Nickel-Mediated Alkyl-, Acyl-, and Sulfonylcyanation of [1.1.1]Propellane

Weizhe Dong; Sebastian Keess; Gary A Molander

doi:10.1016/j.checat.2023.100608

. Author manuscript; available in PMC: 2024 May 18.

Published in final edited form as: Chem Catal. 2023 Apr 19;3(5):100608. doi: 10.1016/j.checat.2023.100608

Nickel-Mediated Alkyl-, Acyl-, and Sulfonylcyanation of [1.1.1]Propellane

Weizhe Dong ¹, Sebastian Keess ², Gary A Molander ^1,^3,^*

PMCID: PMC10572913 NIHMSID: NIHMS1888115 PMID: 37840854

Summary:

The replacement of traditional functional groups with polycyclic scaffolds has been increasingly rewarding in medicinal chemistry programs. Over the decades, 1,₃-disubstituted bicyclo[1.1.1]pentanes (BCPs) have demonstrated the potential for being competent bioisosteres for aryl-, alkyl- and alkynyl substructures. Although highly desired, mild and versatile synthetic methods to access synthetically valuable BCP-containing building blocks remain limited. Herein, a versatile way to access bridgehead substituted BCP nitriles, a useful BCP building block, is described, enabled by the unexpected selectivity of nickel in the multi-component radical cyanation. Commodity materials including carboxylic acids, amines, sulfonyl chlorides, and alkyl chlorides are engaged to provide a broad spectrum of substituted BCP nitriles in a single-step, multi-component fashion.

Graphical abstract

graphic file with name nihms-1888115-f0001.jpg

eTOC blurb

The challenge of accessing useful building blocks for bicyclo[1.1.1]pentane has hindered its use as a promising bioisostere for para-disubstituted phenyl, alkynyl, and tert-butyl groups in drug discovery research. A simple and general method has now been developed for synthesizing versatile bicyclo[1.1.1]pentyl nitriles, allowing successful access to numerous classes of these compounds through a mild nickel/photoredox dual catalytic manifold. This is achieved due to the high selectivity of a nickel catalyst in the alkyl-, acyl-, and sulfonylcyanation of [1.1.1]propellane.

Introduction

Substitution of classic synthetic fragments with their corresponding bioisosteres has a growing impact in early discovery research.^1,2 The introduction of bicyclo[1.1.1]pentane (BCP), a bioisostere of 1,4-disubstituted phenyl-, alkyl- and alkynyl groups, has been rewarding as demonstrated by more and more recent drug discovery research.^3–13 The rigid three-dimensional core of BCP embraces the concept to “Escape from Flatland” and often leads to improvements in physiochemical properties of drug candidates, including solubility, stability and permeability.^14,15 Because BCP is not found in nature, most BCP-containing molecules are ultimately derived from the functionalization of [1.1.1]propellane. Owing to the challenges in handling the unstable and volatile [1.1.1]propellane,¹⁶ converting it to BCP-containing building blocks is generally preferable for synthetic planning. To date, BCP halides (BCP-Hal), BCP pinacol boronates (BCP-Bpin), BCP carboxylates and derivatives, and BCP-amines (BCP-NR₂) are the most used building blocks for the construction of BCP-containing molecules (Figure 1a).¹⁷ Among these, BCP carboxylates and derivatives are unique in that they possess versatile embedded reactivity that can be engaged in both ionic^16,18 and radical pathways^19–23 to access various BCP compounds, making them one of the most frequently used BCP building blocks thus far. Among the more important BCP carboxylate derivatives are BCP nitriles (BCP-CN), which can serve two roles: 1) Bioisosteres for the corresponding para-disubstituted benzonitriles (Figure 1b); and 2) Building blocks for various functional groups and heterocycles. Although BCP-CN has been frequently applied in medicinal chemistry programs as a gateway en route to useful carboxylate derivatives, ketones, aldehydes, amines, and numerous heterocycles, approaches to BCP-containing nitriles remain limited and often require multi-step synthesis,¹⁸ the use of strong organometallic reagents under harsh conditions,²⁴ or special reagents to obtain a certain class of BCP nitriles²⁵ (Figure 1b). To the best of our knowledge, a general single-step approach to BCP nitriles remains elusive. Recently, our group and others have demonstrated that many different disubstituted BCPs can be easily obtained by leveraging multi-component reactions with [1.1.1]propellane.^24,26–34 Therefore, to bridge the gap between the usefulness of BCP nitriles and the lack of accessibility, a multi-component functionalization of [1.1.1]propellane to a broad spectrum of BCP nitriles is highly desired.

Figure 1. — a. The most-used BCP building blocks. BCP carboxylates and derivatives are used most frequently in synthesis.

b. Although BCP-CN is useful in synthetic planning and can be a pharmacophore itself, the accessibility of BCP-CN is rather limited.

c. This work: Accessing BCP-CN from [1.1.1]propellane enabled by a highly selective multi-component radical cyanation mediated by the nickel catalyst. This approach is amenable to a wide range of radical precursors, permitting the installation of alkyls, carbamoyls, and sulfonyls from redox active esters (RAEs), sulfonyl chlorides, and activated alkyl chlorides. MCR = multicomponent reaction.

In the past decade, metallaphotoredox catalysis has emerged as a powerful method to enrich the cross-coupling toolbox.³⁵ The mild single-electron transfer (SET) via an excited-state photocatalyst enables the generation of a radical with intricate and sensitive functional groups. The radical thus formed then undergoes further radical transformations before ultimately being harnessed by the metal catalyst. Challenging bond formations can be achieved from the reductive elimination of the high-valent metal catalyst under mild conditions.³⁶ Based on this strategy, we sought to develop a metallaphotoredox multi-component reaction (MCR) for the cyanation of [1.1.1]propellane (Figure 1c). The reaction would proceed by reductive generation of a radical, which would then undergo a strain-release addition to the central bond of [1.1.1]propellane to form the BCP radical. Subsequently, the BCP radical would be intercepted by a metal catalyst to forge the C_(BCP)-CN bond with a cyanide source. The key challenge would be to perform a selective cyanation of the BCP radical, encompassing a broad chemical space of BCP nitriles, while avoiding the undesired two-component radical cyanation and oligomerization of [1.1.1]propellane. Cognizant of the high reactivity of the BCP radical because of the strain-induced sp² character, we rationalized that lowering the reactivity of the cyanation catalyst would enable a better tendency for the radical addition to [1.1.1]propellane instead of direct radical cyanation, and then the more reactive BCP radical could undergo cyanation competently. Herein, we describe the development of nickel-based complexes as the most suitable catalysts for this transformation, exhibiting high chemoselectivity and efficiency in the cyanation of [1.1.1]propellane.

Results and Discussion

To realize this transformation, we initially chose redox-active ester (RAE) 1 for the generation of the radical under oxidative quenching of the photocatalyst together with TMSCN 3 as the cyanide source for the functionalization of [1.1.1]propellane 2 (Table 1). Inspired by the well-known reactivity of copper complexes in radical alkyl cyanation^37–39 and the copper-catalyzed cyanoalkylation of alkenes from the groups of Mei and Han,⁴⁰ initial optimization of the reaction was conducted by evaluating various copper species as potential cross-coupling catalysts (entries 1–3). Unfortunately, screening of Cu sources as well as ligands showed that the reaction was bottlenecked by moderate yields of the MCR product 4 and poor selectivity, favoring the direct cyanation product 5. We reasoned that the facile radical capture by Cu(II) and the relatively sluggish alkyl radical addition to [1.1.1]propellane resulted in the poor chemoselectivity.⁴¹ Thus, we turned to group 10 metals as their cyanation reactivity is demonstrated to be significantly affected by the coordination of cyanides and often requires slow addition of the cyanide source or the addition of an organic base to avoid catalyst deactivation.^42,43 Although yet to be documented, we surmised that the deactivating effect of the cyanide ligand on group 10 metals could lead to a better selectivity for the cyanation with radicals of higher reactivity, e.g., the BCP radicals. Interestingly, when Pd(OAc)₂ was employed, the formation of 5 was largely suppressed (entry 4), albeit providing a low yield of 4. Fortunately, the less expensive Ni(II) catalyst showed better efficiency for the formation of 4, with excellent chemoselectivity (entry 5). Ligand screening showed that bipyridine-type ligands were the best for carrying out this reaction (entries 6–7). [Ir2] was found to be the better photocatalyst when compared with other metal- and organic-based photocatalysts (entries 8–9). Moreover, using two equivalents of [1.1.1]propellane 2 was found to be optimal (entry 10). Although higher loading of 2 led to a better yield, two equivalents gave the best balance between cost and efficiency. Lastly, control studies show that all reaction parameters, including the nickel catalyst, photocatalyst, and light, are essential for the reaction to progress (entries 11–13).

Table 1.

Optimization of Reaction Conditions


entry	PC	metal source	ligand	4 /%^a	5 /%^a
1	[Ir1]	CuCN (30 mol %)	‐	< 5	< 5
2	[Ir1]	CuCN (30 mol %)	Phen (40 mol %)	39	59
3	[Ir1]	CuCN (30 mol %)	Phen (40 mol %)	28	45
4	[Ir1]	Pd(OAc)₂ (10 mol %)	‐	< 5	0
5	[Ir1]	Ni(dme)Br₂ (20 mol %)	‐	21	< 5
6	[Ir1]	Ni(dMeObpy)Br₂ (20 mol %)	‐	51	< 5
7	[Ir1]	Ni(dtbbpy)Br₂ (20 mol %)	‐	56	< 5
8	[Ir2]	Ni(dtbbpy)Br₂ (20 mol %)	‐	62	< 5
9	4CZIPN	Ni(dtbbpy)Br₂ (20 mol %)	‐	21	< 5
10^b	[Ir2]	Ni(dtbbpy)Br₂ (20 mol %)	‐	78	< 5
11	[Ir2]	‐	‐	0	0
12	‐	Ni(dtbbpy)Br₂ (20 mol %)	‐	0	0
13^c	[Ir2]	Ni(dtbbpy)Br₂ (20 mol %)	‐	0	0

Open in a new tab

Standard condition: 1 (0.1 mmol, 1 equiv), 2 (0.15 mmol, 1.5 equiv), 3 (0.3 mmol, 3 equiv), [PC] (0.002 mmol, 2 mol %), metal and ligand as described in DMA (0.1 M) under 50 W 456 nm LED irradiation for 8 h at rt.

¹H NMR yield using 1,3,5-trimethoxybenzene as an internal standard.

The reaction was run at 0.05 M.

The reaction was run in the absence of light. PC = photocatalyst; Phen = 1,10-phenanthroline; dme = ethylene glycol dimethyl ether; dMeObpy = 4,4′ -dimethoxy-2,2′ -dipyridyl; dtbbpy = 4,4′ -di-tert-butyl-2,2′ -dipyridyl.

After demonstrating the feasibility of this process, the generality regarding the carboxylic acid-derived RAE was subsequently explored (Figure 2). Remarkably, unstabilized and stabilized primary-, secondary-, and tertiary alkyl radicals are all suitable partners in this reaction. Unstabilized primary radicals bearing various functional groups (6–8) as well as heterocycles (9) are compatible under the developed reaction conditions, albeit with a small amount of direct cyanation products formed because of the less nucleophilic character of primary radicals. Notably, 6 and 7 bearing the amino acid scaffold serve as unnatural amino acids of aspartate and glutamate. Next, secondary radicals ultimately derived from the corresponding carboxylic acids were examined. Common amine protecting groups including Boc (4) and Fmoc (11) and the commonly seen pharmacophore 2-aminopyrimidine subunit (12) were tolerated. A chloro handle on arenes can be retained for further derivatizations (13). Electron-rich pyrrolidinyl (14) as well as difluoropyrrolidinyl radicals (15) were demonstrated to be compatible in this transformation. Not only cyclic radicals, but an acyclic radical also leads smoothly to the corresponding BCP nitrile (16). Saccharides are ubiquitous and important bioactive molecules, and modifications of them are of particular interest.^44,45 Notably, a BCP furanose was accessed through the introduction of a furanosyl radical to [1.1.1]propellane (18). The generality of the cyanoalkylation was exemplified by the ability to install tertiary alkyl groups onto the bridgehead of BCPs, leading to vicinal quaternary centers. Strained tertiary alkyls are compatible as well (19–22). Hetero quaternary centers were also formed by engaging electron-rich tertiary radicals (22–26).

Figure 2. — Standard conditions: RAE (0.3 mmol, 1 equiv), 2 (0.6 mmol, 2.0 equiv), 3 (0.9 mmol, 3 equiv), [**Ir2**] (0.006 mmol, 2 mol %), Ni(dtbbpy)Br₂ (0.06 mmol, 20 mol %), DMA (6 mL, 0.05 M), 8 h irradiation with 50 W 456 nm LEDs. All yields are isolated. Substrates containing free alcohols are silylated in situ during the reaction. ^a3 equiv of 2 and 15 mol % of Ni(dtbbpy)Br₂ were used.

The robustness of the cyanation process was further exemplified by late-stage modification of natural products and pharmaceuticals. The introduction of BCP in place of an alkyl chain has been demonstrated to lead to improved performance on drug candidates.¹³ As established by 27 to 30, the feasibility of accessing the corresponding BCP nitriles from pharmaceuticals allows rapid access to bioisosteres of drugs containing alkyl carboxylates, as the cyano group can be easily converted into a carboxylic acid. Moreover, complex polycyclic scaffolds are also compatible without loss of efficiency (31–35).Having exploited the generality of carboxylic acid radical progenitors, we next wondered whether it was feasible to employ other classes of radical precursors to expand the chemical space of the transformation (Figure 3). Given the capability of generating a carbamoyl radical from a carbamoyl RAE under oxidative quenching of the photocatalyst, we surmised that this radical precursor would be compatible in the reaction for the installation of carbamoyl groups. Indeed, the carbamoyl RAE provides modular access to BCP amides, and both N-alkyl- and N-aryl carbamoyl radicals proved viable (36–40). The synthesis of the carbamoyl RAEs can be traced back to secondary amines and oxalyl chloride. The simple assembly of the carbamoyl RAEs from abundant materials allows flexible variation of amide substituents to be installed on the product. Because carbamoyl radicals were amenable in this transformation, analogous sulfonyl radicals were explored. Aryl sulfones are prominent in pharmaceuticals and agrochemicals,⁴⁶ but general approaches to their bioisosteres, specifically sulfonecontaining BCPs, are currently limited, as exemplified by the Anderson group’s recently reported elegant approach to the rapid synthesis of BCP sulfones from sulfinates.⁴⁷ The direct sulfonylation of [1.1.1]propellane offers an attractive route to the valuable BCP sulfones. The commercially available sulfonyl chlorides were examined as potential substrates to generate sulfonyl radicals, given their favorable reduction potentials. Although sulfonyl halides are prone to undergo atom transfer radical addition (ATRA) reactions to form halogenated BCPs,⁴⁷ we surmised that the stronger S(VI)-Cl bond would suppress the undesired halogen-atom abstraction to form the halogenated BCP. The process proved viable as exemplified by the success of employing aryl sulfonyl chlorides (Figure 3). Substituents possessing diverse electronic character para to the sulfonyl group proved compatible (41–44). Chloride handles on aryl- and pyridyl groups were retained and could be used for further functionalizations (45, 47). Both electron-rich and electron-poor heteroaryl-substituted sulfonyl groups proved compatible under the same reaction conditions (46, 47). Additionally, alkyl-substituted sulfonyl chlorides were also successfully employed to generate the corresponding sulfonylated BCP nitrile (48, 49). Moreover, under the same conditions, sulfamoyl radicals were generated from the corresponding sulfamoyl chlorides for the construction of BCP nitriles (50, 51).Inspired by the successful employment of sulfonyl chlorides, we then turned our attention to using abundant alkyl halides as radical precursors. It is difficult to generate electron-deficient alkyl radicals from the corresponding RAEs because of an unwanted SET event,⁴⁸ and we hoped to develop a complementary approach to generate these radicals by the incorporation of activated alkyl chlorides. Fortunately, α-chloro esters undergo reduction and subsequent coupling to propellane to deliver the corresponding BCP nitrile 52 without participating in the undesired ATRA pathway. This prompted us to explore the generality of using activated alkyl chlorides as radical sources. Intriguingly, chloro derivatives of malonate ester, amide, and sulfone, as well as secondary benzylic and estrone-bound alkyl groups participated in the transformation, providing the corresponding MCR products 53–57 in modest to good yields. Furthermore, fluoroalkylation-cyanation was also achieved using fluoroalkyl chlorides (58–61).

Figure 3. — Standard conditions: radical precursor (0.3 mmol, 1 equiv), 2 (0.6 mmol, 2.0 equiv), 3 (0.9 mmol, 3 equiv), [**Ir2**] (0.006 mmol, 2 mol %), Ni(dtbbpy)Br₂ (0.06 mmol, 20 mol %), DMA (6 mL, 0.05 M), 8 h irradiation with 50 W 456 nm LEDs. All yields are isolated. ^aThe corresponding alkyl bromide was used.

The utility of BCP nitriles in the construction of drug candidates bearing the BCP scaffold has been demonstrated in many pioneering studies.^6,18,49 Having established a versatile platform to obtain a wide diversity of BCP nitriles, the synthetic utilities of the BCP nitrile as a versatile building block was demonstrated (Figure 4a). Hydrolysis to acid 62 proceeded in high efficiency under basic conditions. Moreover, under Radziszewski amidation, 4 underwent hydration to primary amide 63 mediated by H₂O₂. Next, the addition of aryl Grignard reagent to 4 led to the formation of BCP ketone 64 after hydrolysis of the imine intermediate. Lastly, instead of hydrolyzing the imine to a ketone, an addition-reduction-acylation sequence was performed in one-pot, leading to amide 65.

Next, we turned our attention to the elucidation of the mechanism of this transformation. The radical nature of the reaction was demonstrated by (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)-trapping experiments, in which no desired product was observed, but the TEMPO-radical adduct was formed (See SI section 6.1 for details). Also, the radical nature of the reaction was confirmed by the radical derived from citronellic acid RAE undergoing 5-exo-trig cyclization to 66 with a minor amount of 67 (Figure 4b). Cyclic voltammetry (CV) studies revealed that the redox potentials of the radical precursors span through a wide range (Figure 4c) (See SI section 6.3 for details). This raised a question as to how radicals were generated as the excited-state of [Ir2] (E_1/2^ox[Ir^IV/*Ir^III] = −0.89 V in MeCN)⁵⁰ is thermodynamically unfavorable to reduce these radical precursors directly. We then reasoned that the reductive generation of radicals could be meditated by Ni(I).^51–53 Although Ni(dtbbpy)Br₂ is also challenging to reduce by the excited-state [Ir2] (See Figure S8 for details), we found that mixing Ni(dtbbpy)Br₂ and TMSCN led to multiple new irreversible reductions, which we tentatively assigned to the reductions of different cyanide-coordinated Ni(II) species. Notably, one of the newly formed irreversible reductions is at −1.0 V, suggesting that a Ni(II)CN species could be reduced by the excited state of [Ir2]. To support this hypothesis, fluorescence quenching was measured with all radical precursors as well as the Ni(dtbbpy)Br₂ and TMSCN mixture (Figure 4d). In this experiment, a mixture of Ni(dtbbpy)Br₂ and TMSCN showed significant quenching of [Ir2], further supporting the feasibility of SET between [Ir2] and the Ni(II)CN species. Furthermore, an attempt to use Ni(COD)₂ to reduce 1 was unsuccessful, ruling out the involvement of Ni(0) in radical generation (See SI section 6.6 for details). Additionally, the evaluation of cyanide sources revealed that the reaction is highly dependent on the reactivity of cyanide sources (Figure 4e), and either strongly cyanidedonating reagents such as NaCN or weakly cyanide-donating reagent such as CuCN are detrimental to the reaction. Based on the strongly deactivating effect of the cyanide anion to Ni(II) and the fact that using Ni(CN)₂ as both catalyst and cyanide source did not lead to any product formation or cyanation event, we tentatively assign the cyanide coordination number on Ni(II) to be one for the on-cycle Ni(II). Lastly, the nickel-mediated cyanation was reported to proceed by a chain mechanism, which can be initiated by a catalytic amount of Zn(0).⁵⁴ Investigation of the nature of this reaction by carrying it out using a catalytic amount of Zn(0) in the absence of photocatalyst and light showed no consumption of the starting material (See SI section 6.6 for details). Also, the quantum yield Φ of the reaction is measured to be 0.11. Both experiments suggest the reaction is unlikely to proceed by a radical-chain mechanism, ruling out the existence of a Ni(I)/Ni(III) dark cycle.

Based on the evidence in hand, a proposed dual photoredox/nickel-catalyzed process is outlined (Figure 4f). Initially, blue LED excitation of the photocatalyst [Ir2] generates a strong reductant in its long-lived excited state. Ni(II)CN 68 is then reduced by the excited-state of [Ir2] via SET to generate Ni(I)CN 69. The Ni(I)CN complex reduces the radical precursor (1 in this example) through either an inner sphere or outer sphere mechanism, which explains the broad applicability of radical progenitors in this transformation. The reduction of 1 leads to generation of the corresponding radical, which performs a strain-release addition onto the inverted σ-bond of [1.1.1]propellane. The sp²-like BCP radical formed after the addition event is highly reactive, and is intercepted by the Ni(II) complex 68 to generate the Ni(III) species 70. Next, the facile reductive elimination of 70 forges the C_(BCP)-CN bond to deliver the BCP-CN 4. Finally, the dual catalytic cycles are closed by regenerating the ground state [Ir2] by oxidizing Ni(I) 71 to Ni(II) 72. TMSCN is then capable of transferring another cyanide moiety onto 72 to regenerate 68.

Conclusion

In summary, a modular synthesis of BCP nitriles by nickel-mediated cyanation of [1.1.1]propellane has been developed. The multi-component reaction was achieved by taking advantage of the deactivating effect of the cyanide ligand on the nickel catalyst, enabling the selective radical addition to [1.1.1]propellane to generate the sp²-like BCP radicals with subsequent cyanation of the more reactive BCP radicals. Remarkably, a broad spectrum of radical progenitors are compatible in this transformation, enabling commonly sought-after functional groups to be installed on BCP nitriles. Rapid access to BCP nitriles from [1.1.1]propellane will allow the facile development of BCP libraries to support applications in drug discovery.

Supplementary Material

NIHMS1888115-supplement-1.pdf^{(264.3KB, pdf)}

NIHMS1888115-supplement-2.pdf^{(17.9MB, pdf)}

The Bigger Picture.

The ever-increasing interest in “Escape from Flatland” has prompted people to seek bioisosteres to replace the ubiquitous phenyl rings in pharmaceuticals. Bicyclo[1.1.1]pentane (BCP), a rigid three-dimensional core, has stood out as a promising candidate. However, limited availability of BCP building blocks and lengthy synthetic routes required to incorporate BCP are hampering early discovery efforts. In this study, we developed a multi-component approach to synthesizing a wide variety of BCP nitriles from the most accessible BCP precursor, [1.1.1]propellane, enabled by nickel/photoredox dual catalysis. Due to the superior selectivity of the nickel catalyst in radical cyanation, alkyl-, acyl-, and sulfonylcyanation were successfully performed on [1.1.1]propellane using commercially available materials. We believe that the broad scope of this transformation, together with the synthetically versatile cyano handle, could facilitate the involvement of BCP in drug discovery research.

Highlights.

A general single-step protocol to various substituted bicyclo[1.1.1]pentyl nitriles.
Radicals of disparate steric and electronic characters can be engaged.
Widely available starting materials are used to ensure broad applicability.
Excellent selectivity of the nickel catalyst enables selective cyanation of BCP radicals.

ACKNOWLEDGMENTS

The authors thank financial support provided by NIGMS (R35 GM 131680 to G.M.). Financial support for this research was provided in part by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. The NSF Major Research Instrumentation Program (award NSF CHE-1827457), the NIH supplements awards 3R01GM118510-03S1 and 3R01GM087605-06S1, as well as the Vagelos Institute for Energy Science and Technology supported the purchase of the NMRs used in this study. We thank Dr. Charles W. Ross, III (UPenn) for mass spectral data.

SUPPORTING INFORMATION

A general procedure for the preparation of starting materials as well as the protocol for the cyanation is described. Derivatization reaction details, mechanistic studies, and full characterization (including NMR spectra) of all materials prepared is also included.

Footnotes

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DECLARATION OF INTERESTS

The authors declare no competing interests.

Materials availability

This study did not involve the design of unique reagents or catalysts for chemical synthesis.

General procedure for the synthesis of BCP nitriles

To an 8 mL reaction vial equipped with a stirrer bar was added [Ir(dF(CF₃)₂ppy)₂(dtbbpy)]PF₆ (6.1 mg, 0.006 mmol, 2 mol %), Ni(dtbbpy)Br₂ (29.2 mg, 0.06 mmol, 20 mol %), and the radical precursor (0.3 mmol, 1 equiv). The reaction vessel was sealed with a cap containing a TFE-lined silicone septum and then was evacuated and backfilled with argon three times. When done, dry degassed DMA (6 mL, 0.05 M) was added. Next, TMSCN (89.3 mg, 0.9 mmol, 3 equiv) was added, and the color of the reaction mixture turned from green to yellow upon mixing. Subsequently, [1.1.1]propellane (0.6 mmol, 2 equiv, 0.6 – 1.0 M solution in Et₂O) was then added, and the vial was quickly sealed with Parafilm^®. The reaction mixture was then irradiated under vigorous stirring at 50 W 456 nm using a Kessil^® lamp at 1 inch distance for 8 h. Room temperature was maintained using a fan. When judged complete as indicated by the color change of the reaction mixture to dark orange, the mixture was then partitioned between EtOAc (10 mL) and satd aq NH₄Cl (10 mL). The aqueous layer was extracted two more times with EtOAc (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried (MgSO₄), filtered, and further dried under vacuum. The crude mixture was then purified by SiO₂ flash column chromatography.

Data and code availability

There is no dataset or code associated with this publication. All relevant procedures and experimental data are provided in the supplemental information.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

NIHMS1888115-supplement-1.pdf^{(264.3KB, pdf)}

NIHMS1888115-supplement-2.pdf^{(17.9MB, pdf)}

Data Availability Statement

There is no dataset or code associated with this publication. All relevant procedures and experimental data are provided in the supplemental information.

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[R15] 15.Lovering F (2013). Escape from flatland 2: complexity and promiscuity. Med. Chem. Commun 4, 515–519. 10.1039/C2MD20347B. [DOI] [Google Scholar]

[R16] 16.Ripenko V, Vysochyn D, Klymov I, Zhersh S, and Mykhailiuk PK (2021). Large-Scale Synthesis and Modifications of Bicyclo[1.1.1]pentane-1,3-dicarboxylic Acid (BCP). J. Org. Chem 86, 14061–14068. 10.1021/acs.joc.1c00977. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[R18] 18.Della EW, and Taylor DK (1994). Synthesis of Some Bridgehead-Bridgehead-Disubstituted Bicyclo[1.1.1]pentanes. J. Org. Chem 59, 2986–2996. 10.1021/jo00090a015. [DOI] [Google Scholar]

[R19] 19.Polites VC, Badir SO, Keess S, Jolit A, and Molander GA (2021). Nickel-catalyzed decarboxylative cross-coupling of bicyclo[1.1.1]pentyl radicals enabled by electron donor–acceptor complex photoactivation. Org. Lett 23, 4828–4833. 10.1021/acs.orglett.1c01558. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[R22] 22.Palkowitz MD, Laudadio G, Kolb S, Choi J, Oderinde MS, Ewing TE-H, Bolduc PN, Chen T, Zhang H, Cheng PTW, Zhang B, Mandler MD, Blasczak VD, Richter JM, Collins MR, Schioldager RL, Bravo M, Dhar TGM, Vokits B, Zhu Y, Echeverria P-G, Poss MA, Shaw SA, Clementson S, Petersen NN, Mykhailiuk PK, and Baran PS (2022). Overcoming Limitations in Decarboxylative Arylation via Ag–Ni Electrocatalysis. J. Am. Chem. Soc 144, 17709–17720. 10.1021/jacs.2c08006. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[R25] 25.Wu Z, Xu Y, Zhang H, Wu X, and Zhu C (2021). Radical-mediated sulfonyl alkynylation, allylation, and cyanation of propellane. Chem. Commun 57, 6066–6069. 10.1039/D1CC02249K. [DOI] [PubMed] [Google Scholar]

[R26] 26.Kondo M, Kanazawa J, Ichikawa T, Shimokawa T, Nagashima Y, Miyamoto K, and Uchiyama M (2020). Silaboration of [1.1.1]propellane: a storable feedstock for bicyclo[1.1.1]pentane derivatives. Angew. Chem. Int. Ed 59, 1970–1974. 10.1002/anie.201909655. [DOI] [PubMed] [Google Scholar]

[R27] 27.Makarov IS, Brocklehurst CE, Karaghiosoff K, Koch G, and Knochel P (2017). Synthesis of Bicyclo[1.1.1]pentane Bioisosteres of Internal Alkynes and para-Disubstituted Benzenes from [1.1.1]Propellane. Angew. Chem. Int. Ed 56, 12774–12777. 10.1002/anie.201706799. [DOI] [PubMed] [Google Scholar]

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PERMALINK

Nickel-Mediated Alkyl-, Acyl-, and Sulfonylcyanation of [1.1.1]Propellane

Weizhe Dong

Sebastian Keess

Gary A Molander

Summary:

Graphical abstract

eTOC blurb

Introduction

Figure 1. Nickel-Mediated Radical Cyanation of [1.1.1]Propellane.