3.2 Reactions with Alkenes (Mizoroki–Heck Reaction)
3.2.3 Reaction Conditions (Bases, Solvents, and Additives)
Since strong acids are formed, the reaction must be carried out in the presence of bases. Coordinating and polar solvents, such as DMF, MeCN, NMP and DMSO, are preferable solvents. DMF is the most widely used. Water, a highly polar liquid, has been found to accelerate some reactions, which are carried out smoothly in aqueous solvents using water-soluble ligands.
Poly(ethylene glycol) (PEG) having molecular weight 2000 (or lower) has been used as a good biphasic solvent for regioselective reaction of n-butyl vinyl ether
to give a single isomer 32 cleanly. It is known that a mixture of regioisomers is formed in other solvents. Furthermore, after the reaction, products can be iso- lated with dry ether. Pd catalyst always stays in the PEG layer and is recycled easily [22a]. HR proceeds rapidly in ionic liquids and catalysts can be recy- cled [18,23,24]. Double HR of bromobenzene with butyl acrylate occurred rapidly under microwave irradiation in bmim PF6 (1-butyl-3-methylimidazolium hexaflu- orophosphate) to give β,β-diphenylacrylate (33) [24]. In addition to the use of the ionic solvent, addition of 1,2,2,6,6-pentamethylpiperidine (PMP) as a base is important for the double HR.
E : Z = 7 : 3 32
bmimPF6, PMP, 45 min 220 °C, 50%
CO2Bu
Ph Ph
CO2Bu +
Pd(OAc)2, Et3N PEG, 80 °C, 82%
Ph-Br MeO
Br
O n-Bu
O n-Bu
+ PdCl2, P(o-Tol)3
33
Uses of some additives are recommended. Addition of Ag2CO3 cleanly sup- presses double bond isomerization in products. In addition, Ag salts accelerate reactions, possibly by removing halide ions strongly attached to Pd from a coor- dination sphere to generate a cationic Pd catalyst, making the insertion easier.
Thallium salts also accelerate reactions, and suppress the double bond isomer- ization. A favorable effect of some alkali halides, such as LiCl and KBr, on the reaction is known [25].
Selection of bases is also important. Trialkylamines and inorganic bases such as K2CO3 and KOAc are commonly used. An unusually good effect of Cs2CO3
in some reactions is now well-known. It behaves as a base better than K2CO3
due to partly better solubility in organic solvents and higher basicity, and is used frequently. Buchwald reported that a bulky amine, Cy2NMe, is a very effective base [26].
Larock found that the reaction of 2-iodo-4-methylbiphenyl (34) with acrylate provided two products 35 and 36 in equal amounts using cesium pivalate as a base. Of course,35 is an expected product [27]. Also the reaction of 37afforded the mixture of35 and 36. Gallagher also discovered a similar migration using 3- bromo-4-phenylpyridine (38) and acrylate to afford 39 and40 [28]. Although the mechanism of the migration process to form the crossover products is not clear, certainly a reversible 1,4-Pd shift of arylpalladium intermediates41and43via the palladacycle42 is occurring.
Reetz reported that a highly active ligandless Pd catalyst for HR of aryl bro- mides can be generated by combining Pd(OAc)2 or PdCl2(PhCN)2 with N,N- dimethylglycine (DMG), and TON 106 700 was obtained with this catalyst in the reaction of bromobenzene with styrene, although the reaction was slow [29,30].
Jeffery made the important observation that a large rate acceleration in HR of aryl iodides occurs by addition of more than equimolar amounts of tetraalky- lammonium salts as a phase-transfer catalyst and solid bases without ligands. The
36
35 35
36 34
37 Me
I
Me Me
CO2Et
CO2Et Pd(OAc)2, PPh3
Me
I
CO2Et
CO2Et +
+
+
50 : 50
CsPiv, DMF 100°C, 86%
CsPiv, DMF 100°C, 87%
Pd(OAc)2, PPh3
+ 49 : 51
39 40
38
+ +
Pd(0)
41 43
N Br
N N
CO2Et
CO2Et CO2Et
42 Br
A
Et3N, MeCN 125°C, 89%
Pd(OAc)2, P(o-Tol)3
Pd-Br
2 : 1
A A A
Pd Pd-Br
conditions are called ‘Jeffery’s ligandless conditions’. Reactions of aryl and alkenyl iodides proceed smoothly by the addition of KHCO3and Bu4NCl in DMF at room temperature [31]. Detailed studies have shown that careful selection of the kinds and amounts of Pd catalysts, bases, solvents, water and particularly tetraalkylam- monium salts, are important to find optimum conditions [32]. As one explanation of the effect of tetraalkylammonium salts, Reetz found using transmission elec- tron microscopy that R4N+X−-stabilized Pd colloids are formed under Jeffery’s ligandless conditions and function as active catalysts [33].
As a recent example, HR of the disubstituted alkenes 44 gave 45 with high stereoselectivity using a ligandless catalyst. In this case, selection of bases is crucial and combined use of methyl(dicyclohexyl)amine and a phase transfer catalyst gave the best results [26].
44
+ Me(Cy)2N (1.5 equiv)
Et4NCl (1 equiv)
95°C, 72% 45 E:Z = 11 : 1 Br
OMe
MeO2C
CO2Me
MeO
CO2Me MeO2C
Pd(OAc)2
It is known that HR of vinyltrimethylsilane with aryl halides affords styrene derivatives by desilylation–arylation. In the presence of Ag salt, normal products are obtained [34]. Jeffery reported that either the normal product 46 or styrene, the desilylation product, from iodobenzene and vinyltrimethylsilane are obtained selectively under mild conditions by slight modification of conditions. In the pres- ence of Bu4NOAc and molecular sieve in DMF, 2-trimethylsilylstyrene (46) is obtained as expected. On the other hand, styrene is obtained selectively as an abnormal product in toluene in the presence of 3 equivalents of KF. Formation of styrene is explained by the combination of three reactions, namely β-H elimina- tion, reverse readdition of H-Pd-X, and subsequent desilylpalladation. Whatever the mechanism, the presence of a large amount of KF, which strongly activates the TMS group, must play an important role [35].
SiMe3 I
SiMe3 MS 4A, DMF, r.t., 99%
toluene, r.t., 94%
+ Pd2(dba)3, KF (3 equiv) n-Bu4NCl (2 equiv)
46 Pd(OAc)2
n-Bu4N(OAc) (2.5 equiv)
As another example of a delicate effect of tetraalkylammonium salts, either 2-phenyl-2,5-dihydrofuran (47) or 2-phenyl-2,3-dihydrofuran (48) was obtained selectively in the arylation of 2,3-dihydrofuran with a slight change of addi- tives [36].
48
I O
O
O 4 A MS, DMF, r.t., 94%
47
DMF, r.t., 92%
Pd(OAc)2, KOAc (2.5 equiv) n-Bu4NCl (2.5 equiv) +
Pd(OAc)2
n-Bu4N(OAc) (2.5 equiv)
Jeffery’s conditions are so mild that reaction of an alkenyl iodide containing a very unstable peroxide group 49 proceeded smoothly without decomposition of the peroxide under the conditions at room temperature [37].
Cyclization of the quinoxaline chloride50to prepare pyrrolo[2,3-b]quinoxaline under usual conditions is slow and the yield is low, because the aminoquinoxa- lines are strong chelating agents and poison Pd catalysts. However, the locked Pd catalyst is released and the reaction proceeds smoothly under Jeffery’s ligandless conditions to give the pyrrolo[2,3-b]quinoxaline 51in 67 % yield [38].
excess +
49
Pd(OAc)2,K2CO3 Bu4NBr, rt
86%
Pd(OAc)2,K2CO3 Bu4NBr, DMF 100°C, 67%
N N
N H Cl
N N
N H I
O
O OMe CO2Me
O
O OMe
CO2Me
50 51
Many successful applications of Jeffery’s conditions have been reported. How- ever, Rawal reported in his alkaloid synthesis that Jeffery’s conditions were not suitable for the attempted cyclization of the iodide corresponding to 52(Br→I), and the cyclization of the vinyl bromide52 proceeded cleanly under a ‘nonpolar’
set of conditions; Pd(OAc)2, PPh3, proton sponge in toluene at 100◦C to give 53 in 82 % yield [39].
proton sponge K2CO3, PhMe,
110 °C, 82%
N
N O
Br
N
N O
H Pd(OAc)2 (5 mol%) H
PPh3 (20 mol%)
52 53
A remarkable effect on rate enhancement under high pressure is known [40].
The enantiomerically pure isoquinoline 55 was obtained from the bromide 54 in 70 % yield and with high diastereoselectivity (16 : 1) under pressure (10 kbar).
The yield was lower than 10 % under normal pressure and even under Jeffery’s conditions [41].
54 55
Br N-Boc
Et
N-Boc Et Pd(PPh3)4, Et3N,
MeCN, DMF 60°C, 10 kbar, 70%
diastereoselectivity = 16 : 1
Also acceleration is observed by microwave irradiation in a solvent-free reaction [24,42]. HR of the steroidal triflate 57 with alkene 56 is a key reaction in prac- tical synthesis of the complex bis-steroidal diene intermediate58. The best yield
O O O
O
O O
H
TfO
O O O O
H
H
O O O O
H O
O
O
O O O
H H
H H
H H
H
H H
+
Pd(OAc)2, Bu4NCl, Cs2CO3 microwave (20 min), 77%
56 57
58
(77 %) was obtained under Jeffery’s ligandless conditions and microwave irradia- tion. Cs2CO3was found to be more effective than K2CO3 [43].