Interrupted intramolecular [3 + 2] to 5-endo-dig cyclization: [3 + 2] cycloaddition of nitrile ylides of diazo esters: photo-induced solvent-free gem-diamination to synthesize α-amino-α-substituted α-amino esters

Abstract

In this work, we transition the blue LED-induced intramolecular [3 + 2] cycloaddition of nitrile ylides, generated from singlet carbenes of diazo esters, towards an intermolecular [3 + 2] cycloaddition with substituted isocyanates. This photolytic reaction efficiently yields α-amino-α-aryl α-amino esters through gem-diamination of readily available diazo esters, using diverse organonitriles and isocyanates as amine sources. The resulting α,α-disubstituted α-amino acids (α-AAs) are known to exhibit enhanced properties compared to conventional amino acids. These reactions, employing nitriles as stoichiometric reagents, are easily scalable to multigram quantities. Control experiments, coupled with density functional theory calculations, provide detailed insight into the reaction mechanism.

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Introduction

α,α-Disubstituted α-amino acids are intriguing and biorelevant building blocks.¹ They not only enhance the chemical and metabolic stability of peptide backbones but also increase lipophilicity and induce unique conformations.^2–5 These amino acids exhibit diverse biological activities and are utilized for studying peptide structures, designing foldamers, and developing peptoid-based therapeutics.^6,7 Currently, 40–60% of new active pharmaceutical ingredients (APIs) suffer from poor aqueous solubility, leading to reduced bioavailability and drug efficacy.⁸ The use of non-proteogenic α,α-disubstituted α-amino acids offers a potential solution to this issue.⁹ Due to their presence in various natural products, they have attracted significant interest from pharmaceutical researchers as valuable building blocks for drug candidates.^10–12

Some α,α-disubstituted α-amino acids arise from post-translational modifications, yet their synthesis, both chiral and achiral, remains challenging. This is largely due to steric hindrance from the four distinct non-hydrogen substituents at the quaternary carbon centre, necessitating multi-step syntheses that preserve the amino and carboxylate functionalities. Among these compounds, gem-diamino carboxylic acid derivatives are particularly important non-proteinogenic amino acids, commonly found in both natural and synthetic bioactive compounds. These derivatives are now recognized as crucial structural subunits in a variety of biologically active molecules (highlighted figure in Scheme 1a).^13–15

Scheme 1 (a) gem-Diamino carboxylic acid containing drug molecules. (b) Conventional strategies to construct α,α-disubstituted α-amino acids. (c) Amidation of imines for gem-amination. (d) Reported hydrolysis of imidazolidinones for the generation of substituted amino acids. (e) The design and concept of our interrupted intramolecular [3 + 2] cycloaddition of nitrile ylides A/A′ for the generation of α-amino-α-substituted amino acids.

The significance of bioactive building blocks has driven numerous synthetic studies. The traditional route, the Strecker synthesis (established in 1850), involves hydrocyanation of activated imines followed by hydrolysis to yield amino esters (Scheme 1b(i)).^16,17 Although an asymmetric variant was later introduced, the process suffers from low yields, toxic cyanides, and ketimine enolization as a side reaction.¹⁸ The low electrophilicity of the iminyl carbon in ketimines further limits its application in synthesizing α,α-disubstituted-α-amino acids. Alternatively, Schiff base enolates have been used with various electrophiles to access these amino acids, though the iminyl carbon's electrophilicity remains critical for product formation (Scheme 1b(ii)).^19,20 Phase transfer-catalysed reactions of achiral Schiff bases offer a milder approach but require multiple steps to prepare the bases. Notably, two examples of gem-diamino carboxylic acid derivatives have emerged (Scheme 1c[i] and [ii]).^21,22 Zeng and colleagues used catalytic Cu(OTf)₂ and PPh₃ for the intermolecular amidation of α-acylimines (Scheme 1c[i]), while Antilla et al. employed chiral VAPOL calcium phosphate with sulfonamides for a similar transformation (Scheme 1c[ii]).^21,22

In the past decade, advances in α,α-disubstituted-α-amino acid synthesis have emerged through metal-free C–H activation, organocatalysis, photo-electrocatalysis, and CO₂ fixation.^23–28

Despite extensive efforts, the synthesis of α-amino-α-aryl α-amino esters remains elusive. Traditional methods like electrophilic amination of Schiff base enolates and nucleophilic Strecker reactions have proven ineffective. Reported imine amidations only produce tertiary carbons, leaving quaternary centers inaccessible. Therefore, a new approach is necessary.

Imidazolidinones are known to hydrolyze into disubstituted α-amino acids (Scheme 1d).^29,30 We propose that dihydro-imidazolidinone X could serve as a precursor, generating the desired α-amino-α-aryl α-amino esters upon hydrolysis (Scheme 1e[i]), provided suitable functionalities are installed. Precursor X could be synthesized via a [3 + 2] cycloaddition between substituted isocyanates and nitrile ylides A, derived from diazo esters 1. Recently, we reported that under blue LED light, nitrile ylide A′ is formed by inserting alkyl nitriles into singlet carbenes from diazo esters, followed by an intramolecular [3 + 2] cycloaddition to yield 1,3-oxazoles (Scheme 1e[ii]).³¹ Here, we aim to interrupt this intramolecular cycloaddition by trapping nitrile ylide A with aryl isocyanates, promoting intermolecular [3 + 2] cycloaddition to access α-amino-α-aryl α-amino esters (Scheme 1e[i]).

We present a novel, modular, solvent-free, and eco-friendly synthesis of α-amino-α-aryl α-amino esters via geminal diamination of diazo esters with alkyl nitriles (including acetonitrile) and substituted isocyanates as aminating agents under blue LED light (456 nm) at room temperature (Scheme 1e[i]). The key step is an intermolecular [3 + 2] cycloaddition between nitrile ylides A and isocyanates. Control experiments helped elucidate the reaction mechanism.

Results and discussion

As a proof of concept, phenyl diazoacetate 1a (1 equiv.) was reacted with phenyl isocyanate 2a (1 equiv.) in acetonitrile 3a (50 equiv.) under blue LED light (456 nm, ∼34 W, see the ESI† for details) at room temperature for 6–7 hours (Scheme 2). Thin layer chromatography revealed the formation of a major product, which was isolated and identified as α-amino-α-phenyl α-amino ester 4a, with a 72% yield. The structure was confirmed by single-crystal X-ray analysis (Scheme 2). Interestingly, acetonitrile and phenyl isocyanate were the amine sources. When tested with other LEDs (white, red, green, and violet), none were as efficient as the blue LED. Solvent mixtures (THF, DCM, toluene, and DCE with acetonitrile) were also less effective and pure acetonitrile afforded the best results. To minimize acetonitrile use due to toxicity concerns, the reaction was optimized with 1–4 equivalents of acetonitrile, with 4 equivalents providing the best yield of 76% (Scheme 2). The final protocol involved irradiating 1a and 2a with a blue LED for 7 hours at room temperature in 4 equivalents of acetonitrile, yielding 4a.

Scheme 2 Proof-of-concept studies for the synthesis of 4a followed by the optimisation of the process.

After optimizing the reaction conditions, we explored the scope of our protocol for synthesizing various α-amino-α-aryl α-amino esters 4 (Scheme 3). A variety of diazo esters 1 and aryl isocyanates 2 were reacted with stoichiometric acetonitrile 3a or propionitrile 3b under blue LED irradiation at room temperature in open air. Depending on the physical state of the diazo esters, 3 equivalents of nitriles were used for liquid diazo esters, and 5 equivalents for solid ones. Initially, diazo esters 1a–1p were reacted with phenyl isocyanate 2a, affording products 4a–4q in 66–93% yields (Scheme 3). Yields varied with the substitution pattern of the aryl diazo esters; electron-withdrawing groups (e.g., para- and meta-fluoro, and meta-trifluoromethyl) gave higher yields than electron-donating ones. This may be due to better stabilization of singlet carbenes by electron-withdrawing substituents. Both acetonitrile and propionitrile worked well, providing products 4l–4q in moderate to excellent yields. Notably, benzyl and phenyl nitrile reactions yielded 1,3-oxazoles via intramolecular [3 + 2] cycloaddition. To further test the robustness of our protocol, various aryl isocyanates 2b–2g were reacted with substituted diazo esters 1a–1q (Scheme 3). Gratifyingly, products 4r–4ar were obtained in moderate to excellent yields. Electron-poor diazo esters (e.g., 1c, 1g, 1h and 1t) combined with electron-rich isocyanates (e.g., 2b, 2d, 2f and 2g) afforded high yields (>88%). The reaction tolerated para- and meta-substituted aryl isocyanates, generating compounds 4ag–4ar. Sensitive groups like –NO₂ (1n), –CO₂Me (1l and 1m), and –CN (2e) were compatible, producing compounds 4aj and 4al–4ap in good yields. The reaction of 3,5-dichlorophenyl diazoacetate 1o with 3-chlorophenyl isocyanate 2f in acetonitrile produced 4ak in 74% yield. Similarly, 3-tolyl isocyanate 2g reacted with diazo esters 1e and 1p to give 4aq and 4ar. Interestingly, reactions of diazo esters 1a–1d with o-tolyl isocyanate 2h did not yield the desired products, instead isolating 1,3-oxazoles 7a–7d, likely due to steric hindrance from ortho-aryl substituents. To demonstrate scalability, reactions of 1b and 1c with 2c and 2d were performed on a gram scale, affording products 4s and 4af in 70% and 88% yield, respectively. The final products were isolated via recrystallization from isopropanol.

Scheme 3 Synthesis of diversely substituted α-amino-α-substituted amino esters.

Next, we wanted to investigate numerous other diazo esters as a suitable substrate for our reaction. Accordingly, dimethyl-2-diazomalonate 5a, diethyl diazomalonate 5b and diisopropyl diazomalonate 5c when reacted with 4-chlorophenylisocyanate 2d in acetonitrile 3a afforded the desired α,α-dicarbonylated aminals 4as–4au in excellent yields (Scheme 4). The resulting α,α-dicarbonylated aminals belong to a class of chemicals that exhibit high potential as synthetic building blocks for diverse frameworks, including bioactive compounds.^32,33 However, unlike ours, the reported strategies are either multistep and or demonstrate installation of the same two amino moieties.^34–42 In another example, the reaction of methyl-2-diazopropanoate 5d with 3-cyanophenyl isocyanate 2e generated the desired final compound 4av in 67% yield (Scheme 4). It is noteworthy that ethyl-2-diazoacetate 5e, methyl diazopropanoate 5f and methyl-2-diazobutanoate 5g failed to generate the α-amino-α-aryl α-amino esters 4.

Scheme 4 Application of our geminal diamination of aryl diazo esters on numerous diazo esters using deuterated acetonitrile, and the expedient functionalisation of felbinac.

Next, we wanted to assess the compatibility of our protocols with alkyl isocyanates. Accordingly, benzyl isocyanate 2i afforded the desired products 4aw–4ay in 45 to 56% yields (no 1,3-oxazole detected) with 1f, 1j and 1p (Scheme 4).

The utility of our newly developed double C–N bond formation strategy was demonstrated through the functionalization of felbinac, a nonsteroidal anti-inflammatory drug (NSAID) used to treat muscle inflammation and arthritis (Scheme 4).^43,44 Felbinac is typically functionalized at the carboxylic acid or biphenyl moiety, but there are no reports of benzylic functionalization.^45,46 We methylated felbinac, installed a diazo group, and used the resultant substrate 1q (see the ESI†). Under optimized conditions, reactions of 1q with isocyanates 2a, 2b, 2d, and acetonitrile 3a yielded methyl 2-([1,1′-biphenyl]-4-yl)-2-acetamido-2-(arylamino) acetates 4az, 4aaa, and 4aab in 69–78% yields, demonstrating late-stage felbinac functionalization (Scheme 4).

In medicinal chemistry, analysing isotopically labelled molecules is essential for understanding mechanisms of action, metabolism, and toxicity in vivo and in vitro. This strategy was applied to synthesize isotope-labelled α-amino-α-aryl α-amino esters (Scheme 4). Reactions of deuterated acetonitrile 3c with aromatic diazo esters 1a, 1p, and 1q, along with isocyanates 2a and 2b, produced deuterium-labeled α-amino-α-aryl α-amino esters 4aac–4aaf, including the deuterated felbinac derivative 4aaf, in 69–75% yields (Scheme 4).

It is noteworthy that the reactions with ethyl 2-diazoacetate resulted in the dimerization of the diazo ester whereas with ethyl 2-diazo-3-oxobutanoate, we have primarily obtained an oxazole as the major product as reported earlier.³¹

To elucidate the reaction mechanism, several experiments were conducted (Scheme 5). First, the reaction of 4-fluorophenyl diazo ester 1c with 4-chlorophenyl isocyanate 2d in acetonitrile 3a under dark conditions failed to yield any product, confirming that blue LED light is essential for generating the singlet carbene (Scheme 5a). Next, performing the same reaction with 2 or 4 equivalents of the radical trapping agent TEMPO afforded 4ad in 88% and 86% yields, respectively, similar to the reaction without TEMPO (78%). This suggests no radical involvement as TEMPO did not inhibit product formation (Scheme 5b).

Scheme 5 Control experiments to delineate the mechanism for the formation of α-amino-α-aryl amino esters 4.

Additionally, the reaction under dry argon was slow, reaching only 40% conversion after 30 hours, indicating that air or moisture aids the reaction (Scheme 5c). When phenyl diazoacetate 1a and 4-chlorophenyl isocyanate 2d were reacted in tetrahydrofuran (THF) under a blue LED, dimerization of 1a occurred, forming 6 and the hydrolyzed product of 2d (Scheme 5d). This suggests that acetonitrile 3a facilitates the formation of a nitrile ylide and its absence leads to dimerization.

Furthermore, irradiation of diethyl diazo malonate 5b with 3a, without isocyanates, exclusively formed 1,3-oxazole 7 through intramolecular [3 + 2] cycloaddition (Scheme 5e), implying that aryl isocyanates act as dipolarophiles for the intermolecular [3 + 2] cycloaddition in our reaction. Finally, reacting 7b with 2d under optimized conditions failed to produce 4ad, confirming that 7 is not involved in the formation of 4 (Scheme 5f).

The mechanism underlying the synthesis of α-amino α-aryl amino esters as realised from the control experiments and previous reports suggested an interrupted intra- to intermolecular [3 + 2] cycloaddition of nitrile ylide A and appropriate isocyanates 2 (Scheme 6a). The original pathway generated 1,3-oxazoles (Scheme 6b) whereas the introduction of 2 steered the transformation towards the formation of 4 (Scheme 6a). To further elucidate this, gas phase DFT calculations were performed using the Gaussian 09 package at the M06-2X/6-31**G level of theory.⁴⁷ In accordance with the expectation, the intermolecular [3 + 2] cycloaddition of the nitrile ylide A (obtained from the insertion of the acetonitrile 3a onto the singlet carbene from 1a) with phenyl isocyanate 2a to form the imidazolidinone intermediate B is highly exergonic (−31.95 kcal mol⁻¹) and happens through a transition state TS1 with a moderate activation barrier (19.57 kcal mol⁻¹) (Scheme 6a). The hydrolysis of the amide carbonyl of B to generate C is mildly exergonic (−2.56 kcal mol⁻¹) through the transition state TS2 with a low activation energy barrier of 4.19 kcal mol⁻¹ (Scheme 6a). Intermediate C opens to afford imine D. This is again mildly exergonic (−0.01 kcal mol⁻¹) through the transition state TS3 with a high activation energy (28.82 kcal mol⁻¹). While subsequent imine hydrolysis of D to E is an endergonic process (8.54 kcal mol⁻¹) through TS4 with a substantially high activation energy of 55.44 kcal mol⁻¹, the data are reasonable for the progress of the reaction (Scheme 6a). Finally, an exergonic decarboxylation of E (−24.05 kcal mol⁻¹) through TS5 (64 kcal mol⁻¹) afforded the final product 4a (Scheme 6a).

Scheme 6 (a) The reaction mechanism for the generation of α-amino-α-aryl amino esters and calculated reaction coordinates as determined at the M06-2X/6-31**G level of theory. Gibbs free energy values were calculated from frequency calculations. (b) The original intramolecular [3 + 2] cycloaddition to afford 1,3-oxazoles.

Interestingly, the reaction of 1a with phenyl isothiocyanate 2j and acetonitrile 3a (8 equivalents) produced a 1 : 1 mixture of 1,3-isoxazole 7b and 2,3-dihydroazete 8a, instead of the expected 4a (Scheme 7a). We believe the generation of 8a is the result of a [3 + 1] cycloaddition between the nitrile ylide A and the singlet carbene from 1a, where 2j acted as an additive to stabilize the singlet carbene. However, in this case, the intramolecular [3 + 2] cycloaddition could not be entirely inhibited. Increasing the volume of 3a to 50 equivalents yielded 7b as the major product (Scheme 7). To improve the yield of 8a, the reaction was attempted with varying amounts of 2j (2, 3, and 5 equivalents), and the best result of 55% of 8a in a 3 : 2 ratio with 7b was obtained using 3 equivalents of 2j and 8 equivalents of 3a (Scheme 7a).

Scheme 7 (a) Synthesis of 2,3-dihydroazete derivatives via blue LED induced competitive interrupted intramolecular [3 + 2] cycloaddition to intermolecular [3 + 1] cycloaddition. (b) Four-membered aza-heterocycles as natural products and drug molecules.

Furthermore, various electron-rich and electron-poor diazo esters (1c, 1e, 1k, 1r, and 1t) reacted with 3a or 3b (8 equivalents) in the presence of 3 equivalents of 2j to generate the desired 2,3-dihydroazetes 8b–8h in 59–65% yields (Scheme 7b). Notably, the drug molecule felbinac was functionalized to 2,3-dihydroazete analogs 8f and 8h in 59% and 63% yields, respectively. However, the reaction of dimethyl malonate diazo ester 5a led exclusively to 1,3-oxazole 7c.

This is significant because four-membered aza-heterocycles are common in natural products and bioactive compounds, typically featuring a β-lactam or azetidine core, such as mugineic acid (an iron transporter) or azetidine-2-carboxylic acid (Aze), found in nicotianamine (Scheme 7).^48–52 These compounds are also known to inhibit the HCMV serine protease enzyme.⁵³ The 2,3-dihydroazetes are unique four-membered aza-heterocycles, being more rigid and less basic than azetidines due to the presence of an sp² carbon in the ring.^54–56 Though a few syntheses of 2,3-dihydroazetes exist, mild, metal- and acid/base-free synthesis under solvent-free conditions remains unreported.

Conclusion

Herein, we have presented a modular, robust and ecofriendly photolytic synthesis of α-amino-α-aryl α-amino esters via gem-diamination of appropriate diazo esters through an intermolecular 5-endo-dig cyclization: [3 + 2] cycloaddition between nitrile ylides A of diazo esters and aryl isocyanates 2. A blue LED induced singlet carbene generation (from diazo esters 1) followed by nitrile 3 insertion into the carbene, affording A. Subsequent hydrolysis of the [3 + 2] cycloadduct provided the desired compounds 4. Control experiments delineated the reaction mechanism.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2324472. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo02332c

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