3.4.3.1 Classification of Reactions
Alkynes are more reactive than alkenes in carbopalladation. Facile insertion of internal alkynes to some Pd—C bonds (carbopalladation of alkynes) generates the alkenylpalladiums 2 and 7 by mainly selective syn addition of organopalladium species1 and 6to alkynes. Formally the species 2can be generated by oxidative addition of appropriately substituted alkenyl halides3to Pd(0).
Terminal alkynes react with aryl halides to form arylalkynes and enynes in the presence of CuI as described in section 3.4.2. Insertion of terminal alkynes also occurs in the absence of CuI, and the alkenylpalladium species2and7are formed and undergo further reactions (Scheme 3.6). The reactions of internal and terminal alkynes via insertion are treated in this section.
4 anion capture
reductive elimination R1 R2
Pd-X
R2 Pd-X R1
Y
R2 X R1
R2 Pd-Y
R1 R2
Y R1
products X
insertion or cis-carbopalladation Pd(0)
R2 = H or alkyl
Pd(0) 3
2
5
insertion of CO, alkenes, alkynes
1 direct nucleophilic attack
oxid. addn.
YH
YH
Pd(0)
R2 R1
R3
Pd-X Pd-X
R3 R3
X
R = aryl, alkenyl
7
products 6
R1 R2
Scheme 3.6 Reactions of alkynes with aryl and alkenyl halides and further transformation.
Whereas alkene insertion is followed by facile dehydropalladation whenever there is a β-hydrogen to afford alkenes and Pd(0) catalytic species, the alkyne insertion produces the thermally stable alkenylpalladium species2and7, which can not be terminated by themselves and further transformations are required in order to terminate the reactions and to regenerate Pd(0) species for catalytic recycling. In other words, it is generally believed that the reaction of generated alkenylpalladium species2 and7can not be terminated, because theβ-H elimination (formation of alkynes or allenes) even in the presence of aβ-hydrogen is not possible. Therefore the carbopalladation of alkynes is a ‘living’ process, in which alkynes play a role of ‘relay’ to pass the ability of carbon–carbon bond formation to other reactants.
However, there have appeared a few reports on the formation of allenes9from 8 by the reaction of alkynes with halides. As one example, clean and selective formation of the allene 13 in good yield by the reaction of the aryl bromide 10 with 4-octyne (11) was reported. It is important to useortho-substituted bromides for the allene formation [1]. The reaction can be understood by β-H elimination from the alkenylpalladium species12. Similar allene forming reactions have been reported [2–4]. At present, the allene formation has been observed only in reac- tions using dialkylacetylenes, and should be regarded as an exceptional process.
Pd(OAc)2, PPh3
Cs2CO3, DMF 130°C, 80%
+
12 10
8
b-H elimination
+ Pd(0) + HBr
13 11
? + Pd(0) + HX
b-H elimination
9 CH2R2
Pd-X
R1 R2
H R1
Me
Me Br
n-Pr CH2Et
Me
Me
n-Pr
Et H
Me
Me
CH2Et Pd-Br n-Pr
•
•
In this section, transformations of2and7are classified and explained by citing proper examples. The formation of 2 is competitive with direct coupling of aryl halides with anions or nucleophiles as a side reaction to give5. Yields of desired
products of domino coupling reaction formed via2and 7are sometimes low due to this side reaction.
3.4.3.2 Intermolecular Reactions
The alkenylpalladium species2and7 are capable of undergoing further insertion or anion trap before termination as summarized in Scheme 3.7. The following species trap the alkenylpalladium species2 and7.
Anionic: H, OAc, N3,CH(CO2R)2,SO2Ph, RCO2
Neutral: NHR2,ROH, CO-ROH Organometallic RM: M=Zn, B, Sn.
2
Arylcarbonylation
Arylalkynylation
Arylarylation Arylalkenylation Arylalkenylation
M'R
NuH
R1 H R
R R1 R2
R2 R1
R CO2R R1 R2
R3
R1 R2 R3
R2 R1
Nu R2 H
Nu R1
R4 R3 R1
CO2R
H R1
R
R
R3 R4 R4
R3 R4 R3 R1
R' R1
R3 R4
R4 R3 R1
R
R M'-R
R' = Ar, vinyl, alkyl
CO, ROH CO, ROH
7
anion capture
Hydroarylation NuH
H−
H−
Scheme 3.7 Intermolecular transformations of aryl- and alkenylpalladium intermediates2 and7.
As a typical intermolecular carbopalladation and termination, hydroarylation of alkynes are carried out extensively in the presence of HCO2H as a hydride source.
Formation of regioisomers is observed in the reaction of asymmetric alkynes, and ratios depend on the nature of the substituents. High regioselectivity was observed in the reaction of the tertiary propargylic alcohol14to give15as a major product [5]. The (Z)-2-arylcinnamates 17, rather than 3-arylcinnamate 18, was obtained by the hydroarylation of methyl phenylpropiolate (16) [6]. 3-Substituted quinoline21was prepared by the regioselective hydroarylation of19, followed by treatment of20 with an acid without isolation [6].
14 MeO
HO
OMe
I
OH MeO
MeO
OH
MeO +
OMe
15
piperidine, DMF, 60 °C
+
+ HCO2H
80% 5%
Pd(OAc)2(PPh3)2
CO2Me OMe
CO2Me MeO
17 18
+
53% 9%
CO2Me
OMe
16 I
+ DMF, 40 °C
Pd(OAc)2 + HCO2K
+ + HCO2K
DMF, 40 °C, 63%
TsOH, EtOH 19
20 21
NHAc OEt
OEt
I
OH
NHAc OEt OEt N
OH
OH
Pd(OAc)2
Fulvenes are obtained by the Pd-catalyzed reaction of alkenyl iodides with two alkynes [7,8]. The pentasubstituted fulvene 23 was obtained in good yield from two molecules of 3-hexyne and the alkenyl iodide 22 in the presence of an equimolar amount of silver carbonate without phosphine [9]. In this reaction,
Pd(OAc)2, Ag2CO3 (100 mol%) MeCN, 20 °C, 3 h, 97%
insertion
23
2 +
Pd(0) 22
23
22
CO2Me X-Pd
Et Et
CO2Me Et
Et
I
CO2Me Et Et CO2Me
Et Et
I
CO2Me Pd-X
Et Et
CO2Me Et
Et
Pd-X
CO2Me
Et Et
Et Et
Pd-X
CO2Me
Et Et
Et Et
Et Et
Et Et
the alkenylpalladium undergoes intermolecular insertion of 3-hexyne twice, and intramolecular Heck-type reaction affords the fulvene23.
3.4.3.3 Intramolecular Reactions; General Patterns of Cyclization
Intramolecular versions and domino reactions involving appropriately function- alized aryl halides and alkynes offer useful synthetic methods for a variety of heterocycles and carbocycles. Few other methods can compete with these Pd- catalyzed cyclizations in versatility. Numerous reports and a number of excellent reviews covering the carbo- and heteroannulations have been published [10]. In order to aid understanding of this somewhat complex chemistry, the cyclizations are classified in to three types (Scheme 3.8).
R1 X
YH Y
R1
R2
R1 R2
X
YH Y
R1
R2 type 1a
type 1c
type 1d
R1 R2
X
A YH
A Y R2
R2
X
A YH A
Y R2
R2 Type 1
Pd(0)
+ R2
type 1b +
+
+
Pd(0)
Pd(0)
Pd(0)
R1 R2
Scheme 3.8
Type 2 type 2a
Y Ar
R
YH R
Y R
Ar YH
R
A
YH Y
A Ar
A
YH
A Y
R R
R +
Ar R type 2f
Pd(0)
type 2d
YH R type 2b
Y R
Ar YH
R
Y R Ar
type 2e type 2c
+ Pd(0)
Ar-X
+ Pd(0)
Ar-X
+ Pd(0)
Ar-X
+ Pd(0)
Ar-X
+ Pd(0)
Ar-X Ar-X
Scheme 3.8
Type 3
X
Pd(0)
A A
R R
Y
X
A R
A
R Y
type 3b
type 3a + YH
Pd(0) + YH
Scheme 3.8 Types of Cyclization Reactions.
3.4.3.4 Cyclization Type 1
At first, syntheses of heterocycles and carbocycles by the reaction of internal alkynes withortho-functionalized aryl halides24are surveyed (Scheme 3.9). The
cyclization proceeds by carbopalladation of alkyne to generate the alkenylpalla- dium 25, followed by attack of a nucleophile YH to form the palladacycle 26.
Reductive elimination produces the cyclic compound27. Overall cis addition to alkyne occurs.
R1 R2
X
R2 Pd-X R1
YH YH
Pd-X
YH
Y R1
R2 Y Pd
R1 R2
R2= H, or alkyl Pd(0)
insertion
25 HX
27 24
reductive
elimination E
HC E YH = OH, NHR, + Pd(0)
26
Scheme 3.9
Pd-catalyzed reaction ofo-iodophenol (26) with alkynes offers a good synthetic method of functionalized benzofurans 27. The silyl group in the benzofuran 27, obtained from tri-isopropylsilylalkyne, can be used for electrophilic substitution or desilylation to yield28 [11]. In the reaction of 26under CO atmosphere (1 atm), the insertion of 4-octyne occurs in preference to the insertion of CO to generate the alkenylpalladium29, to which CO insertion occurs to afford the acylpalladium 30. Finally, intramolecular reaction of 30 yields the coumarin 31. The chromone 32is not obtained [12].
26
87%
Me Si(i-Pr)3
I
OH O
Me
Si(i-Pr)3
O Me
H 28 Pd(OAc)2,n-Bu4NCl
+ LiCl, Na2CO3
DMF, 90%
27 KF
+ Pd(OAc)2, n-Bu4NCl pyridine, DMF 120°C, 63%
+ CO
O O
Pr Pr
32 Pr
I
OH
COPd-X OH
Pr Pr
OHPd-X Pr
Pr
30 31
29 26
O O
Pr
Pr Pr
CO
Reaction of o-iodoaniline (33) with internal alkynes offers a good synthetic method of substituted indoles [13]. A practical synthesis of psilocin was carried out by utilizing the reaction of the iodoaniline derivative34with internal alkyne to form an indole derivative as a key reaction [14]. The thieno[3.2-b]pyrrole37was obtained by the reaction of 2-iodo-3-aminothiophene (35) with the alkyne36 [15].
These reactions of aryl iodides proceed in the absence of phosphine ligands. The isocoumarin39was obtained by the reaction of methylo-iodobenzoate (38). Poor yield was obtained when the free acid was used [11].
K2CO3, 100°C, 50~98%
+
34 33
R I
NH2 N
H R
R +
Steps Pd(OAc)2
PPh3
Et4NCl i-Pr2EtN DMF, 69%
R
psilocin I
NH OMe
BOC
TMS NMe2
N BOC
TMS NMe2
NH
NMe2
OMe OH
Pd(OAc)2, n-Bu4NCl, DMF
AcOK, 100 ˚C, 67%
S
NHBoc
I
t-BuMe2Si CH2OH
S N
35
Boc
SiMe2-t-Bu CH2OH 37
63%
+ Pd(0)
39 36
38 I
CO2Me Et
O Et
O HO
OH Pd(OAc)2,
Bu4NCl, DMF +
MeCN is a good and inert solvent used in various Pd-catalyzed reactions.
However, nitriles participate in Pd-catalyzed intramolecular reactions. The indenone43was obtained by the reaction ofo-iodobenzonitrile (40) with alkynes.
The reaction can be understood by insertion of a nitrile bond to alkenylpalladium intermediate41 or 5-exo cyclization to give the iminopalladium42, hydrolysis of which affords the indenone43 and Pd(II), which is reduced to Pd(0) [4].
Similarly, the six-membered ketone 45 was obtained from 2-(o-iodophenyl)-2- methylpropanenitrile (44). However, the reaction ofo-iodophenylacetonitrile (46) afforded the β-naphthylamine 49, not a ketone. Presumably, 6-exo cyclization of 47 yields the iminopalladium 48. Tautomerization (aromatization) of 48 occurs
to form the amino group 49 in the final step, rather than hydrolysis to give the ketone [16,17].
130 ˚C, 96%
DMF -H2O
43 40
Pd(0) 41
42 I
CN
Ph
Ph O
+ Pd(II) C
Ph Ph
N Pd-X
Ph Ph N-PdI
insertion Pd(dba)2, Et3N
Ph Ph
+
H2O
Pd(dba)2, Et3N
insertion
+ Pd(II) Pd(OAc)2,
n-Bu4NCl
47 DMF - H2O, 96%
Et3N, DMF, 83%
+
48
Pd(0)
49 I
CN
Me Me Me Me
O Ph
Ph
I
Ph Ph CN
N-PdX
Ph Ph
NH2
Ph Ph
Pd-X C N
H
Ph Ph
44
Ph Ph
45
46
+
H2O
Reaction of the imine 50, derived from o-iodoaniline and benzaldehyde, with diphenylacetylene afforded a mixture of the quinoline 53 and the isoindolo[2.1- a]indole 56. Formation of the quinoline can be understood by insertion of the C=N bond in 51, which is regarded as 6-endo cyclization of the intermediate51 to generate 52, followed by β-H elimination to yield the quinoline 53. On the other hand, the isoindolo[2.1-a]indole 56 is formed by 5-exo cyclization of 51 to produce 54. The final step is the electrophilic palladation of the σ-palladium intermediate54to the adjacent aromatic ring to give55, and reductive elimination gives rise to 56[18]. The isoindolo[2.1-a]indole 59 was obtained in high yield from alkylarylacetylene58 and the imine50 [19].
52 +
53
54 55
I
N Ph
Ph Ph
N Ph
Ph
PdX Ph
N PdX
Ph
Ph Ph
N
N Ph
Ph Ph
N Ph PdX
N Ph
Ph
Pd(OAc)2,n-Bu4NCl AcONa, DMF
5-exo
23%
reductive elimination
50 51
56
42%
Pd Ph 6-endo
HX
59 I
N Ph
Ph Et
N Ph
Et Pd(OAc)2,n-Bu4NCl
AcONa, DMF, 81%
58 +
50
The isoquinoline 61 was obtained by the reaction of t-butylimine 60 of o- iodobenzaldehyde with internal alkyne [20]. The reaction was extended to syn- thesis of the γ-carboline 65 from the t-butylimine of N-methyl-2-iodoindole-3- carboxaldehyde 62 [21]. The reaction is explained by 6-endo cyclization of the alkenylpalladium intermediate 63, followed by elimination of β-t-butyl group as isobutylene as shown by 64. This mechanism explains the importance of t- butylimine in this cyclization.
+ Na2CO3, DMF, 96%
Pd(OAc)2, PPh3
60 61
I N
t-Bu
Ph N
Ph Ph Ph
β-elimination 62
64
+ Pd + HI 65 Na2CO3, DMF, 78%
Pd(OAc)2, PPh3 +
63
N I
N t-Bu
Me
Pr
N Me
N Pr Pr N
N t-Bu
MePr Pr PdI
N Me
N I-Pd
Pr Pr
Pr
6-endo cyclization
H
The indenone 70 is obtained by the reaction of o-iodobenzaldehyde (66) with alkyne [22,23]. Two mechanisms are suggested. One of them involves the for- mation of Pd(IV) species 68 from 67 by oxidative addition of aldehyde, and its reductive elimination affords the indenone70. Another possibility is the insertion of carbonyl group (or nucleophilic attack) to form the indenyloxypalladium 69, andβ-H elimination gives the indenone 70.
67 I
CHO Ph
C
Ph t-Bu
O Pd-X
Ph t-Bu O
H
Pd Ph
t-Bu
O X H Ph
t-Bu H O Pd X +
69
+ Pd(0) + HX
70 Bu4NCl, DMF 100°C, 81%
66
Pd(OAc)2, Na2CO3
t-Bu
68
On the other hand, Yamamoto and co-workers observed that the Pd-catalyzed reaction of o-bromobenzaldehyde (71) with 4-octyne in DMF using Pd(OAc)2 gave rise to the indenol74 in 71 % yield. Also it was confirmed that the indenol 74, once formed, was isomerized to the indanone75quantitatively in the presence of Pd(OAc)2and AcOK [24]. Furthermore, reaction ofo-bromoacetophenone (76) with 4-octyne afforded the substituted indenol 77 in 82 % yield, which has no
possibility of isomerization. Yamamoto proposed that the indenols 74and 77 are formed by intramolecular nucleophilic attack of the vinylpalladium species 72 to the carbonyl group to form the Pd alkoxide 73; namely, a hitherto unknown catalytic Grignard-type reaction occurred. However, the formation of 73 may be explained by insertion of a carbonyl group, followed by protonolysis to afford 74 and Pd(II) [25].
72
73 74
75 DMF,100 °C, 24 h, 100%
+ 71
EtOH, DMF 60°C, 71%
76
DMF,100 °C, 82 %
+ Pd(II) Pd(OAc)2, KOAc
77 Br
CHO Pr
C
Pr Pr
O Pd-X H
Pr Pr O Pr
Pr H O Pd X
Pr Pr
H OH
Pr Pr
H OH
Br O
OH Pr Pr Pd(OAc)2, KOAc , DMF
Pd(OAc)2, KOAc 74
+ Pr
Pr Pr
H+
Furthermore, as a related reaction, they obtained the cyclopentanol 79 by the Grignard-type reaction of 1-methyl-2-(o-bromophenyl)ethyl phenyl ketone (78) without alkynes in the presence of Pd(OAc)2, PCy3, Na2CO3 and 1-hexanol. It was confirmed that the addition of 1-hexanol was crucial [26]. These reactions are mechanistically interesting. A similar catalytic reaction has been reported by Vicente. These reactions are considered again in Chapter 3.7.2 [27].
Ph
Pd O
Br
Br Ph
O
Ph O PdBr Ph OH
C6H13-OH, 135 °C, 12 h, 69%
Pd(OAc)2, PCy3, Na2CO3
78
79 C6H13-OH
The substituted naphthalene82was produced from theo-(3-cyano-2-propenyl)- iodobenzene (80) by carbopalladation of 4-octyne, followed by Heck reaction of 81[28].
DMF, 74%
I
n-Pr CN
n-Pr 80
81 82
CN n-Pr n-Pr CN
Pd-I n-Pr n-Pr
Pd(OAc)2, PPh3, NEt3 +
Thecis-heteroannulation of alkyne extended to alkenyl halides 83containing a proximate nucleophilic center to yield the heterocycles86by the reactions via84 and85 similar to those summarized in Scheme 3.9 (Scheme 3.10).
Pd(0), R2
R1 R2
X R2
Pd-X R1
YH YH
Y R1
R2
Y Pd R1
R2
= H or alkyl
84 85
Pd 83
86
HX
Scheme 3.10
The pyran88 andα-pyrone90are prepared from the vinyl bromide87and the vinyl triflate89by intramolecular trapping of the alkenylpalladium intermediates with alcohol and ester [29,30]. The pyridine92was prepared by the iminoannula- tion of the iminoalkenyl iodide91 [31]. The 2-iodo-3-tosylaminocyclohexene 93 underwentcis-carboamination of ethyl phenylpropiolate to give94[32].
Na2CO3, DMF, 61%
87 88
+ Br
OH
Ph CO2Me O
CO2Me Ph Pd(OAc)2, LiCl
Pd(OAc)2, LiCl
89 90
Na2CO3, DMF, 64%
CO2Me
OTf
Me Si(i-Pr)3
O O
Si(i-Pr)3
Me +
91 92
Ph Me
I N
t-Bu
N
CH2OH Ph Ph
Me
+ Ph CH2OH
Pd(OAc)2, PPh3, Na2CO3
DMF, 100 °C, 95%
94 + Pd(OAc)2, LiCl, Na2CO3
DMF, 100 °C, 64%
93 I
NHTs
Ph CO2Et
N CO2Et
Ph
Ts
3.4.3.5 Cyclization Type 2
Another heteroannulation is combination of aryl and alkenyl halides with ortho- functionalized phenylalkynes95 to give heterocycles 97such as benzofurans and indoles (Scheme 3.11). In this reaction, trans addition of Ar-Pd to a triple bond andendo cyclization, as shown by96, occur.
= H or alkyl Ar-Pd-X
YH
R
YH
R
Y Ar
+ Pd + HX
95 96
97
Y Pd-Ar endo-dig
Ar-Pd-X Ar-X
Pd(0)
R2
Scheme 3.11
The alkynes containing proximate nucleophiles (YH) undergo trans addition of the nucleophile and organopalladium species, as shown by 98 and 101, to generate99and102, and reductive elimination produces the cyclizedtransaddition products 100and 103. In this cyclization, eitherexo-dig or endo-dig cyclizations take place depending on the number of carbon atoms between the triple bond and the nucleophilic center to give100 and103 (Scheme 3.12).
reductive elimination
Ar-X ArPd-X
Ar-X Pd(0) ArPd-X
exo-dig
endo-dig
reductive elimination 98
99
102 101
103 100 YH= OH, NHR,
R
A HY
Y A R
Ar-Pd
Y A R
Ar
R
A HY
Y A
R
Pd-Ar
Y A
R Ar E HC
E Pd(0)
Scheme 3.12
The indole synthesis was extended to an elegant synthesis of indolo[2.3-a]carba- zole 106 by bis-annulation of the diacetylene 104 with the dibromomaleimide 105[33].
Pd(PPh3)4, K2CO3
MeCN, 50 °C, 52%
NH HN
COCF3
COCF3
O N O
Br Br
104
105
106 Bn
N
N H N
H Bn
O O
NH HN
COCF3 COCF3
O N O
BrPd Pd-Br
Bn
N
N H
Bn
O O
H2N Pd-Br +
endo-dig
The isoquinoline 108 is prepared from the imine 107 as a variation of the iminoannulation [34]. When the iminoannulation of107 is carried out under CO
atmosphere (1 atm), CO reacts withp-iodoanisole to generate the acylpalladium 110, which undergoes acylpalladation of the triple bond of 107 to afford the 4- aroylisoquinoline 109via111 [35].
+
K2CO3, DMF 100°C, 67%
Pd0)
+ CO
108
107
Ph N
t-Bu
N Ph
+ CO OMe
I
Bu3N, DMF 1 atm, 100 °C, 74%
+
N Ph O MeO
107
Ph N
t-Bu
CO2Et
I
CO2Et
107
OMe
O I-Pd
109 OMe
I
110
Ph N
t-Bu
N t-Bu
O Ph
Pd-I
MeO
111 Pd(PPh3)4
Pd(PPh3)4
Reaction of o-2-propynylphenol (112) with 2-iodothiophene (113) gave the 2- alkylidenedihydrobenzofuran 114and the benzofuran 115[36]. The reaction of a nitrogen analog 116 afforded the pyrrolidine derivative 117 [37]. The propargyl tosylcarbamate 118underwenttrans carboamination with cyclohexenyl triflate to give the oxazolidinone119 in the presence of TFP as a ligand and benzyltriethy- lammonium chloride [38,39].
The 1-(1-alkynyl)cyclobutanol120was expanded by Pd-catalyzed reaction with aryl- and alkenyl halides to produce the 2-(2-arylidene)cyclopentanones 123. The reaction can be understood formally by carbopalladation to give121, and migra- tion of an electron-rich carbon to Pd to form the palladacyclohexanone 122, and the cyclopentanone 123 is obtained by reductive elimination of 122 (see Chapter 3.8.2) [40].
A useful precursor126was prepared by coupling the triflate 124, derived from aγ-lactam, with the alkynyl amine 125. Thecis addition product128was formed in this case via intramolecular amination as shown by127 [41].
+
115
116 117
114 112 113
1. BuLi + PhI
3 : 1
2. Pd(OAc)2, PPh3, 85%
+
2. Pd(OAc)2, PPh3 THF, rt, 75%
1. BuLi
+ Pd(OAc)2, TFP, BnEt3NCl t-BuOK, MeCN, 60%
118
119 O
OH
S
S I
S O
N
Ph
NHTs Ts
OTf
TsHN O
O TsN O
O
+ Ph-I Pd(OAc)2, PPh3,n-Bu4NCl i-Pr2NEt, DMF, 80 °C, 60%
120
121
122 123
OH
Me
O
Ph Me
O Pd I H
Me Ph
Pd
Me Ph
O
127
126 N
NC
Pd-X 124
Pd-X N
NC H2N
N
NC Pd NH
125 N
NC
OTf N HN
NC H2N
Me
70%
126 Pd(PPh3)4, NEt3, THF
128 Me
+
Me
Reaction of the enyne 129 withp-bromoanisole gave the furan 130 smoothly in 53 % yield via Sonogashira coupling and carbopalladation of the triple bond, followed by intramolecular insertion of the double bond (Heck-type reaction) [42].
53%
+ MeCN / H2O (10 : 1) Pd(OAc)2, PPh3 Bu4NHSO4, Et3N
129
130 Heck
O O
OMe
O Ph Br
OMe
OMe
OMe Br
MeO
O Ph
Pd(0)
Ph
cyclization Pd-X
Ph
Ar Ar Br-Pd-Ar
The stereo-defined benzylidenecyclopentane 132 was obtained by trans addi- tion of a phenyl group and a carbanion to the terminal alkyne131.The cyclization proceeds viatrans carbopalladation [43]. As a related reaction, stereo-defined 3- arylidenetetrahydrofuran134was prepared by the reaction of iodobenzene, propar- gyl alcohol, and Michael acceptor 133. The reaction is understood in terms of Michael addition of propargyl alcohol to133, followed by carbopalladation of the triple bond as shown by135 [44].
CO2Me CO2Me
Pd I
CO2Me CO2Me
Ph Pd
CO2Me
CO2Me CO2Me
CO2Me Ph
Ph
132 _
131
+ Ph-I Pd2(dba)3, DPPE t-BuOK, DMSO, 88%
+ 1. n-BuLi
+
DMSO, rt, 89%
2. PdCl2(PPh3)2
133 134
135
I OH
EtO2C CO2Et
O E E Ph Pd
X
O E
E Pd
Ph
Ph
O CO2Et
CO2Et
Ph
3.4.3.6 Cyclization Type 3
In type 3 cyclization, the aryl halides 136 having an alkyne side chain at ortho position undergocis carbopalladation of137to generate138, which is trapped by a nucleophile YH to give the cyclized product139. In this cyclization,cis addition to triple bonds occurs (Scheme 3.13).
X
A R
Pd-X
A
R Pd(0)
oxidative addition
A Y-Pd R
insertion or cis-carbopalladation
136 138
YH anion capture
reductive elimination
A Y R
A Y-Pd R
139
A= (CH2)n, O, NR, S 137
Scheme 3.13
Reaction of 140 with vinyltin reagent yields the cyclized product 141. The conversion can be understood by cis carbopalladation, transmetallation with the Sn reagent, and reductive elimination [45,46]. This reaction is overallcis addition to the triple bond. The intramolecular version of furan synthesis was applied to the preparation of the key intermediate of halenaquinone and halenaquinol syntheses from142 [47].
I
N Me
Ac
Pd(OAc)2
PPh3, 60%
N Ac
Me I-Pd
N Ac
Me CH2=CH−Pd TM
Bu3SnCH=CH2
RE
N Ac 141
O
O OMe
OMe
O
Si(i-Pr)3
OMe OMe
O I
OH O
Si(i-Pr)3
142 140
Pd2(dba)3, K2CO3 DMf, rt, 72%
O
O OH
OH
O halenaquinol
The homopropargylic ether143undergoes 7-exo-dig cyclization in the presence of formic acid to generate the Pd formate144, which is converted to the Pd hydride.
Reductive elimination gives thecis hydroarylation product145 [48]. Cyclobutane was formed by a rare unfavored 4-exo-dig cyclization of theγ-bromopropargylic diol 146and trapped with an alkynyltin reagent to yield the cyclobutanediol 147 in 69 % yield. When a vinyltin reagent was used for the trapping, the unusual strained tricyclic system 148was obtained in 35 % yield by 6π-electrocyclization of an intermediate [49].
O I Me
143
O HCO2-Pd Me
144
CO2 O
H-Pd Me
+ HCO2H
7-exo-trig Pd(OAc)2, PPh3
Et4NCl, piperidine MeCN, 62%
O H-Pd Me
145
Br HO
HO
TMS
Ph TMS HO
Bu3Sn Ph HO
+ Pd2(dba)3, K2CO3
benzene 85°C, 69%
146 147
Br HO
HO
TMS
+ Bu3Sn 35%
HO TMS HO
H
TMS OH
HO
148
The 3-substituted pentynoic acid149 underwent 6-endo-dig cyclization to give rise to theγ-arylidenebutyrolactone 150using TFP as a ligand [50]. On the other
149 I O
OH O
OH
IPd O
O 6-endo-dig
Pd(OAc)2, TFP t-BuOK, DMSO rt, 78%
150