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Arylhalides to methylbenzenes in one easy step
(Rated as: excellent)
Practical methylation of aryl halides by Suzuki–Miyaura coupling
Tetrahedron Letters 41(32), 6237-6240 (2000) (https://www.rhodium.ws/pdf/suzuki.methylation.arylhalides.pdf)
A number of aryl halides (X = Cl, Br, I) can be converted to the corresponding toluenes in 70-90% yield in an operationally simple manner using trimethylboroxine (TMB) as a partner for palladium-catalysed Suzuki–Miyaura coupling.
In the course of recent studies we became interested in methods for regiospecific incorporation of a methyl group into aromatic moieties. An obvious strategy is a metal-catalysed cross-coupling reaction of an organometallic methyl species `CH3M' and an aryl halide ArX (where M=Sn, Mg, Zn, B, Al...).
In particular, the Suzuki–Miyaura coupling (M=B) appeared attractive to us, with mild conditions, broad functional group tolerance, non-toxic and easily removed by-products and conveniently handled reagents as notable features.
The prominent variant of this reaction is sp2–sp2 coupling, although sp3–sp2 coupling is also well established. There are limited reported examples using methylboron derivatives; methylboronic acid (MBA) has been moderately useful to date, whereas methylboranes derived from 9-BBN are more reactive but less readily available. We were discouraged from the use of MBA because it is expensive and not readily available. We now report that the anhydride, trimethylboroxine (TMB), is a useful and cheaper alternative reagent for methylation.
Methylation of electron-poor aryl bromides is efficient, whereas with more electron rich substrates, prolonged reaction times are required, although these can be shortened by the use of the polar solvent DMF at 115°C. Aryl chlorides are usually more readily available (and hence cheaper) than the corresponding aryl bromides or iodides, and pleasingly electron-poor chlorides, including a heteroaromatic chloride, provide the methylated products in good yield. With aqueous dioxane as solvent, TLC analysis indicated complete consumption of starting material within a few hours. Of note is the dimethylation of a dichloro substrate (see Experimental below) which indicates that nitrotoluenes can enter into the cross-coupling. Significantly, the successful methylation of naphthyl halides demonstrate that, under largely unoptimised conditions, substrates without activating groups present can also be methylated in moderate to good yield. Yields obtained with the cheaper TMB are comparable to those obtained with MBA.
The effect of different bases, solvents, catalysts and methyl transfer reagents was investigated, primarily to address reaction rate. The inexpensive base potassium carbonate was one of the better studied, although cesium bases led to the highest conversions (e.g. 95% isolated yield with Cs2CO3). In the absence of base, only low level conversion is achieved. Aqueous dioxane or toluene were notable improvements over control conditions A (dioxane). Here isolated yields were essentially quantitative and, with the former, consumption of starting bromide was rapid.
The best catalyst studied was PdCl2(dppf), giving complete conversion within 3 h (The cheaper and more robust Pd(OAc)2/4PPh3 combination has proved comparable to Pd(PPh3)4 for certain substrates). Reactions with TMB in aqueous dioxane and with MBA in dioxane were both complete within 3 h. Using TMB in aqueous dioxane may involve in situ generation of MBA since hydration of TMB is a facile process. MBA esters MeB(OR)2 were inferior to TMB.
Typical experimental procedure
1,5-Dichloro-2-nitro-4-(trifluoromethyl)benzene (1.02 g, 3.92 mmol), potassium carbonate (1.63 g, 11.76 mmol), Pd(PPh3)3 (0.45 g, 0.39 mmol), 10% aq. 1,4-dioxane (10 mL) and TMB (0.55 mL, 3.92 mmol) were charged to a flask and the contents heated to 105–115°C (oil bath temperature) under nitrogen for 6 h and then stirred overnight at ambient temperature. The reaction mixture was filtered through a pad of Celite®, washed with THF and concentrated in vacuo. Flash column chromatography (SiO2, 10:1 hexane:Et2O) afforded 1,5-dimethyl-2-nitro-4-(trifluoromethyl)benzene as a low melting solid, 0.72 g (84%): Rf 0.45 (5:1 hexane:Et2O).
Preparation of Trimethylboroxine
Trimethylboroxine, (BCH3O)3 - CAS 823-96-1, can be of interest to prepare yourself, as it costs almost $5/g from chem suppliers. Below follows the easiest and most direct methods of preparation at a laboratory scale.
NaBH4 + BH3*THF + CO (BCH3O)3
Carbon monoxide is generated by dripping anhydrous HCOOH into H2SO4, and the gas is lead through a stirred solution of BH3 in THF containing a catalytic amount of NaBH4. When the calculated amount of CO has been taken up, the solution is fractionately distilled to separate the product (bp 80°C) from the THF (bp 63°C) to give pure trimethylboroxine in 84% yield. - JACS 88, 2606-2607 (1966) (https://www.rhodium.ws/pdf/trimethylboroxine.pdf)
BH3*THF is formed by the reaction of a lewis acid (Like BF3*Et2O, I2, H2SO4 etc.) with a THF solution of NaBH4 (or preferably the more soluble LiBH4, available by metathesis from NaBH4/LiCl in THF, followed by filtration of precipitated NaCl).
Trimethylboroxine can also be made by the triple alkylation of trimethylborate with a methyl grignard reagent:
B(OCH3) + CH3MgBr (BCH3O)3 - JACS 79, 5179-5181 (1957)
B(OCH3) + CH3MgI (BCH3O)3 - JACS 62, 2228-2234 (1940)
The article below discusses all of the above procedures:
Organoboranes. 39. Convenient Procedures for the Preparation of Methylboronic Acid and Trimethylboroxin
Herbert C. Brown and Thomas E. Cole
Organometallics 4, 816-821 (1985) (https://www.rhodium.ws/pdf/trimethylboroxin.methylboronic.acid.pdf)
Methylboronic acid and its anhydride, trimethylboroxin, were prepared by three routes. The carbonylation of borane-dimethyl sulfide gives in high yields trimethylboroxin, readily hydrated to methylboronic acid. The reaction of methyllithium with selected trialkoxyboranes and methyl Grignards with 2-methoxy-1,3,2-oxaborinane yields the corresponding esters, readily hydrolyzed to methylboronic acid in good yields. Methylboronic acid can be dehydrated to trimethylboroxin. Each of these routes was studied in detail to develop efficient, relatively simple routes to both methylboronic acid and trimethylboroxin.
|Cross-coupling of Boronic Acids with Methyl Iodide|
A simple and practical protocol for the palladium-catalyzed cross-coupling of boronic acids with methyl iodide
Lukas J. Gooßen
Appl. Organometal. Chem. 18, 602–604 (2004) (https://www.rhodium.ws/pdf/arylboronate.ch3i.pd-coupling.pdf)
A combination of palladium acetate and tris-1-naphthylphosphine was found to be a highly efficient catalyst system for the cross-coupling of arylboronic acids with methyl iodide at room temperature. The new process allows for a convenient introduction of methyl groups into various functionalized arenes under mild conditions.
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