Synthesis of diaryl ethers and alkyl aryl ethers by the reactions of aryl halides with phenols and alcohols has been regarded as a difficult reaction. The Pd-catalyzed reaction of aryl halides with phenols and alcohols has been discovered recently and is now attracting attention as a new synthetic method for aryl ethers. Reductive elimination to form the C—O bond as the last step of the ether formation is a rate-determining step. As supporting evidence, Hartwig isolated the DPPF (XI-1) complex of arylpalladiumt-butoxide1from electronically neutralp-t-butylphenyl bromide, and has shown that complex1 resists reductive elimination to afford the t-butyl ether2, and gives biaryls andt-butylbenzene on heating. On the other hand, the thermally unstable DPPF complex 3 of electron-deficient aryl bromide gives the ether 4 in 85 % yield [1]. Thus a number of bulky and electron-rich ligands which accelerate the reductive elimination are used for successful synthesis of aryl ethers.
Ring arylation of phenols with aryl halides to produce arylphenols is competitive with aryl ether formation. As discussed in Chapter 3.3.2, it is known that the ring arylation proceeds with Pd(0)-PPh3catalyst.
25~80°C
+
+
+
3
4 2
25~80°C 85%
1 (dppf)Pd
O-t-Bu t-Bu
(dppf)Pd O-t-Bu
CHO
t-Bu t-Bu
t-Bu
O-t-Bu OHC
O-t-Bu t-Bu
PPh3
PPh3
Pd(0) Pd(0)
Hartwig and co-workers found that DPPF is a suitable ligand for formation of the ether 4from p-bromobenzaldehyde (5) and t-BuONa, but this ligand is effective only for electron-deficient aryl bromides [1]. Later they found that reaction of electronically neutralo-chlorotoluene with sodium phenoxide5agave6in toluene by using monodentate ferrocenylphosphine FcP(t-Bu)2(VIII-2) as a ligand. Other ligands such as BINAP and DPPF are ineffective [2]. Pentaphenylated ferrocenyl ligand VIII-7 is a very effective ligand, and the t-butyl ether 7 and the diaryl ether 6were obtained by the reactions of o-bromotoluene witht-BuONa and the sodium phenoxide 5aat room temperature [3].
5
+
6 Pd(dba)2, DPPF (XI-1)
toluene, 100 °C 66%
4 Cl
Me
ONa
OMe
O
Me OMe
5a
+ Pd(dba)2, FcP(t-Bu)2 (VIII-2) toluene, 82%
5a
7 Pd(dba)2, Ph5FcP(t-Bu)2 (VIII-7)
6 +
Pd(dba)2, Ph5FcP(t-Bu)2 (VIII-7) toluene, rt, 70 h, 99%
toluene, rt, 14 h, 79%
+
O-t-Bu OHC
OHC Br
Br
Me
O-t-Bu
Me
Br
Me
ONa
OMe
O
Me OMe
t-BuONa
t-BuONa
Buchwald expanded the versatility of the ether formation by finding that biphenyl- or binaphthyl-type phosphines (IV-1, IV-3, IV-4, IV-13, and VI-9) are effective ligands [4]. Reactions of electron-deficient aryl chlorides, bromides, and triflates, and also some electron-neutral halides, and triflates proceed smoothly using these bulky ligands. The triflate8reacts smoothly using biphenylylphosphineIV-1as a ligand.
Good results were obtained in the reactions of electronically neutral or electron-rich aryl bromide 9by using binaphthyl-based aminophosphine VI-9. K3PO4 or NaH is a suitable base. Toluene is the only solvent in which efficient reaction proceeds.
Other solvents such as THF, DME, and dioxane give poor results. For the reaction of highly electron-rich 4-chloroanisole (10), these ligands gave poor results and only diadamantylphosphineI-20gave the aryl ether in 73 % yield.
Me Br
Me
Me OH
Cl OH
O Me
Me Me
O i-Pr
OH O
i-Pr
t-Bu
K3PO4, toluene 110°C, 73%
Pd(OAc)2,IV-1
Pd(OAc)2,I-20 Me
MeO
Me
MeO OTf
t-Bu
Pd(OAc)2,VI-9 +
+ +
K3PO4, toluene 100°C, 95%
8
9
84%
K3PO4, toluene 100°C
10
3.7.4.2 Arylation of Alcohols
Efficient formation of arylt-butyl ethers from electron-rich chlorides or bromides can be carried out using biphenyl-type monophosphines (IV-1, IV-4, IV-12) [5].
The aryl t-butyl ether 12 was prepared from electron-rich m-chloroanisole (11) using IV-4 as a ligand. Thet-butyldimethylsilyl ether 13 was obtained from the electron-deficient bromides5using DPPF (XI-1) [1]. Alsot-butyl ether formation is carried out by using P(t-Bu)3.
12
Pd(dba)2, DPPF (XI-1) t-BuMe2SiONa
+ 11
5 11
12
+ 84%
13 Pd(OAc)2, IV-4
76%
xylene, 120 °C 82%
Pd(OAc)2, P(t-Bu)3
OTBDMS OHC
MeO Cl MeO O-t-Bu
Br
CHO
MeO Br MeO O-t-Bu
t-BuONa
+ t-BuONa
The aryl t-butyl ether 15 and silyl ether 18, prepared by the Pd-catalyzed reaction, can be converted easily to phenols 16, and these reactions offer con- venient synthetic methods for phenols 16 from aryl halides 14 and 17. Based on this reaction, the first synthesis of 4-chlorobenzofuran (18c), which is diffi- cult to synthesize by conventional methods, was carried out. Selective mono-t- butoxylation of 2,6-dichloroacetaldehyde dimethylacetal (18a) using P(t-Bu)3as a ligand gave thet-butyl ether18b, and subsequent treatment with aq. HCl afforded 4-chlorobenzofuran (18c) in 51 % overall yield. Further conversion of 18cto var- ious 4-substituted benzofurans is possible by Pd-catalyzed substitutions of the 4-chloro group in18c [6].
14
17 18
16 15
O-t-Bu
OTBDMS R
R
OH
R Cl
Br R
R
Pd(OAc)2, P(t-Bu)3 t-BuONa, xylene, 120 °C
82%
51%
18a 18b 18c
OMe Cl
Cl OMe
OMe Cl
O-t-Bu
OMe O
Cl HCl
Formation of the alkyl ethers21from alcohols, except t-BuOH which lacksβ- H, is not easy. In this case, the following competing oxidation–reduction reaction of halides with alcohols to afford the arenes20as shown by the intermediate19, should be suppressed. Ethers from electron-rich aryl halides and primary alcohols such as 1-butanol can be prepared using binaphthyl ligands. Aryl alkyl ethers are prepared by Pd-catalyzed reaction of aryl bromides with secondary alcohols in toluene using Tol-BINAP (XV-2) [7]. The alkyl ether 23 and the arene 24 were obtained smoothly from the chloride 22 in a ratio of 8 : 1 from primary alcohols such as 1-butanol by using several biphenyl and binaphthyl-type ligands such as VI-1and VI-9. Cs2CO3 was used as a base [8].
R H
O R
Na
R R
O
Br
R
Pd-Br 19 R
21
H R
20
R H
O R
Pd R
O R
HCR2
+
Pd
Cl Me
Me
O-n-Bu Me
Me
H Me
Me
22 23 24
+ n-BuOH
Pd(OAc)2, VI-9 Cs2CO3, toluene 89%
+
8 : 1
Strongly electron-deficient aryl halides react with alcohols without any catalyst.
Catalyzed reaction is sometimes better than uncatalyzed reaction as shown by the reaction of 4-bromo-2-chlorobenzonitrile (25) with cyclohexanol. The ether 26 was obtained in 80 % yield using Pd(0)-VI-9as a catalyst. On the other hand, the uncatalyzed reaction gave equal amounts of26 and27 [7].
CN
Br Cl
CN
Cl HO
CN
O Cl
CN
Br O
25 26
26 27
Pd(OAc)2, VI-9 Cs2CO3, toluene 80%
uncatalyzed +
54%
1 : 1 DMF
Preparation of cyclic ethers by intramolecular reactions of the primary (29and 33) and the secondary alcohols (31and35) proceeds more easily using Cs2CO3or K3PO4, and binaphthyl-based monophosphine ligands VI-1, VI-9[9]. The five-, six-, and seven-membered cyclic ethers 30, 32, and 34 were prepared from the aryl chloride 31 and bromides 29 and 33. The benzoxazapine 36 was obtained without racemization of chiral alcohol by the cyclization of the optically active bromo alcohol35.
Cs2CO3, toluene 78%
32 Pd(OAc)2, VI-9
Br O
30 OH
Cs2CO3, toluene 85%
Pd(OAc)2, V-6 29
31 Cl
OH Me
O Me
Br O
34 OH
Cs2CO3, toluene 73%
33
Pd(OAc)2, VI-9
t-BuONa, toluene 94%
99% ee 98% ee
Br 35
O N N
Me OH Me
36 Pd(OAc)2, VI-1
An antidepressant MKC-24239was synthesized by applying the cyclization of the optically active alcohol 37 as a key step to form the benzodioxane 38 using aminobiphenylylphosphine (IV-13) as a ligand.
39 37
38
Pd(OAc)2, IV-13 Br
O
O N
OH
N
O Ac
O O
O
O O O
O
H
N O
O O O
Ac
K3PO4, toluene 94%
HCl HCl
MKC-242
3.7.4.3 Arylation of Thiols
Aryl sulfides (thioethers) are prepared by the reaction of aryl halides with mer- captans or thiophenols in DMSO. Synthesis of the phenyl thioether41 using the thiol 40 is an example. DPPF is a good ligand [10,11]. Phenyl n-butyl thioether (43) was prepared by the reaction of triflate 42withn-butylmercaptan. BINAP is an effective ligand, but Tol-BINAP is more effective.t-BuONa is used as a base, but interestingly no t-butyl phenyl ether is formed in this reaction [12]. Total synthesis of chuangxinmycin (45) was carried out by intramolecular reaction of the aryl iodide44[13]. The asymmetric bispyrimidine thioether 48 was prepared in high yield by coupling pyrimidine-2-thiol46with 2-bromopyrimidine (47) [14].
43 42
41 40
DMSO, 76%
Pd2(dba)3, DPPF (XI-1)
+ +
S-Bu AcNH CO2Me
SH S
AcNH I
CO2Me
OTf
t-BuONa, toluene, 94%
Pd(OAc)2, Tol-BINAP (XV-2) n-BuSH
Et3N, 74%
45 44
N H I
CO2Me Me
SH
NH S
CO2Me Me
+ t-BuOK, THF
72 °C, 88%
46
47
48 N
N N
N Me
Me
SH
OH
Br
N Me N
Me
S
OH N Pd(PPh3)4 N
Pd(PPh3)4
Commercially available, air-stable Pd phosphinous acid complex is an active catalyst for the thioether formation by the reaction of 1-cyclopentenyl chloride (49) with thiophenol (50) and hexylmercaptan (52) to give the thioethers51 and 53[15]. 1-Cyclopentenyl phenyl thioether (55) was obtained by the reaction of 1-cyclopentenyl triflate (54) with lithium phenyl sulfide [16].
[(t-Bu)2P(OH)PdCl]2 +
[(t-Bu)2P(OH)PdCl]2 +
t-BuONa, toluene, 88%
49
50 51
52 53
Cl
t-BuONa, toluene, 94%
S
S HS
54 55
HS
49 Cl
OTf SPh
LiSPh +
As a related reaction, thiophenols are prepared from phenols. For example, the Pd-catalyzed reaction of 2-naphthyl triflate with sodium triisopropylsilane thiolate (56) gives the silyl ether of 2-thionaphthol 57. Deprotection of 57 affords 2- thionaphthol (58) [17].
+ THF/benzene
86%
60%
56
57 58
OH
SH OTf
SSi(i-Pr)3
(i-Pr)3SiSNa Pd(PPh3)4
TBAF
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