4 (1.0)
1.0
0.5
1.5
0
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
60
58
35
51
<5
23
26
8
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
25
80
100
3
4
5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
6
CuBr (1.0)
7
CuO (1.0)
8
CuBr2 (1.0)
76
62
34
<5
16
79
25
74
42
20
<5
<5
<5
47
71
9
Cu(OAc)2•2H2O (1.0)
ZnCl2 (1.0)
10
11
12
13
14
15
16
17
18
19
20
21
22
AlCl3 (1.0)
–
Cu(NO3)2•3H2O (0.5)
Cu(NO3)2•3H2O (0.5)
Cu(NO3)2•3H2O (0.2)
Cu(NO3)2•3H2O (2.0)
Cu(NO3)2•3H2O (0.5)
Cu(NO3)2•3H2O (0.5)
Cu(NO3)2•3H2O (0.5)
Cu(NO3)2•3H2O (0.5)
Cu(NO3)2•3H2O (0.5)
Cu(NO3)2•3H2O (0.5)
NMP
DMA
DMSO
DMSO
DMSO
a Reaction conditions: 1a (1.0 mmol), 2c (1.0 mmol), additive, I2, and
solvent (4.0 mL) were added to a pressure vessel, and then stirred at 60 °C
for 5 h.
b Isolated yields.
the absence of I2 (Table 1, entry 4), which emphasized the
crucial role of I2 in the transformation. Copper nitrate also
played an important role in promoting the progress of the
reaction (Table 1, entry 12). According to the control exper-
iments, phenylacetylene was stirred under standard condi-
tions to produce α-iodo acetophenone (4a) and phenyl-
glyoxal (5a) in yield of 38% and 23%, respectively, in the
absence of amino acid substrates (Scheme 3, a). When the
phenylacetylene substrate was replaced with α-iodo aceto-
phenone (4a), the desired product 3ac was obtained in 72%
in the presence of Cu(NO3)2•3H2O and in 56% without
Cu(NO3)2•3H2O (Scheme 3, b and c). The reaction of phenyl-
glyoxal (5a) and 2-amino-4-methylpentanoic acid (2c) also
gave the desired product with satisfactory yields both with
(76% yield) and without (74% yield) Cu(NO3)2•3H2O (Scheme
Having established the scope of the method, we per-
formed the following experiments to gain some insight into
the mechanism of the reaction (Scheme 3). First, it was
found that the reaction was unable to proceed smoothly in
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

C
J. Wang et al.
Letter
Synlett
NH2
R2
N
Cu(NO3)2•3H2O (0.5 equiv)
R2
+
Ar
HOOC
O
Ar
I2 (1.0 equiv), DMSO
60 °C
1
2
3
N
N
O
N
N
O
N
O
Ph
O
O
Ph
3ac
79%
3ad
73%
3aa
77%
3ab
72%
3ae
71%
N
N
N
N
O
N
Ph
O
Ph
Ph
Ph
Ph
O
O
O
3ea
73%
3ca
80%
O
3ba
81%
3da
83%
3fa
81%
N
N
O
N
O
N
N
Ph
Ph
Ph
O
Ph
O
O
F
O
3ha
68%
3ia
73%
3bc
75%
3ga
69%
3ja
72%
Cl
F
N
N
O
N
N
O
N
O
Ph
O
Ph
O
S
3fc
66%
3ka
77%
3lc
71%
S
3kc
72%
O
3la
69%
S
S
Scheme 2 Scope of aryl acetylenes and α-amino acids
O
3, d and e). These results show that 4a and 5a are the cru-
cial intermediates in the process. Hydrated copper nitrate
was irreplaceable in the formation of phenacyl iodine from
phenylacetylene substrate. When the reaction was carried
out under a nitrogen atmosphere, the target product could
still be obtained in a yield of 53% (Scheme 3, f). This sug-
gests that the oxygen atom in the oxazole might not be in-
troduced from oxygen.
On the basis of the results described above and the liter-
ature reports22–25, a plausible mechanism of this transfor-
mation was proposed by taking the reaction of phenylacet-
ylene (1a) and 2-amino-4-methylpentanoic acid (2c) as an
example. The substrate phenylacetylene was converted into
the intermediate α-iodo acetophenone B in the presence of
I2 and Cu(II). Subsequently, B was oxidized by DMSO to
phenylglyoxal C. Then, amino acid 2c reacted with C to af-
ford D, and D isomerized through a [1,5]-H shift, followed
by decarboxylation to obtain intermediate E. Then, the nuc-
leophilic hydroxyl group underwent an intramolecular cy-
clization, and subsequent oxidation gave the desired oxaz-
ole (Scheme 4).
O
O
I
standard conditions
(a)
+
4a (38%)
5a (23%)
1a
N
O
(b)
(c)
I
I
standard conditions
O
COOH
+
3ac (72%)
NH2 2c
4a
N
O
I2 (1.0 equiv),
DMSO, 60 °C
O
COOH
+
3ac (56%)
NH2
2c
4a
N
O
standard conditions
O
O
(d)
COOH
+
3ac (76%)
5a
NH2
2c
O
N
O
I2 (1.0 equiv),
DMSO, 60 °C
(e)
(f)
O
+
COOH
5a
3ac (74%)
NH2
2c
In conclusion, we have developed an I2/Cu(NO3)2•3H2O-
assisted domino reaction for the direct synthesis of 2,5-
disubstituted oxazoles from easily available arylacetylenes
and natural α-amino acids.26 This reaction process involves
the I2/Cu(NO3)2•3H2O-assisted transformation of phenyl-
acetylene to α-iodo acetophenone, Kornblum oxidation to
N
standard conditions
in N2
+
O
COOH
3ac (53%)
1a
NH2
2c
Scheme 3 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

D
J. Wang et al.
Letter
Synlett
phenylglyoxal, condensation to imine, decarboxylation/an-
nulation/oxidation reaction sequence to approach to 2,5-
disubstituted oxazoles.
(5) Momose, Y.; Maekawa, T.; Yamano, T.; Kawada, M.; Odaka, H.;
Ikeda, H.; Sohda, T. J. Med. Chem. 2002, 45, 1518.
(6) Priestap, H. A.; Barbieri, M. A.; Johnson, F. J. Nat. Prod. 2012, 75,
1414.
(7) Todd, P. A.; Brogden, R. N. Drugs 1986, 32, 291.
(8) Hashimoto, H.; Imamura, K.; Haruta, J.-I.; Wakitani, K. J. Med.
Chem. 2002, 45, 1511.
Cu
O
OH
I
I
I
(9) (a) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V.
Chem. Rev. 2013, 113, 3084. (b) Gissibl, A.; Finn, M. G.; Reiser, O.
Org. Lett. 2005, 7, 2325. (c) Atkins, J. M.; Vedejs, E. Org. Lett.
2005, 7, 3351.
HI
I2
B
1a
OH–
DMSO
(10) For selected examples, see: (a) Weng, Y.; Lv, W.; Yu, J.; Ge, B.;
Cheng, G. Org. Lett. 2018, 20, 1853. (b) Hu, Y.; Yi, R.; Wang, C.;
Xin, X.; Wu, F.; Wan, B. J. Org. Chem. 2014, 79, 3052. (c) Wang,
Y.-F.; Chen, H.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134,
11980.
DMS
O
HI
HOOC
HOOC
O
OH
O
NH2
N
N
– CO2
(11) For selected examples, see: (a) Zhou, R.-R.; Cai, Q.; Li, D.-K.;
Zhuang, S.-Y.; Wu, Y.-D.; Wu, A.-X. J. Org. Chem. 2017, 82, 6450.
(b) Xu, Z.; Zhang, C.; Jiao, N. Angew. Chem. Int. Ed. 2012, 51,
11367. (c) Xue, W.-J.; Li, Q.; Zhu, Y.-P.; Wang, J.-G.; Wu, A.-X.
Chem. Commun. 2012, 48, 3485.
(12) For selected examples, see: (a) Zhang, L.; Zhao, X. Org. Lett.
2015, 17, 184. (b) Zheng, J.; Zhang, M.; Huang, L.; Hu, X.; Wu,
W.; Huang, H.; Jiang, H. Chem. Commun. 2014, 50, 3609.
(c) Odabachian, Y.; Tong, S.; Wang, Q.; Wang, M.; Zhu, J. Angew.
Chem. Int. Ed. 2013, 52, 10878.
D
E
C
HI
H
O
O
O
I2
N
N
I
NH
[O]
G
HI
H
F
Scheme 4 Mechanistic proposal
(13) For selected examples, see: (a) Li, X.; Li, C.; Yin, B.; Liu, P.; Li, J.;
Shi, Z.; Li, C. Chem. Asian J. 2013, 8, 1408. (b) Wang, Y.; Li, Z.;
Huang, Y.; Tang, C.; Wu, X.; Xu, J.; Yao, H. Tetrahedron 2011, 67,
7406. (c) Huang, Y.; Ni, L.; Gan, F.; He, Y.; Xu, J.; Wu, X.; Yao, H.
Tetrahedron 2011, 67, 2066.
(14) (a) Zhang, M. L.; Zhang, S. H.; Liu, M. C.; Cheng, J. Chem.
Commun. 2011, 47, 11522. (b) Shen, X.-B.; Zhang, Y.; Chen, W.-X.;
Xiao, Z.-K.; Hu, T.-T.; Shao, L.-X. Org. Lett. 2014, 16, 1984.
(15) (a) Saito, A.; Taniguchi, A.; Kambara, Y.; Hanzawa, Y. Org. Lett.
2013, 15, 2672. (b) Selvi, T.; Srinivasan, K. Chem. Commun. 2014,
50, 10845. (c) Wang, B.; Chen, Y.; Zhou, L.; Wang, J.; Tung, C.-H.;
Xu, Z. J. Org. Chem. 2015, 80, 12718. (d) Zeng, T.-T.; Xuan, J.;
Ding, W.; Wang, K.; Lu, L.-Q.; Xiao, W.-J. Org. Lett. 2015, 17,
4070. (e) Chatterjee, T.; Cho, J. Y.; Cho, E. J. J. Org. Chem. 2016,
81, 6995.
Funding Information
We are grateful to the National Natural Science Foundation of China
(Grants 21772051 and 21472056) and the Natural Science Founda-
tion of Hubei Province (No. 2017CFB355).
N
ati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
7
7
2
0
5
1)Nati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
4
7
2
0
5
6)NaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
H
u
b
e
iPro
v
i
n
c
e
(2
0
1
7
C
F
B
3
5
5)
Acknowledgment
We thank Dr. Chuanqi Zhou, Hebei University, for analytical support.
Supporting Information
(16) Pan, J.; Li, X.; Qiu, X.; Luo, X.; Jiao, N. Org. Lett. 2018, 20, 276.
(17) (a) Han, X. -L.; Zhou, C.-J.; Liu, X.-G.; Zhang, S.-S.; Wang, H.; Li,
Q. Org. Lett. 2017, 19, 6108. (b) Querard, P.; Girard, S. A.; Uhlig,
N.; Li, C.-J. Chem. Sci. 2015, 6, 7332. (c) Wachenfeldt, H. V.; Röse,
P.; Paulsen, F.; Loganathan, N.; Strand, D. Chem. Eur. J. 2013, 19,
7982. (d) Davies, P. W.; Cremonesi, A.; Dumitrescu, L. Angew.
Chem. Int. Ed. 2011, 50, 8931. (e) Bartoli, G.; Cimarelli, C.;
Cipolletti, R.; Diomedi, S.; Giovannini, R.; Mari, M.; Marsili, L.;
Marcantoni, E. Eur. J. Org. Chem. 2012, 630.
(18) (a) Yagyu, T.; Takemoto, Y.; Yoshimura, A.; Zhdankin, V. V.;
Saito, A. Org. Lett. 2017, 19, 2506. (b) Mallick, R.; Prabagar, K. B.;
Sahoo, A. K. J. Org. Chem. 2017, 82, 10583. (c) Yang, W.; Zhang,
R.; Yi, F.; Cai, M. J. Org. Chem. 2017, 82, 5204. (d) Rassadin, V. A.;
Boyarskiy, V. P.; Kukushkin, V. Y. Org. Lett. 2015, 17, 3502.
(e) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482.
(f) Li, X.; Huang, L.; Chen, H.; Wu, W.; Huang, H.; Jiang, H. Chem.
Sci. 2012, 3, 3463.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612087.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
References and Notes
(1) (a) Kibriz, I. E.; Sacmaci, M.; Sahin, E.; Yildirim, I. P. Tetrahedron
2017, 73, 1795. (b) Jin, Z. Nat. Prod. Rep. 2011, 28, 1143. (c) Wan,
C.; Gao, L.; Wang, Q.; Zhang, J.; Wang, Z. Org. Lett. 2010, 12,
3902. (d) Davyt, D.; Serra, G. Mar. Drugs 2010, 8, 2755. (e) Heng,
S.; Gryncel, K. R.; Kantrowitz, E. R. Bioorg. Med. Chem. 2009, 17,
3916. (f) Zhang, J.; Ciufolini, M. A. Org. Lett. 2009, 11, 2389.
(g) Hughes, R. A.; Moody, C. J. Angew. Chem. Int. Ed. 2007, 46,
7930. (h) Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.;
Obach, R. S.; O’Donnell, J. P. Chem. Res. Toxicol. 2002, 15, 269.
(2) Pettit, G. R.; Knight, J. C.; Delbert, L.; Davenport, R.; Pettit, R. K.;
Tucker, B. E.; Schmidt, J. M. J. Nat. Prod. 2002, 65, 1793.
(3) Coqueron, P.-Y.; Didier, C.; Ciufolini, M. A. Angew. Chem. Int. Ed.
2003, 42, 1411.
(19) Cano, I.; Álvarez, E.; Nicasio, M. C. J.; Pérez, P. J. Am. Chem. Soc.
2011, 133, 191.
(20) (a) Ma, J. W.; Wang, Q.; Wang, X. G.; Liang, Y. M. J. Org. Chem.
2018, 83, 13296. (b) Suzuki, S.; Saito, A. J. Org. Chem. 2017, 82,
11859. (c) Asari, N.; Takemoto, Y.; Shinomoto, Y.; Yagyu, T.;
(4) Raju, R.; Gromyko, O.; Fedorenko, V.; Luzhetskyy, A.; Müller, R.
Tetrahedron Lett. 2012, 53, 3009.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E

E
J. Wang et al.
Letter
Synlett
Yoshimura, A.; Zhdankin, V. V.; Saito, A. Asian J. Org. Chem.
2016, 5, 1314. (d) Bay, S.; Baumeister, T.; Hashmi, A. S. K.; Röder,
T. Org. Process Res. Dev. 2016, 20, 1297. (e) Sueda, T.; Kawada,
A.; Urashi, Y.; Teno, N. Org. Lett. 2013, 15, 1560. (f) Hashmi, A. S.
K.; Jaimes, M. C. B.; Schuster, A. M.; Rominger, F. J. Org. Chem.
2012, 77, 6394. (g) Senadi, G. C.; Hu, W.; Hsiao, J.-S.; Vandavasi,
J. K.; Chen, C.-Y.; Wang, J. Org. Lett. 2012, 14, 4478. (h) Hashmi,
A. S. K.; Weyrauch, J. P.; Schuster, A.; Hengst, T.; Schetter, A.;
Littmann, A.; Rudolph, M.; Hamzic, M.; Visus, J.; Rominger, F.;
Frey, W.; Bats, J. W. Chem. Eur. J. 2010, 16, 956.
Wang, M.; Meng, X. G.; Wu, A. Tetrahedron 2014, 70, 7470.
(d) Zhu, Y. P.; Lian, M.; Jia, F. C.; Liu, M. C.; Yuan, J. J.; Gao, Q. H.;
Wu, A. X. Chem. Commun. 2012, 48, 9086. (e) Wu, X.; Gao, Q. H.;
Liu, S.; Wu, A. X. Org. Lett. 2014, 16, 2888.
(24) (a) Viswanadham, K. K. D R.; Reddy, M. P.; Sathyanarayana, P.;
Ravi, O.; Kantc, R.; Reddy, S. B. Chem. Commun. 2014, 50, 13517.
(b) Kalmode, H. P.; Vadagaonkar, K. S.; Chaskar, A. C. Synthesis
2015, 47, 429. (c) Kalmode, H. P.; Vadagaonkar, K. S.; Chaskar, A.
C. RSC Adv. 2014, 4, 60316.
(25) (a) Wan, J. P.; Zhou, Y.; Liu, Y.; Sheng, S. Green Chem. 2016, 18,
402. (b) Cao, S.; Liu, Y.; Hu, C.; Wen, C.; Wan, J. P. ChemCatChem
2018, 10, 5021.
(26) General procedure for synthesis of 3 (3ac as an example)
The mixture of phenylacetylene 1a (1.0 mmol), 2-amino-4-
methylpentanoic 2c (1.0 mmol) was mixed with
Cu(NO3)2•3H2O (0.5 mmol), and I2 (1.0 mmol). The mixture was
heated at 60 °C in 4 mL of DMSO in a sealed vessel for 5 h till
almost completed conversion of the substrates monitored by
TLC analysis. Then 50 mL water was added to the mixture,
which was extracted with EtOAc three times (3 × 50 mL). The
extract was washed with Na2S2O3 solution, dried over anhy-
drous Na2SO4 then the solvent was removed under reduced
pressure. The crude product was purified by column chroma-
tography on silica gel (eluent: petroleum ether/EtOAc = 50/1) to
afford the product 3ac” here
(21) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Schönberg, A.; Moubasher, R. Chem. Rev. 1952, 50, 261.
(c) Domling, A.; Beck, B.; Eichelberger, U.; Sakamuri, S.; Menon,
S.; Chen, Q. Z.; Lu, Y. C.; Wessjohann, L. A. Angew. Chem. Int. Ed.
2006, 45, 7235. (d) Bartoccini, F.; Casoli, M.; Mari, M.; Piersanti,
G. J. Org. Chem. 2014, 79, 3255. (e) Wang, H. Q.; Xu, W. T.; Xin, L.
L.; Liu, W. M.; Wang, Z. Q.; Xu, K. J. Org. Chem. 2016, 81, 3681.
(f) Xiang, J. C.; Cheng, Y.; Wang, Z. X.; Ma, J. T.; Wang, M.; Tang,
B. C.; Wu, Y. D.; Wu, A. X. Org. Lett. 2017, 19, 2997. (g) Xu, W.;
Fu, H. J. Org. Chem. 2011, 76, 3846.
(22) (a) Yan, Y. Z.; Wang, Z. Y. Chem. Commun. 2011, 9513. (b) Xu,
W.; Fu, H. J. Org. Chem. 2011, 76, 3846. (c) Bi, H.-P.; Zhao, L.;
Liang, Y.-M.; Li, C.-J. Angew. Chem. Int. Ed. 2009, 48, 792.
(d) Zhang, C.; Das, D.; Seidel, D. Chem. Sci. 2011, 2, 233.
(23) (a) Xu, W.; Kloeckner, U.; Nachtsheim, B. J. J. Org. Chem. 2013,
78, 6065. (b) Hu, T.; Yan, H.; Liu, X.; Wu, C.; Fan, Y.; Huang, J.;
Huang, G. Synlett 2015, 26, 2866. (c) Xiang, J. C.; Wang, J. G.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–E