Ligand-free Cu-catalyzed O-arylation of aliphatic diols

Article abstract of DOI:10.1039/c5ra12529d

Coupling reaction between aryl iodides and aliphatic diols was realized with a ligand-free copper catalyst under mild conditions. This method was successfully applied in the process of scale-up synthesis of medicinal candidate product EMB-3.

Full text of DOI:10.1039/c5ra12529d

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Ligand-free Cu-catalyzed O-arylation of aliphatic
diols†
Cite this: RSC Adv., 2015, 5, 66104
*
Yufen Zheng, Wenxing Zou, Laichun Luo, Jiabei Chen, Songwen Lin and Qi Sun
Received 29th June 2015
Accepted 27th July 2015
Coupling reaction between aryl iodides and aliphatic diols was realized with a ligand-free copper catalyst
under mild conditions. This method was successfully applied in the process of scale-up synthesis of
medicinal candidate product EMB-3.
DOI: 10.1039/c5ra12529d
www.rsc.org/advances
recently in the O-arylation of aliphatic alcohols (17–59% yields,
Scheme 1a).17 However, the reaction substrate was very narrow
Introduction
and high temperatures were required. In addition, the yield of
desired ethers was very low and was just determined exclusively
using 1H-NMR spectroscopy. Maiti reported an efficient ligand-
free Cu-catalyzed O-arylation of aliphatic alcohols 4 and aryl
iodide 2 to produce alkyl aryl ether 5 in the presence of 2.3
equivalents of NaOt-Bu (Scheme 1b).18 Although this “ligand-
free” methodology was further tested in the one-step synthesis
of 2-(2-(4-uorophenoxy)ethyl)-phenol (CRE 10904: 2-OH, n ¼ 1,
R ¼ 4-F, Scheme 1b), it could not be transposed on industrial
scale because of its relative low yield of 50%. Very recently, Chae
reported a Cu-catalyzed O-arylation of aliphatic alcohols with
aryl bromide as substrate and CuCl2 as catalyst (83–99% yields).
However, this protocol was effective for the aryl bromide and
the required temperature (at 130 ꢀC) was high.19 Therefore,
ligand-free Cu-catalyzed O-arylation of aliphatic alcohols
remains a challenge.
Since Ma et al. reported the rst effective ligand amino acid
(L1, Fig. 1) for copper catalysis in the synthesis of enantiopure
N-aryl-a-amino acids from R-amino acids with aryl halides in
1998,1,2 Brønsted bases,3,4 phenanthroline (L2, Fig. 1),5
1,2-diamino-cyclohexane (L3, Fig. 1)6–8 and several other repre-
sentative ligands (L4–L7, Fig. 1) have been reported as effective
ligands in the CuI-catalyzed aryl amination.9 Based on these
novel ligands, many chemoselective methods, such as Csp2- or
C
sp3-N-arylation,10 Csp2-S-arylation11 and Csp2-O-arylation12 have
been studied. However, only a few reported copper catalyst
systems could facilitate the coupling between aryl halides and
aliphatic alcohols13 because of the weak nucleophilic ability of
aliphatic alcohols. For example, researchers, including Buch-
wald et al., reported a highly efficient phenanthroline ligand
(L2, R1, R2, R3, R4 ¼ Me, Fig. 1) in the amination of aryl iodides
under mild conditions.14–16
Our research group has engaged in metal-catalyzed coupling
transformation including C–C coupling reactions20 and C–S
coupling reactions.21 For the purpose of extending to C–O
coupling reactions, the efficiency of ligand-free copper-catalyzed
Avoiding the use of different complex and expensive ligands,
“ligand-free” copper catalyst systems have been reported
Fig. 1 Representative ligands for the Ullmann reaction.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, 38, Xueyuan Road, Haidian Distract, Beijing 100191, PR
China. E-mail: sunqi@bjmu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra12529d
Scheme 1 Ligand-free Cu-catalyzed O-arylation of aliphatic alcohols.
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Csp3-O-alkyl chain was investigated. Herein, we disclose a simple was increased to 80 ꢀC from 70 ꢀC, the yield of 7a was
and practical ligand-free procedure for the copper-catalyzed unchanged, but a further increase over 80 ꢀC evidently
arylation of different primary and secondary aliphatic diols decreased the yields (Table 1, entries 15–18). When the dosage
(Scheme 1c).
of diol was increased to 5.0 equiv. or decreased to 1.5 equiv., 7a
was isolated in a yield of 78% and 55%, respectively (Table 1,
entries 19 and 20). As shown in Table 1, 7a wasn't obtained
when CuI wasn't used (entry 22) or when a small amount of
water was added (entry 23) or when 1,4-butanediol was replaced
by 1-butanol (Table 1, entry 21), suggesting that 1,4-butanediol
was the starting material and also the ligand. Therefore, reac-
tion conditions were determined to include CuI (10 mol%) as
the catalyst and NaOt-Bu (3.0 equiv.) as the base in DMF at 80 ꢀC
with a 2a/6a molar ratio of 1 : 3 for 18 h (Table 1, entry 15).
To further test this reaction, 6a was reacted with various aryl
iodides under the optimized reaction conditions. As shown in
Table 2, with some electron-withdrawing groups, such as Cl, Br
and phenyl, the desired products were obtained in relatively
moderate yields (Table 2, entries 4, 5 and 9). However, with
other electron-withdrawing groups, such as cyano, tri-
uoromethyl and benzoyl, the corresponding products were
obtained only in very low yield probably due to their strong
electron-withdrawing effects (Table 2, entries 6–8). Iodo-
benzenes bearing one or two electron-donating groups on the
phenyl ring, such as 2j, 2k, 2l, 2m, 2n, 2r and 2s reacted with 6a
to form the coupled products in low to moderate yields (Table 2,
entries 10–14, 18 and 19). In addition to para-substituted
Results and discussion
4-Fluoro-iodobenzene 2a and 1, 4-butanediol 6a were selected
as model substrates in the experiment under various conditions
(Table 1). Aer 2a was treated with 6a (3.0 equiv.) in the pres-
ence of CuI (5 mol%ꢀ) and NaOtꢁBu (3.0 equiv.) in N,N-dime-
thylformamide at 70 C for 18 h, product 7a was isolated with
a yield of 76% (Table 1, entry 1). Upon using CuBr as the cata-
lyst, product 7a was obtained in lower yield (Table 1, entry 2). As
shown in Table 1 (entries 1, 3–5), the amount of CuI had limited
inuence on the yield. Entries 6–9 in Table 1 show that NaOt-Bu
was essential for the coupling reaction because 7a was not
obtained with K2CO3, K3PO4, Cs2CO3 or Et3N. Entries 10–14 in
Table 1 also show that solvent effects were signicant and
product 7a could not be produced in THF, DMSO, 1,4-dioxane,
MeCN or toluene instead of DMF. When reaction temperature
Table 1 Optimization of reaction conditionsa
Table 2 Synthesis of alkyl aryl ethers 7 from aryl iodides 2 and 1,4-
butane-diol 6aa
Entry Copper
Base
Solvent
Temp. (ꢀC) Yieldsb (%)
1
2
3
4
5
6
7
8
CuI (5 mol%) NaOt-Bu DMF
CuBr (5 mol%) NaOt-Bu DMF
CuI (10 mol%) NaOt-Bu DMF
CuI (15 mol%) NaOt-Bu DMF
CuI (20 mol%) NaOt-Bu DMF
70
70
70
70
70
70
70
70
70
70
70
76
58
77
65
76
0
0
0
0
Entry
Ar (Het)
7
Yieldsb (%)
CuI (10 mol%) K2CO3
CuI (10 mol%) K3PO4
DMF
DMF
1
2
3
4
5
6
7
8
2a 4-F-C6H4
2b 3-F-C6H4
2c 2-F-C6H4
2d 4-Br-C6H4
7a
7b
7c
7d
7e
7f
7g
7h
7i
78
68
58
82
80
30
44
38
CuI (10 mol%) Cs2CO3 DMF
9
CuI (10 mol%) Et3N
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CuI (10 mol%) NaOt-Bu THF
CuI (10 mol%) NaOt-Bu DMSO
0
0f
CuI (10 mol%) NaOt-Bu 1,4-dioxane 70
0
0
0
2e 4-Cl-C6H4
CuI (10 mol%) NaOt-Bu MeCN
CuI (10 mol%) NaOt-Bu Toluene
CuI (10 mol%) NaOt-Bu DMF
CuI (10 mol%) NaOt-Bu DMF
CuI (10 mol%) NaOt-Bu DMF
CuI (10 mol%) NaOt-Bu DMF
CuI (10 mol%) NaOt-Bu DMF
CuI (10 mol%) NaOt-Bu DMF
CuI (10 mol%) NaOt-Bu DMF
CuI (0 mol%) NaOt-Bu DMF
CuI (10 mol%) NaOt-Bu DMF
70
70
80
90
100
110
80
80
80
80
80
2f 4-CN-C6H4
2g 4-CF3-C6H4
2h 4-Bz-C6H4
2i 4-Ph-C6H4
78
69
58
67
78c
55d
0e
0f
9
64
10
11
12
13
14
15
16
17
18
19
2j 4-NHAc-C6H4
2k 4-OMe-C6H4
2l 4-Me-C6H4
2m 2-Me-C6H4
2n 4-OCF3-C6H4
2o C6H5
2p 2-Pyridinyl
2q 3-Thiophenyl
2r 3,5-Dimethyl-C6H3
2s 2,4-Dimethoxyl-C6H3
7j
7k
7l
7m
7n
7o
7p
7q
7r
35
63
78 (73c)
58
70
77 (74c)
74 (Traced)
0g
53
72
49
a
Reaction conditions: 2a (0.5 mmol), 6a (1.5 mmol, 3.0 equiv.), copper
catalyst (0.05–0.2 mmol), base (1.5 mmol, 3.0 equiv.), solvent (2 mL),
7s
b
c
18 h. Isolated yields calculated based on 2a. 5.0 equiv. 1,4-butanediol
was used. 1.5 equiv. butanediol was used. 1,4-Butanediol was
d
e
a
Reaction conditions: 2 (0.5 mmol), 6a (1.5 mmol, 3.0 equiv.), CuI
replaced by 1-butanol. 4-(4-Iodophenoxy)butan-1-ol 7t instead of 7a was (0.05 mmol, 10 mol%), NaOt-Bu (1.5 mmol, 3.0 equiv.), DMF (2 mL),
f
obtained and the structure was conrmed by 19F-NMR, 1H-NMR and 80 ꢀC, 18 h. Isolated yields calculated based on 2. At 70 ꢀC. CuI
b
c
d
13C-NMR. g 0.5 mL H2O was added to the reaction system.
was not added.
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Table 3 Synthesis of alkyl aryl ethers 8 from aryl iodides 2 and diols 6a Table 5 Applied synthesis of 12 from N-phenyl-6-iodo-4-quinazo-
linamine 11 and aliphatic diols 6a
Entry
2
6
8
Yieldb [%]
Entry
1
11
6
12
Yieldb [%]
1
2
2l
2l
6b
6c
59
60
11a
6a
82
3
4
2l
2l
6d
6e
61
45
2
3
4
11a
11a
11b
6b
6c
6a
73
76
65
5
6
7
8
2l
6f
76
86
52
77
2l
6g
6f
2o
2a
6g
9
2r
6g
65
a
Reaction conditions: 2 (0.5 mmol), 6 (1.5 mmol, 3.0 equiv.), CuI
(0.05 mmol, 10 mol%), NaOt-Bu (1.5 mmol, 3.0 equiv.), DMF (2 mL),
b
5
6
11b
11c
6b
6a
60
72
80 ꢀC, 18 h. Isolated yields calculated based on 2.
Table 4 Synthesis of alkyl aryl ethers 10 from aryl iodides 2 and 2,5-
hexanediol 9a
7
11c
6b
77
Entry
Ar (Het)
10
Yieldc [%]
1
2
3
4
5
6
7
2a 4-F-C6H4
10a
10b
10c
10d
10e
10f
47
56
64
51
54
78
36
2k 4-OMe-C6H4
2l 4-Me-C6H4
2o C6H5
2p 2-pyridinyl
2r 3,5-dimethyl-C6H3
2m 2-Me-C6H4
a
Reaction conditions: 11 (0.5 mmol), 6 (1.5 mmol, 3.0 equiv.), CuI
(0.05 mmol, 10 mol%), NaOt-Bu (1.5 mmol, 3.0 equiv.), DMF (2 mL),
b
80 ꢀC, 18 h. Isolated yields calculated based on 11.
10g
a
Reaction conditions: 2 (0.5 mmol), 9 (1.5 mmol, 3.0 equiv.), CuI
(0.05 mmol, 10 mol%), NaOt-Bu (1.5 mmol, 3.0 equiv.), DMF (2 mL),
80 ꢀC, 18 h. b Mixture of isomers. c Isolated yields calculated based on 2.
iodobenzene 2a and 2l, meta-substituted substrate 2b, ortho-
substituted substrate 2c and 2m were also successfully applied
to this transformation with relatively low yield (Table 2, entries 2,
3 and 13). Furthermore, iodides with phenyl ring, pyridine ring
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chelation of CuI with diols 6 forms a reactive species 13. In this
process of forming intermediate 13, diols 6 act as reactant and
ligand. The ring strain of intermediate 13 is not supposed to be
too strong. Herein, glycol could not react with CuI to form the
transition state. Subsequent oxidative addition of intermediate
13 with aryl iodides 2 leads to the intermediate 14. Then CuI is
regenerated by a putative reductive elimination, giving the
desired products 7 simultaneously.
Conclusions
Scheme 2 Possible mechanism of copper-catalyzed O-arylation of
In summary, we have successfully developed a ligand-free
Cu-catalyzed protocol to synthesize alkyl aryl ethers from
multi-substituted aryl iodides and aliphatic diols under mild
conditions with moderate to good yields. Furthermore, with this
method, under the optimized reaction conditions, 200 g – scale
synthesis (yield: 82%) of a key intermediate of medicine EMB-3
was realized.
aliphatic alcohols.
or thiophene ring gave the desired coupled products (7o: 77%,
7p: 74% and 7q: 53%) without much yield loss (Table 2, entries
15–17). When reaction temperature was decreased to 70 ꢀC from
ꢀ
80 C, product 7l and 7o were obtained in slightly lower yield
(73 and 74% respectively), proving 80 ꢀC was more efficient than
70 ꢀC (Table 2, entries 12 and 15).
Acknowledgements
When various diols, including aliphatic diols 6b–e and
methyl or benzyl substituted diethanol amine 6f–g, were used,
the desired products were obtained in 45–86% yields (Table 3,
entries 1–9). Compared with 6a, aliphatic diols 6b–e gave the
corresponding products 8a–d in lower yields (Table 3, entries
1–4), which indicated that the chain length of aliphatic diols
might affect the reaction efficiency. Comparing between
N-methyl diethanol amine 6f and N-benzyl diethanol amine 6g,
which had comparable reactivities as 6a, 6g exhibited higher
reactivity with better yields (Table 3, entries, 5 and 6). Aryl
iodides 2a, 2o and 2r reacted with 6f or 6g to afford the desired
products in 52–77% yields (Table 3, entries 7–9).
To further examine the scope of diols, 2,5-hexanediol 9 was
tested under the optimized conditions. As shown in Table 4,
iodobenzene derivatives containing electron-donating or
electron-withdrawing groups on the aryl moiety reacted with
2,5-hexanediol to produce the corresponding products in
36–78% yields, which indicated that the steric hindrance on
diols had limited impact on the reaction.
According to Maiti's excellent work, the ligand-free
Cu-catalyzed chemoselective mono-arylation of aliphatic alco-
hols could be applied to modify Ullmann coupling reaction
between diols 6 and aryl iodides 11 from commercial available
4-chloro-6-iodo-quinazoline and different anilines, thus to
provide [4-phenylamino-6-quinazolinyl]-oxyl-propanol 12, a key
intermediate of anticancer drug candidate EMB-3.22,23 Under the
optimized conditions, 11a–c reacted with aliphatic diols 6a–c to
form the corresponding compounds successfully in 60–82%
yields (Table 5, entries 1–7). And this intermediate 12 could
shorten the synthesis steps of EMB-3 from 6 to 3. Furthermore,
under these optimized reaction conditions, 200 g – scale
synthesis (yield: 82%) of 12a, which was a key intermediate of
anti-tumor compound EMB-3, was realized.
This research was supported by Ministry of Science and Tech-
nology of China (Grant 2012ZX09103101–042).
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