N-Functionalization of 1,2-Azaborines

Abstract

General protocols for the N-functionalization of 1,2-azaborines with C(sp³), C(sp²), or C(sp) electrophiles are described. The syntheses of a new parental BN isostere of trans-stilbene and a BN isostere of a lisdexamfetamine derivative were accomplished with the developed methodology.

BN/CC isosterism has been demonstrated to lead to the diversification of chemical structures and the discovery of unique chemical/physical properties of organic compounds.[1] Late-stage functionalization of 1,2-azaborines, i.e., functionalization after assembly of the BN heterocyclic core, provides a general approach to access a library of structurally diversified molecules. However, implementing such a strategy has been challenging until recently, due to the scarcity of methodologies that enable selective modification around the aromatic ring.[2] Our group and others have demonstrated selective functionalizations of monocyclic 1,2-azaborines at the B, C(3), and C(6) positions (Scheme [1a]). Nucleophilic substitution, Rh-catalyzed B-Cl arylation, and B-H alkenylation have been used to functionalize the boron position.[3] Electrophilic aromatic substitution reactions at C(3) were reported by Ashe and co-workers in 2007,[4] and our group developed a Negishi cross-coupling method involving C(3)-brominated 1,2-azaborines.[5] We also reported a selective Ir-catalyzed C-H borylation, followed by a Suzuki–Miyaura cross-coupling to achieve functionalization of the C(6) position.[6] Subsequently, we disclosed a nonselective C-H borylation at the C(4) and C(5) positions, where the resulting mixture of borylated compounds could be kinetically resolved.[7] To date, only limited examples can be found in the literature for N-functionalization of 1,2-azaborines.[8] [9] Thus, a systematic investigation into methods for N-functionalization would further expand the synthetic toolbox for 1,2-azaborines and promote the expansion of the chemical space of benzenoid aromatic compounds through BN/CC isosterism.

In this work, we report a general synthetic method to functionalize the nitrogen position of 1,2-azaborines through an array of chemical transformations. Electrophilic substitution reactions, N–C(sp²) bond-forming reactions under Buchwald–Hartwig amination conditions,[10] and N–C(sp) bond-forming reactions using copper-catalyzed N-alkynylation[11] afford various N-functionalized 1,2-azaborines. We applied the developed methods to synthesize more-complex BN-containing molecules, applicable to studies in materials science and medicinal chemistry, including the synthesis of a parental BN isostere of trans-stilbene and a BN isostere of a lisdexamfetamine analogue (Scheme [1b]).

First, we investigated electrophilic substitution reactions involving initial deprotonation of NH-containing 1,2-azaborines, followed by reaction with various electrophiles. The pKa of the NH group of N-H-B-phenyl-1,2-azaborine was determined to be ~26,[8a] and potassium hexamethyldisilazide (KHMDS) was a sufficiently strong base to generate the corresponding N-K salt 1 (Table [1]). Electrophilic substitution reactions of 1 afforded the desired N-functionalized products 2a–d in good to excellent yields, including N-Boc, N-alkyl, and N-allyl azaborines (Table [1], entries 1–4). A moderate yield of product 2e was achieved in the reaction with propargyl bromide, presumably due to competing protonation of the N-K salt by the relatively acidic propargylic C–H to regenerate the N-H azaborine starting material (entry 5). Benzoyl chloride was also a suitable electrophile, yielding 72% of the N-benzoyl product 2f (entry 6). Electrophilic substitution with another 1,2-azaborine molecule gave a dimeric species 2g in 98% yield (entry 7). Reaction with epoxides or an aziridine successfully produced the corresponding ring-opened products 2h–j at ambient temperature (entries 8–10).

Table 1 Electrophilic Substitution of 1,2-Azaborines

Entry	Electrophile	Product	Yieldb (%)
1			90
2			98
3a			>99
4a			94
5a			53
6a			72
7			98
8c			97
9c			60
10c			87

^a Substrate 1 was generated in situ by the reaction of N-H-B-phenyl-1,2-azaborine with KHMDS.

^b Isolated yield (average of two runs).

^c The reaction was quenched with HCl.

We next investigated N–C(sp²) bond-formation reactions. Under our optimized Buchwald–Hartwig amination conditions[10] [see the Supporting Information (SI) for a survey of reaction conditions], the reaction proceeded successfully using the ferrocene-based ligand QPhos [1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene] to generate N–C(sp²) coupling products (Table [2]). The reaction with 1,4-dibromobenzene afforded an oligo(ortho-arylene)[12] containing five alternating phenyl/1,2-azaborinyl units (Table [2], entry 2). We were able to obtain its single-crystal X-ray structure, which confirmed our structural assignment. Effective N-alkenylation[13] was achieved using the catalytic system by switching the base from t-BuONa to BuLi. The reaction is stereospecific, giving the corresponding alkenylated products with retention of the configuration of the vinyl bromide starting materials (entries 3 and 4).

Table 2 N–C(sp²) Coupling of 1,2-Azaborines

Entry	RBr	Base	Product	Yielda (%)
1	PhBr	t-BuONa	4a	81
2b		t-BuONa	4b	54
3		BuLi	4c	92
4		BuLi	4d	71

^a Isolated yield (average of two runs).

^b RBr (0.6 equiv) was used, and the yield is based on 0.5 equivalents of 3.

Table 3 N-Alkynylations of 1,2-Azaborines

Entry	R1	R2	Product	Yielda (%)
1	Bu	Ph	6b	84
2	Mes	Ph	6c	98
3	Mes	TIPS	6d	79

^a Isolated yield (average of two runs).

To access N-alkyne functionalities, we chose copper-catalyzed alkynylation reactions with alkynyl bromides under the nonoxidative conditions that had previously been applied to amide, enamide, carbamate, or sulfoximine substrates.[11] We hypothesized that the reactivity of the 1,2-azaborine nitrogen atom would be comparable to that of a nitrogen atom in resonance with a carbonyl, sulfonyl, or alkene. This method also avoids the use of a stoichiometric amount of dioxygen,[14] a reactive species that can decompose 1,2-azaborine.[15] As can be seen from Table [3], under the optimized catalytic conditions, butyl- or mesityl-substituted 1,2-azaborines underwent efficient N-alkynylation with phenyl or silylated alkynyl bromides to furnish the desired products in high yields (Table [3]).

By employing N-vinylation, we were able to synthesize a parental BN isostere of trans-stilbene (Scheme [2]).[16] A benzyl group was chosen as the boron substituent to allow for removal through a three-step oxidative sequence after cross-coupling. Following deprotonation by BuLi, 1,2-azaborine 7 coupled with β-bromostyrene to give the N-alkenylated intermediate 8. The stereochemistry around the newly formed N–C (sp²) bond was unambiguously determined to be trans by X-ray crystal-structure analysis (Scheme [2]). Copper-mediated oxidation was utilized to remove the benzyl group from boron.[8c] Chromatographic purification of the crude materials afforded a mixture of BOR species (dimer and monomer, R = n-C₁₂H₂₅ or R = H), which upon reduction with LiAlH₄, furnished the desired BN-stilbene in moderate yield (38%) over three steps. UV–vis absorption and emission spectra of BN-stilbene 10 and stilbene for direct comparison are included in the SI. A structural analysis revealed that the intraring bond distances of the BN heterocycle in compound 8 [B–C(3): 1.513(4) Å, C(3)–C(4): 1.364(3) Å, C(4)–C(5): 1.413(4) Å, C(5)–C(6): 1.351(4) Å, C(6)–N: 1.379(3) Å, N–B: 1.453(4) Å] are unremarkable and consistent with the distances observed for other 1,2-azaborines.[17] The observed dihedral angle ∠_BNC(α)C(β) = –138.1(3)° in the solid-state structure of compound 8 deviates significantly from planarity due the A_1,3 steric interaction with the N-alkenyl and B-Bn group. In contrast, the crystal structure for BN-stilbene 10 shows coplanarity between the two arene rings.[18]

Table 4 Cation Effect on Electrophilic Substitution Reaction

Entry	Base	Yield (%)
1	KHMDS	92
2	NaHMDS	75
3	LiHMDS	56

To demonstrate the potential utility of the aziridine ring-opening reaction, we aimed to synthesize derivatives of a biologically active molecule. Scheme [3] illustrates the synthesis of a BN analogue of lisdexamfetamine.[19] Starting with enantiomerically pure tert-butyl (S)-2-methylaziridine-1-carboxylate (11), aziridine ring opening occurred efficiently with the N-K salt 1 to form the ring-opened product 12 (80% yield). N-Boc-deprotection under acidic conditions afforded compound 13. Subsequent amide coupling of 13 with the lysine-derived hydroxysuccinimide ester 14 furnished the Boc-protected BN-lisdexamfetamine derivative 15 in excellent yield.

As a note added in proof, we have investigated the effect of the counter-cation in the electrophilic substitution reaction with allyl bromide as the electrophile. As can be seen from Table [4], among the alkali amide bases investigated, KHMDS (Table [4], entry 1) was the best-performing base, followed by NaHMDS (entry 2), and then LiHMDS (entry 3).[20]

In summary, we have developed general synthetic methods to functionalize the nitrogen position of 1,2-azaborines. This work expands the scope of possible functionality on the azaborine skeleton and permits further elaboration to complex BN-containing molecules for future application in materials science and medicinal chemistry.

Conflict of Interest

The authors declare no competing financial interest.

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• 18 The crystal structure of BN-stilbene 10 is disordered due to the apparent centrosymmetric nature of the molecule. Nevertheless, the planar geometry of the solid-state structure of 10 is clearly observed.
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• 20 A similar effect has been reported for the 2,1-borazaronaphthalenes, see ref. 9a.

Corresponding Author

Publication History

Received: 04 May 2023

Accepted after revision: 12 June 2023

Accepted Manuscript online:
12 June 2023

Article published online:
31 July 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
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• References and Notes

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For a study to access N-functionalized 2,1-borazaronaphthalenes, see:
• 9a Wang X, Davies GH. M, Koschitzky A, Wisniewski SR, Kelly CB, Molander GA. Org. Lett. 2019; 21: 2880
  CrossrefPubMedSearch in Google Scholar

For a study to utilize 1,2-azaborinin-1-yls as anionic nitrogen ligands for main group elements, see:
• 9b Lindl F, Lamprecht A, Arrowsmith M, Khitro E, Rempel A, Dietz M, Wellnitz T, Bélanger-Chabot G, Stoy A, Paprocki V, Prieschl D, Lenczyk C, Ramler J, Lichtenberg C, Braunschweig H. Chem. Eur. J. 2023; 29: e202203345
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• 10c Guram AS, Rennels RA, Buchwald SL. Angew. Chem. Int. Ed. 1995; 34: 1348
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• 10d Louie J, Hartwig JF. Tetrahedron Lett. 1995; 36: 3609
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For selected reviews, see:
• 10e Muci AR, Buchwald SL. Top. Curr. Chem. 2002; 219: 131
  CrossrefPubMedSearch in Google Scholar
• 10f Hartwig JF. Angew. Chem. Int. Ed. 1998; 37: 2046
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• 10g Hartwig JF. Acc. Chem. Res. 1998; 31: 852
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• 10h Wolfe JP, Wagaw S, Marcoux J.-F, Buchwald SL. Acc. Chem. Res. 1998; 31: 805
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• 16 BN-Stilbene {1-[(E)-2-Phenylvinyl]-1,2-dihydro-1,2-azaborinine} (10) In a dry box, an oven-dried 50 mL round-bottomed flask was charged with 2-benzyl-1,2-dihydro-1,2-azaborinine (7)⁶ (507 mg, 3.00 mmol) and toluene (15 mL), and the mixture was cooled to –30 °C. A 2.5 M solution of BuLi in hexane (1.26 mL, 3.15 mmol) was added at –30 °C, and the resulting mixture was stirred for 20 min while it slowly warmed to RT. Pd₂(dba)₃ (55 mg, 0.060 mmol), QPhos (170 mg, 0.240 mmol), and β-bromostyrene (476 μL, 3.60 mmol) were added, and the mixture was stirred at 85 °C for 15 h. At the completion of the reaction, the mixture was cooled to RT, then passed through an Acrodisc using CH₂Cl₂ as solvent. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica gel, 2–10% CH₂Cl₂–pentane) to give 8 as a white solid; yield: 497 mg (61%). FTIR (thin film): 3059, 3025, 1644, 1611, 1511, 1492, 1401, 1356, 1260, 1117, 1008, 801, 751, 693, 517 cm^–1. ¹H NMR (500 MHz, CD₂Cl₂): δ = 7.70 (d, J = 14.5 Hz, 1 H), 7.60–7.54 (m, 2 H), 7.48 (d, J = 7.5 Hz, 2 H), 7.41 (t, J = 7.0 Hz, 2 H), 7.34–7.29 (m, 3 H), 7.25–7.22 (m, 2 H), 7.18–7.16 (m, 1 H), 6.65 (d, J = 14.0 Hz, 1 H), 6.58 (d, J = 11.5 Hz, 1 H), 6.40 (t, J = 7.0 Hz, 1 H), 2.91 (s, 2 H). ¹¹B NMR (160 MHz, CD₂Cl₂): δ = 37.9. ¹³C NMR (151 MHz, CD₂Cl₂): δ = 143.8, 143.0, 136.4, 134.1, 133.9, 131.0 (br), 129.7, 129.4, 128.9, 128.1, 126.8, 124.9, 121.5, 111.8, 27.6 (br). HRMS (DART-TOF): m/z [M + H]⁺ calcd for C₁₉H₁₉BN: 272.16105, found: 272.16078. In a dry box, an oven-dried 20 mL microwave vial was charged with 8 (360 mg, 1.33 mmol), dodecanol (346 mg, 1.86 mmol), CuBr (19 mg, 0.13 mmol), pyridine (214 μL, 2.66 mmol), di-tert-butyl peroxide (293 mL, 1.59 mmol), and toluene (13 mL), and the mixture was stirred at 90 °C for 1 h, then cooled to RT and the solvent was removed under reduced pressure. The crude oxidized product was purified by column chromatography (silica gel 2–50% Et₂O–pentane) to isolate a mixture containing the desired product and other byproducts that was used directly to the next step. In a dry box, an oven-dried 25 mL round-bottomed flask was charged with the mixture of oxidized products and Et₂O (10 mL), which was then cooled to –30 °C. LAH (15 mg, 0.40 mmol) was added at –30 °C, and the mixture was stirred for 30 min. A 2.0 M solution of HCl in Et₂O (395 μL, 0.790 mmol) was added at –30 °C and the mixture was stirred for 30 min while it slowly warmed to RT. The solvent was removed under reduced pressure, and the crude product was purified by column chromatography (silica gel, 100% pentane to 2% Et₂O–pentane) to give 10 as a white solid; yield: 91.3 mg (38% over two steps). FTIR (thin film): 3063, 3022, 2539, 1650, 1604, 1508, 1404, 1262, 1152, 973, 755, 693, 596 cm^–1. ¹H NMR (500 MHz, CD₂Cl₂): δ = 7.68–7.64 (m, 2 H), 7.48 (d, J = 14.5 Hz, 1 H), 7.45 (t, J = 8.5 Hz, 2 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.26 (t, J = 7.5 Hz, 1 H), 6.97 (d, J = 10.5 Hz, 1 H), 6.79 (d, J = 14.5 Hz, 1 H), 6.51 (t, J = 6.5 Hz, 1 H), 5.82–4.60 (br, 1 H). ¹¹B NMR (160 MHz, CD₂Cl₂): δ = 33.2 (d, J = 109 Hz). ¹³C NMR (151 MHz, CD₂Cl₂): δ = 144.4, 136.9, 136.4, 134.1, 131.4 (br), 129.3, 127.9, 126.7, 118.8, 113.3. HRMS (DART-TOF): m/z [M + H]⁺ calcd for C₁₂H₁₃BN: 182.11410, found: 182.11324.
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• 18 The crystal structure of BN-stilbene 10 is disordered due to the apparent centrosymmetric nature of the molecule. Nevertheless, the planar geometry of the solid-state structure of 10 is clearly observed.
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• 20 A similar effect has been reported for the 2,1-borazaronaphthalenes, see ref. 9a.

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