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

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I Pd(OAc)2, Et3N

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IV.2.1.2 Double and Multiple Heck Reactions

STEFAN BRÄSE and ARMIN DE MEIJERE

A. INTRODUCTION

The multiple Pd-catalyzed couplings of oligohaloarenes and -alkenes (or perﬂuoroalkyland ﬂuorosulfonates) with alkenes (Heck reactions) offer the possibility of constructing symmetrically oligosubstituted, highly unsaturated carbon frameworks in a single synthetic operation. The Heck reaction of diand oligoethenylarenes with diand oligohaloarenes can be applied to produce conjugated polyvinylenearylene-type polymers that may have important applications in the future. Comparable in scope and limitations to the related multiple Stille and Suzuki couplings, the ready accessibility of starting materials and the ease of removing by-products have made multiple Heck reactions particularly attractive for various synthetic applications.

In this section, a double (or multiple) Heck reaction is deﬁned as a coupling of two (or more) alkene molecules with dior oligohaloarenes or -alkenes as well as a reaction of two (or more) dior oligohaloarenes or alkenes with one alkene molecule.

B. COUPLING OF OLIGOHALOARENES WITH ALKENES

The multiple coupling of oligohaloarenes with alkenes was described early on by Heck and Nolley in one of their ﬁrst papers.[1] Twofold coupling of 1,4-diiodobenzene with styrene furnished the 1,4-distyrylbenzene in 67% yield; shortly afterwards, the double Heck couplings under palladium catalysis of 4,7-diiodoﬂuorene, p-diiodoterphenyl, and p- diiodobiphenyl with various substituted styrenes were disclosed by Japanese chemists in a patent on the synthesis of dye brighteners.[2] Since then, a large number of ortho-, meta-, and para-dihaloarenes and -heteroarenes have been subjected to double Heck reactions with various alkenes (Tables 1–3, Scheme 1).

However, the substitution pattern on the arene is crucial for the success of the Heck reaction. When a second Heck coupling takes place in an ortho position of another alkenyl unit, cyclization of the intermediately formed -( -arylalkyl)palladium complex may occur, as formation of alkylideneindanes and alkylindenes, especially under classical Heck conditions with phosphines in the catalyst cocktail, was observed (Scheme 2, Table 1).

1179

1180	IV	Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION
TABLE 1. Twofold Heck Reactions on 1,2-Dihaloarenes

Arene		Alkene		Product
	X				R
								Yield	Ref-
	X	R			R		Conditions	(%)	erence

X = I		R = Ph		R = Ph			Pd(OAc)2, Bu3N,	37	[1]
							100 °C, 72 h
X = I		R = CO2Me		R = CO2Me			Pd(OAc)2, PPh3,	69	[7]
							Et3N, 100 °C, 48 h
X = Br		R = Ph		R = Ph			Pd(OAc)2, Bu4NBr,	92	[8]
							K2CO3, DMF,
							100 °C, 5 d
X = Br		R = Ph		R = Ph			Pd(OAc)2, P(o-Tol)3,	59	[9]
							Et3N, THF/MeCN,
							55 °C, 1 d, 10 kbar
							Pd(OAc)2, P(o-Tol)3,	65	[10]
							Et3N, 150 °C
							(microwave), 22 min
X = Br		R = CO2Me		R = CO2Me			Pd(OAc)2, Bu4NCl,	86	[11]
							LiCl, K2CO3, DMF,
							100 °C, 12 h
X = Br		R = Me (5 bar)		R = Me			Pd(OAc)2, Bu4NBr,	79	[12]
							LiCl, KHCO3,
							DMF, 100 °C, 12 h
X = Br		R = H (13.8 bar)		R = H			Pd(OAc)2, P(o-Tol)3,	78	[13]
							Et3N, MeCN,
							125 °C
X = Br		R =	Ph	R =	Ph		Pd(OAc)2, PPh3,	65	[14]
X = Br		P		P			Pd(OAc)2, PPh3,	65	[14]
		Me	O	Me	O		Et3N, DMF, 135 °C,
		Me	O	Me	O		36 h
							36 h
X = Br		R = 4-Py		R = 4-Py			Pd(OAc)2, PPh3,	80	[15]
							Et3N, 100 °C, 3 d
X = Br		R = Fc		R = Fc			Pd(OAc) ,	74a	[16]
							2
							(n-Bu)4NBr, K2CO3,
							DMF, 70 °C, 3 d
I	I	O					Pd(OAc)2, PPh3,	77	[17]
		O					Pd(OAc)2, PPh3,	77	[17]
		B		O		O	Et3N, MeCN, reflux
		O		O BO		B O	Et3N, MeCN, reflux
		O		O BO		B O	16 h
							16 h

			IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS				1181
TABLE 1. (Continued )

					Yield		Ref-
Arene	Alkene		Product	Conditions	(%)		erence

	Ph		Pd(OAc)2,Bu4NBr,		35		[18]
Br			K2CO3, LiCl, DMF,
Br			100 °C, 3 d
			100 °C, 3 d
			Ph
	Br		Ph
			Pd(OAc)2, P(o-Tol)3,		46		[19]
			DMF, 100 °C, 2 d
		OH	O			b
	I	OH	Pd(OAc)2, PPh3,		56		[5]
	I

			i-Pr2EtN, DMF,
	I		100	°C, 3 d

aFc = ferrocenyl.

bThe diketone was isolated.

	X		R2	R1			R2
	X	,, Pd	R2				R2
	X		,,			R2
			,,


	X = Br, I; R2 = aryl, alkyl, etc.
	X = Br, I; R2 = aryl, alkyl, etc.
			Scheme 1
							R2
	R2	R1		R2		R1
,,	,,
	Pd				and/or		R2
				R2

Scheme 2

This reaction mode plays a dominant role in the sixfold Heck coupling of hexabromobenzene with styrenes yielding complex mixtures of various isomers of the sixfold coupling product. The analogous sixfold Suzuki and Stille coupling reactions with alkenylboronates and alkenylstannanes, respectively, gave the corresponding pure hexakisalkenylbenzene derivatives in high yields.[3] As shown by various experiments with o- and p-dihaloarenes, the second coupling step is generally accelerated by the first introduced alkenyl substituents in the ortho or para position, while a meta-alkenyl substituent does not significantly influence the rate of the second coupling.[4]

Yield (%) Reference

CO	Product
Me
2
1,3-Dihaloarenes:E=	Alkene (Conditions)
Reactionson	Alkene (Conditions)
TwofoldHeck
TABLE2.	Arene

[7]

a 46

E
		Br
E
	N,
	3
E	,Et
	3
	PPh	h)
	,	100°C,19
	2
	(Pd(OAc)
I		Br
I

[20]

Bn 2 CO

C 2 BnO

NHBoc

OBn

I I

NHBoc

BocHN

NCl, 4 O Bu , 2 (Pd(OAc)

DMF,	h)
,
3
NaHCO	85°C,16

[21]

PhN,

Bu(Pd/C,

I I

115–120 °C, 3 h)

2 R

Br Br

[15]

[14]

	R	-4Py	P(O)MePh
1
		=	=
		2	2
		=H,R	=H,R
		1	1
		R	R
				N,
				3
		,	C,3d)	,Et	C,°36h)
		PPh,	C,3d)	PPh,	C,°36h)
		3		3
		2	100°	2	DMF,135
		(Pd(OAc)	Et	(Pd(OAc)	DMF,135
			N,
			3
1
	R
	R

[22]
b
n.r.
Et
2
=CO
2
=HOCHPh,R
1
R
,
3
,P(o-Tol)	MeCN)
2	MeCN)
(Pd(OAc)	Et
	N,
	3

[23]

Et
2
OH,R=CO
2
=CH
1
R
3	h)
3	1
,
o-Tol) 90°C,
,P(	MeCN,
2	MeCN,
(Pd(OAc)	Et
	N,
	3

[24]

=CN
2
Et,R
2
=CO
1
R
,	7d)
,
Tol)-o 120°C,
3
,P(	MeCN,
2	MeCN,
(Pd(OAc)	Et
	N,
	3

brominesubstituentdoesnottakepartinthecouplingundertheseconditions.	=notreported.
The	n.r.
a b

1182

		Reference
	Yield	(%)
2		Conditions
Et
Me,E =CO
2
Dihaloarenes:E=CO		Product
para-Substituted
1,4-andRelated		Alkene
TwofoldHeckReactionson		Arene
TABLE3.
TABLE3.

[1]			[2]	[25]			[26]
67			a	11			76
67			n.r.	11			76
2 N,		h		2	N,	°C,	2 NCl,	DMF,,		h16
2 N,		h		2	3	°C,	2 NCl,	DMF,,		h16
					3
,	100°C,72		DMFPd,	,	Et,	DMF,100 h17	,	K		800
Pd(OAc) Bu)-n(	100°C,72		DMFPd,	Pd(OAc)	Tol)-oP(	DMF,100 h17	Pd(OAc) Bu)-n(	K		800
3							4 CO		C, °
								3
								2
			-4-t-Bu
			4
	Ph		H			Ph		OR
	Ph		C			Ph		OR
			6
						3
						3

					3



Ph		6		Ph	RO
		4
		H
		-Bu-4-C
		t
			4--t-Bu	Ph	2
	Ph		4--t-Bu	Ph	NMe
	Ph	6					OR
		4
			H
			C			O
					^ =
			-4-I
		4
			H
	I	6		I		I
	I		C	I		I


	4		I
I	H	I	I
	6
	4-I-C

[7]
32
,	N,	h
2	3	100°C,48
Pd(OAc)	PPh	100°C,48
	Et ,
	3

[27]				[28]	(Continued)
89				62
		2:1,			3
					N,
,	,	N/MeCN	70°C,70h	Pd(OAc),2	,Et
2	3	N/MeCN			3
Pd(OAc)	Tol)-P(o	Et			Tol)P(-o h60C,110°
		3

	E		OMe	OMe
	E
OMe	OMe	OMe
MeO	MeO			MeO
	E	MeO	MeO
		MeO	MeO

OMe

OMe	I	OMe	OMe	Br
MeO	I	MeO		Br	MeO

1183

Yield (%) Reference

Conditions

Product

Alkene

3.(Continued)	Arene
TABLE

55 [20]

,		DMF,
2 NCl,		3 h
Pd(OAc) Bu)-n(		,
Pd(OAc) Bu)-n(		NaHCO C,85°16
	4
		Bn
		2
		CO
		BocHN
BocHN	2
	C
	BnO

NHBoc

OBn

81 [21]

N,	h
3	3
Pd/C,(n-Bu)	115–120°C,

[18]

[29]

61			97
61			74
			–
,		d		N,	h
,		CO °C,5		Et,	24
		,		3
2 NBr,		3	Pd(OAc),2		–100120C,°
2 NBr,		2		3
Pd(OAc)	Bu)-n(	LiCl,K DMF,110		P(-oTol)
	4

	,
	2
Ph	NO
Ph	CN,H, C
	29
	H
	10
	2
	R SO

70 [30]

	,
	3	5h
2 CO		5h
,	2
)	2
(PPh	N,K C,°
3
2	3 O,100
PdCl	Bu)n(-	H
		2

[31]

85
2	,
]	3		h
3 CO			h
[P(o-Tol)	N,K	°C,6
	2
2	3 O,100
PdCl	Bu)n(-		H
			2

1184

97 [30],[31]

, 3 -oTol)

P(, 2 PdCl

,
3	3h
CO	3h
K	C,°
2
N,	100
3	100
Bu)-n(	H
	O,
	2

72 [32]

,
2
)	DMF,	24h
(PPh	DMF,	24h
3
2	N,	130°C,
PdCl	Et	130°C,
	3

E′

OEt

OTf

TfO

[14]	[33]
85	39

,
3
,PPh	DMF,	h
2	DMF,	h
Pd(OAc)	Et	135°C,36
	N,
	3
	O
	Me	P
		P

		Me
P

Ph	O

Ph	O
	P
	Me

	,
	3
	,PPh	MeCN,	h
	2	MeCN,	h
	Pd(OAc)	Et	125°C,24
		N,
		3
Ph		2
Ph	P(O)Ph

(O)P 2 Ph

Ph		Ph
	P		O

21 [34]

2	NCl,
,	BnEt
Pd(OAc)	BnEt
	3

82 [35]

	N,
KOAc,25°C, d10	3	h6
KOAc,25°C, d10	PdCl 80DMF,°C,	h6
	Bu)-n(
	,
	2

^ = Ar

[36]			(Continued)
b
42
,	MeCN,
2			h1
(PPh			h1
)
3
2	N,		80°C,
PdCl	Et		80°C,
	3
		Et
			2
		CO

C 2 EtO

Et 2 CO

1185

Yield (%) Reference

Conditions

Product

Alkene

3.(Continued)	Arene
TABLE

[37]
c
90
	N,	h
2	3	5
2	3	C,°
,	Et
Pd(OAc)	,	DMF,80
Pd(OAc)	P(o-Tol)	DMF,80

OHept

59 [20]

, 2 Pd(OAc)

NHBoc

NCl,	DMF,,
NCl,	3 h
Bu)-n(	NaHCO	C,85°16
4
		Bn
		2
		CO

BocHN

C 2 BnO

Ph	NHBoc	OBn	O
N
Et
=		I
R
I	OHept
RO
I		I

24 [38]

2 NBr,
,	Bu)-n(
Pd(OAc)
	4

DMF,	d
3	3
,
CO °C,
2	70
K	70

[39]
74
	N, °C
	3	120
,	Et,	–
2	3	DMF,100
Pd(OAc)	P(o-Tol)	DMF,100
					in12%yield.






BrBr			reported.not=n.r.	productmonosubstitutionThe(iodinereplaced)wasisolatedin22%yield. products.couplingofyieldTotal Themono-α-substitutedstyrenewasisolated		ferrocenyl.=Fc
	bar)(30
			a	b	c	d

1186

IV.2.1.2 DOUBLE AND MULTIPLE HECK REACTIONS

1187

The primary coupling product of 1,2-diiodobenzene with allyl alcohol, a dicarbaldehyde, underwent an intramolecular aldol condensation under the reaction conditions (Scheme 3).[5]

H 81%

Scheme 3

Double and even triple Heck–Diels–Alder cascade reactions involving bicyclopropylidene and 1,4-diiodo- or 1,3,5-triiodobenzene, respectively, have been accomplished. In these sequences, the carbopalladation across the highly strained alkene is followed by a cyclopropylmethyl to homoallyl rearrangement with concomitant -hydride elimination to yield an allylidenecyclopropane, which subsequently undergoes a smooth [4 2] cycloaddition to furnish the spiro[5.2]octene moiety (Scheme 4).[6]

MeO2C

Pd(OAc)2, PPh3,

Bu4NCl, K2CO3,

CO2Me MeCN, 80 °C, 2 d

64%

CO2Me

Pd(OAc)2, PPh3,

Bu4NCl, K2CO3,

MeCN, 80 °C, 2 d

CO2Me

X = Br: 34%

X = I: 72%

MeO2C

CO2Me

Scheme 4

In later studies by Heck and co-workers,[7] extension to threefold and higher multifold couplings with the corresponding oligoiodoarenes failed, and only major fractions of reduced starting materials were observed. This drawback was completely overcome by applying the Jeffery protocol,[40] that is, with a base like potassium carbonate in the presence of a tetrabutylammonium halide.[41],[42] Under these conditions, three alkene units and more can be attached to an arene ring in excellent yields (Tables 4 and 5).

1188	IV Pd-CATALYZED REACTIONS INVOLVING CARBOPALLADATION

TABLE 4. Threefold Heck Reaction on 1,2,3-, 1,2,4-, and 1,3,5-Trihaloarenes: E = CO2Me, Fc = Ferrocenyl

Arene

Yield

Ref-

Alkene

Product

Conditions

(%)

erence

Pd(OAc)2, PPh3,

[7]

Et3N, 100 °C, 12 h

CO2Me

Pd(OAc)2,

46a

[16]

(n-Bu)4NBr, K2CO3,

DMF, 2 h, 60 °C

R = Fc

4-Py

R = 4-Py

2-Py

R = 2-Py

R = H

(8 bar)

R = Ph

C H

-4-OMe

R = C6H4-4-OMe

X X = H, NO2

Pd(OAc)2, PPh3,	70	[43]
Et3N, 100 °C, 3 d	(60)	([15])
Pd(OAc)2, K2CO3,	92	[44]
(n-Bu)4NBr, DMF,
100 °C, 5 d
Pd(OAc)2,	71	[45]
P(o-Tol)3, Et3N,
DMF, 125 °C
Pd(OAc)2,	82	[4]
(n-Bu)4NCl, K2CO3,
LiCl, DMF, 110 °C,
30 h
Pd(OAc)2, PPh3,	>40	[43]
Et3N, 100 °C, 3 d
Pd(OAc)2,	56	[8]
(n-Bu)4NBr, K2CO3,	X = H
DMF, 100 °C, 7 d
Pd(OAc)2,	66	[4]
(n-Bu)4NCl, K2CO3,	X = NO2
LiCl, DMF, 100 °C,
4 d
Pd(OAc)2,	58	[11]
(n-Bu)4NCl, K2CO3,
LiCl, DMF, 3 d,
90 °C

CO2t-Bu

R = CO2t-Bu

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