It has been well-established that organopalladium intermediates are electrophilic, and clearly different from other organometallic compounds such as Grignard reagents which are nucleophilic. It is highly desirable to achieve a catalytic version of Grignard reactions. Yamamoto and co-workers reported a ‘formal’ Pd-catalyzed Grignard-type reaction [55]. They obtained the cyclopentanol 114 in 69 % yield by the reaction of the phenyl ketone111in the presence of Pd(OAc)2,PCy3, and Na2CO3 in DMF. PPh3 is not effective. Furthermore, addition of 1-hexanol (5 equiv.) was crucial. The reaction is explained by nucleophilic attack of the Pd intermediate 112to form 113, from which the cyclopentanol 114is provided. At the same time Pd(II) is generated and reduced to Pd(0) probably with 1-hexanol.
Similarly the cyclopentanol116and the cyclohexanol118were obtained from the bromo ketones115 and117.
The reaction proceeds at high temperature (ca. 150◦C). Interestingly no α- arylation of ketones occurred under these conditions. Also, bromides gave better results than iodides.
+ Pd(II) Br
Pd(0) Ph
O
Ph O-PdBr
Pd(OAc)2, PCy3
112
113 114
Ph OH
Pd O Br
Ph
111
base
Na2CO3, DMF, 1-hexanol 135°C, 12 h, 69%
H+
Ph OH
Bu OH
Br Bu
O
Ph
Br
O 115
117 118
Pd(OAc)2, PCy3
AcOK, DMF, 1-hexanol 150°C, 24 h, 85%
116 Pd(OAc)2, PCy3
AcONa,DMF, 1-hexanol 150°C, 16 h, 62%
Sole and co-workers found the smooth carbonyl addition reaction of amino- tethered aryl iodides and ketones [29]. Treatment of the 2-iodoanilino ketone 119 with PPh3,Et3N and Cs2CO3in toluene afforded the alcohol120. The cyclized prod- uct122was obtained from 2-iodobenzylamino ketone121. The cyclized product124 of the iodo ketone123was converted to the indole derivative125in high yield by acid-catalyzed dehydration. In these reactions, noα-arylation was observed.
PdCl2(PPh3)2, Cs2CO3 Et3N, toluene, 100 °C, 65%
PdCl2(PPh3)2, Cs2CO3
PdCl2(PPh3)2, Cs2CO3
Et3N, toluene, 100°C, 87%
119 120
121 122
cis/trans = 3.5 /1 N
I O
Ac
N HO
N Me O I
N Me
OH Et3N, toluene, 100 °C, 73%
TFA
123 124 125
Ac
N
Bn O
I
N Bn HO
N Bn
The tethered amino groups seem to play an important role. In the mechanis- tic studies, the rare four-membered palladacycle 127 was isolated in high yield as a stable compound by treatment of the iodoaniline-derived ketone 126 with Pd(PPh3)4, and converted to the alcohol130in high yield on heating with Cs2CO3. The cyclization is explained by the formation of the complex 127, which makes insertion of the C=O bond (or carbopalladation) to form the Pd alkoxide 128 easier. The alcohol 130 and Pd(II) are generated by the reaction of 128 with Cs2CO3via129.
127
Pd(0) insertion
Cs2CO3
128
129 130
127 130
110°C 126
N I
Bn
N Pd
I
Bn N
O Pd
L I
Bn
N Cs-O
Bn
L
N HO
Bn O O
Cs2CO3 Pd(II)
H+
So far, these Pd-catalyzed Grignard-type reactions are limited to intramolec- ular versions to form five- and six-membered alcohols. Further extension and mechanistic studies are highly desirable.
Also, it should be added that β-carbon elimination is the reverse process of these reactions (see Chapter 3.8.2).
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