Nickel-catalyzed C-H alkenylation and alkylation of 1,3,4-oxadiazoles with alkynes and styrenes

Article abstract of DOI:10.1021/jo901350j

(Chemical Equation Presented) The addition reaction of 1,3,4-oxadiazoles to alkynes via C-H bond cleavage efficiently proceeds in the presence of a nickel catalyst. This direct coupling allows a facile access to alkenyl-substituted oxadiazoles. The reaction with styrenes in place of alkynes is also available to selectively afford the corresponding branched adducts.

Full text of DOI:10.1021/jo901350j

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SCHEME 1. Rhodium-Catalyzed Alkenylation of 2-Phenyl-1,3,4-
oxadiazole (1a) with Triisopropylsilylacetylene (2h)
Nickel-Catalyzed C-H Alkenylation and Alkylation
of 1,3,4-Oxadiazoles with Alkynes and Styrenes
Tomoya Mukai, Koji Hirano, Tetsuya Satoh, and
Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan
rapid and concise synthesis and modification of the oxadiazole
motif is of considerable importance in organic synthesis.
Recent advances in the transition metal-mediated direct
functionalization of C-H bonds have had a significant impact
on the various fields in synthetic chemistry.4 In particular, since
the pioneering work of Murai and co-workers,5 a variety of
catalytic systems have been explored for the direct alkenylation
as well as alkylation of aromatic and heteroaromatic substrates
with alkynes as well as alkenes via oxidative addition of their
C-H bonds.6 Herein, we report the nickel-catalyzed C-H
alkenylation of 1,3,4-oxadiazoles with alkynes. The reaction
provides an efficient approach to a variety of alkenyl-substituted
oxadiazoles;high-yielding synthetic methods for which have
so far been limited to selenium-mediated processes.7 Moreover,
the alkylation reaction with styrenes is also disclosed.8
Recently, we reported the rhodium-catalyzed and coordi-
nation-assisted direct ortho-alkenylation of N-heterocycle-
substituted arenes with terminal silylacetylenes such as trii-
sopropylsilylacetylene.9 We applied the rhodium-based cat-
alyst system to the reaction using 2-phenyl-1,3,4-oxadiazole
(1a) and found that the alkenylation proceeded at the
5-position rather than the expected 20-position proximal to
the 3-nitrogen to afford the corresponding adduct 3ah in
good yield (Scheme 1). However, the reaction with other
terminal and internal alkynes was unsuccessful.
miura@chem.eng.osaka-u.ac.jp
Received June 25, 2009
The addition reaction of 1,3,4-oxadiazoles to alkynes via
C-H bond cleavage efficiently proceeds in the presence
of a nickel catalyst. This direct coupling allows a facile
access to alkenyl-substituted oxadiazoles. The reaction
with styrenes in place of alkynes is also available to
selectively afford the corresponding branched adducts.
Various aryl-substituted aromatic heterocycles are known to
exhibit interesting biological activities and are also useful as
π-conjugated organic materials.1 1,3,4-Oxadiazole is apparently
among the most significant heterocycle cores. Thus, 1,3,4-
oxadizole derivatives may act as ester and amide bioisosteres
and, hence, are of interest in pharmaceutical and agrochemical
fields.2 Also, much attention has been focused on the oxadiazole
core π-systems as electron-transporting and hole-blocking ma-
terials in the area of organic light-emitting diodes (OLEDs).2c,3
Consequently, the development of effective methods for the
We then turned our attention to the potential of nickel
catalysts. Cavell reported the nickel-catalyzed addition of
the acidic C-H bond at the 2-position of imidazolium salts
to alkenes.10 Nakao and Hiyama also described the efficient
alkenylation and alkylation of the relatively acidic sp2 C-H
bond of heteroarenes and fluoroarenes under nickel cataly-
sis.11 Given the high acidity of the C-H bond at the
5-position of 1a,12 its effective activation by nickel complexes
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6410 J. Org. Chem. 2009, 74, 6410–6413
Published on Web 07/24/2009
DOI: 10.1021/jo901350j
r
2009 American Chemical Society

Mukai et al.
JOCNote
some extent (entry 3). While the electron-rich 2d and 2e showed
lower reactivity (entries 4 and 5), the use of the electron-
deficient 2f quantitatively afforded 3af (entry 6). The unsym-
metrical internal alkyne 2g could couple with 1a to give
alkenylated oxadiazole 3ag exclusively, in which the oxadia-
zole core was connected selectively to the benzylic position
(entry 7). In this case, the use of PPh3 in place of PCy3 gave a
better result (ca. 20% with PCy3). In addition, the terminal
alkyne, triisopropylsilylacetylene (2h), could participate in the
reaction (entry 8). However, other terminal alkynes including
1-octyne and phenylacetylene could not be employed.
Next, we examined the substituent effects of the 2-position
of oxadiazole (Table 2). The oxadiazoles bearing 4-methyl-
phenyl and 1-naphthyl groups as well as the simple phenyl
one underwent alkenylation on treatment with diarylacety-
lenes to produce 3bd and 3dd in 61% and 63% yields,
respectively. Notably, 3bd was obtained essentially as the
single stereoisomer. On the other hand, the reactions with
4-methoxyphenyl- and phenethyl-substituted 1c and 1e gave
3cc and 3ef with moderate yields.
TABLE 1. Nickel-Catalyzed Reaction of 2-Phenyl-1,3,4-oxadiazole (1a)
with Alkynes 2a
Subsequently, we attempted the alkylation of 2-phenyl-
1,3,4-oxadiazole (1a) with styrene (4a). It was of considerable
interest that the reaction led to the exclusive formation of
branched compound 5aa, and no corresponding linear isomer
was detected while the yield was only 17% (Table 3, entry 1).
The observed regioselectivity was in marked contrast to that
in the relevant rhodium- and ruthenium-catalyzed processes,
where linear couplings usually predominate.4 Therefore, an
optimization study was performed by using a series of phos-
phine ligands. Change of PCy3 to PPh3 improved the yield to
40% with maintenance of the unique regioselectivity (entry 2).
Other monodentate triarylphosphines such as P(4-MeOC6H4)3
and P(4-FC6H4)3 resulted in similar yields (entries 3 and 4). To
our delight, use of xantphos was found to dramatically increase
the yield (entries 5 and 6). Considering the observed lower
efficiency of dppe and dppf (entries 7 and 8), the uniquely large
bite angle of xantphos would play an important role in the
catalytic cycle.
With the modified conditions in hand, the reaction of 1a
with a number of styrene derivatives was conducted
(Table 4). Not only styrenes having an electron-donating
substituent but also those with an electron-withdrawing
substituent took part in the reaction to afford the cor-
responding coupled products in good to high yields
(entries 2-4). Moreover, ester function was compatible
under the reaction conditions although a prolonged reaction
period was required for completion of the reaction (entry 5).
Simple aliphatic alkenes and acrylate esters could not be used
in the present reaction. The starting materials were recovered
intact.
aReaction conditions: [1]:[2]:[Ni(cod)2]:[PCy3]=0.25:0.50:
0.0125:0.025 (in mmol), in toluene (1.2 mL) under N2 at
100 °C for 1 h. bE/Z ratio determined by 1H NMR. c1H NMR
yield. dWith 0.38 mmol of 2. eWith PPh3 instead of PCy3.
(11) (a) Nakao, Y.; Kanyiva, K. S.; Oda, S.; Hiyama, T. J. Am. Chem.
Soc. 2006, 128, 8146. (b) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Heterocycles
2007, 72, 677. (c) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem., Int.
Ed. 2007, 46, 8872. (d) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem.
Soc. 2008, 130, 2448. (e) Nakao, Y.; Kashihara, N.; Kanyiva, K. S.; Hiyama,
T. J. Am. Chem. Soc. 2008, 130, 16170.
was anticipated. Indeed, treatment of 1a with 2.0 equiv of
4-octyne (2a) in the presence of 5 mol % of Ni(cod)2 and
10 mol % of PCy3 in toluene at 100 °C for 1 h furnished the
corresponding alkenylated product 3aa in 76% yield with
high stereoselectivity (Table 1, entry 1).13 The longer alkyl
chains of 5-decyne (2b) did not interfere with the reaction
(entry 2). Diarylacetylenes were also available for use. The
reaction with diphenylacetylene (2c) took place without any
difficulties to produce the conjugated oxadiazole 3ac in a
similar yield albeit with the decrease of stereoselectivity to
€
(12) (a) Regel, E.; Buchel, K.-H. Liebigs Ann. Chem. 1977, 159.
(b) Tolmachev, A. A.; Zarudnitskii, E. V.; Yurchenko, A. A.; Pinchuk, A.
M. Chem. Heterocycl. Compd. 1999, 35, 1117. (c) Zarudnitskii, E. V.; Pervak, I.
I.; Merkulov, A. S.; Yurchenko, A. A.; Tolmachev, A. A.; Pinchuk, A. M.
Synthesis 2006, 1279. See also:(d) Fu, K. S. Y.; Li, J.-N.; Liu, L.; Guo, Q.-X.
Tetrahedron 2007, 63, 1568.
(13) Other trialkylphosphines such as P(t-Bu)3, P(n-Bu)3, and PMe3 were
less effective (ca. <10% yield).
J. Org. Chem. Vol. 74, No. 16, 2009 6411

Mukai et al.
JOCNote
TABLE 2. Nickel-Catalyzed Reaction of Various 1,3,4-Oxadiazoles 1
with Alkynes 2a
TABLE 4. Nickel-Catalyzed Reaction of 2-Phenyl-1,3,4-oxadiazole (1a)
with Various Styrenes 4a
aReaction conditions: [1]:[2]:[Ni(cod)2]:[PCy3] = 0.25:
0.50:0.0125:0.025 (in mmol), in toluene (1.2 mL) under N2 at
100 °C for 1 h. 1b: R=4-MeC6H4; 1c: R=4-MeOC6H4; 1d:
R=1-naphthyl; 1e: R=phenethyl. bE/Z ratio determined by
1H NMR.
TABLE 3. Optimization for Nickel-Catalyzed Reaction of 2-Phenyl-1,3,4-
oxadiazole (1a) with Styrene (4a)a
entry
ligand
5aa, yield (%)b
1
2
3
PCy3
PPh3
(17)
(40)
(35)
(31)
(89)
(86) 83
(12)
(8)
aReaction conditions: [1a]:[4]:[Ni(cod)2]:[xantphos]=0.25:
0.50:0.025:0.025 (in mmol), in toluene (1.2 mL) under N2 at
100 °C for 3 h. bReaction time was 6 h.
P(4-MeOC6H4)3
P(4-FC6H4)3
xantphos
xantphos
dppe
4
5c
6d
7
8
dppf
π-benzyl nickel intermediates.11e,14 In addition, the π-benzyl
intermediate formation would be crucial for the catalytic
reaction so that the simple aliphatic alkenes and acrylate
esters could not participate in the reaction.
In summary, we have demonstrated that 2-aryl- and
2-alkyl-1,3,5-oxadiazoles efficiently undergo direct alkeny-
lation at the 5-position upon treatment with alkynes in the
presence of a nickel catalyst. Styrenes can also couple with
the oxadiazoles to selectively afford branched compounds.
Thus, the nickel catalysis appears to provide a facile
approach to the substituted oxadiazoles that are of interest
in both biological and physical properties.
aReaction conditions: 1a (0.25 mmol), 4a (0.50 mmol),
Ni(cod)2 (5 mol %), ligand (P/Ni = 2), in toluene (1.2 mL)
under N2 at 100 °Cfor3h.bGC yield is in parentheses. cReaction
for 6 h. dNi(cod)2 (10 mol %) and xantphos (10 mol %).
Although the exact reaction mechanism for the present
nickel catalysis is not clear at this stage, the most plausible
pathway based on the literature information10,11 may involve
a Ni(0)/Ni(II) redox through (i) oxidative addition of the sp2
C-H bond of oxadiazoles (Cazole-H) to Ni(0) to generate
Cazole-Ni(II)-H, (ii) insertion of alkynes or alkenes to the
Ni-H bond in a syn-fashion, and (iii) reductive elimination
leading to the corresponding coupled products and the
starting nickel species (Scheme 2). The observed regioselec-
tivity in the case of the unsymmetrical alkynes 2g or 2h
(Table 1, entries 7 and 8) would originate from the strong
preference of the metal being located at the position far from
the t-Bu or SiiPr3 group in the insertion step due to steric
reasons. The unusual branch selectivity with styrenes would
result from the preferable formation of the corresponding
Experimental Section
Typical Procedure for Nickel-Catalyzed Alkenylation of 1,3,4-
Oxadiazoles 1 with Alkynes 2. The reaction of 2-phenyl-1,3,4-
oxadiazole (1a) with 4-octyne (2a) is representative (Table 1,
entry 1). With use of a glovebox filled with nitrogen, Ni(cod)2
(0.021 M toluene solution, 0.60 mL, 0.0125 mmol) and PCy3
(14) (a) Shirakura, M.; Suginome, M. J. Am. Chem. Soc. 2008, 130, 5410.
(b) Shirakura, M.; Suginome, M. Org. Lett. 2009, 11, 523.
6412 J. Org. Chem. Vol. 74, No. 16, 2009

Mukai et al.
JOCNote
SCHEME 2. Plausible Mechanism
CDCl3) δ 12.9 (two signals merged), 21.2, 21.3, 28.3, 29.3, 123.2,
124.5, 125.8, 127.9, 130.4, 136.7, 162.8, 164.8; HRMS (EI) m/z (M)
calcd for C16H20N2O 256.1576, found 256.1570.
Typical Procedure for Nickel-Catalyzed Alkylation of 1,3,4-
Oxadiazoles 1 with Styrenes 4. The reaction of 2-phenyl-1,3,4-
oxadiazole (1a) with styrene (4a) is representative (Table 4,
entry 1). With use of a glovebox filled with nitrogen, Ni(cod)2
(0.042 M toluene solution, 0.60 mL, 0.025 mmol) and xantphos
(14 mg, 0.025 mmol) were placed in a reaction flask, and the
flask was taken outside the glovebox. The solution was stirred
for 10 min at room temperature, and a solution of 1a (37 mg,
0.25 mmol), 4a (52 mg, 0.50 mmol), and 1-methylnaphthalene
(ca. 20 mg, internal standard) in toluene (0.60 mL) was then
added. After being heated at 100 °C for 3 h, the consumption of
1a was confirmed by GC analysis. The resulting mixture was
cooled to room temperature, and evaporation followed by silica
gel column purification produced 2-phenyl-5-(1-phenylethyl)-
1,3,4-oxadiazole (5aa, 51 mg, 0.21 mmol) in 83% yield. 5aa: 1H
NMR (400 MHz, CDCl3) δ 1.82 (d, J = 7.3 Hz, 3H), 4.44 (q,
J = 7.3 Hz, 1H), 7.26-7.31 (m, 1H), 7.35 (d, J = 4.4 Hz, 4H),
7.44-7.52 (m, 3H), 7.98-8.00 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 18.6, 36.5, 123.0 (two signals merged), 125.8, 126.3,
126.5, 127.9, 130.5, 139.3, 164.0, 167.7; HRMS (CI) m/z
(M þ H) calcd for C16H15N2O 251.1186, found 251.1187.
(7.0 mg, 0.025 mmol) were placed in a reaction flask, and the
flask was taken outside the glovebox. The solution was then
stirred for 10 min at room temperature. A solution of 1a (37 mg,
0.25 mmol), 2a (55 mg, 0.50 mmol), and 1-methylnaphthalene
(ca. 20 mg, internal standard) in toluene (0.60 mL) was added,
and the mixture was heated at 100 °C for 1 h. After the
consumption of 1a was checked by GC analysis, the resulting
mixture was evaporated under reduced pressure. The residue
was purified by column chromatography on silica gel with
hexane/ethyl acetate as an eluent (90:10, v/v) to furnish
(E)-2-(4-octen-4-yl)-5-phenyl-1,3,4-oxadiazole (3aa, 49 mg,
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. We are grateful to
Profs. T. Hiyama and Y. Nakao of Kyoto University for
useful discussion.
1
0.19 mmol) in 76% yield. 3aa: H NMR (400 MHz, CDCl3) δ
0.99 (t, J= 7.3 Hz, 3H), 1.00 (t, J= 7.3 Hz, 3H), 1.50-1.67 (m, 4H),
2.26-2.32 (m, 2H), 2.60 (t, J= 8.0 Hz, 2H), 6.66 (t, J= 7.7 Hz, 1H),
7.48-7.51 (m, 3H), 8.06-8.08 (m, 2H); 13C NMR (100 MHz,
Supporting Information Available: Characterization data
for all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 16, 2009 6413