Palladium-Catalyzed β−Carbonyl Alkylation of α-Imino Esters with Allylic/Propargyl Alcohols

Palladium-Catalyzed β−Carbonyl Alkylation of α-Imino Esters with Allylic/Propargyl Alcohols | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 13 October 2025 V1 Latest version Share on Palladium-Catalyzed β−Carbonyl Alkylation of α-Imino Esters with Allylic/Propargyl Alcohols Authors : Sijia Shang , Tao Tian , Jiaxuan Zhao , Wanjie Xia , Lei Bai , and Changming Xu 0000-0001-9608-7013 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176035050.04514637/v1 149 views 100 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract A palladium-catalyzed β‑carbonyl alkylation of α-imino esters with readily available allylic/propargyl alcohols has been developed, enabling efficient and redox-neutral synthesis of structurally diverse δ‑carbonyl-α‑amino acid esters and carbonyl-containing pyrrolidine derivatives. Mechanistic studies indicate that the reaction proceeds via a dehydrogenation-Michael addition or [3+2] cyclization pathway. This method offers an atom-economical and operationally straightforward strategy for the synthesis of highly functionalized Δ(1)-pyrrolines and pyrrolidines. Cite this paper: Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.70XXX Palladium-Catalyzed β−Carbonyl Alkylation of α-Imino Esters with Allylic/Propargyl Alcohols Sijia Shang, a Tao Tian, a Jiaxuan Zhao, a Wanjie Xia, a Lei Bai,* , b and Changming Xu* , a a School of Chemistry and Chemical Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China b College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, China Palladium catalysis | β-Carbonyl alkylation | α-Imino esters | Allylic alcohols | Propargyl alcohols | Δ(1)-Pyrrolines | Pyrrolidines | Michael addition Comprehensive Summary A palladium-catalyzed β‑carbonyl alkylation of α-imino esters with readily available allylic/propargyl alcohols has been developed, enabling efficient and redox-neutral synthesis of structurally diverse δ‑carbonyl-α‑amino acid esters and carbonyl-containing pyrrolidine derivatives. Mechanistic studies indicate that the reaction proceeds via a dehydrogenation-Michael addition or [3+2] cyclization pathway. This method offers an atom-economical and operationally straightforward strategy for the synthesis of highly functionalized Δ(1)-pyrrolines and pyrrolidines. Background and Originality Content The α-alkylation of α-imino esters represents a powerful strategy for accessing structurally diverse unnatural α-amino acid esters (α-AAE), which are pivotal building blocks in pharmaceutical development and construction of bioactive molecules. [1] Among these transformations, phase-transfer catalyzed alkylation [2] and transition-metal-catalyzed allylic alkylation, namely Tsuji–Trost reaction, [3] have emerged as prominent protocols for synthesis of highly functionalized α-AAE. Nevertheless, these conventional alkylation methods have suffered from limitations in atom economy and step efficiency, due to highly active alkyl halides or allylic alcohol derivatives have to be employed as substrates. [4] From the perspective of green and sustainable chemistry, the direct utilization of stable and readily accessible allylic alcohols is highly desirable, however, the inherently poor leaving ability of the hydroxyl moiety has rendered catalytic allylic alkylation of such substrates underexplored. [5] Recently, Wang and colleagues reported a Cu/Ir or Cu/Pd dual catalytic strategy to achieve regio- and stereodivergent allylic alkylation of α-imino esters with allylic alcohols by employing Et 3 B as the key activator, which provided both linear and branched C−C double bond-containing α-AAE in high selectivities (Figure 1a). [6] Alternatively, borrowing-hydrogen catalysis has arisen as an attractive and atom-economic strategy for functionalizing inert allylic alcohols. This approach involves temporary activation of alcohols via metal-catalyzed dehydrogenation, generating reactive carbonyl intermediates that participate in C–C bond-forming events. The process is completed by metal-hydride-mediated reduction, thereby ensuring redox neutrality and high atom efficiency. This strategy enabled the synthesis of highly functionalized δ-hydroxy-α-AAE or hydroxyl-containing pyrrolidine derivatives (Figure 1b), [7] and enormously enriched the alkylation of α-imino esters with allylic alcohols. Herein, we reported a palladium-catalyzed β-carbonyl alkylation of α-imino esters with allylic alcohols to access δ-carbonyl-α-AAE or carbonyl-containing pyrrolidine derivatives, which disclosed a distinctive pathway of α-imino esters with allylic alcohols. Notably, propargyl alcohols were also tolerated in this protocol (Figure 1c). Figure 1 Reactions of α-imino esters with allylic alcohols Results and Discussion As part of our ongoing interest in phase-transfer catalyzed-alkylation of α-imino esters, [8] we considered developing the allylic alkylation of α-imino esters with allylic alcohols via a synergistic combination of palladium catalysis and phase-transfer catalysis. Initially, the direct α-allylation of benzophenone-derived ketoimino ester 1a with allylic alcohol 2a was assessed in the promotion of [Pd(allyl)Cl] 2 /PPh 3 and tetrabutylammonium bromide (TBAB) under basic conditions. To our surprise, the δ-carbonyl α-amino acid derivative 3aa was obtained in 30% yield, along with linear allylation product 4 in 12% yield (Table 1, entry 1). Notably, this β-carbonyl alkylation pathway represents an unprecedented transformation in the context of α-imino esters alkylation with allylic alcohols. This unexpected outcome motivated us to delve deeper into this reaction system. When several inorganic bases were tested (entries 1-4), KOH (50%, aq) delivered target product 3aa with 60% yield (entry 4). Further experiment revealed that the reaction proceeded better in the absence of TBAB, giving 3aa in 77% yield (entry 5). When organic base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was used, no reaction occurred (entry 6). The use of CH 3 ONa as the base resulted in slightly lower yield (entry 7). Further examination of the Pd catalysts and phosphine ligands afforded inferior results (entries 8-12). Moreover, reducing the ligand loading proved deleterious to the yield (entry 13). Control reactions showed that omission of base or Pd catalyst resulted in complete inactivity of this catalytic system (entries 14-15). Furthermore, we also tested other metal catalysts, bases and solvents, but no better result could be obtained (see the Supporting Information, Table S1). Table 1 Optimization of reaction conditions a 3aa 4 1 c PPh 3 (10) KOH 7 30 12 2 c PPh 3 (10) CsOH·H 2 O 5 32 24 3 c PPh 3 (10) Cs 2 CO 3 8 31 0 4 c PPh 3 (10) KOH (50%, aq) 7 60 0 5 PPh 3 (10) KOH (50%, aq) 8 77 0 6 PPh 3 (10) DBU 48 NR - 7 PPh 3 (10) CH 3 ONa 12 71 0 8 d PPh 3 (10) KOH (50%, aq) 12 30 0 9 e PPh 3 (10) KOH (50%, aq) 12 31 0 10 DPPE (5) KOH (50%, aq) 8 35 0 11 BINAP (5) KOH (50%, aq) 8 65 0 12 Xantphos (5) KOH (50%, aq) 8 33 0 13 PPh 3 (5) KOH (50%, aq) 8 23 0 14 PPh 3 (10) - 48 NR - 15 f PPh 3 (10) KOH (50%, aq) 20 0 0 a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Pd(allyl)Cl] 2 (2 mol%), ligand, solid base (2 equiv.) or KOH (50%, aq, 0.1 mL), toluene (1 mL), 40 o C, under N 2 . b Isolated yield. c TBAB (10 mol%) was added. d Pd(PPh 3 ) 4 (2 mol%) instead of [Pd(allyl)Cl] 2 . e Pd(PPh 3 ) 2 Cl 2 (2 mol%) instead of [Pd(allyl)Cl] 2 . f Without [Pd(allyl)Cl] 2 . DPPE: 1,2-bis(diphenylphosphino) ethane. BINAP: 2,2’-bis(diphenylphosphino)-1,1’-binaphthalene. Xantphos: 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene. NR: no reaction. With the optimized conditions in hand, we then examined the substrate scope. As summarized in Table 2 (upper part), the electron-donating group substituted phenyl vinyl carbinols 2a - 2f reacted smoothly with 1a to deliver the desired products 3aa - 3af in moderate yields, and the electron-withdrawing group substituted allylic alcohols 2g - 2i and 2-naphthyl vinyl carbinol 2j yielded the target products 3ag - 3aj’ in low yields. In some cases, the Table 2 Reactions of α-ketoimino esters/amides with allylic/propargyl alcohols a,b a Reaction conditions: 1 (0.2 mmol), 2 or 5 (0.4 mmol), [Pd(allyl)Cl] 2 (2 mol%), PPh 3 (10 mol%), KOH (50%, aq, 0.1 mL), toluene (1 mL), 40 o C. b Isolated yield. c The crude reaction mixture was treated with 0.5 N HCl in THF for 1 h. Table 3 Reactions of α-aldimino esters with allylic/propargyl alcohols a,b,c a Reaction conditions: 1 (0.2 mmol), 2 or 5 (0.4 mmol), [Pd(allyl)Cl] 2 (2 mol%), PPh 3 (10 mol%), KOH (50%, aq, 0.1 mL), toluene (1 mL), 40 o C. b Isolated yield. c The dr was the ratio of major diastereomer to other diastereomers and the value was determined by crude 1 H NMR. β-carbonyl alkylation products 3 and their hydrolysis-cyclization products 3’ were formed concomitantly in reaction system. The mixture was treated with acid to afford Δ(1)-pyrrolines 3’ . Moreover, 2-thienyl and 2-furyl vinyl carbinols ( 2k and 2l ) were suitable substrates for this reaction, giving the desired products 3k - 3l in moderate yields. Notably, ketoimino amides 1b and 1c were also proven to be compatible in this process, leading to the corresponding products 3ba and 3ca with 40% and 45% yield, respectively. Unfortunately, when employing a linear allylic alcohol 2m as the substrate, the reaction was messy. To our delight, the reactions with propargyl alcohols 5 worked equally well and delivered the same products 3 or 3’ with low to moderate yields (Table 2, lower part), and the envisioned δ-carbonyl-β,γ-unsaturated-α-AAE were not observed. To extend the scope of this novel transformation, we turned our attention to the use of aldimino esters as summarized in Table 3. Optimization of the conditions for the reaction of aldimino ester 6a with allylic alcohol 2a was detailed in Table S2. To our surprise, reactions of α-phenyl aldimino ester 6a with (het)aryl vinyl carbinols bearing electron-neutral ( 2a , 2j and 2k ) or electron-donating ( 2e and 2f ) substituents gave the carbonyl-containing pyrrolidines 7aa, 7ae - 7aj and 7ak via [3+2] cyclization in moderate yields with >20:1-1:1 dr. When Ar 1 group of aldimino esters 6 was changed to p -F-C 6 H 4 , p -MeO-C 6 H 4 or 2-naphthyl group, these reactions also afforded the corresponding pyrrolidines 7ba - 7da in 36-50% yields with 3.3:1-1:1 dr. Furthermore, α-methyl aldimino ester 6e proved to be compatible with this reaction, providing the product 7ea in 38% yield with 20:1 dr. It should be noted that (het)aryl ethynyl carbinols 5 were also compatible with this [3+2] cyclization process, providing pyrrolidines 7 in moderate yields and higher dr (Table 3, lower part), and the envisioned Δ(3)-pyrrolines were also not observed. The trans/cis configuration of the product 7aa was determined by 1 H- 1 H NOESY (see Supporting Information). Scheme 1 Synthetic transformations To verify the practicality of this method, the product 3aa was converted into the corresponding Δ(1)-pyrroline 3aa’ with 70% yield by acid treatment, which could serve as intermediate for the synthesis of bioactive molecules or ligands. [9] In addition, compound 3aa’ could easily produce pyrrolidine 8 via hydrogenation according to the method reported by Lygo and co-workers. [10] Interestingly, when 3aa’ was treated with diisobutylaluminium hydride (DIBAL-H), its ester group was reduced to deliver product 9 with 71% yield. Similarly, the reaction of 3aa’ with 2 equivalents of Grignard reagent afforded product 10 from the attack on the ester group in excellent yield, and its Δ(1)-pyrroline cycle was preserved. To shed light on the reaction pathway, we carefully investigated the reaction systems of 1a and 6a with allylic alcohol 2a . To our delight, the hydrogen molecules can be detected by gas chromatography (GC) (see the Supporting Information, Figure S1), and the byproduct propiophenone 11 was also obtained from our reaction systems with moderate yields, which indicated that the dehydrogenation product 12 of allylic alcohol 2a may be a key intermediate. With this in mind, the reactions of 1a and 6a with 12 under the standard conditions were carried out, and products 3aa and 7aa were obtained with 29% and 41% yield, respectively. Based on the above results, it was proposed that the reaction proceeded via dehydrogenation-Michael addition process. [11] We also performed the reactions 1a and 6a with the dehydrogenation product alkynone 13 of ethynyl carbinol 5a , but no target product was obtained in these two cases. Scheme 2 Mechanistic studies Based on the above mechanistic studies, a possible mechanism was proposed (scheme 3). In allylic alcohol system, allylic alcohol 2a was dehydrogenated by Pd catalyst to produce the ketene 12 and a Pd hydride intermediate. Compound 12 underwent Michael addition with 1 or [3+2] cyclization with 6 to afford product 3 or 7 . The Pd hydride intermediate released hydrogen gas to regenerate Pd catalyst. Propiophenone 11 may come from isomerization of 2a [12] or reduction of 12 by in suit generated H 2 [13] . In the propargyl alcohol system, the propargylic alcohol 5a was dehydrogenated by Pd catalyst to produce alkynone 13 and a Pd hydride intermediate. Alkynone 13 was reduced by the Pd hydride intermediate to give 12 , [14] followed by Michael addition with 1 or [3+2] cyclization with 6 to afford product 3 or 7 . Scheme 3 Proposed mechanisms Conclusions In summary, we have developed a palladium-catalyzed β-carbonyl alkylation of α-imino esters/amides with allylic or propargyl alcohols, that enables the efficient and redox-neutral synthesise of highly functionalized Δ(1)-pyrrolines and pyrrolidines. The reaction exhibits broad substrate scope, accommodating a variety of (het)aryl-substituted allylic and propargyl alcohols bearing both electron-donating and electron-withdrawing groups, and diverse ketoimino esters/amides and aldimino esters. Preliminary mechanistic studies revealed that the reaction proceeds via a sequence of dehydrogenation-Michael addition or [3+2] cyclization. This work represents a significant advancement in the functionalization of inert allylic and propargyl alcohols and expands the synthetic toolkit for constructing structurally diverse unnatural amino acids and nitrogen-containing heterocycles. Experimental The experimental details are shown in Supporting Information. Supporting Information The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.70XXX. Acknowledgement We acknowledge the financial support from the National Natural Science Foundation of China (NSFC) (Grant No. 22061025 and 22367021), the Natural Science Foundation of Gansu Province (Grant No. 24JRRA134), and the Science and Technology Plan Foundation of Lanzhou (Grant No. 2023-3-113). References 1. (a) Eftekhari-Sis, B.; Zirak, M. α-Imino Esters in Organic Synthesis: Recent Advances. 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Reduction and C(sp²)-H Bond Activation of Ketones Promoted by a Cyclopentadienyl-Osmium-Dihydride-Dihydrogen Complex. Organometallics 2005 , 24, 5989–6000. 14. For a selected example on reduction of alkynones with H 2 , see: Yun, S.; Lee, S.; Yook, S.; Patel, H. A.; Yavuz, C. T.; Choi, M. Cross-Linked “Poisonous” Polymer: Thermochemically Stable Catalyst Support for Tuning Chemoselectivity. ACS Catal. 2016 , 6, 2435–2442. Manuscript received: XXXX, 2024 Manuscript revised: XXXX, 2024 Manuscript accepted: XXXX, 2024 Version of record online: XXXX, 2024 Left to Right: Sijia Shang, Tao Tian, Jiaxuan Zhao, Wanjie Xia, Lei Bai, and Changming Xu Entry for the Table of Contents Palladium-Catalyzed β−Carbonyl Alkylation of α-Imino Esters with Allylic/Propargyl Alcohols Sijia Shang, Tao Tian, Jiaxuan Zhao, Wanjie Xia, Lei Bai,* and Changming Xu* Chin. J. Chem. 2025 , 43 , XXX—XXX. DOI: 10.1002/cjoc.70XXX We have developed a palladium-catalyzed β-carbonyl alkylation α-imino esters with allylic or propargyl alcohols, that enables efficient synthesis of highly functionalized Δ(1)-pyrrolines and pyrrolidines. Supplementary Material File (image6.emf) Download 494.95 KB Information & Authors Information Version history V1 Version 1 13 October 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords allylic alcohols palladium catalysis propargyl alcohols α-imino esters β-carbonyl alkylation δ(1)-pyrrolines Authors Affiliations Sijia Shang Lanzhou Jiaotong University View all articles by this author Tao Tian Lanzhou Jiaotong University View all articles by this author Jiaxuan Zhao Lanzhou Jiaotong University View all articles by this author Wanjie Xia Lanzhou Jiaotong University View all articles by this author Lei Bai Northwest Normal University View all articles by this author Changming Xu 0000-0001-9608-7013 [email protected] Lanzhou Jiaotong University View all articles by this author Metrics & Citations Metrics Article Usage 149 views 100 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Sijia Shang, Tao Tian, Jiaxuan Zhao, et al. Palladium-Catalyzed β−Carbonyl Alkylation of α-Imino Esters with Allylic/Propargyl Alcohols. Authorea . 13 October 2025. 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