Copper-mediated direct arylation of benzoazoles with aryl iodides

Article abstract of DOI:10.1016/j.tetlet.2008.01.042

The direct arylation of 1,3-benzoazole compounds with aryl iodides is effectively promoted by CuI with use of PPh₃ and Na₂CO₃ or K₃PO₄ as ligand and base, respectively, in DMF or DMSO to produce the corresponding 2-arylated products with good yields.

Full text of DOI:10.1016/j.tetlet.2008.01.042

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1598–1600
Copper-mediated direct arylation of benzoazoles with aryl iodides
Tomoki Yoshizumi, Hayato Tsurugi, Tetsuya Satoh, Masahiro Miura *
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Received 29 November 2007; revised 28 December 2007; accepted 10 January 2008
Available online 15 January 2008
Abstract
The direct arylation of 1,3-benzoazole compounds with aryl iodides is effectively promoted by CuI with use of PPh3 and Na2CO3 or
K3PO4 as ligand and base, respectively, in DMF or DMSO to produce the corresponding 2-arylated products with good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Arylation; Aryl iodides; Benzoazoles; Copper
Various aryl-substituted azole compounds having
imidazole, oxazole, and thiazole skeletons are known to
exhibit pharmacological activities and also of importance
in the area of p-conjugated functional materials. Among
the most useful methods to prepare such arylheterocycles
is the palladium-catalyzed cross-coupling of either hetero-
aryl halides with arylmetals or aryl halides with heteroaryl-
metals.1 Meanwhile, it is known that aryl halides can couple
directly with azoles as well as thiophenes and furans at their
2- and/or 5-position(s) in the presence of a palladium- or
rhodium-based catalyst. The direct method has a significant
advantage, not requiring stoichiometric pre-metalation of
the heterocycles, and thus, has been studied extensively in
recent years.2
In our previous work, we found that addition of a
copper(I) species, typically CuI, can effectively enhance the
above palladium-catalyzed direct arylation in some cases.3a
It was also observed that the reaction of azoles with aryl
iodides can proceed to some extent at the 2-position selec-
tively by using the much less expensive copper species alone
as a promoter. The copper-mediated method has been
applied to the synthesis of 2-arylated imidazoles including
combretastatin A-4 analogues4 and COX-2 inhibitors5 with
moderate efficiency. As part of our study of the direct aryl-
ation of heteroarenes,3 we have revisited the copper-
mediated coupling for elaborating the reaction conditions.
It has been found that the reaction of 1,3-benzoazoles is
effectively promoted by CuI with use of PPh3 and Na2CO3
or K3PO4 as ligand and base, respectively, in DMF or
DMSO to produce the corresponding 2-arylated products
with good yields. During the performance of this work,
Do and Dougulis reported an effective copper-based
catalytic system for the reaction with a strong base such
as t-BuOLi, while excess aryl iodide (3 equiv) is usually
required.6 Their report prompted us to disclose our own
results. The present protocol with the mild bases is con-
ducted by using a nearly equimolar amount of aryl iodide
as well as CuI, and thus, seems to be especially useful when
an aryl iodide is relatively valuable.
The arylation of benzoxazole (1) (1 mmol) with iodo-
benzene (2a) (2 equiv) was first examined in the presence
of CuI (0.1 equiv) and PPh3 (0.2 equiv) by using a number
of inorganic bases (2 mmol) in DMF (5 mL) at 160 °C for
8 h (Table 1, entries 1–4). Among the bases tested, K3PO4
was found to be the most effective one under the conditions
employed to afford 2-phenylbenzoxazole (3a) in 87% yield.
The yield of 3a was apparently decreased without the addi-
tion of PPh3 (entry 5). Decreasing the amount of iodobenz-
ene to 1.2 equiv resulted in a poor yield of 3a due to the
formation of a byproduct in a significant amount (entry
*
Corresponding author. Tel.: +81 6 6879 7360; fax: +81 6 6879 7362.
E-mail address: miura@chem.eng.osaka-u.ac.jp (M. Miura).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.042

T. Yoshizumi et al. / Tetrahedron Letters 49 (2008) 1598–1600
1599
Table 1
Table 2
Reaction of benzoxazole (1) with aryl iodides (2)
Reaction of 1-methyl-1H-benzimidazole (4) with aryl iodides (2)
N
N
+
N
+
I
R
I
R
O
2a-f
2a-f
4
1
Me
N
O
N
CuI/PPh3
CuI/PPh
3
R
R
N
Me
Base/DMF
Base/DMF
5a-f
3a-f
Conditionsa
3, % Yieldb
Entry
2, R
Base
Conditionsa
5, % Yieldb
Entry
2, R
Base
1
2
3
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2a, H
2b, OMe
2c, Cl
2d, Br
2e, CO2Me
2f, CN
Na2CO3
A
A
A
A
A
A
B
B
C
C
C
C
C
C
C
3a, 37
3a, 46
3a, 10
3a, 87
3a, 37
3a, 8
3a, 67
3a, 75 (70)
3a, 86 (82)
3a, 26
3b, 78 (71)
3c, 90 (88)
3d, (53)
3e, (43)
3f, (93)
1
2
3
2b, OMe
2b, OMe
2b, OMe
2b, OMe
2b, OMe
2b, OMe
2b, OMe
2b, OMe
2b, OMe
2a, H
Na2CO3
K2CO3
Cs2CO3
K3PO4
A
A
A
A
A
A
A
B
B
B
B
B
B
B
5b, 84 (82)
5b, 46
5b, 10
5b, 53
5b, 49
5b, 15
5b, 42
5b, 81
5b, 19
5a, (75)
5c, (89)
5d, (60)
5e, (52)
5f, (69)
K2CO3
Na3PO4
K3PO4
K3PO4
K3PO4
4
4
5c
6d
7
5c
6d
7e
8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K3PO4
8
9
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
9f
10
11
12
13
14
a
10c
11
12
13
14
15
a
2c, Cl
2d, Br
2e, CO2Me
2f, CN
(A) [4]:[2]:[CuI]:[PPh3]:[Base] = 1:2:1:0.2:2 (in mmol), in DMF (5 mL)
under N2 at 160 °C for 8 h. (B) [4]:[2]:[CuI]:[PPh3]:[Base] = 1:1.2:1:0.2:2 (in
mmol), in DMF (5 mL) under N2 at 160 °C for 8 h.
(A) [1]:[2]:[CuI]:[PPh3]:[Base] = 1:2:0.1:0.2:2 (in mmol), in DMF
(5 mL) under N2 at 160 °C for 8 h. (B) [1]:[2]:[CuI]:[PPh3]:[Base] =
1:1.2:1:0.2:2 (in mmol), in DMF (5 mL) under N2 at 160 °C for 8 h. (C)
[1]:[2]:[CuI]:[PPh3]:[Base] = 1:1.2:1:0.2:2 (in mmol), in DMF (1 mL) under
N2 at 160 °C for 2 h.
b
GC yield. Value in parentheses indicates isolated yield.
[PPh3] = 1 mmol.
Reaction without PPh3.
[CuI] = 0.5 mmol.
c
d
b
e
GC yield. Value in parentheses indicates isolated yield.
Reaction without PPh3.
[2a] = 1.2 mmol.
c
f
Reaction in DMF (1 mL).
d
6, vide infra). When an equimolar amount of CuI was used,
the yield of 3a was increased even by using 1.2 equiv of 2a,
and the weaker base Na2CO3 was superior to K3PO4 under
these conditions (entry 8 vs 7). Furthermore, the rate of the
reaction was increased, when the reaction was carried out
in a concentrated mixture using 1 mL of DMF (entry 9)
to afford 3a in 86% yield within 2 h. Removal of PPh3 from
these conditions also reduced the yield of 3a (entry 10).
Under the conditions employed for entry 9, various 4-
substituted aryl iodides 2b–2f having electron-donating
and -withdrawing substituents gave the corresponding 2-
arylbenzoxazoles 3b–f with fair to excellent yields (entries
11–15). Thus, bromo, ester, and nitrile functions are toler-
able in the present system.
Next, we examined the arylation of 1-methyl-1H-benz-
imidazole (4) as a typical imidazole substrate. The results
for the reaction of 4 (1 mmol) with 2b (2 equiv) in the pres-
ence of CuI (1 equiv) and PPh3 (0.2 equiv) using a number
of bases (2 equiv) in DMF (5 mL) at 160 °C for 8 h are
shown in entries 1–4 of Table 2. In this reaction, Na2CO3
was also the base of choice and the arylated product
5b was obtained in 84% yield (entry 1). The use of Cs2CO3
was, however, effective in the presence of 2 equiv of CuI
as reported previously (73% for 5b).3a The reaction either
with 1 equiv of PPh3 or without the ligand was less effective
(entries 5 and 6). When the amount of CuI was reduced to
0.5 equiv, the yield of 5b was also decreased (entry 7). On
the other hand, decreasing the amount of 2b to 1.2 equiv
only little affected the reaction to afford a satisfactory yield
of 5b (entry 8). Unlike the reaction of benzoxazole,
decreasing the amount of the solvent was not effective
(entry 9). Using the conditions of entry 8, the reactions
of 4 with 2a and 2c–f gave the corresponding 2-arylated
products 5a and 5c–f with substantial yields (entries
10–14).
The arylation of benzothiazole (6) was also conducted.
The effective conditions for the reaction of benzoxazole
(1) were found to be not suitable in this case. The reaction
of 6 (1 mmol) with 2a (2 equiv) in the presence of CuI
(1 equiv), PPh3 (0.2 equiv), and Na2CO3 (2 equiv) in
DMF (1 mL) for 2 h gave 2-phenylbenzothiazole (7a) in
34% yield (Table 3, entry 1). A good yield of 7a was
obtained in the reaction with 1.2 equiv of 2a by using
K3PO4 and DMSO as base and solvent, respectively (entry
4). Under the same conditions, iodides 2b and 2f reacted
with 6 smoothly to afford 7b and 7f (entries 5 and 6).
As described above, the effective set of reaction condi-
tions for each benzoazole is not unity, while each substrate
can be arylated with an almost stoichiometric amount of
aryl iodides. One of the major factors determining their
reactivity may be the acidity of hydrogen at C-2. The order
of acidity follows the sequence: 1 (benzoxazole) > 6 (benzo-

1600
T. Yoshizumi et al. / Tetrahedron Letters 49 (2008) 1598–1600
Table 3
Work is underway toward further development of the
direct method.
Reaction of benzothiazole (6) with aryl iodides (2)
N
+
I
R
Acknowledgments
S
2a,b,f
6
This work was partly supported by a Grant-in-Aid from
the Ministry of Education, Culture, Sports, Science, and
Technology, Japan. We thank Ms. Y. Miyaji of Osaka
University for the measurement of NMR spectra.
N
S
CuI/PPh3
R
Base/DMSO
7a,b,f
Entry
2, R
Base
Conditionsa
7, % Yieldb
1c
2
3
4
5
6
a
2a, H
2a, H
2a, H
2a, H
2b, OMe
2f, CN
Na2CO3
A
A
A
B
B
B
7a, 34
7a, 50
7a, 74
7a, 71 (63)
7b, (78)
7f, (83)
References and notes
Na2CO3
K3PO4
K3PO4
K3PO4
K3PO4
1. (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004; (b) Tsuji, J.
Palladium Reagents and Catalysts, 2nd ed.; John Wiley & Sons:
Chichester, 2004.
2. For recent reviews; see: (a) Satoh, T.; Miura, M. Chem. Lett. 2007, 36,
200; (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174; (c) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173;
(d) Miura, M.; Satoh, T. Top. Organomet. Chem. 2005, 14, 55; (e)
Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
Rev. 2002, 102, 1359.
(A) [1]:[2]:[CuI]:[PPh3]:[Base] = 1:2:1:0.2:2 (in mmol), in DMSO
(1 mL) under N2 at 160 °C for 2 h. (B) [1]:[2]:[CuI]:[PPh3]:[Base] =
1:1.2:1:0.2:2 (in mmol), in DMSO (1 mL) under N2 at 160 °C for 2 h.
b
GC yield. Value in parentheses indicates isolated yield.
Reaction in DMF (1 mL).
c
3. (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467; (b) Okazawa, T.; Satoh, T.;
Miura, M.; Nomura, M. J. Am. Chem. Soc. 2002, 124, 5286; (c)
Yokooji, A.; Okazawa, T.; Satoh, T.; Miura, M.; Nomura, M.
Tetrahedron 2003, 59, 5685; (d) Yokooji, A.; Satoh, T.; Miura, M.;
Nomura, M. Tetrahedron 2004, 60, 6757; (e) Nakano, M.; Satoh, T.;
Miura, M. J. Org. Chem. 2006, 71, 8309.
4. Wang, L.; Woods, K. W.; Li, Q.; Barr, K. J.; McCroskey, R. W.;
Hannick, S. M.; Gherke, L.; Credo, R. B.; Hui, Y.-H.; Marsh, K.;
Warner, R.; Lee, J. Y.; Zielinski-Mozng, N.; Frost, D.; Rosenberg, S.
H.; Sham, H. L. J. Med. Chem. 2002, 45, 1697.
5. (a) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. Eur. J.
Org. Chem. 2006, 693; (b) Bellina, F.; Cauteruccio, S.; Rossi, R. Eur.
J. Org. Chem. 2006, 1379; (c) Bellina, F.; Calandri, C.; Cauteruccio,
S.; Rossi, R. Tetrahedron 2007, 63, 1970.
6. Do, H-. Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
7. Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.; Guo, Q.-X. Tetrahedron 2007, 63,
1568.
thiazole) > 4 (benzimidazole).7 It may be reasonable to
consider that the arylation proceeds via the initial cupra-
tion of C-2 accompanied by deprotonation in the presence
of a base and the reaction of the resulting benzoazolyl-
copper(I) intermediate with an aryl iodide leads to the
corresponding 2-arylbenzoazole.5a
It should be noted that in the reaction of 1 with 2a, the
formation of o-(diphenylamino)phenol (8) as byproduct
was detected in each case and the amount of 8 depended
on the reaction conditions. It was especially significant
when the yield of 3a was low by using a catalytic amount
of CuI (for example, ca. 50% in entry 6 of Table 1). This
seems to be due to the fact that the C-2 hydrogen of 1 is
relatively more acidic and its anion readily undergoes
ring-opening.8 Then o-aminophenol formed by the succes-
sive hydrolysis may be diphenylated with 2a in the reaction
medium to give 8.9 Thus, an enough amount of either an
aryl iodide or CuI seems to be required for an effective
coupling. In the reaction of 6, the formation of diphenyl-
[2-(phenylthio)phenyl]amine (9) was identified, indicating
that the sulfur undergoes phenylation under the conditions
(for example, ca. 6% in entry 2 of Table 3). Such a byprod-
uct was, however, not detected in the reaction of 4, which
may be attributed to the fact that the ring-opening is less
favorable than the corresponding oxazole and thiazole.8b
´
8. (a) Sanchez, R. S.; Zhuravlev, F. A. J. Am. Chem. Soc. 2007, 129,
5824; (b) Boche, G.; Bosold, F.; Hermann, H.; Marsch, M.; Harms,
K.; Lohrenz, J. C. W. Chem. Eur. J. 1998, 4, 814.
9. Forest, J. J. Chem. Soc. 1960, 581; Compound 8: 1H NMR (400 MHz,
CDCl3) d 5.51 (s, 1H), 6.88–6.92 (m, 1H), 6.97–7.03 (m, 7H), 7.06–
7.09 (m, 1H), 7.15–7.17 (m, 1H), 7.19–7.25 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 116.4, 121.4, 121.7, 122.6, 127.6, 128.9, 129.3,
133.0, 146.6, 152.2. MS, m/z 261 (M+). Compound 9: 1H NMR
(400 MHz, CDCl3) d 6.95 (t, J = 8.0 Hz, 2H), 7.01 (d, J = 8.0 Hz,
4H), 7.04–7.09 (m, 2H), 7.13–7.17 (m, 2H), 7.22 (t, J = 8.0 Hz, 4H),
7.26–7.31 (m, 3H), 7.34–7.41 (m, 2H); 13C NMR (100 MHz, CDCl3) d
121.8, 121.9, 126.4, 127.2, 127.8, 128.9, 129.1, 130.1, 130.8, 133.4,
134.0, 137.5, 144.6, 147.1. MS, m/z 353 (M+).
10. Typical procedure [reaction of benzoxazole (1) with iodobenzene (2a),
Table 1, entry 9]: In a 20 mL two-necked flask were added 1 (119 mg,
1 mmol), 2a (245 mg, 1.2 mmol), CuI (190 mg, 1 mmol), PPh3
(52.4 mg, 0.2 mmol), Na2CO3 (212 mg, 2 mmol), 1-methylnaphthalene
(ca. 50 mg, internal standard), and DMF (1 mL). The resulting
mixture was stirred under N2 (with balloon) for 2 h at 160 °C (bath
temperature). After cooling, the mixture was poured into water
containing ethylenediamine (ca. 2 mL), extracted with ether, and dried
over sodium sulfate. Product 3a was isolated by column chromato-
graphy on silica gel using hexane–ethyl acetate (99:1, v/v). The
spectroscopic data were identical with those reported previously.3a
NPh2
SPh
NPh2
OH
9
8
In summary, we have shown some effective protocols for
the copper-mediated arylation of benzoazoles using less
expensive, mild inorganic bases without the aid of a palla-
dium catalyst.10 The amount of aryl iodide required could
be reduced to a nearly equimolar equivalent to the azoles.