3.8 Miscellaneous Reactions of Aryl Halides
3.8.2 Reactions of Alcohols with Aryl Halides Involving β -Carbon
A unique method of oxidation of primary and secondary alcohols was found by Tamaru, who reported that the Pd-catalyzed oxidation of alcohols with aryl halides proceeds under basic conditions involvingβ-H elimination of the alkoxypalladium 1[1]. Guram et al. reported that cheaply available chlorobenzene can be used for the oxidation of benzyl alcohols and some secondary aliphatic alcohols in toluene at 105◦C using biphenylyl(dicyclohexyl)phosphine (IV-2) as a ligand. Sterically hindered aliphatic alcohol was oxidized usingt-BuONa as a base [1a].
OH
H O Pd-Ph
O
Pd(0) Pd(PPh3)4, K2CO3
+ DMF, 110 °C, 88%
+ H-Ph
1 H-Pd-Ph
Ph-Br
+ + PhH
Pd2(dba)3,IV-2, K3PO4 +
Pd2(dba)3,IV-2,t-BuONa toluene, 105 °C 100%
+ PhH O
O
OH
toluene, 105 °C, 92%
O O
CHO
OH
O Cl
Cl
Miura and co-workers made an interesting observation when they treated α,α- disubstituted arylmethanols2with aryl halides. In this case, there is no possibility ofβ-H elimination, and they observed two transformations of the palladium alkox- ide 3: ortho-arylation to give biarylyl alcohol 4; and β-carbon elimination to afford biaryl 5 and ketone [2]. A general aspect of ortho-arylation of aromat- ics is surveyed in Chapter 3.3, and reactions involving β-carbon elimination are treated in this section. Examples ofβ-carbon elimination are still rare, but numbers are increasing.
+ +
R R
OH R
R O-Pd-Ar H
R R
OH 3
4 Ar
Ar
R R
O b. b-carbon
elimination 2
a
b
a. ortho-arylation Pd(0) Ar-Pd-Br
Ar-Br
5
The frequently observedβ-carbon elimination is expressed by the following two types. As discussed in Chapter 1.3.5, the directions of arrows as indicated by6a and 6bhave no exact mechanistic meaning. The arrows are used in this book in order to help synthetic organic chemists understand the chemical transformations.
+
6b
+ X-Pd CHR3R4
R1 R2
O
X-Pd CHR3R4
CHR3R4
R1 R2
O R1 R2
R1
R2 6a
X-Pd
CHR3R4 X-Pd
Miura et al. carried out extensive studies on the reaction of 2-(biphenyl-2-yl)- 2-propanol (7) with aryl bromide and related reactions using Cs2CO3as a suitable base [3]. A mechanistic explanation of the whole process is summarized in the following. In the reaction with bromobenzene, first the phenylpalladium alkoxide 8is formed. They found thatortho-arylation to produce 12(21 %) and 15 (45 %) is the main path when PPh3is used as a ligand as indicated by the paths from8to 15via11,12,13and14. On the other hand, arylative coupling viaβ-elimination of aryl group as indicated by8aoccurs to yieldo-terphenyl (10) in 21 % yield. When bulky bromides such as 2-substituted 1-bromonaphthalenes are used, the ether17 is produced as the major product via the formation of the palladacycle16.
Theβ-carbon elimination becomes the main path when PCy3 is used. Reaction of triphenylmethanol (18) with bromobenzene gave rise to biphenyl (19) in 93 % yield, along with o-terphenyl (10) in 6 % yield. For the arylation, aryl chlorides can be used as coupling partners. The coupling of 2,6-dimethylphenyl(diphenyl)- methanol (20) with chlorobenzene afforded, 2,6-dimethylbiphenyl (21) in 98 %
Cs2CO3, o-xylene
21%
10
11
9
12
13 8a
Me OH
Me
Me Me OH
Me O
Me Pd-Ph
Pd-Ph
21%
Me Me O
7 8
8
Me Me OH Pd-Ph
Me Me O Pd-P
Ph-Br + Pd(OAc)2, PPh3
Me O
Me Pd-Ph
Ph-Pd-Br
14
15
16
17 Ar-Br + 7
Me Me OH
Pd O Me
Me Me Me OH Pd-Ph
Pd(0)
O Me Me 45%
Ar-H
yield without giving biphenyl at all. The result clearly shows that the bond to the bulky aryl group is cleaved preferentially. In other words, the aryl group having one or twoortho substituent(s) is selectively eliminated.
Me
Me OH Ph
Ph
+
88%
OH Ph
Ph
Cs2CO3,o-xylene, 98%
Pd(OAc)2, PCy3 +
10
Br
+
+
Pd(OAc)2, PCy3 Cs2CO3,o-xylene
Ph Ph O 18
19
20 21
Me
Me
93% 6%
Cl
The coupling reaction offers a very useful synthetic method of various biaryls.
Coupling of 2-(2,6-dimethylphenyl)-2-propanol (22) with 2-chloroanisole (23) was carried out and the asymmetric biphenyl 24 was obtained. The smooth coupling of 22 demonstrates a synthetically more useful method than that of 20, because readily removable acetone is the byproduct.
Cl
OMe Me
Me OMe 22
23
24
+ Pd(OAc)2, PCy3
Cs2CO3,o-xylene, 90%
Me
Me OH Me
Me
The coupling of the naphthalene derivatives25 with26using (R)-BINAP as a chiral ligand provided the (R)-enantiomer-enriched binaphthyl 27 with 63 % ee, suggesting a possibility of asymmetric syntheses of substituted chiral binaphthyls.
The coupling can be extended further to heteroaryl derivatives. Reaction of (2- thienyl)diphenylmethanol (28) with chlorobenzene gave 2-phenylthiophene (29) in 89 % yield.
28 29 26
27 +
25
Cs2CO3,o-xylene 83%, 63% ee
Cl
Pd(OAc)2, (R)-BINAP
Pd(OAc)2, PCy3
Cs2CO3,o-xylene, 89%
OMe
OMe
S
Ph
Ph OH
S
Br Me Me
OH
+
β-Carbon elimination is observed in other systems. Ring-opening of tert- cyclobutanols 30 by the reaction with aryl halides has been reported and the reaction is explained to proceed via β-carbon elimination as shown by 31 to generate alkylpalladium32, which is converted to33[4]. Asymmetric arylation of the cyclobutanol34withN,N-dimethylaminobromobenzene (35) using the bulky N-adamantyl derivative of (R), (S)-PPFAVIII-10as a chiral ligand afforded theγ- phenylated ketone36in 89 % yield with 95 % ee. In this reaction, enantioselective C-C bond cleavage (a or b) as explained by 38 occurs to provide one of the enantiomers 39and40. It was concluded that the b-bond cleavage occurred when the ligandVIII-10 was used [5].
33
38 89%, 95% ee
a
(S)-36 Pd(OAc)2, (R,S)-VIII-10
37
31 32
30
40 39 +
b
a 35
b 34
+ Ph-Br
(R,S)-VIII-10
Pd-Ph O R3 R1 R2
H Ph
Ph OH
Br Ph
Ph O
H Ph
Ph O Pd-Ar
H Ph
Ph O Pd-Ar
Ph H Ph
COAr
COAr H
Ph Ph R3
O-Pd-Ph R2
R1 R3
R2 OH R1
Ph O R3 R1
R2
Me2N Me2N
Fe PPh2 N Me Me Ar-Pd-X
Kinetic resolution of the racemic cyclobutanol41occurred by the reaction with bromobenzene using (R), (S)-PPFA (VIII-9) to give the chiral ketone42and the recovered cyclobutanol43with moderate enantioselectivity [6]. It is noted that in this type reaction, less-substituted carbon is eliminated selectively.
+ Ph
OH
Ph O
Ph Me H
Me
Ph OH H
Me H
46%, 59% ee 41
Pd(OAc)2, [(R)-(S)-PPFA]
+ Cs2CO3, toluene, 96%
43 42
45%, 56% ee Ph-Br
Ring expansion occurs by the reaction of allenylclobutanols with halides to cyclopentanones [7]. Intermolecular reaction of the allenylcyclobutanol 44 with iodobenzene afforded the cyclopentanone 45. Larock and Reddy explained the reaction by the following mechanism. The carbopalladation of the allene with Ph- Pd-I generates theπ-allylpalladium 46, and the concerted rearrangement and ring expansion as shown by47provide48, which isomerizes to45 [8].
OH Me
Ph O
O Ph
H O Ph
47 44
Pd(OAc)2, PPh3
O Ph
PdX H
Pd-I
Bu4NCl,i-Pr2NEt DMF, 70%
46 48
45 +
Ph-Pd-I
Ph-I
•
As another possibility, the reaction of 44 might be explained by the formation of palladium alkoxide 49, followed by β-carbon elimination to afford 50.
Carbopalladation (5-exo cyclization) of 50 gives 51, and reductive elimination produces 45 via 48. However, this route seems to be less likely, since more substituted carbon migrates in this type of reactions as demonstrated by the following examples [9].
Iharaet al. carried out interesting applications of the cyclopentanone formation.
Stereoselective synthesis of α-substituted cyclopentanone 54 with a quaternary carbon stereocenter was carried out by the reaction of the allenylcyclobutanol52 with 4-iodoanisole (53) [9]. Intramolecular reactions of the stereoisomers55 and 57in the presence of silver salt in toluene afforded different products depending on their stereochemistry. The macrocyclic dimeric product56 was obtained from
OH
O
Pd-Ph
O Pd-Ph O
Pd-Ph
Me Ph O Ph O
5-exo cyclization 49
50 51
b-carbon elimination mechanism Ph-I + Pd(0)
48 45
b-carbon elimination
reductive elimination
44 Ph-Pd-I
•
•
•
55 in 80 % yield, a surprisingly high yield, and the monomeric product 58 was obtained from57 [7].
toluene, 80%
Pd(PPh3)4, Ag2CO3
55 56
57 58
Pd(PPh3)4, Ag2CO3
toluene, 67%
52 53 54
HO
HO
I
I
O O
O H H
+ Ph HO
O
Ph OMe
I
MeO
Ag2CO3, toluene 72%
Pd(PPh3)4
Similar carbopalladation–ring expansion was observed in the Pd-catalyzed reac- tion of the (hydroxy)- methoxyallenylisoindoline bearing an iodophenyl moiety59.
In this case, carbopalladation of the allene to form theπ-allylpalladium is followed by rearrangement –ring expansion, as shown by 60, to give the isoquinolinedione
61[10]. The allenyl alcohol without the iodophenyl moiety62alone undergoes the Pd-catalyzed rearrangement –ring expansion to give the isoquinolinedione63 [11].
60
61
62
Pd(PPh3)4, K2CO3 THF, 79%
63 N
HO MeO
O
I N
O MeO
O H
Pd-X
N O
O OMe
N HO
MeO
O
Me N
Me O
O OMe 59
Pd(PPh3)4, K2CO3
THF reflux, 74%
•
Interestingly, formation of the cyclopentanone66from the cyclobutanol having propargyl carbonate moiety 64 occurred by treatment with p-cresol (65) using DPPE as a ligand.
OH OCO2Me
n-C7H15
+
OH
Me
O
O
Me
H
H
n-C7H15
H Pd2(dba)3, DPPE dioxane, 80 °C, 80%
64 65 66
Iharaet al. explained the reaction by the formation of the allenylpalladium68, which is attacked by phenoxide to formπ-allylpalladium intermediate69. Finally, ring expansion of69 gives the cyclopentanone70[12].
Larock and Reddy obtained the 2-alkylidenecyclopentanone72 by the reaction of 1-(1-alkynyl)cyclobutanol 71 with iodobenzene. The bicyclononanone 74 was obtained from73. Selective formation of74demonstrates that the more substituted bond a in the cyclobutanol73undergoes exclusive cleavage (or migration) [8,13].
Larock proposed the mechanism of the reaction of75involving ring expansion of 76to form palladacycle77 and reductive elimination to give78.
67 68 69 Pd(0)
70
OH OCO2Me
R R
OH
Pd-OMe
R O
Pd
OPh
O
OPh R
−OPh − +
i-Pr2NEt, DMF, 60%
a
+
+
Pd(OAc)2, PPh3,n-Bu4NCl b
78 OH
Ph
O
Ph Ph
OH
Ph
O Ph Ph
73 74
71 72
i -Pr2NEt, DMF, 70%
75 76 77
Pd(OAc)2, PPh3,n-Bu4NCl
Pd-X
R Ph
O OH H
R
Pd O
R Ph
O
Ph R Ph-Pd-I
Ph-I
Ph-I
A somewhat different example ofβ-carbon elimination was observed by Catel- lani and Chiusoli in 1983 [14]. Reaction of two molecules of norbornene (79) with bromobenzene gave rise to83. Stepwise carbopalladations of norbornene generate 80and81. Thenβ-carbon elimination yields the alkylpalladium82andβ-H elim- ination affords 83. As described in Chapter 3.8.1, the deinsertion of norbornene from 84 to generate norbornene (79) and arylpalladium 85 is an example of β- carbon elimination.
Although no aryl halide is involved, Pd-catalyzed ring cleavage of cyclobu- tanone oximes 86, leading to unsaturated nitriles 89 via β-carbon elimination as shown by 87 to give the alkylpalladium 88, was reported by Nishimura and Uemura [15]. The tricyclicO-benzoyloxime93was converted to the nitrile94by selective bond cleavage. Interestingly the cyclopropanecarbonitrile99was obtained from the spiro compound95. In this reaction, β-carbon elimination generates the alkylpalladium97, which has no possibility ofβ-H elimination. Under basic con- ditions, intramolecular nucleophilic attack of the carbanion to the alkylpalladium provides the palladacyclobutane98, and the cyclopropanecarbonitrile99is formed by reductive elimination.
79
b-carbon elimination
83 b-carbon
elimination
+
85
Pd-Br
Br-Pd
Br-Pd 82
Pd-X R
R
R
R X-Pd anisole, 1−5°C, 41%
Pd(PPh3)4, HC(OEt)3
80
81
79 84
+ PhBr
87
89 86
N OCOR
Ph N
Pd Ph
88
OCOR Pd-X
C Ph
N
C Ph
N Pd(0)
90
+
64 : 36 Pd2(dba)3, BINAP
K2CO3, THF reflux, 79%
91 K2CO3, THF reflux, 71%
Pd2(dba)3, BINAP
92
93 94
N OBz
t-Bu t-Bu CN
t-Bu CN
N OBz CN
Pd2(dba)3, BINAP K2CO3, THF reflux, 67%
97 99
96
98 95
b-carbon elimination
N OBz
Pd(0) N
Pd-OBz
Pd-OBz CN
Pd CN CN
HOBz
As a related reaction, ring opening of cyclopropyl alcohols was reported by the Uemura and Cha groups using Pd(II). Two products 101 and 102 were obtained in a ratio of 1 : 1.2 by the ring opening of bicyclo[1.0.3]hexane 100as shown by 103[16]. Pd(OAc)2 in DMSO under oxygen was used and they claim that the reaction is promoted by Pd(II). On the other hand, Okumoto and co-workers car- ried out the ring cleavage of 104 using ligandless Pd2(dba)3 alone to afford the unsaturated ketone105 and a negligible amount of the saturated ketone106 [17].
Formation of hydridopalladium alkoxide 107 by oxidative addition of Pd(0) to alcohol andβ-H elimination in 108 are assumed in their case.
DMSO, O2 + rt, 73%
100 101 1 : 1.2 102 103
HO
Me OTIPS
O
Me OTIPS
O
Me OTIPS
AcO-Pd-O
Me OTIPS Pd(OAc)2
Pd2(dba)3, MeCN
50°C, 98% +
106
b-H elimination b-carbon
elimination Pd(0)
104 105
107 108
OH Ph
Ph
O
O-Pd-H Ph
Ph
O
Pd-H Ph
O
H2
As described in Chapter 5.3, a number of addition reactions to methylenecyclo- propanes are explained byβ-carbon elimination.
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