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MIDA-protected Boronate Esters

By: Josephine Nakhla , ChemFiles Volume 9 Article 1

Introduction

Josephine Nakhla
Product Manager

The Suzuki-Miyaura cross-coupling reaction is one of the most important and highly utilized reactions in organic chemistry, with applications in polymer science as well as in the fine chemicals and pharmaceutical industries. However, some classes of boronic acids are exceptionally unstable and susceptible to decomposition which renders them inefficient in coupling reactions or makes long-term storage difficult. Additionally, performing iterative Suzuki Miyaura cross-couplings under mild conditions for the synthesis of small molecules is limited due to the reactivity of boronic acids and therefore a method to allow for iterative couplings under mild conditions has not been previously developed. The mechanism of transmetalation in Suzuki reactions may involve formation of an “ate” complex via interactions between the base and the vacant p orbital on the sp2 hybridized boron atom. Burke and coworkers predicted that a trivalent heteroatomic ligand, such as N-methyliminodiacetic acid (MIDA) (Figure 1) on the boron atom would rehybridize this center to sp3 and thereby attenuate transmetalation under cross-coupling conditions. Release of the reactive, sp2-hybridized boron-species under orthogonal mild conditions would enable this reactivity to be turned back on. In practice, it was discovered that the trivalent MIDA is very effective in this role.1 sp3-Hybridized MIDA boronates are unreactive towards transmetalation (see Figure 2 for comparison of sp2 and sp3-hybridized boron species) and the ligand can be cleaved under mild conditions to liberate the corresponding boronic acid. This enables the execution of sequential Suzuki-Miyaura reactions under mild conditions.

The MIDA-protected boronate esters are easily handled, indefinitely bench-top stable under air, compatible with chromatography, and unreactive under standard anhydrous cross-coupling conditions, even at temperatures up to 80 °C. However, deprotection is easily achieved at room temperature under mild aqueous basic conditions using either 1M NaOH, or even NaHCO3.

Sigma-Aldrich® is committed to providing the most extensive portfolio of high-quality boronic acids, boronate and MIDA esters, and trifluoroborate salts for use in Suzuki coupling, and we continually expand our product listing. This ChemFiles is dedicated to our new product portfolio for MIDA esters. If you are unable to find a coupling reagent for your research, “Please Bother Us” at josephine.nakhla@sial.com, or contact your local Sigma-Aldrich office (see back cover).

Figure 1: MIDA (N-methyliminodiacetic acid)

Figure 1

Figure 2: Hybridized MIDA boronates

Figure 2

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MIDA as a Protecting Group and Iterative Cross-Coupling

To demonstrate the efficacy of MIDA as a protecting group, Burke’s group reacted a 1:1 mixture of the MIDA boronate 698229 and 4-butylphenylboronic acid with 4-bromobenzaldehyde under Buchwald’s anhydrous Suzuki-Miyaura conditions (Scheme 1). The resultant product mixture displayed a 24:1 preference for reaction with the unprotected boronic acid. A control experiment using p-tolyl boronic acid in lieu of 698229 provided a 1:1 mixture of the two products. Additionally, when a control reaction employing the N-methyldiethanolamine adduct instead of the N-methyliminodiacetic acid was performed, no selectivity was observed, presumably due to the increased flexibility of the N-methyldiethanolamine derivative.

Scheme 1: Buchwald’s anhydrous Suzuki-Miyaura conditions

Scheme 1

Various halo-containing MIDA-derivatives were prepared, cross-coupled with boronic acids, and sequentially deprotected under basic conditions to release the unprotected boronic acid, thereby demonstrating the utility towards iterative cross-coupling (Scheme 2).

Scheme 2: Various halo-containing MIDA-derivatives

Scheme 2

The potential for iterative cross-couplings using the Burke methodology was further demonstrated in their total synthesis of ratanhine (Scheme 3). trans-1-Propen-1-ylboronic acid was coupled with the benzofuranyl MIDA boronate 1, which was deprotected and cross-coupled with the bulky aryl bromide MIDA boronate 2 at elevated temperature. The subsequent intermediate was deprotected and coupled with vinyl bromide 3 to yield the diMOM ether. Cleavage of the two MOM groups resulted in ratanhine, in seven steps in the longest linear sequence. Enabling features of this type of synthesis include the use of only a single, mild reaction to assemble a collection of easily synthesized, readily purified, and highly robust building blocks. Moreover, the short and modular nature of this pathway enables the easy preparation of analogs simply by substituting modified building blocks into the same iterative cross-coupling sequence.1

Scheme 3: The potential for iterative cross-couplings using the Burke methodology was further demonstrated in their total synthesis of ratanhine

Scheme 3

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Synthesis of Polyene Natural Products Using Polyene MIDA Boronates

Palladium-catalyzed cross-coupling reactions are ideal methods for the synthesis of polyenes because of the stereospecificity of the reactions and the mildness of the reaction conditions. However, polyenylboronic acids are very unstable and therefore difficult to employ in the synthesis of polyenes via Suzuki reactions. In another exemplary demonstration of the MIDA boronates’ stability and efficiency in iterative cross-coupling, Burke and coworkers utilized a common alkenyl MIDA boronate (703478) to create a series of polyenyl building blocks. The MIDA boronate terminus is inert to Heck, Stille, and Suzuki couplings, yielding butadienyl MIDA boronates (Scheme 4).

Scheme 4: MIDA boronate terminus is inert to Heck, Stille, and Suzuki couplings, yielding butadienyl MIDA boronates

Scheme 4

The alkenyl MIDA boronate 703478 was also applied to the synthesis of the carotenoid all-trans-retinal. Demonstrating the feasibility of polyenyl MIDA boronates in synthesis, boron deprotection of the intermediate 4 proceeded smoothly to generate the boronic acid, which was subsequently coupled with the β-bromo enal to provide all-trans-retinal (Scheme 5).

Scheme 5: alkenyl MIDA boronate

Scheme 5

Miyaura borylation (Scheme 6, to provide 6) and Sonogashira and Negishi couplings (to provide 5 and 7, respectively) that yield bis-metalated lynchpin-type reagents were also demonstrated. Synthetic reagent 6 was further elaborated in the polyene natural product synthesis of β-parinaric acid (Scheme 7) and reagent 7 was employed in the preparation of the polyene chain of amphotericin B (Scheme 8).2

Scheme 6: Miyaura borylation

Scheme 6

Scheme 7: polyene natural product synthesis of β-parinaric acid

Scheme 7

Scheme 8: polyene chain of amphotericin B

Scheme 8

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Formation of Complex Boronic Acids from MIDA Boronates

Another extremely useful feature of the MIDA boronates is their compatibility with a wide range of common synthetic reagents, allowing for the elaboration of functionalized MIDA boronates to create structurally complex boronic acid surrogates. This was recently demonstrated by Burke and coworkers with the transformation of the 4-(hydroxymethyl)phenyl MIDA boronate 698105 by a variety of common oxidants and other reagents to create an array of synthetically useful MIDA boronates (Scheme 9). Even harsh reagents such as triflic acid, and Jones oxidant were well tolerated, and the MIDA boronate was left intact. In several cases, transformations can be easily reversed to yield the original 4-(hydroxymethyl)phenyl MIDA boronate.

Scheme 9: synthetically useful MIDA boronates

Scheme 9

The 4-formylphenyl MIDA boronate 697494 was further elaborated in various C-C bond-forming reactions. The results show that MIDA boronates are also compatible with Evans aldol, Horner-Wadsworth- Emmons olefination, and Takai olefination protocols. Reductive amination is also well-tolerated (Scheme 10).

Scheme 10: The 4-formylphenyl MIDA boronate further elaborated in various C-C bond-forming reactions.

Scheme 10

The impact of the exceptional compatibility of the MIDA boronate was exhibited in the total synthesis of (+)-crocacin C starting from an acrolein MIDA boronate (Scheme 11). The MIDA boronate tolerated a Paterson aldol and diastereoselective reduction protocol to yield the diol MIDA boronate, which was purified by silica gel chromatography. The purified MIDA boronate was permethylated with Meerwein’s salt, deprotected with CAN, oxidized with Dess-Martin periodinane and subjected to Takai olefination to yield the stable, crystalline, complex MIDA boronate 9. Stille coupling of 9 with known building block 10, followed by in situ boronic acid release and cross-coupling with bromobenzene provided (+)-crocacin C.3

Scheme 11: The impact of the exceptional compatibility of the MIDA boronate exhibited in the total synthesis of (+)-crocacin C starting from an acrolein MIDA boronate

Scheme 11

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Preparation of trans-(2-bromovinyl) MIDA Boronate and Vinyl MIDA Boronate from the Corresponding Silanes

Due to the instability of some boronic acids, the Burke group has developed very practical syntheses of some of the more challenging MIDA boronates. For instance, while trans-(2-bromovinyl) MIDA boronate (703478) could be prepared via bromoboration of acetylene and reaction with MIDA in the presence of base, a more convenient procedure was subsequently developed. The synthesis of trans-(2-bromovinyl) MIDA boronate is achieved via transmetalation of 1-bromo-2-trimethylsilylethylene with BBr3, followed by trapping with MIDA2-Na2+ to form the MIDA boronate (Scheme 12-(1)). This procedure also gave rise to the very useful building block, vinyl MIDA boronate (704415) (Scheme 12-(2)). Of note, the corresponding boronic acid is very unstable.4

Scheme 12: vinyl MIDA boronate

Scheme 12

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Synthetic Utility of Vinyl MIDA Boronate

The utility of vinyl MIDA boronate was demonstrated via cyclopropanation and epoxidation to the corresponding MIDA cyclopropane and oxirane, respectively. These procedures (Scheme 13) provided air and chromatography-stable solids in both cases, with the oxirane being the first known synthesis of an unsubstituted oxiranylborane (confirmed by X-ray analysis of the oxiranylborane).

Scheme 13: The utility of vinyl MIDA boronate was demonstrated via cyclopropanation and epoxidation to the corresponding MIDA cyclopropane and oxirane, respectively

Scheme 13

Vinyl MIDA boronate was also successfully subjected to Heck and oxidative Heck reactions as well as to olefin metathesis (Scheme 14) to provide the desired alkenyl MIDA boronates. The cross metathesis of vinyl MIDA boronate with various olefins represents a potent strategy for the highly stereoselective construction of substituted vinyl boranes. This method proved successful in the preparation of a variety of disubstituted olefins (Scheme 15) with excellent yields (81-98%) and E:Z selectivities (>20:1). This procedure represents a significant advance relative to the cross metathesis with alkenyl pinacol, which can be limited by instability of the alkenyl boronic ester substrates, the stereoselectivity of the transformation, and/or the ease of purification of the resulting products.4

Scheme 14: Vinyl MIDA boronate successfully subjected to Heck and oxidative Heck reactions as well as to olefin metathesis

Scheme 14

Scheme 15: disubstituted olefins

Scheme 15

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References

  1. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.
  2. Lee, S. J.; Gray, K. C.; Paek, J. S.; Burke, M.D. J. Am. Chem. Soc. 2008, 130, 466
  3. Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084.
  4. Uno, B. E.; Gillis, E. P.; Burke, M. D. Tetrahedron 2008, In Press

Materials

     
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