As in some other cases of Pd-catalyzed cross-coupling, nearly ten or a dozen metals in- cluding Li, Cu, Mg, Zn, B, Al, and Sn have been used as the metal countercations, and trends similar to several other cases have been observed.
1. Li. Despite some early successful results with alkyllithiums,[3] they have scarcely been used in Pd-catalyzed alkylation. This must, in part, be due to their inability to toler- ate many conventional polar functional groups. As discussed earlier, however, the high in- trinsic reactivity of alkyllithiums appears to be responsible for some of the difficulties ob- served with alkyllithiums. In any event, it may be stated that the current scope of Pd-catalyzed alkylation with alkyllithiums is rather limited. In cases where alkylmetals containing other metals are prepared via alkyllithiums, however, it would be desirable and advisable to examine the reaction of alkyllithiums themselves to justify the use of other metals. Some of the favorable results observed with alkyllithiums[3] are summarized in Scheme 2.
2. Cu and Zr. Little is known about the use of Si, Zr, and even Cu in Pd-catalyzed alkylation with alkylmetals. It should be recalled, however, that Cu-promoted or -catalyzed alkylation without the involvement of Pd or other transition metal complexes is a widely ap- plicable and generally satisfactory synthetic methodology.
3. Al and Sn. Both trialkylalanes[7]–[14] and tetraalkyltins[15]–[31] have been used successfully in Pd-catalyzed alkylation. Even so, the current scope with respect to and generally superior and highly satisfactory routes to 1,5-dienes, 1,5-enynes, and re- lated compounds of natural origin and/or of medicinal significance that are difficult to ac- cess. For this reason, these reactions are discussed separately in Sect. III.2.11.2.
alkylalanes is mostly limited to Me3Al, Et3Al, Pr3Al, and (i-Bu)3Al, the only excep- tion being Me3SiCH2AlR2, where R is Me3SiCH2or Me.[9]One practical difficulty is that only one of the three alkyl groups in R3Al can be used in this reaction, which can be a serious limitation in cases where more elaborate and expensive alkyl groups are involved. Alkyltins are generally even less reactive. In many cases, Me4Sn appears to be satisfactory. On the other hand, (n-Bu)4Sn appears to be significantly less reactive.
In general, the scope with respect to alkyltins is almost as limited as in the cases of alkylalanes. Typically, only one out of four alkyl groups is utilized in the reaction.
More recently, however, the use of RSnX3, where X is a halogen, in Pd-catalyzed alkylation has been reported.[30],[31]The use of HO2CCH2CH2SnCl3to achieve alkyla- tion in 71% yield is noteworthy and promising[30](Scheme 3). In most cases, however, Pd-catalyzed alkylation with alkylmetals containing Al and Sn may also be achieved with those containing Mg, Zn, and B. Collectively, these three metals provide satisfac- tory procedures of significantly wider scope. Consequently, the use of other metals, such as Al and Sn, will have to be well justified. Some representative results observed with alkylalanes[7]–[14]and alkylstannanes[15]–[29]are shown in Tables 1 and 2, respec- tively.
HO2CCH2CH2SnCl3 I
COOH
SO3Na Cl2Pd Ph2P
HO2CH2CH2C
COOH
2
71%
H2O, 100°C + cat.
Scheme 3
PhCH=CHBr + Li R cat. PdLn PhCH=CHR
Eor Z R PdLn Yield (%)
Z Me Pd(PPh3)4 90
Z Me Cl2Pd(PPh3)2 95
E Me Pd(PPh3)4 88
Z Bu Ph(PPh3)4 62
Z Bu Cl2Pd(PPh3)2 73
Z Bu Cl2Pd(PBu3)2 14
E Bu Pd(PPh3)4 46
Scheme 2
n-Dec
OP(O)(OPh)2
OP(O)(OPh)2 t-Bu
n-Pr OP(O)(OPh)2
SPh BnO
CO2Me
OP(O)(OPh)2
HO
N N N
N
NH2
O OH OH
Br
HN N NH2
O
Br (or I)
3
Ph
OP(O)(OPh)2
Ph OP(O)(OPh)2
SPh
n-Pr OP(O)(OPh)2 SPh 2-MePhOTf
N
Br CO2CH3
(1)
(1) (1) HO
O R′ OH
R
R′X Catalyst Solvent Yield (%) Reference
DCE
DCE Benzene
Cl2Pd(PPh3)2 _DIBAH
DCE
Benzene
Benzene
91
72 83
53
53 97
95
71−86
80
82
55
24 97 53 13 52
[7]
[7]
[8]
[11]
[10]
[10]
[12]
[13]
[7]
[8]
[8]
[14]
[10]
[12]
[12]
[10]
4-ClPhOTf
PhOTf
PhOTf RM
Me3Al Pd(PPh3)4
Me3Al Pd(PPh3)4
Me3Al Pd(PPh3)4
Me3Al THF
Me3Al Pd(PPh3)4 THF
Me3Al Pd(PPh3)4 THF
Me3Al PdCl2-PPh3 THF
Me3Al Pd(PPh3)4 THF
Et3Al Pd(PPh3)4
Et3Al Pd(PPh3)4
Et3Al Pd(PPh3)4
Et3Al Pd(PPh3)4 THF
Pr3Al Pd(PPh3)4 THF
Pr3Al PdCl2-PPh3 THF
i-Bu3Al PdCl2-PPh3 THF
i-Bu3Al Pd(PPh3)4 THF
TABLE 1. Pd-Catalyzed Cross-Coupling Reactions of Alkylaluminums with Alkenyl and Aryl Electrophiles
R′X Catalyst Solvent
Yield (%)
Ref- erence
PhBr 4-MeC6H4Br 4-FC6H4Br 4-MeCOC6H4Br 3-HO2CC6H4I 4-HO2CC6H4I 4-MeCOC6H4OTf 2,6-(MeO)2C6H3OTf 4-ClC6H4N2BF4
4-NO2C6H4N2PF6
HMPA HMPA HMPA HMPA KOH-H2O KOH-H2O Dioxane DMF CH3CN CH3CN
89 84 89 99 98 82 75 92 88 95
[15]
[15]
[15]
[15]
[30]
[31]
[20]
[24]
[16]
[16]
O HO
Br
OTf MeO
O
OAc OMe OMe
Br O
N N N
N NH2
O OH HO
Br MeOH2C
Dioxane 80 [23]
75 [29]
61 [19]
92 [28]
(2) Z
N O
CO2R′ OTf RCONH
S N O
CO2CHPh2 OTf BuO2CNH
70 [22]
Pd2(dba)3-TFP 85 [25]
RM
PhCH2Pd(PPh3)2Cl PhCH2Pd(PPh3)2Cl PhCH2Pd(PPh3)2Cl PhCH2Pd(PPh3)2Cl PdCl2
PdCl2
Pd(PPh3)4
PdCl2(PPh3)2-LiCl Pd(OAc)2 Pd(OAc)2 Me4Sn
Me4Sn Me4Sn Me4Sn MeSnBr3 MeSnCl3 Me4Sn Me4Sn Me4Sn Me4Sn
Me4Sn Pd(PPh3)4
Me4Sn Cl2Pd(PPh3)2 DMF
Me4Sn Pd(PPh3)4 THF
Me4Sn Pd(PPh3)4 NMP
Me4Sn Cl2Pd(CH3CN)2
LiCl
DMF
Me4Sn NMP
TABLE 2. Pd-Catalyzed Cross-Coupling Reactions of Alkyltins with Alkenyl and Aryl Electrophiles
PhN2BF4 (2)
4-HO2CC6H4I 4-HOC6H4I 3-HO2CC6H4I
[16]
[19]
[31]
[30]
[30]
[17]
[18]
t-Bu OTf
Me Cl
Cr(CO)3
S N O
CO2CHPh2
OTf BuO2CNH
O
O OH
OTf
OH O
O Ph
OH TfO
MeO Cl
Cr(CO)3
4-MeCOC6H4OTf
[21]
[21]
[31]
[25]
Dioxane [20]
[20]
[26]
Dioxane [20]
N OMe
TfO
H Me
7 44 25
<10 71 80 75
82
74
16
82
92
74
N.R.
77 [27]
CH3CN THF KOH-H2O KOH-H2O KOH-H2O Et4Sn
Et4Sn Me2CHSnCl3 HO2C(CH2)2SnCl3 HO2C(CH2)2SnCl3
Bu4Sn THF
4-HO2CC6H4I
4-NO2C6H4OTf
Bu4Sn THF
Bu4Sn THF
BuSnCl3 KOH-H2O
Bu4Sn NMP
Bu4Sn
Bu4Sn DMF
Bu4Sn DMF
(Me3SiCH2)4Sn Me4Sn
Pd2(dba)3, TFP Pd(OAc)2
Pd(PPh3)4 PdCl2 PdCl2
PdCl2 Pd(PPh3)4, LiCl Pd(PPh3)4
Pd(PPh3)4
PdCl2
Pd(PPh3)4
PdCl2(PPh3)2, LiCl
PdCl2(PPh3)2
Pd(PPh3)4 Pd(PPh3)4, LiCl
DMF
R′X Catalyst Solvent
Yield (%)
Ref- erence RM
TABLE 2. (Continued)
Alkylmetal Organic Electrophile Catalysta Yield (%) Ref- erence 100
76 25 81 21 91 68b
4 5 43 51 95c 97c 80c 60d
[1]
[6]
[6]
[6]
[6]
[6]
[6]
[4]
[4]
[4]
[4]
[4]
[4]
[4]
[5]
87 [2]
I Bu-n
I Bu-n
I Bu-n
I Bu-n
I Bu-n
I Bu-n
PhBr PhBr PhBr PhBr PhBr
(E)-BrCH CHPh Br(Me)C CH2
(E)-BrCH CHPh (Z)-BrCH CHPh (E)-ICH CHPh
=
=
=
=
= MeMgBr
EtMgBr n-BuZnCl
n-BuMgBr
H2C=
=
==
CH(CH2)2ZnCl
H2C CH(CH2)2MgBr
Me3SiC C(CH2)2ZnCl
s-BuZnCl
s-BuMgCl s-BuMgCl s-BuMgCl s-BuMgCl s-BuMgCl s-BuMgCl s-BuMgCl t-BuMgCl
A B C D E E E E A
A A A A A A A
TABLE 3. Scope of Pd-Catalyzed Alkylation with Alkylmetals Containing Mg and Zn
aAPd(PPh3)4; BCl2Pd(PPH3)2; CCl2Pd(dppp); DCl2Pd(dppb); ECl2Pd(dppf).
bA 60:40 mixture of s-Bu and n-Bu isomers.
cNo regioisomerization took place.
dAdditionally, the isobutylated product was formed in 16% yield.