Silver-mediated formal [4π + 2σ] cycloaddition reactions of bicyclobutanes with nitrile imines: access to 2,3-diazobicyclo[3.1.1]heptenes

Abstract

Despite recent advances in the synthesis of aza-bicyclo[3.1.1]heptanes (aza-BCHeps, which have an sp³-hybridized nitrogen atom) and azabicyclo[3.1.1]heptenes (aza-BCHepes, which have an sp²-hybridized nitrogen atom), which are bioisosteres of pyridine, construction of 2,3-diazobicyclo[3.1.1]heptenes (2,3-diazo-BCHepes), which have both sp²- and sp³-hybridized nitrogen atoms, has yet to be achieved. Herein, we disclose a method for silver-enabled formal [4π + 2σ] cycloaddition reactions between bicyclobutanes and nitrile imines (generated from hydrazonyl chlorides) to furnish a diverse array of 2,3-diazo-BCHepes, which feature both sp²- and sp³-hybridized nitrogen atoms embedded in a BCHepe framework. These compounds have the potential to serve as bioisosteres of both pyridines and pyridazines. Owing to the presence of the sp³-hybridized nitrogen, 2,3-diazo-BCHepes can be expected to exhibit geometries similar to those of aza-BCHepes and much better solubility. We demonstrated the synthetic utility of our method by carrying out a scaled-up reaction and diverse postcatalytic transformations.

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Introduction

As of 2021, 88% of the drugs approved by the US Food and Drug Administration contained nitrogen heterocycles. In particular, N-heteroarenes such as pyridines and pyridazines are ubiquitous in pharmaceuticals and serve as fundamental building blocks in organic synthesis.¹ However, because the presence of planar moieties such as pyridine rings often results in undesirable pharmaceutical properties, medicinal chemists have been prompted to seek bioisosteres.² In recent years, three-dimensional saturated bridged bicyclic scaffolds such as bicyclo[1.1.1]pentanes,³ bicyclo[2.1.1]hexanes,⁴ and bicyclo[3.1.1]heptanes (BCHeps)⁵ have been developed as arene surrogates because these scaffolds can mimic the structural properties of arene rings and because molecules with these scaffolds tend to have better physicochemical properties and pharmacokinetics than the parent drug molecules. Moreover, the Mykhailiuk group reported that 3-aza-BCHeps (Scheme 1A, left), which have an sp³-hybridized nitrogen atom, are promising saturated bioisosteres of pyridines⁶ and exhibit drug-like solubility, lipophilicity, and metabolic profiles.

Scheme 1 (A) Bioisosteres of pyridines. (B) Construction of aza-BCHeps and aza-BCHepes as bioisosteres of pyridines: state of the art. (C) This work: silver-enabled [4π + 2σ] cycloaddition of bicyclobutenes with nitrile imines for the synthesis of 2,3-diazo-BCHepes.

To meet the increasing demand for 3-aza-BCHeps, the groups of Glorius,⁷ Li,⁸ Deng,⁹ Zhou¹⁰ and Feng¹¹ have recently established methods for synthesizing these compounds by means of Lewis acid-catalyzed cycloaddition reactions between bicyclo[1.1.0]butanes (BCBs) and various 1,3-dipoles (Scheme 1B). Because the sp²-hybridized nitrogen atom of pyridines governs their basicity and hydrogen-bonding ability,¹² incorporation of an sp²-hybridized imine nitrogen atom into the BCHep core can be expected to result in molecules that are more likely to be good mimics of pyridines; both types of compounds have unconjugated lone pair electrons on the nitrogen atom and π electrons in the C=N double bond. In this regard, the Zheng, Li and Wang groups separately reported syntheses of azabicyclo[3.1.1]heptenes (aza-BCHepes), which are regarded as perfect pyridine bioisosteres in terms of 3D conformation and basicity (Scheme 1A, right), from readily accessible vinyl azides and BCBs (Scheme 1B).¹³

Because of the ubiquity of pyridine motifs in drug molecules, exploring novel aza variants of BCHeps is an appealing strategy for drug discovery.¹⁴ Mykhailiuk and colleagues showed that three-dimensional heteroatom-containing bioisosteres of arenes have better water solubility, higher metabolic stability, and lower lipophilicity than their arene and all-carbon bicyclic counterparts.¹⁵ With the goal of designing a framework with a structure similar to that of aza-BCHepes but with much better solubility, we decided to try incorporating an additional nitrogen atom. We expected that by replacing the methylene group of aza-BCHepes with a nitrogen atom to afford 2,3-diazobicyclo[3.1.1]heptenes (2,3-diazo-BCHepes), we could obtain compounds with geometries similar to those of aza-BCHepes and much better solubility (Scheme 1B). Moreover, 2,3-diazo-BCHepes, which have both sp²- and sp³-hybridized nitrogen atoms, might serve as saturated bioisosteres of pyridazines (1,2-diazines), which have planar structures and have been found to have a wide range of pharmacological activities.¹⁶ However, the construction of BCHepe frameworks with both sp²- and sp³-hybridized nitrogen atoms is extremely challenging (Scheme 1B).¹⁷

We reasoned that a [4π + 2σ] cycloaddition strategy might offer an appealing, straightforward route to 2,3-diazo-BCHepes. For this purpose, we evaluated nitrile imines, which are generally prepared by treatment of hydrazonyl halides with stoichiometric amounts of base and are versatile CNN 1,3-dipolar building blocks for the synthesis of nitrogen-containing heterocycles.¹⁸ However, to date, research on nitrile imines has focused mainly on the construction of six-membered nitrogen heterocycles. Cycloaddition reactions of these compounds to form bridged bicyclic nitrogen heterocycles have not yet been reported.

Herein, we report the first method for silver-catalyzed formal [4π + 2σ] cycloaddition reactions of BCBs with hydrazonyl chloride-derived nitrile imines, providing a platform for the synthesis of previously inaccessible 2,3-diazo-BCHepes, which feature both sp²- and sp³-hybridized nitrogen atoms embedded in a BCHepe framework (Scheme 1C).

Results and discussion

To evaluate the feasibility of the cycloaddition reaction and to optimize the conditions, we used phenyl(3-phenylbicyclo[1.1.0]butan-1-yl)methanone (1a) and hydrazonyl chloride 2a as model substrates (Table 1). First, we screened reactions involving various metal Lewis acids (20 mol%) with K₃PO₄ as the base in dichloromethane containing 3 Å molecular sieves at room temperature under argon for 16 h (entries 1–4). To our delight, desired product 2,3-diazo-BCHepe 3a was obtained in 15% yield (as indicated by ¹H NMR spectroscopy) when AgBF₄ was the Lewis acid; the other tested acids gave lower yields. Subsequent variation of the AgBF₄ loading revealed that 100 mol% AgBF₄ gave a slightly better yield (entries 5 and 6). We also found that replacing K₃PO₄ with other bases gave lower yields (entries 7–9). Subsequent screening of various solvents for AgBF₄-catalyzed reactions revealed that dichloromethane was superior (entries 10–12). Notably, decreasing the reaction temperature to −10 °C increased the yield to 40% (entry 13). Performing the reaction with 3 equiv of 1a at −10 °C gave 3a in 65% yield (entry 14); and, notably, decreasing the reaction time to 1 h gave 3a in 64% yield (entry 15). Control experiments showed that the reaction did not occur in the absence of a Lewis acid (entry 16) and that the yield of 3a was 21% in the absence of a base (entry 17). Moreover, when the 3 Å molecular sieves were omitted, 3a was obtained in only 23% yield (entry 18). Ultimately, the optimal conditions were determined to be as follows: 1a (3.0 equiv), 2a (1.0 equiv), and AgBF₄ (100 mol%) in dichloromethane at −10 °C under argon for 1 h (entry 15). The structure of 3a was confirmed by X-ray diffraction analysis of a single crystal (Scheme 2).

Table 1 Optimization of reaction conditions^a

Entry	Lewis acid (mol%)	Base	Solvent	Yield (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), Lewis acid (20–100 mol%), base (0.15 mmol), solvent (1 mL), 3 Å molecular sieves (50 mg), Ar atmosphere, room temperature (r.t.), 16 h. Yields were determined by ^1H NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard. DCM, dichloromethane; NR, no reaction.b Reaction temperature, −10 °C.c 3 equiv of 1a.d Reaction time, 1 h.e Without 3 Å molecular sieves.
1	Sc(OTf)3 (20)	K3PO4	DCM	Trace
2	AgOTf (20)	K3PO4	DCM	12
3	Eu(OTf)3 (20)	K3PO4	DCM	NR
4	AgBF4 (20)	K3PO4	DCM	15
5	AgBF4 (50)	K3PO4	DCM	20
6	AgBF4 (100)	K3PO4	DCM	34
7	AgBF4 (100)	Na2CO3	DCM	9
8	AgBF4 (100)	K2CO3	DCM	7
9	AgBF4 (100)	Et3N	DCM	NR
10	AgBF4 (100)	K3PO4	CH3CN	NR
11	AgBF4 (100)	K3PO4	THF	NR
12	AgBF4 (100)	K3PO4	DCE	33
13^b	AgBF4 (100)	K3PO4	DCM	40
14^b^,^c	AgBF4 (100)	K3PO4	DCM	65
15^b^,^c^,^d	AgBF4 (100)	K3PO4	DCM	64
16^b^,^c^,^d	—	K3PO4	DCM	NR
17^b^,^c^,^d	AgBF4 (100)	—	DCM	21
18^b^,^c^,^d^,^e	AgBF4 (100)	K3PO4	DCM	23

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Scheme 2 Exploration of substrate scope. Reaction conditions: 1 (0.3 mmol), 2 (0.1 mmol), K₃PO₄ (0.15 mmol), AgBF₄ (0.1 mmol, 100 mol%), 3 Å molecular sieves (50 mg), DCM (1 mL), −10 °C, Ar, 1 h. For details, see the ESI†.

Using the optimized conditions, we evaluated the substrate scope with respect to the BCB (Scheme 2, top panel). Aryl BCB ketones bearing an electron-neutral, electron-donating, or electron-withdrawing substituent on the aryl ring at the bridgehead position (aryl ketone bridgehead substituent) were reactive, delivering the desired products (3a–3i) in 26–53% yields. Specifically, phenyl BCB ketones bearing a para methoxy group, fluorine or chlorine atom, or trifluoromethyl group delivered corresponding products 3b–3e in 29–53% yields. In addition, phenyl BCB ketones with a meta methoxy group or chlorine atom were also suitable substrates, affording 3f and 3g, respectively, in 35% and 26% yields. Notably, an ortho-methyl-substituted substrate afforded desired product 3h in 36% yield. Moreover, a multisubstituted phenyl BCB ketone gave 2,3-diazo-BCHepe 3i in 53% yield. In addition to phenyl BCB ketones, other aryl BCB ketones were compatible with the reaction conditions: 2,3-diazo-BCHepes with a naphthalene (3j), furan (3k), thiophene (3l and 3m), or pyridine (3n) moiety were obtained in 16–59% yields. However, a BCB ketone bearing an acyl pyrazole group failed to produce the desired product (see unsuccessful examples, 3ad), probably because the acyl pyrazole was less reactive toward cycloaddition than the ketones. Finally, substituted aryl rings at the other bridgehead position of the BCB ketone were also well tolerated. Specifically, we obtained moderate yields of 2,3-diazo-BCHepes with a para fluorine or chlorine atom on the aryl ring (3o and 3p). Notably, an ortho-methyl-substituted phenyl BCB ketone also underwent the reaction, affording 3q in 54% yield. However, meta-fluorine and ortho-methoxy-substituted phenyl BCB ketones failed to produce the desired products (see unsuccessful examples, 3ae and 3af).

Subsequently, we evaluated the substrate scope with respect to the hydrazonyl chloride by carrying out reactions with 1a (Scheme 2, bottom panel). Initially, the aryl residue bound to the carbon atom of the hydrazonyl chloride was varied. Hydrazonyl chlorides with an electron-neutral, electron-donating, or electron-withdrawing substituent at the para position of the aryl ring were reactive, delivering the desired products (3r–3u) in 30–61% yields. However, para-nitro-substituted hydrazonyl chloride failed to produce the desired products (see unsuccessful examples, 3ag). Notably, an ortho-fluorophenyl-substituted hydrazonyl chloride afforded desired product 3v in 41% yield. Moreover, a multisubstituted hydrazonyl chloride gave 2,3-diazo-BCHepe 3w in 41% yield. In addition to phenyl hydrazonyl chlorides, other aryl hydrazonyl chlorides were compatible with the reaction conditions: specifically, 2,3-diazo-BCHepes with a naphthalene (3x and 3y) or thiophene (3z) moiety were obtained in 42–54% yields. Finally, substituted aryl rings on the nitrogen atom of the hydrazonyl chloride were amenable to the reaction: we were able to obtain products bearing an electron-donating group methyl group (3aa) or methoxy group (3aa and 3ab) or an electron-withdrawing nitro group (3ac).

According to the Mykhailiuk group's strategy for designing benzene bioisosteres, the similarity between the geometric properties of bioisosteres and the substituted benzene moieties that they are modeled after is of great significance.¹⁹ To further explore the potential utility of 2,3-diazo-BCHepes as bioisosteres, we compared their geometric properties with those of structurally related pyridines (Table 2). We compared the d, r and φ exit vectors obtained from X-ray data for 3a with the corresponding vectors for tetrasubstituted pyridine 4 calculated by means of density functional theory. The vectors for 3a were indeed very close to those for 4, indicating that the 2,3-diazo-BCHepe mimicked the pyridine ring well.

Table 2 2,3-Diazo-BCHepe 3a as a promising bioisostere of tetra-substituted pyridine 4

Parameters	X-ray of 3a X^a,b distance a, b, c, d: position of carbon	Values calculated for tetra-substituted pyridine
d1	4.74^1.7 Å	4.95^1.7 Å
r1	2.12^2.6 Å, 2.29^3.5 Å	2.44^2.6 Å, 2.34^3.5 Å
d2	3.06^1.4 Å	3.06^1.4 Å
r2	1.52^2.3 Å, 1.50^5.6 Å	1.41^2.3 Å, 1.41^5.6 Å
d3	5.63^4.7 Å	5.75^4.7 Å
r3	2.65^3.6 Å, 2.69^2.5 Å	2.78^3.6 Å, 2.76^2.5 Å
φ^(8,5,3,4)	114.0°	109.0°
φ^(7,6,2,1)	121.1°	115.1°

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To demonstrate the utility of our cycloaddition method, we performed a 5 mmol-scale reaction to generate 2,3-diazo-BCHepe 3j and observed only a slight decrease in the yield (Scheme 3A). Moreover, we carried out several transformations of 3j (Scheme 3B). Specifically, selective reduction of the ketone of 3j afforded alcohol 5 in 59% yield. Additionally, reaction of 3j with allylMgBr or n-butyl lithium produced tertiary alcohol 6 or 7 in 83% and 53% yields, respectively. As shown in Scheme 3C, oxidation of 3ab and subsequent hydrolysis generated alcohol 8 in 56% yield.

Scheme 3 Gram-scale synthesis of 3j and synthetic transformations of 3j and 3ab.

Having explored the reaction's substrate scope and the utility of the products for various transformations, we conducted mechanistic studies to evaluate the validity of the proposed reaction pathway shown in Scheme 1D. When 1a was subjected to the optimized conditions in the absence of 2a, cyclobutene 9 was obtained in 34% yield (Scheme 4A), indicating that direct activation of 1a by AgBF₄ to form a cationic intermediate was feasible. On the basis of this result and literature reports,^7–11 we propose that the reaction proceeds via the mechanism shown in Scheme 4B. Initially, deprotonation of hydrazonyl chloride 2a and concomitant loss of HCl afford a 1,3-dipolar nitrile imine. Compound 1a is activated by coordination between AgBF₄ and the carbonyl group to give cationic intermediate I, which is trapped by the nitrile imine to form δ-carbanionic intermediate III via intermediate II. Subsequent transannular cyclization of III delivers 2,3-diazo-BCHepe 3a and regenerates the AgBF₄ catalyst.

Scheme 4 Control experiment and the proposed mechanism.

Conclusions

In summary, we have established a method for AgBF₄-enabled formal [4π + 2σ] cycloaddition reactions between BCBs and nitrile imines derived from hydrazonyl chlorides. This method serves as a versatile platform for de novo construction of highly sought after 2,3-diazo-BCHepes, which have both sp²- and sp³-hybridized nitrogen atoms embedded in a BCHepe framework. This method was used for cycloadditions of a wide range of disubstituted BCBs with hydrazonyl chlorides as nitrile imine precursors, affording access to 2,3-diazo-BCHepes for the first time. The synthetic value of this method was demonstrated through a gram-scale reaction and synthetic transformations of two of the products. 2,3-Diazo-BCHepes have the potential to serve as bioisosteres of both pyridazines and pyridines. With their sp³-hybridized nitrogen atoms, 2,3-diazo-BCHepes can be expected to be more water soluble, more metabolically stable, and less lipophilic than 3-aza-BCHepes. We anticipate that the method reported herein will find applications in the discovery of active pharmaceutical ingredients with nitrogen-containing bicyclic scaffolds.

Data availability

The data supporting this article have been included as part of the ESI.† Crystallographic data for 3a (CCDC 2394900) have been deposited at the Cambridge Crystallographic Data Centre.

Author contributions

J. Y. D. and D. X. conceived and directed the project. H. J. L. discovered and developed the reaction. H. J. L., X. C. Z., Q. J., Z. S. L. and F. L. performed the experiments and collected the data. All authors discussed and analyzed the data. J. Y. D. and D. X. wrote the manuscript with contribution from other authors.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was supported by the National Natural Science Foundation of China (22171174 and 22401177), the Fundamental Research Funds for the Central Universities (GK202401008), the Innovation Capability Support Program of Shaanxi (2023-CX-TD-28), the Fundamental Science Research Project of Shaanxi for Chemistry, Biology (22JHZ002), the Young Talent Fund of Association for Science and Technology in Shaanxi, China (20240606), and the Key Research and Development Program of Shaanxi (2024SF2-GJHX32).

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Footnote

† Electronic supplementary information (ESI) available: General information, experimental procedures and characterization data of the synthesized compounds. CCDC 2394900. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4sc08280j

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