Recent Advances in Diazophosphonate Chemistry: Reactions and Transformations

Abstract

Diazophosphonates function as indispensable synthetic intermediates within the domain of organic chemistry, serving as precursors for a diverse range of molecules, with potential applications as bioactive compounds. α-Diazomethylphosphonates showcase expansive reactivity and elevated levels of enantioselectivity in asymmetric transformations, especially in conjunction with suitable catalyst systems. This review compiles the latest advancements in diazophosphonate chemistry from 2016 to 2024, highlighting their reactivity and transformative potential in organic synthesis. Diazophosphonates, regarded as revolutionary compounds, exhibit unique attributes as carbene precursors, driving diverse chemical reactions such as [3+2] cycloaddition, asymmetric [3+2] cycloaddition, asymmetric [3+3] cycloaddition, and asymmetric substitution reactions. Their adaptability in functional group conversions underscores their pivotal role in various synthetic methodologies. The review highlights the growing interest in diazophosphonate reactions among synthetic chemists, fostering novel synthetic strategies and expanding their application horizons. The multifaceted utility of diazophosphonates as reagents, synthetic intermediates, precursors, and catalysts underscores their significance in modern organic chemistry and pharmaceutical applications, prompting further exploration into this dynamic field.

1 Introduction

2 [3+2] Cycloaddition Reactions

3 Asymmetric [3+2] Cycloaddition Reactions

4 Asymmetric [3+3] Cycloaddition Reactions

5 Asymmetric Substitution Reactions

6 Diazophosphonates as Carbene Precursors

7 Diazophosphonates in the Chemistry of Fluorinated Compounds

8 Other Reactions

9 Future Directions

10 Conclusion

Key words

diazophosphonates - carbene precursors - synthetic intermediates - functional group conversion - cycloaddition reactions - enantioselectivity - bioactive compounds - asymmetric transformations

Biographical Sketches

Saif Ullah received his Bachelor’s degree in organic chemistry from Abdul Wali Khan University Mardan, Pakistan, in 2022. He is currently pursuing a Master’s degree at the School of Chemistry and Chemical Engineering, Southwest University in China, under the supervision of Prof. Dr. Yungui Peng. Saif’s research interests focus on asymmetric synthesis, asymmetric catalysis, and organocatalysis.

Zulfiqar Hussain completed his Bachelor’s degree in chemistry in 2018–2022 at the Abdul Wali Khan University Mardan, Pakistan. He is pursuing his Master’s degree in chemistry at the School of Chemistry and Chemical Engineering, Beijing Institute of Technology, China. His research interests include organic synthesis of functional materials, chemistry of heterocyclic compounds, and transition-metal-catalyzed organic reactions.

Dr. Yungui Peng received his BSc from the Southwest Normal University in 1991, his MSc from Beijing Normal University in 1997 with Prof. Baoshan Du, and his PhD from Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences with Prof. Xiaoming Feng and Yaozhong Jiang in 2000. He worked as a research assistant at Hong Kong University with Prof. Tao Ye in 2001. In 2002, he joined the School of Chemistry and Chemical Engineering, Southwest University as an associate professor, and is now a professor. His research interests include asymmetric catalysis and electrocatalytic synthesis. He has supervised over 60 graduate students and published over 70 papers.

1

Introduction

Diazo compounds exhibit substantial synthetic potential, attributable to their heightened reactivity and wide-ranging applicability.[1] They serve as adaptable components in numerous reactions, facilitating diverse functional group conversions.[2] Extensive scrutiny of diazo compound chemistry over the past decades has yielded a plethora of practical reactions, encompassing C–H and heteroatom–H insertion, cyclopropanation, addition, polymerization, and nucleophilic­ olefination, among others.[3] Noteworthy applications include their role as metal–carbene precursors, α-carbon nucleophiles, and terminal nitrogen electrophiles in asymmetric catalytic transformations and cycloaddition reactions.[2] ^, [4] [5] [6] [7] Nitrogen-containing heterocycles are ubiquitous in natural products, various biologically active compounds, and pharmaceutical agents. Incorporation of phosphonates can markedly augment the bioactivities and catalytic properties of these compounds.[8,9] Phosphonates, found in biological and natural products, exhibit antifungal, antibacterial, and antimicrobial properties, and their utility as haptens, catalytic antibodies, enzyme inhibitors, and peptide mimetics underscores their significance in medicinal chemistry. Additionally, phosphonates find diverse applications as herbicides or fungicides.[10] [11] [12] [13]

Diazophosphonates (Figure [1]), characterized by the presence of a λ⁵-phosphorus functionality at the α-position relative to the diazo moiety, serve as versatile reagents in organic chemistry.[14] [15] They can be readily synthesized from easily accessible precursors by utilizing various methods, such as diazotization, Bamford–Stevens-type elimination, and diazo-transfer processes.[16] [17] Strategies for their synthesis include reactions of phosphate esters with N-nitrosoimines, by employing diazo transfer reagents such as tosyl azide or sulfonyl azides, as well as reactions of phosphonate esters with nitrosyl chloride or nitrosyl bromide and diazo compounds in the presence of a transition metal catalyst such as copper or rhodium.[18] [19] Seyferth et al. reported a facile synthesis of dimethylphosphono-substituted diazoalkanes, which react with olefins to yield dimethylphosphono-substituted pyrazolines.[20] [21] [22] Diazophosphonates serve as crucial synthetic intermediates in organic chemistry, acting as precursors for the synthesis of β-amino phosphonates, functional isochromenes, and pyridazine-4-one, with potential applications as enzyme inhibitors and pharmaceuticals.[23] [24] Their transformation into various chiral β-amino phosphoric acid derivatives is of interest for the synthesis of inhibitors of human renin, calpain I, and anti-HIV agents. Racemic phosphonylpyrazoline intermediates in diazophosphonate synthesis can be obtained via 1,3-dipolar cycloaddition reactions of olefinic dipolarophiles with the Bestmann–Ohira reagent (BOR) or Seyferth–Gilbert reagent (SGR) analogue.[25] [26] These phosphonylpyrazolines can then be converted into diazophosphonates in situ under basic reaction conditions.[25] [27] [28]

Figure 1 Structures of some common diazophosphonates

Diazophosphonates find utility in catalyzing asymmetric Mannich reactions with imines, yielding chiral β-amino-α-diazophosphonates and their derivatives, which can further be transformed into β-amino acids, β-amino-α-hydroxy acids, and other common synthetic intermediates, enhancing their versatility in organic synthesis.[29] [30] α-Diazomethylphosphonates demonstrate broad reactivity and high enantioselectivities in asymmetric reactions, particularly when coupled with appropriate catalysts.[30] The use of diazophosphonates as nucleophiles in asymmetric reactions, such as the asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates, presents a significant challenge, yet offers potential for synthesizing chiral diazo-γ-methylenephosphonate derivatives.[31,32] Due to their diverse range of biological activities and applications (Figure [2]), diazophosphonates garner significant interest among researchers.[33] [34] The development of efficient catalysts for the asymmetric addition of α-diazomethylphosphonates expands the synthetic toolbox of organic synthesis, offering new avenues for synthesizing chiral phosphonate-containing compounds.[30] [35]

Given the importance of these compounds, this review aims to collate recent research on reactions and transformations spanning the period of 2016–2024.

2

[3+2] Cycloaddition Reactions

2.1

[3+2] Cycloaddition Reaction of α-Diazoalkylphosphonates for Indazole Synthesis

The 1,3-dipolar cycloaddition between arynes and dipoles represents an exceptionally effective route for constructing indole frameworks, notably focusing on the production of 1H-indazoles, which represent the most thermodynamically favored isomer.[36] [37] Nevertheless, prevalent methodologies primarily afford 3-aryl-1H-indazoles, while the synthesis of 3-alkyl-substituted indazoles encounters constraints related to harsh reaction conditions or specialized substrates.[38,39] In contrast, the exploration of 3H-indazole formation has been comparatively limited due to its inherent tendency to undergo tautomerization to the more thermodynamically stable 1H-isomer and subsequent retro-cycloaddition, leading to nitrogen expulsion.[40] [41] The 1,3-dipolar cyclization of disubstituted diazo compounds with arynes yields 3H-indazoles in moderate yields, albeit with limited substrate applicability. Therefore, there is a critical need for a proficient and adaptable synthetic strategy to enable the synthesis of both 3H-indazoles and 3-alkyl-1H-indazoles.[42] [43]

Figure 2 Diazophosphonates in bioactive compounds

Scheme 1 (a) 1,3-Dipolar cycloaddition of α-diazoalkylphosphonates 1 with arynes and (b) proposed mechanism

Our group has presented a novel method for synthesizing 3-substituted 3H-indole-3-phosphonates, revealing that α-diazoalkylphosphonates 1 engage in 1,3-dipolar cycloaddition with arynes 2a under mild conditions, yielding 3-alkyl/aryl-1H-indazoles 4 and 3-alkyl/aryl-3H-indazole-3-phosphonates 3 (Scheme [1a]).[44] This process involves the generation of a reactive 1,3-dipole intermediate, which subsequently undergoes cycloaddition with the aryne, affording the desired 3-alkyl/aryl-1H-indazole product. The phosphoryl moiety attached to the α-diazoalkylphosphonate acts as a modulating and masking group, dictating product distribution and reaction selectivity. Significant enhancements in the production of 1H-indazoles are attained through the utilization of dimethyl α-diazoalkylphosphonates, while an effective strategy for the synthesis of 3,3-disubstituted 3H-indazole-3-phosphonates is realized employing diisopropyl α-diazoalkylphosphonates (Scheme [1b]).[44] The incorporation of indazole and phosphoryl frameworks within the synthesized compounds demonstrates considerable potential in the realm of medicinal chemistry, with the phosphoryl moiety exhibiting dual functionalities as both a tuning and traceless entity. Considering the wide ranging biological activities associated with indazoles and phosphonates, this pioneering approach exhibits substantial promise for further exploitation within the pharmaceutical sector.[44] [45] [46]

2.2

1,3-Dipolar Cycloaddition of Diazophosphonates to Alkynes for N-H-Pyrazole Synthesis

Pyrazoles, crucial nitrogen-containing heterocyclic compounds, hold substantial academic, industrial, and commercial significance.[22] [47] [48] Current research emphasizes diverse synthetic methods, such as the 1,3-dipolar cycloaddition involving diazo compounds and alkynes, a process first explored by Buchner in 1889.[49,50] While azide–alkyne click chemistry is a well-known example of bioorthogonal cycloadditions, diazo compounds demonstrate comparable efficiency, at times with superior reaction rates.[51–53]

Diazophosphonates 1b, derived from ketophosphonates 6 through hydrazone oxidation (Scheme [2a]), exhibit a distinctive capacity to engage in 1,3-dipolar cycloaddition reactions with alkynes 8, facilitating the synthesis of N-H-pyrazoles 11.[23] [54] Their phosphoryl group endows advantageous characteristics, stabilizing the diazo compound for easier handling. A [1,5] sigmatropic rearrangement of the phosphoryl group during cycloaddition facilitates aromatization and subsequent removal, streamlining the synthesis. With alkynes bearing electron-withdrawing groups, these reactions exhibit enhanced reactivity and regiospecificity (Scheme [2b]). Diazophosphonates, serving as diazoalkane surrogates, offer safer and more stable alternatives, ensuring efficient pyrazole synthesis. Their facile addition to strained alkynes 12 suggests applicability in bioorthogonal reactions, broadening the chemical toolbox for biological applications (Scheme [2c,d]).[23]

2.3

Fluoroalkylphosphonate–Diazo [3+2] Cycloaddition: Synthesis of Pyrazolines

Fluoroalkyl-substituted diazo compounds have become increasingly prominent in organic synthesis since the discovery of 2,2,2-trifluorodiazoethane in 1943.[35] [55] Difluoro-substituted diazoalkanes, which play a pivotal role in the construction of complex molecules containing a CHF₂ group, possess a wide range of applications as masked carbenes, C-nucleophiles, and 1,3-dipoles in [3+2] cycloaddition reactions.[56] [57] Particularly noteworthy is the direct [3+2] cycloaddition with vinyl sulfones, resulting in the formation of biologically active fluoroalkyl- and sulfonyl-substituted pyrazoline derivatives.[53] [58] [59] This reaction, exemplified by Koenigs and Jamison under continuous flow conditions,[56] demonstrates exceptional yields. Additionally, the Mykhailiuk group introduced a streamlined one-pot reaction approach, broadening synthetic horizons.[59] Investigations into difluoromethyldiazomethanes and stable analogues, such as phenylsulfone difluorodiazoethane, have led to the exploration of difluoromethyl-substituted compound synthesis.

Scheme 2 (a) Preparation of diazophosphonates 1b by oxidation of hydrazones; (b) use of diazophosphonate 1b in the synthesis of pyrazole 11; (c) addition of diazophosphonates 1b to strained bicyclo[6.1.0]nonynes 12, and (d) intramolecular cycloaddition of diazo compounds to alkynes

An efficient 1,3-dipolar [3+2] cycloaddition reaction between difluoromethylphosphonate-containing diazoalkanes and vinyl sulfones has been devised, yielding difluoromethylphosphonate-containing sulfonyl pyrazolines 18 and derivatives in satisfactory yields (Scheme [3]).[58] The in situ generation of diazoalkanes using t-BuONO for the diazotization of (β-amino-α,α-difluoroethyl) phosphonates 16 facilitated comprehensive evaluations of their stabilities and reactivities. The stability of newly designed difluoro diazoalkenes is pivotal for advancing the chemistry of fluoro diazoalkanes. The successful upscaling of the 1,3-dipolar cycloaddition reaction between diethyl (2-amino-1,1-difluoro-2-phenylmethyl)phosphonate 16 and (vinylsulfonyl)benzene 17 underscores the efficacy of the proposed strategy for large-scale target compound synthesis.[58]

Scheme 3 [3+2] Cycloaddition reaction of 2-diazo-1,1-difluoroethylphosphonate 1c with vinyl sulfones 17

2.4

Diazophosphonates in Difluoro(phosphoryl)methyl-Substituted Pyrazoline Synthesis

The integration of difluoromethylenephosphonate (DFMP) moieties into heterocyclic frameworks, such as guanine and uridine, has been shown to enhance their biological properties.[22] [60] [61] Pyrazolines, an important category of nitrogen-containing heterocyclic compounds abundant in natural sources, exhibit a wide array of biological activities.[22,35,62] Notably, pyrazolinecarboxylates have demonstrated selective inhibitory activity against monoamine oxidase-B, underscoring the significance of synthesizing potentially bioactive DFMP-incorporated pyrazoline carboxylates.[23,63] Fluorinated diazoalkanes, notably trifluorodiazoethane and difluorodiazoethane, are indispensable building blocks in organic synthesis, facilitating the introduction of fluoroalkyl functionalities into diverse organic molecules.[64] Despite recent progress in difluorodiazoethane transformations, their utilization in the synthesis of DFMP-containing pyrazoline carboxylates remains largely unexplored.[57] Prior research by Yokomatsu et al. involved the use of diazomethane in 1,3-dipolar cycloaddition reactions with (1,1-difluoroallyl)phosphonates for the synthesis of DFMP-containing pyrazoline esters; however, this approach relied on highly reactive diazomethane and had limited exemplifications.[65] Consequently, there is a pressing need to explore alternative methodologies for the synthesis of DFMP-containing pyrazoline carboxylates.[66]

The Han research team has made significant strides in advancing the scientific domain by unveiling a novel [3+2] cycloaddition process, incorporating (β-diazo-α,α-difluoroethyl)phosphonates 1c and highly reactive vinyl sulfones, resulting in the synthesis of pyrazolines enriched with difluoromethylenephosphonate (DFMP) motifs 18 (Scheme [3]).[67] On the basis of this groundbreaking achievement, an expansion of the application of (β-diazo-α,α-difluoroethyl)phosphonates in cycloaddition reactions with less reactive α,β-unsaturated esters was proposed. This strategic maneuver is envisaged as an efficient route to the production of DFMP-containing pyrazoline carboxylates. Through [3+2] dipolar cycloaddition between the in situ generated (β-diazo-α,α-difluoroethyl)phosphonates 1c and α,β-unsaturated esters 19, pyrazolines featuring difluoromethylenephosphonate moieties 20 are formed (Scheme [4]).[67] The reaction showcases a broad substrate scope, as evidenced by the successful participation of various (β-amino-α,α-difluoroethyl)phosphonates bearing electron-donating and halogen groups in the cycloaddition process. The practical applicability of this methodology was further demonstrated through the successful large-scale synthesis of the desired products.[67]

Scheme 4 [3+2] Dipolar cycloaddition reaction of in situ generated β-diazo-α,α-difluoroethylphosphonates 1c

2.5

Base-Catalyzed Synthesis of Functionalized Pyrazole-Chalcones through Diazophosphonates

The pyrazole scaffold possesses significant medicinal properties, including anticancer, antiviral, and antibacterial activities, among others.[23] [68] [69] It is found in natural products, synthetic drugs, pesticides, and herbicides.[70] Pyrazole-derived ligands are utilized in catalysis, metal extraction, and photochemistry due to their versatile coordination chemistry and photophysical properties.[53,71] Pyrazoles are commonly synthesized through condensation reactions or 1,3-dipolar cycloadditions involving diazo compounds. Various dipolarophiles have been employed in these cycloadditions, leading to pyrazoles with diverse substituents and fused structures.[23] [54] While pyrylium salts have numerous applications, their reactions with diazo compounds to produce functionalized pyrazoles have not been explored extensively.[22]

However, recent studies have shown that such reactions can yield diazomethylpyrans and 1H-1,2-diazepines, depending on the specific pyrylium salt used. In this base-catalyzed process, α-diazophosphonates 1d, sulfones, trifluoromethyl compounds, and triaryl/alkyl pyrylium tetrafluoroborate salts 21 are integral components, leading to the formation of functionalized pyrazole-chalcones 22 (Scheme [5a]).[22] These compounds exhibit a mixture of tautomeric configurations 22a and 22b. The mechanistic sequence initiates with the nucleophilic addition of diazo substrates to pyrylium salts, followed by pyrylium ring-opening and intramolecular 1,5-cyclization mediated by bases. The reaction culminates in the generation of 1,3-dipolar cycloaddition product 22, which can be transformed into 23 (Scheme [5b]). By blocking the production of diazo dianion, the base DBU encourages the attack on the 2- and 4-positions of the pyrylium salt to produce 2-(diazomethyl)pyran and 4-(diazomethyl)pyran. The pyrazole intermediate is formed via 1,5-cyclization, base-mediated deprotonation, and C–O bond breakage of the intermediate 2-(diazomethyl)pyran. Following a 1,3-proton shift, 1,3-dipolar cycloadducts are formed, which are a combination of tautomeric forms 22a and 22b (Scheme [5c]).[22]

Scheme 5 (a) Cycloaddition reaction between pyrylium salt 21 and diazophosphonate 1d; (b) conversion of chalcone-pyrazoles 22 into indenylpyrazoles 23; and (c) proposed reaction mechanism

2.6

(Diazomethyl)dimethylphosphine Oxide Synthesis through Diazotization

Grygorenko and co-workers developed a protocol for generating (diazomethyl)dimethylphosphine oxide, a novel diazoalkane reagent, through diazotization under anhydrous conditions.[72] The compound may be prepared as a stable 1.5 M solution in chloroform, which can then be kept cold at –18 °C. This research determined that (diazomethyl)dimethylphosphine oxide 25 exhibited significant reactivity in [3+2] cycloaddition reactions with various dipolarophiles, particularly electron-deficient alkynes 26 and alkenes 28 (Scheme [6]). The addition of methyl propiolate to the solution of the compound led to the formation of the desired pyrazole 27 in a 64% yield. These experimental conditions were further applied to a series of alkynes and alkenes, where mono- and disubstituted alkynes containing at least one strong electron-withdrawing group produced yields ranging from 55% to 75%. Conversely, sterically hindered alkynes demonstrated less than 2% conversion, and phenylacetylene lacking a strong electron-withdrawing group did not yield any target products. Additionally, it was found that alkenes did not react with diazoalkane at either room temperature or 65 °C, instead producing complex mixtures of products at room temperature. The [3+2] cycloaddition was observed to be regiospecific, exclusively yielding 3,5-disubstituted pyrazole/pyrazoline derivatives (Scheme [6]).[72]

Scheme 6 (a) [3+2] Cycloaddition of diazoalkane 25 with alkynes 26 and (b) [3+2] cycloaddition of diazoalkane 25 with alkenes 28

Future research could focus on expanding the scope of applications for (diazomethyl)dimethylphosphine oxide in early drug discovery projects and exploring its potential in various other chemical transformations typical of diazoalkanes. Investigating its reactivity with a wider range of substrates, including different electron-poor alkynes and alkenes, could provide valuable insights into its versatility and potential utility in organic synthesis. The compound’s utility in medicinal chemistry is highlighted, showing its importance in expanding the scope of phosphine oxide reagents.[72]

3

Asymmetric [3+2] Cycloaddition Reactions

3.1

Enantioselective 1,3-Dipolar Cycloaddition of Diazophosphonates for Chiral Phosphonylpyrazoline Synthesis

The synthesis of chiral phosphonylpyrazolines holds significant biological importance, yet methods for their development remain scarce.[22] [23] [73] The unexplored domain of catalytic asymmetric 1,3-dipolar cycloaddition reactions employing the Seyferth–Gilbert reagent (SGR) as a surrogate for diazoacetate in chiral phosphonylpyrazoline synthesis has yet to be explored. The endeavor to formulate a catalytic framework capable of directing enantioselective SGR cycloadditions for the synthesis of various chiral phosphonylpyrazolines remains a challenging and compelling pursuit in the domain of synthetic chemistry.[53] The potential amalgamation of chiral spirocyclic oxindoles with pyrazoline-bearing phosphonate groups offers a promising avenue for further investigation.[74–76]

Our group proposed a catalytic enantioselective Seyferth–Gilbert reagent (SGR) 1d cycloaddition to isatylidene malononitriles 30 utilizing a derivative of cinchona alkaloid as a catalyst, resulting in the formation of chiral spiro-phosphonylpyrazoline-oxindoles 32 with notable yields and exceptional enantioselectivities (Scheme [7]).[25] The adaptability of this approach is exemplified through its utilization in a three-component domino reaction involving isatin, malononitrile, and SGR, which involves sequential Knoevenagel condensation and 1,3-dipolar cycloaddition reactions.

Scheme 7 (a) 1,3-Dipolar cycloaddition reaction between the SGR 1d and isatylidene malononitrile 30 and (b) its proposed mechanism

3.2

Asymmetric [3+2] Cycloaddition Reactions of α-Substituted Diazophosphonates to Access Chiral Pyrazolines

Over the past two decades, successful asymmetric [3+2] cycloaddition methods between diazo substrates and different olefins have been established.[23] [77] While studies using α-substituted diazoacetates have shown only uneven results, the diazo substrates primarily used in these techniques are α-unsubstituted diazoacetates, which yield the appropriate chiral pyrazoline.[23,78] For example, only 15% yield and considerable enantioselectivity (70% ee) were found when α-phenyl-modified diazoacetates were utilized as the 1,3-dipole.[79] By using the Bestmann–Ohira reagent (BOR) in 1,3-dipolar cycloaddition processes of olefinic dipolarophiles, racemic phosphonylpyrazolines have been effectively synthesized. The 1,3-dipolar substrates were restricted to diazophosphonates that were not substituted at the α-position, and they provided chiral pyrazolines in cases where the phosphonyl group was not next to the chiral center.[80] [81]

Our team developed an asymmetric 1,3-dipolar cycloaddition using 3-acryloyl-2-oxazolidinone 35 and α-substituted diazophosphonates 1e to get chiral phosphonylpyrazoline 37, where the phosphonyl group and chiral center are next to each other (Scheme [8]).[53] Subsequent research revealed that magnesium bis(trifluoromethanesulfonyl)amide, Mg(NTf₂)₂ with bis(oxazolines) 36 might catalyze the process as a chiral Lewis acid (Scheme [8a,b]). To expand the utility of diazophosphonates in organic synthesis and procure a diverse array of phosphonate pyrazolidine compounds for biological applications, the readily available chiral 5,5-disubstituted 1H-pyrazoline-5-phosphonates could be subsequently transformed into pyrazolidine and bicyclic pyrazolidine derivatives bearing phosphonate functionalities (Scheme [8c,d]).[53]

3.3

SPINOL Phosphate Catalyzed Asymmetric Cycloaddition Reaction of Diazophosphonates

Through the asymmetric formal 1,3-dipolar cycloaddition process, our group developed an effective approach for producing highly functionalized chiral nonspiro-phosphonylpyrazolines 40 (Scheme [9]).[26] Exceptional stereoselectivities reaching up to 98% ee and diastereomeric ratios of 99:1 were achieved in the asymmetric catalytic 1,3-dipolar cycloaddition reaction employing Seyferth–Gilbert reagent (SGR) 1d and acyclic substituted α,β-unsaturated ketones 38, augmented with an electron-withdrawing nitrile group. These reactions yielded chiral nonspiro-phosphonylpyrazolines, marking their inaugural synthesis (Scheme [9]). The catalytic efficacy of chiral silver phosphates derived from 1,1′-spirobiindane-7,7′-diol (SPINOL)-based chiral phosphoric acids (SPAs) 39 was demonstrated, exhibiting remarkable performance. To get the best outcomes, different chiral phosphoric acids were screened and the reaction conditions were optimized. Moreover, the research explored the substrate scope and extended the reaction to other α,β-unsaturated ketones having an alkyl group at the carbonyl group, demonstrating the synthetic potential of this method.

Scheme 8 (a) Asymmetric [3+2] cycloaddition reactions of α-substituted diazophosphonates 1e with 3-acryloyloxazolidin-2-one 35; (b) proposed transition state model; (c) synthetic utility of phosphonylpyrazoline 37; and (d) synthesis of bicyclic pyrazoline 37d

Scheme 9 1,3-Dipolar cycloaddition reaction of α-diazomethylphosphonate 1d with acyclic α,β-unsaturated ketones 38

Exploring the reaction with different types of α,β-unsaturated ketones 38 and α-diazomethylphosphonates 1d to further understand the synthetic potential of this method can be worthwhile. Additionally, investigating the application of the chiral silver SPINOL phosphate catalyst in other types of asymmetric cycloaddition reactions could provide valuable insights into its catalytic performance and versatility. Furthermore, exploring the potential biological and pharmaceutical applications of the synthesized chiral nonspiro-phosphonylpyrazolines could be an interesting avenue for future research, given the presence of pyrazoline derivatives in biologically active molecules with various therapeutic activities.[26]

3.4

Catalytic Dipolar Cycloaddition Reaction of Diazophosphonates­ and Methyleneindolinones

Spirooxindoles fused with pyrazoline at the C3 position exhibit superior cytotoxicity against MCF-7 cells compared to isoxazoline derivatives.[23] [82] Incorporating a phosphonate group enhances the biological activity of azaheterocycles, making spiro-phosphonylpyrazoline-oxindoles valuable in drug discovery.[83] Anil et al. synthesized racemic spiro-phosphonylpyrazoline-oxindoles from 3-aryl/alkylidene oxindoles using the Bestmann–Ohira reagent.[75] [84] Previously, our group developed an enantioselective 1,3-dipolar cycloaddition of 3-alkylidene oxindoles with Seyferth–Gilbert reagents (SGR), although limited to specific substrates from Knoevenagel condensations (see Scheme 7).[25] Due to the critical role of substituents and stereogenic centers on biological activity, we present an asymmetric synthesis of chiral spiro-phosphonylpyrazoline-oxindoles using SGR, expanding their diversity.

This study describes an asymmetric 1,3-dipolar cycloaddition reaction between substituted methyleneindolinones 41 and α-diazomethylphosphonate 1d to synthesize chiral 3,3′-spiro-phosphonylpyrazoline-oxindoles 43 (Scheme 10).[74] This reaction is catalyzed by 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and a tertiary amine thiourea 42. The methodology exhibits high functional group compatibility, accommodating a broad spectrum of methyleneindolinones with diverse substituents and heterocyclic rings (Scheme 10a). With high diastereoselectivities (up to 20:1 dr) and enantioselectivities (up to 95% ee), a series of chiral spiro-phosphonylpyrazoline-oxindole derivatives were obtained. These derivatives can be further converted by ring contraction into spiro-phosphonylcyclopropane-oxindole derivatives (Scheme 10b). Further evaluation of these organophosphonate compounds for biological activity should be prioritized, since the combination of oxindole, pyrazoline, and phosphonate structural motifs might be important for therapeutic candidate identification.[74]

Scheme 10 (a) Asymmetric [3+2] cycloaddition of methyleneindolinones 41 with α-diazomethylphosphonate 1d and (b) synthetic utility of phosphonylated spiro-pyrazoline-oxindole 43

3.5

Enantioselective Synthesis of Axially Chiral Arylpyrazoles with Diazophosphonates

Scheme 11 (a) Atroposelective Huisgen-type cycloaddition reaction of α-diazo phosphonate 1a with naphthyl-substituted olefin 44; (b) proposed reaction mechanism; and (c) synthetic transformations and gram-scale synthesis

The production of axially chiral arylpyrazoles holds significant importance in both synthetic chemistry and pharmaceutical applications, where they serve as essential components such as chiral ligands, organocatalysts, and materials.[22] [23] [53] However, achieving their enantioselective synthesis poses a significant challenge, especially when utilizing non-precious metal-catalyzed methodologies.[85] [86] Nonetheless, a recent breakthrough has introduced a novel approach to tackle this obstacle, employing dipeptide phosphonium salt catalysis. This innovative and adaptable method involves an atroposelective Huisgen-type cycloaddition–aromatization process between a naphthyl-substituted olefin 44 and α-diazophosphonate 1a, allowing for the precise conversion of central to axial chirality (Scheme [11a]). The study elucidates that the electronic characteristics of the ortho-position substituents exert negligible influence on both yields and enantioselectivities, with steric hindrance exhibiting a modest impact on stereoselectivities. The resultant axially chiral mono-bisphosphine entities efficiently transform atropisomeric monophosphine compounds, showcasing their efficacy as chiral ligands in Pd-catalyzed asymmetric allylation and amination reactions (Scheme [11b]). This innovative reaction platform provides access to a wide array of axially chiral arylpyrazole-based phosphorus compounds, characterized by high chemical yields, extensive substrate versatility, low catalyst loading, and scalability. The execution of gram-scale synthetic procedures and facile modifications underscores the practicality and significance of this methodology (Scheme [11c]), demonstrating its potential for synthesizing novel axially chiral aryl pyrazole phosphines essential in asymmetric catalysis.[87]

4

Asymmetric [3+3] Cycloaddition Reactions

4.1

Enantioselective [3+3] Cycloaddition of α‑Diazomethylphosphonates with Oxyallyl Zwitterions

Scheme 12 (a) [3+3] Cycloaddition between oxyallyl zwitterions 54, generated in situ from α-halo ketones 52, and α-diazomethylphosphonate 1d; (b) mechanism; and (c) synthetic pathway for pyridazine derivatives

The planar structure of oxyallyls presents a challenge in discriminating between their faces, limiting the exploration of catalytic asymmetric reactions involving oxyallyls. Efficient methods for the asymmetric synthesis of pyridazine-4-ones, which possess distinctive bioactive properties, remain notably lacking.[88] While the 1,3-dipolar cycloaddition of diazo compounds presents a potent approach for fabricating heterocyclic compounds, the realm of catalytic asymmetric [3+3] cycloadditions employing diazo compounds remains uncharted, with merely three instances of racemic syntheses documented. The establishment of a chiral imidodiphosphoric acid catalyst (IDP) 53 serves as a pivotal advancement in facilitating the enantioselective [3+3] cycloaddition process involving oxyallyl zwitterions and α-diazomethylphosphonates 1d (Scheme [12a]). This reaction entails the in situ formation of oxyallyl zwitterions 54 from α-haloketones 52, followed by their interaction with α-diazomethylphosphonate 1d through a reactive intermediate, ultimately yielding chiral pyridazin-4(1H)-ones 55. The chiral catalyst controls product stereochemistry, delivering pharmaceutically significant chiral pyridazin-4(1H)-ones with impressive yields (reaching up to 98%) and remarkable stereoselectivities (reaching up to 99% ee, with a diastereomeric ratio exceeding 99:1) (Scheme [12a]). The [3+3] cyclization process might be facilitated by the deprotonated form of the imidodiphosphoric acid catalyst via ion-pairing interactions with both the oxyallyl zwitterion intermediate and α-diazomethylphosphonates. Hypothesized transition states elucidate the stereoselectivity mechanism, wherein the chiral anion, derived from IDP upon interaction with K₃PO₄, activates both α-diazomethylphosphonate and oxyallyl zwitterion, thereby directing nucleophilic addition at the C1 position. The steric hindrance imposed by the 4-tert-butylphenyl substituent promotes nucleophilic addition, facilitating the predominant formation of the anti-(5R,6S) product (Scheme [12b]). The synthetic utility of this method is demonstrated by the successful production of diverse pyridazine derivatives (Scheme [12c]).[88]

4.2

Asymmetric [3+3] Cycloaddition of Diazophosphonates with Isoquinolinium Methylides

The production of enantiomerically enriched heteropolycyclic molecules, incorporating 1,2-dihydroisoquinoline and 1,2,4-triazine frameworks, holds significant importance in the realm of pharmaceutical investigation.[89] [90] Our group achieved this synthesis by employing a profoundly asymmetric [3+3] cycloaddition process between diazophosphonates 1d and isoquinolinium methylides 58, facilitated by a bifunctional chiral phase transfer catalyst (PTC) 59 (Scheme [13]).[91] The outcome of this reaction furnishes chiral [1,2,4]triazino[5,4-a]isoquinoline 60 derivatives exhibiting remarkable yields of 98% alongside elevated enantioselectivities reaching 99%.

Scheme 13 (a) Asymmetric [3+3] cycloaddition reaction of diazo compound 1d and isoquinolinium methylide 58 by use of a phase-transfer catalyst (PTC) and (b) synthetic application

Through the employment of density functional theory calculations, it has been revealed that the chiral phase transfer catalyst (PTC) assumes a central role in promoting deprotonation/protonation, thereby facilitating intricate electrostatic and hydrogen bonding interactions with substrates. This methodology not only facilitates the transformation into densely functionalized polycyclic hetero compounds, replete with multiple stereocenters, but also represents a valuable avenue for the construction of amino acid ester derivatives possessing quaternary carbon centers (Scheme [13b]). Notably, the inclusion of diazophosphonates in the reaction protocol culminates in the synthesis of chiral triazino[5,4-a]dihydroisoquinoline phosphonates 60 achieving notable yields and enantioselectivities.[91]

4.3

Diazophosphonates in Chiral Phosphoryl-1,4-Dihydropyridazine Synthesis

The pursuit of enantiopure 1,4-dihydropyridazines is significant, yet limited reports exist on achieving these chiral variants.[92] The use of α-diazo esters as nucleophiles in asymmetric aldol reactions and allylic alkylation reactions with Morita–Baylis–Hillman (MBH) carbonates has been investigated.[31] [93] α-Diazophosphonates, despite being less investigated due to their poorer nucleophilicity and greater steric interference, have demonstrated promise in asymmetric catalysis, particularly in Mannich reactions and 1,3-dipolar cycloadditions.[33] However, it is still difficult to use them in other asymmetric processes. Notably, asymmetric allylic substitution of MBH carbonates has sparked interest, with diverse nucleophiles such as nitrogen, oxygen, carbon, and phosphorus species being successfully utilized.

A novel strategy has been devised for the synthesis of phosphoryl-1,4-dihydropyridazine derivatives 63 with chirality, employing an innovative sequence involving asymmetric allylic alkylation, intramolecular 1,3-dipolar cycloaddition, and rearrangement (Scheme [14]).[93] This method demonstrates excellent yields and enantioselectivities. Hydroquinidine catalyzes the asymmetric allylic alkylation of MBH carbonates 61 using dialkyl (diazomethyl)phosphonates 1f as nucleophiles, resulting in the synthesis of chiral α-diazo-γ-methylenephosphonates 62. These intermediates can be smoothly transformed into phosphonated azaheterocycles by using Ni(OAc)₂ catalysis without compromising enantioselectivity. Additionally, reducing the allylic alkylation products yields chiral 4,5-dihydropyridazinone derivatives 63, which hold potential biological and pharmaceutical significance (Scheme [14]).[93]

Scheme 14 (a) Asymmetric allylic alkylation of MBH carbonates 61 with diazomethylphosphonates 1f and synthesis of chiral phosphoryl-1,4-dihydropyridazine derivatives 63; (b) proposed mechanism for the transformation of 62 into 63; and (c) synthetic value of the chiral α‑diazo-γ-methylene-phosphonate 62

5

Asymmetric Substitution Reactions

5.1

Asymmetric Addition of α-Diazomethylphosphonates to Vinylogous Imines

The synthesis of 3-sec-alkyl-substituted indoles is vital for the development of therapeutic agents, and functionalizing the C-3 position of indole-containing compounds is crucial for their bioactivities.[44] [94] [95] Current efforts focus on efficient methods for accessing these indoles with various functional groups, including nucleophiles or pronucleophiles added to vinylogous imines synthesized from 3-(1-arylsulfonylalkyl)indoles.[37] [44] However, achieving enantioselectivity, especially for 2-unsubstituted sulfonyl indoles, remains­ challenging, limiting the range of available substrates.[96] [97] Our research group revolutionized the field by proposing an innovative method employing trifunctional BINAP-based monophosphonium phase-transfer catalysts 69 for asymmetrically adding α-diazomethylphosphonates 1d to vinylogous imines, which are spontaneously generated from sulfonyl indoles (Scheme [15]).[32] The technique showcased extensive compatibility with various substrates, notably excelling with 2-unsubstituted sulfonyl indoles, a group historically known for displaying diminished enantioselectivity in analogous reactions involving alternative nucleophiles. It yielded chiral 3-sec-alkyl-substituted indoles featuring α-diazophosphonate with remarkable efficacy, achieving yields as high as 95% alongside exceptional enantioselectivity (Scheme [15a]).

The innovative strategy of using phase-transfer catalysts utilizing phosphonium salts, integrating the axial chirality inherent in the binaphthyl framework with the central chirality characteristic of amino acid derivatives, constitutes a pioneering advancement. The envisaged reaction mechanism entails the nucleophilic engagement of the catalyst’s PPh₂ moiety with the terminal nitrogen of α-diazomethylphosphonate, instigating the formation of a reactive intermediate species 71 (Scheme [15c]). Subsequently, this entity engages with alkylideneindolenine 68, which is spontaneously formed from sulfonyl indoles, resulting in an intermediary product 72 that undergoes subsequent alterations, potentially implicating hydrogen bond engagements and precise nucleophilic interactions. These processes culminate in the production of the targeted chiral 3-sec-alkyl-substituted indoles bearing α-diazophosphonate functionalities 70 (Scheme [15c]). Product 70 may be efficiently converted into products 70a and 70b, demonstrating the synthetic value of this approach (Scheme [15b]).[32]

5.2

Diazophosphonates in Enantioselective Benzylic C–H Functionalization

Attaining enantioselective intermolecular sp³ C–H functionalization, a sophisticated process necessitating precise site selectivity and asymmetric induction is propelled by group-transfer reactions such as those involving metal-bound carbenes.[98] Donor/acceptor carbenes, notably those featuring phosphonates as acceptor moieties, present intriguing prospects owing to their sterically demanding nature.[99] The refined dirhodium catalyst Rh₂(S-di-(4-Br)TPPTL)₄ 75 facilitates exceptionally enantioselective (84–99% ee) and site-selective (>30:1 r.r.) benzylic C–H functionalization of [(aryl)(diazo)methyl]phosphonates 1h (Scheme [16] a).

Scheme 15 (a) Asymmetric addition of α-diazomethylphosphonate 1d to vinylogous imines 68; (b) further transformation of the product 70; and (c) proposed mechanism

Scheme 16 (a) Stereoselective C–H functionalization of [(aryl)(diazo)methyl]phosphonates 1h using dirhodium catalyst 75 and (b) impact of bis(trifluoroethyl) phosphonate 77

The tetrahedral phosphonate group amplifies selectivity towards primary C–H functionalization. Successful late-stage primary C–H functionalization of various derivatives, encompassing estrone and naproxen, underscores the broad applicability of this methodology. [(Aryl)(diazo)methyl]phosphonates 1h emerge as potent carbene precursors, broadening the spectrum of functionalities accessible in enantioselective C–H functionalization. Dimethylphosphonates exhibit enhanced efficacy as substrates, while trifluoroethyl derivatives can serve as viable alternatives if needed (Scheme [16b]). Although necessitating slightly more rigorous conditions, this approach, employing molecular sieves and HFIP (hexafluoroisopropanol), yields satisfactory outcomes. Prospective investigations may expand the methodology’s utility to diverse C–H functionalization reactions and substrates, presenting auspicious avenues for refining carbene-mediated C–H functionalization chemistry.[100]

5.3

Enantioselective Mannich Reaction: Chiral Oxindole Synthesis with Diazophosphonates

Scheme 17 (a) Asymmetric Mannich reaction of α-diazomethylphosphonate 1d with isatins 79 and (b) derivatization of the product 81

The chiral oxindole, with its quaternary stereocenter and amino moiety positioned at C3, is a structural motif that is frequently seen in natural compounds as well as drugs with pharmacological activity.[74] [101] β-Amino phosphoric acid, serving as an isosteric analogue of β-amino acid, demonstrates heightened bioactivity and stability within pharmaceutical investigations.[102] Despite progress made in the development of methods for selectively synthesizing 3-substituted 3-aminooxindoles, there is currently a gap in methodologies for directly accessing chiral β-aminophosphonates utilizing the oxindole scaffold.[25] Employing a chiral silver phosphate catalyst, the enantioselective Mannich reaction between isatin-derived ketimines 79 and α-diazomethylphosphonates 1d yields chiral oxindoles 81 with exceptional yields (up to 95%) and high enantioselectivities (up to 99% ee) (Scheme [17a]).[75] Optimal results are observed with methyl substitution at the N1 position of the isatin ketimine. This approach provides a straightforward pathway to access potential bioactive 3-substituted 3-amino-2-oxindoles by combining oxindole and β-aminophosphonate moieties, thereby enabling the synthesis of densely functionalized spiro-aziridine-oxindole derivatives (Scheme [17b]).[75]

6

Diazophosphonates as Carbene Precursors

6.1

Photochemical Synthesis of (β-Diazo-α,α-difluoroethyl)phosphonates

Incorporating a pair of fluorine atoms into the α-carbon of phosphate (phosphonate) groups produces enhanced phosphate bioisosteres, mimicking oxygen both sterically and electronically, thus holding significance in pharmaceutical contexts.[103] While diazoalkanes are commonly employed in organic synthesis, their fluorinated derivatives and fluoroalkyl-substituted donor–acceptor diazo compounds are less explored.[104] [105] Trifluorodiazoethane (CF₃CHN₂), identified in 1943, stands as the most studied fluorinated diazoalkane, whereas its difluorinated counterpart, difluorodiazoethane (CF₂HCHN₂), was synthesized only in 2015.[106] Various transformations utilizing difluorodiazoethane, such as the generation of difluoromethyl pyrazolines, pyrazoles, and cyclopropanes, have been reported.[56] Despite the potential of difluorodiazoethane as a flexible masked CF₂ group, both its synthesis and practical utilization remain unresolved.

Scheme 18 (a) 2-Diazo-1,1-difluoroethylphosphonates 1c as masked carbenes in coupling reaction with sulfonic acid 85 and (b) proposed mechanism

A pioneering approach has been suggested for producing (2-diazo-1,1-difluoroethyl)phosphonates 1c from (β-amino α,α-difluoroethyl)phosphonates 16. These compounds act as masked carbenes in coupling reactions with sulfonic acids 85 under photochemical conditions. This method involves the synthesis of diazo compounds containing difluoromethyl phosphonate (DFMP) fragments through a visible-light-coupling reaction using selected aromatic amines and sulfonic acids (Scheme [18a]).[107] The process operates through a coupling mechanism, in which a diazo intermediate, generated from the reaction of amine with tert-butyl nitrite and activated by blue light irradiation, experiences protonation and nucleophilic substitution, resulting in the formation of the targeted sulfonate ester product 86 (Scheme [18b]). The newly developed (β-diazo-α,α-difluoroethyl)phosphonate 1c serves as a masked carbene, providing an effective method for the synthesis of functionalized compounds containing (difluoromethyl)phosphonate groups.[107]

6.2

Diazophosphonate Coupling: Catalyst-Driven C–H Functionalization

Transition-metal-catalyzed directed C–H functionalization is highly regarded in organic synthesis, with researchers aiming to uncover novel reactivity using inventive directing groups and exploring functional group transformations after C–H functionalization.[108] Enaminones 88 have emerged as effective directing synthons for Rh(III)- and Co(III)-catalyzed C–H coupling, enabling versatile C–C and C–N bond formations.[109] A recent breakthrough involves Rh(III)-catalyzed enaminone-directed C–H coupling with α-diazo-α-phosphonoacetates 1i, yielding 4-hydroxy-1-naphthoates and α,β-unsaturated esters 89, revealing fluoride-mediated dephosphonation reactivity for intramolecular C–C coupling synthesis (Scheme [19]).[110]

Furthermore, intermolecular C–C coupling reactivity is demonstrated for α-phosphonoacetates and benzaldehydes, providing access to E-selective α,β-unsaturated esters. The utilization of fluoride ion conditions showcases high tolerance towards functional groups, diverging from conventional strongly basic conditions. This study establishes fluoride-mediated dephosphonation as a viable approach for C–C coupling reactions, demonstrating compatibility with various functional groups and offering new prospects in C–C coupling chemistry (Scheme [19]).[110]

6.3

Diazophosphonate-Directed Carbene Insertion for Amino Phosphonate Synthesis

Aminophosphonates exhibit diverse functions ranging from mimicking peptides, inhibiting enzymes, and acting as therapeutic agents, to serving as fundamental constituents for diverse chemical structures.[111] The synthesis of these compounds, especially via the nucleophilic addition of phosphonates to imines using the Kabachnik–Fields reaction mediated by Lewis acids, encounters challenges related to sensitivity to moisture and harsh reaction conditions.[112] To mitigate these issues, researchers have utilized dehydrating agents or Lewis acids that are stable in the presence of water.[113] Additionally, investigators are delving into alternative synthetic routes such as C–H activation and the reduction of iminophosphonates to enhance selectivity and compatibility. Notably, there is a notable surge in interest in metal-complex-catalyzed carbene insertion reactions, with a particular focus on copper catalysts, due to their cost-effectiveness, mild reaction conditions, compatibility with biological systems, high yields accompanied by excellent enantiomeric excess, and chemoselectivity.

Scheme 19 (a) Rh(III)-catalyzed enaminone-directed C–H coupling with α-diazo-α-phosphonoacetate 1i for the identification of fluoride-mediated dephosphonation C–C coupling reactivity; (b) fluoride-mediated dephosphonation for C–C coupling reactions; and (c) proposed mechanism for fluoride-mediated cyclization reaction

A novel and environmentally friendly approach has been devised for the synthesis of aminophosphonates 94, demonstrating remarkable selectivity in aqueous media. This method entails the carbene insertion of diazophosphonate 1b into aniline 93 under mild reaction conditions, yielding highly satisfactory outcomes (Scheme [20]).[114] Extensive screening of transition metal catalysts was conducted to identify an optimal catalyst for the carbene insertion reaction in aqueous environments, ultimately revealing [Cu(CH₂CN)₄]ClO₄ as the most effective catalyst under the specified reaction conditions. The reaction mechanism involves the formation of a copper–carbene intermediate, which subsequently interacts with the N–H bond of the aniline, yielding a copper-bound α-aminophosphonate intermediate. Employing this eco-friendly strategy, a diverse array of aminophosphonates was successfully synthesized, isolated, and characterized using standard analytical and spectroscopic techniques. This innovative methodology holds great promise for the synthesis of various aminophosphonates with potential applications across diverse biological systems, thereby broadening their utility in fields such as biochemistry and protein labeling.[114]

Scheme 20 Carbene insertion of diazophosphonate 1b into the N–H bond of anilines 93

6.4

Diastereospecific Cyclopropenation of Alkynes with Diazophosphonates

Owing to the special structure that combines unsaturation and high strain, cyclopropenes are very flexible molecules that are widely employed in chemical synthesis.[115] To increase the synthetic usefulness of these materials, efficient synthetic techniques are essential. Different catalysts have been designed to facilitate the reaction of alkynes with diazo compounds in catalytic asymmetric techniques.[116] Though progress has been made, stereoselective synthesis of certain derivatives, such as cyclopropenylphosphonates, is still restricted. Similar to α-diazoacetates, α-diazophosphonates provide a range of chemical transformations and the possibility to synthesize molecules with functionalized phosphorus.[14] The synthesis of biologically significant cyclopropylphosphonates has been the subject of a recent study. With the advent of newly formulated α-diazophosphonyl compounds derived from indigenous amino acids, the concurrent execution of C–H functionalization and O–H insertion procedures has become feasible.[117] Furthermore, a regioselective C–H functionalization/S–H insertion procedure catalyzed by boron trifluoride has been established for the synthesis of N and S-acetals containing quaternary centers.[37]

The diastereospecific cyclopropenation of alk-1-ynes 95 employing dialkyl α-diazophosphonates 1h has been utilized for the synthesis of β-amino-α-cyclopropenylphosphonates 96 containing a quaternary stereogenic center. When [Cu(MeCN)₄]BF₄ and boron trifluoride diethyl ether adduct are used as a mixed catalyst, the reaction exhibits good diastereoselectivity and efficiency (Scheme [21a]).[118] Mechanistically, the Cu catalyst causes N₂ to be liberated from the α-diazophosphonate 1h, generating a Cu–carbenoid 98 (Scheme [21b]). This Cu–carbenoid subsequently coordinates with BF₃·Et₂O to generate a metallocarbenoid. After combination of the carbenoid and alkyne triple bond to create a vinyl cation 100, cyclopropenyl phosphonate 96 is formed, the Cu(I) catalyst regenerates, and BF₃·Et₂O is produced. Steric hindrance is responsible for the observed diastereoselectivity, which affects the preferred attack on the carbenoid’s rear face (Scheme [21]).[118]

Scheme 21 (a) Cyclopropenation of diethyl α-diazophosphonates 1h with phenylacetylenes 95 and (b) proposed reaction mechanism

6.5

Enzymatic Transformation for the Synthesis of Optically Active Cyclopropylphosphonates

The relevance of optically active phosphonate-containing compounds in medical and biological research makes the development of strategies for their synthesis highly desirable.[119] The most promising approach for creating cyclopropane rings with phosphonyl decoration is the asymmetric cyclopropanation method that employs diazo compounds containing phosphonyl.[120] Although there are difficulties with the conventional methods that use organo–transition metal catalysts, a viable substitute that enables stereoselective synthesis is enzyme-mediated carbene transfer catalysis. The biocatalytic transformations have been effectively carried out using a range of diazo compounds that are merely acceptors; however, the diversity of products has been restricted to those that include carbon-based electron-withdrawing groups.[121] [122]

Recent studies have explored the use of modified myoglobin-based biocatalysts combined with phosphonyl diazo reagents to provide a highly selective method of olefin cyclopropanation. Demonstrating remarkable stereoselectivity, this method facilitated the production of cyclopropylphosphonate ester compounds 102 and 103 in both (1R,2S) and (1S,2R) enantiomeric configurations (Scheme [22]).[120] According to mechanistic investigations, the phosphonyl diazo reagent’s larger dimethyl phosphonate group causes more steric repulsion in the protein environment than ethyl diazoacetate, which raises the energy barriers. Myoglobin was the hemoprotein with the highest activity when it came to catalyzing the cyclopropanation process with phosphonyl diazo compounds. High diastereomeric and enantiomeric excesses may be achieved by transforming different vinylarene substrates on a preparative scale using this method (Scheme [22]). This study paves the way for the advancement of metalloprotein catalysts tailored for non-natural carbene transfer reactions, thereby broadening the scope of enzymatic-mediated transformations.[120]

Scheme 22 (a) Cyclopropanation of dimethyl diazophosphonate 1d with styrene (101) and (b) gram-scale biocatalytic synthesis of 102 and further functionalization to 104 for crystallographic analysis

6.6

Carbene Cross-Coupling Reactions of Diazophosphonates and Arylboronic Acids

Organophosphorus compounds – (diarylmethyl)phosphonates in particular – have a wide range of uses and are thus highly relevant in many different sectors.[123] The Michaelis–Arbuzov reaction is a popular method of synthesis, although it has drawbacks, including severe reaction conditions and limited availability of diarylmethyl halides.[124] Regioisomer creation and a limited substrate scope are two disadvantages of other approaches, such as the palladium-catalyzed α-arylation process and the Friedel–Crafts reaction, which have demonstrated encouraging results. Steric hindrance has also been studied as potential challenge in techniques involving metal carbene intermediates.[125] [126] (Diarylmethyl)phosphonate synthesis requires the continuing development of effective and adaptable methods. Such synthesis can be achieved using transition-metal-catalyzed carbene cross-coupling reactions, such as the Suzuki-type coupling of diazo compounds.[4] Recent research has shown that α-diazophosphonates can be used as substrates to introduce phosphonate moieties.

A highly efficient approach for the synthesis of (diarylmethyl)phosphonates 106 involves a rhodium-catalyzed cross-coupling reaction between α-diazophosphonates 1h and arylboronic acids 105 (Scheme [23a]).[127] The crucial stage in the transformation is thought to occur when rhodium–carbene intermediates migrate into the reaction and insert themselves. A rhodium–carbene intermediate is created when the α-diazophosphonate and rhodium catalyst interact. An arylrhodium(III) species is created when the rhodium–carbene intermediate and arylboronic acid undergo oxidative addition. (Diarylmethyl)phosphonate product 106 is formed when the arylrhodium(III) species migrates and inserts itself into the α-diazophosphonate’s C–P bond (Scheme [23b]).[127]

Scheme 23 (a) Rhodium-catalyzed cross-coupling reaction between α-diazophosphonate 1h and arylboronic acid 105 and (b) proposed reaction mechanism

6.7

Photocatalytic Intramolecular Cyclization Reaction of Diazophosphonates

Diazo reagents use organic dyes or organometallic photosensitizers to engage in visible-light-mediated reactions as either nucleophiles or carbene precursors. Free carbenes are produced when donor–acceptor diazo compounds are photolyzed in the presence of visible light (Scheme [24]).[128] These carbenes are then used in a variety of processes, such as cyclopropanation, Wolff rearrangement, X–H insertions, ylide production, and cross-coupling with other diazocarbonyl compounds.[129] Diazosulfonium salts or hypervalent iodine–diazo reagents can produce diazoalkyl radicals. Alkyl radicals and enolate vinyl radicals are produced by photocatalytic denitration of diazoalkyl esters and diazo enolates, respectively. These radicals can engage in intramolecular or alkyne-trapping processes. Nevertheless, the vulnerability of enolate vinyl radicals to reduction prevents their broad use in organic synthesis.[130] [131]

Scheme 24 (a) Reactions between α-diazo-β-ketophosphonate 1j and vinyl azides 110 and (b) plausible mechanism

6.8

Water-Mediated Synthesis of α-Fluoro-β-ketophosphonates via (β-Diazo-α,α-difluoroethyl)phosphonate Transformation[132]

α-Fluoro-β-ketophosphonates are crucial in organic synthesis, offering wide-ranging applications in both chemical and biological contexts. Despite various established methods, such as electrophilic fluorination and nucleophilic substitutions, there is a persistent interest in discovering new synthesis approaches.[133] [134] Diazo compounds, versatile in constructing complex molecules, especially those with fluoroalkyl groups, have garnered attention. Recent progress includes stable analogues of difluorodiazoethane and unstable difluorodiazoalkane analogues for synthesizing compounds with difluoromethylenephosphonyl groups.[135] Building on these developments, Han et al. investigated the chemistry of (2-diazo-1,1-difluoroethyl)phosphonate for the production of mono- and difluoromethylphosphonate-containing compounds by use of a water coupling reaction with in situ produced (β-diazo-α,α-difluoroethyl)phosphonate.[107]

The study introduced a new technique for α-fluoro-β-ketophosphonates 118, which involves cleaving the C–F link and hydrating (β-amino-α,α-difluoroethyl)phosphonates 16 via a Rh–carbene intermediate (Scheme [25]). This technique is compatible with a variety of (β-amino-α,α-difluoroethyl)phosphonates 16, which result in high yields of α-fluoro-β-ketophosphonates 118. It is possible to accept several types of substrates with different substituents on amine and phenyl groups. The procedure involves the transformation of (β-diazo-α,α-difluoroethyl)phosphonates 1c into bioactive α-fluoro-β-ketophosphonates, employing in situ generated water as a coupling reagent (Scheme [25]).[105]

Scheme 25 (a) Rh-catalyzed water coupling/C–F bond cleavage of β-diazo-α,α-difluoroethylphosphonates 1c; (b) proposed mechanism; and (c) conversion of product 118 into 124

6.9

Transition-Metal-Catalyzed Coupling Reaction between Diazophosphonates and Ferrocenylacetylenes

Ferrocene derivatives are pivotal in organic synthesis, asymmetric catalysis, materials science, and bioorganometallic chemistry. They hold potential as therapeutic agents for diseases such as malaria and cancer. Functionalizing ferrocene-containing structures is essential for tailoring their properties.[136] [137] Traditional methods for aromatic compounds may not be suitable due to ferrocene’s unique geometric and electronic properties.[138] Allene compounds are notable for their diverse reactivity and presence in natural products and drugs. Allenylphosphonates are particularly significant in medicinal chemistry, synthesized efficiently through copper-catalyzed coupling of diazophosphonates with terminal alkynes.[139] Recent advancements by Chen and colleagues focus on synthesizing novel allene structures incorporating ferrocenyl groups to explore new properties.[140] They have advanced a novel approach to produce ferrocene-containing allenylphosphonates through the coupling of diazophosphonates 1h with ferrocenylacetylenes 125, facilitated by CuI catalysis (Scheme [26]).

Scheme 26 (a) Coupling reaction of diazophosphonates 1h with ferrocenylacetylenes 125 and (b) possible reaction mechanism

This method expands upon their earlier research involving the synthesis and modifications of ferrocenylallenes and yields a variety of trisubstituted allene derivatives 126 including ferrocene, which may be useful in synthetic processes (Scheme [26]). The optimal conditions for the reaction include using CuI as a catalyst, Et₃N as a base, and heating the reaction mixture to 70 °C for two hours under a nitrogen atmosphere. Different substituents on the aryldiazophosphonates 1h and ferrocenylacetylenes 125 were tested, showing that various groups are tolerated in the reaction, resulting in moderate to excellent yields of the desired products. The study contributes to the field by providing a method to synthesize complex molecules involving ferrocene, which could have applications in various areas of chemistry. Ferrocene-containing allenylphosphonates obtained in this work can subsequently be used as building blocks or intermediates for further chemical manipulations to create more complex molecules. These transformations might involve various types of organic reactions such as oxidation, reduction, further coupling reactions, or functional group modifications.[140]

6.10

Hydroarylation of Diazophosphonates and Diazocarboxylates­

Scheme 27 (a) Hydroarylation of diazophosphonates 1b with aryl iodides 130 and (b) mechanism of hydroarylation

Transition-metal-catalyzed transformations of α-diazocarbonyl compounds are pivotal in organic synthesis, mainly for generating carbenes involved in X–H insertion (X = C, N, O, S), cyclopropanation, and cycloaddition.[3] Recent advancements, particularly by J. Wang’s team, have broadened their use to include Pd-catalyzed cross-coupling reactions.[1] These can either preserve the diazo group, resulting in aryl-substituted diazo compounds, or eliminate it, forming organopalladium intermediates that nucleophiles such as formic acid hydride ions capture.[141] Titanyuk et al. innovatively developed a Pd-catalyzed three-component hydroarylation approach using aryl iodides, α-diazocarboxylates/α-diazophosphonates, and formic acid, yielding mono- or diarylacetates and diarylphosphonates.[142] [169]

Recently, the Titanyuk group has sought to broaden their Pd-catalyzed method by reacting a wider range of diazo compounds 1b with aryl iodides 130 and formic acid (Scheme [27]).[142] This results in the creation of diarylated esters or phosphonates 131 with yields up to 71%. This method builds on the transformation of diazophosphonate compounds 1b via palladium catalysis, and presents improved methods for three-component hydroarylation reactions, noting that the choice of catalyst, solvent, and base significantly affects the yield of the product, with palladium catalysts such as PdCl₂ and the solvent 1,2-dichloroethane among the most effective. Extension of this hydroarylation methodology to include a wider variety of substrates beyond aryl iodides and diazocarboxylates/diazophosphonates should be investigated. The development of enantioselective versions of the hydroarylation reaction to synthesize chiral molecules, which are often important in pharmaceutical applications can also be brought into consideration.

6.11

Transition-Metal-Catalyzed Tandem Reaction and Horner–Wadsworth–Emmons Olefination of Diazophosphonates

Scheme 28 (a) Cu(I) catalyzed cross-coupling of α-diazophosphonates 1h with alkynes 137 and (b) proposed reaction mechanism

Wang and collaborators presented a novel Cu(I)-catalyzed three-component cascade process, culminating in the efficient production of 1,3-enynes 139 in favorable yields and notable stereoselectivity (Scheme [28]).[143] The synthesis is practically useful due to the availability and stability of α-diazophosphonates, making it suitable for widespread application. The mechanism of the reaction is the cross-coupling of alkynes 137 with α-diazophosphonates 1h, which is followed by a Horner–Wadsworth–Emmons-type reaction. The procedure affords enyne compounds with stereoselectivity within a straightforward catalytic system and demonstrates applicability across a broad spectrum of easily obtainable aldehydes 138 and α-diazophosphonates (Scheme [28b]). Optimization of the reaction conditions, including the choice of base, catalyst loading, and reaction temperature, to achieve the desired results was reported briefly. Easily available and relatively stable α-diazophosphonates were used, making them suitable for the developed Cu(I)-catalyzed three-component cascade reaction.

This method allows for the efficient creation of conjugated enynes in high yields and stereoselectivity (Scheme [28]). Additionally, α-diazophosphonates 1h exhibit excellent functional group compatibility, further enhancing their utility in the synthesis of 1,3-enynes. Therefore, the use of α-diazophosphonates in the new enyne synthesis provides a practical and versatile approach for the creation of these important organic compounds. The development of this method addresses previous difficulties found in controlling regio- and stereoselectivity in the synthesis of conjugated enynes and the significance of conjugated enynes in synthetic chemistry and material sciences is highlighted, with a focus on their presence in natural products and their role as building blocks for organic conducting polymers.[143]

7

Diazophosphonates in the Chemistry of Fluorinated Compounds

7.1

Fluorinated Pyrazole Synthesis via 1,3-Dipolar Cycloaddition of Diazophosphonates

Pyrazoles and their derivatives are essential nitrogen-containing heterocycles widely utilized in medicinal, agrochemical, and material sciences as critical synthetic intermediates.[23] [53] [144] Fluorine-substituted pyrazoles possess unique properties significantly impacting metabolic degradation, lipophilicity, and reactivity, and serving as fundamental building blocks in various chemistry domains, including­ medicinal and organometallic chemistry.[57,145] Difluoromethylated pharmaceuticals, particularly those containing the CF₂H group, have attracted attention as lipophilic hydrogen-bond donors and bioisosteres for functional groups.[105] [107] Efficient synthesis of difluoromethyl pyrazoles has been achieved through methodologies such as [3+2] cycloaddition, emphasizing atom-economic and regioselective approaches.[146] Difluoromethylphosphonates, mimicking non-hydrolysable phosphates, find applications as antibacterial agents, chemotherapy targets, and dental materials.[35] [147]

Exploration within the realm of fluorinated carbene chemistry has yielded a stable diazo reagent, 2-diazo-1,1,3,3,3-pentafluoropropylphosphonate 150, which effectively facilitates cyclopropanation reactions with terminal alkenes (Scheme [29]).[57] While prior methodologies have successfully synthesized pyrazolines possessing a difluoromethylene phosphonate motif, the synthesis of CF₂P(O)(OEt)₂-substituted pyrazoles has remained unexplored. A pioneering strategy focused on generating functionalized 3H-pyrazoles 152 incorporating a difluoromethyl phosphonate functionality was pursued through a 1,3-dipolar cycloaddition reaction. This approach provides an efficient pathway for the synthesis of fluorinated 3H-pyrazoles without the need for solvents, catalysts, or additional additives. These synthesized compounds hold promise as drug candidates or versatile building blocks for further molecular modifications, highlighting their potential in drug development and synthetic chemistry advancements (Scheme [29]).[57]

Scheme 29 (a) Synthesis of 2-diazo-1,1,3,3,3-pentafluoropropylphosphonate 150; (b) 1,3-dipolar cycloaddition of 150 with alkynes 151; and (c) proposed reaction mechanism

7.2

Aza-Wittig Reaction of Diazophosphonates for the Synthesis of Difluoromethylphosphonate Hydrazones

Diazo compounds, notably difluoroalkyl diazo compounds, serve as crucial intermediates for assembling complex molecules and incorporating difluoroalkyl functionalities.[2] Previous research has examined difluorodiazoethane and its analogues extensively.[35] [105] A new series of difluoroalkyl diazo derivatives, denoted as (β-diazo-α,α-difluoroethyl)phosphonates, has been engineered for intriguing transformations.[56,107] Of particular note, a triphenylphosphine-mediated reaction of these derivatives with aldehydes via an aza-Wittig reagent has been proposed, providing a straightforward route for the preparation of hydrazones containing difluoromethylphosphonate groups.[35] A recent advancement involves the successful execution of the aza-Wittig reaction between (β-diazo-α,α-difluoroethyl)phosphonates 1c and aldehydes under mild conditions, resulting in the formation of arylidene hydrazones bearing difluoromethylphosphonate 155 moieties (Scheme [30]).[35] This process involves the in situ generation of difluoroalkyl diazo derivatives, namely (β-diazo-α,α-difluoroethyl)phosphonates 1c, followed by their interaction with aldehydes 153 in the presence of PPh₃ as catalyst. Demonstrating a wide range of substrate compatibility and delivering products with yields of up to 99%, this reaction is amenable to large-scale synthesis, underscoring its potential for industrial applications.[35]

Scheme 30 (a) Aza-Wittig reaction of β-diazo-α,α-difluoroethylphosphonate 1c with aldehydes 153 and (b) proposed mechanism

7.3

Fluoro-Functionalization of [(Aryl)(diazo)methyl]phosphonates

As a potent inhibitor of protein tyrosine phosphatase, the difluoromethylphosphinic acid motif has prompted scientists to explore synthetic pathways leading to difluoromethylated phosphonate frameworks.[107] [148] While recent developments highlight transition-metal-catalyzed cross-coupling events, conventional approaches employ difluorination or deoxofluorination processes.[149] However, a deficiency in general strategies for synthesizing diverse fluoromethylated phosphonates, particularly from common precursors, necessitates a more accessible approach.[35,57] Studies introduced a successful fluoro-functionalization of α-diazo(aryl)methylphosphonates 1h, offering an efficient route to various fluorinated phosphonate compounds (Scheme [31]).[150] Fluorinated organophosphorus compounds can be synthesized through geminal difunctionalization processes using several fluorination reagents, including difluoroalkanes (RR′CF₂), fluoroalkenes (RR′CHF), bromofluorinated alkanes (RR′CFBr), and difluoroaminoradicals. The resulting fluorinated phosphonates, exhibiting altered physical, chemical, and biological properties, serve as stable surrogates for phosphates, enhancing resistance to metabolic hydrolysis. This approach not only provides practical synthetic methodologies for a wide array of fluorinated phosphonates 157, 158, and 159 but also stimulates subsequent investigations into their biological efficacy and potential utility across various applications.

Scheme 31 (a) Difluorination reactions of (aryl)(diazo)methylphosphonates 1h; (b) hydrofluorination reactions of 1h; (c) bromofluorination reactions of 1h; and (d) synthesis of fluorinated alkenes 160 via HWE reaction of 158

7.4

Chlorination of Diazodifluoroalkylphosphonates: Synthesis of (β-Chlorodifluoroethyl)phosphonates

Compounds bearing difluoromethylphosphonate (DFMP) components are of substantial value in biomedical research, acting as molecular probes.[35] [105] [107] As a result, creating efficient frameworks for their synthesis is critically imperative.[57] A recent breakthrough includes the development of (β-diazocarbonyl-α,α-difluoroethyl)phosphonate, which is utilized in crafting DFMP-enriched pyrazoles, carboxylic acids, and sulfonic esters.[151] Inspired by the prowess of efficient diazo derivatives and the aim of synthesizing DFMP-rich compounds, an efficacious chlorination reaction of (β-diazo-α,α-difluoroethyl)phosphonates 1c has been established.[152] This protocol uses hydrochloric acid as a chlorine source and results in (β-chlorodifluoroethyl)phosphonates 161 in remarkable yields (up to 99%); these can be transformed into other valuable products (Scheme [32a,b]). This method effectively supplants the earlier-employed electrophilic chlorine reagents, representing a significant leap forward in synthetic strategies for such compounds. Representing the first halogenation of difluoroalkyl diazo compounds, it offers a convenient route for synthesizing difluoromethylenephosphonate-containing compounds. Catalyst-free and applicable to various substrates, this method stands as an exceptional approach for (β-chlorodifluoroethyl)phosphonate synthesis 161. The reaction mechanism involves the diazo intermediate generation, protonation, and nucleophilic reaction with chlorine anion, verified through ¹⁹F NMR analysis, showcasing the disappearance of the diazo intermediate and chlorination product formation upon sulfonic acid addition (Scheme [32c]).[152]

Scheme 32 (a) Chlorination reaction of β-diazo-α,α-difluoroethylphosphonates 1c; (b) further transformation of product 161 into 162; and (c) mechanism

7.5

Photocatalytic Radical Transformation of Diazophosphonates­

In light of the enduring versatility of diazo compounds as pivotal constituents in the synthesis of intricate molecules, there has been a concentrated exploration of their transformations, with particular emphasis on the induction of radicals, including carbon radicals, under photocatalytic conditions.[2] [25] [28] The Hantzsch ester (HE) has emerged as a valuable terminal reductant in photoredox reactions, serving as a sacrificial provider of single electrons and hydrogen atoms during the conversion of diazo compounds into carbon radicals.[153] Recent investigations have showcased the efficacy of photocatalytic radical reactions involving diazo compounds, including their reactions with alkenes and multicomponent reactions with aldehydes, amines, and HE, leading to notable advancements in the field.[154] Notably, there remains an underdeveloped aspect concerning the direct generation of carbon radicals from diazo compounds through the hydrogen atom transfer (HAT) process with HE.

In response to this identified gap, a pioneering radical reaction mechanism utilizing difluoroalkyl diazophosphonates 1c has been introduced (Scheme [33]).[155] This innovative approach effectively utilizes diazo compounds as precursors­ for carbon radicals through a HAT process facilitated by HE, catalyzed by [Ru(bpy)₃]Cl₂·6H₂O under photoredox conditions. The chemical process involves a series of sequential steps, including light-induced carbene generation, carbene transformation into a carbon radical via HAT, reduction facilitated by ruthenium(I), and the cleavage of a C–F bond, culminating in the production of α-fluorovinylphosphonates 163 as the end products with exceptional yields and stereochemical precision. Of significant note, this marks the inaugural instance of a radical-mediated pathway for difluoroalkyl diazo compounds, offering a swift and stereochemically precise synthesis of biologically active fluorophosphonates with tangible practical advantages.

Scheme 33 Photocatalytic radical transformation of β-diazo-α,α-difluoroethylphosphonate 1c with Hantzsch ester

7.6

Aza-Wittig Reaction of Difluoromethylphosphonates for α-Fluorovinylphosphonate Synthesis

Phosphonates are vital chemical compounds mimicking phosphates, widely found in nature and utilized in biochemistry.[8] Fluorinated phosphonates, notably α-fluorovinylphosphonates, serve as nonhydrolyzable phosphate substitutes, crucial for various biological inhibitions and synthetic pathways.[35] [107] [134] Efficient synthesis strategies, particularly for stereospecific isomer production, are imperative. Fluorinated diazoalkanes, such as 2,2,2-trifluorodiazoethane, are versatile precursors, yet research on difluorodiazoalkanes is limited due to altered chemical properties.[105] Recent studies have explored difluoro­methylphosphonate-containing diazo compounds, demonstrating their potential in diverse reactions.[58]

However, nothing is known about the aza-Wittig reactions of difluoroalkyl diazo compounds. Investigations into difluoroalkyl diazo compounds have anticipated a triphenylphosphine-facilitated reaction involving (β-diazo-α,α-difluoroethyl)phosphonate and carbonyl compounds through an aza-Wittig reagent pathway. This reaction provides a simple way to synthesize difluoromethylphosphonate-containing hydrazones. Nevertheless, an unexpected interaction between trifluoroacetoacetates 164 and (β-diazo-α,α-difluoroethyl)phosphonates 1c formed in situ was observed, yielding α-fluorovinylphosphonate-containing azo moieties 165 in notable yields and stereoselectivities, contrary to the expected hydrazone products (Scheme [34]).[156] α-Fluorovinylphosphonate compounds 165 exhibiting Z-stereoselectivity are synthesized in 42–94% yield at 60 °C (Scheme [34a]). A series of steps, including the creation of the diazo group, the aza-Wittig reaction, the addition of water to hydrazine, and the breakage of C–F bonds, were identified by mechanistic studies (Scheme [34b]). The diazo reaction content is enhanced by integrating the aza-Wittig reagent and adding water nucleophilically, which expands the synthesis options for bioactive α-fluorovinylphosphonate derivatives.[156]

Scheme 34 (a) Aza-Wittig reaction of β-diazo-α,α-difluoroethylphosphonate 1c with carbonyl compound 164 and (b) possible mechanism

7.7

Synthesis of Diethyl 2-Diazo-1,1,3,3,3-pentafluoropropylphosphonate via Alkene Cyclopropanation with Diazo Reagents and Its Utility

Cyclopropanes, notable for their unique structural and bonding characteristics, are pivotal in pharmaceuticals, materials science, and agricultural chemistry. Their synthetic utility depends significantly on the substitution patterns on the cyclopropane ring, particularly with trifluoromethyl and difluoromethyl groups.[107] [157] These fluorinated cyclopropanes are crucial due to the high electronegativity and low polarizability of fluorine, making them essential in designing biologically active molecules and specialized materials.[158] Extensive efforts have focused on developing synthetic methods for these compounds. Trifluoromethylcyclopropanes are generally synthesized via transition-metal-catalyzed cyclopropanation of alkenes with trifluoromethyldiazoalkanes or through regio- and diastereoselective carbometalation of trifluoromethyl-substituted cyclopropenes.[159] The synthesis of difluoromethylcyclopropanes, though less developed, employs difluorocarbene reagents such as difluorodiazoalkane (HCF₂CH(N₂)), difluoroethylsulfonium salt (Ph_₂S⁺CH₂CF₂H TfO^–), and difluoroacetaldehyde N-triftosylhydrazone. Additionally, limited syntheses of difluoromethylphosphonate-containing cyclopropanes involve cyclopropanation of CF₂P(O)(OEt)₂-containing alkenoates using Corey–Chaykovsky reagents and diazomethane or through photolysis of pyrazolines.[23] [160] [161] These compounds are valuable as nonhydrolyzable phosphate mimics with enhanced lipophilicity, metabolic stability, and bioavailability. The utilization of highly fluorinated diazo derivatives in cyclopropane synthesis is restricted by their limited availability and high volatility. Consequently, geminal trifluoromethyl-substituted cyclopropanes are typically synthesized via deoxofluorination of dicarboxylic acids, thiophilic ring-opening reactions, or reactions with donor-substituted furans and bis(trifluoromethyl)-substituted ethylenes.

A novel synthetic route for the bench-stable fluorinated masked carbene reagent diethyl 2-diazo-1,1,3,3,3-pentafluoropropylphosphonate (170), integrating trifluoromethyl and difluoromethyl groups, has been developed.[161] This reagent has been successfully used in CuI-catalyzed cyclopropanation of aromatic and aliphatic terminal alkenes under mild conditions, producing 16 new cyclopropanes in good to excellent yields (Scheme [35]).[161] The synthesis of the precursor, diethyl 2-diazo-1,1,3,3,3-pentafluoropropylphosphonate (170), involved a three-step process, yielding a stable, nonvolatile liquid. The optimized [2+1] cycloaddition with terminal aromatic and aliphatic olefins, such as 4-methylstyrene, revealed that copper(I) iodide in boiling toluene efficiently converted 74% of the diazo reagent to cyclopropane, unlike dirhodium tetraacetate and catalyst-free UV irradiation. This method favors the formation of one diastereoisomer, signifying a substantial advancement in diazo chemistry.[161]

Scheme 35 Cyclopropanation of 170 with alkenes

7.8

Esterification of (β-Diazo-α,α-difluoroethyl)phosphonate with Carboxylic Acids

Phosphate, a critical component in nucleic acids and phospholipids, is prevalent in nature. α,α-Difluoromethylphosphonates have garnered significant interest due to their biological activity and hydrolytic stability as polar mimetics.[8] [107] [162] Fluorinated phospholipid analogues, such as lysophosphatidic acid (LPA) with ester and difluoromethylene groups, offer new strategies for studying phospholipid signaling mechanisms in biochemistry.[163] Consequently, the development of efficient synthetic methods for these compounds is crucial. Fluorinated diazoalkanes are essential intermediates in organic synthesis, facilitating the incorporation of fluorinated alkyl groups into molecules. Since trifluorodiazoethane’s discovery in 1943, it has been extensively researched.[64] [105] In contrast, difluorodiazoethane, differing by only one hydrogen from CF₃, shows distinct stability and decomposition properties, limiting research­ since its 2015 development.[35] [57] Synthesized from difluoroethanamine and tert-butyl nitrite, difluorodiazoethane has been explored in dipolar cycloaddition, carbene transfer, and esterification reactions.[56] The Ma group developed a stable analogue, phenylsulfone-derived difluorodiazo (PhSO₂CF₂CHN₂), for synthesizing difluoromethyl compounds.[165a] Recently, the Han group developed (β-diazo-α,α-difluoroethyl)phosphonate for S–H insertion and cyclization reactions.[164] [58] In 2016, Liu’s group reported a rhodium-catalyzed asymmetric diazo insertion into carboxylic acid O-H bonds, yielding chiral esters.[3]

Scheme 36 (a) Esterification of β-diazo-α,α-difluoroethylphosphonate 1c with carboxylic acids 172 and (b) proposed mechanism

Inspired by recent advancements, the Han group proposed the esterification of (β-diazo-α,α-difluoroethyl)phosphonate 1c with carboxylic acids 172 as an efficient method to synthesize carboxylic esters containing difluoromethylphosphonate structures (Scheme [36]).[165b] This study reports a visible-light-induced O–H insertion reaction, achieving high yields of ester compounds. The reaction occurs under mild conditions without requiring an inert atmosphere, presenting a novel strategy for synthesizing α,α-difluorophosphonates. The proposed mechanism involves two main steps: in-situ generation of a diazo intermediate and subsequent protonation (Scheme [36b]). Initially, aminophosphonate 16 undergoes diazotization with tert-butyl nitrite, forming diazo intermediate 1c. Blue visible light excites this intermediate to state 174, which reacts with benzoic acid 172a, yielding the protonated intermediate 175. The final coupling between intermediate 175 and benzoate 172b produces the target product 173 and releases nitrogen gas. The reaction can also occur in the dark, suggesting direct protonation of diazo intermediate 1c by benzoic acid 172a. This O–H insertion reaction, yielding α,α-difluoromethylphosphonate-containing carboxylate esters with up to 87% efficiency, demonstrates broad substrate compatibility and offers an effective method for synthesizing α,α-difluorophosphonate derivatives.[165b]

8

Other Reactions

8.1

Diazophosphonate Synthesis via Acylation with N-Acylbenzotriazoles

Scheme 37 (a) Reaction of N-(o-aminobenzoyl)benzotriazoles 176 with 1d and (b) plausible mechanism for trans-phosphorylation reaction

α-Diazo-β-ketoesters, phosphonates and sulphones serve as versatile precursors in organic chemistry, participating in various transformations due to their carbene-forming propensity. Nevertheless, the synthesis of these compounds is constrained by the accessibility of starting materials, intricate procedural steps, and the requirement for delicate reaction conditions.[166] While direct acylation of diazo esters presents an attractive prospect, its exploration has been limited by the absence of appropriate acylating agents. Acylbenzotriazoles, activated derivatives originating from carboxylic acids, offer potential as acylating agents, especially in cases where other reagents are impractical.[167] [168] However, their application in the acylation of diazo compounds remains unexplored.

A new approach for the synthesis of α-diazo-β-ketophosphonates, α-diazo-β-ketocarboxylate esters, and α-diazo-β-ketophenylsulfones has been introduced. This method involves the acylation of diazomethyl anions using N-acylbenzotriazoles. It provides a novel route for producing these important organic synthetic intermediates. The authors discovered that the N-(o-aminobenzoyl)benzotriazoles 176 used in the acylation reaction undergo a unique transphosphorylation reaction, yielding diazoacetyl phenylphosphoramidates, not reported previously (Scheme [37]).[166] The methodology broadens the applicability of the acylation reaction to various diazo compounds and can be conducted on both small and gram scales with comparable yields. The use of acylbenzotriazoles 176 as reagents enables easy isolation and reuse of the benzotriazole byproduct, enhancing the economic feasibility of the reaction.[166]

8.2

Diazo Transfer Reaction for Synthesizing α-Aryl-α-diazophosphonates

Although α-diazophosphonates have not been as extensively researched as diazocarboxylates, recent investigations have begun to shed light on their utility in fabricating an array of phosphonic acid derivatives.[166]

Scheme 38 (a) Methods for the synthesis of α-aryldiazophosphonates 1b-a, 1b-b, and 1b-c; (b) synthesis of indole-containing diazophosphonate 1b-d; and (c) reaction of 2-furylphosphonate 185

In particular, α-aryl-α-diazophosphonates have demonstrated potential in the production of phosphonate-rich cyclopropanes, allenes, diarylphosphonates, imines, and α,β-unsaturated phosphonates.[140] [169] Even though sulfonyl azide-mediated diazo transfer reactions have proven effective for specific compounds, α-aryldiazophosphonate preparation remains a sticking point. Current methods require numerous stages in their syntheses, culminating in low yields and extensive time consumption. Given the importance of α-aryldiazophosphonates 1b, the pursuit of improved, more time-efficient synthetic approaches is an urgent matter. To this purpose, a simplistic synthetic pathway for fabricating α-aryl-α-diazophosphonates 1b via a diazo transfer reaction has been established (Scheme [38]).[16] This involves the reaction of benzyl phosphonate 181, 182, or 183 with tosyl azide (TsN₃) in the presence of potassium tert-butoxide. The yield of diazophosphonates procured was as high as 79%. The method showcased robust generality, allowing for the incorporation of various functional groups, as can be seen in 1b-a, 1b-b, 1b-c, 1b-d, 1b-e, and 186, facilitating the synthesis of a large number of desired compounds.[16]

8.3

Asymmetric 1,6-Conjugate Addition of α-Diazomethylphosphonates to para-Quinone Methides

para-Quinone methides (p-QMs), distinguished by their hexadiene core and para-carbonyl moiety, play a vital role in contemporary organic synthesis, notably in the 1,6-conjugate addition of diverse nucleophiles to p-QMs for the facile synthesis of diarylmethane compounds.[170] Despite notable progress, achieving chirally enriched diarylmethine motifs via asymmetric 1,6-conjugate addition to p-QMs with precise stereocontrol remains a formidable task, primarily due to the inherent challenges in controlling enantioselectivity arising from the significant separation between the carbonyl group and the δ-position where nucleophilic addition occurs.[171] The Seyferth–Gilbert reagent (SGR), renowned for enabling rapid access to phosphonate-functionalized compounds, has been employed in various asymmetric transformations, encompassing cyclopropanation of alkenes, [3+2] cycloaddition reactions, asymmetric aldol reactions, and the Mannich reaction.[120] [172] Drawing inspiration from advancements in asymmetric transformations involving p-QMs and the SGR, our group employed the potential of the SGR as a nucleophilic entity in asymmetric conjugate addition, introducing an innovative catalytic strategy for the synthesis of optically active diarylmethylated diazophosphonates 189 (Scheme [39]).[173] This research presents a synthetic route for accessing chiral functionalized diarylmethylated diazomethylphosphonates with notable efficiency and high product yields (up to 85%) and exceptional­ enantioselectivities (up to 99% ee) via asymmetric 1,6-conjugate addition of dialkyl diazomethylphosphonate 1k to p-QMs 187. Phase-transfer catalysts 188 derived from cinchona alkaloids and containing chiral ammonium ions demonstrate remarkable efficacy in facilitating the reaction (Scheme [39a]). The proposed transition state model 190 delineates the catalytic mechanism (Scheme [39b]), involving hydrogen bonding interactions between the hydroxyl group of the catalyst and the oxygen of p-QM, simultaneous engagement with the oxygen of diazophosphonate, and nucleophilic addition to the p-QM at the δ-position from the Re-face. Additionally, assistance from inorganic bases facilitates deprotonation and the formation of a phenolic anion intermediate, subsequently protonated to yield the 1,6-conjugate addition product.[173]

Scheme 39 (a) Asymmetric 1,6-conjugate addition of diazomethylphosphonate 1k to p-QM 187 and (b) proposed transition state model

8.4

Coupling of Diazophosphonates with Aryl Halides­ for the Synthesis of Vinylphosphonates

The stereoselective synthesis of alkenylphosphates holds significance in organic chemistry, serving as valuable synthetic precursors for pharmacologically active compounds.[174] [175] Conventional methods, such as Suzuki-type reactions and Heck reactions, suffer from limitations such as severe conditions and limited substrate scope. Wang et al. have devised a proficient approach employing palladium-catalyzed coupling reactions between α-diazophosphonates and benzyl or aryl halides to fabricate 1,2-disubstituted and 1,2,2-trisubstituted vinyl phosphonates, thereby overcoming prior limitations.[176]

Palladium-catalyzed olefination of N-tosylhydrazones 191 using aryl halides 192 generated 2,2-diphenylethylene derivatives 193 in favorable yields (Scheme [40a]).[177] This procedure comprises four sequential steps: oxidative addition, migratory insertion, reductive elimination, and β-hydride elimination (Scheme [40b]). β-Diazophosphonates are synthesized via palladium-catalyzed olefination, where the catalyst coordinates with N-tosylhydrazone and the diazophosphonate intermediate inserts into the aryl halide. Migratory insertion leads to β-diazophosphonate formation, which can undergo subsequent reactions to yield vinyl phosphonates. Various aryl halides, including aryl bromides and aryl chlorides, can be used as coupling partners. This method offers advantages such as the use of low-cost catalysts and readily available precursors and broad substrate compatibility, scalability, and further transformations (Scheme [40c]).[177]

Scheme 40 (a) Palladium-catalyzed olefination of N-tosylhydrazones 191 as β-diazophosphonates precursors with aryl halides 192; (b) possible mechanism; and (c) derivatization reactions of products 193 to form 198 and 199

8.5

Diazophosphonates in Regioselective Quinolinone Synthesis

The synthetic production of multipurpose 3-amino-4-dialkylphosphonoquinolin-2-ones featuring β-aminophosphonate and quinolin-2-one heterocycle frameworks is a significant objective owing to their distinctive bioactivity.[178] [179] Regioselective ring expansion of imino isatins offers an efficient approach for their synthesis. However, challenges include moderate yields in nucleophilic additions of diazomethylphosphonates to aldimines and limited investigation into reactions with ketoimines due to their low reactivity.[180,181] Moreover, regioselectivity issues in diazo compound rearrangements pose further challenges. Therefore, synthesizing the multipurpose 3-amino-4-dialkylphosphonoquinolin-2-ones via regioselective ring expansion of imino isatins represents a fascinating and difficult task.[182]

A one-pot synthetic route has been devised, involving nucleophilic addition of diazomethylphosphonate 1f to imino isatin 200, followed by regioselective ring expansion under the catalysis of potassium carbonate and salicylic acid, respectively (Scheme [41]).[182] This optimized protocol demonstrates satisfactory to excellent yields in the synthesis of versatile 3-amino-4-dimethylphosphonoquinolin-2-ones 201. Comparative analyses underscore the superior performance of K₂CO₃ compared to alternative bases such as DBU and 1,1,3,3-tetramethylguanidine (TMG) in facilitating the nucleophilic addition step. This approach exhibits potential for scalable production of multifunctional 3-amino-4-dialkylphosphonoquinolin-2-ones and related quinoline derivatives, with ongoing investigations to explore their biological activity.[182]

Scheme 41 (a) Nucleophilic addition between (imino)isatin 200 and diazomethylphosphonate 1f and (b) nucleophilic addition and subsequent rearrangement of diazomethylphosphonate 1d

8.6

Enantioselective Ring Expansion of Cyclohexanones with Diazophosphonates

Direct α-functionalization techniques have made headway in the synthesis of chiral β-ketophosphonates that feature a stereogenic center at the α-position.[183] [184] Numerous scholarly investigations have elucidated the employment of α-diazophosphonates in asymmetrical reactions to generate chiral phosphonate-derived compounds and, concurrently, additional studies have demonstrated the effectiveness of several Lewis acids in promoting asymmetric homologation processes.[15,185] Despite the successful implementation of asymmetric Tiffeneau–Demjanov-type ring-expansion reactions of carbonyls with diazo compounds catalyzed by Lewis acids, which present a promising avenue for rapid generation of chiral centers at α-positions of ketones, the direct enantioselective incorporation of phosphonates and stereogenic centers at the α-position of inert ketones through homologation remains elusive.[183,186]

Our research group has devised a novel approach for asymmetric ring expansion of 4-substituted cyclohexanones 202, employing α-diazomethylphosphonates 1f as substrates under the catalysis of a chiral boron Lewis acid (Scheme [42]).[183] This method yields β-ketophosphonates 204 with a stereochemically significant α-position, demonstrating remarkable efficiency, with high yields (80%), enantioselectivity (86% ee), and diastereoselectivity (>20:1 dr) (Scheme [42a]). The investigation provided insights into a conceivable stereocontrol mechanism governing the asymmetric homologation reaction, involving the activation of the cyclohexanone carbonyl by the boron Lewis acid, sequential nucleophile addition, and rearrangement processes leading to the desired product formation (Scheme [42b]). The resultant compound underscores the synthetic potential of this reaction, presenting opportunities for further derivatization to 204a,b and application in organic synthesis (Scheme [42c]).[183]

Scheme 42 (a) Desymmetrizing asymmetric ring expansion of 4-substituted cyclohexanones 202 with α-diazomethylphosphonates 1f; (b) stereocontrol mechanism of the asymmetric homologation reaction; and (c) further derivative transformation

8.7

Silver-Catalyzed Synthesis of 3-Benzoxepins via Nucleophilic Addition of Diazophosphonates

The scarcity of synthetic routes to access 3-benzoxepin derivatives, present in natural products with biological activities and crucial for optoelectronics, necessitates novel methods.[187] [188] Conventional techniques usually involve the photochemical isomerization of 7-oxabenzonorbornadiene or a double Wittig reaction with phthalaldehyde. Liu[24b] and Xu[24c] independently reported syntheses of 2-iodo-3-benzoxepins and 2-indole-3-benzoxepins, while Sarlah and colleagues[24d] presented a unique dearomative oxidation method. Despite these advancements, a practical synthetic route for 3-benzoxepins incorporating a phosphonate moiety, which holds the potential for enhancing bioactivity, remains elusive.[24]

To bridge this gap, our team developed a silver-catalyzed cyclization/nucleophilic addition methodology utilizing 2-alkynylacetophenones 207 and diazomethylphosphonates 1d, offering a flexible route for the synthesis of multifunctional isochromanones, with a notable generation of a ring-expanded byproduct, particularly a 1-phospho-3-benzoxepin derivative (Scheme [43]).[24a] This approach aligns with the efficient strategy of ring expansion for constructing heterocycles, as evidenced in successful applications for 2-unsubstituted 3-benzazepines. This innovative methodology yields a range of 1-phosphonate-3-benzoxepin analogues 208 with satisfactory yields (39–95%). The resulting benzoxepins, characterized by halogen and phosphonate moieties, exhibit versatility, facilitating further diversification into various derivatives 213. Significantly, this approach supplements existing techniques for 3-benzoxepin synthesis, constituting a valuable addition to the synthetic array for accessing this biologically pertinent structure. The demonstrated efficacy in producing diverse analogues underscores the robustness and applicability of the devised silver-catalyzed protocol for constructing functionalized 3-benzoxepins.[24]

Scheme 43 (a) Construction of 3-benzoxepin 208 skeletons through a silver-catalyzed ring-expansion reaction; (b) stepwise reaction of 2-acyl compounds and 1d; and (c) scale-up reaction and transformation

8.8

Nucleophilic Addition of α-Diazomethylphosphonates to Isoquinolines for the Synthesis of Chiral 1,2-Dihydroisoquinolines

Efforts in synthesizing 1,2-dihydroisoquinoline derivatives, crucial for their diverse biological and pharmacological properties, including blood-brain barrier permeability and antitumor activity, have focused on methodologies yielding tertiary stereocenters at the C1 position.[189] [190] Notably, nucleophile addition to in situ formed iminium or acyliminium ions via isoquinoline dearomatization is an established method to obtain 1-substituted dihydroisoquinoline analogues.[191] However, the range of nucleophiles used has been limited to certain compounds. In 2020, studies were presented that explored the viability of asymmetric variants of α-diazo compounds as nucleophiles for the addition to iminium or acyliminium ions resulting from isoquinoline dearomatization, broadening the spectrum of existing techniques for producing 1,2-dihydroisoquinoline derivatives with varied functionalities.[192–194]

A highly efficient asymmetric acyl-Mannich reaction employing chiral spiro phosphoric acids as catalysts has been developed (Scheme [44]).[31] It involves the reaction between isoquinolines 214, α-diazomethylphosphonate 1d, and diethyl pyrocarbonate 215, facilitating the formation of chiral 1,2-dihydroisoquinolines containing a tertiary stereocenter at the C1 position. The incorporation of chiral phosphoric acids 216 profoundly impacts enantioselectivity, leading to remarkable yields (up to 98%) and exceptional enantioselectivities (up to 99% ee) in the production of these compounds. Using diazophosphonates as nucleophiles introduces adaptability, allowing for the synthesis of a diverse range of compounds. The resultant chiral α-diazo-β-isoquinoline phosphonates 217 can be further manipulated to generate 1-substituted dihydroisoquinoline derivatives 217a,b, thereby broadening the array of synthetic opportunities available (Scheme [44]).[31]

Scheme 44 (a) Acyl-Mannich reactions of diazomethylphosphonate 1d with isoquinolines 214; (b) product derivatization; and (c) proposed reaction mechanism

8.9

Visible-Light-Mediated Benzannulation of Diazophosphonates with Alkynes

Recent advancements in the field of diazo compound chemistry have seen a surge in interest, particularly in the realm of visible light catalysis.[195] Traditionally, UV irradiation has been the preferred method, but there’s been a notable shift towards utilizing visible light photoredox catalysis, employing metal–polypyridyl complexes or organic dyes as photosensitizers.[196] [197] [198] Suero et al. conducted groundbreaking research utilizing hypervalent iodine substrates along with Ru(bpy)₃Cl₂ photocatalyst to produce diazomethyl radicals under visible light stimulation, essentially acting as carbyne equivalents.[199] Additionally, recent studies have explored the utilization of low-energy visible light for diazo compounds without the need for photosensitizers, demonstrating their versatility in reactions such as Wolff rearrangement and X–H insertions. Challenges persist in generating radical anion/cation species photochemically, requiring suitable one-electron reductants/oxidants. Zhou et al. addressed this by employing single electron transfer (SET) to generate enolated vinyl radical ions, offering a synthetic strategy for carboxylated naphthols. Despite the elegance of this strategy, its dependence on metal photocatalysts contradicts the goal of developing environmentally friendly reactions under visible light catalysis.[200]

Scholars endeavored to devise metal-free methodologies for the synthesis of phosphonylated heterocycles, prompting an investigation into the visible-light-mediated benzannulation of diazophosphonates with alkynes under visible light catalysis (Scheme [45]).[200] Through cyclic voltammetry experiments, researchers unveiled the profoundly negative irreversible reduction potential of α-diazophosphonate 1j (E _red = –1.25 V vs SCE in MeCN), indicating the inadequacy of conventional organic dyes such as rose bengal and eosin Y as photocatalysts for SET to diazophosphonates. A metal-free benzannulation reaction employing a Hantzsch ester as a photosensitizer was established, yielding functionalized phenanthren-10-ols 219 and naphthalen-1-ols 220 (Scheme [45]). The reaction involved photocatalytic single electron transfer, generating enolate vinyl radicals trapped by alkynes or o-aryl groups, demonstrating broad substrate scope and mild conditions for synthesizing functionalized aromatic compounds.[200]

Scheme 45 Visible-light-mediated benzannulation of diazophosphonates 1j with alkynes

8.10

Diazophosphonate-Catalyzed C–C Coupling: Redox-Neutral Pathway to Isocoumarins

Isocoumarins, crucial lactones in biologically active compounds, commonly found with substitutions at the 3-position, exhibit diverse biological activities.[201] Current synthesis methods involve preactivated coupling partners, limiting environmental friendliness. Previous studies on transition-metal-catalyzed carbenoid couplings demonstrated the formation of bonds between carbon atoms, demonstrating the significance of migratory carbene insertion in the process. Given the limited literature on the dephosphonylation of β-ketophosphonates, investigations center on the utilization of α-diazo-β-ketophosphonate as a carbenoid functionalization reagent, specifically tailored for the synthesis of 3-substituted isocoumarins devoid of 4-position substitutions.[202] While mild dephosphonylation methodologies such as Seyferth–Gilbert homologation are documented, conventional approaches often necessitate the use of potent reducing agents such as lithium aluminum hydride.[203] A notable 2016 inquiry by Ramana introduced fluoride-mediated dephosphonylation of α-diazo-β-carbonyl phosphonates.[204] The key challenge lies in achieving a redox-neutral dephosphonylation process conducive to the targeted synthesis of isocoumarins.

Scheme 46 (a) Rh(III)-catalyzed redox-neutral cascade process and dephosphonylative annulation of benzoic acids 221 with α-diazo-β-ketophosphonate 1j and (b) plausible mechanism

A Rh(III)-catalyzed redox-neutral cascade process has been devised for the direct construction of the 3-substituted isocoumarin 222 scaffold through the carbenoid functionalization and dephosphonylative annulation of benzoic acids 221 with α-diazo-β-ketophosphonate 1j (Scheme [46a]).[203] This innovative method circumvents the need for stoichiometric employment of oxidizing agents, presenting a fully redox-neutral approach to synthesizing isocoumarins via a C–H functionalization strategy. Through the utilization of DFT, an in-depth analysis of the catalytic cycle was conducted, revealing a concerted pathway for C–C coupling between the ortho-positioned carbon atom of benzoic acid and the diazo carbon atom, which exhibits lower activation energy compared to the stepwise pathway. The computational investigations offer valuable insights into the mechanistic intricacies of C–C coupling via carbenoid functionalization to a C–H bond, thus advancing the understanding within the synthetic chemistry community and facilitating the exploration of carbenoid functionalization across diverse applications (Scheme [46b]).[203]

8.11

Nucleophilic Addition of the Bestmann–Ohira Reagent to para-Quinone Methides for the Synthesis of α-Diazo-β-diarylphosphonates

Organic synthesis has demonstrated the great potential of the Bestmann–Ohira reagent (BOR), also referred to as α-diazo-β-ketophosphonate.[172] Originally employed for the extension of one-carbon aldehydes to acetylenes, it has subsequently found application in diverse pathways, encompassing the synthesis of heterocycles such as oxazoles.[205] Recent advancements involve its base-mediated deacylation leading to the synthesis of pyrazole phosphonates and deacylative nucleophilic substitution for α-diazo-β-arylphosphonate synthesis.[206] The exploration of deacylative conjugate addition utilizing BOR remains a largely uncharted territory within the scientific community. para-Quinone methides (p-QMs) stand out as notable receptors for 1,6-addition, primarily owing to the subsequent possibility of aromatization after 1,6-addition.[207] Diverse nucleophilic agents have demonstrated their aptitude for engaging p-QMs in a 1,6 manner, thereby highlighting their proficiency as vinylogous Michael acceptors.[208] Particularly noteworthy is the role of Lewis acidic environments in facilitating the 1,6-addition of diazo esters onto p-QMs. Upon scrutinizing the reactivity of the BOR, it emerges as a pivotal precursor for nucleophilic addition reactions, as evidenced by its successful conjugate addition to p-QMs, thereby underscoring its potential as a vinylogous Michael donor.[209]

In the pioneer investigation, the BOR 1j has been introduced as a novel participant in the deacylative 1,6-addition reaction with p-QMs 187a, resulting in the synthesis of α-diazo-β-diarylphosphonates 189a and cis-stilbenyl phosphonates 231 in remarkable yields (Scheme [47a,b]).[209] The reaction initiates with the deacylation of BOR catalyzed by ethanolic KOH, leading to the formation of a 1,3-dipolar intermediate 229 (Scheme [47c]). Subsequently, this intermediate engages in a 1,6-addition to p-QMs, forming a stable intermediate 230 due to the aromaticity of the phenolate ion. Protonation mediated by the solvent promotes the formation of the 1,6-addition product, evidenced by notable infrared peaks corresponding to the diazo group and distinct NMR shifts for benzylic protons and carbons. The confirmation of the 1,6-adduct structures was achieved through thorough spectroscopic analysis and single-crystal X-ray crystallography. The synthesis of cis-stilbenyl phosphonates from diazophosphonates involves the Rh(II)-catalyst-induced heating of diazophosphonates, leading to the formation of a Rh carbenoid. An intramolecular 3-exo-trig cyclization, catalyzed by the nucleophilic attack of the phenolic ring on the carbenic carbon, results in the formation of a spirocyclopropane intermediate. Subsequent rearomatization of this intermediate predominantly yields cis-stilbenyl phosphonates as the E-isomer (Scheme [47c]).[209]

Scheme 47 (a) Deacylative 1,6-addition of Bestmann–Ohira reagent 1j to para-quinone methides 187a; (b) scope of diazophosphonates; and (c) plausible reaction mechanism.

8.12

Ti(IV) Enolates of Diazophosphonates in Regio­selective Enone Addition

Ti(IV) enolates are important nucleophiles that are frequently used in reactions involving imines, ketones, and aldehydes. Because 1,2- and 1,4-addition models are present, their interactions with conjugated enones are very intriguing.[210] Lewis acids increase the carbonyl coefficient of the enone’s LUMO, which in turn promotes 1,2-addition when coordinated to the carbonyl group oxygen of enones.[211] The regioselectivity of these reactions is influenced by both the Lewis acid used and the structure of the Ti(IV) enolate; however, the precise causes of this variance remain to be discovered. To further understand the reaction process, more research on Lewis acid controlled regioselective condensation is advised, particularly with various Ti(IV) enolates.

Utilizing DFT computations alongside empirical investigations, the regioselective addition pathways of Ti(IV) enolates generated from α-diazo-β-keto carbonyl compounds and α-diazo-β-ketophosphonates to conjugated enones were explored (Scheme [48]).[210] The DFT findings elucidate that for the Ti(IV) enolate originating from α-diazo-β-keto carbonyl compounds, the energy barrier for the bridging-chloride-mediated 1,2-addition transition state surpasses that of the 1,4-addition, whereas for the Ti(IV) enolate derived from α-diazo-β-ketophosphonates, it is comparatively lower. Remarkably, this investigation disclosed the nucleophilic addition of these Ti(IV) enolates to conjugated enones as a kinetically and irreversibly favored process for the first time. The selectivity of the addition reactions emerges from the disparate chelation patterns between the titanium-coordinated oxygen group and the bridging chloride architecture (Scheme [48]).[210]

Scheme 48 (a) Regioselective nucleophilic addition of Ti(IV) enolate 232 to cyclohex-2-enone 233 and (b) the addition process of Ti enolates with cyclohex-2-enone 233

8.13

Tandem Nucleophilic Addition/Oxa-Michael Reaction of Chalcone with Diazophosphonate

The tandem reaction’s chemistry was strengthened by the use of dimethyl (diazomethyl)phosphonate to synthesize the non-alkynes phthalans, a basis for the effective synthesis of alkynes using Seyferth–Gilbert homologation of dimethyl (diazomethyl)phosphonate with aldehydes.[212] [213]

To create halogenated phthalans, o-formyl chalcones have been shown to undergo a tandem reaction with strong enough nucleophiles by the Gong group.[214a] The yet undocumented Seyferth–Gilbert chain extension process manifests as a distinctive tandem reaction involving o-formyl chalcones and dimethyl (diazomethyl)phosphonate, characterized by their weak nucleophilicity, under base catalysis. However, despite its significance, this remains an ongoing and intricate subject of study. Our research team has disclosed an innovative tandem nucleophilic addition/oxa-Michael reaction involving o-formyl chalcone 240 and dimethyl (diazomethyl)phosphonate (1d), resulting in the synthesis of 1,3-disubstituted phthalan 241 incorporating a phosphine moiety in satisfactory yield, albeit with the drawback of unregulated diastereoselectivity (Scheme [49]).[214b] This approach may potentially be used in the synthesis of bioactive compounds due to the possible chemical and biological interest of 1,3-disubstituted phthalans containing phosphine. Our team is now investigating further research aimed at the enantioselectivity of this reaction and the application of this method to synthesize natural products.

Scheme 49 (a) Tandem reaction between ortho-formyl chalcone 240 and dimethyl (diazomethyl)phosphonate (1d); (b) possible mechanism; and (c) synthetic utility of the product 241

8.14

Catalytic Tandem Asymmetric Cyclization for Isochromene Synthesis

It is a challenging but potentially rewarding task to develop an effective catalytic methodology to confirm the tandem asymmetric cyclization and a C–C bond formation by a subsequent carbon nucleophile. This is particularly significant to provide isochromenes having tetrasubstituted chiral stereocenters at position 1. A chiral environment is created during the reaction by a transition metal as a catalyst attaching itself to the isobenzopyrylium ion at position 4 even after activating the alkyne bond to carry out the intramolecular cyclization with o-carbonyl compounds. Asymmetric nucleophilic addition might be accomplished at position 1 by utilizing the coordination between the central metal and a chiral ligand with a long enough arm to pass on chiral environmental proximity. Our research group successfully prepared isochromenes 245 featuring four coordinated stereocenters and (diazomethyl)phosphonate at position 1, achieving an impressive yield of 99% with up to 94% ee (Scheme [50]).[212] By transformation of phosphine-containing functional isochromenes to important structural motifs 245a–e, biologically active compounds could be obtained. In addition, the scope of nucleophiles for the reaction can be enlarged to diazoacetate.[212]

Scheme 50 (a) Asymmetric tandem reaction between diazomethylphosphonate 1d and o-alkynylphenyl ketone 243 and (b) derivatization of product 245

Scheme 51 (a) Asymmetric tandem reaction of o-alkynylbenzaldehydes 246, arylamines 247, and diazophosphonate 1d and (b) derivatization of product 249

8.15

Asymmetric Tandem Imine–Yne Cyclization Using Diazomethylphosphonates

Our lab has documented methodologies for the synthesis of 1,2-dihydroisoquinoline 249 derivatives, with a particular emphasis on those featuring a C1 tertiary stereocenter. Such structures are prevalent in numerous bioactive compounds and natural products.[189] [191] [215] O-Alkynyl benzaldehydes 246, amines 247, and diazo compound 1d undergo an asymmetric tandem reaction in which chiral silver imidodiphosphate acts as a catalyst (Scheme [51]).[215] It aims to provide an efficient method to confirm asymmetric tandem imine–yne cyclization/nucleophilic reactions, which is crucial, because the bioactivity of compounds containing the 1,2-dihydroisoquinoline 249 motif is strongly dependent on the absolute configuration of its stereogenic center at the C1 position. The research presents the successful application of this strategy utilizing (diazomethyl)phosphonates 1d as nucleophiles, leading to the synthesis of chiral phosphorus-containing compounds, integrating β-aminophosphonic acids and 1,2-dihydroisoquinolines with various substituents at the C3 position. The study also explores various reaction conditions, including different ligands, solvents, and concentrations to optimize the efficiency and enantioselectivity of the reaction. Additionally, the substrate adaptability of the reaction is investigated, which results in the derivatization of the obtained products, demonstrating the potential to create chiral phosphorus-containing compounds and PARP1-inhibitor analogues.

The resultant compounds derived from the asymmetric tandem reaction involving o-alkynylbenzaldehydes, arylamines, and diazo compounds, catalyzed by chiral silver imidodiphosphate, can be extended to generate diverse chiral phosphorus-containing compounds and analogues of PARP1 inhibitors. This can be achieved through various derivatization processes, such as treating the products with P(Bu)₃ to furnish chiral hydrazones 249a, hydrogenation under catalysis by PtO₂ to provide β-tetrahydroisoquinolin-1-yl phosphonates 249b, and further reduction with NaBH₃CN to obtain chiral acetate 249d (Scheme [51]).[215] These derivatization methodologies facilitate the production of diverse valuable compounds with promising pharmaceutical implications.

8.16

Thiourea-Catalyzed Asymmetric Cycloaddition Reaction of Diazophosphonates

Diazomethylphosphonates, as the isosteres of diazo esters, have been effectively used in asymmetric reactions. These reactions include allylic alkylation/1,3-dipolar cycloaddition and Mannich-type asymmetric reactions as nucleophiles.[29] However, until recently, there have been only a few reports of the reaction of α-diazophosphonate with carbonyl compounds. Among these, the Seyferth–Gilbert homologation is well acknowledged as an effective and straightforward approach for the synthesis of alkynes.[216] [217] Our group described an innovative approach for the asymmetric reaction of diazomethylphosphonate 1d with α-keto esters 250 catalyzed by hydroquinone-derived bifunctional thiourea (Scheme [52]).[29] Numerous chiral α-diazo-β-hydroxyphosphonate tertiary carbinols 252 were successfully synthesized, demonstrating high yields of up to 99% and enantioselectivities reaching up to 98% ee. Hydrogenation could yield a variety of tertiary β-hydroxyphosphonates 252a,b. Furthermore, successive electrophilic halogenation and intramolecular epoxidation reactions yielded chiral α-halogenated fosfomycin derivatives 252c–e, notable α-fluoride analogues, holding promise for therapeutic and biological applications (Scheme [52]).[29]

8.17

Catalytic Regioselective C–H Functionalization of Indoles and Pyrrole with Diazophosphonates

Miao and colleagues investigated the involvement of carbenoid insertion mechanisms in C–C bond formation and the development of synthetic methodologies for the catalytic synthesis of such frameworks.[37] In this investigative approach, BF₃·Et₂O catalyzes the decomposition of α-diazophosphonates, yielding a carbene complex.[218] Subsequently, migration of the phosphonate’s β-hydrogen to the carbene center occurs, leading to the formation of a tertiary carbocation intermediate.

Scheme 52 (a) Asymmetric reaction of α-diazomethylphosphonate 1d with α-keto ester 250 and (b) synthetic utility of α-diazo-β-hydroxyphosphonate tertiary carbinol 252

This technique allows structurally interesting substrates with quaternary carbon centers including nitro atoms to be synthesized in a regiospecific manner. Based on the substitution arrangement of the indole moiety and the carbene migratory model, the reaction methodology exhibited efficacy in achieving regioselective C–H insertion, leading to the synthesis of N-unsubstituted β-(indol-3-yl)phosphonates 255 and β-(pyrrol-2-yl)phosphonates 255a, featuring quaternary carbon centers with yields ranging from moderate to good (Scheme [53]).[37] The study documented optimized reaction parameters and explored the reaction’s scope using diverse α-diazophosphonates and derivatives of indole 254 or pyrrole 254a, underscoring the importance of the indole moiety’s substitution pattern and the reaction’s selectivity. The findings contribute to the development of efficient and versatile routes to complex natural products, making it a significant advancement in the field of organic synthesis. The proposed mechanism elucidates the nucleophilic addition of indole to the electrophilic resonance complex, thereby advancing comprehension of carbenoid insertion reactions and their utility in organic synthesis.[37]

Scheme 53 (a) C–H insertion reactions of α-diazophosphonates 253 with indole 254 and pyrrole 254a and (b) proposed reaction mechanism

In forthcoming investigations concerning the regiospecific intermolecular C–H insertion reactions of α-diazophosphonates with indole or pyrrole derivatives, the substrate’s scope could be widened to encompass diverse heterocyclic compounds and α-diazophosphonates exhibiting diverse substitution patterns. Additionally, investigating the development of new catalytic systems or modifying the existing BF₃·Et₂O-catalyzed reaction to enhance the regioselectivity and yield of the desired products would be a valuable area of research. Subsequent investigations may explore the potential application of the synthesized N-unsubstituted β-(indol-3-yl)- and β-(pyrrol-2-yl)-β-aminophosphonates in the synthesis of intricate natural products and biologically active compounds. This could involve studying the biological activities and potential pharmaceutical applications of these synthesized compounds. Additionally, further research could focus on elucidating the mechanistic details of the C–H insertion reactions and exploring the potential for scaling up the synthesis for practical applications.[37]

Scheme 54 Wolff rearrangement of α-acyl-α-diazophosphonates 1j and Horner–Wadsworth–Emmons olefination of aldehyde

8.18

Diazo(oxo)phosphonates Obtained by Wolff Rearrangement of Diazophosphonates in Acrylamide Synthesis

Scheme 55 (a) Sequential nucleophilic addition/ring-expansion reactions of diazo compound 1d with isatins 264 and (b) proposed mechanism

Dar’in and colleagues reported the synthesis of polysubstituted acrylamides 263, particularly for anticancer applications (Scheme [54]).[219] Their method utilizes a microwave-promoted Wolff rearrangement of α-acyl-α-diazophosphonates, which are subsequently trapped in situ with amines. This approach effectively generates ketenes from α-diazo-β-oxophosphonates 1j via microwave-promoted Wolff rearrangement, followed by in situ trapping with amines, yielding good results. The approach allows for flexible variation in substituent groups, which is crucial for fine-tuning the selectivity and reactivity of the resulting acrylamides for targeted cancer therapeutics. This approach is considered efficient and flexible, allowing for adjustment of the electronic and steric properties for selective targeting in medicinal chemistry, especially for small-molecule inhibitors of thioredoxin reductase, an enzyme overexpressed in cancer cells in cancer cells, pointing towards the potential for developing new anticancer drugs. The detailed investigation outlined in the research aims to provide a more practical, catalyst-free alternative to existing methods for producing phosphonamides 262 from diazo precursors (Scheme [54]).[219]

8.19

Nucleophilic Addition and Ring Expansion Reactions of α-Diazophosphonates and Isatins

Wang, Zhao, Yan, and others presented research on the chemical synthesis of 4-phosphorylated 3-hydroxyquinolin-2-ones (3HQs) 266 (Scheme [55]).[220] The study introduced a sequential protocol using α-diazophosphonate 1d with isatins 264, catalyzed by inorganic bases, to first produce α-diazo-β-hydroxyphosphonate derivatives 265. These derivatives can then undergo a regioselective ring-expansion rearrangement without the need for a catalyst to form 4-phosphorylated 3HQs 266 in varying yields. Due to the vast spectrum of biological and pharmacological activities of 3HQs, including their potential antiviral and anticancer properties, this work is significant in the field of medicinal chemistry. 3HQs with the 4-substitution pattern, in particular, have shown promise in inhibiting human immunodeficiency virus replication and may serve as leads for developing new anti-inflammatory and anticancer agents.

The development of 4-phosphorylated 3HQ analogues has been less explored compared to other 4-substituted 3HQs. The authors of the study believe that incorporating the phosphate group, which is central to many biological processes, into the 3HQs could result in compounds with enhanced or new biological activities. This research contributes an efficient method for synthesizing these phosphorylated compounds, which could be valuable for further pharmacological development.[220]

8.20

Brφnsted Acid Catalyzed Asymmetric Mannich­ Reaction of Dialkyl α-Diazomethylphosphonates with N-Carbamoyl Imines

The catalysis of the asymmetric transition by axially chiral dicarboxylic acid has been studied by the Hashimoto group.[221] Although the β-amino-α-diazophosphonate 275 derivatives (see Scheme [56]) produced had good ee values, more has to be done to increase the catalytic efficiency and application of the imine substrates. Terada and coworkers’ groundbreaking research revealed that chiral phosphoric acid may efficiently and with good enantioselectivity catalyze the asymmetric Mannich reaction between N-acylimines and tert-butyl diazoacetate.[223a] The excellent results of the chiral phosphoric acids in those asymmetric transformations led to research into their potential application in the α-diazomethylphosphonate reaction with N-carbamoyl imines.[222] [223]

Scheme 56 (a) Catalytic asymmetric Mannich reactions of N-carbamoylimines 273 with α-diazomethylphosphonate 1k and (b) synthetic utility of β-amino-α-diazophosphonate 275

To synthesize β-amino-α-diazophosphonate 275 with high enantioselectivity and a wide range of substrates, our group set out to develop an effective catalytic methodology. We found that binaphthyl phosphates 274 can function in the asymmetric Mannich reaction at a 0.1 mol% catalyst loading, resulting in an even higher ee and excellent yield (Scheme [56]).[30] This process, also known as the asymmetric Mannich reaction, is catalyzed by chiral phosphoric acids and results in the production of the corresponding β-amino-α-diazophosphonate in yields up to 97% and >99% ee.[30]

9

Future Directions

Future research in diazophosphonate chemistry should focus on developing novel catalytic systems, such as new chiral and bimetallic catalysts, to improve enantioselectivity and catalytic performance under milder conditions. Expanding the scope of cycloaddition reactions and exploring C–H activation will further enhance the adaptability of diazophosphonates. Mechanistic and theoretical studies, utilizing advanced spectroscopic techniques and predictive modelling, are crucial for understanding reaction mechanisms and designing more efficient processes. Developing methodologies for diastereoselective transformations and investigating functional group tolerance will broaden the synthetic applications of diazophosphonates. Sustainable approaches, including the use of eco-friendly reagents and catalyst recycling, will improve the environmental impact and cost-effectiveness of these reactions. In medicinal chemistry, exploring the synthesis of bioactive compounds and drug conjugates can lead to new pharmaceutical applications. Material science applications, such as the synthesis of functional materials and surface modifications, offer promising avenues for research. Integrating diazophosphonates with emerging technologies such as flow chemistry and photoredox catalysis will open new pathways and enhance reaction control and scalability. By focusing on these areas, researchers can push the boundaries of diazophosphonate chemistry, realizing new synthetic capabilities and applications across diverse fields.

10

Conclusion

The comprehensive examination of recent advances in diazophosphonate-related reactions and transformations underscores the diversity of diazophosphonates as essential organic chemistry reagents. These reactions, including [3+2] cycloaddition, asymmetric [3+2] cycloaddition, asymmetric [3+3] cycloaddition, and nucleophilic substitution, exploit the unique reactivity and broad applicability of diazophosphonates to facilitate diverse functional group conversions. Notably, this review emphasizes their pivotal role as precursors for a wide spectrum of significant compounds, such as β-aminophosphonates, functional isochromenes, and pyridazine-4-one derivatives. Additionally, the innovative development of diazophosphonate-based catalysts for asymmetric Mannich reactions underscores the expanding horizons of diazophosphonates in organic synthesis. Given their importance and demand, this review encourages further exploration and evaluation of the rich chemistry of diazophosphonates. The rapid advancements discussed herein serve as crucial stepping stones for future explorations and practical applications across various domains of chemical science, highlighting the enduring power and potential of diazophosphonates.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 06 June 2024

Accepted after revision: 30 July 2024

Article published online:
05 September 2024