Exploration of the Divergent Outcomes for the Nenitzescu Reaction of Piperazinone Enaminoesters

The Nenitzescu reaction is a condensation reaction between an enamine and a quinone, which can give rise to a wide variety of reaction products depending on the nature of the starting material and the reaction conditions. The most commonly observed products are 5-hydroxyindoles and 5-hydroxybenzofurans. Both classes are of interest since they are known to possess a variety of promising bioactivities. Despite the high chemodivergency for this reaction, it remains an interesting synthetic strategy thanks to the mild reaction conditions, easily accessible starting materials and simple reaction procedures. For these reasons, our research group investigated the Nenitzescu reaction of piperazinone enaminoesters, resulting in the unexpected formation of rearranged 2imidazolidinone benzofurans. In this work, we aimed to develop reaction conditions that favor the formation of 5-hydroxyindoles via an extensive, multivariate optimization study. This led to valuable insights into the parameters that influence regioand chemoselectivity. Furthermore, two novel products were obtained, a pyrrolo[2,3-f ]indole and a benzofuranone, both of which are rarely reported in the literature.


Scheme 2. Overview of alternative reaction products.
Recently, our research group investigated the Nenitzescu reaction of piperazinone enaminoesters [27,43]. This research was inspired by earlier work conducted by Parr and Reiss, who obtained enamino quinone 13 from the condensation of enamine 12 and pbenzoquinone, and O-acylated 4,5-dihydroxyindole 14 upon heating in acetic acid [44] (Scheme 3A). Our research group hypothesized that by replacing acetic acid (AcOH) with trifluoroacetic acid (TFA), thus lowering the nucleophilicity of the acetate, the formation of the O-acylated indole could be suppressed allowing the synthesis of a 5-hydroxyindole [23]. Interestingly, the reaction produced an unexpected rearranged 2-imidazolidinonebenzofuran 16 and not the anticipated 5-hydroxyindole (Scheme 3B). The reaction conditions were optimized towards this novel product, and a stochiometric quantity of BF3·OEt2 (1.2 equiv.) in acetonitrile (ACN) was found to be optimal in combination with 2.2 equivalents of benzoquinone. Interestingly, the optimized reaction conditions were also regioselective for the evaluated monosubstituted quinones [27].
Considering the interesting properties of 5-hydroxyindoles [3,4,[6][7][8][9][10][11]16,45], in this work the Nenitzescu reaction of enaminoesters was further investigated with the aim of developing regioselective conditions favoring 5-hydroxyindole formation. To this end, an extensive, multivariate screening of reaction conditions was performed using the condensation of piperazinone enaminoester 15 and methyl-p-benzoquinone as a model reaction. The use of the latter enabled simultaneous yield and regioselectivity determination by quantitative 1 H NMR ( 1 H qNMR). This screening led to new and important insights into the factors that influence regio-and chemoselectivity. Additionally, two unexpected novel products were synthesized: a pyrrolo[2,3-f ]indole and a benzofuranone.

Results and Discussion
Starting from the optimized reaction conditions for benzofuran 16 formation, a multivariate screening was performed, altering solvent, acid mediator, temperature, reaction time and reactant equivalency ( Table 1, Scheme 4). This resulted in a deepened understanding of the factors that impact the outcome of the reaction. For instance, it was found that acidic additives greatly affect the regio-and chemoselectivity. Reactions mediated by Lewis and Brönsted acids-CuCl 2 , BiCl 3 , FeCl 3 , In(OTf) 3 , trifluoroacetic acid (TFA) and triflic acid (TfOH)-afforded only trace amounts of indoles 18a/b and generated benzofuran 19 as a main cyclization product (Table 1). Zinc halides (ZnI 2 , ZnCl 2 or ZnBr 2 ) promoted cyclization towards 5-hydroxyindoles in all tested solvents, while scandium and zinc triflate facilitated the formation of a novel product: benzofuranone 21a (vide infra). Surprisingly, the nature of the halide counterion influenced the regioselectivity significantly. Moreover, 7-methyl-5-hydroxyindole 18a yields were generally higher with zinc iodide, and 6-methyl-5-hydroxyindole 18b yields were generally higher with zinc chloride. Additionally, the regioisomeric ratio and overall yield also varied depending on the solvent, and nitromethane was the most suitable for 5-hydroxyindole formation in combination with either zinc chloride or zinc iodide. However, the combined yields were only 26% and 27%, respectively, and large quantities of enamino quinone intermediates 20a/b were present in the reaction mixture. Varying the reaction temperature, time, catalyst concentration or reagent equivalence did not improve the outcome of the reaction. On the contrary, increasing temperature and catalyst concentration were detrimental for the product yields, regio-and chemoselectivity.
Next to varying reaction conditions, a control experiment with hydroquinone instead of methyl-p-benzoquinone was performed using one equivalent hydroquinone and 0.1 equivalent zinc triflate in DCM at 40 • C. As expected, no conversion was observed after 22 h.
As mentioned above, scandium and zinc triflate mediation allowed the formation of an alternative reaction product: benzofuranone 21a (Scheme 5). Presumably, this heterocycle is formed via the acid-catalyzed lactonization of hydroquinone intermediate I12 (Scheme 5). This hypothesis is substantiated by the studies of Panisheva et al. and Mikerova et al., which showed that sterically demanding enamino hydroquinones readily cyclize to benzofuranone derivatives in acidic medium [46,47]. Aside from this two-step synthesis via isolated enamino hydroquinones [46,47], benzofuranones have rarely been described as products from the Nenitzescu reaction. Sung et al. reported the formation of benzofuranones via the Blaise-Nenitzescu reaction, which occurs by the condensation of an in situ-generated zinc complexed enaminoester and a quinone [48]. However, the authors were not able to synthesize benzofuranones starting from the isolated enamine (Blaise product). Mbala et al. afforded hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones from the condensation of N-substituted enaminoesters with methoxycarbonyl-1,4-naphthoquinone [49]. However, in this condensation an isoquinolinone ring is formed in addition to the benzofuranone ring. So, it can be stated that there is very little/no precedent for benzofuranone formation as a direct product from the classical Nenitzescu reaction. For this reason, a limited optimization study was undertaken (Table 2). During the optimization, NMR analysis indicated the presence of a small amount of the 6-methyl substituted isomer 21b in the reaction mixtures, though isolation was unsuccessful. bination with either zinc chloride or zinc iodide. However, the combined yields were only 26% and 27%, respectively, and large quantities of enamino quinone intermediates 20a/b were present in the reaction mixture. Varying the reaction temperature, time, catalyst concentration or reagent equivalence did not improve the outcome of the reaction. On the contrary, increasing temperature and catalyst concentration were detrimental for the product yields, regio-and chemoselectivity. Next to varying reaction conditions, a control experiment with hydroquinone instead of methyl-p-benzoquinone was performed using one equivalent hydroquinone and 0.1 equivalent zinc triflate in DCM at 40 °C . As expected, no conversion was observed after 22 h. Mikerova et al., which showed that sterically demanding enamino hydroquinones readily cyclize to benzofuranone derivatives in acidic medium [46,47]. Aside from this two-step synthesis via isolated enamino hydroquinones [46,47], benzofuranones have rarely been described as products from the Nenitzescu reaction. Sung et al. reported the formation of benzofuranones via the Blaise-Nenitzescu reaction, which occurs by the condensation of an in situ-generated zinc complexed enaminoester and a quinone [48]. However, the authors were not able to synthesize benzofuranones starting from the isolated enamine (Blaise product). Mbala et al. afforded hydroxybenzo[g]furo[4,3,2-de]isoquinoline-2,5(4H)-diones from the condensation of N-substituted enaminoesters with methoxycarbonyl-1,4-naphthoquinone [49]. However, in this condensation an isoquinolinone ring is formed in addition to the benzofuranone ring. So, it can be stated that there is very little/no precedent for benzofuranone formation as a direct product from the classical Nenitzescu reaction. For this reason, a limited optimization study was undertaken ( Table 2). During the optimization, NMR analysis indicated the presence of a small amount of the 6-methyl substituted isomer 21b in the reaction mixtures, though isolation was unsuccessful. Scheme 5. Proposed reaction mechanism for benzofuranone formation.
Considering the proposed mechanism, we hypothesized that an excess of methyl-pbenzoquinone might be disadvantageous since it would promote the oxidation of key intermediate I12. In agreement with this hypothesis, lowering the equivalents of methyl-pbenzoquinone from 2 to 1 doubled the combined benzofuranone 21a/b yield (Table 2). Yields were further improved by increasing the reaction temperature from room temperature to 80 °C . Nevertheless, regioisomeric mixtures of benzofuranones 21a/b were formed with a combined yield of only 22%, alongside traces of 5-hydroxyindoles 18a/b and enamino quinones 20a/b. Interestingly, replacing scandium triflate with zinc triflate had no significant impact on benzofuranone formation. We further hypothesized that the nature of the ester might have an influence on the lactonization step. Therefore, methyl ester derivative 22 was evaluated under the optimized reaction conditions for benzofuranone formation (Scheme 6). Interestingly, the change in ester alkoxy group increased Scheme 5. Proposed reaction mechanism for benzofuranone formation. the NMR yield from 22% to 33%, which can be explained by two reasons. Firstly, the lower steric hindrance of the methyl group favors lactonization. Secondly, the slightly lower pKa of methanol compared to ethanol makes the methoxy group a better leaving group.   Considering the proposed mechanism, we hypothesized that an excess of methylp-benzoquinone might be disadvantageous since it would promote the oxidation of key intermediate I12. In agreement with this hypothesis, lowering the equivalents of methylp-benzoquinone from 2 to 1 doubled the combined benzofuranone 21a/b yield (Table 2). Yields were further improved by increasing the reaction temperature from room temperature to 80 • C. Nevertheless, regioisomeric mixtures of benzofuranones 21a/b were formed with a combined yield of only 22%, alongside traces of 5-hydroxyindoles 18a/b and enamino quinones 20a/b. Interestingly, replacing scandium triflate with zinc triflate had no significant impact on benzofuranone formation. We further hypothesized that the nature of the ester might have an influence on the lactonization step. Therefore, methyl ester derivative 22 was evaluated under the optimized reaction conditions for benzofuranone formation (Scheme 6). Interestingly, the change in ester alkoxy group increased the NMR yield from 22% to 33%, which can be explained by two reasons. Firstly, the lower steric hindrance of the methyl group favors lactonization. Secondly, the slightly lower pKa of methanol compared to ethanol makes the methoxy group a better leaving group. To evaluate the impact of the enamine starting material, analogues of enamino 15 ( Figure 1) were evaluated under optimized conditions for 5-hydroxyindole forma To circumvent the regioselectivity issues, the reaction was performed with unsubstit p-benzoquinone 1 instead of methyl-p-benzoquinone 17. Interestingly, the ZnI2-mediated condensation of enamine 23 and p-benzoquinon sulted in the formation of a novel product, which was confirmed to be pyrrolo [2,3- To circumvent the regioselectivity issues, the reaction was performed with unsubstituted p-benzoquinone 1 instead of methyl-p-benzoquinone 17.

Entry Solvent Additive
SM 17 (eq.) To evaluate the impact of the enamine starting material, analogues of enami 15 ( Figure 1) were evaluated under optimized conditions for 5-hydroxyindole for To circumvent the regioselectivity issues, the reaction was performed with unsub p-benzoquinone 1 instead of methyl-p-benzoquinone 17. Interestingly, the ZnI2-mediated condensation of enamine 23 and p-benzoquin sulted in the formation of a novel product, which was confirmed to be pyrrolo[2,3-26 by X-ray diffraction, in addition to small quantities of the corresponding 5-hyd dole (Scheme 7). The formation of pyrrolo[2,3-f]indoles as (side) products of the escu reaction has received little attention in the literature since its first descrip Kuckländer in 1973 [39]. Kuckländer obtained small quantities of pyrrolo[2,3-f] Interestingly, the ZnI 2 -mediated condensation of enamine 23 and p-benzoquinone resulted in the formation of a novel product, which was confirmed to be pyrrolo[2,3-f ]indole 26 by X-ray diffraction, in addition to small quantities of the corresponding 5-hydroxyindole (Scheme 7). The formation of pyrrolo[2,3-f ]indoles as (side) products of the Nenitzescu reaction has received little attention in the literature since its first description by Kuckländer in 1973 [39]. Kuckländer obtained small quantities of pyrrolo[2,3-f ]indoles from the reaction of N-substituted enaminoesters with p-benzoquinone and proposed that their formation occurs by the addition of a second enamine to enamino quinone intermediate I2 followed by cyclization and aromatization [39,42]. This mechanism might explain why pyrrolo[2,3f ]indoles were not observed in any of the condensation reactions of methyl-p-benzoquinone with enamine 15, since the addition of a second enamine is sterically inhibited by the presence of the methyl substituent. their formation occurs by the addition of a second enamine to enamino quinone i diate I2 followed by cyclization and aromatization [39,42]. This mechanism might why pyrrolo[2,3-f]indoles were not observed in any of the condensation reaction thyl-p-benzoquinone with enamine 15, since the addition of a second enamine is s inhibited by the presence of the methyl substituent. The reactions of benzoquinone with enamines 24 and 25 were troublesome. E 24 was insoluble in nitromethane, and the reaction resulted in various insoluble pr Heating the reaction mixture to 70 °C resolved the solubility issues yet resulte formation of an intractable reaction mixture and decomposition products. Simila reaction of enamine 25 afforded a complex mixture.
The reaction of p-benzoquinone with enaminoester 15 was also evaluated un timized conditions for benzofuranone formation (Scheme 8). The expected 5-hydr zofuranone could not be isolated successfully due to significant side product for However, the 5-hydroxyindole 27 could be isolated in a low 9% yield.

Conclusions
In conclusion, we further explored the Nenitzescu reaction of piperazinone noesters 15 and 22-25 with methyl-p-benzoquinone and p-benzoquinone. An ex screening of reaction conditions led to valuable and new insights into the paramet influence the condensation of methyl-p-benzoquinone and enamine 15. Zinc (ZnBr2, ZnCl2 or ZnI2) promoted 5-hydroxyindole formation most efficiently, and ingly the halide counterion affected the regioselectivity significantly. Besides the a diator, the solvent also influenced the regio-and chemoselectivity, and nitrometh found to be the most suitable for indole formation. In addition to 5-hydroxyindol zofurans and enamino quinones, we observed novel reaction products that are ra scribed in the literature: benzofuranones 21a/b. A limited optimization study allo substantiating the proposed reaction mechanism and simultaneously increasing th Nevertheless, finding selective and generally applicable reaction conditions prov challenging. Besides benzofuranones, another novel product was formed, The reactions of benzoquinone with enamines 24 and 25 were troublesome. Enamine 24 was insoluble in nitromethane, and the reaction resulted in various insoluble products. Heating the reaction mixture to 70 • C resolved the solubility issues yet resulted in the formation of an intractable reaction mixture and decomposition products. Similarly, the reaction of enamine 25 afforded a complex mixture.
The reaction of p-benzoquinone with enaminoester 15 was also evaluated under optimized conditions for benzofuranone formation (Scheme 8). The expected 5hydroxybenzofuranone could not be isolated successfully due to significant side product formation. However, the 5-hydroxyindole 27 could be isolated in a low 9% yield.
why pyrrolo[2,3-f]indoles were not observed in any of the condensation reactions thyl-p-benzoquinone with enamine 15, since the addition of a second enamine is st inhibited by the presence of the methyl substituent. The reactions of benzoquinone with enamines 24 and 25 were troublesome. E 24 was insoluble in nitromethane, and the reaction resulted in various insoluble pr Heating the reaction mixture to 70 °C resolved the solubility issues yet resulted formation of an intractable reaction mixture and decomposition products. Simila reaction of enamine 25 afforded a complex mixture.
The reaction of p-benzoquinone with enaminoester 15 was also evaluated un timized conditions for benzofuranone formation (Scheme 8). The expected 5-hydro zofuranone could not be isolated successfully due to significant side product for However, the 5-hydroxyindole 27 could be isolated in a low 9% yield.

Conclusions
In conclusion, we further explored the Nenitzescu reaction of piperazinone noesters 15 and 22-25 with methyl-p-benzoquinone and p-benzoquinone. An ex screening of reaction conditions led to valuable and new insights into the paramet influence the condensation of methyl-p-benzoquinone and enamine 15. Zinc (ZnBr2, ZnCl2 or ZnI2) promoted 5-hydroxyindole formation most efficiently, and ingly the halide counterion affected the regioselectivity significantly. Besides the a diator, the solvent also influenced the regio-and chemoselectivity, and nitrometha found to be the most suitable for indole formation. In addition to 5-hydroxyindol zofurans and enamino quinones, we observed novel reaction products that are ra scribed in the literature: benzofuranones 21a/b. A limited optimization study allo substantiating the proposed reaction mechanism and simultaneously increasing th Nevertheless, finding selective and generally applicable reaction conditions prove challenging. Besides benzofuranones, another novel product was formed, Scheme 8. Reaction of enamine 15 and p-benzoquinone under optimized conditions for benzofuranone formation.

Conclusions
In conclusion, we further explored the Nenitzescu reaction of piperazinone enaminoesters 15 and 22-25 with methyl-p-benzoquinone and p-benzoquinone. An extensive screening of reaction conditions led to valuable and new insights into the parameters that influence the condensation of methyl-p-benzoquinone and enamine 15. Zinc halides (ZnBr 2 , ZnCl 2 or ZnI 2 ) promoted 5-hydroxyindole formation most efficiently, and surprisingly the halide counterion affected the regioselectivity significantly. Besides the acid mediator, the solvent also influenced the regio-and chemoselectivity, and nitromethane was found to be the most suitable for indole formation. In addition to 5-hydroxyindoles, benzofurans and enamino quinones, we observed novel reaction products that are rarely described in the literature: benzofuranones 21a/b. A limited optimization study allowed for substantiating the proposed reaction mechanism and simultaneously increasing the yield. Nevertheless, finding selective and generally applicable reaction conditions proved to be challenging. Besides benzofuranones, another novel product was formed, namely pyrrolo[2,3f ]indole 26. This product was only observed in the condensation of p-benzoquinone with enamine 23.

Materials and Methods
All reagents were purchased from Acros Organics (Geel, Belgium), Alfa Aesar (Kandel, Germany), Fluorochem (Hadfield, UK), Merck (Darm-stadt, Germany) or TCI Europe (Zwijndrecht, Belgium) and used as received. All reactions were performed in screwcapped reaction tubes, using aluminum heating blocks and magnetic stirring. The reaction was monitored by TLC analysis with Macherey-Nagel SILPre-coated ALUGRAM ® Xtra SIL G/UV254 TLC sheets or MilliporeSigmaTM Silica Gel 60 F254 Coated Aluminum-Backed TLC Sheets. Compounds were visualized under UV irradiation (254 nm), visible light or with iodine coated silica. Column chromatography was performed manually with silica 60, 70-230 mesh (Acros, Geel, Belgium) as the stationary phase or with a CombiFlash EZ prep apparatus using BGB Scorpius Silica 60 Å Irregular-50 mm cartridges. Solvents were concentrated under vacuum with a rotary evaporator at 50 • C.
Methyl-benzoquinone and p-benzoquinone slowly decompose over time and should be stored in a sealed vessel, refrigerated, and in the dark [50]. The quality of the quinone was evaluated visually and by 1 H NMR. In the case of an insufficient purity (<95%), the quinone was sublimated according to the literature procedure [50]. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance 400 (400 MHz working frequency). Samples were prepared in CDCl 3 or DMSO-d 6 , and chemical shifts (δ) were reported in parts per million (ppm) with reference to tetramethylsilane (CDCl 3 ) or the internal (NMR) solvent signal (DMSO-d 6 ) [51]. High-resolution mass spectra (HRMS) were measured on a quadrupole orthogonal acceleration time-of-flight mass spectrometer (Synapt G2 HDMS, Waters, Milford, MA, USA) with an infusion rate of 3 mL/min and a resolution of 15,000 (FWHMdfull width at half maximum). Spectra were obtained in positive ionization mode with leucine enkephalin as a lock mass.
Melting points were measured on a Reichert Thermovar apparatus and are uncorrected. Yellow single crystals of pyrrolo[2,3-f ]indole 26 suitable for X-ray diffraction were obtained by recrystallization in DMSO. X-ray intensity data were collected at 293(2) K on an Agilent SuperNova diffractometer with monochromated Mo-K α radiation (λ = 0.71073 Å). The images were interpreted and integrated with CrysAlisPRO [52] and the implemented absorption correction was applied. The structure was solved using Olex2 [53] with the ShelXT [54] structure solution program using Intrinsic Phasing and refined with the ShelXL [55] refinement package using full-matrix least-squares minimization on F 2 . Non-hydrogen atoms were refined anisotropically and hydrogen atoms in the riding mode with isotropic temperature factors were fixed at 1.2 times the U eq of the parent atoms (1.5 times U eq for methyl groups). Hydrogen atom H1 attached to N1 was located in a difference electron density map and subsequently freely refined. The asymmetric unit consisted of half a molecule and one molecule of DMSO. The whole molecule was generated by inversion symmetry. Atom C2 (flap of piperazine ring) and atoms C15 and C16 (ethoxy group) were found to be disordered over two positions, with occupancies of 0.518 (17) The crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre. Copies of the data (CCDC registration number 2236215) can be obtained from the CCDC free of charge by sending an application to the following e-mail address: deposit@ccdc.cam.ac.uk. The crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre. Copies of the data (CCDC registration number 2236215) can be obtained from the CCDC free of charge by sending an application to the following e-mail address: deposit@ccdc.cam.ac.uk.

Synthesis of Piperazinone Enaminoesters
General procedure: Piperazinone enaminoesters 15, 22-25 were prepared according to a modified literature procedure [23]. To a flame-dried, nitrogen-flushed round bottom two-necked flask equipped with a stir bar, 1,2-diamine (20 mmol, 1.00 eq.) and ethanol (8.0 mL) were added. To the stirred solution at room temperature, a solution of diethyl acetylenedicarboxylate (DEAD) or dimethyl acetylenedicarboxylate (DMAD) (20 mmol, 1.00 eq.) in 8.0 mL ethanol was added dropwise (0.3 mL/min) using a syringe pump. After stirring for three hours at room temperature, during which the product crystallized from the reaction mixture, the mixture was vacuum filtered. The obtained solid was washed with small amounts of diethyl ether and dried under vacuum to afford the products as crystalline solids.
Alternatively, product 15 was prepared according to a slightly adapted procedure,

Synthesis of Piperazinone Enaminoesters
General procedure: Piperazinone enaminoesters 15, 22-25 were prepared according to a modified literature procedure [23]. To a flame-dried, nitrogen-flushed round bottom two-necked flask equipped with a stir bar, 1,2-diamine (20 mmol, 1.00 eq.) and ethanol (8.0 mL) were added. To the stirred solution at room temperature, a solution of diethyl acetylenedicarboxylate (DEAD) or dimethyl acetylenedicarboxylate (DMAD) (20 mmol, 1.00 eq.) in 8.0 mL ethanol was added dropwise (0.3 mL/min) using a syringe pump. After stirring for three hours at room temperature, during which the product crystallized from the reaction mixture, the mixture was vacuum filtered. The obtained solid was washed with small amounts of diethyl ether and dried under vacuum to afford the products as crystalline solids.
Ethyl (Z)-2-(3-oxopiperazin-2-ylidene)acetate (15) (see Supplementary Materials). The crystallographic data for the structure reported in this paper have been dep ited with the Cambridge Crystallographic Data Centre. Copies of the data (CCDC re tration number 2236215) can be obtained from the CCDC free of charge by sending application to the following e-mail address: deposit@ccdc.cam.ac.uk.

Synthesis of Piperazinone Enaminoesters
General procedure: Piperazinone enaminoesters 15, 22-25 were prepared accord to a modified literature procedure [23]. To a flame-dried, nitrogen-flushed round bot two-necked flask equipped with a stir bar, 1,2-diamine (20 mmol, 1.00 eq.) and etha (8.0 mL) were added. To the stirred solution at room temperature, a solution of die acetylenedicarboxylate (DEAD) or dimethyl acetylenedicarboxylate (DMAD) (20 mm 1.00 eq.) in 8.0 mL ethanol was added dropwise (0.3 mL/min) using a syringe pump. A stirring for three hours at room temperature, during which the product crystallized f the reaction mixture, the mixture was vacuum filtered. The obtained solid was was with small amounts of diethyl ether and dried under vacuum to afford the product crystalline solids.
Alternatively, product 15 was prepared according to a slightly adapted procedure, using ethylenediamine (0.608 g, 10.12 mmol, 1.00 eq.) and DEAD (1.723 g, 10.13 mmol, 1.00 eq.), each dissolved in 4.0 mL of ethanol. The reaction was performed in oven-dried flasks in an air atmosphere instead of an inert atmosphere. Product 15 was isolated as a crystalline white solid (0.998 g, 5.418 mmol, 54%).

qNMR Optimization Study
General procedure: To a flame-dried, nitrogen-flushed reaction tube equipped with a stir bar, piperazinone enaminoester 15 (184 mg, 1.00 mmol, 1.00 eq.), methyl-p-benzoquinone (244 mg, 2.00 mmol, 2.00 eq.), the appropriate (dry) solvent (4.0 mL) and if applicable, a solid additive, were added. If applicable, the appropriate liquid additive was added dropwise to the stirred mixture cooled to 0 • C in an ice bath. After stirring the reaction mixture at room temperature for 30 min, and at the reaction temperature for the appropriate time, the solution was cooled to room temperature, quenched with NaHCO 3 (20 mL) and water (30 mL), diluted with ethyl acetate (50 mL) and extracted three times with ethyl acetate (3 × 50 mL). The combined organic phases were washed with water (3 × 50 mL) and brine (1 × 50 mL), and dried over Na 2 SO 4 . Benzyl benzoate (140 µL, 0.66 mmol) and DMSO-d 6 (1 mL) were added to the crude mixture, and 0.10 mL of the homogeneous solution was diluted to 0.50 mL with DMSO-d 6 and analyzed by 1 H NMR.
qNMR yield determination: The product yields were determined by the following equation: With I Analyte : integral of the analyte signal, I IS : integral of the internal standard signal, n IS : number of moles of the internal standard, n SM : number of moles of the starting material, N IS : number of protons responsible for the internal standard signal, N Analyte : number of protons responsible for the analyte signal.
Prepared according to a modified version of the general procedure using (1S,2S)diphenylethylenediamine (2.125 mg, 10.01 mmol, 1.00 eq.), and DEAD (1.702 g, 10 mmol, 1.00 eq.). The reaction mixture was stirred for 20 h, dried, and dissolved in DC then filtered over silica using petroleum ether and dried under reduced pressure. Prod 25 was obtained as a crystalline white solid (2.962 g, 8.805 mmol, 88%). 1

qNMR Optimization Study
General procedure: To a flame-dried, nitrogen-flushed reaction tube equipped w a stir bar, piperazinone enaminoester 15 (184 mg, 1.00 mmol, 1.00 eq.), methyl-p-ben quinone (244 mg, 2.00 mmol, 2.00 eq.), the appropriate (dry) solvent (4.0 mL) and if ap cable, a solid additive, were added. If applicable, the appropriate liquid additive w added dropwise to the stirred mixture cooled to 0 °C in an ice bath. After stirring reaction mixture at room temperature for 30 min, and at the reaction temperature for appropriate time, the solution was cooled to room temperature, quenched with NaHC (20 mL) and water (30 mL), diluted with ethyl acetate (50 mL) and extracted three tim with ethyl acetate (3 × 50 mL). The combined organic phases were washed with wate × 50 mL) and brine (1 × 50 mL), and dried over Na2SO4. Benzyl benzoate (140 µ L, 0 mmol) and DMSO-d6 (1 mL) were added to the crude mixture, and 0.10 mL of the hom geneous solution was diluted to 0.50 mL with DMSO-d6 and analyzed by 1 H NMR.
qNMR yield determination: The product yields were determined by the follow equation: (%) = * * * 100 With IAnalyte: integral of the analyte signal, IIS: integral of the internal standard sig nIS: number of moles of the internal standard, nSM: number of moles of the starting m rial, NIS: number of protons responsible for the internal standard signal, NAnalyte: num of protons responsible for the analyte signal.