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Cite This: J. Org. Chem. 2018, 83, 2734−2743

Synthesis of Highly Substituted 3‑Pyrrolin-2-ones from N,NDisubstituted α‑Amino Acids Víctor Samper Barceló and Stefan Bienz* Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland S Supporting Information *

ABSTRACT: Highly functionalized 5-membered N-heterocyclic compounds, 4-aryl-3-chloro-5-methoxy-1-methyl-3-pyrrolin-2ones, have been synthesized in moderate to high yields by the reaction of N,N-dimethylated aromatic α-amino acids with oxalyl chloride, followed by solvolysis with MeOH. The products possess a number of functional groups such as an amide, a mixed amido/alkoxy acetal, a vinyl halide, and an alkene and thus are promising candidates to be used as starting materials for the synthesis of diverse five-membered N-heterocyclic compounds.

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a recent monograph by Pelkey et al.5 Some selected examples of natural products that contain the 3-pyrrolin2-one framework and illustrate the structural variety of this class of compounds are shown in Figure 2. Because of the highly functionalized framework of 8a and the manner of its formation, we expected the unprecedented reaction to allow a flexible access to a variety of 3-pyrrolin-2ones and other five-membered N-heterocycles by variation of the starting materials and by conversion of the compounds of type 8 into further derivatives by subsequent transformations. We thus decided to explore the reaction more deeply, particularly with regards to its mechanism and scope upon variation of the R group in the starting amino acids 7.

INTRODUCTION Five-membered N-containing heterocycles are important chemical frameworks that represent the core structures of many natural products, pharmaceutically active compounds, or agrochemicals.1−8 Some examples of biologically active compounds that contain differently substituted N-heterocycles with different degrees of unsaturation and levels of oxidation are shown in Figure 1. The fully saturated pyrrolidine, for instance, is the common structure of a number of hNK1 antagonists9 represented with structure 1, and the aromatic pyrrole is contained in the naturally occurring pyrrolnitrin (2), which shows antimycobacterial and antifungal activities.10−13 Pyrrolidin-2-ones and pyrrolin-2-ones are found in compounds such as (−)-Clausenamide (3), isolated from Clausena lansium,14,15 and related derivatives,16,17 which are multitarget nootropics, 18 or in structures of type 4, acting as mineralocorticoid receptor antagonists,19 respectively. Furthermore, five-membered cyclic imides are found as frameworks in biologically active compounds. For instance, succinimide represents the core structure of tivantinib (5), a drug against hepatocellular carcinoma that presently is in phase III of clinical studies,20,21 and the maleimide framework is found in MPO0029 (6), a highly potent and selective COX-2 inhibitor.22 In light of the widespread occurrence of five-membered Nheterocycles and their importance as diversely substituted structural cores, any new access to these compounds is of particular interest. Such a new access was accidently found in the attempt to convert N,N-dimethylphenylalanine (7a) into its corresponding methyl ester by treatment of the amino acid with a large excess of (COCl)2 followed by quenching with MeOH. Instead of the expected ester, 3-pyrroline-2-one derivative 8a was obtained in 74% yield (Scheme 1).23 The formation of 3-pyrrolin-2-one derivative 8a from amino acid derivative 7a attracted our attention immediately. 3Pyrrolin-2-one itself represents the core structure of many natural products and biologically active materials, and numerous approaches for the synthesis of 3-pyrrolin-2-one derivatives have been published. This is excellently reviewed in © 2018 American Chemical Society

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RESULTS AND DISCUSSION The reaction of compound 7a to heterocyclic product 8a evidently involves decarboxylation and N-demethylation of the starting amino acid and condensation of the formed intermediate with (COCl)2. Scheme 2 shows two mechanistic paths that were considered to rationalize the transformation. Condensation of amino acids of type 7 with (COCl)2 may form 6-membered cyclic intermediates of type 9 that could decompose directly or after loss of MeCl (formation of 9′) to imine/iminium/enamine intermediates of type 10 and 10′, respectively. Condensation of the enamines with a second equivalent of (COCl)2 could provide 3-pyrrolin-2-ones of type 11 or 11′, the former delivering compounds of type 11′ by loss of MeCl. Methanolysis would then lead to the observed compounds of type 8. Similar reactions as those proposed above are described in literature. The oxidative decarboxylation of N,N-disubstituted α-amino acids was, e.g., synthetically exploited by Weinstein and Craig;32 the condensation of enamines with oxalyl cloride33−36 or with fumarates37 delivering 3-pyrrolin-2-ones has been published as well, and N-dealkylating ring closure38 Received: December 18, 2017 Published: February 6, 2018 2734

DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743

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The Journal of Organic Chemistry

Figure 1. Selected examples of biologically active compounds that contain differently substituted N-heterocycles with different degrees of unsaturation and levels of oxidation.

enamine 10a′ was treated with (COCl)2. Thus, a reaction path proceeding via an intermediate of type 10′ can also be excluded. Treatment of enamine 10a with (COCl)2, on the other hand, provided expected heterocyclic product 8a in substantial amounts. The yield, however, remained much lower than the one obtained with the amino acid precursor 7a; even after extensive optimization of the reaction conditions, not more than 36% of desired product 8a was attained. Because the “short cut” to compounds of type 8 using enamines of type 10 did not turn out to be beneficial, the scope of the title reaction was investigated with starting materials of type 7 varied in group R. To this purpose, the aromatic N,Ndimethylated amino acids 7b−7n and N,N-dimethylated leucine (7o) were prepared by either reductive methylation of the respective commercial nonmethylated amino acid precursors or, in the case of 7k, analogous to literature procedures by a three-step synthesis starting from N,Ndimethyl glycine.39−41 The several amino acids were then treated under standardized conditions with (COCl)2 in CH2Cl2 for 24 h at 20−22 °C and, subsequently after removal of the solvent by evaporation, with an excess of MeOH at 0 °C for 2 h. The results of these experiments are summarized in Table 1 together with the yields that were attained in the syntheses of the starting amino acids of type 7. Evidently, aromatic R groups are required to effect an efficient conversion of compounds of type 7 to pyrrolinones of type 8. Except for the histidine-derived amino acid 7o, all starting materials with aromatic R groups (7a−7n) delivered the desired products with reasonable to very high yields. When the R group was aliphatic, in the case of leucine derivative 7p, mostly decomposition of the starting material was observed, and only a trace amount of pyrrolinone 8p was obtained. This corresponds to our observations with other aliphatic amino acids that we studied in a preliminary substrate evaluation. With regard to the phenylalanine derivatives, the success of the reaction is largely independent of the nature of the substituents attached to the aromatic ring. The lower yields

Scheme 1

finds its precedence. The combination of these reactions in a cascade, however, is new, and also new is the formation of 3chloro-3-pyrrolin-2-one derivatives. Evidence for the formation of compounds of type 11′ is found for 11a′ (R = Ph). The 1H and 13C NMR spectra of the virtually pure crude product obtained after treatment of 7a with (COCl)2 showed signal distributions analogous to those observed for the products of hydrolysis or methanolysis of this intermediate, and in the HR-EI-MS, the respective signal for the M+• ion at m/z 241.0052 (−1.51 ppm) is found. Both mechanistic paths above suggest that two equivalents of (COCl)2 are required and sufficient for the transformation. Thus, a 20-fold excess of the reagent, as used in the original procedure, should not be necessary, and in fact, it turned out that the use of three equivalents of acid chloride is appropriate. Treatment of 7a with 3.1 equiv of (COCl)2 delivered the final product 8a inasmuch as 94% yield. To test whether compounds of the type 9′, 10, and/or 10′ are in fact intermediates in the reaction, N-monomethylated amino acid 12a and enamines 10a and 10a′, prepared from the respective aldehydes by condensation with dimethlyamine or methylamine, were treated with (COCl)2 under standard conditions (Scheme 3). Amino acid 12a delivered under these conditions the proposed intermediate 9a′ almost quantitatively but no product of type 8. Thus, a heterocyclic compound of type 9′ cannot be an intermediate in the formation of the 2pyrrolin-2-ones 8. Furthermore, no product of type 8 but full decomposition of the starting material was observed when 2735

DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743

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The Journal of Organic Chemistry

Figure 2. Selected examples of natural products that contain the 3-pyrrolin-2-one framework (Bilirubin,24 Oteromycin,25 Leuconolam,26 Phenopyrrozin,27 Pukeleimide A,28 Phaeosphaeride A,29 Belamide A,30 and PI-09131).

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CONCLUSIONS We have shown that N,N-dimethylated α-amino acids of type 7 can readily be converted to pyrrolinones of type 8 if the starting amino acids are substituted in the β-position with an aryl group. Thus, the new reaction allows the efficient synthesis of differently 4-aryl-substituted 3-pyrrolin-2-ones of type 8 by variation of the structure of the starting material. The distinctively functionalized compounds of type 8 can be regarded as structural units prone for further modifications and, thus, as starting materials to access diverse target molecules containing the pyrrole, pyrroline/pyrrolinone, or pyrrolidine/pyrrolidone moieties.

obtained with the benzyloxy and bismethoxy-substituted compounds 7f and 7g are attributed to partial cleavage of the O−Bn or O−Me bonds under the strongly acidic reaction conditions rather than to electronic effects. A somewhat more sluggish but still high-yielding reaction was observed with nitro derivative 7h for which the reaction time had to be doubled to attain full conversion. The results obtained with starting materials that carry heteroaromatic R groups are not fully conclusive. All the furyl and thiophenyl derivatives 7k−7n delivered the expected products, but the obtained yields were markedly lower than those attained with the phenyl derivatives. Particularly with the furyl compounds, pronounced decomposition was already observed during the reaction, and substantial amounts of the products were lost in the course of their chromatographic purification. In addition, the products turned out to be rather reactive: they already decomposed partly during the acquisition of their analytical data. A similar high reactivity of a 4-(2furyl)pyrrolinone under acidic conditions has already been reported previously.42 The behavior of histidine derivative 7o was quite different. No reaction whatsoever was observed upon treatment of the compound with (COCl)2. The reason for the special behavior of the heteroaromatically substituted starting materials is not clear, but evidently, the reaction is most successful with phenyl and substituted phenyl derivatives.

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EXPERIMENTAL SECTION

General Information. Unless otherwise stated, all chemicals were of reagent grade and purchased from commercial suppliers and used without further purification. Reactions were carried out under Ar or N2, in dried glass equipment with dry solvents (puriss. grade over molecular sieve). Extracts were washed with H2O and/or brine and dried over anhydrous Na2SO4. Evaporation of the solvents in vacuo was done with a rotary evaporator. Chromatography: Merck silica gel 60 (40−63 μm, 0.1% Ca) with the indicated solvent system. Thin layer chromatography (TLC): Merck TLC plates silica gel 60 on aluminum with the indicated solvent system; the spots were visualized by UV light (254 and 365 nm) and a stain of KMnO4. Specific optical rotation [α]D: JASCO Polarimeter P-2000. Mp: Mettler FP 5 + FP 52 coupled to an Olympus HSC microscope with a heating rate of 2 °C min−1; range 2/3 to fully molten. IR spectra: FT/IR-4100 Spectrometer 2736

DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743

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The Journal of Organic Chemistry Scheme 2

(δ 0.00), CDCl3 (δ 77.00), CD3OD (δ 49.15), CD3CN (δ 1.39), or DMSO-d6 (δ 39.51); multiplicities from DEPT-135 and DEPT-90 measurements. The signal assignments given for 7c, 8c, 8i, 8j, 8k, and 8n are based on HSQC and HMBC data and for 8k additionally on COSY and NOESY data (see Supporting Information). Mass spectrometry (MS): MS (ESI/quadrupole ion trap) spectra were performed on a Bruker ESQUIRE-LC quadrupole ion trap instrument (Bruker Daltonik GmbH, Bremen, Germany) equipped with a combined Hewlett-Packard Atmospheric Pressure Ion (API) source (Hewlett-Packard Co., Palo Alto, CA, USA); the solutions (∼0.1−1 μmol mL−1) were continuously introduced through the electrospray interface with a syringe infusion pump (Cole-Parmer 74900−05, ColeParmer Instrument Company, Vernon Hills, Illinois, USA) at a flow rate of 5 μL min−1; the MS conditions were nebulizer gas (N2), 15 psi; dry gas (N2), 7 L min−1; dry temperature, 300 °C; capillary voltage, 4000 V; end plate, 3500 V; capillary exit, 100 V; skimmer, 130 V; and trap drive, 70. The MS acquisitions were performed at normal resolution (0.6 u at half peak height) under ion charge control (ICC) conditions (10000) in the mass range from m/z 100 to 2000; to obtain representative mass spectra, eight scans were averaged. Highresolution mass spectrometry (HRMS): HRMS (ESI/Orbitrap) spectra were performed on a QExactive (Thermo Fisher Scientific, Bremen, Germany) Orbitrap mass spectrometer equipped with a heated electrospray ionization (ESI) source and connected to a Dionex Ultimate 3000 UHPLC system. The samples were dissolved in MeOH or H2O at a concentration of ∼50 μg mL−1 with 1 μL injected on-flow with an autosampler; the mobile phase (120 μL min−1 flow rate) consisted of MeOH + 0.1% AcOH or MeCN/H2O 2:8 + 0.1% AcOH chosen according to the solubility. Ion source parameters were set as follows: spray voltage, 3.0 kV; capillary temperature, 320 °C; sheath

Scheme 3

(JASCO) equipped with a JASCO MODEL ATR (attenuated total reflection) PRO 410-S single reflection measuring attachment applied as neat samples with 1/λ in cm−1. 1H NMR spectra: Bruker AV-300 (300 MHz); δ in ppm relative to TMS (δ 0.00), CDCl3 (δ 7.26), CD3OD (δ 3.31), CD3CN (δ 1.94), or D2O (δ 4.75), J in Hz. 13C NMR spectra: Bruker AV-300 (75.5 MHz); δ in ppm relative to TMS 2737

DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743

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The Journal of Organic Chemistry

propanoic acid (p-fluoro-DL-phenylalanine, 834 mg, 4.55 mmol) and formaldehyde (37% aq soln, 5.0 mL, 67 mmol) in H2O (100 mL) and MeCN (100 mL) upon which a clear soln was formed. The mixture was stirred at 21 °C for 1 h, and the pH was kept at ∼7 by the successive addition of glacial AcOH. MeCN was evaporated, and the residual aq soln was acidified with concd aq HCl. After the vigorous effervescence ceased, it was washed with Et2O (2 × 150 mL), and the H2O was evaporated under reduced pressure. The residue was dissolved in H2O (40 mL) and applied onto a column of DOWEX 50WX8 (H+ form, 50−100 mesh, 30 mL). The column was washed with H2O (200 mL) and then eluted with an aq soln of NH3 (1 M, 350 mL). The fractions containing the product were combined; the solvent was evaporated under reduced pressure, and the residue was dried under high vacuum to afford pure 7b (951 mg, 4.50 mmol, 99%) as a colorless amorphous solid. Mp (dec): ≥216 °C (after ion exchange chromatography upon evaporation of the solvents). IR: 1619. 1H NMR (CD3OD): 7.36 (ddlike m, “J” = 8.7, 5.4, 2 H), 7.04 (t-like m, “J” = 8.8, 2 H), 3.77 (t, J = 6.9, 1 H), 3.22 (d, J = 6.9, 2 H), 2.86 (s, 6 H). 13C NMR (CD3OD): 172.1 (s), 163.6 (sD, JCF = 243.7), 133.7 (sD, JCF = 3.1), 132.3 (dD, JCF = 8.6, 2 C), 116.5 (dD, JCF = 21.0, 2 C), 73.3 (d), 42.5 (q, 2 C), 34.5 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C11H15FNO2+ 212.1081; found 212.1083. 4.3. 3-(4-Bromophenyl)-2-(dimethylamino)propanoic Acid (7c). Analogous to the preparation of 7b, 2-amino-3-(4bromophenyl)propanoic acid (p-bromo-DL-phenylalanine, 906 mg, 3.71 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1504 mg, 23.93 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 21 °C. For redissolving the crude product, H2O (270 mL), acidified with concd HCl (5 drops), was needed. Ion exchange column chromatography on DOWEX 50WX8 (30 mL) afforded 7c (880 mg, 3.23 mmol, 87%) as a colorless amorphous solid. Mp (dec): ≥257 °C (after ion exchange chromatography upon evaporation of the solvents). IR: 1614. 1H NMR (CD3OD): 7.47, 7.28 (2 d-like m, “J” = 8.5, AA′BB′, 2 × 2 arom. H), 3.77 (t, J = 6.9, CHN), 3.20 (d, J = 6.9, CH2), 2.86 (s, N(Me)2). 13C NMR (CD3OD/(DCl in D2O (10−5 M)) 1:1): 170.2 (s, COOH), 134.4 (s, arom. C), 132.9, 132.2 (2 d, 2 × 2 arom. C), 122.3 (s, arom. CBr), 69.5 (d, CHN), 43.4, 42.0 (2 q, N(Me)2), 33.7 (t, CH2). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C11H15BrNO2+ 272.0281; found 272.0279. 4.4. (S)-2-(Dimethylamino)-3-(4-hydroxyphenyl)propanoic Acid (7d). Analogous to the preparation of 7b, (S)-2-amino-3-(4hydroxyphenyl)propanoic acid (L-tyrosine, 1000 mg, 5.52 mmol) was reacted with formaldehyde (37% aq soln, 4.5 mL, 60 mmol) and Na(CN)BH3 (1200 mg, 19.10 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 23 °C. Purification by ion exchange chromatography and recrystallization in H2O/acetone afforded 7d (1036 mg, 4.64 mmol, 84%) as a colorless amorphous solid. Mp (dec): ≥180 °C (H2O/acetone). [α]D28 70.0 (c 0.99, H2O). IR: 1610. 1H NMR (500 MHz, D2O): 7.18, 6.86 (2 d, J = 8.3, 2 × 2 H), 3.79 (dd, X of ABX, J = 8.8, 5.9, 1 H), 3.25, 3.05 (AB of ABX, JAB = 13.9, JAX = 9.0, JBX = 5.8, 2 × 1 H), 2.95, 2.92 (2 br s, 2 × 3 H). 13C NMR (125 MHz, D2O): 172.8 (s), 155.3 (s), 131.2 (d, 2 C), 127.5 (s), 116.3 (d, 2 C), 72.7 (d), 43.4, 41.1 (2 brd q), 33.8 (t). MS (ESI/ quadrupole ion trap) m/z: 231.9 (100, [M + Na]+), 210.0 (56, [M + H]+). 4.5. (S)-2-(Dimethylamino)-3-(4-methoxyphenyl)propanoic Acid (7e). Analogous to the preparation of 7b, (S)-2-amino-3-(4methoxyphenyl)propanoic acid (O-methyl-L-tyrosine, 890 mg, 4.47 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1522 mg, 24.22 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 22 °C to deliver, after ion exchange chromatography, 7e (963 mg, 4.31 mmol, 95%) as a colorless amorphous solid. Mp (dec): ≥214 °C (after ion exchange chromatography upon evaporation of the solvents). [α]D26 26.9 (c 1.00, MeOH). IR: 1609. 1 H NMR (DCl in D2O (10−5 M)): 6.25, 5.94 (2 d, J = 8.2, 2 × 2 H), 3.27 (dd, X of ABX, J = 8.7, 6.2, 1 H), 2.77 (s, 3 H), 2.36, 2.16 (AB of ABX, JAB = 13.9, JAX = 9.1, JBX = 5.7, 2 × 1 H), 2.01, 1.93 (2 s, 2 × 3

Table 1

a Synthesized from N,N-dimethylglycine. bafter 48 h of reaction with (COCl)2.

gas, 5 L min−1; and s-lens RF level, 55.0. Full scan MS were acquired in the alternating (+)/(−)-ESI mode and over the range m/z 80−1200 at 70000 resolution (full width half-maximum) and with an automatic gain control (AGC) target of 3.00 × 106. The maximum allowed ion transfer time (IT) was 30 ms; masses were calibrated below 2 ppm accuracy between m/z 130.0662 and 1621.9651 in positive and between 265.1479 and 1779.9653 in negative ESI mode using the Pierce ESI calibration solutions (ThermoFisher Scientific, Rockford, USA). Additionally, contamination of erucamide (m/z 338.3417, (+)-ESI) and palmitic acid (m/z 255.2330, (−)-ESI) were used as lock masses in (+)- and (−)-ESI, respectively. HRMS (ESI/Q-TOF) spectra were performed on a Bruker maXis QTOF high-resolution mass spectrometer (Bruker Daltonics, Bremen, Germany); the samples were dissolved in an appropriate solvent at a concentration of ∼1 μmol mL−1 and measured under continuous flow at 3 μL min−1. The mass spectrometer was operated in positive electrospray ionization mode at 4000 V capillary voltage and −500 V end plate offset with a N2 nebulizer pressure of 0.8 bar and dry gas flow of 4 L min−1 at 180 °C. MS acquisitions were performed in the mass range from m/z 50 to 2000 at 20000 resolution (full width at half-maximum) and 1.0 Hz spectra rate. Masses were calibrated between m/z 158 and 1450 or 2721 prior to analysis below 2 ppm accuracy with a 2 mM solution of sodium formate or with a Fluka electrospray calibration solution that has been diluted 100× with MeCN, respectively. HRMS (EI/doublefocusing magnetic sector) spectra were performed on a Thermo DFS (ThermoFisher Scientific, Bremen, Germany) double-focusing magnetic sector mass spectrometer (geometry BE); mass spectra were measured in electron impact (EI) mode at 70 eV with solid probe inlet, a source temperature of 200 °C, an acceleration voltage of 5 kV, and a resolution of 10000. The instrument was scanned between, e.g., m/z 300 and 350 at a scan rate of 100−200 s/decade in the electric scan mode; perfluorokerosene (PFK, Fluorochem, Derbyshire, UK) served for calibration. 4.2. 3-(4-Fluorophenyl)-2-(dimethylamino)propanoic Acid (7b). Na(CN)BH3 (1518 mg, 24.16 mmol) was added at 21 °C in small portions to a stirred suspension of 2-amino-3-(4-fluorophenyl)2738

DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743

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The Journal of Organic Chemistry

Mp (dec): ≥223 °C (upon evaporation of MeOH). IR: 1600. 1H NMR (CD3OD): 7.86−7.80 (m, 4 H), 7.52−7.42 (m, 3 H), 3.95 (t, X of ABX, J = 6.9, 1 H), 3.51−3.36 (symm. m, 8 distinctive lines, AB of ABX, 2 H), 2.87 (s, 6 H). 13C NMR (100 MHz, DMSO-d6 + 5 drops of DCl (37% in D2O)): 169.2 (s), 133.7, 133.4, 132.9 (3 s), 129.0, 128.7, 128.4, 128.3, 128.2, 127.3, 127.0 (7 d), 68.0 (d), 42.0 (q, 2 C), 34.0 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C15H18NO2+ 244.1332; found 244.1332. 4.10. (S)-2-Dimethylamino-3-(1-naphthyl)propanoic Acid (7j). Analogous to the preparation of 7b, (S)-2-amino-3-(1-naphthyl)propanoic acid (3-(1-naphthyl)-L-alanine, 1018 mg, 4.73 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1532 mg, 24.38 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 22 °C to deliver, after ion exchange chromatography, 7j (1082 mg, 4.45 mmol, 94%) as a colorless amorphous solid. Mp (dec): ≥211 °C (upon evaporation of MeOH). [α]D26 78.0 (c 1.00, MeOH). IR: 1615. 1H NMR (CD3OD): 8.19 (d, J = 8.4, 1 H), 7.88 (d-like m, “J” = 8.0, 1 H), 7.80 (d, J = 8.2, 1 H), 7.60−7.39 (m, 4 H), 3.99 (t, J = 7.4, 1 H), 3.70 (d, J = 7.4, 2 H), 2.87 (s, 6 H). 13C NMR (CD3OD): 172.2 (s), 135.7, 133.7, 133.2 (3 s), 130.2, 129.3, 129.1, 127.7, 127.0, 126.7, 124.6 (7 d), 72.7 (d), 42.2 (q, 2 C), 32.8 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C15H18NO2+ 244.1332; found 244.1332. 4.11. 2-(Dimethylamino)-3-(2-furyl)propanoic Acid (7k). Analogous to the preparation of 7b, 2-amino-3-(2-furyl)propanoic acid (3-(2-furyl)-DL-alanine, 737 mg, 4.75 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1569 mg, 24.97 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 22 °C to deliver, after ion exchange chromatography, 7k (837 mg, 4.57 mmol, 96%) as a slightly brownish amorphous solid. Mp (dec): ≥170 °C (upon evaporation of MeOH). IR: 1626. 1H NMR (CD3OD): 7.47 (dd-like m, “J” = 1.8, 0.7, 1 H), 6.37 (dd, J = 3.2, 1.9, 1 H), 6.31 (brd d-like m, “J” = 3.2, 1 H), 3.89 (dd, X of ABX, J = 6.9, 5.2, 1 H), 3.44, 3.33 (AB of ABX, JAB = 16.3, JAX = 6.9, JBX = 5.3, 2 × 1 H), 2.83 (s, 6 H). 13C NMR (CD3OD): 171.6 (s), 151.3 (s), 143.5, 111.9, 109.5 (3 d), 70.6 (d), 42.4 (q, 2 C), 27.6 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C9H14NO3+ 184.0968; found 184.0969. 4.12. 2-(Dimethylamino)-3-(3-furyl)propanoic Acid (7l). NaH (60% in mineral oil, 2.40 g, 60.0 mmol) was washed with hexane (3 × 10 mL) and suspended in Et2O (45 mL), and MeOH (244 μL, 6.0 mmol) was added. It was cooled to 0−5 °C, and furane-3carboxaldehyde (2.88 g, 30.0 mmol) followed by methyl 2-(N,Ndimethylamino)acetate (methyl N,N,-dimethylglycinate, 10.5 g, 90.0 mmol) were added dropwise. It was allowed to warm to 22 °C and stirred for 16 h. The mixture was cooled again to 0−5 °C; ice-H2O (45 mL) was added, and it was extracted with CH2Cl2 (4 × 45 mL) to afford, after drying over Na2SO4 and removal of the solvents in vacuo, crude methyl 2-(dimethylamino)-3-(3-furyl)propenoate (intermediate 1, 6.02 g) as a reddish-brown, oily liquid, which was used without further purification in the next step. A soln of intermediate 1 (979 mg, corresponding to 4.88 mmol of the original starting material) in dry THF (10 mL, containing some bromocresol green) was adjusted to a pH of ∼4 (yellow color) by the addition of an HCl soln (1.25 M in MeOH). A soln of Na(CN)BH3 (793 mg, 12.60 mmol) in MeOH (15 mL) was added slowly at 22 °C, upon which the color of the soln turned blue. HCl soln (1.25 M in MeOH) was added again until the color of the mixture changed to yellow, and it was stirred at 22 °C for 1 h. The solvents were removed in vacuo, and the residue was taken up into a sat. aq soln of KHCO3. It was extracted with Et2O (3 × 50 mL); the extracts were dried with Na2SO4, and the solvent was removed in vacuo. The residue was dissolved in an aq soln of HCl (1 M, 10 mL) and washed with AcOEt (3 × 10 mL). The aq phase was basified by the addition of an aq soln of NH3 (25%) and extracted with AcOEt (3 × 10 mL), and the extracts were dried with Na2SO4 to deliver, after evaporation of the solvent in vacuo, a crude amino ester (679 mg, intermediate 2). Intermediate 2 (593 mg, corresponding to 4.26 mmol of the original starting material) was dissolved in THF (3 mL); a soln of LiOH·H2O

H). 13C NMR (CD3OD): 172.4 (s), 160.5 (s), 131.5 (d, 2 C), 129.4 (s), 115.3 (d, 2 C), 73.4 (d), 55.8 (q), 42.5 (q, 2 C), 34.5 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C12H18NO3+ 224.1281; found 224.1282. 4.6. (S)-3-(4-Benzyloxyphenyl)-2-(dimethylamino)propanoic Acid (7f). Analogous to the preparation of 7b, (S)-2-amino-3-(4benzyloxyphenyl)propanoic acid (O-benzyl-L-tyrosine, 1232 mg, 4.54 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1555 mg, 24.75 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 22 °C to deliver, after ion exchange chromatography, 7f (1025 mg, 3.42 mmol, 75%) as a colorless amorphous solid. Mp (dec): ≥208 °C (after ion exchange chromatography upon evaporation of the solvents). [α]D26 17.9 (c 0.10, MeOH). IR: 3400, 1609. 1H NMR (CD3OD + 1 drop of DCl (37% in D2O)): 7.44−7.28 (m, 5 H), 7.26, 6.97 (2 d-like m, “J” = 8.7, AA′XX′, 2 × 2 H), 5.07 (s, 2 H), 4.30 (dd, X of ABX, J = 8.9, 5.5, 1 H), 3.38, 3.19 (AB of ABX, JAB = 14.2, JAX = 8.9, JBX = 5.5, 2 × 1 H), 3.02, 2.95 (2 br s, 2 × 3 H). 13C NMR (CD3OD + 5 drops of DCl (37% in D2O)): 170.0 (s), 159.5, 138.4 (2 s), 131.7, 129.6 (2 d, 2 × 2 C), 129.1 (d), 128.7 (d, 2 C), 127.6 (s), 116.4 (d, 2 C), 71.1 (t), 69.9 (d), 43.2, 42.4 (2 q), 34.1 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C18H22NO3+ 300.1594; found 300.1592. 4.7. (S)-3-(3,4-Dimethoxyphenyl)-2-(dimethylamino)propanoic Acid (7g). Analogous to the preparation of 7b, (S)-2amino-3-(3,4-dimethoxyphenyl)propanoic acid (m,p-dimethoxy-L-phenylalanine, 829 mg, 3.68 mmol) was reacted with formaldehyde (37% aq soln, 4.0 mL, 54 mmol) and Na(CN)BH3 (1350 mg, 21.48 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 22 °C to deliver, after ion exchange chromatography, a product (963 mg) that was redissolved in MeOH and dried over anhydrous MgSO4 to deliver, after evaporation of the solvent and drying of the residue in vacuo in a desiccator, 7g (885 mg, 3.49 mmol, 95%) as a colorless amorphous solid. Mp (dec): ≥184 °C (after ion exchange chromatography upon evaporation of the solvents). [α]D26 27.0 (c 0.50, MeOH). IR: 1611. 1 H NMR (TFA-d): 7.08−6.99 (m, 3 H), 4.59 (t, X of ABX, J = 7.4, 1 H), 3.98 (s, 6 H), 3.59, 3.46 (AB of ABX, JAB = 15.1, JAX = 8.0, JBX = 6.9, 2 × 1 H), 3.27, 3.18 (2 s, 2 × 3 H). 13C NMR (100 MHz, CD3OD): 172.3 (s), 150.9, 149.9, 130.4 (3 s), 122.9, 114.3, 113.4 (3 d), 73.3 (d), 56.64, 56.62 (2 q), 42.5 (q, 2 C), 34.9 (t). HRMS (ESI/ Orbitrap) m/z: [M + H]+ calcd for C13H20NO4+ 254.1387; found 254.1386. 4.8. 2-(Dimethylamino)-3-(4-nitrophenyl)propanoic Acid (7h). Analogous to the preparation of 7b, 2-amino-3-(4-nitrophenyl)propanoic acid (p-nitro-DL-phenylalanine, 946 mg, 4.50 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1544 mg, 24.57 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 22 °C to deliver, after ion exchange chromatography, 7h (1056 mg, 4.43 mmol, 98%) as a slightly orange amorphous solid. Mp (dec): ≥223 °C (after ion exchange chromatography upon evaporation of the solvents). IR: 1622, 1509, 1344. 1H NMR (CD3OD + 1 drop of DCl (37% in D2O)): 8.21, 7.64 (2 d-like m, “J” = 8.7, AA′XX′, 2 × 2 H), 4.48 (dd, X of ABX, J = 10.1, 4.8, 1 H), 3.63, 3.37 (AB of ABX, JAB = 13.8, JAX = 10.1, JBX = 4.8, 2 × 1 H), 3.06 (s, 6 H). 13 C NMR (TFA-d): 172.2 (s), 149.7, 143.4 (2 s), 132.4, 126.7 (2 d, 2 × 2 C), 70.6 (d), 44.9, 43.6 (2 q), 34.6 (t). HRMS (ESI/Orbitrap) m/ z: [M + H]+ calcd for C11H15N2O4+ 239.1026; found 239.1027. 4.9. 2-(Dimethylamino)-3-(2-naphthyl)propanoic Acid (7i). Analogous to the preparation of 7b, 2-amino-3-(2-naphthyl)propanoic acid (3-(2-naphthyl)-DL-alanine, 1023 mg, 4.75 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1547 mg, 24.62 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 22 °C to deliver, after ion exchange chromatography, a product (1110 mg). MeOH was added until no more of the solid was dissolved. After filtration of the suspension, the solvent of the filtrate was evaporated to deliver 7i (820 mg, 3.37 mmol, 71%) as a colorless amorphous solid. 2739

DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743

Article

The Journal of Organic Chemistry

1.90−1.73 (m, 2 H), 1.64−1.54 (m, 1 H), 1.01, 1.00 (2 d, J = 6.5, 2 × 3 H). 13C NMR (CD3OD): 173.3 (s), 71.3 (d), 41.9 (q, 2 C), 38.3 (t), 26.9 (d), 24.1, 22.0 (2 d). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C8H18NO2+ 160.1332; found 160.1333. 4.17. 3-Chloro-5-methoxy-1-methyl-4-phenyl-1,5-dihydro2H-pyrrol-2-one (8a). Method A: From (S)-2-(dimethylamino)-3phenylpropanoic acid (N,N-dimethyl-L-phenylalanine, 7a), (COCl)2 (0.14 mL, 1.63 mmol) was added dropwise to a suspension of 7a (100 mg, 0.52 mmol) in CH2Cl2 (2.0 mL). A vigorous evolution of gas was observed. The yellow soln was stirred for 24 h at 21 °C. Evaporation of the solvent delivered crude 3,5-dichloro-1-methyl-4-phenyl-1,5-dihydro-2H-pyrrol-2-one (11a′). The orange solid was cooled in an ice/ H2O bath and dissolved in MeOH (2.0 mL), and it was stirred for 2 h while the cooling was continued. Evaporation of the solvent delivered a crude product (133 mg) that was chromatographed (20 mL SiO2, hexane/AcOEt, gradient from 6:1 to 1:1) to afford 8a (116 mg, 0.49 mmol, 94%) as yellowish rhombic crystals. Method B: From N,N-dimethyl-2-phenylethenamine (10a), to a soln of 10a (102 mg, 0.69 mmol) in CH2Cl2 (2.0 mL) was added (COCl)2 (0.13 mL, 1.52 mmol) dropwise at 22 °C, and the mixture was stirred for 3.5 h. Evaporation of the solvent and the excess of (COCl)2 in vacuo delivered a residue that was cooled with an ice bath. MeOH (2.0 mL) was added and stirred for 10 min. Evaporation of the solvent delivered a crude material that was dissolved in a mixture of AcOEt (5 mL), H2O (5 mL), and brine (2 mL). The organic phase was separated, and the aqueous phase was extracted with AcOEt (4 × 5 mL). The combined organic phases were washed with brine (3 × 5 mL), dried with MgSO4, and chromatographed (hexane/AcOEt, 4:1) to deliver 8a (60 mg, 0.25 mmol, 36%) as yellowish rhombic crystals. Mp: 106.0−106.9 °C (AcOEt). IR: 1711. 1H NMR (CDCl3): 7.97− 7.90 (m, 2 H), 7.53−7.43 (m, 3 H), 5.76 (s, 1 H), 3.05 (s, 3 H), 2.95 (s, 3 H). 13C NMR (CDCl3): 164.7 (s), 143.0 (s), 130.3 (d), 129.5 (s), 128.8, 127.8 (2 d, 2 × 2 C), 125.6 (s), 87.8 (d), 48.8 (q), 27.0 (q). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C12H13ClNO2+ 238.0629; found 238.0629. (For single-crystal X-ray analysis, see Supporting Information). 4.18. 3-Chloro-4-(4-fluorophenyl)-5-methoxy-1-methyl-1,5dihydro-2H-pyrrol-2-one (8b). Analogous to the preparation of 8a (method A), (COCl)2 (0.14 mL, 1.63 mmol) was reacted with 7b (110 mg, 0.52 mmol) in CH2Cl2 (2.0 mL) for 24 h at 20 °C and for 2 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/AcOEt 3:1), 8b (116 mg, 0.45 mmol, 87%) as colorless rhombic crystals. Mp: 108.0−108.6 °C (AcOEt). IR: 1711. 1H NMR (CDCl3): 7.99 (dd-like m, “J” = 9.0, 5.3, 2 H), 7.19 (t-like m, “J” = 8.7, 2 H), 5.76 (s, 1 H), 3.06 (s, 3 H), 2.95 (s, 3 H). 13C NMR (CDCl3): 165.2 (s), 163.2 (sD, JCF = 217.6), 141.8 (s), 130.0 (dD, JCF = 8.6), 125.6 (sD, JCF = 3.9), 125.1 (sD, JCF = 1.9), 116.0 (dD, JCF = 21.8), 87.7 (d), 48.7 (q), 27.0 (q). 19F-NMR (282 MHz, CDCl3, δ relative to CFCl3 (0.0)): −108.7 (tt, J = 8.5, 5.4). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C12H12ClFNO2+ 256.0535; found 256.0534. 4.19. 4-(4-Bromophenyl)-3-chloro-5-methoxy-1-methyl-1,5dihydro-2H-pyrrol-2-one (8c). Analogous to the preparation of 8a (method A), (COCl)2 (0.14 mL, 1.63 mmol) was reacted with 7c (140 mg, 0.51 mmol) in CH2Cl2 (2.0 mL) for 24 h at 22 °C and for 1.5 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/ AcOEt, gradient from 7:1 to 3:1), 8c (153 mg, 0.48 mmol, 94%) as colorless rhombic crystals. Mp: 119.8−121.3 °C (AcOEt). IR: 1713. 1H NMR (CDCl3): 7.84, 7.62 (2 d-like m, AA′BB′, “J” = 8.8, 2 × 2 arom. H), 5.74 (s, CHOMe), 3.06 (s, NMe), 2.94 (s, OMe). 13C NMR (CDCl3): 164.5 (s, CON), 141.8 (s, ArylC), 132.1, 129.2 (2 d, 2 × 2 arom. C), 128.3 (s, arom. C), 126.2 (s, CCl), 124.9 (s, arom. CBr), 87.6 (d, CHOMe), 48.8 (q, OMe), 27.1 (q, NMe). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C12H12BrClNO2+ 315.9735; found 315.9735. 4.20. 3-Chloro-4-(4-hydroxyphenyl)-5-methoxy-1-methyl1,5-dihydro-2H-pyrrol-2-one (8d). Analogous to the preparation of 8a (method A), (COCl)2 (1.00 mL, 11.66 mmol) was reacted with 7d (100 mg, 0.48 mmol) in CH2Cl2 (5.0 mL) for 24 h at 23 °C and for

(139 mg, 3.31 mmol) in H2O (15 mL) was added slowly at 22 °C and stirred for 3 h. The mixture was washed with CH2Cl2 (3 × 15 mL) and with MeCN (3 × 5 mL) before the aq soln was concentrated in vacuo to deliver the Li salt of 7l, which upon ion exchange column chromatography on DOWEX 50WX8 (H+ form, 50−100 mesh, 15 mL), evaporation of the solvents and drying under high vacuum afforded 7l (540 mg, 2.95 mmol, 69% over three steps) as a slightly yellowish amorphous solid. Mp (dec): ≥186 °C (after ion exchange chromatography upon evaporation of the solvents). IR: 1615. 1H NMR (CD3OD): 7.51 (brd s-like m, 1 H), 7.46 (t-like m, ″J″ = 1.7, 1 H), 6.48 (d-like m, ″J″ = 0.9, 1 H), 3.73 (t, J = 5.9, 1 H), 3.14 (d, J = 5.9, 2 H), 2.86 (s, 6 H). 13C NMR (CD3OD): 172.2 (s), 144.7, 142.3 (2 d), 120.5 (s), 112.5 (d), 71.8 (d), 42.6 (q, 2 C), 25.0 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C9H14NO3+ 184.0968; found 184.0970. 4.13. 2-(Dimethylamino)-3-(2-thienyl)propanoic Acid (7m). Analogous to the preparation of 7b, 2-amino-3-(2-thienyl)propanoic acid (3-(2-thienyl)-DL-alanine, 773 mg, 4.51 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1508 mg, 24.00 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 21 °C to deliver, after ion exchange chromatography, 7m (839 mg, 4.21 mmol, 93%) as a yellowish amorphous solid. Mp (dec): ≥202 °C (upon evaporation of MeOH). IR: 1606. 1H NMR (CD3OD): 7.30 (dd, J = 5.1, 1.3, 1 H), 7.06 (dd, J = 3.4, 0.9, 1 H), 6.96 (dd, J = 5.1, 3.5, 1 H), 3.83 (t, X of ABX, J = 6.4, 1 H), 3.61− 3.46 (symm. m, 7 distinctive lines, AB of ABX, 2 H), 2.86 (s, 6 H). 13C NMR (CD3OD): 171.6 (s), 139.3 (s), 128.4, 128.3, 126.2 (3 d), 72.8 (d), 42.5 (q, 2 C), 29.4 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C9H14NO2S+ 200.0740; found 200.0739. 4.14. (S)-2-(Dimethylamino)-3-(3-thienyl)propanoic Acid (7n). Analogous to the preparation of 7b, (S)-2-amino-3-(3-thienyl)propanoic acid (3-(3-thienyl)-L-alanine, 813 mg, 4.75 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1548 mg, 24.63 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 22 °C to deliver, after ion exchange chromatography, 7n (909 mg, 4.56 mmol, 96%) as a slightly orange amorphous solid. Mp (dec): ≥189 °C (upon evaporation of MeOH). [α]D26 9.6 (c 1.00, MeOH). IR: 1623. 1H NMR (CD3OD): 7.40 (dd, J = 4.9, 2.9, 1 H), 7.33 (brd s-like m, 1 H), 7.13 (dd, J = 4.9, 1.2, 1 H), 3.84 (t, X of ABX, J = 6.3, 1 H), 3.41−3.27 (symm. m, 7 distinctive lines, AB of ABX, 2 H), 2.83 (s, 6 H). 13C NMR (CD3OD): 172.3 (s), 137.6 (s), 129.6, 127.4, 124.3 (3 d), 72.3 (d), 42.5 (q, 2 C), 29.8 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C9H14NO2S+ 200.0740; found 200.0742. 4.15. (S)-2-(Dimethylamino)-3-(1H-4-imidazolyl)propanoic Acid (7o). Analogous to the preparation of 7b, (S)-2-amino-3-(1H4-imidazolyl)propanoic acid (L-histidine, 698 mg, 4.50 mmol) was reacted with formaldehyde (37% aq soln, 8.0 mL, 107 mmol) and Na(CN)BH3 (2005 mg, 31.91 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 21 °C to deliver, after ion exchange chromatography and drying in vacuo in a desiccator, 7o (709 mg, 3.87 mmol, 86%) as a colorless, amorphous, and hygroscopic solid. Mp (dec): ≥176 °C (upon evaporation of MeOH). [α]D26 10.7 (c 1.00, MeOH). IR: 3589−2119, 1618. 1H NMR (CD3OD): 7.69 (d-like m, J = 1.1, 1 H), 7.04 (brd. d-like m, J = 0.9, 1 H), 3.84 (t, X of ABX, J = 6.1, 1 H), 3.36−3.20 (m, AB of ABX, 2 H), 2.87 (s, 6 H). 13C NMR (CD3OD): 172.1 (s), 136.5 (d), 134.5 (s), 117.7 (d), 71.6 (d), 42.4 (q, 2 C), 27.1 (t). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C8H14N3O2+ 184.1081; found 184.1083. 4.16. (S)-2-(Dimethylamino)-4-methylpentanoic Acid (7p). Analogous to the preparation of 7b, (S)-2-amino-4-methylpentanoic acid (L-leucine, 593 mg, 4.52 mmol) was reacted with formaldehyde (37% aq soln, 5.0 mL, 67 mmol) and Na(CN)BH3 (1516 mg, 24.12 mmol) in H2O (100 mL) and MeCN (100 mL) for 1 h at 22 °C to deliver, after ion exchange chromatography, a solid (746 mg) that was recrystallized from MeOH and dried in a desiccator to afford 7p (720 mg, 4.52 mmol, 100%) as colorless cubic crystals. Mp: 203.9−204.5 °C (MeOH). [α]D26 35.1 (c 1.00, MeOH). IR: 1601. 1H NMR (CD3OD): 3.48 (dd, J = 10.0, 4.4, 1 H), 2.86 (s, 6 H), 2740

DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743

Article

The Journal of Organic Chemistry

HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C12H12ClN2O4+ 283.0480; found 283.0479. 4.25. 3-Chloro-5-methoxy-1-methyl-4-(2-naphthyl)-1,5-dihydro-2H-pyrrol-2-one (8i). Analogous to the preparation of 8a (method A), (COCl)2 (0.14 mL, 1.63 mmol) was reacted with 7i (126 mg, 0.52 mmol) in CH2Cl2 (2.0 mL) for 24 h at 21 °C and for 2.5 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/ AcOEt 3:1), 8i (115 mg, 0.40 mmol, 77%) as slightly orange rhombic crystals. Mp: 108.7−109.8 °C (AcOEt). IR: 1712. 1H NMR (600 MHz, CDCl3): 8.42 (brd d-like m, ″J″ = 1.1, arom. H), 8.06 (dd, J = 8.7, 1.8, arom. H), 7.92 (d-like m, ″J″ = 8.2, 2 arom. H), 7.87 (d-like m, ″J″ = 8.5, arom. H), 7.59−7.53 (symm. m, 11 distinctive lines, 2 arom. H), 5.88 (s, CHOMe), 3.09 (s, NMe), 2.96 (s, OMe). 13C NMR (150 MHz, CDCl3): 164.9 (s, CON), 143.0 (s, ArylC), 133.8, 132.9 (2 s, 2 arom. C), 128.9, 128.5, 128.4, 127.72, 127.68 (5 d, 5 arom. C), 126.9 (s, arom. C), 126.8 (d, arom. C), 125.8 (s, CCl), 124.3 (d, arom. C), 87.9 (d, CHOMe), 48.8 (q, OMe), 27.1 (q, NMe). HRMS (ESI/ Orbitrap) m/z: [M + H]+ calcd for C16H15ClNO2+ 288.0786; found 288.0786. 4.26. 3-Chloro-5-methoxy-1-methyl-4-(1-naphthyl)-1,5-dihydro-2H-pyrrol-2-one (8j). Analogous to the preparation of 8a (method A), (COCl)2 (0.14 mL, 1.63 mmol) was reacted with 7j (125 mg, 0.51 mmol) in CH2Cl2 (2.0 mL) for 24 h at 22 °C and for 2 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/ AcOEt, gradient from 5:1 to 1:1), 8j (134 mg, 0.47 mmol, 92%) as colorless rhombic crystals. Mp: 137.3−138.2 °C (AcOEt). IR: 1714. 1H NMR (CDCl3): 7.97− 7.91 (m, 2 arom. H), 7.79−7.74 (m, arom. H), 7.59−7.53 (m, 3 arom. H), 7.45 (dd, J = 7.1, 1.1, arom. H), 5.77 (s, CHOMe), 3.11 (s, NMe), 3.05 (s, OMe). 13C NMR (150 MHz, CDCl3): 164.4 (s, CON), 146.5 (s, ArylC), 133.8 (s, arom. C), 130.4 (d, arom. C), 129.64 (s, arom. C), 129.56 (s, CCl), 129.0 (d, arom. C), 127.5 (s, arom. C), 126.9, 126.7, 126.4, 125.2, 125.1 (5 d, 5 arom. C), 89.7 (d, CHOMe), 50.9 (q, OMe), 27.4 (q, NMe). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C16H15ClNO2+ 288.0786; found 288.0784. 4.27. 3-Chloro-4-(2-furyl)-5-methoxy-1-methyl-1,5-dihydro2H-pyrrol-2-one (8k). Analogous to the preparation of 8a (method A), (COCl)2 (0.15 mL, 1.75 mmol) was reacted with 7k (95 mg, 0.52 mmol) in CH2Cl2 (2.0 mL) for 24 h at 21 °C and for 2 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/AcOEt 3:1), 8k (30 mg, 0.45 mmol, 25%) as a colorless amorphous solid. Mp: 106.8−107.8 °C (after chromatography upon evaporation of the solvents). IR: 1713. 1H NMR (600 MHz, CDCl3): 7.64 (dd, J = 1.8, 0.7, arom. H), 7.14 (dd, J = 3.5, 0.7, arom. H), 6.60 (dd, J = 3.6, 1.9, arom. H), 5.67 (s, CHOMe), 3.04 (s, OMe), 3.03 (s, NMe). 13C NMR (150 MHz, CDCl3): 164.8 (s, CON), 145.7 (s, ArylC), 145.0 (d, arom. C), 134.3 (s, arom. C), 121.8 (s, CCl), 114.6, 112.3 (2 d, 2 arom. C), 86.9 (d, CHOMe), 49.4 (q, OMe), 27.0 (q, NMe). HRMS (ESI/ Orbitrap) m/z: [M + H]+ calcd for C10H11ClNO3+ 228.0422; found 228.0422. 4.28. 3-Chloro-4-(3-furyl)-5-methoxy-1-methyl-1,5-dihydro2H-pyrrol-2-one (8l). Analogous to the preparation of 8a (method A), (COCl)2 (0.14 mL, 1.63 mmol) was reacted with 7l (96 mg, 0.52 mmol) in CH2Cl2 (2.0 mL) for 24 h at 21 °C and for 2 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/AcOEt 3:1), 8l (38 mg, 0.17 mmol, 33%) as a slightly orange amorphous solid. Mp: 76.5−78.8 °C (after chromatography upon evaporation of the solvents). IR: 1715. 1H NMR (CDCl3): 8.14 (s, 1 H), 7.54 (s-like m, 1 H), 7.04 (s-like m, 1 H), 5.53 (s, 1 H), 3.02, 3.00 (2 s, 2 × 3 H). 13C NMR (CDCl3): 164.9 (s), 143.8, 143.7 (2 d), 137.3 (s), 123.5 (s), 116.3 (s), 108.3 (d), 87.6 (d), 48.8 (q), 26.9 (q). HRMS (ESI/ Orbitrap) m/z: [M + H]+ calcd for C10H11ClNO3+ 228.0422; found 228.0423. 4.29. 3-Chloro-5-methoxy-1-methyl-4-(2-thienyl)-1,5-dihydro-2H-pyrrol-2-one (8m). Analogous to the preparation of 8a (method A), (COCl)2 (0.15 mL, 1.75 mmol) was reacted with 7m (104 mg, 0.52 mmol) in CH2Cl2 (2.0 mL) for 24 h at 21 °C and for 2 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2,

20 h with MeOH (2.0 mL) to deliver, after chromatography, 8d (80 mg, 0.38 mmol, 79%) as a yellowish amorphous solid. Mp (dec): ≥156 °C (MeOH). IR: 3230, 1690. 1H NMR (500 MHz, CD3CN): 7.82, 6.94 (2 d-like m, AA′XX′, “J” = 8.8, 2 × 2 H), 5.79 (s, 1 H), 2.94, 2.89 (2 s, 2 × 3 H). 13C NMR (125 MHz, CD3CN): 165.8 (s), 159.9 (s), 144.8 (s), 131.0 (d, 2 C), 123.3, 122.6 (2 s), 116.6 (d, 2 C), 88.9 (d), 49.4 (q), 27.4 (q). HRMS (ESI/QTOF) m/z: [M + Na]+ calcd for C12H12ClNO3Na+ 276.0398; found 276.0403. 4.21. 3-Chloro-5-methoxy-4-(4-methoxyphenyl)-1-methyl1,5-dihydro-2H-pyrrol-2-one (8e). Analogous to the preparation of 8a (method A), (COCl)2 (0.14 mL, 1.63 mmol) was reacted with 7e (115 mg, 0.52 mmol) in CH2Cl2 (2.0 mL) for 24 h at 22 °C and for 2 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/AcOEt, gradient from 9:1 to 1:1), 8e (121 mg, 0.45 mmol, 87%) as colorless rhombic crystals. Mp: 86.7−88.1 °C (AcOEt). IR: 1710. 1H NMR (CDCl3): 7.96, 7.00 (2 d-like m, AA′XX′, “J” = 9.0, 2 × 2 H), 5.73 (s, 1 H), 3.87 (s, 3 H), 3.05 (s, 3 H), 2.93 (s, 3 H). 13C NMR (CDCl3): 165.1 (s), 161.0 (s), 142.4 (s), 129.5 (d, 2 C), 122.9, 122.0 (2 s), 114.1 (d, 2 C), 87.6 (d), 55.3 (q), 48.5 (q), 26.9 (q). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C13H15ClNO3+ 268.0735; found 268.0735. 4.22. 4-(4-Benzyloxyphenyl)-3-chloro-5-methoxy-1-methyl1,5-dihydro-2H-pyrrol-2-one (8f). Analogous to the preparation of 8a (method A), (COCl)2 (0.14 mL, 1.63 mmol) was reacted with 7f (156 mg, 0.52 mmol) in CH2Cl2 (2.0 mL) for 24 h at 22 °C and for 2 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/AcOEt, gradient from 9:1 to 1:1), 8f (134 mg, 0.39 mmol, 75%) as yellowish rhombic crystals. Mp: 106.2−107.2 °C (CDCl3). IR: 1710. 1H NMR (CDCl3): 7.96 (d-like m, AA′ of AA′XX′, “J” = 9.1, 2 H), 7.47−7.35 (m, 5 H), 7.06 (d-like m, XX′ of AA′XX′, “J” = 9.1, 2 H), 5.72 (s, 1 H), 5.13 (s, 2 H), 3.04 (s, 3 H), 2.93 (s, 3 H). 13C NMR (CDCl3): 165.2 (s), 160.2 (s), 142.4 (s), 136.2 (s), 129.6, 128.7 (2 d, 2 × 2 C), 128.2 (d), 127.5 (d), 123.2, 122.3 (2 s), 115.0 (d, 2 C), 87.8 (d), 70.0 (t), 48.6 (q), 27.0 (q). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C19H19ClNO3+ 344.1048; found 344.1054. 4.23. 3-Chloro-4-(3,4-dimethoxyphenyl)-5-methoxy-1-methyl-1,5-dihydro-2H-pyrrol-2-one (8g). Analogous to the preparation of 8a (method A), (COCl)2 (0.14 mL, 1.63 mmol) was reacted with 7g (129 mg, 0.51 mmol) in CH2Cl2 (2.0 mL) for 24 h at 21 °C and for 2.5 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/AcOEt, gradient from 7:1 to 1:1), 8g (106 mg, 0.36 mmol, 71%) as an orange amorphous solid. Mp: 107.2−107.9 °C (after chromatography upon evaporation of the solvents). IR: 1711. 1H NMR (CDCl3): 7.63 (d, J = 2.1, 1 H), 7.58 (dd, J = 8.5, 2.1, 1 H), 6.96 (d, J = 8.6, 1 H), 5.75 (s, 1 H), 3.954, 3.947 (2 s, 2 × 3 H), 3.05 (s, 3 H), 2.96 (s, 3 H). 13C NMR (CDCl3): 165.0 (s), 150.7, 148.7 (2 s), 142.4 (s), 123.1, 122.2 (2 s), 121.6, 110.8, 110.3 (3 d), 87.7 (d), 55.8 (q, 2 C), 48.6 (q), 26.9 (q). HRMS (ESI/ Orbitrap) m/z: [M + H]+ calcd for C14H17ClNO4+ 298.0841; found 298.0840. 4.24. 3-Chloro-5-methoxy-1-methyl-4-(4-nitrophenyl)-1,5dihydro-2H-pyrrol-2-one (8h). Analogous to the preparation of 8a (method A), (COCl)2 (0.18 mL, 2.10 mmol) was reacted with 7h (123 mg, 0.52 mmol) in CH2Cl2 (3.0 mL) for 48 h at 21 °C and for 2.5 h with MeOH (3.0 mL). Evaporation of the solvent delivered a crude product that was dissolved in a mixture of H2O (50 mL), AcOEt (30 mL), and a sat. aq soln of Na2CO3 (20 mL). The aqueous layer was extracted with AcOEt (2 × 15 mL) and the combined organic layers were washed with H2O/brine (3:2, 50 mL), brine (50 mL), and H2O (50 mL). After evaporation of the solvent, the residue was chromatographed (SiO2, hexane/AcOEt 2:1) to afford 8h (119 mg, 0.42 mmol, 81%) as yellowish cubic crystals. Mp: 177.7−179.1 °C (after chromatography upon evaporation of the solvents). IR: 1719, 1518, 1346. 1H NMR (CDCl3): 8.34, 8.15 (2 d-like m, AA′BB′, “J” = 9.1, 2 × 2 H), 5.84 (s, 1 H), 3.09 (s, 3 H), 2.98 (s, 3 H). 13C NMR (CDCl3): 163.8 (s), 148.1 (s), 140.7 (s), 135.4 (s), 129.4 (s), 128.7, 123.9 (2 d, 2 × 2 C), 87.7 (d), 49.0 (q), 27.1 (q). 2741

DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743

Article

The Journal of Organic Chemistry

IR: 1711. 1H NMR (CDCl3): 7.81−7.75 (m, 2 H), 7.55−7.48 (m, 3 H), 6.31 (s, 1 H), 3.18 (s, 3 H). 13C NMR (CDCl3): 164.4 (s), 146.1 (s), 130.6 (d), 128.8 (d, 2 C), 128.7 (s), 128.0 (d, 2 C), 125.2 (s), 73.2 (d), 27.7 (q). HRMS (EI/double-focusing magnetic sector) m/z: M +• calcd for C11H9Cl2NO+• 241.0056; found 241.0052.

hexane/AcOEt 7:1), 8m (67 mg, 0.27 mmol, 52%) as brownish rhombic crystals. Mp: 131.2−132.2 °C (upon evaporation of CDCl3 added to the solid obtained after chromatography). IR: 1708. 1H NMR (CDCl3): 7.79 (dd, J = 3.8, 1.0, 1 H), 7.62 (dd, J = 5.1, 1.0, 1 H), 7.19 (dd, J = 5.0, 3.9, 1 H), 5.68 (s, 1 H), 3.05, 3.01 (2 s, 2 × 3 H). 13C NMR (CDCl3): 164.8 (s), 138.3 (s), 131.9 (s), 130.2, 129.6, 127.6 (3 d), 122.3 (s), 87.9 (d), 48.8 (q), 27.0 (q). HRMS (ESI/Orbitrap) m/z: [M + H]+ calcd for C10H11ClNO2S+ 244.0194; found 244.0194. (For single-crystal X-ray analysis, see Supporting Information). 4.30. 3-Chloro-5-methoxy-1-methyl-4-(3-thienyl)-1,5-dihydro-2H-pyrrol-2-one (8n). Analogous to the preparation of 8a (method A), (COCl)2 (0.14 mL, 1.63 mmol) was reacted with 7n (104 mg, 0.52 mmol) in CH2Cl2 (2.0 mL) for 24 h at 22 °C and for 2 h with MeOH (2.0 mL) to deliver, after chromatography (SiO2, hexane/AcOEt, gradient from 5:1 to 1:1), 8n (94 mg, 0.39 mmol, 75%) as brownish rhombic crystals. Mp: 120.0−120.3 °C (upon evaporation of CDCl3 added to the solid obtained after chromatography). IR: 1707. 1H NMR (CDCl3): 8.13 (dd, J = 3.0, 1.3, arom. H), 7.80 (dd, J = 5.2, 1.3, arom. H), 7.45 (dd, J = 5.1, 3.0, arom. H), 5.65 (s, CHOMe), 3.04 (s, NMe), 2.98 (s, OMe). 13C NMR (CDCl3): 165.0 (s, CON), 138.7 (s, ArylC), 130.7 (s, arom. C), 127.7, 126.3, 126.2 (3 d, 3 × arom. C), 123.2 (s, CCl), 87.9 (d, CHOMe), 48.7 (q, OMe), 26.9 (q, NMe). HRMS (ESI/ Orbitrap) m/z: [M + H]+ calcd for C10H11ClNO2S+ 244.0194; found 244.0195. 4.31. 3-Chloro-4-isopropyl-5-methoxy-1-methyl-1,5-dihydro-2H-pyrrol-2-one (8p). Analogous to the preparation of 8a (method A), (COCl)2 (0.67 mL, 7.81 mmol) was reacted with 7p (397 mg, 2.49 mmol) in CH2Cl2 (10 mL) for 24 h at 21 °C and for 2 h with MeOH (10 mL) to deliver, after column chromatography (SiO2, hexane/AcOEt, 4:1) followed by preparative TLC (Merck TLC plates silica gel 60 F254, hexane/AcOEt 4:1), 8p (8 mg, 0.04 mmol, 2%) as a colorless oil. IR: 1725. 1H NMR (400 MHz, CDCl3): 5.22 (s, 1 H), 3.05 (s, 3 H), 2.98−2.87 (symm. m, 1 H), 2.95 (s, 3 H), 1.29, 1.24 (2 d, J = 7.1, 2 × 3 H). 13C NMR (125 MHz, CDCl3): 165.0 (s), 153.2 (s), 126.1 (s), 87.7 (d), 49.7 (q), 27.2 (d), 26.9 (q), 19.84, 19.80 (2 q). HRMS (ESI/ Orbitrap) m/z: [M + H]+ calcd for C9H15ClNO2+ 204.0786; found 204.0789. 4.32. 5-Benzyl-4-methylmorpholine-2,3,6-trione (9a′). (COCl)2 (3.0 mL, 35.0 mmol) was added dropwise to a suspension of N-methyl-L-phenylalanine (12a, 295 mg, 1.65 mmol) in CH2Cl2 (6.0 mL). The mixture was stirred for 21 h at 25 °C. Evaporation of the solvent delivered crude 9a′ (424 mg) as a brown amorphous solid. The sample was characterized without further purification because it decomposed gradually upon storage and purification. 1 H NMR (CD3CN): 7.33−7.31 (m, 3 H), 7.10−7.05 (m, 2 H), 4.89−4.86 (m, X of ABX, 1 H), 3.40−3.22 (m, AB of ABX, 2 H), 3.13 (s, 3 H). 13C NMR (CD3CN): 163.7, 151.7, 151.3 (3 s), 133.9 (s), 130.9, 130.1 (2 d, 2 × 2 C), 129.3 (d), 64.0 (d), 38.7 (t), 33.5 (q). 4.33. (E)-N,N-Dimethyl-2-phenylethenamine (10a). Phenylacetaldehyde (3.2 mL, 27.4 mmol) was added to Me2NH·HCl (2.06 g, 25.3 mmol). It was stirred at 22 °C for 3 min; Et2O (5 mL) was added, and it was stirred for an additional 4 min. Et3N (3.8 mL, 27.4 mmol) was added dropwise over a period of 40 min, and it was stirred at 22 °C for an additional 1 h. The mixture was filtered, and the filtrate was dried with MgSO4. Evaporation of the solvent delivered virtually pure 10a (3.63 g, 24.7 mmol, 98%) as an orange-yellowish oil. IR: 1636, 1595. 1H NMR (CDCl3): 7.26−7.14 (m, 4 H), 6.99−6.93 (m, 1 H), 6.74 (d, J = 13.9, 1 H), 5.16 (d, J = 13.9, 1 H), 2.78 (s, 6 H). 13 C NMR (CDCl3): 140.1 (d), 139.7 (s), 128.5, 123.6 (2 d, 2 × 2 C), 123.3 (d), 98.3 (d), 40.7 (q, 2 C). HRMS (ESI/Q-TOF) m/z: [M + H]+ calcd for C10H14N+ 148.1121; found 148.1122. 4.34. 3,5-Dichloro-1-methyl-4-phenyl-1,5-dihydro-2H-pyrrol-2-one (11a′). (COCl)2 (0.14 mL, 1.63 mmol) was added dropwise to a suspension of 7a (100 mg, 0.52 mmol) in CH2Cl2 (2.0 mL). A vigorous evolution of gas was observed. The yellow soln was stirred for 24 h at 21 °C. Evaporation of the solvent delivered virtually pure 11a′ (127 mg, 0.52 mmol, 100%) as a yellowish amorphous solid.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b03187. 1 H and 13C NMR spectra for all compounds, HSQC and HMBC spectra for 7c, 8c, 8i, 8j, 8k, and 8n, NOESY and COSY spectra for 8k, and single-crystal X-ray data for 8a and 8m (PDF) Crystallographic data for compounds 8a and 8m (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Stefan Bienz: 0000-0002-5262-6756 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank C. Schnider and L. Topf for their contribution with some preliminary investigations and the members of our analytical laboratories for their support in the acquisition of the analytical data, in particular Prof. Dr. A. Linden for the determination of the X-ray structures of 8a and 8m, the respective data processing, and the preparation of the X-ray data for publication.

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REFERENCES

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DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743

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DOI: 10.1021/acs.joc.7b03187 J. Org. Chem. 2018, 83, 2734−2743