Negishi E. 2002 Handbook of organopalladium chemistry for organic synthesis / 0721 766

III.2.14.2 CROSS-COUPLING INVOLVING -HETERO-SUBSTITUTED COMPOUNDS

731

Although symmetrically structured, (E )-1,2-bis(stannyl)ethylene[50] can be either selectively monosubstituted or exhaustively disubstituted. The available results indicate that, like halogens, the second Sn group accelerates the Pd-catalyzed cross-coupling. Some very attractive applications of both (E )- and (Z )-1,2-bis(stannyl)ethylenes include their Pd-catalyzed double cross-coupling reactions with , -diiodo compounds to produce macrocycles in the syntheses of rapamycin[51] and dynemicin A,[52] discussed in

Sect. III.2.18.

C.iii. Other 1,2-Hetero-Disubstituted Alkene Derivatives

Various other types of 1,2-hetero-disubstituted alkene derivatives have been employed in Pd-catalyzed cross-coupling. Some act primarily as electrophiles, and representative examples are shown in Table 4. The others serve as nucleophiles and are summarized in

Table 5.

TABLE 4. Some -Hetero-Substituted Electrophiles

Example of

Product

Electrophile

Nucleophile

Yield (%)

Reference

COOR

S

Br

ZnCl

85

[55]

Br

(R = Me, Et)

Br

COOR

PhZnCl

79

[55]

Br

(R = Me, Et

)

I

SOTol-p

Ph

87

[56]

SnBu3

Br

SOTol-p

HC

CCH2OH

84

[57]

(CuI, DBU)

SO2Ph

TfO

COOMe

68

[58]

Bu3Sn

Ph

PhI+

OTs

SnBu3

80

[59]

SPh

O

Me3Al

80

[60]

(PhO)2P

(Continued )

732

III

Pd-CATALYZED CROSS-COUPLING

TABLE 4. (Continued )

Example of

Product

Electrophile

Nucleophile

Yield (%)

Reference

SiMe3

n-OctMgBr

75

[61]

Br

ZnBr

SiMe3

86

[62]

Br

SiMe3

O

C

CZnCl

81

[63]

Br

SiMe2Ph

Br

94

[64]

Ar

TBSO

SnBu3

O

Br

79

[54]

B

ZnCl

O

Br

B(OPr-i)2

PhC

CZnCl

64

[65]

Bu

Me

Br

BBr2

74

[66]

ZnCl

O

Br

B

[67]

ZnCl

78

O

The presence of -heteroatom substituents offers various synthetically attractive possibilities. For example, silyl-substituted dienynes[63] can undergo Si-assisted Nazarovtype cyclization, as exemplified in Scheme 14.

-Alkoxyethenyl derivatives are useful two-carbon synthons for the synthesis of heterocycles,[74] as indicated by the synthesis of arene-fused pyrones shown in

Scheme 15.

SiMe3							O			O
	HOAc
	H2SO4								+
	65%								18%
	Scheme 14

III.2.14.2 CROSS-COUPLING INVOLVING -HETERO-SUBSTITUTED COMPOUNDS

733

TABLE 5. Some -Hetero-Substituted Nucleophiles

An Example of

Product

Nucleophile

Electrophile

Yield (%)

Reference

R

N

O

I

78

[68]

EtO

B

O

N

NH2

Me

Bu

[69]

F2C

C

PhCH

CHBr

82

BBu2

PhBr

78

[70]

EtO

SnBu3

O2N

Ph

OTf

78

[71]

SO

SnMe3

Ph

CH2

75

[72]

CHCH2Br

Me3Si

SnBu3

BrCH

CHBr

58

[73]

Me3Si

ZnCl

Br

COOEt

6N HCl

cat. PdLn

OEt

O

Br

N

COOEt

COOEt

PPA

76% O

Bu3Sn

OEt

cat. PdLn

N

OEt

N

O

Br

COOEt

45% O

N

COOEt

cat. PdLn

OEt

PPA

O

N

COOEt

N

60% O

Scheme 15

734	III Pd-CATALYZED CROSS-COUPLING

D. Pd-CATALYZED CROSS-COUPLING OF , -UNSATURATED CARBONYL DERIVATIVES CONTAINING -HALOGEN

OR -METAL GROUPS

D.i. Background

Introduction of simple hydrocarbon groups in the -position of ketones and other carbonyl compounds is most typically achieved by alkylation of enolates and related compounds.[75] As basic and important as it is, it has been associated with some limitations and undesirable features. First, the alkali and alkaline earth metal-based methodology is limited to the introduction of sp3 carbon groups of relatively low steric requirements, such as Me, primary alkyl, allyl, benzyl, and propargyl groups. Introduction of sterically hindered groups, such as tertiary alkyl and many secondary alkyl groups, is not practical, and sp2 and sp carbon groups, such as aryl, alkenyl, and alkynyl groups, cannot be introduced. Second, the reaction is prone to multiple substitution, and it is often difficult to achieve clean monosubstitution. Third, although so called “kinetic” and “thermodynamic” enolates can selectively be generated in a number of cases, strict regiochemical control requires special procedures, such as generation of enolates via conjugate reduction of , -unsaturated enones, which must then be followed by regiospecific alkylation. Despite all these difficulties and limitations, -substitution of carbonyl compounds is a highly desirable synthetic operation. Critically needed is a methodology permitting introduction of all types of carbon groups, especially aryl, alkenyl, and alkynyl groups with strict control of the degree of substitution and regiochemistry. Pdor Ni-catalyzed cross-coupling of either -halo- , -unsaturated carbonyl compounds or the corresponding -metallo derivatives has proved to be a very attractive alternative to the classical enolate alkylation. A few representative enone-based -substitution methodologies are shown in Scheme 16.

It has also been shown that further modifications of the -haloenone-based methodology shown in Scheme 16 are desirable in some cases. Various strategies and protocols

MH (or MR1)

OM +

RX

O

R

(Pd or Ni cat.)

H(R1)

H(R1)

C

C

C

C

C

C

direct -substitution

H

methodology

H

O

MH

(or MR1)

C

C

C

H

O

MR

O

C

C

C

Pd or Ni cat.

C

C

C

halogenation

X

R

-haloenone-based

methodology

O

RX

Pd or Ni cat.

C

C

C

metallation

M

Scheme 16

III.2.14.2 CROSS-COUPLING INVOLVING -HETERO-SUBSTITUTED COMPOUNDS

735

developed since the mid-1980s are summarized in Scheme 17 and discussed below. For the sake of simplicity, -substitution of 2-cyclopentenones, 2-cylohexenones, and their derivatives are shown in Scheme 17 as representative cases.

Protocols IA and IB

1. RM, cat. PdLn

2.

2N HCl

O

O O X

Protocol IA

O

1. halogenation

1.

n-BuLi

R

2. (CH2OH)2, TsOH

2.

ZnX2

n

n

n

3.

RX, cat. PdLn

4.

2N HCl

Protocol IB

Protocols IIA and IIB

O

O

iodination

I

RM, cat. PdLn

O

n

Protocol IIA

Z

O

R

n

RI

n

metallation

M

cat. PdLn

Protocols IIIA and IIIB

n

Protocol IIB

O

1. iodination

OZ1

1. RM, cat. PdLn

Z

I

2.

deprotection

2. NaBH4, CeCl3

3.

oxidation

n

3. protection

n

Protocol IIIA

O

metallation

R

1. RX, cat. PdLn

n

OZ1

2.

deprotection

M

3.

oxidation

Protocol IIIB

n

n = 1 or 2. M = Zn, Sn, Cu, B, and other metals. R = C group.

Z = H, Si, or Sn group. X = I, Br, or Cl. Z1 = Si or another protecting group.

Scheme 17

D.ii. Pd-Catalyzed -Substitution of -Haloenones, -Metalloenones,

and Their Derivatives

D.ii.a. Pd-Catalyzed -Arylation and -Alkenylation of Acetal-Protected Enone Derivatives (Protocol I). The reaction of 2-bromo-2-cyclohexenone and 2-iodo-2- cyclohexenone with bis[(E )-1-hexenyl]zinc in the presence of 5 mol % of a Pd – PPh3 complex in THF at 25 °C gives 2-[(E )-1-hexenyl]-2-cyclohexenone in 0 % and 31% yield, respectively.[76] In sharp contrast, the corresponding reaction of 3-bromo-2- cyclohexenone provides 3-[(E )-1-hexenyl]-2-cyclohexenone in 75% yield, with the balance of the starting bromoenone still remaining unreacted. The sluggish nature of - substitution and the greater instability of -haloenones are clearly indicated in the competitive experiment summarized in Scheme 18.[76]

736

III

Pd-CATALYZED CROSS-COUPLING

O

O

) Zn

O

O

n-Bu

I

2

n-Bu

0.55 equiv

+

+

I

3% Pd(PPh3)4

n-Bu

62%

0%

1 equiv

THF, 25 °C

1 equiv

O

O

+

I

+

I

37%

0%

Scheme 18

In view of the low intrinsic reactivity and high instability of -haloenones in Pdcatalyzed cross-coupling, acetal-protected -bromoenones were employed as key intermediates in an early study.[77] The Pd-catalyzed cross-coupling reaction of acetalprotected -bromoenones with organozincs and other organometals has turned out to be sluggish. On the other hand, their conversion to the corresponding zinc derivatives via lithiation with butyllithium permits clean and high-yield cross-coupling not only with aryl halides but, more significantly, with both E and Z alkenyl iodides using 1 mol % of Pd(PPh3)4 (Scheme 19).[77] The corresponding alkenyllithiums are totally ineffective under comparable conditions. Conjugate reduction of 2-[(E )-1-octenyl]-2-cyclopen- tenone with LiAlH(OMe)3 and CuI[78] followed by protonolysis with 2 N HCl at 0 °C cleanly provides 2-[(E)-1-octenyl]cyclopentanone in excellent yield. Thus, the putative dienolate intermediate must undergo exclusive protonation. Full retention of the regiochemistry is clearly indicated in the exclusive formation of 2-[(E )-1-octenyl]-6-

O

1. Br2, NEt3

O

O

Br 1. n-BuLi

2. (CH2OH)2

TsOH

2. ZnCl2

Me

1. I

Me

O

1% Pd(PPh3)4

80%

O

2. 2 N HCl

1. I

Hex-n

Hex-n

O

O

ZnCl

1% Pd(PPh3)4

92%( >98% E)

2. 2 N HCl

O

1. I

Hex-n

Hex-n

1% Pd(PPh3)4

85%( >98% Z )

O

LiAlH(OMe)3

OM

O

Hex-n

Hex-n

Hex-n

2 N HCl

CuBr

Scheme 19

III.2.14.2 CROSS-COUPLING INVOLVING -HETERO-SUBSTITUTED COMPOUNDS	737
methylcyclohexanone from 6-methyl-2-cyclohexenone in 55% overall	yield

(Scheme 20).[77] Thus, the feasibility, dependability, and highly selective nature of Protocol IB have been firmly established by the results shown in Schemes 19 and 20.

Later studies have further demonstrated that alkenyland alkynylstannanes also react analogously (Scheme 21).[79]–[81]

Despite its dependability and high selectivity, Protocol I is indirect and cumbersome, and a more direct method—Protocol II— is clearly desirable.

1.

n-BuLi

2. ZnCl2

Hex-n

O

1. Br2, NEt3

3.

I

O

O

O

2. (CH2OH)2

Me

1% Pd(PPh3)4

Me

Br

Me

Hex-n

TsOH

4. 2 N HCl

1. LiAlH(OMe)3

O

CuBr

Me

Hex-n

2. 2 N HCl

Scheme 20

X

Pd (%)

Yield (%)

O

O

Bu3Sn

O

O

Br

Pd(PPh3)4 (5)

<5

X

cat. PdLn

I

Pd(PPh3)4 (5)

80

[79]

OTf

Cl2Pd(PPh3)2 (3)

85

O

O

Bu3SnC

CBu-t

O

O

Bu-t

I

cat. Pd(PPh3)4

[80]

O

O

O

O

Bu3Sn

I

cat. Cl2Pd(PPh3)4, DMF

[81]

Ph

Ph

Ph

Ph

Scheme 21

D.ii.b. Pd-Catalyzed -Arylation and -Alkenylation of -Iodoenones (Protocol IIA).

Although the

reaction

of 2-iodo-2-cyclohexenone with bis[(E )-1-hexenyl]zinc in

the presence of a Pd catalyst (5 mol %) generated by the treatment of Cl2Pd(PPh3)2 with 2 equiv of n-BuLi in THF was sluggish, it was soon found that the use of polar aprotic solvents would significantly improve the product yield. Thus, the use of DMF, DMSO, and NMP (N-methylpyrrolidone) improved the cross-coupling yields to 88%, 80%, and 74%, respectively.[76] (E )-1-Hexenyldialkylaluminums prepared by treating (E )-1-hexenyllithium with ClAlMe2 and ClAl(Bu-i)2 were also satisfactory, producing the

738	III Pd-CATALYZED CROSS-COUPLING

desired product in 71% and 89% yields, respectively, whereas alkenylaluminums generated by hydroalumination were less effective. Also unsatisfactory was the corresponding zirconocene derivative, which led only to a 27% yield of the desired product. The n-Bu3Sn-containing reagent was practically unreactive at room temperature, but it gave the desired product in 64% yield in 13 h at 60–65 °C. These results of reaction condition optimization are summarized in Table 6.[76] In summary, the use of organozinc reagents and DMF as a solvent appears to be optimal. In most cases, Cl2Pd(PPh3)2 and

TABLE 6. Effects of Reaction Parameters in the Pd-Catalyzed Reaction of 2-Iodo-2- cyclopentenone with (E)-1-Hexenylmetals a

O

Pd catalyst

O

I

Bu-n

+

M

Bu-n

solvent

Bu-n

Temperature

Time

Product

M

Pd Catalystb

Solvent

( °C)

(h)

Yield (%)c

Zn

Bu-n

I

THF

25

1

31

2

Zn

Bu-n

I

THF-DMF

25

1

87

2

Zn

Bu-n

I

DMF

25

1

100 (86d)

2

Zn

Bu-n

II

DMF

25

1

88

2

Zn

Bu-n

I

DMSO

25

1

80

2

Zn

Bu-n

I

NMP

25

1

74

2

Me2Al

Bu-n

I

DMF

25

1

71

i-Bu2Al

Bu-n

I

DMF

25

1

89

Bu-ne

i-Bu2Al

I

DMF

25

1

44

Bu-ne

ClCp2Zr

I

DMF

25

1

27

Bu3Sn

Bu-n

I

DMF

25

1

Trace

Bu-n

Bu3Sn

I

DMF

60−65

13

64 f

aThe alkenylmetals were prepared by treatment of (E )-1-hexenyllithium with appropriate metal halides, unless otherwise mentioned.

bI = Cl2Pd(PPh3)2 + 2n -BuLi. II = Pd(PPh3)4.

cBy1 H NMR and/or GLC.

dIsolated yield.

ePrepared by appropriate hydrometallation of 1-hexyne.

f2-Iodo-2-cyclopentenone remained unreacted to the extent of 18%.

III.2.14.2 CROSS-COUPLING INVOLVING -HETERO-SUBSTITUTED COMPOUNDS

739

Pd(PPh3)4 are satisfactory catalysts. In some more demanding cases, however, the use of more effective catalysts, for example, Cl2Pd[P(2-furyl)3]2,[82]–[84] Pd2(dba)3 AsPh3,[85] and Pd(OAc)2 AsPh3,[86] has been shown to be desirable (Scheme 22).

O

I

Bu-n

+Zn

O

OTf

Bu-n

+ Zn

O

5% Cl2Pd(PPh3)2

10% n-BuLi Bu-n

25 °C, 1 h

2				81 (75)%
	[76]
	5% Cl2Pd(PPh3)2			O
							Bu-n
	10% n-BuLi
2	25 °C, 1 h						83%
	[76]

O

OMOM

5% Cl2Pd(PPh3)2

O

OMOM

I

10% n-BuLi

Pent-n

+ BrZn

Pent-n

25 °C, 1 h

89%

[76]

O

5% Cl2Pd(PPh3)2

O

OTf

Bu-n

Bu-n

10% n-BuLi

+

Zn

25 °C, 1 h

58 (45)%

2

[76]

Me

Me

Bu-n

I

5% Cl2Pd(PPh3)2

Bu-n

10% n-BuLi

O +

Zn

2

25 °C, 1 h

O

[76]

82 (66)%

n-Pent

OSiMe2Bu-t

I

OSiMe2Bu-t

O +

Pd cat.

O

BrZn

Pent-n

[76]

Pd Catalyst

Solvent

Temperature (°C)

Time (h)

Yield (%)

Cl2Pd(PPh3)2 + 2 n-BuLi

DMF

25

1

13

Pd(dba)2

+ 2 P(2-furyl)3

THF

50

24

<5

Pd(dba)2

+ 2 P(2-furyl)3

DMF

20

3

87 (75)

Note: The yields are determined by NMR and/or GLC. The numbers in parentheses are isolated yields.

Scheme 22

As indicated in Table 6, organotins are considerably less reactive than organozincs, but their reactions proceed satisfactorily in many cases at elevated temperatures, typically around 100 °C.[87] An exception to the above generalization is -arylation of -triflyloxy- substituted enones with arylstannes in the presence of Pd2(dba)3 and either AsPh3 or LiCl,

740 III Pd-CATALYZED CROSS-COUPLING

which proceeds well even at room temperature.[88],[89] Under those conditions that are satisfactory for organozincs, the corresponding organoboron compounds show little reactivity.[76] However, the use of Ph3As as a ligand together with an excess of Ag2O (1.5–6.0 equiv relative to the substrates) permits facile -arylation in THF even at 25 °C.[90] Some representative results observed with organotins[87]–[93] and organoborons[90] are summarized in Table 7. The organotin-based method has been applied to the synthesis of ( )-methyl shikimate[94] and ( )-epibatidine[95] (Scheme 23).

O

several

I

O

O

SnBu3

steps

O

cat. Cl2Pd(PhCN)2

Ph3As, CuI, NMP

O

OAc

O

MeOOC

OH

O

several

(−)-methyl shikimate[94]

steps

O

OH

OAc

OH

OMe

O

O

Bu3Sn

OMe

N

I

N

several

4 steps

5% Cl2Pd[P(Tol-p)3]2

steps

16% ZnBr2

95%

NHBOC

DMF, 65 °C

NHBOC

OMe

CF3CON

Cl

Cl

CF

CON

POCl3,

NaOMe

HN

3

N

N

N

DMF

MeOH

( )-epibatidine[95]

Scheme 23

D.ii.c. Pd-Catalyzed -Alkynylation of -Iodoenones (Protocol IIA). Discovery of natural products of various potentially significant biological activities featuring-alkynylenones within the last decade prompted the development of procedures for-alkynylation of enones that might be more direct and more satisfactory than those discussed earlier.[98]–[101] Several independent studies have shown that applications of the methods for -arylation and -alkenylation discussed above involving Sn[102] and Zn[103] permit the desired -alkynylation in good yields. The Cu-based Sonogashira alkynylation was reported in one study to be unsatisfactory for the synthesis of tricholomenyn A,[104] but some other studies have shown that satisfactory results may be obtained using this reaction.[93],[105] These procedures have been applied to very efficient synthesis of harveynone and tricholomenyn A (Scheme 24).[103]–[105] Since their synthesis does not require subsequent conjugate reduction, these recently reported syntheses appear to represent some ultimately satisfactory constructions of this class of compounds. Some other results of -alkynylation are shown in Schemes 25–27.