Stereochemistry of Pd-catalyzed allylation of nucleophiles has been studied extensively. In the first step, formation of π-allylpalladium complexes37 by the attack of Pd(0) on allylic compounds36proceeds with inversion of configuration (anti attack). Subsequent reaction of 37 with nucleophiles occurs in different stereochemistry depending on the nature of the nucleophiles. The ‘soft’ (stabilized) nucleophiles which are derived from conjugate acids with pKa<25, such as active methylene compounds, attack37from the backside of the Pd atom to give 38 with inversion of stereochemistry. Thus overall retention is observed. On the other hand, ‘hard’ nucleophiles (pKa>25), typically organometallic compounds of main group metals (Mg, Zn, B, Sn and others) generate39by transmetallation, and subsequent reductive elimination affords 40. Both the transmetallation and
40 retention
R'M
inversion
retention
R R R
Pd OAc
Pd R'
R R
R'
OAc Nu
Nu− Pd(0)
(retention)
36 37 38
39
inversion
(inversion)
reductive elimination proceed with retention, and hence overall inversion is observed with hard nucleophiles. However, Kurosawa and co-workers observed both inversion and retention of stereochemistry in the oxidative addition of 5- (methoxycarbonyl)-2-cyclohexenyl chloride to Pd(0) depending on the ligands and solvents used [18].
Pd-catalyzed allylation of nucleophiles with substitutedπ-allyl systems usually occurs at the less substituted allylic terminus with high regioselectivity. Excep- tional regioselectivity has been reported depending on the substrates and ligands.
Hayashi found that regiochemistry of allylation of NaCMe(CO2Me)2 with allyl acetates is partially retained in the final products when(η3-allyl-PdCl)2and bulky ligands are used [19]. For example, attack at the less-substituted terminus of 41 occurred to give the product42when bulky (R)-MeO-MOP (VI-12) was used as a ligand. Substitution took place with preference at the position originally occupied by the leaving acetate group in 41. On the other hand, substitution of the allyl acetate 44 occurred at the more crowded carbon of 44 to give 43 as the major product. This is known as a memory effect. Similar memory effect of π-allylic ligands was observed by the reaction of the deuterated cyclic allyl acetates 45 and46. The substituted cyclohexene47was obtained mainly from the acetate45, while the acetate 46 afforded 48 as a major product. The results show that the geometrical isomerization of π-allylpalladium intermediates is slow when bulky ligands are used. The original regiochemistry was lost when PPh3was used.
OAc
79 : 21 Ph
Ph Nu
Ph OAc
Ph Nu
(R)-MeO-MOP
THF, rt, 96% 23 : 77 + NaCMe(CO2Me)2
(R)-MeO-MOP THF, rt, 99%
(h3-allyl-PdCl)2
(h3-allyl-PdCl)2
42 + 43
+ 41
44
42 43
+ NaCMe(CO2Me)2
D OAc
AcO D
D Nu Nu D
47 48
+ NaCMe(CO2Me)2
(h3-allyl-PdCl)2
(R)-MeO-MOP THF, rt, 85%
(R)-MeO-MOP THF, rt, 95%
+
83 : 17
17 : 83 47 + 48 45
46
(h3-allyl-PdCl)2
+ NaCMe(CO2Me)2
Aremoglu and Williams found a strong memory effect in the reaction of the allylic acetate50 to give 52by using bulky aliphatic phosphines, typically PCy3 [20]. No memory effect was observed in the reaction of the acetate 49. In these
+ NaCH(CO2t-Bu)2
+ NaCH(CO2t-Bu)2 (h3-allyl-PdCl)2
1.6 : 1 P(t-Bu)3, THF, 99%
1 : 58 51 + 52
+ 49
Me OAc
Me Nu
Me OAc
Me Nu
50
51 52
(h3-allyl-PdCl)2 P(t-Bu)3, THF, 96%
reactions, P(t-Bu)3 is a more effective ligand than PCy3. Also ferrocenyl phos- phines showed large memory effect [21,22].
Retention of geometry, perfect chirality transfer, and high reactivity have been observed by the reaction of the chelated Zn enolate of amino acid ester 53 even when PPh3 was used [23]. In addition, the non-stabilized enolate 53 was found to be very reactive. Reaction of the allylic carbonates 54and 56with the enolate 53 gave 55 and 57 with perfect chirality transfer and high diastereoselectivity.
The carbonates and the enolates are highly reactive and the reaction starts even at −78◦C. Lower selectivity was observed by the reaction of the corresponding allylic acetate.
LHMDS
53 TfaN CO2t-Bu
Zn O TfaN
Ot-Bu ZnCl2
+
97% ee
−78°C rt, 73%
96% ee
+
(S)-56 97% ee
96% ee 53
57 55
53 (S)-54
(h3-allyl-PdCl)2
Ph
OCO2Et TfaNZn O Ot-Bu
Ph
CO2t-Bu NHTfa
OCO2Et
Zn O TfaN
Ot-Bu
Ph CO2t-Bu
NHTfa
Ph PPh3
−78°C rt, 69%
(h3-allyl-PdCl)2 PPh3
Remarkable control of regioselectivity has been observed by the use of some chiral ligands. For example, the diallylation of 2-iodoresorcinol (58) with the allyl carbonate 59 occurred regioselectively at the substituted terminus to give 60 in very high yield (97 %) with a good diastereomeric ratio (dr) (dr=92/8) using one of the Trost ligands (R,R)-Trost L-2[24]. No attack at the unsubstituted terminus took place. In addition, efficient deracemization of the racemic carbonate 59occurred. Reductive Heck reaction of60using HCO2H afforded61with 87 % ee. Use of the sterically hindered base pentamethylpiperidine (PMP) gave good
PMP, DMF
Ac2O, Et3N OH
I
OH
OCO2Me
O I
O CN
CN
O
OAc CN
O O
O
MeO OH
R Pd2(dba)3, (R, R)-Trost L-2
CH2Cl2, rt, 97%, dr 92/8
58
81%, 87% ee 59
60
61 +
HCO2H, PdCl2(MeCN)2
furaquinocin (R)
CN
(R)
results. Concise total synthesis of furaquinocin has been achieved employing these two Pd-catalyzed reactions in key steps.
Allylation of the phenol 62 with geranyl methyl carbonate (63) provided the more congested allyl aryl ether64with excellent regioselectivity (92 : 8) and 76 % ee when Trost L-1 was used. The reaction offers a good synthetic method of chroman [25]. On the other hand, curiously Shishido and co-workers found that the congensted isomer67 was obtained as a single product in 82 % yield by the allylation of the phenol65with the allyl carbonate66even when PPh3was used. It is puzzling why this unusual regioselective reaction occurred under normal reaction conditions [26].
+
+
85%, 76% ee Me
Me OH MeO
Me
Me
Me O MeO
Me
OH MOMO
Me O
MOMO Me i-BuO O
Me Me O
Me Me OCO2Me
O MeO
H 62
63
64
65 66
67 steps
THF, 82%
Pd2(dba)3, (R, R)-Trost L-1
chroman
Pd(PPh3)4
Some tethered alkene affects regioselectivity remarkably. The reaction of the diene 68 with malonate occurred at the more substituted allylic terminus prox- imal to the tethered alkene to give 69, having a quaternary stereocenter with
complete regiocontrol. Thus the double bond at this position showed complete regiocontrol [27]. The seven-membered ring was obtained regioselectively as a single product by the cyclization of the asymmetric allylic acetate69a. Substitution occurred at the allylic terminus proximal to the amino group [28].
(h3-allyl-PdCl)2, PPh3
NaH, THF, 38%
69a
(h3-allyl-PdCl)2, PPh3, THF 65% (>95 : 5)
68 69
+ LiCH(CO2Me)2
OBz Me
CH(CO2Me)2 Me
Me2N
OAc
CO2Me CO2Me
NMe2 MeO2C
MeO2C
Substituents in allylic systems also control regiochemistry. The TMS group is one of these substituents. The vinylsilane 71 was obtained exclusively by the reaction of TMS-substituted allyl carbonate 70. Desilylation of 71 afforded 72.
In this way, nucleophilic substitution at the more substituted carbon of 73 can be achieved indirectly by using 70[29]. Unusual 1,2-addition of a nucleophile to TMS-substituted vinyloxirane74was observed to afford vinylsilane 75.
Pd2(dba)3, P(n-Bu)3
+
70 71
71 72
74
75 +
88%
C5H11 COMe CO2Me TMS
OCO2Me
C5H11
TMS
COMe MeO2C
TMS O
TMS
COMe MeO2C
COMe OH CO2Me C5H11 TMS
COMe MeO2C
C5H11
COMe MeO2C
C5H11 OCO2Me THF, rt, 81%
73 p-TsOH
Pd2(dba)3, P(n-Bu)3 THF, rt, 76%
EWGs show a decisive effect on regioselectivity, and nucleophiles selectively attack the electron deficient side of π-allyl systems as expected. Reaction of α- acetoxy-β,γ-unsaturated nitrile 76 with a nucleophile afforded the γ-substituted α,β-unsaturated nitrile77 and the ester 81 exclusively by 1,3-transposition. Also the reaction of γ-acetoxy-α,β-unsaturated ester80 gave 81 regioselectively [30].
Clean 1,5-transposition occurred by the reaction of the dienyl carbonate 78 with NaN3 to afford79 [31].
C5H11
CHO
C5H11
CN OAc
THF, rt, 97%
COMe CO2Me
+ C5H11CH(CO2Me)2
C5H11 CN
CO2Me OAc
THF, rt, 54%
CO2Me 76
MeO2C CO2Me C5H11
77
86%
E/Z = 1/1
78 79
81 CN CN
OCO2Et N3
80
+ NaN3
CH MeO2C COMe
Pd(PPh3)4
HCN Ac2O
Pd(PPh3)4
Pd(PPh3)4
Regioselective reaction of sulfone-substituted allyl carbonate 82 with acetoac- etate generated83, which underwent Michael-type addition to afford 4-substituted dihydrofuran84in one step [32].
Pd2(dba)3
cis/trans = 78/22
Me SO2Ph
OCO2Me
COCH3
CO2Et
Me SO2Ph
EtO2C
O EtO2C
Me
SO2Ph
83
84 82
Me
O Me DPPE, THF
100°C, 76%
+