Aryl ethers are common structures in numerous pharmaceutically and agriculturally important compounds (Scheme 1).1 Traditional methods for the preparation of these compounds include the Williamson ether synthesis,2 direct nucleophilic substitution reactions3 and Ullmann-type couplings of alkoxides with aryl halides.4 Each of these reactions, however, typically requires either highly reactive aryl halide, an excess of the alkoxide or harsh conditions such as high temperature (125–300 oC) and stoichiometric or greater amount of copper reagent which, on scale-up, leads to problem of waste disposal.5 To overcome these drawbacks, much attention has been focused in recent years to develop catalytic systems for C-O bond formation by cross-coupling reactions.
Vancomycin Type Compound
C-O cross coupling
OH
I
I NH2
O HO
O I
OH I
I
I NH2
O HO
L- Thyroxine
C-O cross coupling OH
B OH HO
HN NH
MeO2C
OH N N Br
N
O
O Br HN
NH MeO2C
O N N Br
N
O
O
Scheme 1
3.1.1 Palladium Catalysts
Palladium based catalysts are considerably studied for cross-coupling of aryl halides with hydroxy compounds.6 The coupling of aliphatic alcohols with aryl bromide is studied by the combined use of Pd2(dba)2 and (S)-(-)-2,2`-bis(di-p-tolyl phosphino)-1,1`-binapthyl 1
in the presence of NaH in toluene (Scheme 2).6a Aryl bromides having electron with drawing groups undergo coupling effectively in high yields.
+
1.5 mol% Pd2(dba)3
Toluene, 50 oC, 24 h Yield 80%
3.6 mol% 1 2 equiv NaH
P(o-tol)2 P(o-tol)2 1
Me Me
OH O Me
NC Me Br
CN Scheme 2
Hartwig and Mann reported the coupling of aryl alkoxides with aryl bromides using Pd(dba)2 and CF3-dppf 2 [dppf =1,1’-bis (trifluoromethyl)phenyl phosphino ferrocene)]
in a mixture of THF and toluene (Scheme 3).6b Series of aryl bromides bearing electron withdrawing groups are investigated with high yields.
ONa O
+
5-10 mol% Pd (dba)2 6-11 mol% 2
Yield 74% CN
PX2 PX2 Fe
9:1 Toluene:THF 100-120 oC, 6-30 h 2 Br
CN
CF3
X Scheme 3
These authors also further demonstrated the coupling of aryl alkoxide with aryl bromide using Pd(dba)2-P(t-Bu)3 in toluene (Scheme 4).6c Under these conditions aryl chlorides undergo reactions more efficiently compared to aryl bromides and –iodides at moderate temperature.
.
X = Cl, 9 h, Yield 82%
X = Br, 12 h Yield 85%
X ONa
OMe
Me O +
5 mol% Pd(dba)2 5 mol% P(t-Bu)3
Toluene, 80 oC Me
OMe
Scheme 4
Buchwald and co-workers showed the cross-coupling of phenols with aryl halides by the combined use of Pd2(dba)3 and electron rich and bulky aryl dialkyl phosphine 3 in the presence of NaH or K3PO4 in toluene (Scheme 5).6d The coupling of aryl chlorides, bromides and triflates is demonstrated in high yields. In these reactions, the bulkiness of the ligand is believed to be responsible for the acceleration of the rate of the reductive elimination of the diaryl ether from palladium.
Me Cl
Me
O Me
Me
Me
Me NMe2
(t-Bu)2P +
0.75 mol% Pd2(dba)3 2.25 mol% 3
Toluene, 110 oC, 24 h
Yield 78% 3
1.4 equiv NaH OH
Me Me Scheme 5
Intramolecular C-O cross-coupling of hydroxy groups with aryl halides is accomplished using Pd(dba)2-Ph5FcP(t-Bu)2 4 in toluene at ambient temperature (Scheme 6).6e Turnovers of rougly 1000 are observed for reactions with unactivated aryl bromides or chlorides.
P(t-Bu)2 Ph 5 mol% Pd (dba)2 Fe
5 mol% 4
Toluene, RT, 10 min.
Yield 93%
Br MeMe O
HO MeMe
Ph Ph
Ph Ph
4 Scheme 6
More recently, the coupling of alcohols with aryl bromides using Pd(OAc)2 and ligand 5 is reported in the presence of Cs2CO3 at 70 oC in toluene (Scheme 7).6f Under these conditions, n-butanol undergoes reaction with 2-bromotoluene in 85% yield.
P(t-Bu)2 2 mol% Pd (OAc)2
2. 5 mol% 5
Toluene, 70 oC, 21 h
Yield 85% 5
Me
1.5 equiv Cs2CO3 O +
Br
OH
NMe2 Me
Scheme 7
3.1.2 Copper Catalysts
Copper based catalytic systems are significantly studied for the C-O cross-coupling reactions.7 The coupling of phenols with aryl iodides and -bromides is accomplished using (CuOTf)2.benzene in the presence of Cs2CO3 in toluene (Scheme 8).7a In these reactions, 1-naphthoic acid enhances the solubility of the phenoxides.
I Me
Me
OH Me Me O Me
Me +
2.5 mol% (CuOTf)2 (PhH)
5 mol% EtOAc
Toluene, 110 oC, 12-26 h Yield 85%
2.5 equiv Cs2CO3 2.5 equiv naphthoic acid
.
Scheme 8
The use of copper(I) salt in combination with phenanthroline based ligands 6-8 is described for the coupling of aryl iodides and –bromides with hydroxy compounds in the presence of Cs2CO3 (Scheme 9).7b-d Aryl iodides exhibited greater reactivity compared to aryl bromides. The reactions of phenols and primary alcohols are found to be successful under these conditions.
Br
Me
OH O
+
10 mol% 6
Toluene, 110 oC, 36 h
Yield 99%
2.5 equiv Cs2CO3
N N
Me Cu Me
Ph3P 6 Br Me
Me Me
I MeO
OH
O
OMe N N
+
10 mol% CuI 20 mol% 7
Neat, 110 oC, 24 h Yield 75%
2 equiv Cs2CO3
7 OH
+ O
5 mol% CuI 10 mol% 8
Toluene, 110 oC,12 h 1.5 equiv Cs2CO3
Yield 95% 8
I
OMe OMeMe N N
Me Me
Me
Scheme 9 Br
Me
OH O
+
0.56 mol% CuCl
NMP, 110 oC, 7.5 h Yield 63%
2 equiv Cs2CO3 9
F
Me F
O O
11 mol% 9
Br
Me
OH O
+
10 mol% CuBr
DMSO, 80 oC, 36 h Yield 72%
2.1 equiv Cs2CO3 Me 20 mol% 10
10 O
OEt O
Scheme 10
The coupling of aryl iodides and –bromides with hydroxy compounds is also demonstrated using copper(I) salt and 1,3-dicarbonyl compounds in the presence of Cs2CO3 under moderate temperature (Scheme 10).7e-f These reaction conditions are also suitable for the C-N and C-S cross-coupling reactions. Few studies are showed the coupling of phenols with aryl bromides and –iodides using CuI in combination with amino acid, amino phosphonate or imine as ligands in the presence of Cs2CO3 (Scheme 11).7g-i These reactions are effective at moderate temperature with high yields. Aryl iodides exhibited greater reactivity compared to aryl bromides.
I OH
O +
4 mol% CuI/15 mol% 11
Dioxane, 90 oC, 18 h 86%
2 equiv Cs2CO3/
11
N OH
O
.HCl
10 mol% CuI/ 20 mol% 12
DMF, 110 oC, 15 h
2 equiv Cs2CO3/ 95% 12
NH
PO OHOPh
OH
Me Me
O Me
Me N
N N
N +
10 mol% CuI/ 5 mol% 13
CH3CN, 80 oC, 24 h, N2
2 equiv K3PO4/ 96%
13 I
NOH
14 5 mol% CuI/20 mol% 14 OH
CH3CN, 82 oC, 24 h, N2
2 equiv Cs2CO3/ 97%
Reaction Conditions Yield
Reaction Conditions Yield
Scheme 11
3.1.3 Iron Catalyst
Iron(III) chloride in combination with l,3-dicarbonyl compound 9 is used for the coupling of phenol with aryl iodide in the presence of Cs2CO3 in DMF (Scheme 12).8 Aryl bromide is moderately reactive under these conditions.
.
10 mol% FeCl3 20 mol% 9
OH O
+ 2 equiv Cs2CO3
Yield 85%
DMF,135 oC, 20 h I
Scheme 12