Iron-Catalyzed Meerwein Carbooxygenation of Electron-Rich Olefins: Studies with Styrenes, Vinyl Pyrrolidinone, and Vinyl Oxazolidinone.

The arylative oxygenation of the electron-rich olefins styrene, α-methylstyrene, vinyl pyrrolidinone, and vinyl oxazolidinone was accomplished using arenediazonium salts and catalytic amounts of FeSO4 in an effective single electron transfer radical process. A broad range of aryldiazonium salts was tolerated using water, methanol, or their combination with acetonitrile to furnish the corresponding carbohydroxylated and carbomethoxylated products (42 examples), including functionalized dihydroisocoumarin and dihydrobenzofuran systems in good to excellent yields (up to 88%). The protocols developed for the Fe(II)-catalyzed carbohydroxylation were also compared to Ru(II) and Ir(III) photoredox carbooxygenations of these electron-rich olefins. The Fe(II)-catalyzed process proved to be highly competitive compared to the photoredox and the uncatalyzed processes. The proposed mechanism for the Fe(II)-catalyzed reactions involves the synergic combination with an effective Fe+2/Fe+3 redox system and a radical polar crossover mechanism featuring an unprecedented capture of the reactive N-acyliminium in the case of vinyl pyrrolidinone and vinyl oxazolidinone.

Introduction

Arenediazonium salts are synthetically versatile compounds which are prone to thermal and photochemical decomposition allowing the preparation of a variety of aryl radicals (Scheme A).[1,2] For many decades, these well-known reactive intermediates have been useful tools for the construction of C–C bonds, and recently, they have also been instrumental in the realization of quite a number of important transformations.[2] Besides the thermal and photochemical procedures, aryl radicals can also be generated by single electron transfer (SET) from electron-rich olefins to arenediazonium salts,[3] although such procedures usually require large excesses of the olefins. Despite their efficiency, such procedures make these reactions less viable as a synthetic method when we consider cost, sustainability, as well as its practical aspects with respect to the isolation and purification of the desired product (Scheme B).[4,5] The formation of aryl radicals from arenediazonium salts can be also promoted by transition metals, such as Fe, Cu, and Ti. Examples are well documented in the literature, usually in stoichiometric or over stoichiometric amounts to achieve synthetic relevant results (Scheme C).[6] Among the available approaches to generate aryl radicals from arenediazonium salts, the use of Fe is particularly attractive due to its availability, low cost, low toxicity, and versatility in ionic and radical processes,[6a] but, surprisingly, its catalytic version is unprecedented in the literature. Inspired by recent developments and applications of aryl radicals in organic synthesis,[1] we decided to investigate the Fe-catalyzed carbohydroxylation/carbomethoxylation of readily available electron-rich olefins, such as styrenes, vinyl pyrrolidinone, and enecarbamates (Scheme D). We also briefly compared our Fe-catalyzed protocols with some already established photoredox processes, to take into account their relative efficiency and practicality.

Scheme 1

Application of Aryldiazonium Salts in Radical Reactions

Results and Discussion

Our studies began with the styrenes due to their well-recognized synthetic potential and the precedents available in the literature.[7] We selected α-methylstyrene and 4-CF3-benzenediazonium tetrafluoroborate as a reaction model to compare the FeSO4·7H2O-catalyzed conditions and the photoredox conditions using [Ru(bpy)3]Cl2·6H2O and Ir(ppy)3 as photocatalysts. Additionally, the use of styrenes provided us the opportunity to reinvestigate the excellent work reported by Heinrichet al., where SET conditions were employed to promote their arylation but using a 6-fold excess of the starting styrene to achieve good yields of the carbohydroxylated products.[4]

After some experimentation (see Supporting Information for optimization), we found that the use of 11 mol % FeSO4·7H2O and just 1.5 equivalents of α-methylstyrene in MeCN/H2O (4:1) furnished the carbohydroxylated product 3 in an 87% isolated yield after 4 h at 60 °C (Table , entry 1), whereas the protocol of Kindt et al. using 6 equivalents of α-methylstyrene is reported to furnish 3 in 57% in 15 min at 70 °C (Table , entry 2). For comparative purposes, we also carried out some photoredox reactions of this model reaction using commercially available Ru and Ir catalysts. The photoredox arylations gave product 3 in 70 and 63% yields after 12 h, using 5 mol % [Ru(bpy)3]Cl2·6H2O and Ir(ppy)3, respectively (Table , entries 3 and 4). Somewhat surprisingly, the noncatalyzed reaction furnished a 65% yield of the carbohydroxylated product 3, but only after 12 h at 60 °C (Table , entry 5). This latter result indicates a clear tendency of electron-deficient arenediazonium salts to generate aryl radicals under thermal or photochemical conditions and was not totally surprising. However, it should be pointed out that this result was achieved after a long period of time (12 h). In contrast, the FeSO4-catalyzed arylation provided a higher yield (90% yield) of compound 3 in only 4 h, clearly demonstrating the influence of catalytic FeSO4 in the arylation process.

Table 1

Carbohydroxylation Reaction of α-Methylstyrene 1 under Fe-Catalyzed, Ru, and Ir Photoredox, and Uncatalyzed Conditionsa

entry	catalyst (mol %)	1 (equiv)	T (°C)	time (h)	yield (%)d
1	FeSO4·7H2O (11.0)	1.5	60	4	90
2	none	6.0	70	0.25	60b
3	[Ru(bpy)3]Cl2·6H2O (5.0)	1.5	25	12	70c
4	Ir(ppy)3 (5.0)	1.5	25	12	63c
5	none	1.5	60	12	65

Reaction conditions: α-methylstyrene (17.7 mg, 0.15 mmol), 4-CF3-benzenediazonium tetrafluoroborate 2 (26 mg, 0.1 mmol), ZnCO3 (19 mg, 1.5 equiv), MeCN/H2O (4:1) (0.5 mL), and the corresponding catalyst under nitrogen atmosphere.

Yield and conditions as reported by Kindt et al.; for details, see ref (4).

25 W household white bulb was employed as light source.

Yields were determined by 1H NMR employing 1-bromo-3,5-bis(trifluoromethyl)benzene as an internal standard.

In view of the encouraging results with the FeSO4-catalyzed carbohydroxylation, the scope of this process was then evaluated employing several electronically distinct arenediazonium salts having styrene, and α-methylstyrene as substrates (Table ).

Table 2

Scope of the Fe(II)-Catalyzed Carbooxygenation of Styrenesa

Reaction conditions: aryldiazonium tetrafluoroborate 2a–n (0.3 mmol, 1 equiv), styrene 1a–c (0.45 mmol, 1.5 equiv), ZnCO3 (56 mg, 0.45 mmol, 1.5 equiv), FeSO4·7H2O (9.2 mg, 11 mol %), MeCN/H2O (4:1 v/v, 1.5 mL), 4 h for 3a–i and 18 h for 3j–q. Isolated yields were calculated from an average of two runs.

Yields determined by 1H NMR spectroscopy using 1-bromo-3,5-bis(trifluoromethyl)benzene as an internal standard and the data agree well with the literature report.[4]

Compound 3h agree well with literature report.[9]

Compound 3i agree well with literature report.[10]

Reaction performed in pure MeCN.

The protocol allowed the synthesis of carbohydroxylated systems from arenediazonium salts containing electron-donating, electron-neutral, and electron-withdrawing substituents. Most importantly, the privileged dihydroisocoumarin and dihydrobenzofuran systems were obtained in good yields (up to 73%) using ortho-hydroxy benzenediazonium and ortho-carbomethoxy benzenediazonium tetrafluoroborates. These bicyclic systems constitute the framework for many bioactive natural products such as silvestrol and amycofuran.[8] Notably, compounds 3e, 3g, 3h, and 3i synthesized in somewhat lower yields of 38, 48, 26, and 23%, respectively, were obtained by Kindt et al. in only 6, 23, 10, and 12% yields using large excesses of the starting styrenes.[4] In spite of these low yields with the Fe-catalyzed reactions, they highlight the clear synthetic advantage of the Fe catalysis on rather challenging substrates. Furthermore, the FeSO4-catalyzed carbooxygenations displayed in Table indicate that the radical polar crossover mechanism as proposed by Heinrich to explain the formation of the carbohydroxylated products does not seem to be the major pathway operating under the Fe-catalyzed conditions since the polar crossover mechanism is more efficient when using large excesses of styrenes. Therefore, the main involvement of a Fe+2/Fe+3 redox mechanism seems to be a more plausible rationale for outcome of these reactions. The lower yields obtained with electron-rich arenediazonium salts are due to their lower efficiency to propagate the radical chain reaction under SET conditions, mainly in the case of styrenes.[1]

Having established a successful Fe(II)-catalyzed route to the carbooxygenation reaction of styrenes, we then sought to evaluate the generality of our protocol with other olefins. Vinyl pyrrolidinone, a readily available and inexpensive olefin used in a number of studies aiming at the development of new synthetic methods, was then chosen as a viable substrate for the Fe-catalyzed carbooxygenations.[11]

The distinct electronic characteristic of vinyl pyrrolidinone we compared to the styrenes was another interesting feature to choose it as a new substrate for our studies. We then selected 4-methoxyphenyldiazonium tetrafluoroborate 2e as the arylating partner, ZnCO3 as base, and water as the solvent for a preliminary investigation toward the carbohydroxylation of vinyl pyrrolidinone 4 (Table ). Water was chosen for its greener nature and because all reaction components are soluble in this solvent. Starting with two equivalents of olefin in the absence of FeSO4, the carbohydroxylated product 5e was obtained in 40% after 24 h, with only partial consumption of the aryldiazonium salt (Table , entry 1). In agreement with literature reports,[4,5] a large execess of the olefin 4 (7 equiv) accelerated the reaction, furnishing a moderate 68% yield of the carbohydroxylated product 5e after 1 h (Table , entry 2). Carbooxygenation of olefin 4 (2 equiv) and 5.5 mol % FeSO4 at 40 °C provided 5e in 62% yield after 24 h (entry 3). However, to our delight, raising the reaction temperature to 60 °C gave a good yield (79%) of the desired product 5e after only 30 min (entry 4). Performing the reaction under open-flask conditions provided 5e in 70% after 3 h, demonstrating a surprising tolerance of the reaction to oxygen (entry 5).[12]

Table 3

Reaction Conditions Optimization for the Formation of 5ea

entry	FeSO4·7H2O (mol %)	4 (equiv)	T (°C)	time (h)	yield (%)b
1	none	2	40	24	40
2	none	7	40	1	68
3	5.5	2	40	24	62
4	5.5	2	60	0.5	79
5	5.5	2	60	3	70c

Reaction conditions: vinyl pyrroldinone (22.2 mg, 0.2 mmol), 4-methoxyphenyldiazonium tetrafluoroborate 2e (22 mg, 0.1 mmol), ZnCO3 (19 mg, 1.5 equiv), H2O (0.5 mL), nitrogen atmosphere. Bold text highlights the best reaction conditions.

Yields were determined by 1H NMR employing 1-bromo-3,5-bis(trifluoromethyl)benzene as internal standard,.

Reaction performed under open-flask condition.

With the basic reaction parameters established, we evaluated the reaction scope using water or methanol as a solvent to give the method a greener aspect (Table ). Therefore, contrary to the protocol developed for styrenes, the carbooxygenation of vinyl pyrrolidinone can be carried out in pure H2O or methanol avoiding the use of acetonitrile as co-solvent.

Table 4

Scope: Synthesis of 1-(1-Hydroxy-2-aryllethyl)pyrrolidin-2-ones and 1-(1-Methoxy-2-(aryl)ethyl)pyrrolidin-2-ones (5a–r)a

Reaction conditions: aryldiazonium tetrafluoroborate (0.3 mmol, 1 equiv), 1-vinyl-2-pyrrolidinone 4 (67 mg, 0.6 mmol, 2 equiv), ZnCO3 (56 mg, 0.45 mmol, 1.5 equiv), FeSO4·7H2O (4.6 mg, 5.5 mol %), H2O for 5a–o,and MeOH for 5p–r (1.5 mL), nitrogen atmosphere. Isolated yields were calculated from an average of two runs.

Reaction performed in gram scale.

Having water as the solvent, the method provided good yields of the carbohydroxylate product regardless of the electronic nature of the arenediazonium salts or its substitution pattern, with the exception of the naphthyldiazonium salt, which furnished the product 5i in 37% yield.

The robustness of the protocol was further demonstrated by performing the synthesis of carbohydroxylated product 5j at the gram scale (73% yield, 1.14 g, 4.75 mmol). The reaction also proved effective in methanol, but with a significant decrease in yields. The methoxylated products 5p–r were achieved with yields of 34, 39, and 56% respectively. The use of anhydrous methanol did not improve the yields.

Once the feasibility of the FeSO4-catalyzed carbohydroxylation of vinyl pyrrolidinone was demonstrated, photoredox approaches for the carbohydroxylation of 4 employing 3-CF3-benzenediazonium tetrafluoroborate 2h were investigated in a way to compare our best Fe-catalyzed result in Table (5h) with photoredox alternatives. Under our standard reaction conditions, the N,O-hemiacetal 5h was obtained in an excellent 81% isolated yield after 30 min (Table , entry 1). The Ru and Ir photoredox reactions furnished 70 and 45% yield of 5h, respectively, after 12 h of light irradiation (entries 2 and 3), whereas the uncatalyzed reaction provided only 38% of 5h after 12 h (entry 4). As observed with the styrenes, the FeSO4-catalyzed carbohydroxylations of vinyl pyrrolidinone exhibited a superior performance to both photoredox reactions.

Table 5

Comparison of the FeSO4-Catalyzed Carbohydroxylation with the Ru and Ir Photoredox Methods for the Synthesis of Compound 5ha

entry	catalyst (mol %)	T (°C)	time (h)	yield (%)
1	FeSO4·7H2O (5.5)	60	0.5	81
2	[Ru(bpy)3]Cl2·6H2O (5.0)	25	12	70b,c
3	Ir(ppy)3 (5.0)	25	12	45b,c
4	none	60	6	38b

Reaction conditions: 3-CF3 phenyldiazonium tetrafluoroborate (0.1 mmol, 1 equiv), 1-vinyl-2-pyrrolidinone 4 (22.3 mg, 0.2 mmol, 2 equiv), ZnCO3 (19 mg, 0.15 mmol, 1.5 equiv), nitrogen atmosphere, catalyst.

Yields were determined by 1H NMR employing 1-bromo-3,5-bis(trifluoromethyl)benzene as internal standard.

25 W household white bulb was employed as light source.

Taken together, the results shown above with the styrenes and vinyl pyrrolidinone encouraged us to extend the FeSO4-catalyzed carbooxygenation to another electron-rich olefin, the readily available exocyclic enecarbamate 6. However, due to its low solubility in water, the addition of acetonitrile as co-solvent was necessary, as well as a catalyst loading of 11 mol % FeSO4 to reach yields comparable to those observed with vinyl pyrrolidinone and styrenes (Tables and 4).

The carbohydroxylation/carbomethoxylation of enecarbamate 6 proved to be reasonably efficient for different arenediazonium salts, providing the products 7c–t in yields ranging from 43 to 69% regardless of the electronic nature of the arenediazonium salt (Table ).

Table 6

Fe(II)-Catalyzed Carbohydroxylation and Carbomethoxylation of Vinyl Oxazolidinone 6; Synthesis of 3-(1-hydroxy-2-arylethyl)oxazolidin-2-ones (7c–t)a

Reaction conditions: aryldiazonium tetrafluoroborate (0.3 mmol, 1 equiv), vinyl oxazolidinone 6 (68 mg, 0.6 mmol, 2 equiv), ZnCO3 (56 mg, 0.45 mmol, 1.5 equiv), FeSO4·7H2O (9.2 mg, 11 mol %), MeCN/H2O (1:4 v/v, 1.5 mL). Isolated yields were calculated from the average of two runs.

Reactions performed in methanol.

Following the procedures adopted before, for comparative purposes, the photoredox carbohydroxylation of vinyl oxazolidinone 6 with Ru and Ir catalysts was carried out, together with the uncatalyzed reaction. To our satisfaction, the results shown in Table indicate that the Fe (II)-catalyzed carbohydroxylation of olefin 6 is highly competitive with the photoredox protocols.

Table 7

Fe(II)-Catalyzed Carbohydroxylation of Vinyl Oxazolidinone 6 and Its Comparison with Ru and Ir Photoredox and Uncatalyzed Reactionsa

entry	catalyst (mol %)	T (°C)	reaction time (h)	yield (%)b
1	FeSO4·7H2O (11)	60	0.5	72
2	[Ru(bpy)3]Cl2·6H2O (5.0)	25	12	56c
3	Ir(ppy)3 (5.0)	25	12	47c
4	none	60	4	16

Reaction conditions: 4-CF3-phenyldiazonium tetrafluoroborate (0.1 mmol, 1 equiv), vinyl oxazolidinone 6 (22.3 mg, 0.2 mmol, 2 equiv), ZnCO3 (19 mg, 0.15 mmol, 1.5 equiv), nitrogen atmosphere, catalyst.

Yields were determined by 1H NMR employing 1-bromo-3,5-bis(trifluoromethyl)benzene as an internal standard.

25 W household white bulb was employed as light source.

To demonstrate that these stable carbohydroxylated products (N,O-hemiacetals) can be converted into potentially synthetic intermediates, the N,O acetal 5j was selected for some straightforward transformations. The carbohydroxylated product 5j was then efficiently converted into the corresponding unsaturated compound (90% isolated yield) under mild acidic conditions with Amberlyst. Oxidation of compound 5j with o-iodoxybenzoic acid (IBX) gave the corresponding imide in 57% isolated yield, as demonstrated in Scheme (nonoptimized conditions).

Scheme 2

Derivatization of the 1-(1-hydroxy-2-aryllethyl)pyrrolidin-2-one 7j

Reagents and reaction conditions: (i) 5j (0.3 mmol), Amberlyst 15 hydrogen form (75 mg), acetone (7.5 mL), rt, 1 h. (ii) 5j (0.3 mmol), IBX (126 mg, 1.5 equiv), EtOAc (6 mL), 65 °C, 8 h. Isolated yields in both cases.

Although a radical mechanism for these transformations was anticipated in view of literature precedents,[1] the role and impact of the Fe+2/Fe+3 redox system, as well as the putative formation of an intermediate iminium ion/carbocation—the point of entry of a nucleophile—were not evident under our protocol conditions. Therefore, to confirm the nature of the intermediates involved, we carried out the reaction of arenediazonium salt 2e with vinyl pyrrolidinone 4 in the presence of TEMPO. Gratifyingly, the reaction provided the TEMPO adduct 8, which was isolated and characterized (Scheme ), thus indicating the presence of the expected radical intermediates in the carbohydroxylation/carbomethoxylation reactions.

Scheme 3

Proposed Catalytic Cycle for the Fe(II)-Catalyzed Reaction of Vinyl Pyrrolidinone and the Vinyl Oxazolidine with Arenediazonium Salts

With this finding in hand, it was possible to rationalize the formation of the carbohydroxylated/carbomethoxylated products 3, 5, and 7 involving the contribution of several factors (Scheme ): the aryl radical A can be generated from the aryldiazonium salt by three different pathways: (i) the formation of a thermolyzable electron donor–electron acceptor complex between the electron-rich olefin and the diazonium salt,[13] (ii) via single electron transfer (SET) with a Fe(II) species, or (iii) by a radical polar crossover mechanism. Subsequently, the aryl radical A undergoes anti-Markovnikov radical addition to olefin B, generating the intermediate C, which can then perform another SET process with a Fe(III) species, regenerating the Fe(II) catalyst, or yet, reacting directly with another aryldiazonium salt through a radical polar crossover mechanism.[4]

The polar crossover mechanism proposed by Heinrich for the carbooxygenation of styrenes appears to play a secondary role when associated with the Fe+2/Fe+3 redox system. The carbooxygenation reactions of styrenes, vinyl pyrrolidinone, and vinyl oxazolidinone using catalytic Fe(II) are usually fast, whereas the uncatalyzed reactions of these olefins lead to low yields of the carbooxygenated product after a long period of time. For example, the uncatalyzed carbohydroxylation of α-methylstyrene (1.5 equiv) gives a reasonable yield of 65% of 3d only after a period of 12 h (Table , entry 5). Nevertheless, a synergic combination of the Fe+2/Fe+3 redox system and the radical polar crossover mechanism cannot be entirely discarded in the case of styrenes. A rationale for the Fe(II)-catalyzed carbohydroxylation of the styrenes is presented in Scheme .

Scheme 4

Proposed Catalytic Cycle for the Fe(II)-Catalyzed Carbohydroxylation of Styrenes with Arenediazonium Salts

Conclusions

In conclusion, we have developed a synthetically useful Fe(II)-catalyzed carbohydroxylation/carbomethoxylation protocol for electron-rich olefins such as styrenes, vinyl pyrrolidinone, and vinyl oxazolidinone. To the best of our knowledge, these studies constitute the first examples of a Fe-catalyzed carbohydroxylation/carbomethoxylation of these olefins. Overall, our results demonstrate that for vinyl pyrrolidinone and vinyl oxazolidinone, the putative N-acyliminium intermediates can be effectively trapped by a nucleophile to yield the corresponding carbohydroxylation/carbomethoxylation products, which are frameworks found in several natural products and useful advanced intermediates.[8,14−16] In the case of styrenes, in contrast to a literature report,[4] only a small excess of the starting olefin was required for effective Fe(II)-catalyzed carbohydroxylation or carbomethoxylation.

The effective production of aryl radicals from arenediazonium salts by a Fe-catalyzed ground-state electron-transfer process has allowed the synthesis of valuable intermediates, including dihydrocoumarin and dihydrobenzofuran systems in good to excellent yields under mild conditions.

Experimental Section

General Information

Unless otherwise indicated, all common reagents and solvents employed were obtained from commercial suppliers and no further purification was performed. The aryldiazonium salts were prepared from methods described in the literature.[17] 1-Vinyl-2-pyrrolidone and styrenes were distilled under reduced pressure prior to their use. Iron(II) sulfate heptahydrate was purified following the literature procedure.[18] 3-Vinyloxazolidin-2-one 6 was synthesized following the literature procedure.[19]

All NMR spectra were acquired on a Bruker Avance 400 or 500 MHz spectrometer, employing residual nondeuterated solvent signal as an internal reference (CHCl3 = 1H 7.26 ppm, 13C 77.0 ppm). All results are reported as follows: chemical shift (δ) (multiplicity, coupling constant, integration). Splitting patterns are indicated as follows: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, dd = doublet of doublets, td = triplet of triplets, m = multiplet, b = broad, app = apparent. All coupling constants (J) are reported in hertz (Hz). Note: the CDCl3 employed in the NMR analysis was previously passed through a short pad of basic alumina to avoid decomposition of the N,O-acetals.

High-resolution mass spectrometry (HRMS) was conducted using electrospray ionization (ESI) (Waters Xevo Q-Tof, Thermo LTQ - FT Ultra, or Thermo Q Exactive).

Analytical thin-layer chromatography was performed employing Merck Silica gel 60 F254 plates using short-wave (254 nm) UV light and ethanolic phosphomolybdic acid solution (5% m/v) as a color reagent.

IR spectra were recorded on an Agilent Technologies Cary 630 FTIR using attenuated total reflectance technique, with scans between 4000 and 650 cm–1, with 8 cm–1 resolution. The compounds were analyzed in its pure form on a germanium sample holder. The maximum absorbing frequencies are reported in cm–1.

Chromatographic purifications were performed on a Biotage—Isolera One flash purification system employing Biotage SNAP Ultra 10 g cartridges and operating in a gradient mode (EtOAc/hexanes) with a flow rate of 36 mL/min.

Melting points were determined on a capillary melting point apparatus and are uncorrected.

Isolated yields were calculated from an average of two runs.

General Procedure for the Meerwein Carbooxygenation of Styrenes, Vinyl Pyrrolidinone, and Vinyl Oxazolidinone (3, 5, 7)

A screw-capped vial containing a magnetic stirring bar was charged with FeSO4·7H2O (5.5–11 mol %), solvent (1.5 mL), olefin (0.45 mmol, 1.5 equiv for 1 or 0.60 mmol, 2.0 equiv for 4 and 6), ZnCO3 (57 mg, 0.45 mmol, 1.5 equiv), and the corresponding arenediazonium salt (0.3 mmol, 1 equiv) (this order of addition must be followed since it plays an important role in the overall reaction). For compound 3, MeCN/H2O (4:1, v/v) was used as the solvent; for the specific case of compound 3q, the solvent was anhydrous MeCN. For compounds 5, the solvent was pure H2O, except for compounds 5p–r, when MeOH was used. For compound 7, H2O/MeCN (4:1, v/v) was used as solvent, except for 7r–t, when MeOH was used.

The vial content was slightly shacked after each addition. The vial was then sealed with a cap containing a polytetrafluoroethylene (PTFE) septum, and the system was flushed with N2 for 2 min. A nitrogen balloon connected to a needle was attached to the vial through a septum, and the reaction mixture was stirred at 60 °C for the defined reaction time. Next, the vial was opened and the reaction mixture was placed on the top of a sodium sulfate/silica gel plug and then rinsed with EtOAc (3 × 20 mL). The solvent was evaporated, and the products were purified by flash chromatography.

General Procedure for the Synthesis of (E)-1-(3-Chlorostyryl)pyrrolidin-2-one (9)

A 25 mL round-bottom flask containing a magnetic stirring bar was charged with N,O-hemiacetal (0.3 mmol, 1 equiv), Amberlyst 15 hydrogen form (75 mg), and acetone (7.5 mL). The round-bottom flask was sealed, and the reaction mixture was stirred at room temperature for 1 h. The vial was opened, and the crude reaction mixture was filtered through a cotton plug, which was then rinsed with EtOAc (2 × 15 mL). The filtrate was evaporated on a rotary evaporator under reduced pressure, and the residue was purified by flash chromatography.

General Procedure for the Synthesis of 1-(2-(3-Chlorophenyl)acetyl)pyrrolidin-2-one (10)

A screw-capped vial containing a magnetic stirring bar was charged with N,O-hemiacetal (0.3 mmol, 1 equiv), IBX (o-iodoxybenzoic acid, 126 mg, 0.45 mmol, 1.5 equiv), and ethyl acetate (6 mL). The vial was sealed with a cap containing a PTFE septum, and the system was flushed with N2 for 2 min. A nitrogen balloon was attached to the system through the septum, and the reaction mixture was stirred at 65°C for 5 h. After cooling to room temperature, the vial was opened and an extra amount of IBX (50 mg) was added. The system was again closed, flushed with N2, and left under stirring at 65°C overnight. Next, the reaction mixture was diluted with CH2Cl2, filtered through a short plug of Celite, and the plug was rinsed with more CH2Cl2 (3 × 15 mL). The solvent was evaporated on a rotary evaporator under reduced pressure, and the product was purified by flash chromatography.

Characterization Data for the Compounds

1-(4-Chlorophenyl)-2-phenylpropan-2-ol (3a)

Rf = 0.5 (10:90 EtOAc/hexanes). Yellow oil. Yield: 60 mg, 80%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.38–7.32 (m, 4H), 7.27–7.25 (m, 1H), 7.17 (d, J = 8.0, 2H), 6.90 (d, J = 7.9, 2H), 3.09 (d, J = 13.4, 1H), 2.99 (d, J = 13.3, 1H), 1.84 (br, 1H), 1.57 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 147.1, 135.3, 132.5, 131.8, 128.1, 128.0, 126.8, 124.9, 74.4, 49.8, 29.3. (These data agree well with the literature reports).[4]

1-(4-Bromophenyl)-2-phenylpropan-2-ol (3b)

Rf = 0.4 (10:90 EtOAc/hexanes). Yellow oil. Yield: 76 mg, 88%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.38–7.32 (m, 6H), 7.27–7.24 (m, 1H), 6.85 (d, J = 8.2, 2H), 3.07 (d, J = 13.4, 1H), 2.98 (d, J = 13.4, 1H), 1.83 (br, 1H), 1.57 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 147.0, 135.8, 132.2, 131.0, 128.1, 126.8, 124.9, 120.6, 74.4, 49.8, 29.3. (These data agree well with the literature reports).[4]

1-(4-Nitrophenyl)-2-phenylpropan-2-ol (3c)

Rf =0.2 (10:90 EtOAc/hexanes). Yellow oil. Yield: 60 mg, 78%. 1H (500 MHz, CDCl3, 25 °C) δ = 8.02 (d, J = 8.6, 2H), 7.35–7.30 (m, 4H), 7.27–7.25 (m, 1H), 7.12 (d, J = 8.5, 2H), 3.18 (d, J = 13.0, 1H), 3.13 (d, J = 13.2, 1H), 1.88 (br, 1H), 1.62 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 146.7, 146.5, 145.0, 131.3, 128.2, 127.1, 124.8, 122.8, 74.6, 50.3, 29.5. (These data agree well with the literature reports).[4]

2-Phenyl-1-(4-(trifluoromethyl)phenyl)propan-2-ol (3d)

Rf = 0.3 (10:90 EtOAc/hexanes). Yellow oil. Yield: 73 mg, 87%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.46 (d, J = 7.9, 2H), 7.39–7.33 (m, 4H), 7.27 (t, J = 6.5, 1H), 7.10 (d, J = 7.9, 2H), 3.17 (d, J = 13.3, 1H), 3.09 (d, J = 13.3, 1H), 1.83 (br, 1H), 1.59 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 147.0, 141.1, 130.8, 128.8 (q, 2JC–F = 32), 128.2, 126.9, 124.9, 124.7 (q, 3JC–F = 4), 124.3 (q, 1JC–F = 272), 74.5, 50.2, 29.3. (These data agree well with the literature reports).[4]

1-(4-Methoxyphenyl)-2-phenylpropan-2-ol (3e)

Rf = 0.3 (10:90 EtOAc/hexanes). Yellow oil. Yield: 18 mg, 25%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.40–7.38 (m, 2H), 7.34–7.31 (m, 2H), 7.26–7.23 (m, 1H), 6.90 (d, J = 8.6, 2H), 6.75 (d, J = 8.7, 2H), 3.76 (s, 3H), 3.08 (d, J = 13.5, 1H), 2.97 (d, J = 13,5, 1H), 1.81 (br, 1H), 1.56 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 158.4, 147.6, 131.5, 128.7, 128.0, 126.6, 125.0, 113.5, 74.5, 55.2, 49.6, 29.4. (These data agree well with the literature reports).[4]

1-(3-Fluorophenyl)-2-phenylpropan-2-ol (3f)

Rf = 0.5 (10:90 EtOAc/hexanes). Yellow oil. Yield: 51 mg, 74%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.40–7.39 (m, 2H), 7.34 (t, J = 7.5, 2H), 7.28–7.26 (m, 1H), 7.18–7.15 (m, 1H), 6.92–6.89 (m, 1H), 6.78 (d, J = 7.3, 1H), 6.71 (d, J = 9.8, 1H), 3.12 (d, J = 13.4, 1H), 3.02 (d, J = 13.4, 1H), 1.86 (br, 1H), 1.58 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 162.4 (d, 1JC–F = 245), 147.2, 139.4 (d, 3JC–F = 7), 129.3, (d, 3JC–F = 8), 128.1, 126.8, 126.2 (d, 4JC-F = 2), 124.9, 117.4 (d, 2JC–F = 21), 113.4 (d, 2JC–F = 21), 74.4, 50.2, 29.3. (These data agree well with the literature reports).[4]

1,2-Diphenylpropan-2-ol (3g)

Rf = 0.4 (10:90 EtOAc/hexanes).Yellow oil. Yield: 30 mg, 48%. 1H (400 MHz, CDCl3, 25 °C) δ = 7.42–7.40 (m, 2H), 7.36–7.32 (m, 2H), 7.28–7.22 (m, 4H), 7.02–7.00 (m, 2H), 3.14 (d, J = 13.3, 1H), 3.04 (d, J = 13.3, 1H), 1.89 (br, 1H), 1.58 (s, 3H). 13C (100 MHz, CDCl3, 25 °C) δ = 147.6, 136.8, 130.6, 128.1, 126.7, 126.7, 125.0, 74.5, 50.5, 29.4. (These data agree well with the literature reports).[4]

Methyl 2-(2-Hydroxy-2-phenylpropyl)thiophene-3-carboxylate (3j)

Rf = 0.3 (20:80 EtOAc/hexanes). Yellow oil. Yield: 50 mg, 62%. 1H (400 MHz, CDCl3, 25 °C) δ = 7.49–7.46 (m, 2H), 7.35–7.31 (m, 3H), 7.26–7.21 (m, 1H), 6.60 (d, J = 5.0, 1H), 3.88 (s, 3H), 3.87 (s, 1H), 3.59 (d, J = 13.6, 1H), 3.40 (d, J = 13.5, 1H), 1.59 (s, 1H). 13C (100 MHz, CDCl3, 25 °C) δ = 164.8, 148.1, 146.4, 132.4, 130.0, 128.1, 128.0, 126.5, 124.9, 75.2, 52.3, 43.5, 29.6.HRMS (ESI): C15H16O3SNa (M + Na) requires 299.0717/found: 299.0711. IR (neat, cm–1): 3462, 2974, 1687, 1437, 1277.

Methyl 3-(2-Hydroxy-2-(4-methoxyphenyl)propyl)thiophene-2-carboxylate (3k)

Rf = 0.3 (20:80 EtOAc/hexanes). Yellow oil. Yield: 58 mg, 63%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.37 (d, J = 8.6, 2H), 7.31 (d, J = 5.0, 1H), 6.85 (d, J = 8.6, 2H), 6.58 (d, J = 4.9, 1H), 3.87 (s, 3H), 3.80 (s, 3H), 3.76 (s, 1H), 3.56 (d, J = 13.5, 1H), 3.37 (d, J = 13.5, 1H), 1.57 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 164.8, 158.2, 146.5, 140.3, 132.4, 129.9, 128.0, 126.1, 113.3, 75.0, 55.3, 52.3, 43.7, 29.8. HRMS (ESI): C16H18O4SNa (M + Na) requires 329.0823/found: 329.0818. IR (neat, cm–1): 3445, 2931, 1687, 1437, 1244.

7-Bromo-3-methyl-3-phenylisochroman-1-one (3l)

Rf = 0.3 (10:90 EtOAc/hexanes). Yellow oil. Yield: 55 mg, 57%. 1H (500 MHz, CDCl3, 25 °C) δ = 8.14 (s, 1H), 7.57 (d, J = 8.0, 1H), 7.37 (d, J = 7.7, 2H), 7.29 (t, J = 7.5, 2H), 2.21 (app t, J = 7.1, 1H), 7.11 (d, J = 8.0, 1H), 3.49 (d, J = 16.5, 1H), 3.35 (d, J = 16.4, 1H), 1.76 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 163.9, 143.2, 136.8, 136.7, 132.8, 129.3, 128.7, 127.7, 127.0, 124.6, 121.2, 83.9, 38.6, 30.3. HRMS (ESI): C16H13BrO2Na (M + Na) requires 338.9996/found: 338.9985. IR (neat,cm–1): 3060, 2982, 1721, 1264, 1136.

3-Methyl-7-nitro-3-phenylisochroman-1-one (3m)

Rf = 0.2 (20:80 EtOAc/hexanes). Orange solid: mp 158–159 °C. Yield: 58.7 mg, 70%. 1H (400 MHz, CDCl3, 25 °C) δ = 8.81 (d, J = 2.4, 1H), 8.30 (dd, J = 8.3, 2.4, 1H), 7.46 (d, J = 8.3, 1H), 7.38–7.35 (m, 2H), 7.28 (t, J = 7.4, 2H), 7.22–7.18 (m, 1H), 3.69 (d, J = 16.8, 1H), 3.53 (d, J = 16.8, 1H), 1.81 (s, 3H). 13C (100 MHz, CDCl3, 25 °C) δ = 163.2, 147.5, 144.6, 142.5, 129.2, 128.8, 128.2, 128.0, 126.7, 125.2, 124.6, 84.1, 39.1, 30.5. HRMS (ESI): C16H13NO4Na (M + Na) requires 306.0742/found: 306.0742. IR (neat, cm–1): 3086, 2982, 1719, 1529, 1059.

3-Methyl-3-phenylisochroman-1-one (3n)

Rf = 0.5 (10:90 EtOAc/hexanes). Yellow oil. Yield: 53 mg, 75%. 1H (400 MHz, CDCl3, 25 °C) δ = 8.00 (d, J = 7.6, 1H), 7.45 (td, J = 11.3, 1.1, 1H), 7.41 (d, J = 7.5, 2H), 7.30–7.26 (m, 3H), 7.22–7.17 (m, 2H), 3.52 (d, J = 16.4, 1H), 3.40 (d, J = 16.4, 1H), 1.75 (s, 3H). 13C (100 MHz, CDCl3, 25 °C) δ = 165.3, 143.7, 137.9, 133.9, 130.0, 128.5, 127.7, 127.6, 127.5, 125.3, 124.7, 83.6, 39.2, 30.2. (These data agree well with the literature reports).[4]

7-Bromo-3-(4-methoxyphenyl)-3-methylisochroman-1-one (3o)

Rf = 0.3 (20:80 EtOAc/hexanes).Yellow oil. Yield: 75.8 mg, 73%. 1H (500 MHz, CDCl3, 25 °C) δ = 8.12 (s, 1H), 7.57 (d, J = 8.0, 1H), 7.27 (d, J = 8.6, 2H), 7.10 (d, J = 8.0, 1H), 6.79 (d, J = 8.6, 2H), 3.73 (s, 3H), 3.46 (d, J = 16.4, 1H), 3.32 (d, J = 16.4, 1H), 1.73 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 164.0, 158.9, 136.8, 136.7, 135.2, 132.8, 129.3, 127.0, 126.0, 121.1, 113.9, 83.8, 55.2, 38.6, 30.5. HRMS (ESI): C17H15BrO3H (M + H) requires 347.0282/found: 347.0251. IR (neat, cm–1): 3064, 2978, 1715, 1244, 1134.

3-(4-Methoxyphenyl)-3-methyl-7-nitroisochroman-1-one (3p)

Rf = 0.2 (10:90 EtOAc/hexanes). Yellow oil. Yield: 55 mg, 60%. 1H (500 MHz, CDCl3, 25 °C) δ = 8.82 (d, J = 1.7, 1H), 8.32 (dd, J = 8.2, 2.0, 1H), 7.46 (d, J = 8.3, 1H), 7.27 (d, J= 8.7, 2H), 6.79 (d, J = 8.7, 2H), 3.73 (s, 3H), 3.65 (d, J = 16.8, 1H), 3.49 (d, J = 16.8, 1H), 1.79 (s, 3H). 13C (125 MHz, CDCl3, 25 °C) δ = 163.2, 159.0, 147.4, 144.7, 134.4, 129.0, 128.1, 126.8, 126.0, 125.2, 114.1, 84.0, 55.2, 39.1, 30.7. HRMS (ESI): C17H15NO5Na (M + Na) requires 336.0847/found: 336.0849. IR (neat, cm–1): 3084, 2931, 1717, 1514, 1251.

1-(2-(4-Chlorophenyl)-1-hydroxyethyl)pyrrolidin-2-one (5a)

Rf = 0.2 (80:20 EtOAc/hexanes). White solid: 82-83 °C. Yield: 51.5 mg, 71%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.24 (d, J = 8.3, 2H), 7.14 (d, J = 8.5, 2H), 5.64 (t, J = 5.8, 1H), 4.42 (d, J = 2.2, 1H), 3.56–3.51 (m, 1H), 3.35–3.31 (m, 1H), 3.02 (dd, J = 14.1, 7.4, 1H), 2.82 (dd, J = 14.4, 6.5, 1H), 2.33–2.22 (m, 2H), 2.03–1.84 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.1, 135.2, 132.5, 130.5, 128.6, 75.7, 42.2, 39.4, 31.7, 18.1. HRMS (ESI): C12H14ClNO2Na (M + Na) requires 262.0611/found: 262.0603. IR (neat, cm–1): 3358, 2926, 1672, 1421, 1277, 1018.

1-(2-(4-Bromophenyl)-1-hydroxyethyl)pyrrolidin-2-one (5b)

Rf = 0.2 (80:20 EtOAc/hexanes). Orange solid: mp 101–102 °C. Yield: 58.8 mg, 69%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.40–7.39 (m, 2H), 7.10–7.08 (M, 2H), 5.64, (t, J = 6.8, 1H), 4.24 (br, 1H), 3.55–3.51 (m, 1H), 3.36–3.31 (m, 1H), 3.01 (dd, J = 14.1, 7.4, 1H), 2.82 (dd, J = 14.1, 6.3, 1H), 2.30–2.26 (m, 2H), 1.98–1.90 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.1, 135.6, 131.5, 130.8, 120.6, 75.7, 42.1, 39.4, 31.7, 18.1. HRMS (ESI): C12H14BrNO2Na (M + Na) requires 306.0106/found: 306,0099. IR (neat, cm–1): 3317, 2926, 1657, 1423, 1272, 1013.

1-(1-Hydroxy-2-(4-nitrophenyl)ethyl)pyrrolidin-2-one (5c)

Rf = 0.1 (80:20 EtOAc/hexanes). Yellow solid: mp 117–118 °C. Yield: 45.2 mg, 60%. 1H (500 MHz, CDCl3, 25 °C) δ = 8.16 (d, J = 8.7, 2H), 7.41 (d, J = 8.7, 2H), 5.73–5.70 (m, 1H), 3.67 (d, J = 3.5, 1H), 3.57–3.54 (m, 1H), 3.40–3.36 (m, 1H), 3.18 (dd, J = 14.0, 7.8, 1H), 2.99 (dd, J = 14.1, 5.7, 1H), 2.36–2.32 (m, 2H), 2.04–1.96 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.1, 146.9, 144.3, 130.1, 123.7, 75.7, 42.3, 39.9, 31.6, 18.2. HRMS (ESI): C12H14N2O4Na (M + Na) requires 273.0851/found: 273.0846. IR (neat, cm–1): 3324, 2955, 1668, 1519, 1348, 1082.

1-(1-Hydroxy-2-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (5e)

Rf = 0.2 (80:20 EtOAc/hexanes). White solid: mp 89–90 °C. Yield: 50.7 mg, 73%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.14 (d, J = 8.5, 2H), 6.83 (d, J = 8.5, 2H), 5.65–5.61 (m, 1H), 3.78 (s, 3H), 3.52–3.46 (m, 2H), 3.39–3.35 (m, 1H), 3.02 (dd, J = 14.1, 7.3, 1H), 2.86 (dd, J = 14.1, 6.3, 1H), 2.32 (t, J = 8.1, 2H), 2.00–1.92 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.1, 158.4, 130.1, 128.5, 114.0, 76.7, 55.2, 42.6, 39.2, 31.7, 18.2. HRMS (ESI): C13H17NO3Na (M + Na) requires 258.1106/found: 258.1095. IR (neat, cm–1): 3294, 2957, 1646, 1415, 1182, 1035.

1-(1-Hydroxy-2-phenylethyl)pyrrolidin-2-one (5g)

Rf = 0.2 (80:20 EtOAc/hexanes). White solid: mp 78–79 °C. Yield: 45.5 mg, 74%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.29–7.27 (m, 2H), 7.22–7.21 (m, 3H), 5.71–5.68 (m, 1H), 4.18 (br, 1H), 3.55–3.49 (m, 1H), 3.39–3.34 (m, 1H), 3.07 (dd, J = 14.0, 7.3, 1H), 2.89 (dd, J = 14.0, 6.5, 1H), 2.28 (t, J = 8.3, 2H), 1.99–1.87 (m, 2H).13C (125 MHz, CDCl3, 25 °C) δ = 176.1, 136.6, 129.0, 128.4, 126.6, 76.1, 42.3, 40.0, 31.7, 18.1. HRMS (ESI): C12H15NO2Na (M + Na) requires 228.1000/found: 228.0995. IR (neat, cm–1): 3358, 2924, 1657, 1421, 1287, 1044.

1-(1-Hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)pyrrolidin-2-one (5h)

Rf = 0.2 (80:20 EtOAc/hexanes). Orange solid: mp 64–65 °C. Yield: 66.4 mg, 81%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.48–7.47 (m, 2H), 7.42–7.37 (m, 2H), 5.68–5.64 (m, 1H), 4.50 (br, 1H), 3.58–3.53 (m, 1H), 3.38–3.33 (m, 1H), 3.10 (dd, J = 14.1, 7.8, 1H), 2.90 (dd, J = 14.1, 5.8, 1H), 2.33–2.21 (m, 2H), 1.99–1.89 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.1, 137.8, 132.6, 130.7 (q, 2JC–F = 32), 128.9, 125.9 (q, 3JC–F = 4), 125.2 (q, 1JC–F = 272), 123.5 (q, 3JC–F = 4), 75.6, 42.2, 39.8, 31.7, 18.1. HRMS (ESI): C13H14F3NO2Na (M + Na) requires 296.0874/found: 296.0867. IR (neat, cm–1): 3319, 2926, 1672, 1423, 1331, 1072.

1-(1-Hydroxy-2-(naphthalen-1-yl)ethyl)pyrrolidin-2-one (5i)

Rf = 0.2 (80:20 EtOAc/hexanes). Red solid: mp 106–107 °C. Yield: 28.3 mg, 37%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.81–7.79 (m, 3H), 7.68 (s, 1H), 7.47–7.42 (m, 2H), 7.37 (dd, J = 8.4, 1.7, 1H), 5.82–5.79 (m, 1H), 3.59 (d, J = 4.87, 1H), 3.54–3.49 (m, 1H), 3.43–3.38 (m, 1H), 3.25 (dd, J =14.1, 7.4, 1H), 3.09 (dd, J = 14.1, 6.4, 1H), 2.31 (t, J = 8.1, 2H), 1.99–1.87 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.2, 134.1, 133.5, 132.4, 128.2, 127.7, 127.6, 127.4, 127.4, 126.1, 125.6, 76.5, 42.6, 40.3, 31.7, 18.2. HRMS (ESI): C16H17NO2Na (M + Na) requires 278.1157/found: 278.1151. IR (neat, cm–1): 3304, 2929, 1668, 1423, 1288, 1054.

1-(1-Hydroxy-2-(3-chlorophenyl)ethyl)pyrrolidin-2-one (5j)

Rf = 0.2 (80:20 EtOAc/hexanes). Yellow solid: mp 98–99°C. Yield: 60.1 mg, 83%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.24–7.21 (m, 3H), 7.13–7.11 (m, 1H), 5.67–5.63 (m, 1H), 3.74 (d, J = 4.82, 1H), 3.54–3.49 (m, 1H), 3.39–3.35 (m, 1H), 3.05 (dd, J = 14.1, 7.5, 1H), 2.87 (dd, J = 13.9, 6.1, 1H), 2.35–2.31 (m, 2H), 2.02–1.93 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.2, 138.6, 134.2, 129.8, 129.3, 127.3, 126.9, 76.2, 42.5, 39.8, 31.7, 18.1. HRMS (ESI): C12H15ClNO2 (M + H) requires 240.0791/found: 240.0783. IR (neat, cm–1): 3321, 2924, 1672, 1421, 1270, 1082.

1-(1-Hydroxy-2-(2-bromophenyl)ethyl)pyrrolidin-2-one (5l)

Rf = 0.3 (80:20 EtOAc/hexanes). Yellow solid: mp 93–94 °C. Yield: 62.7 mg, 73%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.52 (dd, J = 8.0, 1.1, 1H), 7.26 (dd, J = 7.6, 1.7, 1H), 7.22 (td, J = 7.4, 1.1, 1H), 7.07 (td, J = 7.6, 1.8, 1H), 5.74 (t, J = 6.6, 1H), 4.59 (br, 1H), 3.55–3.50 (m, 1H), 3.43–3.39 (m, 1H), 3.18–3.09 (m, 2H), 2.32–2.28 (m, 2H), 2.00–1.90 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.2, 136.2, 132.8, 131.2, 128.4, 127.5, 124.8, 75.1, 42.7, 40.0, 31.8, 18.2. HRMS (ESI): C12H14BrNO2Na (M + Na) requires 306.0106/found: 306.0098. IR (neat, cm–1): 3319, 2931, 1657, 1421, 1270, 1044.

1-(1-Hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl)pyrrolidin-2-one (5m)

Rf = 0.1 (80:20 EtOAc/hexanes). Orange oil. Yield: 54.5 mg, 61%. 1H (400 MHz, CDCl3, 25 °C) δ = 6.43 (s, 2H), 5.70 (t, J = 6.8, 1H), 4.25 (br, 1H), 3.81 (s, 6H), 3.79 (s, 3H), 3.57–3.51 (m, 1H), 3.38–3.32 (m, 1H), 2.99 (dd, J = 14.2, 7.8, 1H), 2.80 (dd, J = 14.2, 6.0, 1H), 2.32–2.28 (m, 2H), 2.00–1.89 (m, 2H). 13C (100 MHz, CDCl3, 25 °C) δ = 175.9, 153.1, 136.6, 132.3, 105.9, 75.7, 60.7, 56.0, 42.2, 40.2, 31.7, 18.1. HRMS (ESI): C15H21NO5Na (M + Na) requires 318.1317/found: 318.1311. IR (neat, cm–1): 3335, 2933, 1657, 1421, 1238, 1121.

1-(1-Hydroxy-2-(2-methoxyphenyl)ethyl)pyrrolidin-2-one (5n)

Rf = 0.2 (80:20 EtOAc/hexanes). White solid: mp 92–93 °C. Yield: 54.5 mg, 77%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.21 (t, J = 7.88, 1H), 7.16 (d, J = 7.25, 1H) 6.88 (t, J = 7.42 1H), 6.85 (d, J = 8.18, 1H), 5.74–5.71 (m, 1H), 3.96 (d, J = 5.01, 1H), 3.83 (s, 3H), 3.51–3.46 (m, 1H), 3.41–3.36 (m, 1H), 3.07 (dd, J = 14.2, 7.3, 1H), 2.99 (dd, J = 13.9, 6.1, 1H), 2.31 (t, J = 8.1, 2H), 1.98–1.88 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 175.8, 157.4, 130.9, 128.1, 124.9, 120.6, 110.3, 75.7, 55.3, 42.5, 35.0, 31.8, 18.2. HRMS (ESI): C13H18NO3Na (M + Na) requires 258.1106/found: 258.1099. IR (neat, cm–1): 3335, 2937, 1665, 1495, 1244, 1028.

1-(1-Hydroxy-2-(p-tolyl)ethyl)pyrrolidin-2-one (5o)

Rf = 0.2 (80:20 EtOAc/hexanes). White solid: mp 100–101°C. Yield: 47 mg, 71%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.11–7.07 (m, 4H), 5.67 (t, J = 6.5, 1H), 4.19 (s, 1H), 3.55–3.50 (m, 1H), 3.39–3.34 (m, 1H), 3.03 (dd, J = 14.0, 7.2, 1H), 2.85 (dd, J = 14.0, 6.6, 1H), 2.30–2.27 (m, 5H), 1.98–1.88 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.1, 136.2, 133.5, 129.2, 128.9, 76.2, 42.3, 39.6, 31.8, 21.1, 18.2. HRMS (ESI): C13H17NO2Na (M + Na) requires 242.1157/found: 242.1149. IR (neat, cm–1): 3332, 2922, 1657, 14239, 1287, 1050.

1-(1-Methoxy-2-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (5p)

Rf = 0.3 (80:20 EtOAc/hexanes). Colorless oil. Yield: 25 mg, 33%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.13–7.10 (m, 2H), 6.83–6.80 (m, 2H), 5.40 (t, J = 6.9, 1H), 3.77 (s, 3H), 3.42–3.36 (m, 1H), 3.35–3.29 (m, 1H), 3.23 (s, 3H), 3.01 (dd, J = 14.3, 6.9, 1H), 2.75 (dd, J = 14.3, 6.7, 1H), 2.47–2.36 (m, 1H), 2.35–2.27 (m, 1H), 2.06–1.90 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.1, 158.3, 130.0, 128.3, 113.8, 83.0, 55.8, 55.2, 41.2, 38.1, 31.6, 18.3. HRMS (ESI): C14H19NO3Na (M + Na) requires 272.1262/found: 272.1259. IR (neat, cm–1): 2928, 1678, 1514, 1246, 1089.

1-(1-Methoxy-2-phenylethyl)pyrrolidin-2-one (5q)

Rf = 0.3 (70:30 EtOAc/hexanes). Yellow oil. Yield: 26 mg, 39%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.29–7.26 (m, 2H), 7.22–7.19 (m, 3H), 5.45 (t, J = 6.9, 1H), 3.43–3.39 (m, 1H), 3.35–3.31 (m, 1H), 3.23 (s, 3H), 3.08 (dd, J = 14.2, 7.1, 1H), 2.82 (dd, J = 14.2, 6.6, 1H), 2.44–2.38 (m, 1H), 2.34–2.27 (m, 1H), 2.05–1.90 (m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 176.1, 136.3, 129.0, 128.4, 126.6, 82.8, 55.8, 41.2, 39.1, 31.5, 18.3. HRMS (ESI): C13H17NO2Na (M + Na) requires 242.1157/found: 242.1157. IR (neat, cm–1): 2928, 1680, 1415, 1270, 1078.

1-(1-Methoxy-2-(4-nitrophenyl)ethyl)pyrrolidin-2-one (5r)

Rf = 0.3 (80:20 EtOAc/hexanes). Yellow oil. Yield: 44 mg, 55%. 1H (400 MHz, CDCl3, 25 °C) δ = 8.14 (d, J = 8.8, 2H), 7.39 (d, J = 8.8, 2H), 5.44 (dd, J = 7.6, 5.7, 1H), 3.46–3.40 (m, 1H), 3.34–3.28 (m, 1H), 3.21 (s, 3H), 3.15 (dd, J = 14.2, 7.7, 1H), 2.90 (dd, J = 14.2, 5.8, 1H), 2.49–2.31 (m, 2H), 2.10–1.93 (m, 2H).13C (100 MHz, CDCl3, 25 °C) δ = 176.1, 146.9, 144.2, 130.0, 123.6, 82.3, 55.9, 41.2, 39.1, 31.4, 18.3. HRMS (ESI): C13H16N2O4Na (M + Na) requires 287.1007/found: 287.1007. IR (neat, cm–1): 2929, 1680, 1516, 1270, 1089.

3-(1-Hydroxy-2-(4-nitrophenyl)ethyl)oxazolidin-2-one (7c)

Rf = 0.2 (70:30 EtOAc/hexanes). Orange solid: mp 166–167 °C. Yield: 40 mg, 53%. 1H (400 MHz, CDCl3, 25 °C) δ = 8.14 (d, J = 8.8, 2H), 7.42 (d, J = 8.7, 2H), 5.58 (t, J = 6.7, 1H), 4.39–4.26 (m, 3H), 3.83 (app q, J = 8.4, 1H), 3.51 (app td, J = 13.1, 5.3, 1H), 3.16 (dd, J = 14.2, 7.7, 1H), 2.99 (dd, J = 14.2, 5.7, 1H). 13C (100 MHz, CDCl3, 25 °C) δ = 158.6, 147.0, 144.1, 130.1, 123.7, 77.4, 62.7, 40.1, 39.3. HRMS (ESI): C11H12N2O5Na (M + H) requires 253.0824/found: 253.0824. IR (neat, cm–1): 3363, 2924, 1721, 1516, 1249, 1037.

3-(1-Hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)oxazolidin-2-one (7d)

Rf = 0.22 (70:30 EtOAc/hexanes). Pink solid: mp 102–103°C. Yield: 56.7 mg, 69%. 1H (400 MHz, CDCl3, 25 °C) δ = 7.54 (d, J = 8.1, 2H), 7.35 (d, J = 8.0, 2H), 5.59–5.55 (m, 1H), 4.59 (d, J = 4.0, 1H), 4.31 (app td, J = 13.3, 5.4, 1H), 4.24 (app q, J = 8.6, 1H), 3.80 (app q, J = 8.7, 1H), 3.47 (app td, J = 13.2, 5.4, 1H), 3.11 (dd, J = 14.2, 7.4, 1H), 2.93 (dd, J = 14.2, 6.1, 1H). 13C (100 MHz, CDCl3, 25 °C) δ = 158.6, 140.4, 129.4, 129.0 (q, 2JC–F = 32), 125.3 (q, 3JC–F = 4), 124.1, (q, 1JC–F = 272), 77.4, 62.6, 39.9, 39.1. HRMS (ESI): C12H12F3NO3Na (M + Na) requires 298.0667/found: 298.0648. IR (neat, cm–1): 3386, 1722, 1324, 1210.

3-(1-Hydroxy-2-(4-methoxyphenyl)ethyl)oxazolidin-2-one (7e)

Rf = 0.2 (70:30 EtOAc/hexanes). Colorless oil. Yield: 37 mg, 52%. 1H (400 MHz, CDCl3, 25 °C) δ = 7.14 (d, J = 8.7, 2H), 6.83 (d, J = 8.7, 2H), 5.54 (td, J = 6.7, 3.3, 1H), 4.36–4.28 (m, 1H), 4.23 (app q, J = 8.5, 1H), 3.93 (d, J = 3.2, 1H), 3.78 (s, 3H), 3.49 (app td, J = 13.2, 5.4, 1H), 3.01 (dd, J = 14.2, 7.1, 1H), 2.84 (dd, J = 14.2, 6.6, 1H). 13C (100 MHz, CDCl3, 25 °C) δ = 158.6, 158.5, 130.0, 128.2, 114.0, 78.1, 62.6, 55.3, 39.4, 39.3. HRMS (ESI): C12H15NO4Na (M + Na) requires 260.0898/found: 260.0896. IR (neat, cm–1): 3367, 2920, 1721, 1514, 1244, 1033.

3-(1-Hydroxy-2-phenylethyl)oxazolidin-2-one (7g)

Rf = 0.3 (70:30 EtOAc/hexanes). Colorless oil. Yield: 32.2 mg, 52%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.31–7.28 (m, 2H), 7.25–7.22 (m, 3H), 5.61–5.58 (m, 1H), 4.34–4.29 (m, 1H), 4.22 (app q, J = 8.4, 1H), 4.11 (d, J = 3.9, 1H), 3.78 (app q, J = 8.4, 1H), 3.50 (app td, J = 13.1, 5.3, 1H), 3.08 (dd, J = 14.2, 7.1, 1H), 2.90 (dd, J = 14.2, 6.6, 1H). 13C (125 MHz, CDCl3, 25 °C) δ = 158.5, 136.1, 128.9, 128.5, 126.8, 77.9, 62.5, 40.1, 39.2. HRMS (ESI): C11H13NO3Na (M + Na) requires 230.0793/found: 230.0793. IR (neat, cm–1): 3375, 2924, 1721, 1423, 1247, 1033.

3-(1-Hydroxy-2-(3-(trifluoromethyl)phenyl)ethyl)oxazolidin-2-one (7h)

Rf = 0.3 (70:30 EtOAc/hexanes). Colorless oil. Yield: 52 mg, 63%. 1H (400 MHz, CDCl3, 25 °C) δ = 7.50–7.48 (m, 2H), 7.44–7.38 (m, 2H), 5.58–5.54 (m, 1H), 4.52 (d, J = 2.9, 1H), 4.31 (app td, J = 13.3, 5.3, 1H), 4.24 (app q, J = 8.6, 1H), 3.80 (app q, J = 8.5, 1H), 3.48 (app td, J = 13.1, 5.3, 1H), 3.10 (dd, J = 14.2, 7.6, 1H), 2.92 (dd, J = 14.2, 5.8, 1H). 13C (100 MHz, CDCl3, 25 °C) δ = 158.7, 137.4, 132.5, 130.8 (q, 2JC–F = 32), 129.0, 125.9 (q, 3JC–F = 4), 124.1, (q, 1JC–F = 272), 123.7 (q, 3JC–F = 4),77.6, 62.7, 40.0, 39.2. HRMS (ESI): C12H12F3NO3Na (M + Na) requires 298.0667/found: 298.0669. IR (neat, cm–1): 3378, 2926, 1722, 1424, 1251, 1072.

3-(2-(2-Bromophenyl)-1-hydroxyethyl)oxazolidin-2-one (7l)

Rf = 0.2 (60:40 EtOAc/hexanes). Pink oil. Yield: 42 mg, 49%. 1H (400 MHz, CDCl3, 25 °C) δ = 7.53 (dd, J = 8.0, 0.9, 1H), 7.28 (dd, J = 7.6, 1.8, 1H), 7.24 (td, J = 7.5, 1.0, 1H), 7.09 (td, J = 7.7, 1.6, 1H), 5.67 (t, J = 6.7, 1H), 4.40 (br, 1H), 4.32 (app td, J = 13.2, 5.3, 1H), 4.25 (app q, J = 8.6, 1H), 3.81 (app q, J = 8.6, 1H), 3.57 (app td, J = 13.1, 5.2, 1H), 3.13 (d, J = 6.7, 1H). 13C (100 MHz, CDCl3, 25 °C) δ = 158.6, 135.9, 132.9, 131.2, 128.6, 127.6, 124.8, 76.9, 62.7, 40.1, 39.5. HRMS (ESI): C11H12NO3BrNa (M + Na) requires 307.9898/found: 307.9898. IR (neat, cm–1): 3371, 2924, 1721, 1424, 1251, 1028.

3-(1-Hydroxy-2-(2-methoxyphenyl)ethyl)oxazolidin-2-one (7n)

Rf = 0.2 (70:30 EtOAc/hexanes). Yellow solid: mp 98–99 °C. Yield: 45.2 mg, 64%. 1H (600 MHz, CDCl3, 25 °C) δ = 7.22 (td, J = 7.8, 1.5, 1H), 7.16 (dd, J = 7.4, 1.1, 1H), 6.89 (t, J = 7.4, 1H), 6.85 (d, J = 8.2, 1H), 5.64 (td, J = 9.8, 4.3, 1H), 4.28 (app td, J = 13.5, 5.2, 1H), 4.20 (app q, J = 8.6, 1H), 4.15 (d, J = 4.2, 1H), 3.81 (s, 3H), 3.76 (app q, J = 8.8, 1H), 3.55 (app td, J = 13.2, 5.3, 1H), 3.04 (dd, J = 14.0, 6.8, 1H), 2.98 (dd, J = 13.9, 6.6, 1H). 13C (150 MHz, CDCl3, 25 °C) δ = 158.3, 157.4, 130.7, 128.2, 124.4, 120.6, 110.4, 77.0, 62.4, 55.3, 55.2, 39.2, 35.1, 35.0. HRMS (ESI): C12H15NO4Na (M + Na) requires 260.0898/found: 260.0822. IR (neat, cm–1): 3386, 1722, 1324, 1210.

3-(1-Methoxy-2-(4-nitrophenyl)ethyl)oxazolidin-2-one (7r)

Rf = 0.3 (70:30 EtOAc/hexanes). Orange solid: mp 136–137 °C. Yield: 50.3 mg, 63%. 1H (500 MHz, CDCl3, 25 °C) δ = 8.17 (d, J = 8.5, 2H), 7.41 (d, J = 8.4, 2H), 5.25–5.22 (m, 1H), 4.44–4.39 (m, 1H), 4.36–4.31 (m, 1H), 3.63 (app q, J = 8.4, 1H), 3.57–3.49 (m, 1H), 3.29 (s, 3H), 3.17 (dd, J = 14.2, 7.9, 1H), 2.96 (dd, J = 14.2, 5.3, 1H). 13C (125 MHz, CDCl3, 25 °C) δ = 158.1, 147.1, 143.7, 130.0, 123.8, 84.8, 62.4, 56.2, 39.4, 38.8. HRMS (ESI): C12H14N2O5Na (M + Na) requires 298.0800/found: 289.0782. IR (neat, cm–1): 2926, 1748, 1519, 1348.

3-(1-Methoxy-2-(4-(trifluoromethyl)phenyl)ethyl)oxazolidin-2-one (7s)

Rf = 0.4 (70:30 EtOAc/hexanes). Brown oil. Yield: 39mg, 45%. 1H (400 MHz, CDCl3, 25 °C) δ = 7.55 (d, J = 8.1, 2H), 7.35 (d, J = 8.0, 2H), 5.25–5.22 (m, 1H), 4.38 (app td, J = 13.3, 6.4, 1H), 4.30 (app q, J = 8.3, 1H), 3.62 (app q, J = 8.4, 1H), 3.49 (app td, J = 13.2, 6.3, 1H), 3.29 (s, 3H), 3.13 (dd, J = 14.2, 7.6, 1H), 2.90 (dd, J = 14.3, 5.8, 1H). 13C (100 MHz, CDCl3, 25 °C) δ = 158.2, 140.2, 129.4, 129.2 (q, 2JC–F = 32), 125.4 (q, 3JC–F = 3), 124.2 (q, 1JC–F = 272), 85.0, 62.3, 56.1, 39.3, 38.8, 29.7. HRMS (ESI): C13H14F3NO3Na (M + Na) requires 312.0823/found: 312.0819. IR (neat, cm–1): 2925, 1745, 1326, 1069.

3-(2-(4-Bromophenyl)-1-methoxyethyl)oxazolidin-2-one (7t)

Rf = 0.5 (70:30 EtOAc/hexanes). Orange oil. Yield: 38.9 mg, 43%. 1H (400 MHz, CDCl3, 25 °C) δ = 7.41 (d, J = 8.4, 2H), 7.09 (d, J = 8.4, 2H), 5.20–5.16 (m, 1H), 4.36 (app td, J = 13.4, 6.3, 1H), 4.31–4.25 (m, 1H), 3.62–3.56 (m, 1H), 3.47 (app td, J = 13.4, 6.3, 1H), 3.28 (s, 3H), 3.02 (dd, J = 14.3, 7.4, 1H), 2.79 (dd, J = 14.3, 6.1, 1H). 13C (100 MHz, CDCl3, 25 °C) δ = 158.2, 135.0, 131.7, 130.8, 120.8, 85.1, 62.3, 56.1, 38.9, 38.8. HRMS (ESI): C12H14BrNO3Na (M + Na) requires 322.0054/found: 322.0055. IR (neat, cm–1): 2931, 1745, 1247, 1089.

1-(2-(4-Methoxyphenyl)-1-((2,2,6,6-tetramethylpiperidin-1-yl)oxy)ethyl)pyrrolidin-2-one (8)

Rf = 0.4 (50:50 EtOAc/hexanes). White solid. Yield: 41.5 mg, 37%.1H (500 MHz, CDCl3, 40 °C) δ = 7.08 (d, J = 8.5, 2H), 6.79 (d, J = 8.7, 2H), 5.88 (dd, J = 10.4, 4.6, 1H), 3.76 (s, 3H), 3.47–3.43 (m, 1H), 3.32–3.27 (m, 2H), 2.89 (dd, J = 14.7, 10.6, 1H), 2.25–2.19 (m, 1H), 2.12–2.04 (m, 1H), 1.91–1.82 (m, 1H), 1.80–1.72 (m, 1H), 1.55 (br, 3H), 1.45 (br, 4H), 1.29 (br, 3H), 1.10–1.06 (m, 9H). 13C (125 MHz, CDCl3, 25 °C) δ = 175.2, 158.2, 129.8, 128.4, 113.8, 86.6, 60.7, 59.0, 55.2, 40.1, 36.2, 33.5, 33.0, 31.4, 20.4, 20.1, 17.6, 17.1. HRMS (ESI): C22H34N2O2Na (M + Na) requires 397.2467/found: 397.2448. IR (neat, cm–1): 2929, 1700, 1516, 1249, 1013.

(E)-1-(3-Chlorostyryl)pyrrolidin-2-one (9)

Rf = 0.6 (70:30 EtOAc/hexanes). White solid: mp 104–103 °C. Yield: 59.8 mg, 90%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.62 (d, J = 14.8, 1H), 7.33 (s, 1H), 7.22–7.20 (m, 2H), 7.15–7.12 (m, 1H), 5.80 (d, J = 14.8, 1H), 3.65 (t, J = 7.1, 2H), 2.56 (t, J = 8.2, 2H), 2.18 (qui, J = 7.7, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 173.5, 138.4, 134.6, 129.9, 126.4, 125.7, 124.7, 123.6, 110.3, 45.2, 31.2, 17.5. HRMS (ESI): C12H12ClNONa (M + Na) requires 244.0505/found: 244.0503. IR (neat, cm–1): 2924, 2853, 1709, 1646, 1398, 1236.

1-(2-(3-Chlorophenyl)acetyl)pyrrolidin-2-one (10)

Rf = 0.4 (50:50 EtOAc/hexanes). Yellow oil. Yield: 40.6 mg, 57%. 1H (500 MHz, CDCl3, 25 °C) δ = 7.29 (s, 1H), 7.24–7.23 (m, 2H), 7.18–7.16 (m, 1H), 4.24 (s, 2H), 3.83 (t, J = 7.2, 2H), 2.62 (t, J = 8.1, 2H), 2.08–2.02 (9m, 2H). 13C (125 MHz, CDCl3, 25 °C) δ = 175.4, 171.4, 136.2, 134.2, 129.9, 129.6, 128.0, 127.2, 45.7, 42.4, 33.7, 17.1. HRMS (ESI): C12H12ClNO2Na (M + Na) requires 260.0454/found: 260.0455. IR (neat, cm–1): 2955, 1734, 1687, 1359, 1242, 1082.