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Volume 46 | Number 32 | 2010

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An Efficient Method for Heck-Catellani Reaction of Aryl Halides Xiaojin Wu and Jianrong (Steve) Zhou*

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We describe herein a new method that allows selective production of Catellani-Heck isomers for various aryl halides, including ones without ortho-groups. Under previous conditions, unhindered aryl halides were plagued with the formation of simple Heck isomers and multiple arylation and norbornene insertion. The use of bulky PtBu3 ligand accelerates C-C reductive elimination from the key palladacycle. In Heck reaction, insertion of acyclic olefins into aryl-Pd bonds led to simple arylated olefins. The reaction is now widely used to prepare drugs, fragrance, agrochemicals and advanced material.1 In 1985, Catellani et al. first reported Pd-catalyzed insertion into norbornene, which resulted in strained norbornane-fused arenes (isomer A in Fig 1).2 The key arylnorbornyl-Pd species lacks βhydrogens for syn elimination and chooses to cleave aryl orthoCH bonds. These early examples provided the foundation for recent development of palladacycle-directed CH activation/C-C couplings.3 Unfortunately, after many years, selective formation of Catellani isomers is still limited to phenyl and orthosubstituted aryl halides. For more common unhindered aryl halides without ortho groups, the reactions show poor selectivity. Very often, they are contaminated with Heck isomers and other byproducts derived from multiple arylation and/or norbornene insertion.2b,5 This kind of ortho effect was also observed recently by Lautens et al.4 Herein, we disclose a rather general method that can couple various aryl halides to give cleanly Catellani isomers, which are difficult to prepare otherwise. Initially, in a model reaction of p-t-butylphenyl bromide and norbornene (nbe), Catellani’s conditions gave about 1:1 ratio of Catellani and Heck isomers (Fig 1a-b). Under Lautens' conditions, the desired isomer was obtained in only 31% yield (Fig 1c). Under the three conditions (a-c), no reduction of ArOTf was detected; the rest of material was byproducts derived from multiple arylation and/or nbe insertion (by GC and GCMS). After many experiments, we found that the use of bulky PtBu3 ligand led to selective production of the Catellani isomer (Fig 1d). tBu

tBu

tBu

Fig. 1 A model Heck-Catellani reaction.

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A sampling of auxilary ligands is shown in Table 1. PtBu3 formed a very active catalyst. Other bulky, electron-rich trialkylphosphines also performed well, such as P(1-Ad)nBu, PtBu2Me and PCy3. Less-donating monophosphines gave only unsatisfactory yield, including PPh3, P(o-Tol)3 and Buchwaldtype biarylphosphines. In the presence of chelating bisphosphines and N-heterocyclic carbenes (IPr and IMes), ArX reduction was the main pathway. Palladium complex Pd(PtBu3)2 alone was also highly active for this transformation. Pd(OAc)2, Pd(dba)2 and PdCl2 worked equally well as Pd source. In entries that did not give good material balance, multiple arylation and/or norbornene insertion gave byproducts of high molecular weighs. During condition optimization, we found that proper choice of base and solvent was also important to high selectivity in this reaction. Among various bases, NaOPh was optimal. Other bases can also give good yield, including LiOPh, KOPh, NaOtBu and KOtBu. In DMF, the model reaction gave very good yield; in DMA, 1,4-dioxane and 2-methyltetrahydrofuran, the yield was around 70%. In dioxane, the main side reaction was the reduction of ArBr (20%). Table 1 Effect of ligands on Catellani reaction using norbornene (conversion and yield determined by GC). tBu-phenyl Br + nbe (2 equiv)

H

A Catellani isomer

(nbe)

a) 10% Pd(PPh3)4, KOPh, anisole, 105

H

oC,

Ar B Heck isomer

24 h (by Catellani et al.): 42% A and 42% B

b) Same as a) except 2,6-tBu2-4-MePhONa as base (by Catellani et al.): 49% A and 31% B c) 10% Pd(OAc)2, 22% PPh3, nBu4NOH, 1:1 tol/water, 80 oC, 24 h (Lautens et al.): 31% A and 0% B d) 4% Pd(dba)2, 8% PtBu3, NaOPh, DMF, 120 oC, 24 h (this work): 95% A and 1% B

This journal is © The Royal Society of Chemistry [year]

tBu +

NaOPh, DMF 120

oC,

A H

24 h

H

+ Ph-tBu

Ar

C

B

Entry

Ligand

Conv (%)

A (%)

B (%)

C (%)

1

PtBu3

100

95

1

1

2

P(1-Ad)2nBu

100

94

1

3

3

PtBu2Me

100

90

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3

4

PCy3

100

81

5

12

5

PPh3

100

25

6

4

6

P(o-Tol)3

100

5

3

2

7

XPhos

100

36

1

4

8

tBu-XPhos

92

12

3

25

9

dppp

54

0

0

37

10

dppf

100

10

2

30

Br XPd

4% Pd(dba)2 8% ligand

[journal], [year], [vol], 00–00 | 1

Chemical Communications Accepted Manuscript

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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x

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Published on 02 October 2013. Downloaded by FORDHAM UNIVERSITY on 02/10/2013 20:13:40.

10

IPr⋅HCl

100

0

0

54

12

IMes⋅HCl

100

0

0

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Our new method can be applied to couplings of various aryl bromides (Fig. 2). Both electron-donating and withdrawing groups can be present at ortho and para positions. For p-Brbenzoate, the solvent and base need to be changed to 1,2dimethoxybenzene and Cs2CO3, which improved the yield from

An efficient method for the Heck-Catellani reaction of aryl halides.

We describe herein a new method that allows selective production of Catellani-Heck isomers from various aryl halides, including ones without ortho-gro...
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