The Catellani Reactions using Norbornene as a Template for

3.8 Miscellaneous Reactions of Aryl Halides

3.8.1 The Catellani Reactions using Norbornene as a Template for

In continuing studies on Pd-catalyzed reactions of norbornene (1), Catellani has discovered very interesting reactions, in which norbornene shows unique behavior [1]. Catellani and co-workers carried out a three-component reaction of iodobenzene, methyl acrylate, andn-butyl iodide in the presence of 1 equivalent of norbornene (1), and obtained methyl 2,6-di-n-butylphenylacrylate (2) in 93 % yield using cis-exo-2-phenylnorbornylpalladium chloride as a catalyst. Norbornene (1) was recovered after the reaction [2]. No direct Heck reaction of iodobenzene with acrylate occurred showing that the strained double bond in norbornene undergoes insertion much faster than that of acrylate. The behavior of norbornene (1) is truly remarkable.

I CO2Me

CO2Me n-Bu

n-Bu

+ [Pd], K2CO3, DMA

20°C, 30 h, 93%

+

+

[Pd]= cis-exo-2-phenylnorbornylpalladium chloride

2 1

1

n-Bu-I +

This reaction revealed several very interesting and unexpected (or curious) steps. The mechanistic explanation given by Castellani can be summarized in the following scheme. First, syn insertion of 1 to Ph-Pd-I affords the cis, exo complex3. In this case, syn β-H elimination to give phenylnorbornene is impos- sible due to the rigid trans configuration of the Pd atom and β-hydrogen. The

next step is facile formation of the palladacycle 4 under mild conditions mainly by virtue of the coordination of the aromatic ring to Pd. The complex 4 was isolated. The reaction corresponds to activation of an inert aromatic C—H bond.

In general, reductive elimination in a five-membered palladacycle 4 to form a cyclobutane is disfavored, and hence unusual oxidative addition of n-BuI occurs to give 5, which is an uncommon Pd(IV) species. The reductive elimination gives theortho-n-butylphenylnorbornylpalladium iodide 6without undergoing β- H elimination of the butyl group. Then similar steps, namely the palladation of 6 to form the palladacycle 7, the oxidative addition of n-BuI to give 8, and the reductive elimination to afford the 2,6-dibutylphenylnorbornyl complex9, are repeated. The 2,6-di-n-butylation is explained in this way. Then interestingly,β- carbon elimination of 9 (deinsertion of 1 or decarbopalladation) occurs to yield 2,6-di-n-butylphenylpalladium iodide (10) and 1 is regenerated. Several further transformations of10, such as Heck, Suzuki, and Sonogashira reactions, are pos- sible as expected. Formation of 2,6-di-n-butylphenylacrylate (2) via insertion of acrylate to 10 and β-H elimination is understandable. The total yields of 2 after multi-step reaction were remarkably high (93 %). The Suzuki and Sonogashira reactions of 10 are shown later. Examples of this type of palladacycle formation by electrophilic attack on benzene rings are increasing (Chapter 3.3.4).

palladation n-Bu-I

n-Bu-I

I Pd

Pd n-Bu I

Pd Pd

n-Bu I I

Pd n-Bu

n-Bu n-Bu n-Bu

n-Bu Pd I

Pd n-Bu

n-Bu I

CO2Me n-Bu CO2Me

n-Bu

Pd I 1

8 9

b-carbon elimination

2

Pd(0) palladation

3

10 OA

RE

b-H elimination

+ Pd(0)

4 5 6

7

Pd I

OA

RE

insertion

1

insertion

HI

HI

The reaction of o-iodotoluene (11) with acrylate and a large excess of n-PrI in the presence of 1 proceeded more efficiently using ligandless Pd(OAc)2, and 2-methyl-6-n-propylphenylacrylate (12) was obtained [3].

11

+ AcOK, DMF, 55 °C, 74%

12 Me

I

CO2Me

CO2Me Me

n-Pr Pd(OAc)2,1, K2CO3

+ n-Pr-I

There are several interesting features in this reaction, although they may be understood by high reactivity of the strained double bond in norbornene:

1. Facile selective oxidative addition of alkyl halide to 4, which is regarded as uncommon.

2. Noβ-H elimination of n-butyl group in 5.

3. Easy formation of the palladacycles4and 7, which undergo further reactions.

4. Facileβ-carbon elimination (deinsertion of1) in 9.

5. No direct Heck reaction and Suzuki coupling of aryl halides occur at all in the three-component reactions of aryl halide, alkyl halide, and alkene (or phenyl- boronic acid).

6. Smooth reactions with ligandless Pd catalysts. The process shows a new and unique type of ‘catalysis’ by1.

The Catellani’s alkylation–alkenylation sequence using norbornene offers a useful synthetic method for 2,6-dialkylated 1-substituted benzenes. Lautens applied the reaction to the synthesis of fused aromatic compounds usingortho-substituted iodobenzenes and bromoalkenes. Reaction of o-iodotoluene (11) with ethyl 6- bromo-2-hexenoate (13) afforded the benzocarbocycle 14via monoalkylation and intramolecular Heck reaction. It is important to use tri-2-furylphosphine (I-3) as a ligand [4]. Similarly the 2,5-disubstituted 4-benzoxepine17 was obtained in 72 % yield by the reaction of 1-iodonaphthalene (15) with the unsaturated bromo ester 16[5].

Me I

Br CO2Et

EtO2C

I Br

O CO2Et

O CO2Et Me

16 13

Pd(OAc)2, TFP(I-3),I Cs2CO3, MeCN, 90%

+

Pd(OAc)2, TFP(I-3) +

I, Cs2CO3, MeCN 72%

14

17 11

15

Similar to the formation of the ortho-alkylated phenylnorbornyl complex 6, ortho arylation is possible. Reaction of the palladacycle 18, which has an ortho methyl group, with methylp-iodobenzoate afforded the substituted biphenyl22 [6].

The formation of22can be understood by oxidative addition of iodobenzoate to18 to generate19, reductive elimination to form20by sp2–sp2 C—C bond formation,

and deinsertion of norbornene from 20 to provide 21. Treatment of 21 with H2

produced themeta-substituted biphenyl22. Although the reaction is stoichiometric, it shows the possibility ofortho arylation.

1

K2CO3, DMF rt, 61%

I

MeO2C Pd

Me

22 21

Pd I

CO2Me Me

18 19

b-carbon elimination +

20 Me

CO2Me Pd-I

I-Pd Me

CO2Me

Me

CO2Me H2

The ortho arylation was combined with the Heck reaction. Reaction of o- iodotoluene (11) with methyl acrylate in the presence of 1 gave rise to the sub- stituted biphenylylacrylate23[7]. This Pd-catalyzed reaction is understood by the sequential formation of 24, 25 and 26. It is very interesting that no direct Heck reaction of11with acrylate occurs at all under the conditions due to higher reactiv- ity of norbornene compared with acrylate. The reaction of allyl alcohol provided 3-biphenylylpropanal [7a].

The norbornene-catalyzed reaction has also been extended to synthesis of 2,6- dialkyl-1,1-biphenyl28by 2,6-dialkylation of aromatic ring via palladacycles and Suzuki –Miyaura coupling. The reaction of phenylboronic acid (27), iodobenzene, and n-propyl bromide (excess) in the presence of norbornene (1) afforded 2,6-di- n-propyl-1-biphenyl (28) in 95 % yield via29 and30.

30 27

1 b-carbon elimination B(OH)2

I

n-Pr

n-Pr

Pd-Br n-Pr n-Pr

PdBr n-Pr n-Pr

+ Pd(OAc)2,

K2CO3, DMF, rt, 95%

2n-PrBr

27

1

steps 28

29 +

1

I, Pd(OAc)2, K2CO3 DMF, 105 °C, 79%

+

1 Pd

I Pd-I

Me Me

I Me

CO2Me CO2Me

23

24 25 26

Me

Me

23 11

Me

Me

Me

I-Pd

Me b-carbon

elimination

CO2Me

Me

MeO2C Me

The reaction proceeds via the formation of the palladacycles4and7a. After the formation of29 by 6-propylation of31, elimination ofβ-carbon regenerates nor- bornene (1) and 2,6-dipropylphenylpalladium bromide30. At the final step, Suzuki coupling of30with27gives 2,6-di-n-propyl-1-biphenyl (28) in a surprisingly high yield (95 %) after so many steps [8].

7a steps

RE 27 4

n-Pr-Br

Pd Pd

n-Pr

Pd Br n-Pr

n-Pr

Pd Br n-Pr

n-Pr

Pd-Br n-Pr

n-Pr

n-Pr

n-Pr 28 30

1 29

b-carbon elimination

31

Combination of the ortho arylation with Suzuki coupling as a good synthetic method of terphenyls was carried out [9]. Reaction of o-iodotoluene (11) with phenylboronic acid (27) afforded dimethylterphenyl32in 88 % yield. The reaction is easily understandable by formation of the biphenylylpalladium 26 via 24 and 25. The Suzuki coupling of26with27 yields the terphenyl32 as expected.

24 + I Me

Me

Me B(OH)2

1, Pd(OAc)2, K2CO3

32 DMF, 105 °C, 88%

27 11 1

26 25

27

When sodium formate is used as a terminating agent, hydrogenolysis of aryl- palladium occurs [10]. Reaction of iodobenzene, n-propyl bromide, and sodium formate afforded 1,3-di-n-propylbenzene (35) in 78 % yield. In this case, the 2,6- di-n-propylphenylpalladium 30was hydrogenolyzed with sodium formate, and35 was obtained via Pd formate 33 and hydridopalladium 34. This is not only very interesting, but also useful, becausemeta dialkylation of benzene can be achieved in this way, which is difficult to carry out by conventional methods.

2n-PrBr

34 +

+ I

H n-Pr

n-Pr

33 Pd-Br

n-Pr

n-Pr

Pd-O2CH n-Pr

n-Pr

Pd-H n-Pr

n-Pr 30

Pd(OAc)2,1, K2CO3

DMF, rt, 78%

35 HCO2Na

HCO2Na

The reaction can be combined with Sonogashira coupling to give o, o-dialky- lated diphenylacetylenes [11]. Pd-catalyzed reaction of iodobenzene, ethyl bro- mide, and phenylacetylene (36) afforded 2,6-diethyldiphenylacetylene 37 in 78 % yield with remarkable chemoselectivity. In this reaction, CuI as a cocatalyst was not used. The direct Sonogashira coupling of iodobenzene with phenylacetylene (36) was suppressed by slow addition of excess ethyl bromide and phenylacetylene at room temperature.

+ I

Et

Et

Ph Ph

+ Pd(OAc)2,1, AcOK

DMF, rt, 77%

37 36

2 Et-Br

Substituted phenanthrene 38 was prepared by the reaction of o-iodotoluene (11) with diphenylacetylene in the presence of n-Bu4NCl in 82 % yield [12].

The reaction is explained by insertion of diphenylacetylene to the biphenylyl- palladium26 to form39, which undergoes well-known cyclization to provide the dimethyldiphenylphenanthrene38.

38 11

26

39

25 I + Pd(OAc)2,1, K2CO3,

n-Bu4NBr, DMF 105°C, 82%

18

Ph Me

Ph

Ph Ph

24

Pd Pd

I

Me Me

Me

Me

Me PdI

Me Pd-I

Me

Ph Ph

Me

Me

Ph Ph

Pd-I

Ph Ph

Me

Me Me

Me

RE

38

1

11

b-carbon elimination

1

Although norbornene is recovered at the end of the reactions, it is used in a large amount, and it is not a true catalyst in the exact sense. However, the remarkably high chemoselectivity of the norbornene ‘catalyzed’ reactions is impressive.

References

1. Account: M. Catellani,Synlett, 298 (2003).

2. M. Catellani, F. Frignani, and A. Rangoni, Angew. Chem. Int. Ed. Engl., 36, 119 (1997).

3. M. Catellani and F. Cugini,Tetrahedron,55, 6595 (1999).

4. M. Lautens and S. Piguel,Angew. Chem. Int. Ed.,39, 1045 (2000).

5. M. Lautens, J. F. Paquin, S. Piguel, and M. Dahlmann,J. Org. Chem.,66, 8127 (2001).

6. M. Catellani and E. Motti, New J. Chem., 759 (1998).

7. E. Motti, G. Ippomei, S. Deledda, and M. Catellani,Synthesis, 2671 (2003) in press 7a. M. Catellani, S. Deledda, B. Ganchegui, F. Henin, E. Motti, and J. Muzart, J.

Organomet. Chem.,687, 473 (2003).

8. M. Catellani, E. Motti, and M. Minari,Chem. Commun., 157 (2000).

9. E. Motti, A. Mignozzi, and M. Catellani, J. Mol. Catal. A : Chem., 204/205, 115 (2003).

10. M. Catellani and F. Cugini, unpublished results. See ref. 1.

11. M. Catellani, M. Rissetti, and E. Motti, unpublished results. See ref. 1.

12. M. Catellani, E. Motti, and S. Barratta,Org. Lett.,3, 3611 (2001).