Structure-Based Kinetic Control in a Domino Process: A Powerful Tool

Article pubs.acs.org/joc

Structure-Based Kinetic Control in a Domino Process: A Powerful Tool Toward Molecular Diversity in Chromone Series Thomas Lepitre,*,† Clement Denhez,‡,§ Jan Moncol,⊥ Mohamed Othman,† Ata Martin Lawson,*,† and Adam Daïch† †

Normandie University, UNILEHAVRE, URCOM, EA 3221, INC3M, FR 3038 CNRS, F-76600 Le Havre, France ICMR, CNRS UMR 7312, UFR Pharmacie, Universite de Reims Champagne Ardenne, 51 rue Cognacq-Jay, 51096 Cedex Reims, France § Université de Reims Champagne Ardenne, Multiscale Molecular Modelling Platform, UFR Sciences Exactes et Naturelles, F-51687 Cedex 2 Reims, France ⊥ Slovak University of Technology, Department of Inorganic Chemistry, Institute of Inorganic Chemistry, Technology and Materials, Radlinskeho 9, SK-81237 Bratislava, Slovakia ‡

S Supporting Information *

ABSTRACT: Two successive original routes leading to two novel families of polyheterocycles starting from the versatile chromone-based Michael acceptors platform are reported herein. The major aspect of this work is the selective access to these frameworks by changing the course of the domino process involved in their formation. First, enaminochromanones were selectively accessed under uncommon kinetic control. In this study, we showed that the tuning of the selectivity toward the kinetic product could be achieved by key structural modifications of the different reaction partners involved in the domino process. Once selectivity was efficiently controlled, enaminochromanones were ultimately transformed into a more complex family of polyheterocycles containing the pyrrolo-oxazinone framework. Here, the modulation of the domino sequence toward these particularly scarce structures was enabled by a pivotal switch in reactivity induced by aryl-λ3-iodanes.

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INTRODUCTION Over the past decade, the access to molecular diversity has gained considerable interest within the community of synthetic chemists due to its pivotal role in drug discovery.1 In this context, new strategies have emerged to overcome this formidable challenge such as substrate-based folding2 and branching3 pathways, the build/couple/pair 4,5 (B/C/P) approach, or single reactant replacement (SRR) in multicomponent reactions.6 Powerful tools such as domino processes, currently recognized for their great ability to generate architectural complexity,7,8 still remain less exploited in this research area. However, quite recently, such processes have revealed their high potential to generate molecular diversity starting from common substrates by ingeniously acting on the course of the concerned reaction sequences.9,10 In this perspective, we recently reported access to diverse (poly)heterocyclic structures starting from the same platform of chromone-based Michael acceptors, reacting with various primary amines. In these reported studies, 2-pyridones,11 dihydro-oxazolopyridines,12 and indolizines13 were selectively accessed by acting on the courses of the domino processes © 2017 American Chemical Society

involved, through (i) the diversification of the amines coupling partners, (ii) the pertinent modulation of the Michael acceptors structures, and/or (iii) the reactivity tuning induced by external agents such as catalysts, additives, and/or specific reagents (Scheme 1). In 2013, our group11 and others14 described an efficient synthesis of 2-pyridones through a domino sequence involving diester Michael acceptors in chromone series and primary amines (Scheme 2, upper part). During this work, we showed in particular that 2-pyridones could exclusively be obtained under thermodynamic control by heating at high temperature and/or using CsF as catalyst. On the other hand, the screening of experimental conditions and a mechanistic examination allowed the structural elucidation of the sporadically observed kinetic product reported as enaminochromanone (Scheme 2). The original structure of this kinetic product, bearing the versatile enaminone unit,15 prompted us to investigate its selective access. Received: August 8, 2017 Published: October 20, 2017 12188

DOI: 10.1021/acs.joc.7b01996 J. Org. Chem. 2017, 82, 12188−12201

Article

The Journal of Organic Chemistry Scheme 1. Previous Works on Chromone-Based Michael Acceptors

Scheme 2. Structure-Based Kinetic Control toward Pyrrolo-oxazinones Derivatives

Scheme 3. Pivotal Steps Impacting the Reaction Course

In keeping with this work, we recently showed that the introduction of Mitsunobu agents within the reaction mixture containing aminoalcohols and chromone-based Michael acceptors triggered an interesting Mitsunobu-type concerted

sequence leading to dihydro-oxazolopyridines. Because this transformation proceeded through the solely observed thermodynamic 2-pyridone intermediate, we now wish to report how the course of the domino process can in fact be 12189


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The Journal of Organic Chemistry Scheme 4. Impact of the Amino-Alcohol Structures onto the Reaction Control

of the diester group, making the proton less reactive by removing one ester group could prevent the ring reopening step and thus stabilize the enaminochromanone form. To support these considerations, we then evaluated the impact of (i) the structure of various 2-aminoethanols and (ii) the monoester 1,6-Michael acceptor onto the selectivity of the domino process. As displayed in Scheme 4, reacting the chromone-based Michael acceptor 1a with 2-aminoethanol coupling partner led to a poor kinetic control because thermodynamic product 2′a was almost exclusively obtained (Scheme 4, entry 1). It is worth mentioning that in one of our previous works,12 the same reaction was conducted in the presence of the diester 1,6-Michael acceptor, and only the thermodynamic product was observed. This result indicates that the sole modulation of the chromone-based Michael acceptors structure by removing only one ester group is not sufficient to shift the course of the domino process toward a kinetic control. Interestingly, the use of a more hindered amino-alcohol bearing a phenyl group at α-position of the nitrogen atom, increased the ratio of the enaminochromanone kinetic product 2h from 8 to 58% (Scheme 4, entry 2). Moreover, the alcohol function of the amino-alcohol derivatives appeared to be pivotal for tuning the selectivity. Indeed, Oprotection of 2-aminoethanol with a methyl group favored the kinetic control because enaminochromanone ratio was increased by 53% (Scheme 4, entry 3 vs entry 1). Interestingly, the use of a more hindered protecting group such as trimethylsilyl (TMS) led to an even higher kinetic control because 2a was observed in a 84% ratio in the crude mixture (Scheme 4, entry 4). It is worth mentioning that TMS has the valuable asset to serve as a temporary protecting group because it could be efficiently removed in acidic media at the end of the reaction. The TMS protection was thus applied onto the 2-phenylglycinol, which satisfactorily led to a high kinetic control of the domino process because product 2h was almost exclusively obtained at the end of the reaction (Scheme 4, entry 5). Finally, in the case of important steric hindrance at αposition of the nitrogen atom, no protection of the alcohol function was required to control the competition in favor of the kinetic product. Indeed, the use of 2-dimethylethanolamine led

switched toward a kinetic control under the action of the same aminoalcohols. This switch was allowed by the judicious structural modulation of both entities involved in the process, the chromone-based Michael acceptors, and these particular amines. In this context, once selectivity was achieved toward enaminochromanones, they were ultimately transformed into a new and uncommon family of compounds containing the pyrrolo-oxazinone backbone.16 This time, the recovery of the thermodynamic product was prevented by a key switch in reactivity induced by aryl-λ3-iodanes (PIFA).17

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RESULTS AND DISCUSSION A thorough examination of the domino process mechanism allowed the discrimination of two pivotal steps which must be controlled to shift the course of the reaction toward the formation of kinetic product. The first key step is an equilibrium between two competitive stereoisomers (Scheme 3a), leading to enaminochromanones (Z-form) or to 2pyridones (E-form). We hypothesized that the reaction could be subjected to kinetic control by acting onto the parameters governing this equilibrium. In this perspective, the nucleophilicity of both the nitrogen atom and the phenol group appeared at first sight as a pertinent parameter for controlling this competition. Indeed, it could be envisioned to weaken the nucleophilicity of the nitrogen atom to prevent the 2-pyridone ring formation and, on the contrary, strengthen the phenoxide nucleophilicity to favor its addition onto the β-position of the diester moiety, leading to enaminochromanones. However, the modulation of this parameter could negatively impact the whole process and was thus not taken into consideration. On the other hand, along our previous studies, we could observe that the structure of the amine group could influence the equilibrium in favor of the Zform isomer (Scheme 3). Indeed, sterically hindered amines appeared to afford higher ratios of enaminochromanones kinetic products. Therefore, we decided to mainly consider the steric effects to shift the course of the reaction. The second key step that must imperatively be controlled is the reopening of the γ-pyranone ring once the kinetic product is formed (Scheme 3b). Indeed, this relative instability takes the process back to the equilibrium described above. Because this undesired reactivity relies upon the proton lability at α-position 12190


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The Journal of Organic Chemistry to a 97/3 1H NMR ratio in favor of enaminochromanone 2j (Scheme 4). To highlight the pivotal role of the proton lability onto the stability of the kinetic product, enaminochromanones bearing one and two ester groups, respectively, were heated at 65 °C in THF in the presence of Et3N as organic base. As underlined in Scheme 5, only 54% of diester-enaminochromanone derivative

2s was recovered after 1 h (Scheme 5, entry 1), whereas monoester enaminochromanone derivative 2j was not affected at all under the same reaction conditions (Scheme 5, entry 2). These results confirmed the difficulty to shift the reaction toward a kinetic control in the case of diester Michael acceptors. On the other hand, as postulated, the removal of one ester group completely inhibits at 65 °C in THF the reverse reaction toward the thermodynamic product once the enaminochromanone is formed. To conclude this part, the removal of one ester group within the chromone-based Michael acceptors as well as the insertion of the TMS protecting group onto the amino-alcohol coupling partners can be considered as the key structural parameters to bring the domino process under kinetic control. These results were corroborated by DFT calculations using the state of the art M06-2X functional at the 6-31G(d,p) level of theory (Scheme 6). The solvent effect was taken into account using the PCM (polarizable continuum model) formalism during optimization and frequency calculations.18 In this study, monoester Michael acceptor 1a and ethanolamine vs 2,2-dimethyl-ethanolamine were chosen as reaction coupling partners. In this context, the calculations were mainly focused onto the two crucial steps above presented in Scheme 3.

Scheme 5. Pivotal Role of the Ester α-Proton Lability onto the Reaction Control

Scheme 6. Energetic Profiles of Thermodynamic (Blue) vs Kinetic (Red) Pathways Computed at the PCM/M06-2X/6-31G(d,p) Level of Theory (Calculated Free Gibbs Energies Related to 1 and t-1 Intermediates)

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The Journal of Organic Chemistry As a first result, the substitution in α-position of the nitrogen atom of the amino-alcohol was confirmed to have remarkable impact on the key equilibrium between the two competitive pathways (2 to TS2a/TS2b and t-2 to t-TS2a/t-TS2b, Scheme 6). Indeed, in the case of ethanolamine (Scheme 6a), the reaction was computed to preferentially follow a thermodynamic pathway because a much lower activation barrier was required to reach transition state TS2a from the intermediate 2 (3.34 kcal/mol) when compared to the 12.03 kcal/mol required for transition state TS2b. On the contrary, in the case of 2-dimethylethanolamine (Scheme 6b), the kinetic compound resulting from the cyclization process was computed to be favored over the thermodynamic one (Δ(ΔG°(t-TS2a/tTS2b)) by +2.85 kcal/mol from common t-2 intermediate). A limiting step (t-4a to t-TS2a) within the thermodynamic pathway appeared to be mainly responsible for this shift in selectivity toward the kinetic pathway. Indeed a high activation barrier of 13.07 kcal/mol is required for this single step, making the accessibility to the thermodynamic product very unfavorable over the kinetic one. In addition, it is interesting to note that comparison of the two reaction profiles (ethanolamine vs. 2,2-dimethylethanolamine) showed that substitution at αposition of the nitrogen atom mainly impacted the thermodynamic pathway (Δ(ΔG°(t-TS2a/TS2a)) by +10.00 kcal/mol) without really affecting the kinetic one (Δ(ΔG°(t-TS2b/ TS2b)) by +1.44 kcal/mol). This can be correlated with the existence of an unfavorable zone (steric hindrance) between the proton of the enamine moiety and one methyl group within t-TS2a, mainly responsible for the important increase in the activation barrier level to reach this transition state (Figure 1). Finally, the

2e, 2k, 2l, 2n, and 2p were isolated in more than 90% yield, proving the pertinence of the chosen structural modifications. Finally, it is worth mentioning that the protection of alcohol function with TMS group allowed the introduction of various amino-alcohols, not substituted (2a, 2f, and 2q) to α,βdisubstituted ones (2o and 2p), without drastically affecting the efficiency of the kinetic control. The structure of 2a was confirmed by X-ray diffraction analysis (CCDC 1552693), confirming the presence of an intramolecular hydrogen bonding within the enaminone subunit (Figure 2). Because selectivity toward the kinetic products was efficiently controlled, the study was pursued to emphasize the great potential of a domino process to reach a variety of structures when wisely modulated. The reactivity of the enaminochromanone core was thus studied to access a novel family of polyheterocyclic systems. In this line, it was hypothesized that the course of the previously described O-ring opening, followed by O- or N-ring closure step (Schemes 3a and b), could be shifted if the nitrogen atom would act not as a nucleophile but as an electrophile. In this line, aryl-λ3-iodanes reagents such as phenyliodine bis(trifluoroacetate) (PIFA) or phenyliodine diacetate (PIDA) are well-known to induce this switch in reactivity within an amine function.19 In these cases, ring closure steps often occur onto the nitrogen atom. We thus anticipated that this switch in reactivity applied onto enaminochromanones could ultimately lead to the pyrrole ring through the proposed mechanism bellow (Scheme 8). The oxidative cyclization process would be initiated by the nucleophilic attack of the secondary amine onto the first equivalent of hypervalent iodine (here PIFA), to form intermediate A′. The latter would then undergo the unchanged O-ring opening step (step 1 in Scheme 8), leading to intermediate B (Z-isomer) in equilibrium with B′ (E-isomer). At this stage, the electrophilic character of the nitrogen atom would induce the key shift within the O- or N-ring closure sequence, triggering instead a consecutive O-, C-double cyclization (step 2 in Scheme 8), leading to dihydropyrrole intermediate C. Finally, the formation of chromeno-pyrrole 3a results from the ultimate oxidation of C through the action of a second equivalent of PIFA. To support our hypothesis, enaminochromanone 2a was reacted with 2.05 equiv of PIFA at 50 °C for 1 h in various solvents, and the results are highlighted in Table 1. Gratifyingly, in ethyl acetate, the desired chromeno-pyrrole 3a was obtained in 52% yield (entry 1), which confirmed the ability of PIFA to alter the course of the ring closure step. Along the screening, the solvent appeared to have a great impact onto the reaction efficiency (entries 1−8). Only ethereal solvents afforded 3a in good yields (entries 4, 6, and 7) with best result obtained with THF (entry 4). Two other cyclization agents, PIDA (entry 9) and lead(IV) acetate20 (entry 10), were then tested, but none of them afforded complete conversion into the desired product 3a. The use of 1.5 equiv of PIFA (entry 11) also afforded incomplete conversion even after 5 h of reaction time, proving that two equivalents of PIFA are indeed involved in the oxidation sequence. Finally, in a last experiment (entry 12), the course of the reaction was carefully monitored by TLC and, satisfyingly, full conversion was observed in only 20 min. In this case, 3a was isolated in 91% yield. This increase in yield by 13%, when compared to the 78% obtained after 1 h of stirring (entry 4), may be explained by the reduction of the contact time with the 4 equiv of TFA

Figure 1. Noncovalent interactions analysis of TS2a vs t-TS2a transition states using NCI-plot software.

stabilization of the kinetic product induced by the removal of one ester group was also examined. As expected, starting from Kinect or t-Kinect enaminochromanones (Scheme 6, see Supporting Information for details), the energetic barrier levels to form 4b/t-4b intermediates back were considerably increased. In the case of ethanolamine, for instance, the transition barrier raised from 26.92 kcal/mol (diester) to 43.67 kcal/mol (monoester),18 confirming the experimental observations (Scheme 5). With these interesting theoretical results in hand, we then designed a short library of enaminochromanone derivatives (Scheme 7). As expected, the substitution of the chromone core with electron-donating groups such as 3,4,5-trimethoxy (2c), pbenzoyl (2d), or p-methyl (2e) led to an important enhancement of the reaction time, up to 60 h for product 2c. This can be explained by the induced weakening of the position 2 electrophilic character, negatively impacting the first azaMichael addition. In some cases, the selectivity toward the kinetic product was very high because enaminochromanones 12192


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The Journal of Organic Chemistry Scheme 7. Short Library of Enaminochromanones Kinetic Products

Figure 2. X-ray structure of 2a (left) and its supramolecular chains through O−H···O hydrogen bonds (right).

generated during the process that would lead to degradation or generation of undesired side products. With the best conditions in hands for the construction of the chromeno-pyrrole 3a (step 1), we then turned our attention onto its architectural refinement. In this line, we envisioned the intramolecular trans-esterification (step 2) of chromeno-pyrrole 3a that would afford complex ring-fused polyheterocyclic frameworks containing the scarcely reported pyrrolo-oxazinone skeleton. For this purpose, classical conditions were tested with

PTSA (para-toluenesulfonic acid) as a Brönsted acid catalyst under reflux in toluene. Surprisingly, usual catalytic loadings of PTSA (10−30 mol %) did not afford conversion into the desired product 4a. This was probably due to its chelation by the other oxygenated sites within the molecule because the reiteration of the reaction with 2.0 equiv of PTSA afforded the desired pyrrolo-oxazinone 4a in only 30 min and 79% yield (Scheme 9). 12193


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The Journal of Organic Chemistry Scheme 8. Proposed Mechanism for Oxidative Cyclization of 2a

not appear to have any impact on the two step sequence, leading to ring fused pyrrolo-lactones. On the other hand, substitution at α-position of the nitrogen atom with hindered groups such as dimethyl (2d), phenyl (2h), cyclohexyl (2k), and benzyl(methyl)sulfane (2i) groups negatively impacted the first synthetic step. Indeed, the latter afforded corresponding oxazolo-pyrroles 4d, 4h, 4k, and 4i in respectively 52, 53, 44, and 58% yield. It was reasoned that steric hindrance may decrease the efficiency of the process at the ring closure stage (B′ to C, Scheme 8), which may become more challenging to achieve. The trans-esterification step was generally achieved in good yields even in the case of secondary (4m, 4o, and 4p) or tertiary (4n) alcohols. Moreover, α,βdisubstituted amino-alcohols (2o and 2p) were also welltolerated, increasing the architectural complexity that can be accessed through such transformations. Finally, 7-oxazinone ring was also attempted, but the trans-esterification step appeared to be limiting because only intermediate 3q was recovered after 2 h of reaction time.

Table 1. Screening of Reaction Conditions

entry

oxidant (2.05 equiv)

solvent

yield (%)b

1a 2 3 4 5 6 7 8 9 10 11c 12d

PIFA PIFA PIFA PIFA PIFA PIFA PIFA PIFA PIDA Pb(OAc)4 PIFA PIFA

AcOEt DCM acetone THF EtOH Et2O dioxane ACN THF THF THF THF

52 24 30 78 7 71 69 43 -c -c -c 91

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CONCLUSION In conclusion, we demonstrated how two novel families of polyheterocyclic systems could be efficiently accessed by successively governing and shifting the course of a domino process, starting from the chromone-based Michael acceptor platform. Remarkable kinetic control was enabled here by pertinent structural modifications within the reaction partners, leading to enaminochromanones. Then, the increase in architectural complexity was triggered by a key switch in reactivity. This allowed the incorporation of a consecutive double ring closure sequence within the reaction route, leading, in two short steps, to pyrrolo-oxazinone derivatives. These novel families contribute to shedding light on the great potential of a domino process to reach architectural complexity but also structural diversity.

a

Reactions were performed with 2a (0.16 mmol) in the presence of an oxidant (2.05 equiv) in solvent (3 mL) at 50 °C for 1 h. bIsolated yields. Blank cells represent incomplete conversion. cReaction performed with 1.5 equiv of PIFA for 5 h. dReaction time = 20 min.

Scheme 9. Intramolecular Trans-Esterification of 3a

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Before this trans-esterification step, an adequate workup (column chromatography) to efficiently remove the previously formed TFA is required. Indeed, under PTSA activation, its presence in the crude mixture led to a competitive intermolecular trans-esterification that dramatically impacted the yield. These two short transformations were then applied to the previously synthesized enaminochromanone kinetic products to study the scope and limitations (Scheme 10). As it could be anticipated, substitution of the chromone moiety did

EXPERIMENTAL SECTION

General Details. Unless otherwise specified, reagents and starting materials were purchased from traditional suppliers and used without further purification. Reactions were carried out in standard glassware. NMR spectra were recorded at 300 MHz for 1H and 75 MHz for 13C at room temperature in deuterated chloroform (CDCl3) or DMSO (DMSO-d6) using TMS as internal standard (δ = 0). High-resolution ESI mass spectra were measured on a Q-TOF System spectrometer. Chromatographic purifications were performed using Si2O (40−63 μm) as the solid phase and a mixture of cyclohexane:ethyl acetate or 12194


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The Journal of Organic Chemistry Scheme 10. Scope of Accessible Pyrrolo-Oxazinone Derivatives

7.37 (d, J = 23.9 Hz, 1H), 7.28 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). NMR data are in accordance with those reported in the literature.21 (E)-Ethyl 3-(1-Oxo-1H-benzo[f ]chromen-2-yl)acrylate (1b). White powder, Rf = 0.41, eluent (cyclohexane:ethyl acetate 8:2), 1.00 g scale reaction (in 5 mL of pyridine then 50 mL of EtOH), 0.89 g were isolated, 68% yield. 1H NMR (300 MHz, CDCl3): δH 10.00 (d, J = 7.8 Hz, 1H), 8.13−8.08 (m, 1H), 8.08−8.01 (m, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.82−7.70 (m, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.56−7.42 (m, 2H), 7.31−7.21 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H). NMR data are in accordance with those reported in the literature.22 (E)-Ethyl 3-(5,6,7-Trimethoxy-4-oxo-4H-chromen-3-yl)acrylate (1c). White powder, Rf = 0.17, eluent (cyclohexane:ethyl acetate 7:3), mp = 152−153 °C, 0.60 g scale reaction (in 3 mL of pyridine then 20 mL of EtOH), 0.40 g were isolated, 53% yield. IR (νmax/ cm−1): 1698, 1648, 1610, 1584, 1453, 1295. 1H NMR (300 MHz, CDCl3): δH 7.92 (s, 1H), 7.34 (d, J = 15.9 Hz, 1H), 7.16 (d, J = 15.8 Hz, 1H), 6.65 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.86 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 174.5, 167.4, 158.0, 155.3, 153.8, 153.0, 140.9, 135.4, 121.5, 119.5, 113.1, 96.2, 62.0, 61.4, 60.3, 56.3, 14.3. HRMS (ESI+): calcd for C17H19O7 [M + H]+ 335.1131, found 335.1130. (E)-Ethyl 3-(6-(Benzyloxy)-4-oxo-4H-chromen-3-yl)acrylate (1d). White powder, Rf = 0.47, eluent (cyclohexane:ethyl acetate 7:3), mp = 150−151 °C, 0.78 g scale reaction (in 4 mL of pyridine then 40 mL of EtOH), 0.33 g were isolated, 35% yield. IR (νmax/cm−1): 1696, 1651, 1611, 1583, 1453, 1293. 1H NMR (300 MHz, CDCl3): δH 8.11 (s,

dichloromethane:ethyl acetate as the eluent. Melting points were recorded on a Scientific Analyzer SMP 10 apparatus and are uncorrected. Infrared spectra were performed neat on a FT-IR spectrophotometer, and only broad or strong signals are reported. Specific rotations were measured on a 241 polarimeter. All the chromone-based Michael acceptor derivatives were synthesized according to literature procedure.16 General Procedure for Chromone-Based Michael Acceptor Synthesis (See Supporting Information Pages S2−S9). Michael acceptors bearing the chromone core were prepared according to Chand’s procedure.21 To a stirring solution of 3-formylchromone derivative (1.0 equiv) in pyridine was added malonic acid (1.5 equiv), and the reaction mixture was heated at 115 °C for 1.5 h. After cooling at room temperature, the solvent was removed under reduced pressure, and the crude solid obtained was triturated in cold diethyl ether and filtered. After being washed with diethyl and dried several times, the chromone-based acrylic acid was added to a stirring solution of ethanol and concentrated sulfuric acid (4−5 drops), and the reaction mixture was refluxed overnight. The remaining ethanol was then removed under reduced pressure, and the precipitated solid was filtered, washed with cold diethyl ether and water, and dried to yield the desired chromone-based Michael acceptor. (E)-Ethyl 3-(4-Oxo-4H-chromen-3-yl)acrylate (1a). White powder, Rf = 0.40, eluent (cyclohexane:ethyl acetate 7:3), 5.00 g scale reaction (in 25 mL of pyridine then 100 mL of EtOH), 6.52 g were isolated, 93% yield. 1H NMR (300 MHz, CDCl3): δH 8.30 (d, J = 7.9 Hz, 1H), 8.14 (s, 1H), 7.76−7.67 (m, 1H), 7.48 (td, J = 8.0, 7.6, 5.1 Hz, 2H), 12195


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The Journal of Organic Chemistry 1H), 7.73 (d, J = 3.0 Hz, 1H), 7.50−7.27 (m, 9H), 5.17 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 175.7, 167.4, 157.1, 156.5, 150.4, 136.1, 135.5, 128.7 (2×), 128.3, 127.7 (2×), 124.9, 124.4, 122.0, 119.6, 118.5, 106.7, 70.7, 60.5, 14.3. HRMS (ESI+): calcd for C21H19O5 [M + H]+ 351.1232, found 351.1237. (E)-Ethyl 3-(6-Methyl-4-oxo-4H-chromen-3-yl)acrylate (1e). White powder, Rf = 0.42, eluent (cyclohexane:ethyl acetate 7:3), 0.60 g scale reaction (in 3 mL of pyridine then 20 mL of EtOH), 0.42 g were isolated, 51% yield. 1H NMR (300 MHz, CDCl3): δH 8.08 (s,1H), 8.01 (d, J = 2.3 Hz, 1H), 7.47 (dd, J = 8.6, 2.2 Hz, 1H), 7.43− 7.32 (m, 2H), 7.25 (d, J = 15.8 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.44 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H). NMR data are in accordance with those reported in the literature.22 (E)-Ethyl 3-(6,8-Dichloro-4-oxo-4H-chromen-3-yl)acrylate (1f). White powder, Rf = 0.46, eluent (cyclohexane:ethyl acetate 7:3), mp = 161−162 °C, 1.00 g scale reaction (in 5 mL of pyridine then 40 mL of EtOH), 0.79 g were isolated, 61% yield. IR (νmax/cm−1): 1704, 1646, 1583, 1437, 1272. 1H NMR (300 MHz, CDCl3): δH 8.20 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.43−7.24 (m, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 174.0, 167.0, 156.9, 149.9, 134.2, 134.1, 131.6, 125.9, 124.5, 124.4, 123.5, 119.6, 60.7, 14.3. HRMS (ESI+): calcd for C14H11Cl2O4 [M + H]+ 313.0034, found 313.0036. (E)-Ethyl 3-(6-Chloro-7-methyl-4-oxo-4H-chromen-3-yl)acrylate (1g). White powder, Rf = 0.42, eluent (cyclohexane:ethyl acetate 7:3), mp = 179−180 °C, 0.57 g scale reaction (in 3 mL of pyridine then 20 mL of EtOH), 0.39 g were isolated, 56% yield. IR (νmax/ cm−1): 1706, 1651, 1613, 1583, 1272. 1H NMR (300 MHz, CDCl3): δH 8.18 (d, J = 1.3 Hz, 1H), 8.07 (s, 1H), 7.44−7.32 (m, 2H), 7.25 (d, J = 18.3 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 174.7, 167.2, 157.1, 153.8, 143.4, 135.0, 132.6, 125.9, 123.2, 122.5, 119.9, 119.2, 60.5, 20.8, 14.3. HRMS (ESI+): calcd for C15H14ClO4 [M + H]+ 293.0581, found 293.0582. General Procedure for Enaminochromanones Synthesis (See Supporting Information, Pages S10−S27). To a solution of chromone based Michael acceptor (1.0 equiv) and NEt3 (1.3 equiv) in DCM at 40 °C, was added the appropriate TMS-protected aminoalcohol derivative (1.3 equiv). The reaction was then stirred and monitored by TLC until complete consumption of starting material was observed. After cooling at 0 °C a few drops of conc. sulfuric acid were added and the reaction mixture was stirred again at 0 °C for 20 min saturated aqueous NaHCO3 was then added dropwise, at room temperature until no bubbling was observed. The organic layers were then extracted by DCM (3 × 10 mL), dried over anhydrous MgSO4 and concentrated. The resulting mixture led to pure enaminochromanone after purification on silica gel column chromatography. (Z)-Ethyl 2-(3-(((2-Hydroxyethyl)amino)methylene)-4-oxochroman-2-yl)acetate (2a). Yellow solid, Rf = 0.12, eluent (dichloromethane:ethyl acetate 8:2), mp = 103−104 °C, 2.00 g scale reaction (in 10 mL of DCM) for 20 h, 1.46 g were isolated, 58% yield. IR (νmax/cm−1): 1729, 1632, 1539, 1463. 1H NMR (300 MHz, CDCl3): δH 10.15−9.99 (m, 1H), 7.87 (dd, J = 7.8, 1.8 Hz, 1H), 7.38 (ddd, J = 8.2, 7.2, 1.8 Hz, 1H), 7.03 (td, J = 7.5, 1.1 Hz, 1H), 6.94−6.86 (m, 2H), 5.31 (t, J = 7.1 Hz, 1H), 4.20−4.08 (m, 2H), 3.79−3.72 (m, 2H), 3.44−3.35 (m, 2H), 2.90 (br s, 1H), 2.88 (dd, J = 15.1, 7.5 Hz, 1H), 2.64 (dd, J = 15.1, 6.9 Hz, 1H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 181.0, 170.5, 157.1, 151.8, 134.0, 126.2, 123.1, 121.5, 117.8, 100.3, 75.6, 62.2, 60.7, 51.4, 41.4, 14.2. HRMS (ESI+): calcd for C16H20NO5 [M + H]+ 306.1341, found 306.1341. (Z)-Ethyl 2-(2-(((1-Hydroxy-2-methylpropan-2-yl)amino)methylene)-1-oxo-2,3-dihydro-1H-benzo[f ]chromen-3-yl)acetate (2b). Yellow solid, Rf = 0.46, eluent (dichloromethane:ethyl acetate 8:2), mp = 157−158 °C, 0.40 g scale reaction (in 4 mL of DCM) for 18 h, 0.39 g were isolated, 74% yield. IR (νmax/cm−1): 1725, 1639, 1538, 1464. 1H NMR (300 MHz, CDCl3): δH 10.42 (d, J = 13.0 Hz, 1H), 9.39 (dd, J = 8.6, 1.1 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 7.79− 7.73 (m, 1H), 7.60 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.41 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.14−7.04 (m, 2H), 5.39 (t, J = 7.2 Hz, 1H), 4.22−

4.09 (m, 2H), 3.52 (s, 2H), 2.97 (dd, J = 15.2, 7.4 Hz, 1H), 2.76 (dd, J = 15.2, 7.0 Hz, 1H), 2.43 (br, 1H), 1.34 (s, 3H), 1.33 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 182.6, 170.7, 157.9, 147.0, 135.2, 131.7, 129.8, 128.3, 128.2, 126.3, 124.3, 118.9, 115.4, 100.7, 76.2, 70.8, 60.7, 55.9, 40.2, 24.3, 24.3, 14.2. HRMS (ESI+): calcd for C22H26NO5 [M + H]+ 384.1811, found 384.1811. (Z)-Ethyl 2-(3-((((R)-2-hydroxy-1-phenylethyl)amino)methylene)5,6,7-trimethoxy-4-oxochroman-2-yl)acetate (2c). Viscous yellow oil, Rf = 0.20, eluent (dichloromethane:ethyl acetate 7:3), [α]20D = +176.55 (c 0.63, CH2Cl2), 0.20 g scale reaction (in 3 mL of DCM) for 60 h, 0.14 g were isolated, 68% yield. IR (νmax/cm−1): 1731, 1644, 1597, 1453, 1244. Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): δH 10.54−10.41 (m, 1H), 7.37−7.26 (m, 5H), 6.82 (d, J = 12.4 Hz, 1H), 6.18 (s, 1H), 5.16 (t, J = 7.1 Hz, 1H), 4.40 (dd, J = 8.4, 4.6 Hz, 1H), 4.16−4.07 (m, 2H), 3.96 (s, 3H), 3.91−3.83 (m, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.25 (br s, 1H), 2.85 (dd, J = 15.1, 7.9 Hz, 1H), 2.62 (dd, J = 15.1, 6.3 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.7, 170.3, 157.9, 155.4, 154.1, 149.3, 138.5, 137.4, 128.9 (2×), 128.1, 126.9 (2×), 110.7, 101.0, 96.5, 75.9, 66.7, 64.9, 61.8, 61.3, 60.6, 56.0, 40.3, 14.2. Diastereoisomer 2: 1H NMR (300 MHz, CDCl3): δH 10.54−10.41 (m, 1H), 7.37−7.26 (m, 5H), 6.82 (d, J = 12.4 Hz, 1H), 6.18 (s, 1H), 5.16 (t, J = 7.1 Hz, 1H), 4.40 (dd, J = 8.4, 4.6 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.96 (s, 3H), 3.91− 3.83 (m, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.12 (br s, 1H), 2.85 (dd, J = 15.1, 7.9 Hz, 1H), 2.62 (dd, J = 15.1, 6.3 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.6, 170.4, 157.8, 155.4, 154.1, 149.3, 138.4, 137.4, 128.9 (2×), 128.1, 126.9 (2×), 110.7, 101.2, 96.5, 75.9, 66.7, 64.9, 61.8, 61.2, 60.7, 56.0, 40.2, 14.1. HRMS (ESI+): calcd for C25H30NO8 [M + H]+ 472.1971, found 472.1968. (Z)-Ethyl 2-(6-(Benzyloxy)-3-(((1-hydroxy-2-methylpropan-2-yl)amino)methylene)-4-oxochroman-2-yl)acetate (2d). Yellow solid, Rf = 0.49, eluent (dichloromethane:ethyl acetate 7:3), mp = 106−107 °C, 0.25 g scale reaction (in 3 mL of DCM) for 48 h, 0.26 g were isolated, 82% yield. IR (νmax/cm−1): 1721, 1708, 1641, 1538, 1464, 1286. 1H NMR (300 MHz, CDCl3): δH 10.43 (d, J = 13.2 Hz, 1H), 7.48−7.32 (m, 6H), 7.15−7.01 (m, 2H), 6.83 (d, J = 8.9 Hz, 1H), 5.30 (t, J = 7.2 Hz, 1H), 5.07 (s, 2H), 4.20−4.08 (m, 2H), 3.51 (s, 2H), 3.09 (br s, 1H), 2.89 (dd, J = 15.1, 7.2 Hz, 1H), 2.65 (dd, J = 15.1, 7.0 Hz, 1H), 1.32 (s, 6H), 1.25 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.2, 170.7, 153.5, 151.3, 148.0, 137.0, 128.6 (2×), 128.0, 127.6 (2×), 123.3, 122.9, 118.9, 109.0, 100.0, 75.7, 70.6, 70.6, 60.7, 56.1, 41.2, 24.3, 24.2, 14.2. HRMS (ESI+): calcd for C25H30NO6 [M + H]+ 440.2073, found 440.2070. (Z)-Ethyl 2-(3-((((R)-2-Hydroxy-1-phenylethyl)amino)methylene)6-methyl-4-oxochroman-2-yl)acetate (2e). Viscous yellow oil, Rf = 0.36, eluent (dichloromethane:ethyl acetate 9:1), [α]20D = +211.82 (c 0.76, CH2Cl2), 0.25 g scale reaction (in 3 mL of DCM) for 48 h, 0.35 g were isolated, 90% yield. IR (νmax/cm−1): 1728, 1640, 1606, 1546, 1484, 1280. Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): δH 10.67−10.51 (m, 1H), 7.68 (d, J = 1.3 Hz, 1H), 7.37−7.25 (m, 5H), 7.18 (dd, J = 8.4, 2.3 Hz, 1H), 6.89 (dd, J = 12.6, 10.0 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.25 (t, J = 7.1 Hz, 1H), 4.51−4.37 (m, 1H), 4.17−4.07 (m, 2H), 3.99−3.77 (m, 2H), 3.73 (br s, 1H), 2.84 (dd, J = 15.0, 7.9 Hz, 1H), 2.55 (dd, J = 15.0, 7.9 Hz, 1H), 2.32 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 181.3, 170.5, 155.1, 150.4, 138.2, 135.1, 130.9, 129.0 (2×), 128.2, 126.9 (2×), 126.1, 122.7, 117.7, 101.0, 75.5, 66.7, 64.8, 60.7, 41.2, 20.6, 14.2. Diastereoisomer 2: 1H NMR (300 MHz, CDCl3): δH 10.67−10.51 (m, 1H), 7.68 (d, J = 1.3 Hz, 1H), 7.37−7.25 (m, 5H), 7.18 (dd, J = 8.4, 2.3 Hz, 1H), 6.89 (dd, J = 12.6, 10.0 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.22 (t, J = 7.1 Hz, 1H), 4.51−4.37 (m, 1H), 4.07−3.95 (m, 2H), 3.99−3.77 (m, 3H), 2.84 (dd, J = 15.0, 7.9 Hz, 1H), 2.55 (dd, J = 15.0, 7.9 Hz, 1H), 2.32 (s, 3H), 1.14 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 181.3, 170.3, 155.1, 150.5, 138.2, 135.1, 130.9, 129.0 (2×), 128.2, 126.9 (2×), 126.1, 122.7, 117.7, 101.1, 75.5, 66.7, 64.9, 60.6, 41.4, 20.6, 14.1. HRMS (ESI+): calcd for C23H26NO5 [M + H]+ 396.1811, found 396.1810. (Z)-Ethyl 2-(6,8-dichloro-3-(((2-hydroxyethyl)amino)methylene)4-oxochroman-2-yl)acetate (2f). Yellow solid, Rf = 0.35, eluent (dichloromethane:ethyl acetate 1:1), mp = 77−78 °C, 0.50 g scale 12196


Article

The Journal of Organic Chemistry

(Z)-Ethyl 2-(3-(((1-Hydroxy-2-methylpropan-2-yl)amino)methylene)-4-oxochroman-2-yl)acetate (2j). Viscous yellow oil, Rf = 0.34, eluent (dichloromethane:ethyl acetate 7:3), 0.47 g scale reaction (in 4 mL of DCM) for 35h, 0.54 g were isolated, 85% yield. IR (νmax/cm−1): 1715, 1638, 1584, 1463, 1294. 1H NMR (300 MHz, CDCl3): δH 10.38 (d, J = 13.3 Hz, 1H), 7.81 (dt, J = 7.0, 3.0 Hz, 1H), 7.39−7.28 (m, 1H), 7.10−6.93 (m, 2H), 6.83 (dd, J = 8.5, 4.4 Hz, 1H), 5.28 (t, J = 7.2 Hz, 1H), 4.14−4.04 (m, 2H), 3.88 (br s, 1H), 3.47 (d, J = 4.9 Hz, 2H), 2.83 (dd, J = 15.1, 7.4 Hz, 1H), 2.59 (dd, J = 15.1, 6.5 Hz, 1H), 1.26 (2xs, 6H), 1.19 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.2, 170.6, 156.9, 148.1, 133.8, 126.0, 123.1, 121.5, 117.7, 99.7, 75.7, 70.5, 60.7, 56.2, 41.4, 24.3, 24.1, 14.2. HRMS (ESI+): calcd for C18H24NO5 [M + H]+ 334.1654, found 334.1655. (Z)-Ethyl 2-(3-(((1-(Hydroxymethyl)cyclohexyl)amino)methylene)-4-oxochroman-2-yl)acetate (2k). Viscous yellow oil, Rf = 0.32, eluent (dichloromethane:ethyl acetate 8:2), 0.35 g scale reaction (in 3 mL of DCM) for 30 h, 0.49 g were isolated, 91% yield. IR (νmax/cm−1): 1727, 1638, 1586, 1465, 1287. 1H NMR (300 MHz, CDCl3): δH 10.25 (d, J = 13.3 Hz, 1H), 7.79 (dd, J = 7.8, 1.7 Hz, 1H), 7.35−7.23 (m, 1H), 7.03 (d, J = 13.3 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.22 (t, J = 7.1 Hz, 1H), 4.10−3.98 (m, 2H), 3.77 (br s, 1H), 3.42 (s, 2H), 2.79 (dd, J = 15.1, 7.4 Hz, 1H), 2.56 (dd, J = 15.1, 7.0 Hz, 1H), 1.72 (t, J = 5.6 Hz, 2H), 1.56−1.38 (m, 7H), 1.29−1.19 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.2, 170.6, 156.9, 148.9, 133.7, 126.0, 123.1, 121.4, 117.7, 99.9, 75.7, 70.1, 60.6, 57.9, 41.4, 32.3, 31.9, 25.6, 21.0, 20.9, 14.1. HRMS (ESI+): calcd for C21H28NO5 [M + H]+ 374.1967, found 374.1966. (Z)-Ethyl 2-(3-((((S)-1-Hydroxy-3-methylbutan-2-yl)amino)methylene)-4-oxochroman-2-yl)acetate (2l). Viscous yellow oil, Rf = 0.39, eluent (dichloromethane:ethyl acetate 8:2), [α]20D = −33.54 (c 0.43, CH2Cl2), 0.37 g scale reaction (in 3 mL of DCM) for 20 h, 0.50 g were isolated, 96% yield. IR (νmax/cm−1): 1727, 1640, 1585, 1465, 1290. Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): δH 10.15− 10.00 (m, 1H), 7.80 (td, J = 7.7, 1.7 Hz, 1H), 7.32 (ddt, J = 8.9, 7.5, 1.7 Hz, 1H), 6.97 (tdd, J = 7.5, 2.4, 1.1 Hz, 1H), 6.90−6.80 (m, 2H), 5.28 (t, J = 7.2 Hz, 1H), 4.24−4.15 (m, 1H), 4.15−4.00 (m, 2H), 3.73−3.55 (m, 2H), 2.99−2.87 (m, 1H), 2.78 (dd, J = 15.1, 7.7 Hz, 1H), 2.53 (dd, J = 15.1, 6.7 Hz, 1H), 1.93−1.76 (m, 1H), 1.19 (t, J = 7.1, Hz, 3H), 0.91 (d, J = 2.8 Hz, 3H), 0.89 (d, J = 2.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.7, 170.3, 157.1, 152.4, 133.9, 125.9, 122.9, 121.5, 117.8, 99.6, 75.5, 68.4, 63.8, 60.5, 41.4, 29.6, 19.7, 17.9, 14.1. Diastereoisomer 2: 1H NMR (300 MHz, CDCl3): δH 10.15− 10.00 (m, 1H), 7.80 (td, J = 7.7, 1.7 Hz, 1H), 7.32 (ddt, J = 8.9, 7.5, 1.7 Hz, 1H), 6.97 (tdd, J = 7.5, 2.4, 1.1 Hz, 1H), 6.90−6.80 (m, 2H), 5.13 (t, J = 7.2 Hz, 1H), 4.15−4.00 (m, 2H), 3.73−3.55 (m, 3H), 2.99−2.87 (m, 1H), 2.78 (dd, J = 15.1, 7.7 Hz, 1H), 2.53 (dd, J = 15.1, 6.7 Hz, 1H), 1.93−1.76 (m, 1H), 1.19 (t, J = 7.1, Hz, 3H), 0.91 (d, J = 2.8 Hz, 3H), 0.89 (d, J = 2.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.5, 170.5, 157.0, 151.9, 133.9, 126.0, 123.1, 121.4, 117.8, 99.5, 75.3, 68.1, 63.9, 60.7, 41.2, 29.7, 19.7, 18.0, 14.1. HRMS (ESI+): calcd for C19H26NO5 [M + H]+ 348.1811, found 348.1810. (Z)-Ethyl 2-(3-((((S)-2-Hydroxypropyl)amino)methylene)-4-oxochroman-2-yl)acetate (2m). Viscous yellow oil, Rf = 0.27, eluent (dichloromethane:ethyl acetate 7:3), [α]20D = +40.60 (c 0.34, CH2Cl2), 0.20 g scale reaction (in 3 mL of DCM) for 20 h, 0.19 g were isolated, 72% yield. IR (νmax/cm−1): 1727, 1643, 1585, 1465, 1288. Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): δH 10.15− 10.02 (m, 1H), 7.85 (dt, J = 7.7, 1.7 Hz, 1H), 7.35 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.00 (td, J = 7.5, 1.1 Hz, 1H), 6.92−6.82 (m, 2H), 5.29 (t, J = 7.1 Hz, 1H), 4.19−4.05 (m, 2H), 3.90 (br s, 1H), 3.36−3.23 (m, 2H), 3.20−3.08 (m, 1H), 2.86 (dd, J = 15.1, 7.6 Hz, 1H), 2.61 (dd, J = 15.1, 6.7 Hz, 1H), 1.26−1.16 (m, 6H). 13C NMR (75 MHz, CDCl3): δC 180.8, 170.5, 157.0, 152.0, 134.0, 126.2, 123.1, 121.5, 117.8, 100.1, 75.5, 67.2, 60.7, 56.5, 41.4, 20.3, 14.2. Diastereoisomer 2: 1H NMR (300 MHz, CDCl3): δH 10.15−10.02 (m, 1H), 7.85 (dt, J = 7.7, 1.7 Hz, 1H), 7.35 (ddd, J = 8.6, 7.3, 1.7 Hz, 1H), 7.00 (td, J = 7.5, 1.1 Hz, 1H), 6.92−6.82 (m, 2H), 5.29 (t, J = 7.1 Hz, 1H), 4.19−4.05 (m, 2H), 3.90 (br s, 1H), 3.36−3.23 (m, 2H), 3.20−3.08 (m, 1H), 2.86 (dd, J = 15.1, 7.6 Hz, 1H), 2.61 (dd, J = 15.1, 6.7 Hz, 1H), 1.26−1.16 (m, 6H).

reaction (in 4 mL of DCM) for 16 h, 0.41 g were isolated, 69% yield. IR (νmax/cm−1): 1712, 1647, 1546, 1461, 1284. 1H NMR (300 MHz, CDCl3): δH 10.20−10.03 (m, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 6.99 (d, J = 12.9 Hz, 1H), 5.40 (t, J = 7.2 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.74 (t, J = 5.0 Hz, 2H), 3.50−3.27 (m, 3H), 2.84 (dd, J = 15.1, 8.0 Hz, 1H), 2.59 (dd, J = 15.1, 6.5 Hz, 1H), 1.22 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 178.2, 170.1, 152.9, 151.3, 133.3, 126.5, 125.0, 124.4, 123.6, 99.3, 76.6, 61.9, 61.0, 51.6, 41.6, 14.1. HRMS (ESI+): calcd for C16H18Cl2NO5 [M + H]+ 374.0562, found 374.0565. (Z)-Ethyl 2-(6-chloro-3-(((1-hydroxy-2-methylpropan-2-yl)amino)methylene)-7-methyl-4-oxochroman-2-yl)acetate (2g). Viscous yellow oil, Rf = 0.46, eluent (dichloromethane:ethyl acetate 8:2), 0.25 g scale reaction (in 3 mL of DCM) for 30 h, 0.25 g were isolated, 75% yield. IR (νmax/cm−1): 1727, 1637, 1575, 1452, 1175. 1H NMR (300 MHz, CDCl3): δH 10.35 (d, J = 13.3 Hz, 1H), 7.77 (s, 1H), 7.06 (d, J = 13.3 Hz, 1H), 6.74 (d, J = 0.9 Hz, 1H), 5.27 (t, J = 7.2 Hz, 1H), 4.17−4.08 (m, 2H), 3.51 (d, J = 5.3 Hz, 2H), 3.18 (br s, 1H), 2.84 (dd, J = 15.1, 7.4 Hz, 1H), 2.61 (dd, J = 15.1, 7.0 Hz, 1H), 2.34 (s, 3H), 1.31 (s, 3H), 1.31 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 179.1, 170.5, 155.2, 148.1, 142.3, 127.3, 126.0, 122.2, 119.9, 99.3, 76.0, 70.6, 60.7, 56.2, 41.4, 24.3, 24.1, 20.6, 14.2. HRMS (ESI+): calcd for C19H25ClNO5 [M + H]+ 382.1421, found 382.1422. (Z)-Ethyl 2-(3-((((R)-2-Hydroxy-1-phenylethyl)amino)methylene)4-oxochroman-2-yl)acetate (2h). Viscous yellow oil, Rf = 0.32, eluent (dichloromethane:ethyl acetate 8:2), [α]20D = +200.06 (c 0.72, CH2Cl2), 0.29 g scale reaction (in 3 mL of DCM) for 30 h, 0.34 g was isolated, 75% yield. IR (νmax/cm−1): 1725, 1641, 1583, 1465, 1289. Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): δH 10.71−10.50 (m, 1H), 7.88 (dd, J = 7.9, 1.8 Hz, 1H), 7.41−7.27 (m, 6H), 7.04 (dt, 1H), 6.97−6.85 (m, 2H), 5.26 (t, 7.2 Hz, 1H), 4.56−4.39 (m, 1H), 4.19− 4.07 (m, 2H), 3.97−3.80 (m, 2H), 3.38 (br s, 1H), 2.85 (dd, J = 15.4, 7.9 Hz, 1H), 2.58 (dd, J = 15.4, 7.9 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H). 13 C NMR (75 MHz, CDCl3): δC 181.1, 170.2, 157.2, 150.8, 138.2, 134.1, 129.0 (2×), 128.2, 126.9 (2×), 126.2, 123.0, 121.6, 117.9, 100.7, 75.6, 66.6, 65.1, 60.6, 41.3, 14.2. Diastereoisomer 2: 1H NMR (300 MHz, CDCl3): δH 10.71−10.50 (m, 1H), 7.88 (dd, J = 7.9, 1.8 Hz, 1H), 7.41−7.27 (m, 6H), 7.04 (dt, 1H), 6.97−6.85 (m, 2H), 5.26 (t, 7.2 Hz, 1H), 4.56−4.39 (m, 1H), 4.19−4.07 (m, 2H), 3.97−3.80 (m, 2H), 3.38 (br s, 1H), 2.85 (dd, J = 15.4, 7.9 Hz, 1H), 2.58 (dd, J = 15.4, 7.9 Hz, 1H), 1.16 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 181.0, 170.5, 157.2, 150.5, 138.2, 134.1, 129.0 (2×), 128.2, 126.8 (2×), 126.2, 123.1, 121.5, 117.9, 100.9, 75.5, 66.7, 64.8, 60.7, 41.5, 14.1. HRMS (ESI+): calcd for C22H24NO5 [M + H]+ 382.1654, found 382.1655. (Z)-Ethyl 2-(3-((((R)-1-(Benzylthio)-3-hydroxypropan-2-yl)amino)methylene)-4-oxochroman-2-yl)acetate (2i). Viscous yellow oil, Rf = 0.39, eluent (dichloromethane:ethyl acetate 8:2), [α]20D = −153.82 (c 0.48, CH2Cl2), 0.30 g scale reaction (in 3 mL of DCM) for 20 h, 0.42 g were isolated, 77% yield. IR (νmax/cm−1): 1726, 1640, 1585, 1466, 1288. Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): δH 10.13− 9.98 (m, 1H), 7.84 (dd, J = 7.6, 1.7 Hz, 1H), 7.38−7.22 (m, 6H), 7.04−6.96 (m, 1H), 6.87 (dd, J = 8.2, 5.0 Hz, 1H), 6.78 (dd, J = 12.6, 6.2 Hz, 1H), 5.32 (t, J = 7.4 Hz, 1H), 4.34−4.25 (m, 1H), 4.20−4.07 (m, 2H), 3.75−3.62 (m, 4H), 3.21 (br s, 1H), 2.84 (dd, J = 15.1, 8.0 Hz, 1H), 2.69−2.48 (m, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.8, 170.5, 157.2, 150.6, 137.9, 134.1, 129.0 (2×), 128.7 (2×), 127.3, 126.1, 123.1, 121.5, 117.9, 100.3, 75.5, 64.2, 61.5, 60.7, 41.3, 37.1, 33.7, 14.2. Diastereoisomer 2: 1H NMR (300 MHz, CDCl3): δH 10.13−9.98 (m, 1H), 7.84 (dd, J = 7.6, 1.7 Hz, 1H), 7.38− 7.22 (m, 6H), 7.04−6.96 (m, 1H), 6.87 (dd, J = 8.2, 5.0 Hz, 1H), 6.78 (dd, J = 12.6, 6.2 Hz, 1H), 5.21 (t, J = 7.4 Hz, 1H), 4.20−4.07 (m, 2H), 3.97−3.88 (m, 1H), 3.75−3.62 (m, 4H), 3.21 (br s, 1H), 2.84 (dd, J = 15.1, 8.0 Hz, 1H), 2.69−2.48 (m, 3H), 1.23 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 181.0, 170.4, 157.2, 151.0, 137.9, 134.1, 129.0 (2×), 128.6 (2×), 127.3, 126.2, 122.9, 121.6, 117.9, 100.2, 75.6, 64.0, 61.8, 60.7, 41.5, 37.1, 33.5, 14.2. HRMS (ESI+): calcd for C24H28NO5S [M + H]+ 442.1688, found 442.1689. 12197


Article


1698, 1578, 1568, 1454, 1295. 1H NMR (300 MHz, CDCl3): δH 10.03 (dd, J = 12.5, 6.2 Hz, 1H), 7.80 (dd, J = 7.8, 1.7 Hz, 1H), 7.33−7.26 (m, 1H), 6.95 (td, J = 7.5, 1.1 Hz, 1H), 6.88−6.79 (m, 2H), 5.30−5.23 (m, 1H), 4.13−4.01 (m, 2H), 3.63 (t, J = 6.0 Hz, 2H), 3.52 (br s, 1H), 3.34 (q, J = 6.5 Hz, 2H), 2.82 (dd, J = 15.2, 7.7 Hz, 1H), 2.58 (dd, J = 15.2, 6.6 Hz, 1H), 1.79−1.69 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.5, 170.5, 156.9, 151.8, 133.9, 126.1, 123.1, 121.5, 117.7, 99.7, 75.6, 60.6, 58.9, 46.1, 41.4, 33.2, 14.1. HRMS (ESI+): calcd for C17H22NO5 [M + H]+ 320.1498, found 320.1503. General Procedure for Pyrrolo-Oxazinones Synthesis (See Supporting Information, Pages S28−S48). Step 1: To a stirring solution of enaminochromanone product 2 (50.0 mg, 1.0 equiv) in THF (3 mL) at 50 °C was added PIFA (2.05 equiv). The reaction mixture was then allowed to stir for 20 min (TLC monitoring). After removal of the solvent under reduced pressure, the crude reaction mixture was immediately purified on silica gel column chromatography to afford pure chromeno-pyrrole derivative 3. Step 2: To a stirring solution of previously purified chromenopyrrole compound 3 (1.0 equiv) in toluene (3 mL) under reflux was added PTSA (2.00 equiv). The reaction mixture was then allowed to stir for 30 min (TLC monitoring). After removal of the solvent under reduced pressure, the crude reaction mixture was purified on silica gel column chromatography or triturated in ethanol to yield pure pyrrolooxazinone derivative 4. Ethyl 2-(2-Hydroxyethyl)-9-oxo-2,9-dihydrochromeno[2,3-c]pyrrole-3-carboxylate (3a). White solid, R f = 0.11, eluent (dichloromethane:ethyl acetate 7:3), mp = 166−167 °C, 44.9 mg were isolated (step 1), 91% yield. IR (νmax/cm−1): 1711, 1623, 1583, 1569, 1432, 1273. 1H NMR (300 MHz, DMSO-d6): δH 8.14 (dd, J = 7.9, 1.7 Hz, 1H), 7.89 (s, 1H), 7.77 (td, J = 8.7, 7.1, 1.8 Hz, 1H), 7.52 (dd, J = 8.5, 1.0 Hz, 1H), 7.41 (td, J = 7.5, 7.1, 1.1 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.50 (t, J = 5.3 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.71 (q, J = 5.3 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, DMSOd6): δC 173.2, 159.8, 156.7, 149.4, 135.0, 126.6, 126.3, 124.4, 122.2, 118.5, 110.3, 106.2, 60.6, 60.4, 53.2, 14.6. HRMS (ESI+): calcd for C16H16NO5 [M + H]+ 302.1028, found 302.1034. Ethyl 2-(3-Hydroxypropyl)-9-oxo-2,9-dihydrochromeno[2,3-c]pyrrole-3-carboxylate (3q). White solid, R f = 0.14, eluent (dichloromethane:ethyl acetate 7:3), mp = 170−171 °C, 38.1 mg were isolated (step 1), 77% yield. IR (νmax/cm−1): 1713, 1626, 1581, 1571, 1441, 1273. 1H NMR (300 MHz, CDCl3): δH 8.32 (dd, J = 7.9, 1.7 Hz, 1H), 7.75−7.64 (m, 2H), 7.51 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 4.66 (t, J = 6.5 Hz, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.63 (t, J = 5.5 Hz, 2H), 2.53 (br, 1H), 2.11 (p, J = 6.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 174.4, 160.5, 157.0, 149.9, 134.1, 126.6, 124.8, 123.8, 122.3, 118.2, 111.2, 106.7, 60.6, 58.4, 47.4, 33.8, 14.4. HRMS (ESI+): calcd for C17H18NO5 [M + H]+ 316.1185, found 316.1188. 3,4-Dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7dione (4a). White solid (trituration in EtOH), Rf = 0.28, eluent (dichloromethane:ethyl acetate 8:2), mp = 314−315 °C, 30.1 mg were isolated (steps 1 and 2), 79% yield (step 2). IR (νmax/cm−1): 1700, 1657, 1584, 1452, 1208. 1H NMR (300 MHz, DMSO-d6, 80 °C): δH 8.19 (dd, J = 7.9, 1.8 Hz, 1H), 7.97 (s, 1H), 7.81 (ddd, J = 8.7, 7.1, 1.9 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.50−7.41 (m, 1H), 4.70−4.64 (m, 2H), 4.53−4.45 (m, 2H). 13C NMR (75 MHz, DMSO-d6, 80 °C): δC 173.1, 156.8, 156.7, 149.3, 135.1, 126.5, 124.7, 122.6, 121.9, 118.5, 111.9, 104.1, 66.5, 44.6. HRMS (ESI+): calcd for C14H10NO4 [M + H]+ 256.0610, found 256.0611. 11,11-Dimethyl-10,11-dihydrobenzo[5′,6′]chromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-8,14-dione (4b). White solid (column chromatography), Rf = 0.39, eluent (dichloromethane:ethyl acetate 1:1), mp = 278−279 °C, 21.8 mg were isolated (steps 1 and 2), 67% yield (step 1), 75% yield (step 2). IR (νmax/cm−1): 1705, 1586, 1565, 1461, 1202. 1H NMR (300 MHz, CDCl3): δH 10.07 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 9.1 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.80−7.66 (m, 3H), 7.60 (t, J = 7.5 Hz, 1H), 4.40 (s, 2H), 1.70 (s, 6H). 13C NMR (75 MHz, CDCl3): δC 176.2, 158.6, 156.5, 149.2, 136.3, 131.4, 130.4, 129.3, 128.3, 127.0, 126.1, 118.5, 116.9, 115.0, 114.9, 102.6, 74.9, 55.4,

C NMR (75 MHz, CDCl3): δC 180.8, 170.5, 157.0, 152.0, 134.0, 126.2, 123.1, 121.5, 117.8, 100.1, 75.5, 67.1, 60.7, 56.5, 41.4, 20.4, 14.2. HRMS (ESI+): calcd for C17H22NO5 [M + H]+ 320.1498, found 320.1494. (Z)-Ethyl 2-(3-(((2-Hydroxy-2-methylpropyl)amino)methylene)-4oxochroman-2-yl)acetate (2n). Yellow solid, Rf = 0.31, eluent (dichloromethane:ethyl acetate 8:2), mp = 58−59 °C, 0.25 g scale reaction (in 3 mL of DCM) for 18 h, 0.30 g was isolated, 89% yield. IR (νmax/cm−1): 1722, 1643, 1582, 1465, 1146. 1H NMR (300 MHz, CDCl3): δH 10.11 (dt, J = 12.9, 6.6 Hz, 1H), 7.82 (dd, J = 7.8, 1.7 Hz, 1H), 7.30 (ddd, J = 8.6, 7.4, 1.8 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.89−6.76 (m, 2H), 5.27 (t, J = 7.1 Hz, 1H), 4.18−3.94 (m, 2H), 3.29 (br s, 1H), 3.22−3.07 (m, 2H), 2.80 (dd, J = 15.1, 7.1 Hz, 1H), 2.58 (dd, J = 15.1, 6.7 Hz, 1H), 1.21−1.12 (m, 9H). 13C NMR (75 MHz, CDCl3): δC 180.7, 170.4, 157.0, 152.4, 133.9, 126.2, 123.1, 121.5, 117.7, 99.9, 75.5, 70.2, 60.6, 60.3, 41.4, 26.8, 26.7, 14.1. HRMS (ESI+): calcd for C18H24NO5 [M + H]+ 334.1654, found 334.1658. (Z)-Ethyl 2-(3-((((1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl)amino)methylene)-4-oxochroman-2-yl)acetate (2o). Yellow solid, Rf = 0.42, eluent (dichloromethane:ethyl acetate 8:2), mp = 145−146 °C, [α]20D = +114.42 (c 0.59, CH2Cl2), 0.35 g scale reaction (in 3 mL of DCM) for 25 h, 0.45 g were isolated, 79% yield. IR (νmax/cm−1): 1728, 1645, 1583, 1536, 1465, 1283. Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): δH 10.38−10.22 (m, 1H), 7.84 (dd, J = 7.8, 1.9 Hz, 1H), 7.40−7.33 (m, 1H), 7.29−7.18 (m, 4H), 7.04−6.92 (m, 2H), 6.88 (ddd, J = 8.3, 4.4, 1.1 Hz, 1H), 5.33 (t, 7.2 Hz, 1H), 4.65 (dd, J = 7.8, 5.0 Hz, 1H), 4.61−4.51 (m, 1H), 4.18−4.06 (m, 2H), 4.03 (d, J = 4.4 Hz, 1H), 3.11−2.89 (m, 2H), 2.87 (dd, J = 15.1, 7.5 Hz, 1H), 2.62 (dd, J = 15.1, 6.6 Hz, 1H), 1.24 (t, J = 7.1, 3H). 13C NMR (75 MHz, CDCl3): δC 180.9, 170.5, 157.1, 150.3, 140.5, 139.7, 134.0, 128.7, 127.1, 126.3, 125.6, 124.7, 123.1, 121.5, 117.8, 100.5, 75.7, 73.9, 66.3, 60.7, 41.4, 39.1, 14.2. Diastereoisomer 2: 1H NMR (300 MHz, CDCl3): δH 10.38−10.22 (m, 1H), 7.84 (dd, J = 7.8, 1.9 Hz, 1H), 7.40−7.33 (m, 1H), 7.29−7.18 (m, 4H), 7.04−6.92 (m, 2H), 6.88 (ddd, J = 8.3, 4.4, 1.1 Hz, 1H), 5.28 (t, 1H), 4.61−4.51 (m, 2H), 4.18−4.06 (m, 2H), 3.82 (d, J = 5.4 Hz, 1H), 3.11−2.89 (m, 2H), 2.86 (dd, J = 15.2, 7.9 Hz, 1H), 2.61 (dd, J = 15.2, 6.7 Hz, 1H), 1.24 (t, J = 7.1, 1.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.6, 170.5, 157.2, 150.7, 140.6, 139.6, 134.0, 128.7, 127.2, 126.2, 125.6, 124.7, 123.2, 121.4, 117.8, 100.6, 75.7, 73.7, 66.1, 60.7, 41.4, 39.2, 14.2. HRMS (ESI+): calcd for C23H24NO5 [M + H]+ 394.1654, found 394.1650. (Z)-Ethyl 2-(3-((((1R,2R)-2-Hydroxycyclohexyl)amino)methylene)4-oxochroman-2-yl)acetate (2p). Viscous yellow oil, Rf = 0.36, eluent (dichloromethane:ethyl acetate 8:2), [α]20D = −67.91 (c 0.48, CH2Cl2), 0.30 g scale reaction (in 3 mL of DCM) for 30 h, 0.50 g were isolated, 90% yield. IR (νmax/cm−1): 1727, 1640, 1605, 1585, 1465, 1287. Diastereoisomer 1: 1H NMR (300 MHz, CDCl3): δH 10.05−9.90 (m, 1H), 7.78 (ddd, J = 7.9, 6.1, 1.7 Hz, 1H), 7.30 (ddt, J = 7.3, 6.4, 2.0 Hz, 1H), 6.99−6.86 (m, 2H), 6.80 (td, J = 8.1, 1.0 Hz, 1H), 5.26 (dd, J = 8.0, 6.2 Hz, 1H), 4.48 (br, 1H), 4.15−3.99 (m, 2H), 3.38−3.26 (m, 1H), 2.86 (m, 1H), 2.74 (dd, J = 15.1, 7.8 Hz, 1H), 2.50 (dd, J = 15.1, 6.4 Hz, 1H), 2.00−1.87 (m, 2H), 1.68−1.59 (m, 2H), 1.34−1.18 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.4, 170.5, 157.0, 150.9, 133.8, 126.0, 123.0, 121.4, 117.8, 99.4, 75.4, 73.8, 65.4, 60.5, 41.1, 33.6, 32.0, 24.6, 24.1, 14.2. Diastereoisomer 2: 1H NMR (300 MHz, CDCl3): δH 10.05−9.90 (m, 1H), 7.78 (ddd, J = 7.9, 6.1, 1.7 Hz, 1H), 7.30 (ddt, J = 7.3, 6.4, 2.0 Hz, 1H), 6.99−6.86 (m, 2H), 6.80 (td, J = 8.1, 1.0 Hz, 1H), 5.11 (dd, J = 7.7, 6.6 Hz, 1H), 4.15−3.99 (m, 2H), 3.88 (br, 1H), 3.38−3.26 (m, 1H), 2.86 (m, 1H), 2.74 (dd, J = 15.1, 7.8 Hz, 1H), 2.50 (dd, J = 15.1, 6.7 Hz, 1H), 2.00− 1.87 (m, 2H), 1.68−1.59 (m, 2H), 1.34−1.18 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δC 180.3, 170.3, 157.0, 151.3, 133.8, 126.0, 123.2, 121.3, 117.7, 99.6, 75.6, 73.7, 64.9, 60.6, 41.5, 33.6, 31.9, 24.6, 24.1, 14.2. HRMS (ESI+): calcd for C20H26NO5 [M + H]+ 360.1811, found 360.1810. (Z)-Ethyl 2-(3-(((3-Hydroxypropyl)amino)methylene)-4-oxochroman-2-yl)acetate (2q). Yellow viscous oil, Rf = 0.31, eluent (dichloromethane:ethyl acetate 7:3), 0.30 g scale reaction (in 3 mL of DCM) for 20 h, 0.26 g were isolated, 66% yield. IR (νmax/cm−1): 13

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The Journal of Organic Chemistry 24.5 (2×). HRMS (ESI+): calcd for C20H16NO4 [M + H]+ 334.1074, found 334.1083. (R)-8,9,10-Trimethoxy-4-phenyl-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4] oxazine-1,7-dione (4c). White solid (column chromatography), Rf = 0.43, eluent (dichloromethane:ethyl acetate 7:3), mp = 118−119 °C, [α]20D = −125.36 (c 0.52, CH2Cl2), 25.5 mg were isolated (steps 1 and 2), 73% yield (step 1), 78% yield (step 2). IR (νmax/cm−1): 1717, 1608, 1586, 1456, 1399, 1245. 1H NMR (300 MHz, CDCl3): δH 7.53−7.47 (m, 3H), 7.37−7.30 (m, 2H), 7.19 (d, J = 0.8 Hz, 1H), 6.93 (s, 1H), 5.46 (dd, J = 8.1, 5.1 Hz, 1H), 4.75−4.65 (m, 2H), 3.98 (s, 3H), 3.96 (s, 3H), 3.91 (s, 3H). 13C NMR (75 MHz, CDCl3): δC 172.7, 158.2, 156.6, 155.3, 153.8, 149.7, 139.8, 132.3, 130.3, 129.7 (2×), 128.1 (2×), 120.3, 113.7, 111.1, 103.6, 97.3, 70.8, 62.0, 61.5, 58.7, 56.5. HRMS (ESI+): calcd for C23H20NO7 [M + H]+ 422.1240, found 422.1239. 9-(Benzyloxy)-4,4-dimethyl-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7-dione (4d). White solid (column chromatography), Rf = 0.44, eluent (dichloromethane:ethyl acetate 6:4), mp = 236−237 °C, 14.4 mg were isolated (steps 1 and 2), 52% yield (step 1), 63% yield (step 2). IR (νmax/cm−1): 1706, 1649, 1584, 1452, 1256. 1H NMR (300 MHz, CDCl3): δH 7.79 (d, J = 3.1 Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 9.1 Hz, 1H), 7.51−7.35 (m, 6H), 5.17 (s, 2H), 4.37 (s, 2H), 1.68 (s, 6H). 13C NMR (75 MHz, CDCl3): δC 173.9, 156.4, 155.3, 151.8, 150.7, 136.4, 128.6 (2×), 128.2, 127.7 (2×), 124.4, 122.7, 119.9, 117.0, 112.5, 107.6, 102.8, 74.8, 70.6, 55.4, 24.4 (2×). HRMS (ESI+): calcd for C23H20NO5 [M + H]+ 390.1341, found 390.1348. (R)-9-Methyl-4-phenyl-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7-dione (4e). White solid (column chromatography), Rf = 0.49, eluent (dichloromethane:ethyl acetate 8:2), mp = 286−287 °C, [α]20D = −200.03 (c 0.27, CH2Cl2), 23.3 mg were isolated (steps 1 and 2), 61% yield (step 1), 87% yield (step 2). IR (νmax/cm−1): 1709, 1647, 1583, 1569, 1433, 1272. 1H NMR (300 MHz, CDCl3): δH 8.01 (dt, J = 1.9, 0.9 Hz, 1H), 7.53−7.47 (m, 5H), 7.38−7.33 (m, 2H), 7.24 (d, J = 0.9 Hz, 1H), 5.49 (dd, J = 8.8, 4.6 Hz, 1H), 4.78−4.67 (m, 2H), 2.45 (s, 3H). 13C NMR (75 MHz, CDCl3): δC 174.0, 156.5, 155.1, 150.7, 135.7, 134.1, 132.1, 130.4, 129.8 (2×), 128.2 (2×), 125.9, 121.9, 120.3, 118.3, 112.9, 104.1, 70.7, 58.9, 20.8. HRMS (ESI+): calcd for C21H16NO4 [M + H]+ 346.1079, found 346.1082. 9,11-Dichloro-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7-dione (4f). White solid (trituration in EtOH), Rf = 0.11, eluent (dichloromethane:ethyl acetate 9:1), mp = 344−345 °C, 24.1 mg were isolated (steps 1 and 2), 73% yield (step 1), 75% yield (step 2). IR (νmax/cm−1): 1710, 1646, 1581, 1433, 1296. 1H NMR (300 MHz, DMSO-d6, 80 °C): δH 8.08 (d, J = 2.6 Hz, 1H), 8.06−8.01 (m, 2H), 4.68 (t, J = 5.2 Hz, 2H), 4.50 (t, J = 5.2 Hz, 2H). 13C NMR (75 MHz, DMSO-d6, 80 °C): δC 171.3, 156.3, 151.2, 148.4, 134.4, 128.8, 124.9, 124.6, 124.0, 122.2, 111.1, 104.7, 66.5, 44.8. HRMS (ESI+): calcd for C14H8Cl2NO4 [M + H]+ 323.9830, found 323.9836. 9-Chloro-4,4,10-trimethyl-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7-dione (4g). White solid (column chromatography), Rf = 0.36, eluent (dichloromethane:ethyl acetate 6:4), mp = 333−334 °C, 21.1 mg were isolated (steps 1 and 2), 60% yield (step 1), 81% yield (step 2). IR (νmax/cm−1): 1705, 1667, 1579, 1451, 1219. 1H NMR (300 MHz, CDCl3): δH 8.24 (s, 1H), 7.68 (s, 1H), 7.53 (s, 1H), 4.38 (s, 2H), 2.52 (s, 3H), 1.68 (s, 6H). 13C NMR (75 MHz, CDCl3): δC 172.9, 156.3, 155.1, 150.4, 143.8, 130.7, 126.2, 121.4, 120.4, 117.1, 112.5, 103.1, 74.8, 55.5, 24.5 (2×), 20.9. HRMS (ESI+): calcd for C17H15ClNO4 [M + H]+ 332.0690, found 332.0694. (R)-4-Phenyl-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7-dione (4h). White solid (column chromatography), Rf = 0.47, eluent (dichloromethane:ethyl acetate 8:2), [α]20D = −192.12 (c 0.25, CH2Cl2), mp = 200−201 °C, 19.9 mg were isolated (steps 1 and 2), 53% yield (step 1), 86% yield (step 2). IR (νmax/cm−1): 1711, 1649, 1586, 1461, 1253. 1H NMR (300 MHz, CDCl3): δH 8.28 (dd, J = 7.9, 1.7 Hz, 1H), 7.73 (td, J = 7.7, 6.9, 1.7 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.57−7.47 (m, 3H), 7.42−7.32 (m, 3H), 7.28 (s, 1H), 5.50 (dd, J = 8.3, 5.0 Hz, 1H), 4.82−4.65 (m, 2H). 13C NMR (75 MHz, CDCl3): δC 174.0, 156.9, 156.4, 150.6, 134.6, 132.1, 130.5, 129.8 (2×),

128.1 (2×), 126.5, 124.3, 122.3, 120.4, 118.6, 112.9, 104.2, 70.7, 58.9. HRMS (ESI+): calcd for C20H14NO4 [M + H]+ 332.0923, found 332.0928. 4-(Benzylthiomethyl)-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1c][1,4]oxazine-1,7-dione (4i). White solid (column chromatography), Rf = 0.41, eluent (dichloromethane:ethyl acetate 9:1), mp = 160−161 °C, [α]20D = −23.91 (c 0.37, CH2Cl2), 13.7 mg were isolated (steps 1 and 2), 44% yield (step 1), 70% yield (step 2). IR (νmax/cm−1): 1712, 1652, 1580, 1454, 1293. 1H NMR (300 MHz, CDCl3): δH 8.30 (dd, J = 8.0, 1.7 Hz, 1H), 7.71 (ddd, J = 8.7, 7.1, 1.8 Hz, 1H), 7.60 (dd, J = 8.5, 1.1 Hz, 1H), 7.53 (s, 1H), 7.43−7.29 (m, 6H), 4.62 (d, J = 2.9 Hz, 2H), 3.99−4.07 (m, 1H), 3.77−3.66 (m, 2H), 3.00−2.81 (m, 2H). 13C NMR (75 MHz, CDCl3): δC 173.9, 156.8, 156.0, 150.3, 137.2, 134.6, 129.0 (2×), 128.9 (2×), 127.9, 126.5, 124.3, 122.3, 120.5, 118.5, 112.8, 102.6, 68.0, 54.6, 37.2, 32.9. HRMS (ESI+): calcd for C22H18NO4S [M + H]+ 392.0957, found 392.0956. 4,4-Dimethyl-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7-dione (4j). White solid (column chromatography), Rf = 0.50, eluent (dichloromethane:ethyl acetate 7:3), mp = 230−231 °C, 21.9 mg were isolated (steps 1 and 2), 71% yield (step 1), 72% yield (step 2). IR (νmax/cm−1): 1710, 1652, 1581, 1451, 1295. 1H NMR (300 MHz, CDCl3): δH 8.30 (dd, J = 7.9, 1.7 Hz, 1H), 7.75−7.68 (m, 2H), 7.62 (dd, J = 8.5, 1.1 Hz, 1H), 7.39 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H), 4.38 (s, 2H), 1.68 (s, 6H). 13C NMR (75 MHz, CDCl3): δC 174.1, 156.9, 156.4, 150.6, 134.5, 126.5, 124.2, 122.3, 118.5, 117.1, 112.9, 103.0, 74.8, 55.4, 24.4 (2×). HRMS (ESI+): calcd for C16H14NO4 [M + H]+ 284.0923, found 284.0925. 1H-Spiro[chromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-4,1′-cyclohexane]-1,7(3H)-dione (4k). White solid (column chromatography), Rf = 0.33, eluent (dichloromethane:ethyl acetate 8:2), mp = 241−242 °C, 23.4 mg were isolated (steps 1 and 2), 58% yield (step 1), 93% yield (step 2). IR (νmax/cm−1): 1717, 1656, 1579, 1456, 1400, 1250. 1H NMR (300 MHz, CDCl3): δH 8.30 (dd, J = 8.0, 1.8 Hz, 1H), 7.77 (s, 1H), 7.74−7.67 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 4.55 (s, 2H), 2.14 (d, J = 12.9 Hz, 2H), 1.97−1.82 (m, 5H), 1.65−1.37 (m, 3H). 13C NMR (300 MHz, CDCl3): δC 174.1, 156.9, 156.6, 150.6, 134.5, 126.5, 124.1, 122.4, 118.5, 116.8, 112.8, 103.3, 70.4, 58.1, 33.3 (2×), 24.9, 22.5 (2×). HRMS (ESI+): calcd for C19H18NO4 [M + H]+ 324.1236, found 324.1238. 4-Isopropyl-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7-dione (4l). White solid (column chromatography), Rf = 0.39, eluent (dichloromethane:ethyl acetate 8:2), mp = 197−198 °C, [α]20D = +21.34 (c 0.32, CH2Cl2), 20.2 mg were isolated (steps 1 and 2), 60% yield (step 1), 79% yield (step 2). IR (νmax/cm−1): 1706, 1655, 1581, 1450, 1295. 1H NMR (300 MHz, CDCl3): δH 8.30 (dd, J = 7.9, 1.7 Hz, 1H), 7.71 (ddd, J = 8.7, 7.0, 1.8 Hz, 1H), 7.66−7.58 (m, 2H), 7.39 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 4.76−4.61 (m, 2H), 4.03 (dt, J = 7.9, 2.8 Hz, 1H), 2.42−2.22 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H). 13C NMR (300 MHz, CDCl3): δC 174.1, 156.9, 156.6, 150.1, 134.5, 126.5, 124.2, 122.4, 120.5, 118.5, 112.4, 103.4, 67.3, 60.9, 30.1, 19.5, 19.2. HRMS (ESI+): calcd for C17H16NO4 [M + H]+ 298.1079, found 298.1084. (S)-3-Methyl-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7-dione (4m). White solid (column chromatography), Rf = 0.20, eluent (dichloromethane:ethyl acetate 7:3), mp = 263−264 °C, [α]20D = +87.02 (c 0.45, CH2Cl2), 23.2 mg were isolated (steps 1 and 2), 68% yield (step 1), 80% yield (step 2). IR (νmax/cm−1): 1712, 1652, 1582, 1453, 1293. 1H NMR (300 MHz, CDCl3): δH 8.27 (dt, J = 8.0, 1.5 Hz, 1H), 7.71 (ddd, J = 8.8, 7.0, 1.7 Hz, 1H), 7.62−7.54 (m, 2H), 7.38 (td, J = 7.5, 6.9, 1.1 Hz, 1H), 4.84−4.96 (m, 1H), 4.35 (dd, J = 13.4, 3.0 Hz, 1H), 4.14 (dd, J = 13.3, 10.2 Hz, 1H), 1.61 (d, J = 6.4 Hz, 3H). 13C NMR (300 MHz, CDCl3): δC 173.9, 156.8, 156.7, 149.9, 134.5, 126.4, 124.2, 122.3, 120.3, 118.5, 112.8, 103.5, 73.4, 50.0, 18.0. HRMS (ESI+): calcd for C15H12NO4 [M + H]+ 270.0766, found 270.0765. 3,3-Dimethyl-3,4-dihydrochromeno[2′,3′:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7-dione (4n). White solid (column chromatography), Rf = 0.29, eluent (dichloromethane:ethyl acetate 7:3), mp = 280−281 °C, 22.4 mg were isolated (steps 1 and 2), 72% yield (step 1), 73% yield (step 2). IR (νmax/cm−1): 1703, 1655, 1583, 1450, 1293. 1H NMR 12199



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(300 MHz, CDCl3): δH 8.31 (dd, J = 7.9, 1.7 Hz, 1H), 7.72 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.66−7.56 (m, 2H), 7.39 (ddd, J = 8.1, 6.9, 1.3 Hz, 1H), 4.22 (s, 2H), 1.56 (s, 6H). 13C NMR (300 MHz, CDCl3): δC 174.0, 156.9, 156.2, 149.8, 134.6, 126.5, 124.2, 122.4, 120.5, 118.5, 112.9, 103.1, 79.5, 53.8, 25.4 (2×). HRMS (ESI+): calcd for C16H14NO4 [M + H]+ 284.0923, found 284.0925. (5aR,15aS)-5H-Chromeno[2′,3′:3,4]pyrrolo[1,2-d]indeno[2,1-b][1,4]oxazine-7,13 (5aH,15aH)-Dione (4o). White solid (column chromatography), Rf = 0.26, eluent (dichloromethane:ethyl acetate 9:1), mp = 321−322 °C, [α]20D = −212.33 (c 0.31, CH2Cl2), 27.7 mg were isolated (steps 1 and 2), 82% yield (step 1), 77% yield (step 2). IR (νmax/cm−1): 1716, 1646, 1578, 1456, 1293. 1H NMR (300 MHz, CDCl3): δH 8.33 (d, J = 7.9 Hz, 1H), 7.78 (s, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.40 (q, J = 6.2, 5.0 Hz, 3H), 7.32 (q, J = 5.0 Hz, 2H), 5.70 (d, J = 4.7 Hz, 1H), 5.63−5.53 (m, 1H), 3.44 (t, J = 3.2 Hz, 2H). 13C NMR (300 MHz, CDCl3): δC 174.1, 157.0, 155.3, 150.2, 139.1, 136.1, 134.6, 130.3, 128.2, 126.6, 126.1, 124.3, 123.9, 122.3, 120.3, 118.6, 113.4, 102.4, 80.4, 60.2, 37.7. HRMS (ESI+): calcd for C21H14NO4 [M + H]+ 344.0923, found 344.0931. (4aR)-1,2,3,4,4a,14a-Hexahydrobenzo[b]chromeno[2′,3′:3,4]pyrrolo[1,2-d][1,4]oxazine-6,12-dione (4p). White solid (column chromatography), Rf = 0.42, eluent (dichloromethane:ethyl acetate 8:2), mp = 329−330 °C, [α]20D = −57.69 (c 0.26, CH2Cl2), 28.3 mg were isolated (steps 1 and 2), 78% yield (step 1), 84% yield (step 2). IR (νmax/cm−1): 1706, 1655, 1587, 1434, 1294. 1H NMR (300 MHz, CDCl3): δH 8.28 (dd, J = 7.9, 1.7 Hz, 1H), 7.71 (ddd, J = 8.7, 7.0, 1.7 Hz, 1H), 7.64−7.58 (m, 2H), 7.38 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 4.33 (ddd, J = 11.5, 10.2, 4.5 Hz, 1H), 4.03 (td, J = 10.5, 4.4 Hz, 1H), 2.75−2.67 (m, 1H), 2.40−2.31 (m, 1H), 2.03 (ddd, J = 15.5, 12.2, 2.9 Hz, 2H), 1.84−1.45 (m, 4H). 13C NMR (300 MHz, CDCl3): δC 174.1, 156.9, 156.8, 150.4, 134.5, 126.5, 124.2, 122.4, 118.5, 117.1, 112.8, 104.5, 80.2, 57.5, 29.8, 27.1, 23.4, 23.3. HRMS (ESI+): calcd for C18H16NO4 [M + H]+ 310.1079, found 310.1083.

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ASSOCIATED CONTENT

* Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01996. Products characterization data, including 1H and 13C NMR spectra and quantum chemical calculation details (PDF) Single crystal X-ray diffraction data for compound 2a CCDC number 1552693 (CIF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ata Martin Lawson: 0000-0002-1641-4190 Adam Daïch: 0000-0002-6942-0519 Notes

The authors declare no competing financial interest.

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REFERENCES

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ACKNOWLEDGMENTS

We are grateful to the “Ministère de l′Enseignement Supérieur et de la Recherche Scientifique-MESRST” for the Graduate Fellowship awarded to T.L. and the “Université Le Havre Normandie” for financial and technical help. We also thank MŠVVaŠ of the Slovak Republic within the Research and Development Operation Program for the project “University Science Park of STU Bratislava” (ITMS Project 26240220084) cofounded by the European Regional Development Fund. 12200


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