Azaborines are a unique class of aromatic boron and nitrogen containing heterocycles isoelectronic and isostructural to carbon-containing aromatic compounds such as benzene. These novel compounds possess unique electronic characteristics that provide them unprecedented and adaptable reactivity and photophysical properties. Their properties enable them to greatly alter molecular reactivity without impacting molecular structure which makes them useful to biochemical, pharmaceutical, and catalytic applications. Several classes of isomers have been synthesized with varying stabilities and electronic properties: monocyclic 1,2-, 1,3-, and 1,4-azaborine compounds have been reported. Azaborines were first reported in the late 1950s by Dewar and White, but more recent advances have enabled the synthesis, characterization, and functionalization of these benzene isosteres. The synthesis and study of these molecules has helped further understanding of aromaticity and carbon heteroatom bonding and created novel opportunities in a variety of chemical fields.
Development and synthesis
Development Dewar, and later White, first reported polycyclic boron and nitrogen containing analogs of phenanthrene in 1958. The attempted synthesis of this compound resulted from the observation of Dewar, Kubba, and Pettit that replacement of one carbon atom of benzene with nitrogen yielded a cationic arene and that there no such single-atom replacement of carbon for boron, which should yield an anionic arene. Thus, they predicted that a benzene derivative featuring boron and nitrogen would yield a neutral aromatic compound. Interest in synthesizing new examples of compounds displaying Hückel aromaticity and novel boron-containing aromatic compounds drove investigations into these compounds. Their report of the synthesis and characterization of a polycyclic boron and nitrogen containing heteroarene shown in Figure 1 predicted the synthesis of 1,2-, 1,3- and 1,4-azaborines shown in Figure 2.
Monocyclic azaborines were reported shortly after their polycyclic relatives. Marr and Dewar reported the synthesis of a monocyclic 1,2-azaborine (Figure 3) in 1962 that displayed significant stability, which they interpreted as evidence for aromatic character.
In 1963, White reported the synthesis of a less substituted 1,2-azaborine (Figure 4). Although prepared in a separate manner compared to previously reported examples, White's azaborine was also classified as aromatic due to its inertness.
Numerous examples of polycyclic and monocyclic 1,2 azaborines were reported shortly after these key papers However, functionalization of the moiety and development of the other isomers stalled until the early 21st century due to the few viable synthetic methods. The advent of a ring closing metathesis strategy in 2000 enabled the field to flourish again.
The synthesis of the 1,3- and 1,4-azaborine's predicted in Dewar's initial paper was not realized until the early 2010s. In 2011, Liu and coworkers reported the novel synthesis of a monocyclic 1,3-azaborine, 3-(diisopropylamino)-1-methyl-1,3-azaborine Figure 5. Theoretical studies of the three monocyclic azaborine isomers describe 1,3-azaborine as the least thermodynamically stable of the three. Shortly afterward in 2012, Braunschweig and coworkers reported the synthesis of a monocyclic 1,4-azaborine, 1,4-di-tert-butyl-1,4-azaborine.
Synthesis and functionalization The syntheses of each isomer differ greatly in strategy and variety. The chemical procedures for synthesizing various 1,2-azaborines are more established than the syntheses of 1,3- and 1,4-azaborines due to their earlier discovery and greater stability.
1,2-Azaborines
Synthesis of 1,2-azaborines In 1962, Dewar and Marr reported the first synthesis of a monocyclic azaborine. They reported the synthesis of 2,3-diphenyl-6-(2-carbomethoxy-ethyl) -2,1-azaborine via the reduction of methyl 2-styryl-3-nitrothiophene-5-carboxylate using tin and hydrochloric acid. The product of this step is then condensed with phenyl dichlorobornite yielding 2-carbomethoxy-5,6-diphenyl-5,4-borazarothiophene. Treatment with Raney nickel yields the desired monocyclic 1,2-azaborine shown in Figure 3.
Since the first synthesis, more modern methods have become common place. In 2000, Ashe and coworkers reported the synthesis of 1,2-azaborines via a ring-closing metathesis of allyl aminoboranes using Grubbs catalyst (Figure 6). The synthesis reliably provided a high yield of the 1,2-azaborine. The synthesis started with allyltributyl tin and the addition of boron trichloride to introduce the boron moiety. The product of this reaction was reacted with ethylallylamine and Grubbs catalyst was used to close the ring and produce the product with an 86% yield.
Additionally, Ashe and coworkers reported the synthesis of 1,2-azaborine through a carbenoid ring expansion of 1,2-azaborolide to yield the 1,2-azaborine (Figure 7). This procedure enabled the synthesis of aryl and alkyl substituted 1,2-azaborines.
In 2006, Liu and coworkers reported the synthesis of 1,2-dihydro-1,2-azaborine, a valuable building block in furthering azaborine chemistry. This procedure built off of previously reported syntheses 1,2-azaborines that were functionalizable at the heteroatoms. Liu's protecting group free synthesis utilized a molybdenum catalyst to perform the ring closing metathesis and uses an allyl amine as the leaving group to be replaced by n-butanol. Subsequently, the parent 1,2-dihydro-azaborine results from the reduction of boron with lithium aluminum hydride and an acidic workup.
Functionalization of 1,2-azaborines In 2006 Ashe and coworkers reported that a 1,2-dihydro-1,2-azaborine underwent electrophilic aromatic substitution at the 3 and 5 positions.Pan, J.; Kampf, J. W.; Ashe, A. J. Electrophilic Aromatic Substitution Reactions of 1,2-Dihydro-1,2-Azaborines. Org. Lett. 2007, 9 (4), 679–681. https://doi.org/10.1021/ol062968r. This reactivity displayed in Figure 8 validated its analogous relationship to benzene and established that typical aromatic reactivities may be used to develop novel methods of functionalization for these compounds. Their report demonstrated electrophilic aromatic substitution with several functionalities and produced 1,2-azaborine compounds displayed in Figure 9 and substituted with deuterium, nitrile, bromine, and hydroxyl. Additionally, competition experiments demonstrated that 1-ethyl-1,2-dihydro-2-phenyl-1,2-azaborine is a highly nucleophilic aromatic compound compared to 2-methylfuran, furan, and thiophene. Substitution at the boron atom has been similarly documented and thought to proceed through an associative mechanism.
In 2024, Nature Chemistry published an article detailing synthetic methods that opened up novel space for the functionalization of 1,2-azaborines via a benzannulation. The reported synthesis enables the development of multifunctionalized monocyclic 1,2-azaborines. To demonstrate the widespread utility of the procedure, the authors reported the synthesis of a boron-nitrogen containing isostere of a PD-1/PD-L1 inhibitor, an important class of molecules for cancer treatments.
1,3-Azaborines
Synthesis of 1,3-azaborines In 2011, Liu and coworkers completed the long sought-after synthesis of 1,3-azaborine with their procedure for the synthesis of 3-(diisopropylamino)-1-methyl-1,3-azaborine. Figure 10 demonstrates that the procedure utilizes a ring closing metathesis performed by a Grubbs catalyst. The last step of the synthesis requires a dehydrogenation. At the time, Liu noted that there were no published observations of aromatization by the removal of two meta hydrogen atoms. As the dehydrogenation produces both the hydrogenated and dehydrogenated product in varying rations, accomplishing this novel step required significant optimization of the catalyst identity and loading, solvent, and temperature to maximize the yield and ratio of dehydrogenated product to hydrogenated product (Figure 11). Liu and coworkers reported their product was isolated by distillation as a pale yellow liquid in 25% yield.
Functionalization of 1,3-azaborines The functionalization of 1,3-azaborines has been reported at the boron and nitrogen positions (Figure 12) as well as on the carbon backbone, With their report of the first 1,3-azaborine in 2011, Liu and coworkers recorded the electrophilic aromatic substitution of 1,3-azaborines with Böhme's salt to yield a 1,3-azaborine substituted meta to the nitrogen at the six position of the aromatic heterocycle. The substitution occurs in mild conditions and high yield to produce the highly substituted azaborine product. Additionally, published procedures enable functionalization at boron. The starting precursor 1,3-azaborine is relatively resistant to substitution at the boron position, but can be readily functionalized in an acidic environment. After the first synthesis 1,3-azaborine, later publications detail procedures for the inclusion of chloro, cyano, fluoro and hydroxy groups at boron to take advantage of the azaborine's reactivity in an acidic environment to yield a diverse set of products.
Just as the lewis basic nitrogen can undergo electrophilic substitution, the boron of 1,3-azaborines can undergo nucleophilic substitution due to its lewis acidity and empty p orbital. The general strategy takes advantage of the acidic substitution conditions to provide a better leaving group for a nucleophilic attack at the boron atom. Figure 13 demonstrates a procedure which enables the synthesis of alkyl substituted boron atoms in 1,3-azaborines via pivalic acid and n-butyllithium in tetrahydrofuran(THF).
1,4-Azaborines
Synthesis of 1,4-azaborines Shortly after the report of the synthesis of 1,3-azaborine, Braunschweig and coworkers completed the synthesis of a 1,4-azaborine (Figure 14). The synthesis of this novel monocyclic 1,4-azaborine did not utilize a ring closing metathesis like many of the other syntheses did. Instead, utilized a [2+2+2] cycloaddition between di-tert-butyl-iminoborane and acetylene facilitated by a rhodium catalyst. This reaction surprisingly broke the triple bond between boron and nitrogen to form the 1,4-di-tert-butyl-1,4-azaborine.
Structure and bonding Boron and nitrogen containing heterocycles are isostructural and isoelectronic to all-carbon aromatic compounds. Both early and recent reports characterize the molecules as aromatic as they feature six π electrons. Despite the heteroatoms present in the system, azaborines obey Hückel's Rule because nitrogen contributes two π electrons and boron does not contribute any π electrons but maintains the cyclic array of p orbitals with its empty pz orbital. In contrast to pyridine, nitrogen in azaborines donate two electrons to the pi system. Similar to the parent all-carbon compounds, azaborines feature planar calculated structures.
1,2-azaborines feature a boron-nitrogen bond with boron ortho to the nitrogen, where 1,3- and 1,4-azaborines do not. The boron has a meta and para relationship to the nitrogen for 1,3- and 1,4- azaborines, respectively. The relationship between the heteroatoms in each isomer are depicted in Figure 2. For 1,2-azaborines, the interaction between adjacent atoms gives the boron-nitrogen bond π character and could be depicted as a double bond. A boron-nitrogen double bond would be formally zwitterionic and thus a significantly polarized bond, but as described in Figure 15, the flow of electrons from the boron to the nitrogen in σ symmetry opposes the flow of electrons from the nitrogen lone pair to the empty p orbital of boron in π symmetry. The observation and rationalization of relatively nonpolarized boron-nitrogen bonds possessing double bond character contributes to reports that these compounds are aromatic in nature and share electrons across all six atoms in the ring.