Pd-catalyzed O-allylation of aliphatic alcohols is sluggish particularly in the inter- molecular version due to poor nucleophilicity of alcohols. As one solution, metal alkoxides are used to make nucleophilicity of alcohols stronger. Lee reported that Zn alkoxides are good coupling partners. Reaction of the cyclic allyl acetate 176 with benzyl alcohol proceeded smoothly at room temperature in the presence of Et2Zn (0.5 equiv.) using Pd(OAc)2with bulky biphenyl-based phosphineIV-1and gave two ethers with retention of stereochemistry in high yield (70 %) in a ratio
of 40 : 1. On the other hand, inversion occurred to give a ratio of 1 : 2 in low yield (20 %) when PPh3 was used [68]. Interestingly allylation of OH group in aβ-L- ribose177with the cyclic allylic acetate178proceeded smoothly using Pd2(dba)3
and PPh3in dichloromethane to afford the disaccharide precursor with 96 % de in 55 % yield without activation of OH group [69].
CO2Me
OAc
+ BnOH
CO2Me
OBn
CO2Me Et2Zn (0.5 eq), THF
+
OBn
20%
70%
Pd(OAc)2,IV-1 176
177
(−)-178
> 40 : 1 1 : 2
+ Pd2(dba)3, PPh3
55%, 96% de O
O OH
RO O
O
O O
RO O
O O
O
O AcO
Pd(PPh3)4
Stereoselective formation of 3-methylenetetrahydrofuran such as 180 by intra- molecular allylation of alcohol with allyl benzoate in179was utilized in synthetic studies of the core of amphidinolide [70]. Thus treatment of 179 with Pd(OAc)2 and PPh3 in the presence of Me3SnCl (1 equiv.) and NaH in THF afforded the cis-tetrahydrofuran 180 stereoselectively in 77 % yield. In this reaction, the less reactive hydroxy group was converted to the more reactive tin alkoxide by the reaction of Me3SnCl (1 equiv.) and NaH.
Pd(OAc)2, PPh3
NaH, Me3SnCl, THF, 60 C, 77%
179
180 Bu3Sn
Me OTIPS
H
H OH
OBz
OTBS O
Bu3Sn OTIPS H
H O
O
Me TBSO
H H H
Tetrahydrofuran formation proceeds with high stereocontrol. Cyclization of (E)- allylic ester 181 proceeded at room temperature with overall retention of con- figuration to give the 2,5-cis-tetrahydrofuran 182 using Pd(PPh3)4 in the pres- ence of neocuprone (2,9-dimethyl-1,10-phenanthroline). On the other hand, overall inversion occurred in the reaction of (Z)-allylic ester183to afford the 2,5-trans- tetrahydrofuran184with (E)-alkene [71].
neocuprone, THF
65°C, 79%
neocuprone, THF 25°C, 76%
neocuprone = PivO
O
O OH
R*O2C
CO2R*
OPiv OPiv
OPiv OH
PivO CO2R*
R*O2C OPiv
182 181
183 184
N N
Me Me
Pd(PPh3)4
Pd(PPh3)4
Formal total synthesis of uvaricin was achieved by applying double cyclization of vicinal diol bis(allylic acetate) to afford bis-THF core selectively using chiral ligand Trost L-1as a key reaction [72]. Thus the cyclization of 185afforded the diene186with two new stereocenters in 97 % yield as a single diastereomer.
Pd2(dba)3 (R,R)-Trost L-1 THF, 97%
185 186
OAc
OAc HO
HO H
H
O
O H
H H
H
The F-ring of the polyether macrolide halichondrin was constructed by Pd- catalyzed selective monocyclization of187 and 189. No dicyclization took place due to steric reasons. Desymmetrization of themeso-diol187gave the tetrahydro- furan188 in high yield using Trost L-1as a chiral ligand, and cyclization of the C2symmetric diacetate189afforded the desired diastereoisomeric tetrahydrofuran 190[73].
Pd2(dba)3
Pd2(dba)3
(R,R)-Trost L-1 THF, 0 °C, 87%
(R,R)-Trost L-1 THF, 81%
187 188
189 190
OAc
OAc
OAc
OAc HO
HO
HO HO
O
OAc H
HO H
O H OAc
HO H
In contrast to less efficient allylation of alcohols, allylation of phenols proceeds much more smoothly. In the enantioselective synthesis of (−)-galanthamine by Trost, two Pd-catalyzed reactions were utilized. Asymmetric allylation of the bro- movanillin191with the cyclic allylic carbonate 192 gave the ether193 by using (η3-allyl-PdCl)2 and chiral Trost L-2. Subsequent Heck reaction of 194 afforded 195in 91 % yield when DPPP was used as a ligand. DPPF and DPPE gave lower yield [74].
(h3-allyl-PdCl)2, Trost L-1 MeO
OH Br
CHO
Troc = 2,2,2-trichloroethoxycarbonyl 72%, 87~88% ee
Pd(OAc)2, DPPP
CO2Me TrocO
Ag2CO3, toluene 107°C, 91%
191
192
193
(-)-galanthamine 194
MeO O
CHO CO2Me Br
195 MeO
O
CHO Br
CN MeO
CHO O
H
CN MeO
O H
NMe OH steps +
In the total synthesis of callipeltoside, Pd-catalyzed asymmetric allylation ofp- methoxyphenol with the allylic carbonate196was carried out. When chiral ligand (R,R)-TrostL-2was used, a mixture of regioisomers197and198was obtained in high yield. The regioselectivity to form the branched and linear isomers was 3 : 1, and the diastereomeric ratio was 19 : 1. The branched isomer197 was the major product [75].
+ Pd2(dba)3, (R,R)-Trost L-2 n-Bu4NCl, CH2Cl2
rt, 100% conv.
+
dr=19/1 196
197 198
OTBS
OTroc MeO
OTBS
MeO OPMP
OMe
HO
OTBS
OPMP MeO
3 : 1
The enantioselective total synthesis of (+)-aflatoxin B1has been achieved by O- allylation withγ-acyloxybutenolide and reductive Heck reaction [76]. The couma- rin derivative 199 was O-allylated with γ-O-Boc-butenolide 200, which is an
allyl carbonate, to give 201 in 89 % yield in the presence of Bu4NCl and Trost L-1. Reductive Heck reaction of 201 by using ligandless Pd catalyst afforded the coumarin 202 in 93 % yield with higher than 95 % ee, and aflatoxin B1 was prepared from 202. Efficient deracemization of the butenolide by differentiation of the enantioface occurred.
Bu4NCl, CH2Cl2, rt, 89%
Et3N, DMF, 50°C 93%, > 95% ee HCO2H, PdCl2(MeCN)2,
Pd2(dba)3, (R,R)- Trost L-1
aflatoxin B1 200 +
199
201 202
O O EtO2C
OH I
MeO
O O EtO2C
O I
MeO O O
O O EtO2C
MeO O
O H O
H
O O
MeO O
O H
H O
O O
BocO
Efficient intramolecular O-allylation of L-N-benzoylphenylalaninol derivative 203to formtrans-oxazoline204with high diastereoselectivity (14 : 1) was utilized for the enantioselective total synthesis of (+)-preussin [77].
(+)-preussin Pd(PPh3)4,
K2CO3 MeCN, 83%
203 HN
Ph O OAc
N O
Ph
NMe C9H19
OH
204
4.2.4.2 Allylation of Nitrogen Nucleophiles
Amines are reactive nucleophiles and allylation of amines proceeds smoothly using various ligands. Santelli reported that amination of allylic acetates proceeds
smoothly in water by using tetradentate Tedicyp (X-1) as a ligand. Allylmorpho- line was obtained in 96 % yield by allylation of morpholine in water alone when the substrate/catalyst ratio of 100 000/1 was used. But 1000/1 was necessary for diallylamine formation from allylamine in 85 % yield. Pd-Tedicyp is soluble in water [78].
OAc
N O
HN
O + (h3-allyl-PdCl)2,,X-1
H2O, K2CO3
55°C, 20 h, 96%
amine : Pd cat = 100000 : 1
Reaction ofmeso-bis-carbonate204with the sulfonamide205afforded206with 99 % ee. The second regio- and diastereoselective allylation of the amine207with 206gave the diamine208using DPPB as a ligand. Ru-catalyzed metathesis of the diene208afforded 209and tetraponaine was synthesized [79].
208
209
206 MeO2CO
MeO2CO
NsNH
MeO2CO
Ns N
NsNH
OC2H5
OC2H5
N
Ns N
OC2H5
N N
N N H H Ns
OC2H5
Ns
Ns OC2H5
OC2H5
204
Pd2(dba)3, (S,S)-Trost L-1
207
99% ee
metathesis
steps
79% overall one pot
tetraponaines
Ns= 205
O2N SO2
DPPB +
Asymmetric synthesis of nucleoside has been carried out based on desym- metrization of the meso form of cis-2,5-dibenzoyloxy-2,5-dihydrofuran diester (210), which possesses two allylic leaving groups at 2,5-positions with correct stereochemistry. N-allylation of 6-chloropurine (211) with210using Pd(0)-(R,R)- Trost L-1 afforded 212. Reaction of 212 with a malonate derivative using PPh3
afforded214, which was converted to adenosine216. The enantiomeric adenosine 217 was prepared via 213 and 215 simply by using (S,S)-Trost L-1 in the first allylation [80].
O
PhOCO OCOPh
N O OCOPh
PhOCO O N
N N N
N N
N
Cl Cl
N N N NH
Cl 212
210
211
213
215
217 216
214 N O N N
N Cl
CbzO CO2Bn
CO2Bn O N
N N
N Cl Cs2CO3, Pd2(dba)3
PPh3, 96%, 93% ee
O N
+
N N N NH2 steps
85%
Pd2(dba)3
(S,S)-Trost L-1 Pd2(dba)3
(R,R)-Trost L-1
O N
N N
N NH2
Cs2CO3, Pd2(dba)3
PPh3, 97%, 93% ee
74%
OH
BnO2C OCbz BnO2C
steps
HO
CbzOCH(CO2Bn)2 CbzOCH(CO2Bn)2
Allylation of ammonia gives a mixture of products, and it is difficult to prepare primary amines from ammonia, and several ammonia surrogates are used. Allyla- tion of sodium diformylamide (219) with the allyl acetate218proceeded smoothly by using DPPF as a ligand to afford 220, which was hydrolyzed to provide the primary allylamine221. The reaction was sluggish when PPh3was used. The pri- mary allylamine 224with high ee (95.5 %) was obtained from 94 via223by the use of (S)-BINAP [81].
218 219 220
224 219
221
94 223
Me Me
OAc
(h3-allyl-PdCl)2
+ Me Me
N(CHO)2
DPPF, MeCN 60°C, 79%
(h3-allyl-PdCl)2, (S)-BINAP ClCH2CH2Cl,
0°C 85%, 95.5% ee
Me Me
NH2
Ph Ph
OAc
Ph Ph
N(CHO)2
Ph Ph
NH2
NaN(CHO)2
NaN(CHO)2 +
Tosyl isocyanate (226) was allylated smoothly with the alkenyloxirane225using isopropyl phosphite as a ligand to give the oxazolidinone227in 75 % yield, which was converted to thesyn amino alcohol228in high yield. Oxazolidinone formation proceeds with overall retention of configuration, and is used for the synthesis of regioisomers of sphingosine [82].
228
225 226
227
Pd2(dba)3, P(O-i-Pr)3
THF, rt, 75%
+
BnO C13H27
O
BnO C13H27
OH NH2
BnO C13H27
O H
Pd-X
O NTs
BnO
C13H27
O
O=C=NTs TsN=C=O
Azide is a reactive nucleophile and is used as an ammonia surrogate. Desym- metrization of the dicarbonate 229 occurred by the reaction with TMS azide to afford azide 230 in 82 % yield with higher than 95 % ee. The reaction is a key step in the asymmetric total synthesis of (+)-pancratistatin [83].
229
230
pancratistatin steps
OCO2Me
OCO2Me O O
OCO2Me
N3
O O CH2Cl2,
rt, 82%,
>95% ee (h3-allyl-PdCl)2, (R,R)-Trost L-1 + Me3SiN3
2-Allyltetrazoles are selectively prepared by three-component coupling of allyl carbonate, TMS azide and nitrile. Reaction of dimethylcyanamide (231) afforded 2-allyl-4-(dimethylamino)tetrazole232using TFP (1–3) as a ligand.π-Allylpalla- dium tetrazole is the proposed intermediate [84].
231
232 Pd2(dba)3,
TFP(I-3)
OCO2Me N
N N N Me2N octane,
100°C, 52%
+ Me2N-CN + Me3SiN3
A lactam analog of epothilone has been synthesized by replacing allylic (and lactonic) OH with amino group in epothilone B233 via Pd-catalyzed reaction of allylic lactone233with NaN3to provide the azide 234[85].
O
OH O
OH S
N
O O
N3
OH O
OH S
N
O HO2C
234
70%
233
+ NaN3
Pd(PPh3)4
Allyl cyanamide 236 was prepared in good yield by the reaction of aryl iso- cyanide 235, allyl carbonate, and TMS azide by using DPPE as a ligand [86].
A proposed mechanism is the following. Insertion of isocyanide to Pd-azide generatesπ-allylpalladium intermediate237. Elimination of N2 generates the Pd- carbodiimide complex238, and 1,3-migration ofπ-allylpalladium group from the nitrogen toα-nitrogen atom affords the cyanamide complex239. It should be noted that the conversion from 237 to238 is a π-allylpalladium mimic of the Curtius rearrangement. The complex238is in equilibrium with the Pd-cyanamide complex 239. Then reductive elimination provides the allyl cyanamide 240.
235 236
237 238 239 240
NC
OCO2Me MeO
N MeO
CN
N N N N
R
N C R N
Pd Pd
Pd
R N C N
N R
C N
+ +
Pd2(dba)3, DPPE toluene, 60°C 99%
Me3SiN3
N2
Asymmetric cyclization of the cyclic allyl carbonate 241 is a good synthetic method for 9-azabicyclo[4.2.1]non-2-ene system 242, which can be converted to
242 Pd2(dba)3,L-6
CH2Cl2, 0 °C 90%, 88% ee
L-6 (XIII-6) CO2Me TsNH
OCO2Me
Ts N
NH HN N
O O
PPh2
MeO2C
241 anatoxin-a
HN
O
anatoxin-a [87]. Cyclization of cis-amino carbonate 241 was a delicate reaction.
No cyclization occurred in DMF using TrostL-1 as a ligand. Good results (90 % yield, 88 % ee) were obtained using monophosphine ligand Trost L-6(XIII-6) in dichloromethane. Net retention took place in the cyclization, and no cyclization of the correspondingtrans-amino carbonate occurred.
Allylation of the bis-indole lactam243with fucose-derived glycal (cyclic allyl carbonate) 244 proceeded at room temperature using PPh3, affording the single regio- and stereoisomer245 in 87 % yield [88].
Pd2(dba)3, PPh3
THF, rt, 87%
Bn N
NH N
H
O O
O O BocO
O
243 244
245 Bn N
N N
H O
O
BocO OH +
Due to ring strain, π-allylpalladium is generated by ring-opening of 2-vinyla- zetidine 246. It undergoes different reactions depending on the substituent on nitrogen. When triflyl group was used as N-protection, N-allylation between two molecules occurred to afford N,N-1,7-bis(trifluoromethanesulfonyl)-1,7-diazacy- clododeca-3,9-diene 247a as a cyclic dimer in very high yield as shown by 247.
No dimerization occurred when theN-tosyl group was used [89].
Alper carried out reaction of N-cyclohexyl-2-vinylazetidine with phenyl iso- cyanate at room temperature and obtained the 4-vinyltetrahydropyrimidin-2-one in high yield. Formal insertion of C=N bond of isocyanate occurred as explained by 247b[90].
Even strain-free 2-vinylpyrrolidine can be cleaved by Pd to generate the π- allylpalladium intermediate, and the 1,3-diazepin-2-one248awas obtained by the reaction with phenyl isocyanate as shown by248. The use of Pd2(dba)3and DPPP is important. When Pd(OAc)2and PPh3were used, conjugated diene was obtained by elimination [91].
THF, 60 °C, 62%
246
Pd2(dba)3, PPh3
Pd(OAc)2, PPh3 THF, 0 °C, 95%
247
Pd2(dba)3, DPPP + Ph-N=C=O
THF, rt, 89%
+ Ph-N=C=O
Ph-N=C=O 247b
248a 247a
248 NTf
N N
Tf
Tf NTfPd
PdTfN
NCy
Pd O C N Ph
N
Cy N
N Ph O
N N
Ph
O Bu N
Bu
Cy
Pd
N Bu