Ligand and solvent-free iron catalyzed oxidative alkynylation of azoles with terminal alkynes

Article abstract of DOI:10.1016/j.tetlet.2011.08.083

A highly efficient and versatile iron catalyzed oxidative alkynylation of azoles with terminal alkynes under ligand and solvent-free conditions is described.

Full text of DOI:10.1016/j.tetlet.2011.08.083

Tetrahedron Letters 52 (2011) 5617–5619
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ligand and solvent-free iron catalyzed oxidative alkynylation of azoles
with terminal alkynes
⇑
Sachin S. Patil, Rahul P. Jadhav, Sachin V. Patil, Vivek D. Bobade
Department of Chemistry, HPT Arts and RYK Science College, Nasik 422 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient and versatile iron catalyzed oxidative alkynylation of azoles with terminal alkynes
under ligand and solvent-free conditions is described.
Received 17 May 2011
Revised 10 August 2011
Accepted 14 August 2011
Available online 23 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Oxidative alkynylation
Azoles
Iron
Terminal alkynes
Di-tert-butyl peroxide (DTBP)
An efficient strategy for the direct functionalization of C–H
We herein describe a new procedure15 for the oxidative alkyny-
lation of azoles with terminal alkynes using ferrous chloride as the
1
bonds using transition-metal catalyst has been reported. Mostly
ruthenium, rhodium,3 and palladium-based4 catalysts have been
applied to effect either C–C or C–Het (Het = heteroatom) bond for-
mation by the activation of a C–H bond. A few procedures have
2
2
catalyst and (t-BuO) as the oxidant under solvent and ligand-free
condition (Scheme 1).
5-Methylbenzoxazole 1a and phenylacetylene 2a were chosen
as model substrates in order to optimize the oxidative alkynylation
conditions. The results of the study are summarized in Table 1.
In the initial study of reaction conditions we observed that the
desired product 3a was obtained albeit in a moderate yield when
5
been described that employ iron as a catalyst which is particularly
attractive due to its low cost and low toxicity. In addition, the
application of C–H functionalization of heterocycle has been scarce
until now.
On the other hand, the alkynyl substituted azoles have attracted
more attention in both industrial and academic fields for decades.
The alkynyl substituted azoles act as DNA cleavage agents and
FeCl
(t-BuO)
2
catalyst was used in the presence of di-tert-butyl peroxide
in solvent DMSO at 100 °C for 16 h (Table 1, entry 1). No
2
6
improvement in the yield was observed with change in the solvent
(Table 1, entry 2). We also examined other oxidants such as TBHP
(tert-butyl hydroperoxide 5 M solution in n-hexane) which re-
sulted in a low yield of the product. No reaction was observed
when ceric ammonium nitrate (CAN) and iodobenzene diacetate
(IBD) were employed (Table 1, entries 4 and 5). Other iron species
such as Fe(acac)
yield, respectively, (Table 1, entries 9–11). The best result was ob-
served with a combination of 10% mole of FeCl , 3 mol equiv of (t-
BuO) under solvent-free condition at 100 °C, (Table 1, entry 6) and
atmospheric pressure. By lowering the catalyst loading and molar
azole containing p-conjugated molecules are found in many natu-
7
ral products, pharmaceutical, and functional materials. Owing to
their important applications various synthetic methodologies for
alkynylation of azoles have been reported. Literature methods in-
volved direct alkynylation of azoles with alkynyl bromides in the
8
9
presence of catalysts Ni and Pd and their efficiency was observed
2 3 3
, FeCl , Fe(acac) gave 3a in 20%, 70%, and 63%
2
to be dependent on the ease of C(sp )–H bond activation. Recently
literature survey revealed that terminal alkynes can be coupled
2
1
0
11
with azoles under oxidative catalytic conditions using Au, Cu,
2
1
2
13
Ni, and Pd catalytic systems. However, these catalysts are de-
rived from heavy or rare metals and their toxicity and prohibitive
prices constitute severe drawbacks for their applications. In con-
trast, iron being the most abundant metal on earth, and does not
require coordination with expensive or/and toxic ligands, it was
chosen as the catalyst.14
R
R
N
Z
N
Z
FeCl2 10% mol
H
R1
R1
H
(t-BuO)
2
, air
o
100 C
1
a
2a
3a
⇑
Corresponding author.
E-mail address: v_bobade31@rediffmail.com (V.D. Bobade).
Scheme 1. Oxidative alkynylation of azoles with terminal alkynes.
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.083

5
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S. S. Patil et al. / Tetrahedron Letters 52 (2011) 5617–5619
Table 1
FeIII OBut
O-But
Optimization of reaction conditions
t-(BuO)2
Entry
Catalyst
% mol)
Oxidant
(mol equiv)
Solvent
Temp (°C)
Yielda (%)
(
H
R
N
Z
1
2
3
4
5
6
7
8
9
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
2
2
2
2
2
2
2
2
(10)
(10)
(10)
(10)
(10)
(10)
(5)
(t-BuO)
(t-BuO)
TBHP (2)
CAN (2)
IBD (2)
2
(2)
(2)
DMSO
EDC
80
80
80
80
51
37
40
0
R
H
FeII
2
DMSO
DMSO
DMSO
FeIII OBu-t
R
80
0
b
tBuOH
(t-BuO)
(t-BuO)
(t-BuO)
(t-BuO)
(t-BuO)
(t-BuO)
2
2
2
2
2
2
(3)
(3)
(2)
(3)
(3)
(3)
__
100
100
100
100
100
100
85
43
68
20
70
63
H
__
__
__
__
__
(10)
N
Z
R
Fe(acac)
FeCl (10)
Fe(acac)
2
(10)
tBuOH
+
Product
1
1
0
1
3
3
Scheme 2. A proposed mechanism for the alkynylation of azole.
a
Yield is based on 1a.
b
‘
‘—’’, indicate reaction carried out without solvent.
2
using (t-BuO) as the oxidant, under solvent, base and ligand-free
conditions. This methodology is beneficial from the economical
point of view.
Table 2
Iron catalyzed alkynylation of azoles
Entry
Z
R
R1
Yielda Time (h) mp/bp (°C) (lit.)b
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
Me
C
6
H
5
85
52
64
50
90
88
63
65
67
72
75
66
84
81
88
86
16
20
16
16
16
16
20
20
16
16
20
20
16
16
16
16
102–104 (103–104)13
156–158 (157–158)9
165–167 (166–167)1
Acknowledgment
Me 4-CF
Me 4-Cl-C
Me 4-F-C
H
H
H
3
-C
6
H
4
3
6
H
4
The author thanks UGC, New Delhi, India, for the financial
support.
13
6
H
4
118–119 (117–118)
9
4-MeO-C
C H
6 5
1-Napthyl
4
H
4
120–123(122–123)
101–102 (100)8
8
116–118 (119)
1
3
References and notes
Me 1-Napthyl
104–106 (104–105)
1
8
3
Me n-C
n-C
6
H
H
13
oil bp <250
oil bp <250
H
6
13
1. For recent reviews of CH functionalization using transition metals, see: (a)
Alberico, D.; Scott, E. M.; Lautens, M. Chem. Rev. 2007, 107, 174; (b) Godula, K.;
Sames, D. Science 2006, 312, 67; (c) Kakiuchi, F.; Chatani, N. Adv. Synth. Catal.
2003, 345, 1077; (d) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. Rev. 2002, 102, 1731.
2. For selected examples, see: (a) Matsuura, Y.; Tamura, M.; Kochi, T.; Sato, M.;
Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858; (b) Murphy, J. M.;
Lawrence, J. D.; Kawamura, K.; Incarvito, C.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
1
3
Me Thiophene
Me Pyridyl
Me Si(i-Pr
H
H
H
93–94 (93–94)
1
3
112–114 (113–115)
1
1
1
2
2
2
3
3
3
)
)
)
oil bp <250
oil bp <250
oil bp <300
Si(i-Pr
Si(i-Pr
C
8
S
H
6 5
72–75 (75)
1
28, 13684; (c) Ackermann, L.; Althammer, A.; Born, R. Angew. Chem., Int. Ed.
a
2006, 45, 2169.
Yield is based on compound 1.
b
3. (a) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J. Am. Chem.
Soc. 2007, 129, 7500; (b) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem.
Soc. 2007, 129, 5332; (c) Williams, K.; Fiori, DuBois. J. J. Am. Chem. Soc. 2007,
(
Lit) compound have been previously reported; physical and spectral data were
comparable.
1
29, 562; (d) Ravisekhara, P. R.; Davies, H. M. L. Org. Lett. 2006, 8, 5013.
4.
For selected examples, see: (a) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am.
Chem. Soc. 2007, 129, 12072; (b) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007,
2
ratio of (t-BuO) the yield was found to be low (Table 1, entries 7
and 8). We explored the scope of this reaction with optimized reac-
tion conditions and the results are summarized in Table 2.
1
(
2
29, 11904; (c) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 6066;
d) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett. 2007, 9,
931; (e) Delcamp, J. H.; White, M. C. J. Am. Chem. Soc. 2006, 128, 15076.
It was found that phenylacetylene bearing a wide range of sub-
stituents undergoes an oxidative coupling reaction with 1 to afford
the desired products in a good yield (Table 2, entries 3a–3h). The
reaction of phenylacetylene bearing an electron donating group
provides a higher yield (Table 2, entry 3e) while the electron with-
drawing substituents resulted in lower yield of the products due to
dimerization of the alkynes. The sterically hindered 1-naphthyl-
acetylene also reacted under optimized conditions (Table 2, entries
5. (a) Guo, X.; Yu, R.; Li, H.; Li, H. J. Am. Chem. Soc. 2009, 131, 17387; (b) Li, H.; He,
Z.; Guo, X.; Li, W.; Zhao, X.; Li, Z. Org. Lett. 2009, 11, 4176; (c) Pan, S.; Liu, J.; Li,
H.; Wang, Z.; Guo, X.; Li, Z. Org. Lett. 2010, 12, 1932; (d) Guo, I.; Pan, S.; Liu, J.; Li,
Z. J. Org. Chem. 2009, 74, 8848; (e) Guan, Z. H.; Yan, Z. Y.; Ren, Z. H.; Liu, X. Y.;
Liang, M. Y. Chem. Commun. 2010, 46, 2823; (f) Rao, C. M.; Volla, Vogel. P. Org.
Lett. 2009, 11, 1701; (g) Shirakawa, E.; Uchiyama, N.; Hayashi, T. J. Org. Chem.
2011, 76, 25.
6
. Kumar, D.; David, W. M.; Kerwin, S. M. Bioorg. Med. Chem. Lett. 2001, 11, 2971.
7. (a) Hassan, J.; S e´ vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002,
102, 1359; (b) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
8
9
.
.
Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11, 4156.
Kim, S. H.; Chang, S. Org. Lett. 2010, 12, 1868.
3
g and 3h).The silylethylnyl group could also be readily functional-
ized to benzoxazole and benzothiazole core (Table 2, entries 3n
and 3o). The aliphatic terminal alkynes also participated in this
coupling reaction. (Table 2, entries 3i and 3j). The alkynylation of
1
0. Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512.
11. Wei, Y.; Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc. 2010, 132, 2522.
1
2. Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12,
358.
3. Hwan, S.; Yoon, K. J.; Chan, S. Org. Lett. 2011, 13, 1474.
2
1
with heterocyclic acetylene with high efficiency provided good
1
yield of the product (Table 2, entries 3k and 3l).
14. (a) Fürstner, A.; Martin, R.; Krause, H.; Seidel, G.; Goddard, R.; Lehmann, C. W. J.
Am. Chem. Soc. 2008, 130, 8773. and references therein; (b) Sherry, B. D.;
Fürstner, A. Acc. Chem. Res. 2008, 41, 1500; (c) Plietker, B. Iron Catalysis in
Organic Chemistry; Wiley-VCH: Weinheim, 2008; (d) Bauer, E. B. Curr. Org.
Chem. 2008, 12, 1341; (e) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura,
E. J. Am. Chem. Soc. 2008, 130, 5858; (f) Enthaler, S.; Junge, K.; Beller, M. Angew.
Chem., Int. Ed. 2008, 47, 3317; (g) Carril, M.; Correa, A.; Bolm, C. Angew. Chem.,
Int. Ed. 2008, 47, 4862; (h) Volla, C. M. R.; Vogel, P. Angew. Chem., Int. Ed. 2008,
47, 1305; (i) Loska, R.; Volla, C. M. R. Adv. Synth. Catal. 2008, 350, 2859; (j)
Reymond, S.; Ferri e´ , L.; Guerinot, A.; Capdevielle, P.; Cossy, J. Pure Appl. Chem.
Although more comprehensive studies are required to describe
the mechanistic details, a plausible pathway of the alkynylation of
azole is shown in Scheme 2. It is postulated that an initial reaction
III
t
2
of t-butyl peroxide with FeCl generates Fe –O Bu and t-butyl rad-
ical. The deprotonation of an azole C(2)–H bond takes place by the
action of t-butoxy radical leading to an azole radical that subse-
quently reacts with an in situ generated iron acetylide complex
to give the 2-alkynylazole product and Fe(II) species.
In summary, we have described an effective iron catalyst sys-
tem for the direct alkynylation of azoles with terminal alkynes
2008, 80, 1683; (k) Volla, C. M. R.; Vogel, P. Tetrahedron Lett. 2008, 49, 5961.
1
5. General procedure for the iron-catalyzed oxidative alkynylation of azoles
FeCl2 (0.1 mmol), benzoxazole (1 mmol), terminal alkyne (1.2 mmol) and tert-
butyl peroxide (3 mmol) were placed in a tube. The tube was purged with air

S. S. Patil et al. / Tetrahedron Letters 52 (2011) 5617–5619
5619
and then sealed with a cap under a positive pressure of air. The reaction
mixture was stirred at 100 °C for the time mentioned in Table 2. After the
completion of the reaction it was cooled to room temperature and diluted with
dichloromethane (30 mL) and filtered through a pad of celite. The filtrate was
concentrated under reduced pressure (rotavaporator). The residue was purified
by flash chromatography on silica gel mesh size 60–120 (hexane/EtOAc, 97:3)
as an eluent to give the desired product.