Negishi E. 2002 Handbook of organopalladium chemistry for organic synthesis / 1179 120

			IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS			1189
TABLE 4. (Continued )
	Arene				Yield	Ref-
	Alkene		Product	Conditions	(%)	erence
	Br		Ph
Br				Pd(OAc)2,	37	[18]
		Ph		(n-Bu)4NBr, K2CO3,
Br
				LiCl, DMF, 100 °C,
		Ph		3 d
	Ph
				Pd(OAc)2,	51	[46]
Br	Br	Ph	Ph	P(o-Tol)3, Et3N,
				MeCN, 100 °C, 3 d
	Br
	Ph		Ph
Br	Br	E	E	Pd(OAc)2,	63	[47]
				P(o-Tol)3, Et3N,	E =
				MeCN, 80 °C, 5 h	CO2Me
	Br
	E		E
aFc = ferrocenyl.

TABLE 5. Fourfold Heck Reaction on 1,2,4,5- and Related Tetrahaloarenes

Arene

Yield

Alkene

Product

Conditions

(%)

Reference

X

X

R

R

X

X

R

R

R

X = I, R = CO2Me

Pd(OAc)2, PPh3, Et3N,

16

[7]

100 °C, 48 h

X = Br, R = H

Pd(OAc)2, P(o-Tol)3,

76

[45]

Et3N, DMF, 125 °C, 8 d

X = Br, R = Ph

Pd(OAc)2, BnEt3NCl,

62

[8]

K2CO3, LiCl, DMF,

110 °C, 3 d

(Continued )

1190	IV	Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 5. (Continued )
Arene					Yield
Alkene		Product		Conditions	(%)	Reference
Br		Ph
	Br		Ph	Pd(OAc)2, (n-Bu)4NBr,	70	[18]
	Br			K2CO3, LiCl, DMF,
Br			Ph	100 °C, 3 d
	Ph	Ph
Br	Br	Ph	Ph	as above	45	[18]
Br	Br
	Ph	Ph	Ph
Br	Br	Fc	Fc	as above, no LiCl,	17	[38]
				80 °C, 6 d
Br	Br
	Fca	Fc	Fc
aFc = ferrocenyl.

Similarly, the reaction of tetrahaloarenes with alkenes gives rise to the formation of tetraalkenylarenes.

Arenediazonium salts, which are readily available from a large stock of anilines, have proved to be valuable starting materials for Heck reactions since their reactivities exceed even those of the corresponding triflates and hence allow coupling at lower temperatures. Twofold Heck reactions of bisdiazonium salts with various substitution patterns have been investigated (Table 6).[48]

Even a fourfold Heck reaction utilizing the tetradiazonium salt with a tetraphenylmethane framework has been demonstrated with various alkenes to yield the corresponding fourfold coupling products.[49] Allyl alcohols did not couple with the tetradiazonium salt, but the tetrakis( p-iodophenyl)methane did yield the tetraaldehyde upon coupling with allyl alcohol (Scheme 5).[49]

The multiple Heck reaction with oligohaloheteroarenes provided a general access to highly symmetrical, often biologically active, molecules. The failure of 2,6-dihalopyri- dine to undergo a twofold Heck coupling was associated with the presence of a heteroatom.[50] However, 2,5-dihalothiophenes are excellent substrates for a twofold Heck coupling, even with 1,1-dimethylallene, the product of which subsequently undergoes a twofold Diels – Alder reaction (Scheme 6, Table 7).[51],[52]

IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS

1191

TABLE 6. Twofold Heck Reaction of Arenebisdiazonium Salts[48]: E = CO2Me

Arene			Yield
Alkene	Product	Conditions	(%)

+N2

N2+

E

2 BF

–

4

CO2Me

R1

R1

R2

+N2

N2+

2 BF

–

4

R2

X

+N2	2 BF	–	N	+	E
				2
	4
	CO2Me
+N2				N2+	E
	2 BF –
	4

CO2Me

E

Pd(OAc)2,

83

MeOH,

65 °C, 1 h

R1

R1

R2

Pd(OAc)2,

Et OH,80 °C,

1 h

R1 = H, R2 = CO2Me

70

R1 = Me, R2 = CO2Me

73

R1 = Me, R2 = Ph

60

X

Pd(OAc)2,

EtOH, 80

°C,

E

1 h

X = O

80

X = SO2

60

Pd(OAc)2,

60

EtOH, 80

°C,

E

1 h

TABLE 7. Twofold Heck Reaction on Dihaloheteroarenes: E = CO2Et

				Yield	Ref-
Arene	Alkene	Conditions	Product	(%)	erence

I	I	Pd(OAc)2, PPh3,	E	E	86	[53]
	O	E
		Et3N, DMF,

O

Br		Br	E Pd(OAc)2, PPh3,	E	E	83–85	[51]
	S		Et3N, MeCN,		S

100 °C, 12–20 h

1192	IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION

R

			Pd(OAc)2, EtOH/H2O
X		X			R, 80 °C
						X = N2+BF4–
									R
						X = I			OHC
X		X
			Pd(OAc)2,Bu4NCl,
			NaHCO3, CH2						CHCH2OH,
			THF/DMF, r.t., 48 h
R = Ph (80%); CO2Et (75%), SO2Ph (20%)
									OHC
							Scheme 5
							Pd(OAc)2, PPh3
							Ag2CO3, PhMe,			S
I	S	I +		•				120 °C, 48 h
								50%

S

R

R

CHO

CHO

O	N	O
		H		H	H		H
	Me
		O	N	O	O	N	O
			Me			Me
		Scheme 6

C. MULTIPLE HECK COUPLINGS OF 1,2-DIBROMOCYCLOALKENES AND RELATED COMPOUNDS

Double Heck reactions of vicinal cis-1,2-dihaloalkenes provide an easy access to (E,Z,E)- 1,3,5-hexatrienes, which are valuable building blocks for organic synthesis.[11],[40],[54] The first example of a twofold double, that is, essentially a fourfold, Heck reaction with a bis(dibromo)cycloalkene has been conducted on the strained 1,2,9,10-tetrabromo[2.2] para- cyclophane-1,9-diene, which is available in multigram quantities. The Heck reaction proceeded cleanly under phase transfer conditions, as developed by Jeffery,[41],[42] to give the tetraalkenylated products in moderate to good yields (Table 8). The resulting bishexatrienes

Yield (%) Reference

	Conditions
1,2-DibromocycloalkenesandRelatedCompounds	Oligobromocycloalkenes
Reactionon	Alkene
TABLE8.MultipleHeck	Oligobromocycloalkenes

[40]

[54]

[40],[54]

[54]

a

a

(20)

(0)38

(50)50

(80)58

b

a

3d

C,70° 36h

C,70° 2d

d

2

DMF,100°C,

2

DMF,40°C,2

NBr,

NBr,

4

4

,Bu

K

above,As

above,As

,Bu

K

Pd(OAc)

Pd(OAc)

,

,

3

3

CO

CO

2

2

Me

F-4-

=RCHO

CO-4-

2

4

4

Ar

Ar

Ph

H

H

R

R

C

C

6

6

Ar=

Ar=

Ar=

Ar				Ar	R				R
Ar					R
Br				Br	Br				Br

Br

Br

Br

Br

			[11],[56]		[56]	[11]
						b
			55		69	57(41)
		N,				20h
3					4d
		Et		h
,			C,°72		90°C,	90°C,
		PPh,
3
2				DMF,100	Asabove,	Asabove,
		Pd(OAc)
				Me		t-Bu
			2			2
				R=CO	R=Ph R=CO
R				R
R
Br				Br

N, 3 Et, 3 PPh,

2 Pd(OAc)

R

R

X

[9],[56]	[9]			[56]
81	82			90
	N,		N,
	3
	Et	1d,	3
	3		Et,
h	,		AgNO 2C,°d,
	Tol)P(-o °C,
DMF,100°C,40	Pd(OAc)	THF/MeCN,55 kbar10	3	Arbar5
			Pd(OAc) DMSO,20
	,		,
	2		2
Me	Ph		3
CO			SiMe
2
R= R=			R=
	R				ofyieldIsolated1,2-dicouplingproductafteraromatization.	ofyieldIsolatedthereducedmonocouplingproduct.
	X X=Br		X=I
	BrX=
					a	b

1193

1194	IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION

upon heating underwent a clean twofold 6 -electrocyclization to yield, after subsequent dehydrogenation, the bisbenzoannelated [2.2]paracyclophanediene derivatives (Scheme 7).

In contrast, the twofold alkenylations of cis-1,2-dibromoethene, 1,2-dibromocyclopen- tene, and 1,2-dibromocyclohexene proceed in better yields under the classical Heck conditions (Table 8).[11] The (E,Z,E)-1,3,5-hexatrienes resulting from 1,2-dibromocycloalkenes undergo 6 -electrocyclizations reasonably cleanly upon heating (130–150 °C) in an inert

Br			Br	Pd(OAc)2, Bu4NBr			R				R
				K2CO3 or NaHCO3
				DMF, 40–100 °C, 12 h to 5 d
Br			Br				R				R
				15–57%
+ 4		R					R				R
					DDQ or S8
					0–80%		R				R

R = H, SiMe3, CHO, CO2Me, Ph, p-MeO2C-C6H4, p-F-C6H4, p-t-Bu-C6H4, p-Ph-C6H4

Scheme 7

solvent such as di-n-butyl ether or xylene in the absence of oxygen to give the ring-annelated cis-5,6-disubstituted 1,3-cyclohexadienes. In the presence of oxygen these products are easily dehydrogenated to the corresponding ring-annelated benzene derivatives (Scheme 8). Another use of these hexatrienes was demonstrated by the epoxidation of the tetrasubstituted double bond to give dialkenylepoxides, which in turn were selectively ring-opened by Pdcatalyzed reduction. The alcohols resulting from the sixand seven-membered ring epoxides, upon deprotonation at 78 °C, undergo an oxyanion-accelerated Cope rearrangement to give the corresponding trans-cycloalkenones.[55],[56]

R

( )n

R

R

Br

[O2]

Pd(OAc)2, PPh3,

R

(n-Bu)2O, N2

R

Et3N, DMF,

40−100 °C,

150 °C, 5 h

( )n Br

( )n

55−81%

( )n

R

50−94%

R

n = 1, 2, 3

1. MCPBA or DMDO

n = 1, 2, 3

R = CO2Me, CO2t-Bu, Ph

79−87%

2. Pd0, HCO H, 20 °C

O

2

OH

O

KHMDS, 18-c-6

KHMDS, 18-c-6

R

R

R

THF, –78 °C

THF, –78 °C

n = 1

( )n

R

51−94%

( )n

R

R

24−83%

H

n = 2, 3

n = 1, 2, 3

Scheme 8

IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS

1195

As alternatives to the 1,2-dihalocycloalkenes, 1-halo-2-perfluoroalkanesulfonyloxycy- cloalkenes may serve as starting materials for twofold Heck reactions. Since they can easily be prepared from the corresponding ketones via the -haloketones and subsequent sulfonylation of the enolates, this sequence provides a straightforward access to various substituted 1,3,5-hexatrienes (Scheme 9, Table 9).[57]

O 1. LDA, THF, –78 °C, 0.5 h, → 20 °C

Hal 2. (RFSO2)2O or (RFSO2)2NPh or

RFSO2F

		R
	OSO2RF	Pd(OAc)2, PPh3,
		Et3N, LiCl, DMF,
		40 −100 °C

Hal

RF = CF3 or n-C4F9

Hal = Br, Cl

Scheme 9

R

R

TABLE 9. Twofold Heck Reaction on 1-Halo-2-perfluoroalkanesulfonyloxycyclo-

alkenes[56],[57]

1-Halo-2-perfluoroalkane-
sulfonyloxycycloalkane			Yield
Alkene	Product	Conditions	(%)

OTf

E

Pd(OAc)2, PPh3, Et3N,

Br

E

LiCl, DMF, 90 °C, 96 h

73

E

E = CO2t-Bu

OTf

E

Pd(OAc)2, PPh3, Et3N,

86

Br

E

LiCl, DMF, 90 °C, 40 h

E

R = CO2t-Bu

OTf

E

Br

E

OR

OR

E

R = SiMe2t-Bu

Pd(OAc)2, PPh3, Et3N,

64

E = CO2t-Bu

DMF, 80 °C, 20 h

ONf

E

Pd(OAc)2, PPh3, Et3N,

71

Br

E

LiCl, DMF, 90 °C, 40 h

E

E = CO2Me

ONf

E

Cl

E

E

Pd(OAc)

, PPh , Et N,

23 (64)a

2

3

3

E = CO2Me

DMF, 75 °C, 8 d

a Yield of the monocoupling product in parentheses.

1196	IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION

D. INTRA–INTERMOLECULAR TWOFOLD HECK COUPLING

OF 1,3-BIS(NONAFLUOROBUTANESULFONYLOXY)CYCLOHEXADIENE

The intra–intermolecular Heck reaction of dienediol bisnonaflates containing an -alkenyl substituent with an external alkene such as an acrylate gives rise to the formation of a bicyclic tetraene by an intramolecular coupling followed by an intermolecular

Heck reaction (Scheme 10).[58]

			O
			t -BuO
Ph			Pd(OAc)2, PPh3					O		Ph
NfO		ONf	Et3N, DMF
			80 °C, 12 h				t-BuO
			43%

Scheme 10

E. MULTIPLE HECK 1,1- AND 1,2-BISARYLATIONS OF ETHYLENE AND RELATED COMPOUNDS

The twofold Heck arylation of ethylene[13],[59] and ethylene equivalents provides an easy access to stilbene derivatives (Scheme 11, Table 10). In the case of ethylene, the pressure has to be carefully controlled, otherwise styrene derivatives, which are the primary products in this process, will be found as major products. In general, slightly pressurized (1 – 5 bar) reaction conditions are suitable for the twofold coupling and lead to stilbenes in up to 91% yield and with turnover numbers up to 18,200. The linear dependency on ethylene pressure in the arylation of ethylene with aroyl chlorides to give stilbenes (low pressure of ethenyl) or styrenes (high pressure) has been shown previously.[60]

X

,,

+ H2C CH2

Pd ,,

Scheme 11

Besides ethylene, ethenylsilanes and ethenyl acetate, which are easy to handle, can yield stilbenes by 1,2-arylation with elimination of the functionality, in good yields (Scheme 12, Table 11).

X

,,

+ Y

Pd ,,

Y = Si(OEt)3, OAc, etc.

Scheme 12

	IV.2.1.2	DOUBLE AND MULTIPLE HECK REACTIONS		1197
TABLE 10. Double Heck 1,2-Arylations of Ethylene
	Ethylene	Product	Yield (%)
Halorene	(Pressure)	(Conditions)	(Reference)

Br

Me

Br

X

COCl

R1–3

8 examples

R

R = H or SO3H

20 psi

Me

Me

(Pd(OAc)2, P(o-Tol)3, MeCN, 125 °C, 20 h)

120 psi

X

X = NHAc

X

(Pd(OAc)2, P(o-Tol)3, DMF, 125 °C, 2 h)

X = CHO

(as above, 8 h, 1 bar ethylene)

1 bar

R1–3

8 examples

R1–3

(Pd(OAc)2, P(o-Tol)3, BnMe2N or N-ethylmorpholine, p-xylene, 120 °C, 4.5–7.5h)

Br 1.5 bar R

R

R = H or SO3H

(Pd(OAc)2, P(o-Tol)3, Et3N, MeCN or NMP, 125 °C)

34 (54)a ([13])

48

([13])

75

([61])

45

([60])

66−72 ([59])

a Yield of the styrene formed is given in parentheses.

In general, the Heck coupling of aryl halides with terminal alkenes yields styrene derivatives. However, under certain conditions such as with an excess of the aryl halide,[64] at elevated temperatures, under high pressure,[65] and with electron-deficient alkenes, a terminal twofold coupling to yield 1,1-diarylalkene derivatives may take place (Scheme 13,

Table 12).

Under high pressure (10 kbar), the -hydride elimination is retarded and the metastable -alkylpalladium halide may insert into the double bond of a second acrylate

1198	IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 11. Double Heck 1,2-Diarylation of Ethylene Equivalents
		Ethylene	Product	Yield (%)
	Haloarene	Equivalent	(Conditions)	(Reference)
	O	OAc	O
	O	I	O
O			O
				50
	O		O
	O		(polymer supported Pd, Bu3N, MeCN,	([62])
			130 °C, 16 h)
	N2+BF4–	Si(OEt)	I
		3
I
			I	62
			(Pd (OAc)2, PPh3, MeOH, 25 °C,	([63])
			30 min)

X

	,,		,,
+	R		Pd

R

Scheme 13

TABLE 12. Double Heck 1,1-Arylation of Acrylates and Related Compounds

Haloarene			Yield (%)
Alkene	Product	Conditions	(Reference)

PhBr

Ph

CO2Me

Pd(OAc)2, P(o-Tol)3, Et3N,

78

CO2Me

100 °C, 34 h

([64])

Ph

excess

Ph

Pd(OAc)2, P(o-Tol)3, Et3N,

52

PhI

CO2Me

CO2Me

MeCN, 100 °C, 43 h

([66])

Ph

excess

CHO

Pd(OAc)2(PPh3)2, Et3N,

73

HO

I

MeCN, 80 °C, 10 h

([67])

CHO

HO

OH

PhI

Ph

CN

PdCl2 on modified

90

CN

montmorillonite, Bu3N,

([68])

Ph

100 °C, 4 h

PhI

Ph

CO2Et

Pd(OAc)2(PPh3)2,Et3N,

76

CO2Et

DMF, 140 °C, 4 h, 10 kbar

([65])

Ph