Triborane (B₃H₇)-mediated regioselective substitution reactions of pyridine derivatives

Abstract

There exists an interplay between borane and a Lewis base in their adducts. However, studies on these adducts so far have mainly focused on the different reactions of B–H bonds with limited attention given to the influence of borane on the chemistry of the Lewis base, except for BF₃ and BAr₃. Herein, we have synthesized novel borane adducts with pyridine derivatives, Py·B₃H₇, in which the coordination of B₃H₇ efficiently achieved the intra-molecular charge transfer. The strong B–N bond in these adducts resulted in the formation of stable dearomatic intermediates of pyridine derivatives, confirmed by ¹H and ¹¹B NMR spectroscopy, from which different reactions have transpired to realize C(sp³)–H and C(sp²)–H functionalization under mild conditions. The B₃H₇ pyridine derivatives are stable and do not dissociate or decompose during the reaction process. The high stability of the B–N bond makes this method a good option for boron-containing drugs with potential for use in boron neutron capture therapy (BNCT).

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Introduction

Simple boranes, such as BH₃ and BF₃, denoted as B, cannot exist stably due to the electron deficiency of the boron atom. Usually they form a Lewis acid–base adduct L·B with a Lewis base (L = THF, Me₂S, NH₃, Me₃N, etc.) through a dative bond. There is no doubt that the interplay between the Lewis acid and base exists in these adducts (Scheme 1a). However, while the influence of L on the properties and reactivity of B has been extensively explored (Scheme 1aI)¹ and the steric interrelationship results in frustrated Lewis pair (FLP) complexes that are also well-known (Scheme 1aII),² the influence of boranes (B) on a Lewis base (L) has been relatively underexplored (Scheme 1aIII).

Scheme 1 Properties and reactions of borane Lewis base adducts.

Most studies on the influence of boranes (B) on a Lewis base (L) have mainly focused on the impacts of BF₃, BAr₃, and B₂pin₂ on pyridine derivatives. BF₃ mediated C-2 or C-4 selective functionalization,³ C-2 methyl group deprotonation,⁴ and asymmetric synthesis of pyridine derivatives⁵ have been extensively studied. BAr₃ and B₂pin₂ mediated C-3 alkylation,⁶ trifluoromethylthiolation,⁷ allylation,⁸ and cyanation⁹ of pyridine have become hot research fields recently (Scheme 1b). In contrast, the effects of the boron hydrogen complexes, such as BH₃, on the Lewis base have rarely been reported because of their strong reducing ability¹⁰ and weak Lewis acidity. Recent studies from our group have found that NaNH₂BH₃ could directly react with esters to form amides,¹¹ which did not work for NaNH₂ (Scheme 1c).¹² This result suggested that BH₃ could change the reactivity of the Lewis base of adducts.

Multinuclear boranes are usually used as reducing agents in organic synthesis.¹³ Recently, multinuclear boranes, such as carborane, [B₁₀H₁₀]²⁻, [B₆H₆]²⁻, and [HCB₁₁Cl₁₁]⁻ have also been used as borylation reagents¹⁴ or catalysts.¹⁵ However, there has been hardly any research into the influence of the Lewis acid properties of multinuclear boranes on reactions.

We have systematically studied the syntheses and properties of octahydridotriborate (B₃H₈⁻) and its neutral derivatives (L·B₃H₇), indicating that B₃H₇ as a Lewis acid possesses remarkable features.¹⁶ Compared with BH₃, B₃H₇ exhibits greater stability, weaker reducing ability, and a higher ability to coordinate with metals.¹⁷ Compared with BF₃, B₃H₇ has relatively low acidity. In addition, B₃H₇ has a steric effect and σ aromaticity. All these properties may enable the B₃H₇ group to mediate different organic reactions (Scheme 1d).

Results and discussion

Synthesis and properties of Py·B₃H₇

To explore the effects of B₃H₇ on a Lewis base, we selected pyridine, which is widely used in pharmaceutical chemistry, functional materials, and natural products as a Lewis base.¹⁸ We synthesized Py·B₃H₇ through a reaction of pyridine with THF·B₃H₇, formed in situ by reacting KB₃H₈ with HCl·Et₂O. The Py·B₃H₇ adduct 1a was obtained as a white solid in 91% yield (Scheme 2). This novel compound showed excellent stability towards both acid and base in aqueous solutions at room temperature (see ESI, Fig. S1†), offering an opportunity to examine their reactivity. The results indicated that a rapid dearomatic reaction of pyridine derivatives occurred, which then further reacted with electrophiles or oxidants to provide the rearomatic products (Scheme 1d).

Scheme 2 Synthesis of the pyridine B₃H₇ adduct.

B₃H₇ mediated dearomatic reaction of Py derivatives

A direct dearomatic reaction of pyridine is impossible under mild conditions. The dearomatic intermediates of BF₃ coordinated pyridine derivatives are potential products in most situations.¹⁹ We found that the B₃H₇ mediated dearomatic reaction of 4-methylpyridine rapidly proceeded by reacting with KO^tBu to form 4-methylene dihydropyridine at low temperatures. This intermediate was identified spectrally (Fig. 1e) but not isolated, which indicated that B₃H₇ could stabilize the dihydropyridine derivatives. To explore the universality of such an effect, we conducted a reaction of the B₃H₇ mediated addition of Grignard reagents to pyridines bearing an electron-withdrawing substituent. Similarly, the dihydropyridine intermediates were stable under these conditions, which could also be characterized by ¹¹B, ¹H, and ¹H{¹¹B} NMR spectra (ESI, Fig. S7–S9†).

Fig. 1 ¹H NMR in CDCl₃ of (a) 4-methylpyridine, (b) 1b, (c) 1c, (d) 1d, and (e) 4-methylene dihydropyridine 3a in THF-d₈ at −78 °C.

These observations differ from the BF₃ mediated similar reactions of pyridine derivatives under the same conditions where no dihydropyridine derivative intermediates were detected. We further set up control experiments to explore the different influences of BH₃, BF₃, and B₃H₇ on pyridine in their adducts. The ¹H NMR spectra of 4-methylpyridine of the corresponding B₃H₇ adduct 1b, BH₃ adduct 1c, and BF₃ adduct 1d showed that the chemical shifts of the protons at the C3 and C5 position and the methyl downfield-shifted in the adducts in comparison with 4-methylpyridine.

The impact of the BF₃ group was the most significant and those of the BH₃ and B₃H₇ groups were almost the same, but the B₃H₇ group was slightly larger than that of BH₃ (Fig. 1a–d). Therefore, we speculated that the impacts of these three Lewis acids on their coordinated Lewis base should be BF₃ > B₃H₇ > BH₃.

Surprisingly, the ¹¹B{¹H} NMR signals of the B₃H₇ coordinated 4-methylene dihydropyridine anion 3a and ethyl 4-isopropyl 3-carboxylate dihydropyridine complex 3b changed significantly in comparison with those of their parent complexes. The top boron atom connected with the nitrogen atom shifted to a lower field and the two base boron atoms to a higher field (Fig. 2), in contrast to the general B-signals of the B₃H₇ adducts.^13a Furthermore, the signal shifts in 3a and 3b are different (Fig. 2b and d). The exploration of the reason for such a difference is underway in our laboratory.

Fig. 2 (a) ¹¹B{¹H} NMR of 1b in CDCl₃. (b) ¹¹B{¹H} NMR of 4-methylene dihydropyridine 3a in THF-d₈ at −78 °C. (c) ¹¹B{¹H} NMR of ethyl nicotinate·B₃H₇6a in CDCl₃. (d) ¹¹B{¹H} NMR of ethyl 4-isopropyl 3-carboxylate dihydropyridine complex 3b in THF-d₈ at room temperature.

B₃H₇ mediated the nucleophilic substitution reaction of 4-alkylpyridine

Based on the formation of the dearomatic intermediates, we further explored the B₃H₇ mediated nucleophilic substitution reactions of pyridine derivatives by selecting the 4-ethylpyridine B₃H₇ adduct 1e as the model substrate, reacting with methyl iodide (Table S4†). After systematically screening reactions with different bases in various solvents, we found that the methylation product 4a was obtained at an 88% yield in CH₃CN when a mild base KO^tBu was used (entry 1 in Table S4†). In contrast, no reaction occurred when the BH₃ adduct 1f was used (entry 18 in Table S4†) and the product decomposed when the BF₃ adduct 1g was used (entry 19 in Table S4†). Only a trace amount of the product was detected. The reaction with 4-ethyl pyridine, without B₃H₇ coordinated, was also conducted at similar conditions and no reaction occurred (entry 20 in Table S4†). As expected, the starting material 4-ethyl pyridine was collected. These results suggested that the Py·B₃H₇ adducts have a unique stability and reactivity.

Considering the excellent stability of the Py·B₃H₇ adducts and the importance of boron-containing compounds in BNCT, we further examined the scope of the electrophiles (Table 1). Firstly, different alkyl iodides were detected. As shown in Table 1, regardless of whether the alkyl iodides were primary or secondary, products (4b–4r) were obtained in moderate to good yields. Additionally, this transformation shows a high functional group tolerance, such as allyl, ester, trifluoromethyl, cyclopropyl, and alkoxy were all compatible. We also found that the yields of the reactions using the alkyl bromides were significantly low compared to the alkyl iodines. Encouraged by these results, we further screened other electrophilic reagents and found that acyl chlorides could also be used in this reaction to produce stable Py·B₃H₇ derivatives (4s–4w). The scope for the pyridine core was assessed next (4x–4ae). Gratifyingly, our method showed a good C4 regioselectivity for the pyridines that contained multiple methyl groups at C2, C3, or C6 (4z–4ab). We thought this was because the high steric hindrance of B₃H₇ decreased the reactivity of the C2 and C6 positions, and the acidity of the methyl group at the C3 position is relatively weak. It was worth noting that the reaction of 4-methyl Py·B₃H₇ with methyl iodide gave a mixture of 4-ethyl Py·B₃H₇, 4-isopropyl Py·B₃H₇, and 4-tert-butyl Py·B₃H₇. Introducing methyl groups to the C2 and C6 positions could weaken the acidity of the C4 methyl to give the mono-methylation products (4z, 4aa) in high yields. The structure of 4aa was determined by single-crystal X-ray diffraction. Regardless of whether the substituent group at the C4 position was the primary, secondary, or tertiary alkyl group, the reactions transpired smoothly in high yields. In addition, the halogen atom (4x, 4y) and ester group (4ad, 4ae) were compatible in this transformation.

Table 1 Reaction scope^a

a Conditions: 1 (0.5 mmol, 1.0 eq.), 2 (1.25 mmol, 2.5 eq.), and base (1.25 mmol, 2.5 eq.) in CH₃CN (15 mL) at room temperature for 1 hour. Isolated yield. The d.r. value was determined by ¹H NMR analysis of the crude reaction mixture. b Conditions: 4 (0.5 mmol, 1.0 eq.), MeOH : H₂O (5 : 0.5 mL), 60 °C, 12 h.

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To remove B₃H₇ from pyridine derivatives has also been explored to expand the application of this protocol. After a series of explorations for the reaction conditions, the B₃H₇ unit was successfully removed with MeOH and H₂O at 60 °C, and the corresponding pyridine compounds were obtained in almost quantitative yields (5a, 5b).²⁰

The B₃H₇ mediated nucleophilic addition of Grignard reagents to electron deficient pyridines and their subsequent oxidation

The BF₃ promoted C4 direct alkylation of functionalized pyridines has been reported, in which BF₃-mediated 4-isopropyl-dihydropyridine was considered a potential intermediate.^4a We have obtained the dearomatic dihydropyridine intermediate by the nucleophilic addition of ⁱPrMgCl·LiCl to ethyl nicotinate B₃H₇ adduct (Fig. 2d), further oxidation aromatization mediated by chloranil provided the 4-alkylated product 8a in 71% yield (Table 2). Based on this, we examined the scope of Grignard reagents and pyridine derivatives and successfully introduced different alkyl and aryl groups into the C4 position of electron-deficient pyridines (Table 2). In these reactions, moderate yields of products could be obtained (8b–8g). The low yields of 8h and 8i are probably due to using strong bases such as organic lithium reagents. The ethyl nicotinate B₃H₇ adduct would be destroyed by strong bases to produce the pyridine BH₃ adduct, decreasing the yield. In addition, the electronic effects also played an important role in this reaction. The strength and stability of the electron-withdrawing group at the C3 position would affect the yields of products (8j, 8k, 8m, 8o, and 8s). When the pyridine had electron-donating groups, the yield would decrease due to the increase of the electron density at the C4 position (8l, 8n, 8p–8r). For all the low-yield reactions, the starting materials could be detected and recovered, such as the starting material for 8l could be recovered in 72%.

Table 2 The C-4 substitution reaction scope^a

a Conditions: 6 (0.5 mmol, 1.0 eq.), 7 (0.5 mmol, 1 eq.), and chloranil (1 mmol, 2 eq.). Isolated yield. b R–Li (0.5 mmol, 1 eq.).

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Mechanistic studies

To gain insight into the reaction mechanism, quantum chemical studies using density functional theory (DFT) have been performed. From the theoretical data, the reaction mechanism is proposed, as shown in Fig. 3.

Fig. 3 The energy profile of the reaction calculated at M06-2X-D3-SMD/def2-QZVP//B3LYP-D3(BJ)/6-311G(d,p)/SDD level of theory.

First, the reactants 4-methyl Py·B₃H₇ and potassium tert-butoxide form the reaction complex RC. The relative free energy of RC is 6.8 kcal mol⁻¹. In RC, the K⁺ cation interacted with the H of the B₃H₇ fragment, the K–H bond is 2.80 and 2.84 Å, and a hydrogen bond exists between the O of tert-butoxy and the H of the methyl group with a bond length of 2.10 Å. Subsequently, RC traverses transition state TS1 to yield a complex of intermediate (IM) and a tert-butanol with a relative free energy of −6.1 kcal mol⁻¹. From RC to TS1, the K–H bond shortened to 2.77 Å and the O–H bond shortened from 2.10 Å to 1.37 Å. At the same time, the C–H bond enlarged from 1.11 Å to 1.29 Å. The relative free energy of TS1 is 10.4 kcal mol⁻¹, indicating a modest energy barrier of 3.6 kcal mol⁻¹ for this step. Then tert-butanol dissociates, leaving behind IM. Following this, a new complex, IM with CH₃I, formed with a relative energy of 0.9 kcal mol⁻¹ with the I–C bond of 2.23 Å. The subsequent reaction of IM and CH₃I via transition state TS2 results in the final product. During this step, the I–C bond enlarged to 2.53 Å, and the C–C bond formed with a bond length of 2.47 Å. The relative energy of TS2 is 14.3 kcal mol⁻¹, implying a barrier of 13.4 kcal mol⁻¹ for the second step. With the Walden inversion of CH₃, the final product formed and exhibits a relative free energy of −52.5 kcal mol⁻¹. The negative ΔG of the whole reaction and the low energy barrier indicate that this reaction will easily proceed spontaneously. The charge distribution of CH₃Py, CH₃PyB₃H₇, KCH₃PyB₃H₇⁺, and CH₂PyB₃H₇⁻ was further analysed by using Natural Population Analysis (NPA). As delineated in Table S5,† the formation of the N–B dative bond and the preferential association of the K ions near the B₃H₇ fragment caused the electron concentration to be towards the B₃H₇ fragment. Such intramolecular charge transfer facilitates the deprotonation.

The proposed mechanism is supported by the experimental results of the capture of the reaction intermediate (Scheme 3a–c). The ¹H NMR spectroscopy showed that the B₃H₇ coordinated 4-methylene dihydropyridine anion intermediate 3a (IM) was formed in an almost quantitative yield by the deprotonation of 4-methyl Py·B₃H₇1b with KO^tBu in THF-d₈ at −78 °C (Fig. 1e).²¹ The intermediate of 4-alkalene dihydropyridine was frequently discussed in the literature.²² However, the BH₃ and BF₃ coordinated 4-methylene dihydropyridine anion intermediates 3c and 3d could not be formed in similar reactions (Scheme 3b and c).

Scheme 3 A mechanism study.

These results were consistent with the theoretical prediction that the interaction between the alkali metal cation and the NB₃H₇ moiety induced the additional intramolecular charge transfer from CH₃/CH₂ to the B₃H₇ end to facilitate the reaction and also stabilized the formed 4-methylene dihydropyridine intermediate (Table S5†). This result was further confirmed by the fact that the addition of 18–C-6 to the reaction mixture would decrease the yields from 88% to 54% (Fig. S2†) because the formation of the K-18–C-6 complex weakened the interaction between the K cation and the B₃H₇ moiety.

¹⁰B-labeled ¹⁰B₃H₇ reactions

To evaluate the potential of this protocol in BNCT,²³ a ¹⁰B-labeled ¹⁰B₃H₇ was introduced to the pyridine core (Scheme 4). Firstly, the ¹⁰B-labeled Na¹⁰B₃H₈ was synthesized by the reaction of Na¹⁰BH₄ with I₂. The reaction of 4-ethyl pyridine with the THF·¹⁰B₃H₇ formed the in situ produced 4-ethyl Py·¹⁰B₃H₇9 in 60% yield.²⁴ The ¹⁰B-labeled 4-ethyl Py·¹⁰B₃H₇ could also react with alkyl iodide under KO^tBu to afford the alkylated product 10 in a good yield.

Scheme 4 ¹⁰B-labeled experiments.

Conclusions

In summary, we have synthesized a novel class of Py·B₃H₇ compounds and studied the reactions of 4-alkyl Py·B₃H₇ with different electrophiles and pyridine bearing an electron-withdrawing group with nucleophiles. The relatively high stability of the Py·B₃H₇ adducts results in the formation of stable dearomatic intermediates, dihydropyridine, under mild conditions, from which the rearomatization has further transpired to form different alkylation and acylation products. The mechanistic study reveals that the coordination of the B₃H₇ unit led to the intra-molecular charge transfer from the pyridine ring to borane, realizing the alkylation and acylation reactions of the C(sp³)–H bond of the C-4 position with excellent regioselectivity and high yields under mild reaction conditions. The B₃H₇ coordinated dihydropyridine intermediate was obtained in solution and characterized by ¹H and ¹¹B NMR. Such an intra-molecular charge transfer also promoted C-4 direct alkylation of the pyridines bearing an electron-withdrawing group to provide the 4-alkylated products. Compared with BH₃ and BF₃, B₃H₇ possesses remarkable features, such as relatively higher stability, a weaker reducing ability, and a higher ability to coordinate with metals, as well as steric effects and σ aromaticity. All these properties will enable the B₃H₇ group to mediate different organic reactions. In addition, stable Py·B₃H₇ will play a significant role in boron-containing drugs and organic synthesis. Further research into the effect of B₃H₇ on other series of Lewis bases and the reaction mechanisms is underway in our laboratory.

Data availability

Data for all compounds in this manuscript are available in the ESI,† which includes experimental details, characterisation data, computational data and copies of ¹H, ¹³C, ¹⁹F, and ¹¹B NMR spectra. The data supporting this article have been included as part of the ESI.† Crystallographic data have been deposited with the Cambridge Crystallographic Data Center as supplementary publication no. CCDC-2308054 (1a) and CCDC-2308050 (4aa).

Author contributions

Y.-N. M. and X. C. conceived and designed the study; Z.-H. F., Q.-J. P., L. C., S. J., and X.-M. C. performed the experiments. J.-X. K. and C.-Q. X. performed the mechanistic and DFT studies. Y.-N. M. and X. C. prepared the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work is supported by the National Natural Science Foundation of China (No. 22171246 and 22271256).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2308054 (1a) and 2308050 (4aa). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4sc03109a

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