Reactions of Internal and Terminal Alkynes with Aryl and Alkenyl Halides via Insertion

Một phần của tài liệu Palladium reagents and catalysts new perspectives for the 21st century tsuji (Trang 243 - 277)

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

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