Suzuki alkylboronic acids

While the introduction of aryl groups has been well documented, the use of alkylboronic acids to decorate the pyridazine core is hitherto not well explored. Wermuth and co-workers nicely showed that hydroboration of alkenes with 9-BBN followed by Suzuki coupling with 3-iodopyridazines 180 and 182 yielded the corresponding 3-alkylpyr-idazines 181 and 183 in good yield (Schemes 43 and 44) <2002SL1123>. 

Keywords iodobenzene, alkylboronic acid, Suzuki coupling, palladium-doped... 

Alkylboronic acids and arylboronic acids, RB(OH)2, and ArB(OH)2, respectively, are increasingly important in organic chemistry. The palladium catalyzed coupling reaction of aryl halides and aryl triflates with arylboronic acids (the Suzuki-Miyaura... 

Alkylboronic acids are coupled to aryl halides using a palladium catalyst, " analogous to the Suzuki reaction in 13-12. Conversely, arylboronic acids can be coupled to aliphatic halides Arylboronic acids can be coupled to allylic alcohols as well. " Arylboronic acids (12-28) were shown to react directly with benzene in the presence of Mn(OAc)3. " Arylboronic acids also couple with alkyl halides in... 

Suzuki-Miyaura cross-coupling reactions of alkylboronic acid derivatives or alkyltrifluoroborates widi aryl, alkenyl or alkyl halides and triflates ,... 

Arylethylamines. The title compound is transformed into an alkylboronic acid via hydroboration and its Suzuki coupling with Arl affords ArCH2CH2NHCbz. 

Table 2 Alkyl bromides and aryl-, vinyl-, and alkylboronic acids used in Suzuki crosscoupling reactions...

Suzuki-Miyaura Cross-Coupling Reactions of Alkylboronic Acid Derivatives or Alkyltrifluoroborates with Aryl, Alkenyl or Alkyl Halides and Triflates Doucet, H. Eur. J. Org. Chem. 2008, 2013. 

Alkylboronic acids, which are often less reactive in Suzuki reactions than aryl-boronic acids, are suitable substrates for this catalyst, with turnover numbers (TONs) as high as 9700 being achieved with this system. In addition, Fu was able to demonstrate that the air-stable and crystalline tetrafluoroborate salt, P(t-Bu)3HBp4 was equally efficient as the low-melting and air-sensitive free phosphine P(t-Bu)3 [29],... 

More recently, Kwong and Chan disclosed a very similar diphenylferrocene ligand for Suzuki coupUngs of aryl chlorides. Activated aryl chlorides can undergo reactions at ambient temperature, while alkylboronic acids can be used in addition to arylboronic acids (Equation 2.28) [49, 50]. 

Compared to aryl- and alkenylboronic adds, alkylboronic acids and esters have found limited use as synthetic intermediates aside for their oxidation into alcohols (Section 1.5.2.1). This is due in part to their inferior shelf-stability. In addition, their trans-metallation with transition metal catalysts such as palladium is presumed to be more difficult than that of the unsaturated and aromatic boronic acid derivatives [296]. For example, alkylboronic adds have long been known to be reluctant substrates in the Suzuki-cross-couphng reaction, and they have become eflfident in this apphcation only very recently with the use of special bases and the advent of new and highly active catalyst systems (Section 1.5.3.1). Perhaps the most synthetically useful class of alkylboronic adds are the a-haloalkyl derivatives popularized by Matteson (Section 1.3.8.4), and their elegant chemistry is described in Chapter 8. 

Alkenylboronic acids and esters are also very useful substrates (Equation 71, Figure 1.38) [405], in particular to access substituted olefins and dienyl moieties commonly encountered in several classes of bioactive natural products [282, 406]. To this end, Kishi and co-workers examined the influence of the base, and developed an optimal variant using thallium hydroxide [281]. Recently, allylic alcohols were found to couple directly with alkyl and alkenyl boronic acids without the aid of a base [407]. In rare cases, the Suzuki reaction has been applied to the use of alkylboronic acids [296, 408], including cyclopropylboronic acids [409]. Hitherto notorious for their tendency to undergo [3-hydride elimination, alkyl bromides are now suitable as electrophiles under carefully optimized conditions that even allow Csp -Csp couplings with alkylboronic acids (Equation 72) [410]. The Suzuki reaction has also been applied very successfully in solid-phase chemistry and combinatorial library synthesis [411]. It has been applied industrially [412], especially in medicinal chemistry, e.g. in the production of the antihypertensive drug losartan [195]. 

Cross-coupling of Boronic Acids. Ag20 can significantly enhance the reactivity of various boronic acids in Suzuki-Miyaura cross-coupling reactions. Alkylboronic acids, which, oftentimes, lead to poor conversions of the desired coupled product, are rendered more reactive by the addition of Ag20 (eq 24). Use of excess Ag20 facilitates the cross-coupling of various unactivated w-alkylboronic acids to either aryl or alkenyl halides/trifiates. The reaction conditions are very mild and furnish excellent yields of the desired coupled product. 

Scheme 3.84 Ag(l)-promoted Suzuki-Miyaura cross-coupling of functionalized n-alkylboronic acids.

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