Room temperature direct alkynylation of 1,3,4oxadiazoles with alkynyl bromides under copper catalysis

Article abstract of DOI:10.1021/jo9025622

("Figure Presented") The direct alkynylation reaction of 1,3,4-oxadiazoles with alkynyl bromides efficiently proceeds in the presence of a copper catalyst at room temperature to create the corresponding heteroaryl-alkynyl linkage in good yields. This direct coupling provides a rapid and convergent access to oxadiazole core Π-conjugated systems.

Full text of DOI:10.1021/jo9025622

pubs.acs.org/joc
the room temperature direct arylation6 and alkynylation7
Room Temperature Direct Alkynylation of 1,3,4-
Oxadiazoles with Alkynyl Bromides under Copper
Catalysis
under palladium or gold catalysis, the substrates are still
limited to the highly electron-rich heterocycles such as
indoles, pyrroles, and imidazolines. Moreover, some cases
require use of the special hypervalent iodine reagents as
aryl or alkynyl sources.6a,7 Thus, further developments of
catalyst systems are quite appealing for milder reaction
conditions.
Recently, relatively common and less expensive copper
salts and complexes have received much attention in the field
of direct arylation8 and alkenylation.9 In addition to its
economical benign effect, the unique catalytic activity of
copper is also observed.8e Herein, we report an efficient
example of the copper-catalyzed direct alkynylation of a
useful heteroarene core having an electron-deficient nature.
Tsuyoshi Kawano, Naoto Matsuyama, Koji Hirano,
Tetsuya Satoh, and Masahiro Miura*
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, Suita, Osaka 565-0871, Japan
miura@chem.eng.osaka-u.ac.jp
Received December 3, 2009
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The direct alkynylation reaction of 1,3,4-oxadiazoles with
alkynyl bromides efficiently proceeds in the presence of a
copper catalyst at room temperature to create the corre-
sponding heteroaryl-alkynyl linkage in good yields. This
direct coupling provides a rapid and convergent access to
oxadiazole core π-conjugated systems.
Metal-mediated direct functionalization of C-H bonds
has grown rapidly in modern synthetic chemistry because of
its possibility for concise increase of molecular complexity
from the ubiquitous C-H bonds.1 In particular, the catalytic
direct transformation of C-H to C-C bonds with organic
halides or pseudohalides has had a significant impact on the
conventional cross-coupling reactions with organometallic
compounds2 since the inevitable preactivation step, metala-
tion, can be obviated in such methodologies. So far, a variety
of catalyst systems have been explored, and the direct aryla-
tion,3 alkenylation,4 and alkynylation5 of arenes and hetero-
arenes has become possible. However, these catalytic
reactions generally suffered from the need for drastic
conditions such as elevated temperature and longer reac-
tion periods. Although current efforts by Sanford, Chen,
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M. J. J. Am. Chem. Soc. 2008, 130, 8172. (e) Phipps, R. J.; Gaunt, M. J.
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1764 J. Org. Chem. 2010, 75, 1764–1766
Published on Web 01/14/2010
DOI: 10.1021/jo9025622
r
2010 American Chemical Society

Kawano et al.
JOCNote
Thus, the copper-based process has been found to allow the
direct functionalization of 1,3,4-oxadiazoles with alkynyl
bromides even at room temperature.10,11 As certain oxadia-
zole derivatives are known to act as ester and amide bioisos-
teres and π-conjugated systems involving the heterocycle
unit may have good electron-transporting and hole-blocking
abilities, this transformation also appears to be of interest in
pharmaceutical and materials chemistry.12
TABLE 1. Optimization for Room Temperature Copper-Catalyzed
Direct Alkynylation of 2-Phenyl-1,3,4-oxadiazole (1a) with (Bromoethynyl)-
benzene (2a)a
entry
catalyst
ligand
3aa, yield (%)b
During our recent studies on the nickel-catalyzed direct
alkynylation of azoles, we found that a copper cocatalyst
such as CuI dramatically accelerated the reaction.5f When we
applied the cooperative catalyst system of Ni(cod)2, dppbz
(1,2-bis(diphenylphosphino)benzene), and CuI to the reac-
tion of 2-phenyl-1,3,4-oxadiazole (1a) with (bromoethynyl)-
benzene (2a) in the presence of LiO-t-Bu, the coupling
product 3aa was produced even at room temperature albeit
with a low yield (Table 1, entry 1). However, to our surprise,
some additional investigation revealed that the use of CuI
alone gave the better result in this transformation (entry 2).
Therefore, we turned our attention to the optimization
studies based on copper catalysts. An increase in the amount
of LiO-t-Bu to 4.0 equiv gave the positive effect on yield
(entry 3). Then, various ligands were surveyed. Among the
N-based ligands, 2,20-bipyridine (bpy) and N,N0-dimethy-
lethylenediamine (dmeda) did not affect reaction efficiency
(entries 5 and 6), while 1,10-phenanthroline (phen) slightly
improved the yield to 70% (entry 4). On the other hand, the
phosphorus ligand, PPh3, was detrimental to the direct
coupling (entry 7). The choice of copper salts was also crucial
for the reaction, as exemplified by entries 8 and 9: CuBr or
Cu(OTf)2 instead of CuI resulted in the large drop of the
yield. Notably, either use of other bases such as NaO-t-Bu,
KO-t-Bu, and Cs2CO3 or that of a polar solvent (e.g., DMF)
instead of toluene sluggishly afforded 3aa (not shown).
With the conditions employed for entry 4 of Table 1, we
carried out the room temperature direct alkynylation of an
array of oxadiazoles 1 with 2a (Table 2). The oxadiazoles
bearing electron-donating 4-methylphenyl and 4-methoxy-
phenyl groups as well as the simple phenyl one underwent
alkynylation smoothly to furnish 3ba and 3ca in 67% and
64% yields, respectively (entries 1-3). Electron-withdraw-
ing trifluoromethyl substituent did not interfere with the
reaction (entry 4). Notably, the carbon-chloride moiety on
the benzene ring was tolerant under the standard reaction
conditions, which could enjoy further manipulation based
on the palladium chemistry (entry 5). The bulky naphthalene
motif also could be introduced to the oxadiazole-alkyne
conjugation without any difficulties (entry 6). On the other
hand, phenethyl-substituted oxadiazole 1g showed moderate
reactivity (entry 7).
1
2
Ni(cod)2 and CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
Cu(OTf)2
dppbz
none
none
phen
bpy
- (19)
- (36)
- (66)
70 (73)
- (65)
- (67)
- (48)
- (40)
- (11)
3c
4c
5c
6c
7c
8c
9c
dmeda
PPh3
d
phen
phen
aReaction conditions: [1a]:[2a]:[LiO-t-Bu]:[catalyst]:[lgand] = 0.50:0.60:-
1.0:0.025:0.025 (in mmol), in toluene (2.5 mL) under N2 at room tempera-
ture for 1 h. bGC yield is in parentheses. cWith 2.0 mmol of LiO-t-Bu.
dWith 0.050 mmol of PPh3.
TABLE 2. Copper-Catalyzed Room Temperature Direct Alkynylation
of Various 1,3,4-Oxadiazoles 1 with (Bromoethynyl)benzene (2a)a
Subsequently, we examined the substitution effect at the
alkyne terminus of alkynyl bromide (Table 3). As shown in
Table 2, the reactions with electron-rich substrates 2b and 2c
and sterically demanding 2d completed at room temperature
(10) Copper-catalyzed direct C-H arylation of 1,3,4-oxadiazoles with
aryl iodides: ref 8i.
aReaction conditions: [1]:[2a]:[LiO-t-Bu]:[CuI]:[phen] = 0.50:0.60:2.0:-
0.025:0.025 (in mmol), in toluene (2.5 mL) under N2 at room temperature
for 1 h.
ꢁ
(11) Besselievre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553.
(12) (a) Mitschke, U.; Bauerle, P. J. Mater. Chem. 2000, 10, 1471.
€
(b) Leung, D.; Du, W.; Hardouin, C.; Cheng, H.; Hwang, I.; Cravatt,
B. F.; Boger, D. L. Bioorg. Med. Chem. Lett. 2005, 15, 1423. (c) He, G. S.;
Tan, L.-S.; Zheng, Q.; Prasad, P. N. Chem. Rev. 2008, 108, 1245.
(d) Zarudnitskii, E. V.; Pervak, I. I.; Merkulov, A. S.; Yurchenko, A. A.;
Tolmachev, A. A. Tetrahedron 2008, 64, 10431.
to afford the corresponding alkynyloxadiazoles 3ab, 3ac,
and 3ad in good yields (entries 1-3). In contrast, the
J. Org. Chem. Vol. 75, No. 5, 2010 1765

Kawano et al.
JOCNote
TABLE 3. Copper-Catalyzed Room Temperature Direct Alkynylation
based on the literature information8,9 may involve the se-
quential cupration of oxadiazole with the aid of LiO-t-Bu/σ-
bond metathesis with alkynyl bromide. Nevertheless, the
pathway including addition/elimination14 or formation of
Cu(III) species15 at the step of the reaction with alkynyl
bromide could not be completely excluded.
of 2-Phenyl-1,3,4-oxadiazole (1a) with Various Alkynyl Bromides 2a
In summary, we have demonstrated that 2-aryl- and 2-
alkyl-1,3,4-oxadiazoles efficiently undergo direct alkynyla-
tion upon treatment with readily accessible alkynyl bro-
mides16 in the presence of a copper catalyst. The reaction
proceeds very smoothly even at room temperature.17 Thus,
the copper catalysis can compensate for the conventional
Sonogashira coupling and provide a facile approach to the
substituted oxadiazoles of interest in both biological and
physical properties.
Experimental Section
Typical Procedure for Copper-Catalyzed Room Temperature
Direct Alkynylation of 1,3,4-Oxadiazoles 1 with Alkynyl Bro-
mides 2. The reaction of 2-phenyl-1,3,4-oxadiazole (1a) with
(bromoethynyl)benzene (2a) is representative (Table 2, entry 1).
CuI (4.8 mg, 0.025 mmol), 1,10-phenanthroline (4.5 mg, 0.025
mmol), LiO-t-Bu (160 mg, 2.0 mmol), 2-phenyl-1,3,4-oxadiazole
(1a, 73 mg, 0.50 mmol), (bromoethynyl)benzene (2a, 109 mg, 0.60
mmol), toluene (2.5 mL), and 1-methylnaphthalene (ca. 50 mg,
internal standard) were placed in a 20 mL two-necked reaction
flask. After the mixture was stirred at room temperature for 1 h,
the consumption of 1a was checked by GC analysis. The resulting
mixture was then poured into water. The mixture was extracted
with ethyl acetate, and the organic layer was dried over sodium
sulfate. Concentration in vacuo followed by silica gel column
purification (hexane:ethyl acetate = 95:5) gave 2-phenyl-5-(phe-
nylethynyl)-1,3,4-oxadiazole (3aa, 86 mg, 0.35 mmol) in 70%
1
yield. 3aa: H NMR (400 MHz, CDCl3) δ 7.40-7.44 (m, 2H),
7.46-7.59 (m, 4H), 7.65 (dd, J = 8.1, 1.4 Hz, 2H), 8.10 (dd, J =
8.1, 1.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 73.1, 97.2, 119.8,
123.3, 127.1, 128.7, 129.1, 130.6, 132.1, 132.3, 150.7, 164.8; HRMS
m/z (Mþ) calcd for C16H10N2O 246.0793, found 246.0792 .
Acknowledgment. This work was partly supported by
Grants-in-Aid from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
aReaction conditions: [1a]:[2]:[LiO-t-Bu]:[CuI]:[phen] = 0.50:0.60:2.0:-
0.025:0.025 (in mmol), in toluene (2.5 mL) under N2 at room tempera-
ture for 1 h. bGC yield is in parentheses. cWith 1.0 mmol of 2. d8 h. e24 h.
f6 h. g2 h.
Supporting Information Available: Characterization data
for all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
electron-deficient nature of trifluoromethyl group caused the
rapid decomposition of alkynyl bromide under the reaction
conditions, and the desired product was detected in only
13% GC yield (entry 4). However, the silyl-protected 2f and
2g coupled with 1a in acceptable yields so as to complement
the lack of generality with electron-poor substrates through
the subsequent desilylation/Pd-catalyzed Sonogashira cou-
pling sequence (entries 5 and 6). It is noteworthy that the
conjugate enyne 2h and aliphatic alkyne 2i were also avail-
able for use (entries 7 and 8).13
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(17) Among other azoles examined, benzoxazole, benzothiazole, and 3,4-
diphenyl-1,2,4-triazole participated in the present direct coupling at the
expense of reaction temperature; the reactions with 2a in toluene at 135 °C
(bath temperature) for 1 h gave the corresponding alkynylated products in
62%, 19%, and 32% GC yields, respectively. During the preparation of this
Although the exact reaction mechanism for the copper
catalysis is not clear at this stage, the most plausible course
(13) Relatively difficult in the precedent direct sp2 C-H alkynylation. See
ref 5.
(14) Zanini, M. L.; Menegheti, M. R.; Ebeling, G.; Livotto, P. R.;
Rominger, F.; Dupont, J. Polyhedron 2003, 22, 1665.
ꢁ
manuscript, Besselievre and Piguel reported the CuBr SMe2/DPEphos-
catalyzed direct alkynylation of various azoles with alkynyl bromides in
3
dioxane at 120 °C: ref 11.
1766 J. Org. Chem. Vol. 75, No. 5, 2010