Cu/Fe/O=PPh3-catalyzed etherification for the synthesis of aryl 3-benzo[b]thienyl ethers

Article abstract of DOI:10.1246/cl.180425

Cu/Fe-cocatalyzed cross-coupling reactions between 3-bromobenzo[b]thiophene and hydroxyaryls are described herein. The combination of Cu and Fe catalysts is important for the progress of the reactions, and the use of triphenylphosphine oxide as a ligand suppresses the dehalogenation of 3-bromobenzo[b]thiophene, and promptly facilitates the reaction. The obtained aryl benzo[b]thienyl ethers can be converted to π-extended thienobenzofuran derivatives via Pd-catalyzed dehy-drogenative cyclizations.

Full text of DOI:10.1246/cl.180425

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Cu/Fe/O=PPh3-Catalyzed Etherification for the Synthesis of Aryl 3-Benzo[b]thienyl Ethers
Koichi Mitsudo,* Takuya Asada, Tomohiro Inada, Yuji Kurimoto, Hiroki Mandai, and Seiji Suga*
Advance Publication on the web June 21, 2018
doi:10.1246/cl.180425
© 2018 The Chemical Society of Japan
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1
Cu/Fe/O=PPh3-Catalyzed Etherification for the Synthesis ofAryl 3-Benzo[b]thienyl Ethers
Koichi Mitsudo,* Takuya Asada, Tomohiro Inada, Yuji Kurimoto, Hiroki Mandai, and Seiji Suga*
Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka,
Kita-ku, Okayama 700-8530
E-mail: insert corresponding e-mail address
1
2
3
4
5
6
7
8
9
Cu/Fe-cocatalyzed cross-coupling reactions between 3-
49
We considered that a fine-tuning of the reaction
bromobenzo[b]thiophene and hydroxyaryls are described
herein. The combination of Cu and Fe catalysts is important
for the progress of the reactions, and the use of
50 conditions could enhance the efficiency of the Ullmann-type
51 coupling reaction of 3-bromobenzo[b]thiophene, which
52 would be a powerful tool for the synthesis of aryl
53 benzo[b]thienyl ethers. We examined the reaction
54 conditions for an Ullmann-type reaction with 3-
55 bromobenzo[b]thiophene, and found an efficient Cu/Fe
56 catalytic system, using triphenylphosphine oxide as a ligand.
57 To the best of our knowledge, there has been no report on a
58 copper- or iron-catalyzed Ullmann-type reaction using
59 triphenylphosphine oxide as a ligand.9
triphenylphosphine oxide as
a ligand suppresses the
dehalogenation of 3-bromobenzo[b]thiophene, and proceeds
promptly the reaction. The obtained aryl benzo[b]thienyl
ethers can be converted to π-extended thienobenzofuran
derivatives via Pd-catalyzed dehydrogenative cyclizations.
10 Keywords: Aryl thienyl ether, Cu/Fe-cocatalyst, Cross-
11 coupling
60
First, we chose 3-bromobenzo[b]thiophene (1) and p-
12
Diaryl ethers are known as common skeletal motifs of
61 cresol as model compounds and performed a screening of
62 copper salts for the Cu/Fe-cocatalyzed etherification
63 between them (Table 1). In the presence of a Cu source
64 ([Cu], 5 mol %), Fe(acac)3 (5 mol %), and K2CO3 (2.0
65 equiv), 3-bromobenzo[b]thiophene (1) was treated with p-
66 cresol (1.5 equiv). Without the Cu source, only a trace
67 amount of the desired product was obtained, and most of the
68 starting material 1 was recovered (entry 1). In contrast, with
69 copper powder, the coupling reaction between 1 and p-
70 cresol proceeded smoothly to afford the coupling product 2a
71 in 55% yield with a considerable amount (41%) of the
72 dehalogenated compound, benzo[b]thiophene (3) (entry 2).
73 With Cu(I) salts such as CuCl, CuBr, and CuI,5f,5h 2a was
74 obtained in the respective yields of 48%, 50%, and 57%
75 (entries 3–5). When the reaction was performed without
76 Fe(acac)3, the yield of 2 decreased and that of 3 increased
77 (entry 4). Among several Cu(I) salts, copper thiophene-2-
78 carboxylate (CuTC) provided the best result. With CuTC,
79 the desired compound 2a was obtained in 60% yield, but 3
80 was also obtained in 33% yield (entry 8). We then examined
81 several Cu(II) salts (entries 9–13) and found that the use of
82 Cu(acac)2 afforded 2a in the highest yield (62% yield, entry
83 13).
13 natural products and bioactive compounds, and several
14 synthetic methods have been reported thus far.1 Among the
15 known diaryl ethers, aryl thienyl ethers are important
16 because they can be used as precursors for π-extended
17 thieno[3,2-b]furan derivatives,2 which are potential
18 candidates for organic materials.
19
While copper-mediated Ullmann couplings have been
20 used for a long time for the synthesis of diaryl ethers, these
21 reactions usually require the use of a stoichiometric amount
22 of copper salts as well as high reaction temperatures.3
23 Recently,
a breakthrough was accomplished by the
24 discovery of efficient ligands for Ullmann couplings.4 These
25 ligands realize catalytic Ullmann-type coupling under mild
26 conditions. Another breakthrough is the use of an iron salt
27 as a co-catalyst; several excellent works based on the
28 combination of copper and iron catalysts were recently
29 reported.5 Thus, new possibilities have been reported for the
30 synthesis of diaryl ethers; however, applying such reactions
31 to the synthesis of diaryl ethers bearing an electron-rich
32 heteroaryl, such as benzo[b]thiophene, is challenging
33 because dehalogenation of the substrate often competes with
34 the desired coupling reaction.6 Buchwald and co-workers
35 reported that picolinic acid was an efficient ligand for Cu-
36 catalyzed Ullman-type etherifications.7 They reported the
37 reaction of 3-bromo-2-formyl-benzo[b]thiophene, but the
38 reaction of 3-bromobenzo[b]thiophene, which could be used
39 for thieno[3,2-b]furan, was not reported. Quite recently, Ma
40 and co-workers reported CuI/N-(2-phenylphenyl)-N′-benzyl
41 oxalamide-catalyzed diaryl ether syntheses.8 While the
42 catalytic system could be used for the synthesis of a wide
43 variety of diaryl ethers, they used 3-iodobenzo[b]thiophene
44 as the benzo[b]thiophene source. To the best of our
45 knowledge, there has been no efficient method for a Cu-
46 catalyzed etherification using 3-bromobenzo[b]thiophene,
47 which is commercially available and cheaper than 3-
48 iodobenzo[b]thiophene.
84
Then, we examined the effect of the iron source (Table
85 2) and Fe(acac)3 was the best iron source among the studied
86 sources. Using FeCl2•4H2O, FeCl3, or FeBr3, the yield of 2a
87 decreased to 43%–47% (entries 2–4).
88
The screening of the copper and iron sources revealed
89 that the combination of Cu(acac)2 and Fe(acac)3 was
90 efficient for the Cu/Fe-cocatalyzed etherification of 1 and p-
91 cresol; however, dehalogenation of 1 to 3 was still
92 problematic. Therefore, we investigated the effect of ligands
93 (Table 3). Diamine ligands such as 2,2ʹ-bipyridyl (bpy) and
94 1,10-phenanthroline (phen), which are commonly used with
95 Cu, were ineffective for the reactions, and the yield of 2a
96 decreased (entries 1–2). We then evaluated oxygen ligands
97 (entries 3 and 4) and found that with 1,1'-bi-2-naphthol
98 (BINOL),5i the yield of 2a increased to 51%, but 3 was also

2
a
1
2
3
4
5
6
7
8
9
obtained in 41% yield (entry 3). The use of 2,2,6,6-
tetramethylheptane-3,5-dione (TMHD)5a,5j provided a good
result (72% yield, entry 4). The use of phosphine ligands
was also investigated and found that the triphenylphosphine
(PPh3) was also effective, affording 2a in 73% yield and a
15% suppression of the generation of 3 (entry 5). Further
screening revealed that electron-donating phosphine ligands
such as P(p-tol)3 and PCy3 were ineffective (entries 6 and 7).
In contrast, the etherification proceeded smoothly with P(2-
31
Reaction conditions: 1 (0.5 mmol), p-cresol (0.75
32 mmol), [Cu] (5 mol %), Fe(acac)3 (5 mol %), K2CO3 (2.0
33 equiv), toluene (0.63 M), 145 °C, 24 h. Performed in a
34 sealed tube.
35 without Fe(acac)3.
36 carboxylate.
37
b
c
Determined by 1H NMR.
Performed
d
CuTC = copper thiophene-2-
38 Table 2. Effect of the Fe source on the Cu/Fe-cocatalyzed
39 etherification reaction a
10 furyl)3, which is a slightly electron-deficient ligand (79%
11 yield), but afforded 3 in 18% yield (entry 8). Other electron-
12 deficient ligands were not effective (entries 9–11). Finally,
13 we found that dehalogenation of 1 was suppressed by the
14 use of triphenylphosphine oxide (O=PPh3), affording a 10%
15 yield (entry 12). Using 10 mol % of Cu(acac)2, and 10
16 mol % of Fe(acac)3, the yield of 2a increased to 82% (79%
17 isolated yield) with 12 % yield of 3 (entry 13). The ratio of
18 O=PPh3 to Cu(acac)2 and Fe(acac)3 is singnificant.
19 Increasing or decreasing the amount of O=PPh3, the yields
20 of 2a decreased (entries 14 and 15). The temperature highly
21 influenced the reaction, and the yield of 2a decreased to
22 69% at 135 °C (entry 16). While the reason for the
23 suppression of the dehalogenation of 1 is unclear, we
24 assume that a catalyst bearing O=PPh3 would be highly
25 active and the cross-coupling reaction would proceed faster
26 than the dehalogenation.
40
Entry [Fe]
Yield of 2ab/%
Yield of 3b/%
1
2
3
4
Fe(acac)3
62
30
17
23
28
FeCl2•4H2O 43
FeCl3
FeBr3
45
47
a
41
Reaction conditions: 1 (0.5 mmol), p-cresol (0.75
42 mmol), Cu(acac)2 (5 mol %), [Fe] (5 mol %), K2CO3 (2.0
43 equiv), toluene (0.63 M), 145 °C, 24 h. Performed in a
44 sealed tube. b Determined by 1H NMR.
45
27
28 Table
1.
Cu/Fe-Cocatalyzed
etherification
of
3-
46
We then examined the scope of the etherification
29 bromobenzo[b]thiophene using several catalysts a
47 reactions. Several hydroxyaryls were terated with 3-
48 bromobenzo[b]thiophene under optimized conditions (Table
49 4). The reaction with phenol afforded the corresponding
50 coupling product 2b in 73% yield. Not only p-cresol but
51 also o- and m-cresol could be used for the reaction to give
52 the corresponding coupling products 2c and 2d in the
53 respective yields of 62% and 69%. Hydroxyaryls bearing
54 electron-donating groups, such as t-Bu and methoxy groups,
55 gave the coupling products in moderate to good yields (2e:
56 71%, 2f: 56%). Reactions with hydroxyaryls bearing an
57 electron-withdrawing group were also examined. Reactions
58 with hydroxyaryls bearing a halogen atom, such as F and Cl,
59 at the p-position gave the desired coupling products (2g:
60 76%, 2h: 64%). Hydroxylaryls bearing much stronger
61 electron-withdrawing groups at the p-position, such as
62 trifluoromethyl or nitro groups, were unfortunately not
63 applicable, probably due to their electronic effect. In
64 contrast, the reaction with m-trifluoromethylphenol, which
65 has an electron-withdrawing group at the m-position,
66 proceeded smoothly to give the desired coupling product 2k
67 in 62% yield. We performed out the coupling reaction with
68 more π-extended hydroxy aryls. p-Phenylphenol could be
69 used for the reaction to afford 2l in 71% yield. With 1-
70 naphthol or 2-naphthol, the coupling products 2m and 2n
71 were obtained in the respective yields of 15% and 54%.
72
30
Entry [Cu]
Yield of 2ab/% Yield of 3b/%
1
none
<1
<1
2
Cu powder
CuCl
55
41
3
48
25
4
CuBr
50 (42)c
57
32 (45)c
26
5
CuI
6
Cu2O
54
17
7
CuCN
CuTCd
CuCl2
CuBr2
CuO
53
33
8
60
33
9
46
17
10
11
12
13
54
40
60
23
73
74
Cu(OAc)2
Cu(acac)2
47
43
75 Table 3. Optimization of ligands a
62
30

3
1
Entry
Ligand
Yield of
2ab/%
41
Yield of
3b/%
35
26
1
bpyc
2
phend
39
50
41
18
15
0
3
BINOL
TMHDe
PPh3
51
4
72
5
73
6
P(p-tol)
PCy3
15
7
0
0
8
P(2-furyl)3
P(C6F5)3
P(C6H4-p-CF3)
P(OPh)3
O=PPh3
O=PPh3
O=PPh3
O=PPh3
O=PPh3
79
18
0
9
26
10
11
12
13f
14h
15i
56
14
10
10
12
8
26
73
82 (79)g
68
27
a Reaction conditions: 1 (0.5 mmol), hydroxyaryl (0.75
63
7
28 mmol), Cu(acac)2 (10 mol %), Fe(acac)3 (10 mol %),
29 O=PPh3 (40 mol %), K2CO3 (2.0 equiv), toluene (0.63 M),
30 145 °C, 24 h. Performed in a sealed tube. Isolated yield.
31
16f,j
69
9
a
2
3
4
5
6
7
8
9
Reaction conditions: 1 (0.5 mmol), p-cresol (0.75
mmol), Cu(acac)2 (5 mol %), Fe(acac)3 (5 mol %), ligand
(bidentate: 10 mol %, monodentate: 20 mol %), K2CO3 (2.0
equiv), toluene (0.63 M), 145 °C, 24 h. Performed in a
32 Scheme 1. Sequential double Cu/Fe-cocatalyzed etherification
b
1
c
sealed tube.
bipyridyl.
Determined by H NMR.
phen = 1,10-phenanthroline.
bpy = 2,2ʹ-
d
e
TMHD =
Performed with
Cu(acac)2 (10 mol %), Fe(acac)3 (10 mol %), O=PPh3 (40
f
2,2,6,6-tetramethylheptane-3,5-dione.
g
h
10 mol %). Isolated yield. Performed with Cu(acac)2 (10
11 mol %), Fe(acac)3 (10 mol %), O=PPh3 (20 mol %).
i
12 Performed with Cu(acac)2 (10 mol %), Fe(acac)3 (10 mol %),
13 O=PPh3 (60 mol %). j Performed at 135 ºC.
14
33
34
35
15
16 synthesis of diethers (Scheme 1). The Cu/Fe
17 -catalyzed reaction between resorcinol and 3-
18 bromobenzo[b]thiophene (1) afforded 1,3-
This reaction system could also be applied for the
As an application of the thus-obtained 2, this
36 compound was transformed into thienobenzofurans using a
37 modified Pd-catalyzed dehydrogenative cyclization method,
38 which was reported independently by Satoh and Miura,10
39 and by Kanai and Kuninobu.11 In the presence of Pd(OPiv)2
40 (10 mol %) and AgOPiv (2.0 equiv) in PivOH, the
41 cyclization of 2f and 2g was performed at 120 °C for 20 h
42 (Scheme 2). The corresponding thienobenzofuran
43 derivatives 7f and 7g were obtained in high yields from each
44 precursor, which had an electron-donating or an electron-
45 withdrawing group.12
19 bis(benzo[b]thiophen-3-yloxy)benzene (4) in 54% yield.
20 Similarly, the reaction with (1,1′-biphenyl)-4,4′-diol (5)
21 gave the corresponding diether 6 in 74% yield.
22
23
24
25 Table 4. Scope of the Cu/Fe-cocatalyzed etherification a

4
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77
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1
2
3
4
Scheme
2.
Representative
examples
of
Pd-catalyzed
dehydrogenative cyclization for the synthesis of thienobenzofuran
derivatives 7 a
6
5
6
7
8
9
In summary, we developed Cu/Fe/O=PPh3-catalyzed
etherfication reactions for the synthesis of aryl
benzo[b]thienyl ethers. The use of triphenylphosphine oxide
10 as
a
ligand suppresses the dehalogenation of 3-
11 bromobenzo[b]thiopehene, and enables an efficient
12 synthesis of aryl benzo[b]thienyl ethers. Further applications
13 of this strategy for other heteroaryl ethers are on-going in
14 our laboratory.
7
8
D. Maiti, S. L. Buchwald, J. Org. Chem. 2010, 75, 1791.
Y. Zhai, X. Chen, W. Zhou, M. Fan, Y. Lai, D. Ma, J. Org.
Chem. 2017, 82, 4964
Li and co-workers reported Cu/O=PPh3-catalyzed cyanation
reaction, see: R.-J. Song, J.-C. Wu, Y. Liu, G.-B. Deng, C.-Y.
Wu, W.-T. Wei, J.-H. Li, Synlett 2012, 23, 2491.
9
15
This work was supported in part by a Grant-in-Aid for
16 Scientific Research (C) (Nos. 25410042, 16K05695) from
17 JSPS, Japan, Okayama Foundation for Science and
18 Technology, and by JST, ACT-C, Japan.
19
20 Supporting
21 http://dx.doi.org/10.1246/cl.******.
84 10 a) H. Kaida, T. Satoh, K. Hirano, M. Miura, Chem. Lett. 2015, 44,
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89 12 For the details of the dehydrogenative cyclization reactions, see
the Supporting Information.
Information
is
available
on
90
22 References and Notes
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5