A Nitrilium-Type N-Heterocyclic Aryne

Abstract

The first solution-phase synthesis and reactivity of a nitrilium-type N-hetaryne are described. The 1,2-azaborine-derived 1,6-BN-aryne 2 exhibits [4 + 2], [3 + 2], and [2 + 2] cycloadditions and electrophilic aromatic substitution (EAS) reactivity. The observed regio- and diastereoselectivities of the cycloaddition and EAS products are consistent with a polarized aryne/nitrilium species. The free 1,6-BN-aryne 2 was isolated and characterized under matrix isolation conditions. A Lewis structure description where the 1,6-BN-aryne 2 resonates between two limiting (ketenimine (dominant) vs nitrilium) forms is consistent with DFT calculations. New 1,2-azaborine structures that are functionalized at the C6- and N-positions, including highly strained derivatives that were previously not accessible, can now be accessed using 1,6-BN-aryne 2 as a versatile synthetic building block.

A rynes as reactive species have continuously fascinated chemists because of their synthetic utility and their unique bonding and electronic structure.¹ Recently, heterocyclic arynes (or hetarynes), in particular N-hetarynes such as pyridyne and indolynes, have garnered significant attention as versatile synthetic building blocks for constructing complex natural products (Scheme 1a).² Paton, Houk, Garg, and co-workers developed a computational model that can predict the synthetic accessibility of hetarynes and the preferred site of attack.³ In 2024 Roberts and co-workers successfully generated the previously inaccessible 2,3-indolynes via stabilization with Ni and demonstrated their synthetic utility.⁴ To date, the vast majority of N-hetarynes investigated involve the formation of CC-type arynes (Scheme 1a). The corresponding CN-type (nitrilium) N-hetarynes have been explored only sparsely (Scheme 1b). For example, attempts to study 1,2-pyridyne in solution have been unsuccessful;⁵ however, gas-phase studies have provided evidence for this species.⁶ To the best of our knowledge, 1,2-indolynes and 1,2-pyrrolynes have remained elusive.

Scheme 1. CC-Type and CN-Type (Nitrilium) N-Hetaryne^a.

^aIllustrated charges are formal charges. The π-bond drawn outside of the heterocyclic structure is orthogonal to the ring π-system.

We have been interested in exploring the chemistry of reactive intermediates of boron–nitrogen (BN) heterocycles, specifically 1,2-azaborines.⁷ Our team previously isolated and characterized the 1,2-azaborine-derived 1,2-BN-aryne along with its N₂, CO, and Xe adducts under matrix isolation conditions (Scheme 1c).⁸ Given the electronic structure similarities between 1,2-azaborine, pyridine, and pyrrole (Scheme 1d), we envisioned that the BN-heterocyclic motif could provide an entry point to investigate the reactivity of the virtually unexplored nitrilium-type N-hetaryne. In this Letter, we report the first solution-phase synthesis and reactivity of a nitrilium-type N-hetaryne. The 1,2-azaborine-derived 1,6-BN-aryne (Scheme 1e) exhibits [4 + 2], [3 + 2], and [2 + 2] cycloaddition reactivity in a stereospecific fashion, consistent with aryne behavior. Additionally, we demonstrate that 1,6-BN-aryne can serve as an electrophile in electrophilic aromatic substitution (EAS) reactions with exclusive regioselectivity.

We envisioned that the target species 1,6-BN-aryne 2 as a nitrilium N-hetaryne could be accessed by a base-promoted elimination of H─Br from C6-brominated precursor 1 (Scheme 2). We prepared the C6-bromo-B-mesityl-1,2-azaborine 1 from the previously reported Bpin compound Ab-Bpin⁹ via a deborylative bromination with copper(II) bromide.¹⁰ Given the predicted reactive nature of 1,6-BN-aryne 2, we sought to trap it as a cycloadduct with classic arynophiles, and the observation of the trapped cycloadduct would be consistent with the successful formation of the reactive species 2 upon in situ deprotonation of C6-brominated precursor 1.

Scheme 2. Synthetic Strategy toward 1,6-BN-Aryne 2.

We chose furan as a prototypical arynophile,¹¹ and indeed, when precursor 1 was treated with LiHMDS as a base in the presence of 5 equiv of furan, we could isolate the furan adduct (compound 3) of 1,6-BN-aryne 2 in 91% yield (eq 1).

(1)

We then explored the generality of this [4 + 2] cycloaddition reaction. As can be seen from Table 1, a variety of furan arynophiles are suitable coupling partners for the 1,6-BN-aryne species, in addition to the parental furan. For example, the unsymmetrical 2-methylfuran produces the cycloadducts 4a and 4a′ in a 2:1 ratio, respectively. Similarly, 3-bromofuran also generates a mixture of regioisomeric adducts 4b and 4b′ in a 1.9:1 ratio. The major isomer 4b was isolated, and its connectivity was determined by 2D NOESY spectroscopy (see Supporting Information). The more sterically hindered 2,5-dimethylfuran is also a compatible arynophile and furnishes cycloadduct 4c in 73% yield. Furan adduct 4d can be accessed by utilizing 4,5-dibromoisobenzofuran¹² as an arynophile in moderate yield. We were able to grow crystals of 4d suitable for single-crystal X-ray diffraction analysis and thus unambiguously confirm our structural assignment for 4d (CCDC entry 2414514). Furthermore, we demonstrate that a C3,C6-dibromo-1,2-azaborine substrate¹³ is compatible as a nitrilium N-hetaryne precursor to generate cycloadduct 4e in the presence of furan. The ORTEP of 4e (CCDC 2414518) shown in Table 1 establishes adduct formation without the loss of the C3─Br functional group in the BN-heterocycle.

Table 1.

Scope of [4 + 2] Cycloaddition of 1,6-BN-Aryne with Furan Arynophiles^a

^aYields are of isolated products and are reported as an average of two runs. Some hydrogen atoms in ORTEPs illustrated for compounds 4d and 4e have been omitted for the sake of clarity. Thermal ellipsoids are drawn at the 50% probability level.

The 1,6-BN-aryne can also be trapped in other [4 + 2], [3 + 2], and [2 + 2] cycloaddition reactions with polar arynophiles in a regioselective fashion (Table 2). For example, Danishefsky’s diene as an electron-rich arynophile affords 5a in 59% yield (entry 1). Benzyl azide gives BN-benzo“triazole” 5b with four connected nitrogen atoms in 55% yield (entry 2). The illustrated X-ray structure of 5b (CCDC 2414515) unambiguously establishes its structural assignment and bond connectivity. Silyl ketene acetal A (entry 3) undergoes a [2 + 2] cycloaddition with 1,6-BN-aryne, the cycloadduct of which is however not stable toward silica gel column purification. Thus, the crude reaction mixture was instead treated with anhydrous 2 N HCl in diethyl ether to furnish the strained but isolable BN-benzocyclobutanone product 5c, which we were able to crystallographically characterize as well (CCDC 2414516). The direct [2 + 2] cycloadduct 5d of the more sterically encumbered silyl ketene acetal B with 1,6-BN-aryne is stable toward silica gel chromatography purification and can be isolated in 53% yield (entry 4). To probe the stereospecificity of the [2 + 2] cycloaddition, we prepared the E and Z isomers of the tert-butyl-substituted silyl ketene acetals C (E:Z ~ 7:1) and D (Z:E ~ 9:1),¹⁴ respectively. The cycloaddition between the E-configured silyl ketene acetal C and 1,6-BN-aryne produces the adduct 5e in a 7:1 mixture of anti:syn diastereomers with the relative anti (t-Bu vs OTBS) stereochemistry established by 2D NOESY spectroscopy. Similarly, the coupling between the Z-configured silyl ketene acetal D and 1,6-BN-aryne results in a 9:1 mixture of syn:anti diastereomers with adduct 5f constituting the major diastereomer. The observed stereospecific nature of the reaction suggests that the [2 + 2] cycloaddition occurs in a concerted or a fast-stepwise fashion and is consistent with the involvement of a nitrilium N-hetaryne.¹⁵ The observed exclusive regioselectivity of the coupling between 1,6-BN-aryne and polar arynophiles (Table 2) is in stark contrast to the reactivity of CC-type hetarynes (e.g., indolynes) where typically a mixture of regioisomers is observed (e.g., with azides and silyl ketene acetals)¹⁶ and is consistent with the nitrilium electronic structure description with the nitrilium carbon (C6) being significantly electrophilic.

Table 2.

Scope of [4 + 2], [3 + 2], and [2 + 2] Cycloaddition Partners with 1,6-BN-Aryne^a

^aYields are of isolated products and are reported as an average of two runs. Some hydrogen atoms in ORTEPs illustrated for compounds 5b and 5c have been omitted for the sake of clarity. Thermal ellipsoids are drawn at the 50% probability level.

During the survey of cycloaddition partners, we discovered that N-methylpyrrole did not engage in [4 + 2] cycloaddition. Instead, we observed a formal C─H activation of N-methylpyrrole to yield biaryl compound 6a in 92% yield (Table 3, entry 1). The coupling likely proceeds through an electrophilic aromatic substitution (EAS) mechanism, in which the electron-rich pyrrole attacks the electrophilic C6-position of the 1,6-BN-aryne. Similarly, N-methylindole furnishes 6b in 78% yield (entry 2). On the other hand, 1,3,5-trimethoxybenzene gives only a trace amount of the EAS product and instead forms BN biphenylene 6c in 27% yield (entry 3). To the best of our knowledge, compound 6c represents the first synthetically accessed molecular BN biphenylene structure.¹⁷ The use of aryne^1b and nitrilium¹⁸ intermediates as electrophilic partners to other aromatic rings has been reported previously.

Table 3.

Coupling with Electron-Rich Arenes

^aYields are of isolated products and are reported as an average of two runs.

Control experiments with brominated 1,2-azaborine precursor 1 in the presence of either furan, benzyl azide, silyl ketene acetal A, or N-Me pyrrole without the LiHMDS base or in the presence of pyridine as a weak base resulted in the recovery of the starting materials, even at 80 °C.

We also demonstrate further functionalization of some of the cycloaddition products. For example, the alkene double bond of furan adduct 4c can be selectively hydrogenated under mild conditions to furnish 7 (eq 2). The intraring C═C bonds in the BN heterocycle remain unreactive under those conditions.¹⁹ We were able to obtain the crystal structure of 7 (CCDC 2414517), thus indirectly confirming our structural assignment for the [4 + 2] cycloadduct 4c. Furthermore, furan cycloadduct 3 can be reduced with B₂Pin₂ in the presence of 1 mol % Pt(dba)₃ as the catalyst²⁰ to generate B-Mes-9,1-BN-naphthalene 8 (eq 3).²¹

(2)

(3)

Beyond chemical reactivity as evidence for the formation of nitrilium N-hetaryne 2, we are able to isolate and characterize this reactive intermediate²² under matrix isolation conditions. When furan adduct 3 is subjected to flash vacuum thermolysis conditions, a retro-Diels–Alder reaction occurs to allow 1,6-BN-aryne 2 to be trapped and identified by IR spectroscopy at 4 K in solid N₂ and Ar (the Ar data are given in the Supporting Information). Thermolysis at 455 °C is almost quantitative and shows clear formation of furan (labeled as “f” in Figure 1, black trace) compared to an authentic furan sample (Figure 1, red trace). In addition, bands at 1990, 1614, 1444, 1363, and 1291 cm⁻¹ are observed in solid N₂ that are due to neither furan, the precursor 3, or typical contaminants (H₂O, CO₂). The newly observed bands are in good agreement with the vibrational frequencies for 2 computed at the B3LYP-D3(BJ)/6-311+G-(d,p) level of theory (Figure 1, green trace). Particularly characteristic is the broad band at roughly 1990 cm⁻¹, as this indicates a strained polar multiple bond. The computations show that this is due to a stretching vibration of the CN⁽⁺⁾ unit. This stretching vibration ranges from 2300 to 2420 cm⁻¹ in linear alkyl- and aryl-substituted nitrilium salts.²³ The substantial weakening of the force constant of the CN⁽⁺⁾ unit of 2 is consistent with the strong deviation from the preferred linear C─N─C arrangement.²³ A similarly strong deviation was observed for the (weak) CC triple bond stretching vibration of 1,2-didehydrobenzene (ortho-benzyne) at 1846 cm⁻¹ in Ne compared to typical linear alkynes at 2100–2150 cm⁻¹.²⁴ It is noteworthy that while 1,2-BN-aryne readily reacts with N₂ to form a Lewis acid–base adduct under cryogenic matrix isolation conditions,^8a this is not observed for the 1,6-BN-aryne studied here. Computations (B3LYP-D3(BJ)/6-311+G(d,p)) show that the formation of the N₂ adduct is strongly endothermic (see Supporting Information), consistent with the successful trapping of free 1,6-BN-aryne 2 in solid N₂ without N₂ adduct formation.

Figure 1.

IR spectra of furan (red), furan adduct 3 (blue), and products of pyrolysis (black) in a solid N₂ matrix at 4 K. The bands of furan are labeled with “f” in the black spectrum. For comparison, the IR spectrum of 1,6-BN-aryne 2 computed at B3LYP-D3(BJ)/6-311+G(d,p) is illustrated in green.

Finally, we have characterized the electronic structure of nitrilium N-hetaryne (or 1,6-BN-aryne) 2 using DFT calculations at the CAM-B3LYP/6-311G(d,p) level of theory. Figure 2a illustrates the frontier orbitals of 2, and we note that the electronic structure of the HOMO is very similar to the corresponding HOMO of a 1,2-azaborine.²⁵ The LUMO is relatively low in energy at −0.924 eV and mostly represents the π* contribution of the in-plane C─N π-bond. The LUMO’s energetic positioning and orbital coefficient distribution (e.g., largest contribution at the C6-position) are consistent with the observed reactivity/selectivity. Figure 2b shows the calculated Mayer bond order²⁶ where a single bond is represented by a value of 1.0 and a double bond by a value of 2.0. The calculated bond orders for C5─C6 and C6─N bonds are 1.48 and 2.17, respectively, thus intermediary between the Lewis structure representations 2′ and 2″ (Figure 2d). The optimized geometry for 2 as illustrated in Figure 2c highlights the “linearized” ∠C5─C6─N angle of 145.3° and the short C6─N bond distance of 1.186 Å. In comparison, the ∠C5─C6─N angle in a 1,2-azaborine is typically ~120°, and the C6─N bond distance is ~1.38 Å (see Table 1 for select distance parameters for compound 4e as an example). As an additional reference, a typical CN bond distance in Bsp²─C≡N─R is ~1.15Å.²⁷ Thus, the calculated structural parameters for nitrilium N-hetaryne 2 are consistent with a resonance between two limiting structures with a stronger contribution of the ketenimine resonance form 2′ than that of the nitrilium resonance form 2″.

Figure 2.

Electronic structure calculations at the CAM-B3LYP/6-311G(d,p) level for 1,6-BN-aryne 2. a) Orbital diagrams and energies for the frontier orbitals. b) Mayer bond order. c) Select bond length (Å) and bond angles (deg) for the optimized structure of 2. d) Lewis structure representation of 2.

In summary, we described the first solution-phase synthesis and reactivity of a nitrilium-type N-hetaryne exemplified by 1,2-azaborine-derived 1,6-BN-aryne 2. The reactivity exhibited by 2 includes [4 + 2], [3 + 2], and [2 + 2] cycloadditions and EAS reactions. The observed regio- and diastereoselectivity of the cycloaddition and EAS products are consistent with aryne behavior, however, with the distinction that the nitrilium carbon is significantly positively polarized compared to a CC-type (het)aryne. We also isolated and characterized 1,6-BN-aryne 2 under matrix isolation conditions at 4 K in solid N₂ and Ar as a fragment of its furan adduct. DFT electronic structure calculations are consistent with a Lewis structure description where 1,6-BN-aryne 2 resonates between two limiting structures with a stronger contribution from the ketenimine form relative to the nitrilium form. In addition to the new fundamental insights obtained for a novel reactive species, we have demonstrated that 1,6-BN-aryne 2 serves as a versatile synthetic building block to access new 1,2-azaborine structures that are functionalized at the C6- and N-positions, including highly strained derivatives that are previously not accessible.

Supplementary Material

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c05146.

Experimental procedures, compound characterization data (NMR, Hi-res MS and IR data, NMR spectra for all new compounds), computational (Cartesian coordinates of all computed structures) and crystallographic information (PDF)