Organoboranes for Syntheses - American Chemical Society

Chapter 11

Downloaded by UNIV OF CALIFORNIA SANTA CRUZ on October 14, 2014 | http://pubs.acs.org Publication Date: February 26, 2001 | doi: 10.1021/bk-2001-0783.ch011

Organoboron Chemistry on Alumina: The Suzuki Reaction G . W . Kabalka, R. M. Pagni, C. M. Hair, J. L. Norris, L. Wang, and V. Namboodiri Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600

A solventless Suzuki coupling reaction has been developed using both thermal and microwave enhancement. A potassium fluoride-alumina mixture is utilized along with palladium powder.

Introduction The formation of carbon-carbon bonds via the metal-catalyzed coupling of organometallic reagents with organic halides has become an important reaction in modern organic synthesis. In 1972, Kumada (1,2,3,4,5) and Corriu (6) independently reported that Ni(II) complexes greatly enhanced the rate of reactions of Grignard reagents with aryl and alkenyl halides. Similar results were later reported by Murahashi for palladium catalyzed coupling reactions (7). Negishi (8,9) and coworkers then reported an alkynyl transfer from 1 -alkynyl(trialkyl)borate to iodobenzene through a palladium-catalyzed, additionelimination sequence analogous to the Heck reaction (10). The palladium catalyzed coupling of neutral organoborane derivatives was first reported by Miyaura and Suzuki in 1981 and the reaction has become an integral part of

148

© 2001 American Chemical Society In Organoboranes for Syntheses; Ramachandran, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

149


modern organic synthesis (11,12). The popularity of the Suzuki reaction is a consequence of the ready availability of a wide variety of functionally substituted boron derivatives and the mildness of the coupling reaction itself Consequently, it is now possible to build rather complex structures from synthons containing reactive functional groups such as carboxylic acids, amides, carbonyl groups, etc. The synthesis of ethyl 3,5-dimethyl-4-phenylpyrrolecarboxylate as a precursor to a tetramethyltetraphenylporphyrin (eq 1) illustrates the utility of the Suzuki reaction (13).

95%

Suzuki reactions generally employ organic solvents such as tetrahydrofuran and ethers as well as palladium complexes which are soluble in these solvents. The palladium reagents tend to be expensive and sometimes difficult to manipulate and recover. The organic solvents also pose recyclability (and waste handling) problems of their own. To counteract the costs related to waste handling and reagent recycling, ecologically friendly chemistry (Green chemistry) has been evolving at a remarkable rate. One aspect of this chemistry is the use of solidphase reagents in an attempt to minimize the use of solvents (14,15,16,17,18). Our efforts in this area have centered on the use of alumina surfaces (19). We have found alumina to be particularly interesting because it can be modified in a variety of ways which enhance its reactivity with organic reagents. What is unusual about alumina is that it can be used as a catalyst, support, or reagent. γ-Alumina is simply a hydrated form of aluminum oxide. It has a very large surface area (> 100m/g) and, in its hydrated form, the surface presents a layer of hydroxy 1 groups which are bonded to a substructure of aluminum ions (20). As the hydrated alumina is heated, water is driven from the surface which leaves both oxide ions (basic) and aluminum ions (acidic) exposed on the surface. Thus, depending on the temperature of dehydration, the alumina surface contains mixtures of aluminum ions, oxide ions, and hydroxyl groups and thus individual surface sites can act as an acid, base, or nucleophile. The fact that alumina can contain strongly basic and acidic sites adjacent to each other allows for chemistry that cannot be achieved in solution reactions.

In Organoboranes for Syntheses; Ramachandran, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

150


In early studies, we capitalized on the relative ease with which water can be removed and then replenished on an alumina surface. By first dehydrating alumina and then "rehydrating" it with deuterium oxide, we were able to replace active hydrogens in organic molecules with deuterium under very mild conditions, eq 2 (21,22). We then found that the surface could be modified to affect a variety

of organic reactions including halogenations, oxidations and reductions; the surface oxides were also capable of acting as nucleophiles. We also found that alumina could be useful in organoborane reactions (23,24,25). For example, we were able to carry out halogenation reactions in which boronic acids were attached to the surfaces to form mixed anhydrides, eq 3. X*s^B(OH) Κ ^

2

0)Al O3 2

x

• (2) X

+

R

2

η X

Ε

(3)

Ζ

when: R = C1(CH ) , X = I; E:Z = 74 : 26 when: R = C1(CH ) , X = Br; E : Z = 20 : 80 2 3

2 3

These early results led us to investigate the feasibility of carrying out Suzuki coupling reactions on alumina in the absence of solvents. We investigated both thermal and microwave-assisted reactions, eq 4. Microwave irradiation of organic reactions has gained in popularity in recent years since it was found to accelerate a wide variety of transformations (26,27)

fVi \=y

Pd(0) on

H

+

%HTV HO'

\=y

KFA /2 l 3

°> f V f V «>

No solvent

\=/ \=/ Yield = 88 - 98%


151


Results and Discussion The initial studies focused on more traditional thermal reactions. A number of parameters were investigated. A n important observation was made early in the study concerning the chemical form of the palladium catalyst. Most palladium catalyzed coupling reactions involving boron reagents utilize complexes of palladium. These tend to be expensive and may also be sensitive to water and oxygen (depending on the ligand.) We discovered that palladium metal (obtained as a submicron powder) worked quite well. Commercially available, palladium powder is simply mixed with the alumina to achieve the desired reactions. The initial studies focused on the addition of bases to the reaction mixtures since the Suzuki reactions require the presence of a base. Just as in solution, the solid-state reactions do not proceed in the absence of base (Table I). A variety of bases successfully induced the reaction of tolylboronic acid with iodobenzene to form 4-methylbiphcnyl but potassium phosphate and potassium fluoride were most effective, Table I. Table I. Base Survey

Ο *X> Base*

Reaction Time

o-o Yield (%)

NaOH

3 hr

23

K C0

3 hr

27

3 hr

71

KF

3 hr

86

NaF

4hr

5

6hr

0

2

K P0 3

3

4

A 1 0 (basic) 2

a

5% Pd(0)

3

The base (40% by weight) was added to the alumina prior to reaction.

Since K F / A 1 0 is commercially available, we utilized it for the thermal studies. The quantity of palladium required was then investigated. The results are 2

3


152 presented in Table II. For a reaction time of 4 hours, palladium concentrations of 4 - 5 % are most efficient. If time is not an important factor, lower loadings can be utilized. For the remainder of the study, we utilized 5% palladium for convenience. It should be noted that, since the catalyst is a solid, it can be separated from the reaction mixture by simple filtration and recycled. We are currently investigating the efficiency of the recycling process.


Table II. Effect of Palladium Concentration

ρ

ΚΓ ΛΙί

O"* "°K>* " ' °'· C K > Palladium (%)

Average Yield (%)

1

70.3

2

76.1

3

83.3

4

95.6

5

96.0

Commercially available K F / A 1 0 can be used in the solid-state reactions or it can be prepared by simply dissolving potassium fluoride in water or methanol, adding the appropriate quantity of alumina and then allowing the solvent to evaporate under reduced pressure. The percentage of K F added to the alumina is important. From earlier studies, we determined that there are approximately 3.2 mmoles of active sites (hydroxyl groups under normal conditions) per gram of alumina. Since one equivalent of K F presumably reacts with one equivalent of hydroxyl groups, we would assume that no more than 3.2 mmoles of "base" are generated per gram of K F alumina (28,29,30). Commercial K F / A 1 0 contains approximately 4.5 mmoles of K F per gram which is sufficient to react with all available hydroxyl sites. It is also important to note that the reaction is most efficient if the surface is exposed to moisture in the air. Reactions utilizing freshly prepared K F / A 1 0 , obtained from commercial sources often produce lower yields than identical reactions carried out with K F / A 1 0 that has been opened to the atmosphere. We generally allow a new bottle of K F / A 1 0 to stand overnight in 2

3

2

2

3

2

3

2

3


3

153


the open air. For samples that we prepare, we remove solvent (water or methanol) only until the powder flows freely. The reactions were generally complete in a matter of hours but the time, as expected, was inversely proportional to the temperature. For convenience, we carried out the inital reactions at 100 °C. Suzuki reactions are normally very effective when coupling arylboronic acids with aromatic iodides. The reactions are less effective when aromatic bromides and chlorides are utilized. A parallel trend is observed when alumina is utilized in the absence of solvents, Table III. Table III. Halide Survey

R—X

\

__/~"\_

5%Pd(0)on KF/A1 Q

)

\ = /

100 ° C , 4 H r

2

Yield (%)

3

_f~\_

R

\==/

Recovered Halide (%)

Iodobenzene

99

Organoboranes for Syntheses - American Chemical Society

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