Negishi E. 2002 Handbook of organopalladium chemistry for organic synthesis / 1651 165

RI + Et2Zn	cat. Pd	RZnI

IV.11 Palladium-Catalyzed

Carbozincation

PAUL KNOCHEL

A. INTRODUCTION

The carbopalladation is a central reaction in organopalladium chemistry and is extensively presented in Part IV. In most reactions, a discrete organopalladium intermediate adds to a double or triple bond. In this section, the reaction of an alkyl iodide with diethylzinc in the presence of a palladium(0) catalyst is presented. Such reaction conditions generate an alkyl radical that readily adds intramolecularly to a double bond, leading to an organozinc derivative (Scheme 1). The combination of a radical cyclization with the formation of an organometallic product allows new synthetic applications that will be discussed. Closely related Ni-catalyzed cyclizations will also be briefly presented.

B. MECHANISTIC STUDIES

The iodine–zinc exchange[1],[2] is a convenient method for preparing diorganozincs. It is catalyzed by copper(I) salts[2] and proceeds at temperatures between 50 and 60 °C. Other metallic salts catalyze this exchange reaction and especially palladium(II) salts give excellent results, allowing the conversion of octyl iodide to octylzinc iodide (and not dioctylzinc as shown by gravimetric analysis)[3] (Scheme 2). Functionalized primary alkyl iodides such as EtO2C(CH2)3I or NC(CH2)3I react within 1 0 – 30 min at 25 °C ( 90% yield) without the formation of any -hydride elimination product. In order to clarify the mechanism of the reaction, other precursors were used. It was found that alkyl tosylates or mesylates do not react. The reaction is inhibited by small amounts of nitrobenzene and does not proceed with Me2Zn. The exchange reaction is also very slow in ether. The treatment of either exo- or endo-7-iodobicyclo[2.1.0]heptane[4] with Et2Zn (ca. 2 equiv) in the presence of PdCl2(dppf) in THF furnishes the exo-substituted bicyclic organozinc reagent, which was allylated in a stereoconvergent manner, suggesting a radical to be a reaction intermediate (Scheme 3).

The insertion of Pd(0) into an alkyl iodide may therefore proceed via a radical pathway.[5],[6] The fast oxidative insertion may also indicate that a palladate species[7] such as 1 may be responsible for an electron transfer reaction[8] (Scheme 4). By using 5-hexenyl

Handbook of Organopalladium Chemistry for Organic Synthesis, Edited by Ei-ichi Negishi ISBN 0-471-31506-0 © 2002 John Wiley & Sons, Inc.

1651

1652

IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION

I

Et2Zn

PdCl2L2

ZnI

Scheme 1

Et2Zn, 50 °C, 12 h

Et2Zn, THF, 25 °C, 2 h

Oct2Zn

Oct-I

Oct-ZnI

CuI (0.3 mol %)

PdCl2(dppf) (1.5 mol %)

−H2C=CH2 −H3C CH3

Scheme 2

I				H
	Et2Zn, Pd(0) cat.			Et2Zn, Pd(0) cat.
H				ZnI
H			H	H
H				exo/endo = 96:4

endo

1.CuCN 2 LiCl

2.COOEt Br

H

COOEt

H

60%

H

Scheme 3

Et2Zn

R

Pd(0)

EtPd ZnEt

EtPd + R

−EtZnI

1

Scheme 4

H

I

H

H exo

EtPd R

iodide as a substrate, a radical cyclization occurs, affording cyclopentylmethylzinc iodide (Scheme 1). This synthetic procedure allows one to perform radical ring closures[9] but affords as a product an organometallic species (organozinc halide) that can be used to form further carbon–carbon bonds. The stereoselectivity observed in the ring closure follows Beckwith rules[10] and is also stereoconvergent. Thus, the cyclization of the iodides 2a and 2b provides only the trans-product via a chair transition state such as 4

(Scheme 5).

A complete trans-stereoselectivity is observed between C(1) and C(2) of products 3a-b. The cyclization leads as expected[10] to lower stereoselectivity for the ring closure, affording the allylated product 5 as a cis/trans mixture of 78:22. This selectivity can dramatically be improved by using the 3-substituted secondary alkyl iodide 6. Although

H

I Et2Zn (2 equiv)

RO

PdCl2(dppf) 1.5 mol % 25 °C, 20 h

2a: R = Bn

2b: R = Bz

IV.11	PALLADIUM-CATALYZED CARBOZINCATION							1653
							EtO2C
H						99:1
			1. CuCN • 2 LiCl			RO
RO	H
				COOEt				67%
	H H		2.
				Br		3a: R = Bn 73%
	4					3b: R = Bz 47%
	Scheme 5

6 is used as a 1:1 mixture of diastereoisomers, only one stereoisomer 7 is obtained. Its formation is easily rationalized by assuming a chair transition state such as 8 (Scheme 6).[4],[11] The stereoconvergence of the reaction supports the radical mechanism of the ring closure.

Et2Zn (2 equiv)

Me

PdCl2(dppf)

	I	1.5 mol %
		25	°C, 2 h

Et2Zn (2 equiv)

BnO I

PdCl2(dppf)

	Me	1.5 mol %
		25	°C, 5 h

6

EtO2C

1. CuCN • 2 LiCl

Me

78:22

H

COOEt

2.

Br

Me

H

5

80%

EtO2C

99:1

H

95:5

1. CuCN • 2 LiCl

Me

BnO

Me

BnO

2.

COOEt

H H

Br

7 67%

8

Scheme 6

C. SCOPE AND LIMITATION OF THE CYCLIZATION

The cyclization of 4-substituted 5-hexenyl iodides proceeds well, leading to cyclopentylzinc iodides that can be trapped with various electrophiles such as 3-iodo-2-cyclohexenone, iodine, acid chlorides, allylic halides, and ethyl propiolate (carbocupration) (Scheme 7).[4]

Various substitution patterns allow a successful cyclization. Also, a range of functional groups like esters or nitriles are tolerated in the ring closure (Scheme 8).

The presence of an oxygen functionality (O-centered leaving group) is also compatible with the reaction conditions and the 2-pivaloyloxyalkyl iodide 9 leads after allylation to the expected cyclopentane derivative 10 (Scheme 9).[4]

1654

IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION

Ph

O

1. CuCN • 2 LiCl

Ph

2.

O

I2

I

I

90%

Ph

Et2Zn, THF

Ph

25 °C, 2h

1. CuCN • 2 LiCl

Ph

PdCl2(dppf)

ZnI

CO2Et

CO2Et

2.

1.5 mol %

I

>98% trans

64% >95% E

1. CuCN • 2 LiCl

1. CuCN • 2 LiCl

2. CO2Et

Br

Ph

2. PhCOCl

CO2Et

Ph

O

73%

76%

Scheme 7

I

Et2Zn (2 equiv)

1. CuCN • 2 LiCl

ZnI

PdCl2(dppf )

CO2Et

1.5 mol %

2.

Br

CO2Et

25 °C, 2 h

FG

FG

FG

FG = CN 83%

FG = OCOt-Bu 62%

I

ZnI

1. CuCN • 2 LiCl

Bu Ph

Et2Zn (2 equiv)

Bu

PdCl2(dppf )

Bu

2.

NO2

NO2

1.5 mol %

25 °C, 2 h

Ph

81%

Scheme 8

IV.11 PALLADIUM-CATALYZED CARBOZINCATION

1655

I

E	Et2Zn (2 equiv)

E PdCl2(dppf )

1.5mol % 25 °C, 2 h

E = CO2Et

R

I

Et2Zn (2 equiv)

PdCl2(dppf ) 1.5 mol % 25 °C, 2 h

R = Me, Et, c-Hex

R

I

Et2Zn (2 equiv)

PdCl2(dppf ) 1.5 mol % 25 °C, 2 h

R = (CH2)4OAc, Et, (CH2)3CN

R

I

Et2Zn (2 equiv)

PdCl2(dppf ) 1.5 mol % 25 °C, 2 h

R = (CH2)4OAc, (CH2)3CN

OAc

I

Et2Zn (2 equiv)

PdCl2(dppf ) 1.5 mol % 25 °C, 2 h

	1. CuCN • 2 LiCl								E
	2.		CO2Et						E	73%
					Br					CO2Et
									E = CO2Et
									R
	1. CuCN • 2 LiCl
										O
	2.					O
									62−81%
			I						cis/trans ca. 70:30
									R
	1. CuCN • 2 LiCl
	2.			COOEt
					Br					CO2Et
									75−87%
									cis/trans	ca. 78:22
									R
	1. CuCN • 2 LiCl									CO2Et
	2.				CO2Et

51−71% cis/trans ca. 78:22

OAc

1. CuCN • 2 LiCl
2.
Cl			OAc	AcO

52% cis/trans 77:23

Scheme 8 (Continued )

				EtO2C
I	Et2Zn		ZnI	1. CuCN • 2 LiCl		80:20
OPiv				CO2Et
	PdCl2(dppf )		OPiv
	1.5 mol %			2.		OPiv
				Br
	25 °C, 2 h

9

10 87%

Scheme 9

1656	IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION

Various domino cyclizations using substrates like 1 1–13 have been used successfully (Scheme 10).[4],[11]

The intramolecular addition to unsaturated esters was also possible. Best results are obtained with a t-amyl ester, which leads to a product that is less prone to undergo Claisen condensation. The same reaction is observed with the corresponding acetylenic ester (Scheme 11).[4]

I

1. Et2Zn		CO2Et
PdCl2(dppf ) cat.
25 °C, 2 h
2. CuCN • 2 LiCl
COOEt		90% endo/exo 80:20
Br

	1. Et2Zn
	PdCl2(dppf ) cat.
I		25 °C, 2 h
	2. CuCN • 2 LiCl
11				CO2Et
n	1. Et2Zn (2 equiv)
	Ni(acac)2 (2.5 mol %)
		0 °C, 3h
I	2. CuCN • 2 LiCl
				CO2Et

12n = 1

13n = 2

CO2R

I

Br

Scheme 10

Et2Zn, THF PdCl2(MeCN)2 (1.5 mol %)

−78 °C to 25 °C, 4 h

CO2Et

70% endo/exo 80:20

EtO2C

n = 1: 85 % endo/exo 1:2 n = 2: 63 % endo/exo 1:2

CH2 CO2R

R = Et				R = Et 57%
R = t-Am				R = t-Am 74%
			CO2Me	Et2Zn ( 2 equiv), THF			CO2Me
		I
				PdCl2(MeCN)2 ( 1.5 mol % )
				25 °C, 4 h
				73%
				Scheme 11

IV.11 PALLADIUM-CATALYZED CARBOZINCATION

1657

The reactivity observed with acetylenic ketones is more complex and the two iodoalkynyl ketones 14 and 15 behave in a different way (Scheme 12). Thus, the phenyl ketone 14 undergoes carbopalladation of the triple bond followed by a reductive elimination, furnishing the exo-alkylidenecyclopentane derivative 16. On the other hand, the methyl ketone 15 undergoes, after carbopalladation, a subsequent Michael addition, leading to the ketone 17 in 52% yield.

COPh

Et2Zn, THF

COPh

I

PdCl2(MeCN)2 (1.5 mol %)

Et

25 °C, 4 h

14

16

60%

COMe

Et2Zn, THF

COMe

I

PdCl2(MeCN)2 (1.5 mol %)

Et

25 °C, 4 h

15

17 52%

Scheme 12

The scope of the reaction can be extended to unsaturated alkyl bromides as substrates by using Ni(acac)2 as a catalyst[12],[13] instead of Pd(II) complexes. The use of Ni(acac)2 as a catalyst even with several polyfunctional alkyl iodides gives better results. Thus, in the key step for the synthesis of methyl epijasmonate 18, the alkyl iodide 19 undergoes a smooth cyclization using Ni(acac)2 and Et2Zn (Scheme 13).[12]

OBn	1. Et2Zn, Ni(acac)2 cat						OBn
	THF, 25 °C
CO2Me	2. CuCN • 2 LiCl						Et
	3. Br					Et
							CO2Me
I	−55 °C, 48 h
19							86%
							95:5

O

Et

CO2Me

18 epijasmonate

Scheme 13

Polyfunctional alkyl bromides have been cyclized with Ni(acac)2/Et2Zn for the construction of various heterocycles[13] as well as for the antitumor antibiotic ( )-methylenolactocin 20. In this case, the alkyl bromide 21 is cyclized and selectively oxidized to the aldehyde 22, which is converted in a standard way to the natural product

20 (Scheme 14).

1658

IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION

Me3Si

Br

1. Et2Zn, LiI

ZnX

OHC

Ni(acac)2

O

SiMe3

THF, 40 °C

O

C

Pent

O

OBu

2. O2, TMSCl

Pent

O

OBu

THF, −5 °C

OBu

21

Pent

O

22

55%

HO2C

HO2C

Jones reagent

acetone,

Pent

O

O

Pent

O

O

0 °C, 15 min

90 %

20: (−)-methylenolactocin

Scheme 14

D.SUMMARY

1.The treatment of an alkyl iodide with Et2Zn in the presence of catalytic amounts of palladium(II) salts leads to the corresponding organozinc iodide.

2.The reaction proceeds via a radical intermediate and can be used to perform radical cyclizations affording five-membered rings. However, the products of these reactions are organozinc reagents, which can be reacted with a wide range of electrophiles.

3.The cyclizations are stereoselective following the Beckwith rules and allow the elaboration of highly substituted cyclopentane derivatives.

4.Domino cyclizations can be performed.

5.Unsaturated alkyl bromides can be used as substrates if the Pd(II) catalyst is replaced by Ni(acac)2.

REFERENCES

[1]M. J. Rozema, S. AchyuthaRao, and P. Knochel, J. Org. Chem., 1992, 57, 1956.

[2]M. J. Rozema, C. Eisenberg, H. Lütjens, R. Ostwald, K. Belyk, and P. Knochel, Tetrahedron Lett., 1993, 34, 3115.

[3]H. Stadtmüller, R. Lentz, W. Dörner, T. Stüdemann, C. E. Tucker, and P. Knochel, J. Am. Chem. Soc., 1993, 115, 7027.

[4]H. Stadtmüller, A. Vaupel, C. E. Tucker, T. Stüdemann, and P. Knochel, Chem. Eur. J., 1996, 2, 1204.

[5]A. V. Kramer, J. A. Labinger, J. S. Bradley, and J. A. Osborn, J. Am. Chem. Soc., 1974, 96, 7145.

[6]A. V. Kramer and J. A. Osborn, J. Am. Chem. Soc., 1974, 96, 7832.

[7]C. Amatore, E. Carré, A. Jutand, H. Tanaka, Q. Ren, and S. Torii, Chem. Eur. J., 1996, 2, 957.

[8]M. Chanon, Bull. Soc. Chim. Fr., 1982, 2, 197.

[9]D. P. Curran, in Comprehensive Organic Chemistry, Vol. 4, B. M. Trost and I. Fleming, Eds., Pergamon Press, New York, 1991, 779.

IV.11 PALLADIUM-CATALYZED CARBOZINCATION

1659

[10]A. L. J. Beckwith, T. Lawrence, and A. K. Serehis, J. Chem. Soc. Chem. Commun., 1980, 484.

[11] H. Stadtmüller, C. E. Tucker, A. Vaupel, and P. Knochel, Tetrahedron Lett., 1993, 34, 7911.

[12]H. Stadtmüller and P. Knochel, Synlett, 1995, 463.

[13]A. Vaupel and P. Knochel, J. Org. Chem., 1996, 61, 5743.