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Published in final edited form as: J Am Chem Soc. 2019 May 23;141(22):9072–9078. doi: 10.1021/jacs.9b03611

1,2-Azaborine’s Distinct Electronic Structure Unlocks Two New Regioisomeric Building Blocks via Resolution Chemistry

Cameron R McConnell 1, Fredrik Haeffner 1, Andrew W Baggett 1,†, Shih-Yuan Liu 1,*
PMCID: PMC6609151  NIHMSID: NIHMS1038481  PMID: 31082254

Abstract

Two new 1,2-azaborine building blocks that enable the broad diversification of previously not readily accessible C4 and C5 ring positions of the 1,2-azaborine heterocycle are developed. 1,2-Azaborine’s distinct electronic structure allowed the resolution of a mixture of C4- and C5-borylated 1,2-azaborines. The connection between the electronic structure of C4 and C5 positions of 1,2-azaborine and their distinct reactivity patterns is revealed by a combination of reactivity studies and kinetic measurements that are supported by DFT calculations. Specifically, we show that oxidation by N-methylmorpholine N-oxide (NMO) is selective for the C4-borylated 1,2-azaborine, and the Ir-catalyzed deborylation is selective for the C5-borylated 1,2-azaborine via kinetically controlled processes. On the other hand, ligand exchange with diethanolamine takes place selectively with the C4-borylated isomer via a thermodynamically controlled process. These results represent the first examples for chemically distinguishing a mixture of two aryl mono-Bpin-substituted isomers.

Graphical Abstract

graphic file with name nihms-1038481-f0001.jpg

INTRODUCTION

BN/CC isosterism has emerged as a viable strategy to expand the chemical space of carbon-based compounds.1 Benzene is a versatile, ubiquitous, carbon-based structural motif, and as a consequence, our group has been focusing on the development of its BN isosteres,2,3 specifically the 1,2-dihydro-1,2-azaborine isomer, or simply 1,2-azaborine.4 Applications of BN-containing arenes are emerging, including advances in materials chemistry,5,6 in biomedical research,7 ligand design in homogeneous catalysis,8 and, more recently, in organic synthesis.9As an emerging field, progress in azaborine chemistry however is still limited by the synthetic access to new derivatives for further exploration. The N-TBS-B-Cl-1,2-azaborine (Scheme 1, TBS = t-butyldimethylsilyl) is now commercially available.10

Scheme 1.

Scheme 1

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Late-Stage Building-Block Functionalization Approach

Thus, the development of late-stage functionalization technologies from the assembled 1,2-azaborine heterocycle will enable ready synthetic access to new substituted derivatives and inspire further development in azaborine chemistry. To this end, the “building block” functionalization approach is an attractive strategy, where a versatile functional group (e.g., Bpin) can variably control the fate of a specific ring position, allowing for broad diversification at a “late stage” of the synthesis.11

The late-stage building block functionalization strategy has been successfully developed for the C3 and C6 positions of 1,2-azaborine. For example, bromination with Br2 has been determined to occur selectively at the C3 position of the 1,2-azaborine, and subsequent cross coupling with the C3–Br-substituted 1,2-azaborine has been accomplished.12 We have also demonstrated that Ir-catalyzed C−H borylation occurs selectively at the C6 position, which bears the most acidic C– H proton.13 The C6-Bpin-substituted 1,2-azaborine also readily engages in cross-coupling chemistry. Furthermore, we were able to access BN polyparaphenylene (BN-PPP) and discover the NH···arene interaction as a new conformational orientation feature as a direct consequence of the synthetic availability of the difunctionalized C3–Br–C6-Bpin-1,2-azaborine monomer building block (Scheme 2).14

Scheme 2.

Scheme 2

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New 1,2-Azaborine Building Blocks via Resolution Chemistry

To date, however, no general functionalization strategies have been developed for the C4 and C515 positions of the 1,2-azaborine heterocycle, which is a significant limitation for its envisioned application as a pharmacophore in medicinal chemistry or as a synthon in organic synthesis. In this work, we take advantage of the distinct electronic properties of the C4 and C5 positions of the 1,2-azaborine heterocycle to access C4- and C5-borylated 1,2-azaborine building blocks via resolution chemistry. Specifically, we show that oxidation by N-methylmorpholine N-oxide (NMO) is selective for the C4-borylated 1,2-azaborine, and the Ir-catalyzed deborylation is selective for the C5-borylated 1,2-azaborine via kinetically controlled processes. On the other hand, ligand exchange with diethanolamine takes place selectively with the C4-borylated isomer via a thermodynamically controlled process.

RESULTS AND DISCUSSION

While C–H borylation is selective for functionalization of the C6 position of a B-monosubstituted 1,2-azaborine,13 we determined that borylation of N,B-disubstituted-1,2-azaborines such as 1 (regioselectivity is primarily influenced by steric, not electronic factors in this case)16 occurs only at an elevated temperature and in a nonregioselective fashion, affording a 1:1.2–1.4 mixture of C4- and C5-borylated regioisomers (eq 1).

graphic file with name nihms-1038481-f0002.jpg (1)

Physical methods to separate the mixture, such as chromatography or recrystallization, were unsuccessful. There- fore, we turned to reaction-based methods. Certain bis-Bpin-substituted alkenes/arenes can exhibit differential reactivity at each of their pinacol boronate esters.17 However, to the best of our knowledge, there are no examples for chemically distinguishing a mixture of monoaryl-Bpin-substituted isomers.18 Because each position of the 1,2-azaborine ring is electronically distinct,19 we envisioned that the asymmetry of the electronic structure of 1,2-azaborine would impart differential reactivity to the two borylated regioisomers 4Bpin and 5Bpin. Our hypothesis is as follows: because of partial localization of the nitrogen lone pair on nitrogen, the C5 carbon of 5Bpin should be more electron rich than the C4 carbon of the 4Bpin, and the boron in the Bpin of the 5Bpin isomer should be less Lewis acidic than the Bpin boron in 4Bpin (Figure 1). The extra resonance contribution provided by the Bpin in 5Bpin should also result in added stability of 5Bpin relative to the 4Bpin isomer.

Figure 1.

Figure 1

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Electronic structure calculations (M062X/6–31G(d,p), computed using polarizable continuum model (PCM) simulating CH2Cl2 solvent): select Löwdin charges in parentheses (au), LUMO energies, and orbital illustrations.

DFT electronic structure calculations20 indeed indicate significant differences between 4Bpin and 5Bpin. (1) 5Bpin is thermodynamically more stable than 4Bpin by 3.8 kcal/mol (see Figure 2). (2) The pz-atomic orbital on the boron atom in the Bpin of 4Bpin significantly contributes to the LUMO of the molecule, in stark contrast to the corresponding orbital on the Bpin boron atom of 5Bpin (Figure 1). (3) The calculated LUMO energy of 4Bpin (−0.00923 eV) is significantly lower than the LUMO energy of 5Bpin.21 (4) The calculated Löwdin partial charge is more positive on the boron atom of the 4Bpin than the one on the boron atom of 5Bpin. These calculated trends are consistent with our originally stated hypothesis based on simple Lewis dot structure analysis; i.e., 5Bpin should be thermodynamically more stable than 4Bpin, and the Bpin boron atom in 4Bpin should be significantly more reactive toward Lewis bases.

Figure 2.

Figure 2

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Calculated Gibbs free energy reaction coordinate profile of the NMO oxidation of 4Bpin and 5Bpin, computed at 298 K and 1 atm using the M062X/6–31G(d,p) method. The polarizable continuum model (PCM) was used to model the effects on the reaction by the CH2Cl2 solvent. Energies are in kcal/mol. All H atoms as well as the methyl on the pinacol, mesityl, and t-butyl substituents have been omitted for clarity.

OXIDATION WITH N-METHYLMORPHOLINE-N-OXIDE (NMO)

In our initial attempt to kinetically resolve the mixture of 4Bpin and 5Bpin with a Lewis basic reagent, we discovered that NMO indeed selectively oxidizes the 4Bpin isomer over the 5Bpin isomer.22 Thus, under our optimized conditions (4 equiv of NMO at room temperature for 24 h in CH2Cl2), compound 4OH can be isolated in 30% yield, while 53% of the unreacted 5Bpin (based on 55% available starting material) was recovered (Scheme 3).

Scheme 3.

Scheme 3

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Resolution of 5Bpin and 4Bpin via Selective Oxidation of 4Bpin

We independently measured the rate of the oxidation of the 4Bpin isomer and the rate of decomposition of the 5Bpin isomer23 by 1H NMR against an internal standard (vide infra for the isolation of the 4Bpin compound) and determined that the rate of the oxidation is approximately 29 times faster than the rate of decomposition, resulting in an effective kinetic resolution of the two borylated compounds. As a reference, we determined the rate of NMO oxidation of phenyl boronic acid pinacol ester (PhBpin) to be 20-fold slower than the corresponding rate for 4Bpin (Scheme 3).

The experimentally observed relative rates are consistent with the calculated free energy reaction coordinate profile (M062X/6–31G(d,p); see Supporting Information for details). As can be seen from Figure 2, 5Bpin is calculated to be more stable than 4Bpin by 3.8 kcal/mol. The oxidation with NMO involves the NMO-Bpin adduct as the intermediate, which then subsequently rearranges to the borate ester with concomitant release of the N-methyl morpholine.22d,e Our DFT calculations predict the second step (C to O migration) to be the rate-determining step for both 4Bpin and 5Bpin. The rate-limiting activation barrier for 4Bpin (23.8 kcal/mol) is smaller than the corresponding barrier for the 5Bpin compound (27.7 kcal/mol), which is consistent with the selective oxidation of the 4Bpin isomer. Overall, it appears that the extra stability of the ground state (due to additional resonance with the lone pair of nitrogen) relative to its rate-limiting transition state exhibited by 5Bpin as compared to 4Bpin is responsible for the kinetic resolution.

IRIDIUM-CATALYZED PROTODEBORYLATION

With a method for accessing the 5Bpin isomer in hand, we pursued resolution chemistry that could be used to access 4Bpin. Thus, we needed a reaction that would preferentially react with the less Lewis acidic and more stable 5Bpin isomer. According to our electronic structure calculations (Figure 3), the C5 carbon in 5Bpin is more electron rich than the C4 carbon in 4Bpin. Although the HOMO orbital energies for 4Bpin and 5Bpin are similar, the HOMO orbital coefficient of the C5 carbon in 5Bpin (0.11) is significantly larger than the one for the C4 carbon in 4Bpin (0.01). Overall, the results indicate stronger nucleophilic character for the C5 carbon in 5Bpin than the C4 carbon in 4Bpin. Thus, we hypothesize that a transmetalation-type reaction24 would favor 5Bpin over 4Bpin, and we chose the Ir-catalyzed protodeborylation for our investigation.25,26

Figure 3.

Figure 3

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Electronic structure calculations (M062X/6–31G(d,p), computed using polarizable continuum model (PCM) simulating CH2Cl2 solvent): select Löwdin charges in parentheses (au), HOMO energies, and orbital illustrations.

When a 1:1.4 mixture of 4Bpin and 5Bpin was subjected to protodeborylation catalyzed by [Ir(COD)OMe]2 with methanol as the proton source, 4Bpin was isolated in 25% yield based on 42% available starting material (Scheme 4).

Scheme 4.

Scheme 4

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Kinetic Resolution via Ir-Catalyzed Protodeborylationa

aIndependent rate measurements performed at 40 °C.

Smith observed that in the case of bisborylated compounds the first Bpin to be installed on the molecule was also the first to be protodeborylated.25b Interestingly, 5Bpin is selectively deborylated despite the fact that both C4 and C5 positions of azaborine undergo C–H borylation with nearly equal propensity. We measured the independent rates of the protodeborylation reaction for 4Bpin and 5Bpin at 40 °C and found that the rate of protodeborylation of 5Bpin is about 23 times faster than that of 4Bpin, consistent with the kinetic resolution that occurs on the preparative scale. We also determined the rate of protodeborylation of the benchmark compound PhBpin to be similar to that of 4Bpin (Scheme 4).

TRANSESTERIFICATION WITH DIETHANOLAMINE

We also investigated the transesterification27 of the boron pinacolate ester with diethanolamine with the aim to convert the mixture of the Bpin isomers into a separable mixture of differentially borylated compounds. Diethanolamine when bound to an organoboron compound typically forms a zwitterionic 4-coordinate borate. When the transesterification from pinacol to diethanolamine is performed in a nonpolar ethereal solvent, the charged diethanolamine adduct tends to precipitate out of the solution.28 We hypothesize that the more Lewis acidic 4Bpin should be the favored reactant in a transesterification with diethanolamine. Thus, when we treated a 1:1 mixture of 4Bpin and 5Bpin with diethanolamine in methyl-tert-butylether (MTBE), we observed a white precipitate that was separated from the reaction mixture. The precipitate contained only the 4BO2N isomer (50% yield, 25% based on available starting material), and the filtrate was enriched in the 5Bpin isomer (Scheme 5).

Scheme 5.

Scheme 5

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Reaction of Borylated Isomers with Diethanolamine

Addition of more equivalents of diethanolamine and changing the temperature did not drive the reaction forward to the diethanolamine product but instead resulted in an erosion of the selectivity.

We conducted studies to determine whether the transesterification reaction is kinetically or thermodynamically controlled. Here, we used THF as the solvent to ensure that the reaction mixture formed a homogeneous solution. Monitoring the transesterification reaction for each isomer independently by 1H NMR at room temperature revealed that the transesterification had reached equilibrium within 3 h. All four components were observed in the reaction mixture: boron pinacol ester (A), free diethanolamine (B), diethanolamine adduct (C), and free pinacol (D). Initial rates of the transesterification reaction of each isomer were measured using reaction calorimetry and were found to be nearly identical (see Supporting Information for details). Determination of the concentration of each component in the reaction mixture by 1H NMR yielded the equilibrium constant, Keq, for each isomer. We found that the Keq(4Bpin) is larger than the Keq(5Bpin) by a factor of 29 (Scheme 6).

Scheme 6.

Scheme 6

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Kinetic and Thermodynamic Studies of Transesterification Reaction

The observed relative binding propensity Keq(4Bpin):Keq(5Bpin) is corroborated by DFT calculations. The Gibbs free energy of formation of the 5BO2N adduct is ΔG = −5.1 kcal mol−1, while the formation of 4BO2N is more favorable with ΔG = −6.1 kcal mol−1. Thus, the separation of the mixture of borylated 1,2-azaborine, as illustrated in Scheme 5, is an example of a thermodynamically controlled resolution process.

FUNCTIONALIZATION OF THE 4- AND 5-POSITIONS OF THE 1,2-AZABORINE

The isolated 4Bpin or 5Bpin building blocks can undergo Suzuki–Miyaura cross-coupling with an aryl halide to afford triaryl 4ptol or 5ptol in good yields (Scheme 7a). It is also possible to generate new electrophilic building blocks at the 4 and 5 positions of the 1,2-azaborine utilizing the versatile transformations of organoboron compounds. For example, compound 4OH, generated via the NMO oxidation of 4Bpin, can be converted into the tosylate 4OTs (Scheme 7b).29 Subsequent Kumada coupling of 4OTs with an aryl Grignard reagent furnishes 4ptol (Scheme 7c).30 An iodine group can be installed at the C5 position using a procedure adapted from the Evans modification of the Zweifel reaction (Scheme 7d).31 5I undergoes facile Suzuki–Miyaura coupling at room temperature with p-tolylboronic acid to afford 5ptol (Scheme 7e).

Scheme 7.

Scheme 7

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Functionalizations of 4Bpin and 5Bpin

CONCLUSION

We have developed the synthesis of two new 1,2-azaborine building blocks that enables the ready diversification of C4 and C5 ring positions of 1,2-azaborine. We took advantage of 1,2-azaborine’s distinct electronic structure to resolve a mixture of borylated 1,2-azaborines. By means of kinetic and thermodynamic studies and DFT calculations we have been able to rationalize the difference in reactivities of 4Bpin and 5Bpin at their C4 and C5 positions. NMO selectively oxidizes the more Lewis acidic 4Bpin 1,2-azaborine isomer, whereas Ir-catalyzed protodeborylation selectively deborylates the more nucleophilic 5Bpin 1,2-azaborine isomer. Transesterification of the pinacol group with diethanolamine also favors the more Lewis acidic 4Bpin in a thermodynamically controlled process. The aforementioned resolution methods provide access to the previously inaccessible C4-Bpin and C5-Bpin building blocks which could be further functionalized using cross-coupling chemistry. The availability of a general approach to the functionalization of the C4- and C5-positions of the 1,2-azaborine will undoubtedly advance BN/CC isosterism as a versatile strategy for expanding the currently available chemical space and enable emerging applications in the biomedical and materials science fields.

Supplementary Material

SI

ACKNOWLEDGMENTS

We thank Prof. Todd Marder for helpful discussions. This work was supported by NIH NIGMS (R01-GM094541) and Boston College start-up funds.

Footnotes

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.9b03611.

Experimental procedures and compound characterization data (PDF)

The authors declare no competing financial interest.

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