I2-Mediated Synthesis of N,N′,N″-Substituted Guanidines and

Science and Technology, and ∥Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thai...
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Ph3P/I2‑Mediated Synthesis of N,N′,N″‑Substituted Guanidines and 2‑Iminoimidazolin-4-ones from Aryl Isothiocyanates Sirilak Wangngae,†,‡ Mookda Pattarawarapan,*,†,§,∥ and Wong Phakhodee*,†,§,∥ †

Department of Chemistry, Faculty of Science, ‡Graduate School, §Center of Excellence in Materials Science and Technology, and Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand

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S Supporting Information *

ABSTRACT: A convenient one-pot procedure for the synthesis of acyclic and cyclic guanidines mediated by the Ph3P/I2 system is described. Sequential condensation of aryl isothiocyanates with amines followed by dehydrosulfurization and guanylation could lead to both symmetric and unsymmetric N,N′,N″-substituted derivatives. Through a tandem guanylation−cyclization, a series of 2-iminoimidazolin-4-ones could also be prepared in good yields from the reaction of aryl isothiocyanates with amino acid methyl esters.

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INTRODUCTION In recent years, considerable attention has been paid toward the synthesis of guanidines due to their diverse applications in medicinal chemistry, anion recognition, and coordination chemistry.1 While N,N′-dialkyl guanidines have been applied as superbases as well as organoligands,2 several N-arylsubstituted derivatives have been reported for their interesting biological and pharmacological activities which are potentially useful in drug discovery.3 For example, N,N′-diaryl-substituted guanidine I is a potent human A3 adenosine receptor antagonist,4 phenylguanidines such as II are potent and selective antagonists at the human melanocortin-5 receptor,5 3,5-disubstituted phenylcyanoguanidine III is a potent activator of Kir6.2/SUR1KATP channels as well as an inhibitor of insulin release from beta cells which could have beneficial effects in patients suffering from type 1 or type 2 diabetes,6 IV inhibits the thromboxane A2 synthase in human gel-filtered platelets,7 trisubstituted guanadinoacetic acid such as V is a well-known superpotent sweetner,8 and cyclic guanidines such as leucettine (VI) are a potent inhibitor of cdc2-like kinases which are involved in the development of Alzheimer’s disease and Down syndrome9 (Figure 1). Among the existing methods for the preparation of substituted guanidines including catalytic and noncatalytic approaches,3a,10 guanylation of amines with electrophilic reagents, especially carbodiimides, is still by far the most © 2017 American Chemical Society

frequently used reaction due to the cost-effective and readily accessible thiourea reactants. Although a number of desulfurization agents have been reported for in situ generation of carbodiimides from thioureas including mercury(II) chloride,11 copper(II) sulfate−silica gel,12 copper(II) chloride,13 cyanuric chloride,14 ethyl-3-aminopropyl carbodiimide hydrochloride (EDCI),15 and the Mukaiyama reagent,16 these systems still suffer from various limitations such as the use of toxic metals, expensive reagents, limited substrate scope, and long times. Moreover, the starting thioureas are often prepared in a separate step. Organic reactions mediated by phosphines play important roles in various functional group transformations.17 Due to strong oxophilicity of the phosphine intermediates, oxygencontaining functional groups such as alcohols, carbonyl compounds, carboxylic acids, and their derivatives as well as ureas can be readily activated through the release of thermodynamically favorable phosphine oxide as a key driving force. Although a similar mode of activation is also possible with sulfur-containing compounds, there are only a few studies that investigate the use of phosphine-type reagents in the desulfurization process. For example, in the early report by Received: July 19, 2017 Published: September 12, 2017 10331

DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340

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The Journal of Organic Chemistry

Figure 1. Representative examples of bioactive guanidines.

Table 1. Optimization of the Reaction Conditionsa

Appel,18 carbodiimides were prepared by removal of the sulfur atom of thioureas using Ph3P/CCl4/triethylamine. The same reagent combination was applied for removal of sulfur from macrocyclic alkyl-substituted thioureas under refluxing in dichloromethane.19 Conversion of N,N′-disubstituted thioureas into carbodiimides has been reported using triphenylphosphine (Ph3P) with additives such as carbon tetrabromide,20 diethyl azodicarboxylate,21 and bromine.22 In a continuation of our study involving the Ph3P/I2mediated reactions,23 we are interested in using the Ph3P/I2 system to replace the traditional promoters for the guanylation of thiourea derivatives. To eliminate an extra synthetic and purification step, herein, we wish to report our study in a onepot synthesis of substituted guanidines starting directly from an aryl isothiocyanate as a thiourea precursor. The protocol was further extended toward the preparation of 2-iminoimidazolin4-ones through a tandem guanylation−cyclization of aryl isothiocyanates and amino acid methyl esters. The mechanism for the Ph3P/I2-mediated guanylation was also proposed based on the 31P{1H} NMR and control experiments.

entry

base

solvent

% yield

1 2 3 4 5 6 7 8

K2CO3 pyridine imidazole i Pr2NEt Et3N Et3N Et3N

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 toluene THF

0 0 0 0 71 90 55 78

a

Reaction conditions: 4-nitrophenyl isothiocyanate (0.28 mmol), benzylamine (0.56 mmol), Ph3P (0.33 mmol), I2 (0.33 mmol), and base (1.4 mmol), solvent 2 mL, 0 °C-RT for 15 min.

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isothiocyanates with different amine nucleophiles (Scheme 1). Electron-deficient isothiocyanates reacted readily with primary aliphatic amines to afford guanidines 2a−c in high yields within 15−20 min. Sterically hindered isoproylamine also gave good yields of the products 2d−f though with extended reaction times (up to 75 min). Despite the difference in the pKa values of secondary amines and aromatic amines, the guanylation toward the products 2g−i proceeded effectively, possibly due to the high reactivity of the formed intermediates. In the reaction with cyclohexylamine, the electron-rich p-tolyl isothiocyanate gave lower conversion when comparing with the substrates containing an electron-withdrawing group (see compounds 2j− l). As expected, electron-donating groups when attaching to the aromatic ring of aryl isothiocyanates make the π system of the intermediate less electrophilic toward the reaction with amines. Notably, comparing with the metal-catalyzed guanylation of amines with 1,3-dialkylcarbodiimides,25 our method enables the preparation of N,N′-dialkylsubstituted guanidines under much milder conditions using less time and low-cost reagents. Unsymmetrical N,N′,N″-substituted guanidines could also be prepared in one pot starting from aryl isocyanates without the necessity to isolate the formed thioureas. According to Scheme 2, the synthesis of guanidines 3 was carried out through a onepot three-component coupling of an aryl isothiocyanate with two different amines. Typically, after the formation of

RESULTS AND DISCUSSION In the optimization study of the reaction using 4-nitrophenyl isothiocyanate (1a) and benzylamine as the model substrates (Table 1), the combination of Ph3P and iodine (I2) in dichloromethane without base gave no conversion with the remaining thiourea (entry 1). A similar result was also observed when the guanylation was performed using weak organic and inorganic bases (entries 2−4). Changing the base to diisopropylethylamine led to better conversion to guanidine 2a (entry 5), whereas using triethylamine led to the formation of the product in high yield (entry 6). Nevertheless, replacing the reaction media from dichloromethane to other solvents, including toluene and THF, significantly decreased the product yield (entries 7 and 8), suggesting an instability of the phosphine intermediates as well as a solubility problem of the reactants or intermediates in such solvents. In polar media, charge separation to form a highly reactive phosphonium iodide ion pair is favorable.24 This intermediate is less stable than the pentavalent phosphorane species and more susceptible to decomposition into phosphine oxide through the reaction with moisture. With the optimized conditions established, we first explored the scope of the substrates by treating various aryl 10332

DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340

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The Journal of Organic Chemistry Scheme 1. One-Pot Synthesis of Symmetrical Substituted Guanidines 2

Scheme 2. One-Pot Synthesis of Unsymmetrical Substituted Guanidines 3

substituted thiourea using a 1:1 mol ratio of the first amine and an aryl isothiocyanate, the reaction mixture was treated with Ph3P and I2 before adding another amine. A series of unsymmetrical guanidines 3 was obtained in high yields starting from an electron-deficient 4-nitrophenyl isothiocyanate. The reaction also proceeded well with sterically hindered diisopropylamine (see compound 3e). Nevertheless, using electron-rich isothiocyanates led to lower yields of the guanidines 3h−l as some of the corresponding carbodiimides still remained.

It should be noted that when the reactivity of the two amines is similar, the order of reagent addition sequence has no significant effect on the yields of products. For example, guanidine 3g was obtained in comparative yields when switching the order of addition of the two different amines, though slightly longer times were required for guanylation with primary amine instead of with cyclic secondary amine. Nevertheless, for the reaction with the less nucleophilic aromatic amines such as in the synthesis of 3j, it is suggested that arylamine should be introduced first to make the 10333

DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340

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The Journal of Organic Chemistry Scheme 3. Previously Reported Methods for the Synthesis of 2-Iminoimidazolin-4-ones

Scheme 4. One-Pot Synthesis of 2-Iminoimidazolin-4-ones 4

antibacterial agent,27 kinase inhibitor,28 anticonvulsant,29 CHK1 inhibitor,30 as well as BACE1 inhibitor.31 Thus far, both solid-phase32 and solution-phase33 syntheses of 2-iminoimidazolin-4-one derivatives have been reported. These approaches involved the formation of carbodiimide intermediate prior to an intramolecular cyclization as summarized in Scheme 3. Although the solid-phase approach enables rapid production of the iminoimidazolinones library, the method requires multistep synthesis with protection and deprotection steps, the use of a large excess of reagents, and relatively costly resins. Despite less synthetic steps being required in the solution-phase method, the starting α-azido esters or isoselenocyanates are not commercially available and difficult to synthesize. Additionally, amino amides are expensive, while N-amido-substituted

intermediate more electrophilic toward subsequent reaction with the incoming aliphatic amine. It is noted also that when using alkyl isothiocynate to react with alkyl amines, the formed dialkyl-substituted thioureas can be converted into the corresponding carbodiimides. However, no further guanylation has been observed under the applied conditions. With the success in the synthesis of acyclic guanidines, the scope of the method was further extended toward the synthesis of 2-iminoimidazolin-4-ones. These cyclic guanidines also known as 2-iminohydantoins are of importance to synthetic and medicinal chemists since a combination of guanidine and imidazole pharmacophores appears to be crucial for their biological activities including anticancer,26 antifungal agent,27 10334

DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340

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Furthermore, key HMBC correlations of the carbonyl carbon at δC 172.3 (C-4) and methine proton at C-5 (δH 4.38−4.35, m) as well as methylene protons at δH 3.28 (dd) and δH 2.97 (dd) suggested that the cyclization proceeded through N-3 to C-4. In addition, based on the chiral HPLC analysis of compound 4d and its enantiomeric form which was synthesized from (D)phenylalanine methyl ester hydrochloride, no significant racemization was observed under our applied conditions (see Figure S2 in ESI). The one-pot reaction between an aryl isothiocyanate with two equivalents of amino acid methyl esters was also attempted following the procedure used in Scheme 1. As shown in Scheme 5, aryl isothiocyanates containing an electron-with-

derivatives require multistep preparation. Thus, simple one-pot methods for the synthesis of iminoimidazolinone scaffolds using inexpensive and readily accessible reactants and reagents under mild conditions are still highly desirable. By simply replacing one of the amines used in our system with an α-amino acid methyl ester, formation of 2iminoimidazolin-4-ones could be envisaged through a tandem guanylation and cyclization of the intermediate guanidine tethered to carbonyl ester as similarly shown in Scheme 3 (route b). To our delight, when a thiourea derived from a combination of 4-nitrophenyl isothiocyanate with cyclohexylamine was subjected to the Ph3P−I2 system prior to treatment with glycine methyl ester hydrochloride, the desired cyclized product 4a was obtained in 85% yield after 1 h stirring at room temperature (Scheme 4). The reaction of the in situ generated substituted thioureas with different amino acid methyl esters was thus further evaluated. On the basis of the results obtained for compounds 4a−d, increasing the steric hinderance of the side chain of the amino acids did not significantly interfere with the imidazolone ring formation. When cyclic amino acid ester such as L-proline methyl ester hydrochloride was applied to the present conditions, bicyclic-fused 2-iminoimidazolinones 4e was obtained in high yield. A clear correlation between the electronic effects of the substituents on the N-aryl and the product yields was also observed. Electron-deficient isothiocyanates reacted smoothly to provide the products 4f−h in high yields. However, the electron-neutral and electron-rich substrates are less effective, leading to lower yields of 4i−k with extended reaction times. Using two different α-amino esters as the amine nucleophiles also provided iminoimidazolinones 4l−p in satisfactory yields. The presence of a free hydroxy group in the tyrosine side chain was tolerated in the synthesis of 4p. Considering the equal spatial proximity of nitrogens N1 and N3 of the guanidine intermediate prior to cyclization, formation of two regioisomeric imidazolinones is possible. Nevertheless, presumably due to the higher reactivity of the less steric amino group of glycine with respect to that of the other amino estercontaining α-substituent, compounds 4l−p were produced without detectable formation of other possible regioisomers. According to Figure 2 the regioselective cyclization of 4n was

Scheme 5. One-Pot Synthesis of 2-Iminoimidazolin-4-ones 5

drawing nitro and chloro group reacted smoothly with glycine or alanine methyl esters to give high yields of products 5a, 5c, and 5d within 1 h. Electron-rich isocyanate having a methyl group gave a lower yield of 5b due to incomplete conversion of the formed intermediates. To gain insight into the reaction mechanism, some control experiments were carried out. When carbodiimides such as Ncyclohexyl-N-phenylcarbodiimide and N-cyclohexyl-N-(ptolyl)carbodiimide were directly used to condense with morpholine to prepare 3h and 3i, respectively, guanylation did not proceed even with prolonged stirring for 16 h in the presence of base. This data strongly indicated the involvement of other reactive species which could be carboimidoyl iodide34 in the Ph3P−I2-mediated guanylation. Further NMR experiments were conducted to obtain more evidence for the formation of phosphorus-containing intermediates. The progress of the reaction between 1-cyclohexyl-3(4-nitrophenyl)thiourea and glycine methyl ester was thus followed using the 31P{1H} NMR technique. According to 31P{1H} NMR spectra of the reaction mixture (see Figure S3 in ESI), addition of thiourea into the Ph3P−I2 solution gave rise to a new sharp signal at 43.3 ppm corresponding to Ph3PS35 along with another signal at 3.54 ppm. The signal at 3.54 ppm could be attributed to a pentacoordinate phosphorane intermediate derived from phosphorylation of the sulfur atom of the thiourea by Ph3PI2. To the best of our knowledge, no 31P{1H} NMR data of this type of phosphorane species has been reported, and we can only assume that the corresponding phosphonium iodide if present should exhibit a high positive signal in the low-field region as commonly observed in other phosphonium salts.36 After treatment with triethylamine, the signal at 3.54 ppm rapidly disappeared, implying the formation of carboimidoyl iodide as well as carbodiimide intermediates. It is noted that a low-intensity signal of Ph3PO also appeared at 30.3 ppm, possibly due to the reaction of phosphonium intermediates with moisture. Further addition with glycine methyl ester

Figure 2. Key HMBC NMR correlations observed in compound 4n.

unambiguously determined based on both 1H NMR and HMBC techniques. In the high-field region of the 1H NMR spectrum, the signals observed at δH 2.97 (dd, J = 14.0, 8.0 Hz, 1H), 3.28 (dd, J = 14.0, 4.0 Hz, 1H), 4.35 (s, 2H), and 4.38− 4.35 (m, 1H) were assigned to two types of methylene protons H-1″ and H-1′ and methine proton H-5. In addition, a methoxy group signal at δH 3.76 (3H, s, −OCH3) was also observed. In the HMBC spectrum, methylene proton attached to C-1′ at δH 4.35 and the protons of the methoxy group at δH 3.76 showed strong correlations with the carbonyl group at δC 167.6 (C-2′). 10335

DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340

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The Journal of Organic Chemistry Scheme 6. Proposed Mechanism for the Ph3P−I2-Mediated Guanidine Formation

caused no further change in the 31P{1H} NMR spectrum, indicating no involvement of phosphorus-containing species during this process. On the basis of the above results, the mechanism for the formation of substituted guanidine was proposed as shown in Scheme 6. Initial condensation of an aryl isothiocyanate with an amine leads to the formation of a thiourea which undergoes phosphorylation with triphenylphosphinediiodide. Substitution of the formed pentacoordinate phosphorane intermediate I with an iodide ion then gives rise to II with a concomitant release of Ph3PS. In the presence of base, carboimidoyl iodide III would be generated in equilibrium with the carbodiimide IV (when R = H) or the carbodiimide salt V (when R ≠ H). Subsequent nucleophilic addition with an amine finally furnishes guanidine formation.

stirring at room temperature until complete formation of thiourea (ca. 5−10 min), the mixture was cooled to 0 °C; then triphenylphosphine (0.086 g, 0.33 mmol) and iodine (0.083 g, 0.33 mmol) were added in one portion. The reaction mixture was stirred at room temperature until reaction completion as indicated by TLC. The crude reaction was washed with water, and the combined organic layers were dried over anhydrous Na2SO4 before being concentrated in vacuo. The residue was purified by flash column chromatography (CC) using 10−50% ethyl acetate in hexane. General Procedure for the Synthesis of Unsymmetrical Substituted Guanidines 3 and 2-Iminoimidazolones 4. Amine or amino ester (0.28 mmol) was added to aryl isothiocyanate in CH2Cl2 (2 mL), and the reaction mixture was stirred at room temperature until complete formation of thiourea. The mixture was then cooled to 0 °C before adding triphenylphosphine (0.086 g, 0.33 mmol) and iodine (0.083 g, 0.33 mmol) in one portion. After that triethylamine (0.19 mL, 1.4 mmol) was added, followed by addition of the second amine or amino ester (0.28 mmol). The reaction mixture was then stirred at room temperature until reaction completion as indicated by TLC. The crude reaction was washed with water, and the combined organic layers were dried over anhydrous Na2SO4 before being concentrated in vacuo. The residue was purified by flash column chromatography (CC) using 10−50% ethyl acetate in hexane. 1,3-Dibenzyl-2-(4-nitrophenyl)guanidine37 (Scheme 1, 2a). Yellow solid (0.0910 g, 90% yield); mp 128−129 °C; Rf 0.33 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.2 Hz, 2H), 7.38−7.25 (m, 10H), 6.98 (d, J = 9.2 Hz, 2H), 4.41 (s, 4H); 13 C{1H} NMR (100 MHz, CDCl3) δ 157.8, 151.5, 141.3, 138.1, 128.9, 127.7, 127.3, 125.5, 123.1, 46.0. 1,3-Dibenzyl-2-(4-(trifluoromethyl)phenyl)guanidine (Scheme 1, 2b). Colorless oil (0.0862g, 80% yield); Rf 0.36 (30% EtOAc/hexane); 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.4 Hz, 2H), 7.35−7.22 (m, 10H), 7.01 (d, J = 8.4 Hz, 2H), 4.36 (s, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.3, 151.1, 138.4, 128.8, 127.6, 127.2, 126.6 (q, JC−F = 3.7 Hz), 123.5, 46.1; TOF-HRMS calcd for C22H21F3N3 [M + H]+ 384.1688, found 384.1687. 1,3-Dibutyl-2-(4-nitrophenyl)guanidine38 (Scheme 1, 2c). Yellow oil (0.0788 g, 96% yield); Rf 0.21 (30% EtOAc/hexane);1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 9.2 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H), 3.18 (t, J = 7.2 Hz, 4H), 1.55 (quin, J = 7.2 Hz, 4H), 1.35 (sex, J = 7.2 Hz, 4H), 0.91 (t, J = 7.2 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.9, 153.1, 141.8, 125.5, 122.1, 42.4, 31.6, 20.0, 13.7. 1,3-Diisopropyl-2-(4-nitrophenyl)guanidine25d (Scheme 1, 2d). Yellow solid (0.0659 g, 89% yield); mp 123−124 °C; Rf 0.31 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 3.88 (s, 2H), 3.77 (sep, J = 6.4 Hz, 2H), 1.17 (d, J = 6.4 Hz, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.3, 150.6, 140.8, 125.6, 122.7, 43.5, 23.2. 2-(4-Fluorophenyl)-1,3-diisopropylguanidine25d (Scheme 1, 2e). Brown solid (0.0501 g, 75% yield); mp 132−133 °C; Rf 0.25 (50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 6.96−6.77 (m, 4H), 3.77−3.70 (m, 4H), 1.15 (d, J = 6.4 Hz, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.4 (d, JC−F = 237.8 Hz), 150.9, 124.5 (d, JC−F = 7.7 Hz), 115.9 (d, JC−F = 21.8 Hz), 43.4, 23.3.

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CONCLUSIONS In summary, a simple one-pot method for the preparation of highly substituted guanidines as well as 2-iminoimidazolin-4ones directly from aryl isothiocyanates was reported. Using the Ph3P−I2/Et3N combination as a dehydrosulfurizing system, both symmetrical and unsymmetrical substituted guanidines could be obtained through a sequential-controlled threecomponent coupling of aryl isothiocyanates and amines. The reaction of aryl isothiocyanates with amino acid methyl esters also proceed readily via a tandem guanylation−cyclization to provide a variety of 2-iminoimidazolin-4-ones in satisfactory yields under mild conditions. Control experiments and NMR study suggested that carboimidoyl iodide is a key reactive species in the Ph3P/I2-mediated guanylation.

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EXPERIMENTAL SECTION

Material and Methods. All reagents were obtained from SigmaAldrich Co., USA, and used without further purification. The reaction was monitored by thin-layer chromatography carried out on silica gel plates (60F254, MERCK, Germany) and visualized under UV light (254 nm). Melting points were determined using Mettler Toledo DSC equipment at a heating rate of 6 °C/min and are uncorrected. NMR spectra were determined using a Bruker AVANCE (400 MHz for 1H). Chemical shifts were reported in parts per million (ppm, δ) downfield from TMS. Splitting patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), quintet (qui), sextet (sex), multiplet (m), broad (br), doublet of doublets (dd), triplet of doublets (td), and doublet of doublet of doublets (ddd). High-resolution mass spectra (HRMS) were recorded using the LC-DAD-ESI-MS/MS system consisting of a Waters Alliance 2695 LC-DAD and a Q-TOF 2 (quadrupole mass filter-time-of-flight) mass spectrometer with a Z-spray ES source. General Procedure for the Synthesis of Symmetrical Substituted Guanidines 2 and 2-Iminoimidazolones 5. Amine or amino ester (0.56 mmol) and triethylamine (0.19 mL, 1.4 mmol) were added to a solution of aryl isothiocyanate (0.28 mmol) in CH2Cl2 (2 mL). After 10336

DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340

Article

The Journal of Organic Chemistry 2-(4-Chlorophenyl)-1,3-diisopropylguanidine39 (Scheme 1, 2f). Yellow oil (0.0542 g, 76% yield); Rf 0.28 (50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 3.73 (sep, 6.4 Hz, 4H), 1.15 (d, J = 6.4 Hz, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ 150.5, 129.3, 128.5, 126.5, 124.8, 43.4, 23.3. N-(Dimorpholinomethylene)-4-nitroaniline23a (Scheme 1, 2g). Yellow solid (0.0766 g, 85% yield); mp 158−159 °C; Rf 0.38 (EtOAc); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 3.65 (br s, 8H), 3.16 (br s, 8H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.3, 141.4, 132.0, 125.3, 121.4, 66.3, 49.2. N-(Dimorpholinomethylene)-4-(trifluoromethyl)aniline (Scheme 1, 2h). White solid (0.0743g, 77% yield); mp 118−119 °C ; Rf 0.39 (EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 3.64 (br s, 8H), 3.15 (br s, 8H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.8, 132.0, 128.5, 126.2 (q, JC−F = 3.7 Hz), 121.7, 66.4, 49.2; TOF-HRMS calcd for C16H21F3N3O2 [M + H]+ 344.1586, found 344.1585. 1,3-Bis(4-methoxyphenyl)-2-(4-nitrophenyl)guanidine38 (Scheme 1, 2i). Brown oil (0.1036 g, 94% yield); Rf 0.44 (50% EtOAc/hexanes); 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 4H), 6.81 (d, J = 8.8 Hz, 4H), 3.75 (s, 6H). 13C{1H} NMR (100 MHz, CDCl3) δ 157.1, 147.1, 142.0, 131.9, 126.0, 125.2, 124.7, 121.3, 114.8, 114.7, 55.5. 1,3-Dicyclohexyl-2-(4-nitrophenyl)guanidine25b (Scheme 1, 2j). Yellow solid (0.0947 g, 98% yield); mp 154−155 °C ; Rf 0.47 (50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.46 (br s, 2H), 3.45−3.39 (m, 2H), 2.02−1.94 (m, 4H), 1.71−1.56 (m, 6H), 1.35−1.26 (m, 4H), 1.19− 1.15 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.9, 151.0, 141.0, 125.6, 122.4, 50.7, 33.5, 25.4, 24.8. 1,3-Dicyclohexyl-2-(4-fluorophenyl)guanidine39 (Scheme 1, 2k). Colorless solid (0.0581 g, 65% yield); mp 169−170 °C; Rf 0.23 (50% EtOAc/hexanes) ; 1H NMR (400 MHz, CDCl3) δ 6.98−6.89 (m, 4H), 3.38−3.31 (m, 2H), 1.94−1.90 (m, 4H), 1.71−1.54 (m, 6H), 1.31−1.10 (m, 10H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.1 (d, JC−F = 239.7 Hz), 152.1, 124.7 (d, JC−F = 7.9 Hz), 116.0 (d, JC−F = 22.1 Hz), 51.2, 33.5, 25.4, 24.8. 1,3-Dicyclohexyl-2-p-tolylguanidine25b (Scheme 1, 2l). Colorless solid (0.0407 g, 46% yield); mp 155−156 °C; Rf 0.20 (30% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 7.07 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 8.0 Hz, 2H), 3.36 (br s, 2H), 2.29 (s, 3H), 1.87 (br s, 4H), 1.67−1.51 (m, 6H), 1.28−1.10 (m, 10H); 13C{1H} NMR (100 MHz, CDCl3) δ 153.0, 133.7, 130.7, 130.0, 123.2, 51.7, 33.2, 25.2, 24.7, 20.8. 1-Benzyl-3-cyclohexyl-2-(4-nitrophenyl)guanidine (Scheme 2, 3a). Yellow solid (0.0831 g, 84% yield); mp 109−110 °C ; Rf 0.33 (30%EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.8 Hz, 2H), 7.38−7.26 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 4.68 (br s, 2H), 4.39 (s, 2H), 3.41−3.36 (m, 1H), 1.92−1.88 (m, 2H), 1.66−1.52 (m, 3H), 1.32−1.22 (m, 2H), 1.17−1.06 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.4, 151.6, 141.4, 138.0. 128.9, 127.8, 127.4, 125.5, 122.6, 50.7, 46.3, 33.4, 25.3, 24.6; TOF-HRMS calcd for C20H25N4O2 [M + H]+ 353.1978, found 353.1974. 1-Benzyl-3-butyl-2-(4-nitrophenyl)guanidine (Scheme 2, 3b). Yellow oil (0.0815 g, 89% yield); Rf 0.30 (30% EtOAc/hexanes) ; 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.8 Hz, 2H), 7.39−7.28 (m, 5H), 6.97 (d, J = 8.8 Hz, 2H), 4.42 (s, 2H), 3.14 (t, J = 7.2 Hz, 2H), 1.46 (quin, J = 7.2 Hz, 2H), 1.26 (sex, J = 7.2 Hz, 2H), 0.87 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.4, 152.1, 141.6, 138.0, 129.0, 127.9, 127.4, 125.5, 122.8, 46.2, 42.0, 31.6, 19.9, 13.7; TOF-HRMS calcd for C18H23N4O2 [M + H]+ 327.1821, found 327.1827. 1-Benzyl-3-isopropyl-2-(4-nitrophenyl)guanidine23a (Scheme 2, entry 3c). Yellow oil (0.0728 g, 83% yield); Rf 0.32 (30% EtOAc/ hexanes); 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 8.8 Hz, 2H), 7.38−7.28 (m, 5H), 6.95 (d, J = 8.8 Hz, 2H), 4.40 (s, 2H), 3.75 (sep, J = 6.4 Hz, 1H), 1.14 (d, J = 6.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.9, 151.3, 141.4, 138.1, 128.9, 127.8, 127.4, 125.6, 122.8, 46.2, 43.8, 23.1.

N-Benzyl-N′-(4-nitrophenyl)morpholine-4-carboximidamide (Scheme 2, 3d). Yellow solid,(0.0813g, 85% yield); mp 150−151 °C; Rf 0.27 (50% EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 9.2 Hz, 2H), 7.35−7.21 (m, 5H), 6.79 (d, J = 9.2 Hz, 2H), 4.25 (s, 2H), 3.68 (t, J = 4.8 Hz, 4H), 3.27 (t, J = 4.8 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.0, 155.7, 141.2, 138.0, 128.9, 127.9, 127.7, 125.4, 121.5, 66.3, 48.7, 47.8; TOF-HRMS calcd for C18H21N4O3 [M + H]+ 341.1614, found 341.1617. 3-Benzyl-1,1-diisopropyl-2-(4-nitrophenyl)guanidine (Scheme 2, 3e). Yellow oil (0.0866g, 87% yield); Rf 0.42 (50% EtOAc/hexane);1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.0 Hz, 2H), 7.34−7.19 (m, 5H), 6.79 (d, J = 8.0 Hz, 2H), 4.03 (s, 2H), 3.95−3.89 (m, 2H), 1.29 (d, J = 5.2 Hz, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.9, 140.4, 138.8, 137.7, 128.9, 128.0, 125.8, 119.9, 48.8, 47.9, 21.8; TOFHRMS calcd for C20H27N4O2 [M + H]+ 355.2134, found 355.2127. 1-Cyclohexyl-3-(4-methoxyphenyl)-2-(4-nitrophenyl)guanidine (Scheme 2, 3f). Yellow oil (0.0819 g, 79% yield); Rf 0.35 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 9.2 Hz, 2H), 7.05−7.01 (m, 4H), 6.84 (d, J = 9.2 Hz, 2H), 4.55 (s, 2H), 3.78 (s, 3H), 3.72−3.66 (m, 1H), 2.01−1.97 (m, 2H), 1.67−1.55 (m, 3H), 1.37−1.25 (m, 2H), 1.17−1.06 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 157.6, 149.4, 4 141.4, 126.1, 125.4, 122.6, 114.9, 55.5, 50.2, 33.3, 25.5, 24.8, TOF-HRMS calcd for C20H25N4O3 [M + H]+ 369.1927, found 369.1927. N-Cyclohexyl-N′-(4-nitrophenyl)morpholine-4-carboximidamide (Scheme 2, 3g). Yellow oil (0.0793g, 85% yield); Rf 0.40 (30% EtOAc/hexane); 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 3.69 (t, J = 4.8 Hz, 4H), 3.25 (t, J = 4.8 Hz, 4H), 3.22−3.17 (m, 1H), 1.91−1.87 (m, 2H), 1.70−1.54 (m, 3H), 1.28−1.17 (m, 2H), 1.16−1.02 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 155.4, 146.8, 141.3, 125.4, 121.6, 66.3, 52.7, 48.0, 33.7, 25.3, 24.9; TOF-HRMS calcd for C17H25N4O3 [M + H]+ 333.1927, found 333.1926. N-Cyclohexyl-N′-phenylmorpholine-4-carboximidamide 40 (Scheme 2, 3h). Colorless oil (0.0421 g, 52% yield); Rf 0.25 (40% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J = 7.6 Hz, 2H), 7.00 (t, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 2H), 3.72−3.69 (m, 4H), 3.23−3.21 (m, 4H), 3.07 (m, 1H), 1.87−1.84 (m, 2H), 1.67− 1.53 (m, 3H), 1.27−1.16 (m, 2H), 1.10−1.01 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 156.2, 141.5, 129.3, 122.5, 66.6, 53.8, 48.6, 33.8, 25.3, 25.2. N-Cyclohexyl-N′-p-tolylmorpholine-4-carboximidamide 41 (Scheme 2, 3i). White solid (0.0467 g, 55% yield); mp 79−80 °C; Rf 0.27 (50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.04 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 3.72 (t, J = 4.8 Hz, 4H), 3.21 (t, J = 4.8 Hz, 4H), 3.04−2.98 (m, 1H), 2.27 (s, 3H), 1.86−1.82 (m, 2H), 1.67−1.51 (m, 3H), 1.27−1.16 (m, 2H), 1.07−0.86 (m, 3H); 13 C{1H} NMR (100 MHz, CDCl3) δ 156.1, 147.1, 131.2, 129.7, 122.4, 66.8, 52.0, 48.7, 34.0, 25.4, 25.2. N,N′-Diphenylmorpholine-4-carboximidamide41 (Scheme 2, 3j). Yellow solid (0.0664 g, 84% yield). mp 130−131 °C; Rf 0.36 (40% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.27−7.23 (m, 5H), 7.00−6.94 (m, 5H), 5.20 (s, 1H), 3.66 (t, J = 4.8 Hz, 4H), 3.33 (t, J = 4.8 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 151.1, 129.4, 122.7, 120.6, 66.3, 47.1. 1-Cyclohexyl-3-isopropyl-2-phenylguanidine (Scheme 2, 3k). Colorless solid (0.0358 g, 49% yield); mp 129−130 °C; Rf 0.22 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.24 (t, J = 8.0 Hz, 2H), 6.93 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 3.77 (sep, J = 6.4 Hz, 1H), 3.42−3.35 (m, 1H), 2.00−1.96 (m, 2H), 1.71−1.57 (m, 3H), 1.38−1.28 (m, 2H), 1.19−1.04 (m, 3H), 1.16 (d, J = 6.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 150.3, 149.8, 129.3, 123.6, 121.5, 50.3, 43.4, 33.8, 25.6, 24.9, 23.3; TOF-HRMS calcd for C16H26N3 [M + H]+ 260.2127, found 260.2124. 1-Cyclohexyl-3-isopropyl-2-p-tolylguanidine (Scheme 2, 3l). Yellow oil ; (0.0415 g, 54% yield); Rf 0.25 (50% EtOAc/hexanes); 1 H NMR (400 MHz, CDCl3) δ 7.03 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 8.0 Hz, 2H), 3.79−3.73 (m, 1H), 3.37 (brs, 1H), 2.27 (s, 3H), 1.98− 1.96 (m, 2H), 1.69−1.56 (m, 3H), 1.37−1.25 (m, 2H), 1.18−1.04 (m, 3H), 1.15 (d, J = 6.4 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 10337

DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340

Article

The Journal of Organic Chemistry

5.04 (br s, 1H), 4.74 (s, 2H), 4.18 (dd, J = 6.8, 4.4 Hz, 1H), 3.10 (dd, J = 14.0, 4.4 Hz, 1H), 2.96 (dd, J = 14.0, 6.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.8, 149.5, 146.3, 136.0, 135.1, 129.5, 129.4, 128.7, 128.5, 128.3, 128.2, 127.5, 127.3, 123.7, 58.4, 42.5, 38.0; TOFHRMS calcd for C23H2135ClN3O (M + H+) 390.1373, found 390.1376; calcd for C23H2137ClN3O [M + H]+ 392.1343, found 392.1347. 3,5-Dibenzyl-2-(phenylimino)imidazolidin-4-one (Scheme 4, 4i). Colorless solid (0.0678 g, 68% yield); mp 77−78 °C; Rf 0.27 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.78−7.73 (m, 1H), 7.57−7.45 (m, 2H), 7.35−7.24 (m, 7H), 7.14−7.11 (m, 2H), 7.06 (d, J = 7.6 Hz. 1H), 6.89 (d, J = 7.6 Hz, 2H), 4.79 (s, 2H), 4.20 (dd, J = 7.2, 4.4 Hz, 1H), 3.14 (dd, J = 9.6, 4.4 Hz, 1H), 2.97 (dd, J = 14.0, 7.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.8, 149.0, 136.2, 135.3, 132.3, 131.6, 129.53, 129.47, 128.8, 128.7, 128.53, 128.50, 127.6, 127.3, 123.3, 122.3, 58.6, 42.6, 38.2; TOF-HRMS calcd for C23H22N3O [M + H]+ 356.1763, found 356.1759. 3,5-Dibenzyl-2-(p-tolylimino)imidazolidin-4-one (Scheme 4, 4j). Yellow solid (0.0582 g, 56% yield); mp 162−163 °C; Rf 0.32 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.31−7.25 (m, 8H), 7.12 (d, J = 7.6 Hz, 4H), 6.78 (d, J = 8.4 Hz, 2H), 4.78 (s, 2H), 4.19 (dd, J = 6.8, 4.4 Hz, 1H), 3.12 (dd, J = 14.0, 4.4 Hz, 1H), 2.95 (dd, J = 14.0, 6.8 Hz, 1H), 2.32 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 149.3 136.2, 135.3, 132.6, 130.0, 129.5, 128.7, 128.5, 128.4, 127.5, 127.3, 122.1, 58.6, 42.5, 38.1, 20.8; TOF-HRMS calcd for C24H24N3O [M + H]+ 370.1919, found 370.1926. 5-Benzyl-3-butyl-2-(phenylimino)imidazolidin-4-one (Scheme 4, 4k). Yellow oil (0.0462 g, 51% yield); Rf 0.34 (20% EtOAc/hexanes); 1 H NMR (400 MHz, CDCl3) δ 7.32−7.25 (m, 5H), 7.15 (d, J = 7.2 Hz, 2H), 7.02 (t, J = 7.2 Hz, 1H), 6.87 (d, J = 7.2 Hz, 2H), 4.63 (s, 1H), 4.15 (dd, J = 7.6, 4.0 Hz, 1H), 3.58 (td, J = 7.2, 1.6 Hz, 2H), 3.13 (dd, J = 14.0, 4.0 Hz, 1H), 2.92 (dd, J = 14.0, 7.6 Hz, 1H), 1.54 (qui, 7.2 Hz, 2H), 1.30−1.21 (m, 2H), 0.91 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.0, 149.5, 147.8, 135.5, 129.6, 129.5, 128.8, 127.4, 123.2, 122.4, 58.5, 39.1, 38.5, 29.8, 20.1, 13.9; TOFHRMS calcd for C20H24N3O [M + H]+ 322.1919, found 322.1921. Methyl 2-(5-oxo-2-(phenylimino)imidazolidin-1-yl)propanoate (Scheme 4, 4l). Yellow oil (0.0492 g, 67% yield); Rf 0.23 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.51−7.43 (m, 1H), 7.32−7.25 (m. 2H), 7.05 (t, J = 7.2 Hz, 1H), 6.97−6.94 (m, 1H), 4.42 (s, 2H), 4.11 (q, J = 6.8 Hz, 1H), 3.77 (s, 3H), 1.41 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.2, 167.9, 148.8, 129.5, 128.4, 123.5, 122.5, 53.6, 52.6, 40.1, 18.2; TOF-HRMS calcd for C13H16N3O3 [M + H]+ 262.1192, found 262.1195. Methyl 3-methyl-2-(5-oxo-2-((4-(trifluoromethyl)phenyl)imino)imidazolidin-1-yl)butanoate (Scheme 4, 4m). Yellow oil (0.0743 g, 74% yield); Rf 0.43 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.45 (s, 2H), 4.01 (d, J = 3.6 Hz, 1H), 3.77 (s, 3H), 2.28−2.20 (m, 1H), 1.01 (d, J = 7.2 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.7, 167.7, 150.2, 128.9, 126.8 (q, JC−F = 3.7 Hz), 123.0, 121.8, 63.2, 52.7, 40.1, 30.9, 18.9, 16.3; TOF-HRMS calcd for C16H19F3N3O3 [M + H]+ 358.1379, found 358.1376. Methyl 2-(4-benzyl-2-((4-nitrophenyl)imino)-5-oxoimidazolidin1-yl)acetate (Scheme 4, 4n). Yellow oil (0.0838 g, 78% yield); Rf 0.36 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 9.2 Hz, 2H), 7.35−7.17 (m, 5H), 6.93 (d, J = 9.2 Hz, 2H), 5.10 (br s, 1H), 4.38−4.35 (m, 1H), 4.35 (s, 2H), 3.76 (s, 3H), 3.28 (dd, J = 14.0, 4.0 Hz, 1H), 2.97 (dd, J = 14.0, 8.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.3, 167.6, 154.4, 148.9, 143.2, 135.4, 129.0, 127.6, 125.4, 124.3, 122.9, 59.2, 52.7, 40.1, 38.4; TOF-HRMS calcd for C19H19N4O5 [M + H]+ 383.1355, found 383.1348. Methyl 2-(5-oxo-2-(phenylimino)imidazolidin-1-yl)-3-phenylpropanoate (Scheme 4, 4o). Yellow oil (0.0579 g, 61% yield); Rf 0.22 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.33−7.24 (m, 5H), 7.17 (d, J = 7.2 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 7.2 Hz, 2H), 4.38 (s, 2H), 4.27 (dd, J = 8.4, 4.0 Hz, 1H), 3.75 (s, 3H), 3.25 (dd, J = 14.0, 4.0 Hz, 1H), 2.91 (dd, J = 13.6, 8.4 Hz, 1H); 13 C{1H} NMR (100 MHz, CDCl3) δ 172.7, 167.7, 148.7, 135.7, 129.5, 129.4, 128.9, 127.4, 123.7, 122.5, 59.1, 52.6, 40.1, 38.5; TOF-HRMS calcd for C19H20N3O3 [M + H]+ 338.1505, found 338.1502.

150.5, 146.4, 130.7, 129.9, 123.3, 50.3, 43.3, 33.8, 25.6, 24.9, 23.3, 20.8; TOF-HRMS calcd for C17H28N3 [M + H]+ 274.2283, found 274.2286. 3-Cyclohexyl-2-((4-nitrophenyl)imino)imidazolidin-4-one (Scheme 4, 4a). Yellow solid (0.0722 g, 85% yield); mp 191−192 °C; Rf 0.21 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.10 (s, 1H), 4.15−4.07 (m, 1H), 3.86 (s, 2H), 2.33−2.22 (m, 2H), 1.86−1.62 (m, 5H), 1.39− 1.16 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.2, 155.4, 151.3, 142.8, 125.3, 123.0, 52.6, 46.8, 28.9, 26.0, 25.2; TOF-HRMS calcd for C15H19N4O3 [M + H]+ 303.1457, found 303.1458. 3-Cyclohexyl-5-methyl-2-((4-nitrophenyl)imino)imidazolidin-4one (Scheme 4, 4b). Yellow solid (0.0755 g, 85% yield); mp 161−162 °C; Rf 0.31 (50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.01 (dd, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 5.62 (s, 1H), 4.09− 4.01 (m, 1H), 3.92 (q, J = 6.8 Hz, 1H), 2.27−2.16 (m, 2H), 1.81−1.58 (m, 5H), 1.35−1.12 (m, 3H), 1.32 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.7, 155.6, 150.3, 142.5, 125.1, 123.0, 52.9, 52.3, 28.8, 25.9, 25.1, 17.9; TOF-HRMS calcd for C16H21N4O3 [M + H]+ 317.1614, found 317.1617. 3-Cyclohexyl-5-isopropyl-2-((4-nitrophenyl)imino)imidazolidin-4one (Scheme 4, 4c). Yellow oil (0.0782 g, 81% yield); Rf 0.30 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J = 9.2 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 4.09 (d, J = 4.0 Hz, 1H), 3.79−3.69 (m, 2H), 2.36−2.25 (m, 1H), 2.17−1.91 (m, 2H), 1.72−1.66 (m, 2H), 1.64−1.58 (m, 1H), 1.46−1.33 (m, 2H), 1.21−1.12 (m, 3H), 1.10 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.0, 149.6, 138.2, 132.2, 127.6, 125.4, 117.3, 50.6, 33.4, 33.2, 31.8, 25.7, 24.9, 24.8, 18.9; TOF-HRMS calcd for C18H25N4O3 [M + H]+ 345.1927, found 345.1923. 5-Benzyl-3-cyclohexyl-2-((4-nitrophenyl)imino)imidazolidin-4-on (Scheme 4, 4d). Yellow oil (0.0903 g, 82% yield); Rf 0.51 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 9.0 Hz, 2H), 7.36−7.18 (m, 5H), 6.90 (d, J = 9.0 Hz, 2H), 5.01 (s, 1H), 4.20 (t, J = 5.2 Hz, 1H), 4.01−3.95 (m, 1H), 3.11−3.09 (m, 2H), 2.24− 2.15 (m, 2H), 1.85−1.79 (m, 2H), 1.67−1.60 (m, 2H), 1.48−1.20 (m, 4H).; 13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 155.5, 150.0, 142.9, 134.9, 129.8, 128.7, 127.5, 125.4, 123.0, 57.9, 52.4, 38.0, 28.85, 28.59, 26.00, 25.96, 25.2; TOF-HRMS calcd for C22H25N4O3 [M + H]+ 393.1927, found 393.1925. 2-Cyclohexyl-3-((4-nitrophenyl)imino)hexahydro-1H-pyrrolo[1,2c]imidazol-1-one (Scheme 4, 4e). Yellow oil (0.0769 g, 80% yield); Rf 0.37 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 9.2 Hz, 2H), 7.05 (d, J = 9.2 Hz, 2H), 4.08−4.01 (m, 2H), 2.92− 2.87 (m, 1H), 2.80−2.75 (m, 1H), 2.36−2.15 (m, 3H), 2.00−1.60 (m, 8H), 1.38−1.14 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.4, 155.4, 154.4, 142.2, 125.0, 122.6, 64.4, 53.1, 50.1, 28.9, 28.7, 28.4, 27.3, 26.01, 25.94, 25.2; TOF-HRMS calcd for C18H23N4O3 [M + H]+ 343.1770, found 343.1765. 3,5-Dibenzyl-2-((4-nitrophenyl)imino)imidazolidin-4-one (Scheme 4, 4f). Yellow solid (0.0968 g, 86% yield); mp 159−160 °C; Rf 0.45 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.8 Hz, 2H), 7.26−7.10 (m, 10H), 6.89 (d, J = 8.8 Hz, 2H), 4.71 (d, J = 14.8 Hz, 1H), 4.67 (d, J = 14.8 Hz, 1H), 4.28 (t, J = 4.8 Hz, 1H), 3.13−3.01 (m, 2H), 2.93 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.0, 155.1, 149.8, 142.7, 135.7, 134.7, 129.6, 128.5, 128.4, 128.0, 127.5, 127.3, 125.1, 122.9, 58.5, 42.5, 37.5; TOF-HRMS calcd for C23H21N4O3 [M + H]+ 401.1614, found 401.1612. 3,5-Dibenzyl-2-((4-fluorophenyl)imino)imidazolidin-4-one (Scheme 4, 4g). Yellow oil (0.0849 g, 81% yield); Rf 0.36 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.34−7.25 (m, 8H), 7.14−7.10 (m, 2H), 7.02−6.98 (m, 2H), 6.83−6.80 (m, 2H), 4.78 (s, 2H), 4.21 (dd, J = 7.2, 4.0 Hz, 1H), 3.15 (dd, J = 13.8, 4.0 Hz, 1H), 2.97 (dd, J = 13.8, 7.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.7, 159.1 (d, JC−F = 240.0 Hz), 149.5, 136.2, 135.3, 129.5, 128.8, 128.6, 128.52, 128.47, 127.6, 127.4, 123.4 (d, JC−F = 7.8 Hz), 116.1(d, JC−F = 22.0 Hz), 58.6, 42.6, 38.2; TOF-HRMS calcd for C23H21FN3O [M + H]+ 374.1669, found 374.1664. 3,5-Dibenzyl-2-((4-chlorophenyl)imino)imidazolidin-4-one (Scheme 4, 4h). Colorless solid (0.0856 g, 78% yield); mp 128−129 °C; Rf 0.31 (20% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.30−7.23 (m, 10H), 7.10−7.08 (m, 2H), 6.79 (d, J = 8.8 Hz, 2H), 10338

DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340

The Journal of Organic Chemistry Methyl2-(2-((4-chlorophenyl)imino)-5-oxoimidazolidin-1-yl)-3(4-hydroxyphenyl)propanoate (Scheme 4, 4p). Yellow oil (0.0741 g, 68% yield); Rf 0.22 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.21 (d, J = 8.8 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 8.4 Hz, 2H), 4.91 (br s, 1H), 4.33 (s, 2H), 4.17 (dd, J = 8.0, 4.0 Hz 1H), 3.69 (s, 3H), 3.08 (dd, J = 14.2, 4.0 Hz, 1H), 2.82 (dd, J = 14.2, 8.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.0, 168.0, 155.6, 149.2, 145.3, 130.5, 129.6, 128.8, 126.7, 123.9, 115.8, 59.2, 52.8, 40.0, 37.5; TOF-HRMS calcd for C19H1835ClN3NaO4 (M + Na+) 410.0884, found 410.0878; calcd for C19H1837ClN3NaO4 [M + H]+ 412.0854, found 412.0857. Methyl 2-(2-((4-nitrophenyl)imino)-5-oxoimidazolidin-1-yl)acetate (Scheme 5, 5a). Yellow solid (0.0697 g, 85% yield); mp 137−138 °C; Rf 0.45 (50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 9.2 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H), 5.40 (br s, 1H), 4.39 (s, 2H), 4.04 (s, 2H), 3.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.7, 167.7, 154.5, 150.1, 143.0, 125.2, 123.1, 52.7, 47.3, 40.1; TOF-HRMS calcd for C12H13N4O5 [M + H]+ 293.0886, found 293.0884. Methyl 2-(5-oxo-2-(p-tolylimino)imidazolidin-1-yl)acetate (Scheme 5, 5b). Yellow oil (0.0405 g, 55% yield); Rf 0.27 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.0 Hz, 2H), 4.79 (br s, 1H), 4.42 (s, 2H), 3.96 (s, 2H), 3.77 (s, 3H), 2.29 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.1, 167.9, 149.6, 144.3, 132.9, 130.1, 122.2, 52.6, 47.2, 40.0, 20.9; TOF-HRMS calcd for C13H16N3O3 [M + H]+ 262.1192, found 262.1189. Methyl 2-(4-methyl-2-((4-nitrophenyl)imino)-5-oxoimidazolidin1-yl)propanoate (Scheme 5, 5c). Yellow oil (0.0773 g, 86% yield); Rf 0.32 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 8.4 Hz, 2H), 5.25 (s, 1H), 5.00−4.98 (m, 1H), 4.16−4.11 (m, 1H), 3.77 (s, 3H), 1.69 (d, J = 5.2 Hz, 3H), 1.45 (d, J = 4.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.5, 170.0, 154.6, 148.9, 143.0, 125.3, 122.9, 53.4, 52.7, 48.7, 18.0, 14.5; TOFHRMS calcd for C14H17N4O5 [M + H]+ 321.1199, found 321.1196. Methyl 2-(2-((4-chlorophenyl)imino)-4-methyl-5-oxoimidazolidin-1-yl)propanoate (Scheme 5, 5d). Yellow oil (0.0669 g, 77% yield); Rf 0.50 (30% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 5.02−4.95 (m, 1H), 4.80 (br s, 1H), 4.08−4.02 (m, 1H), 3.75 (s, 3H), 1.67 (d, J = 7.2 Hz, 3H), 1.39 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 173.7, 170.3, 148.6, 146.0, 129.6, 128.5, 123.8, 53.3, 52.7, 48.6, 18.3, 14.6; TOF-HRMS calcd for C14H1735ClN3O3 [M + H]+ 310.0958, found 310.0961; calcd for C14H1737ClN3O3 [M + H]+ 312.0955, found 312.0959.

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ACKNOWLEDGMENTS

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REFERENCES

Financial support from The Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/ 0206/2556) to S.W., Center of Excellence in Materials Science and Technology, Chiang Mai University, under the administration of Materials Science Research Center, Faculty of Science, Chiang Mai University, the Center of Excellence for Innovation in Chemistry (PERCH-CIC), Office of the Higher Education Commission, Thailand, are gratefully acknowledged. We also gratefully acknowledge Chulabhorn Research Institute (CRI), Thailand, for assistance on ESI-MS analysis.

(1) (a) Berlinck, R. G. S.; Burtoloso, A. C. B.; Trindade-Silva, A. E.; Romminger, S.; Morais, R. P.; Bandeira, K.; Mizuno, C. M. Nat. Prod. Rep. 2010, 27, 1871. (b) Ishikawa, T. Chem. Pharm. Bull. 2010, 58, 1555. (c) Leow, D.; Tan, C.-H. Chem. - Asian J. 2009, 4, 488. (d) Selig, P. Synthesis 2013, 45, 703. (2) (a) Boerner, J.; dos Santos Vieira, I.; Jones, M. D.; Doering, A.; Kuckling, D.; Floerke, U.; Herres-Pawlis, S. Eur. J. Inorg. Chem. 2011, 2011, 4441. (b) Viehmann, P.; Hecht, S. Beilstein J. Org. Chem. 2012, 8, 1825. (c) Raab, V.; Harms, K.; Sundermeyer, J.; Kovacevic, B.; Maksic, Z. B. J. Org. Chem. 2003, 68, 8790. (d) Herres-Pawlis, S.; Floerke, U.; Henkel, G. Eur. J. Inorg. Chem. 2005, 2005, 3815. (e) Herres-Pawlis, S.; Neuba, A.; Seewald, O.; Seshadri, T.; Egold, H.; Floerke, U.; Henkel, G. Eur. J. Org. Chem. 2005, 2005, 4879. (f) Herres-Pawlis, S.; Seshadri, T.; Florke, U.; Henkel, G. Z. Anorg. Allg. Chem. 2009, 635, 1209. (g) Hoffmann, A.; Boerner, J.; Floerke, U.; Herres-Pawlis, S. Inorg. Chim. Acta 2009, 362, 1185. (h) Maronna, A.; Bindewald, E.; Kaifer, E.; Wadepohl, H.; Himmel, H.-J. Eur. J. Inorg. Chem. 2011, 2011, 1302. (i) Reinmuth, M.; Neuhaeuser, C.; Walter, P.; Enders, M.; Kaifer, E.; Himmel, H.-J. Eur. J. Inorg. Chem. 2011, 2011, 83. (3) (a) Tahir, S.; Badshah, A.; Hussain, R. A. Bioorg. Chem. 2015, 59, 39. (b) Berlinck, R. G. S.; Trindade-Silva, A. E.; Santos, M. F. C. Nat. Prod. Rep. 2012, 29, 1382. (c) Saczewski, F.; Balewski, L. Expert Opin. Ther. Pat. 2009, 19, 1417. (4) Baraldi, P. G.; Baraldi, S.; Saponaro, G.; Aghazadeh Tabrizi, M.; Romagnoli, R.; Ruggiero, E.; Vincenzi, F.; Borea, P. A.; Varani, K. J. Med. Chem. 2015, 58, 5355. (5) Chen, C.; Yu, J.; Fleck, B. A.; Hoare, S. R. J.; Saunders, J.; Foster, A. C. J. Med. Chem. 2004, 47, 4083. (6) Tagmose, T. M.; Schou, S. C.; Mogensen, J. P.; Nielsen, F. E.; Arkhammar, P. O. G.; Wahl, P.; Hansen, B. S.; Worsaae, A.; Boonen, H. C. M.; Antoine, M.-H.; Lebrun, P.; Hansen, J. B. J. Med. Chem. 2004, 47, 3202. (7) Soyka, R.; Guth, B. D.; Weisenberger, H. M.; Luger, P.; Mueller, T. H. J. Med. Chem. 1999, 42, 1235. (8) (a) Müller, G. W.; Walters, D. E.; DuBois, G. E. J. Med. Chem. 1992, 35, 740. (b) Chen, J.; Pattarawarapan, M.; Zhang, A. J.; Burgess, K. J. Comb. Chem. 2000, 2, 276. (9) (a) Debdab, M.; Carreaux, F.; Renault, S.; Soundararajan, M.; Fedorov, O.; Filippakopoulos, P.; Lozach, O.; Babault, L.; Tahtouh, T.; Baratte, B.; Ogawa, Y.; Hagiwara, M.; Eisenreich, A.; Rauch, U.; Knapp, S.; Meijer, L.; Bazureau, J.-P. J. Med. Chem. 2011, 54, 4172. (b) Tahtouh, T.; Elkins, J. M.; Filippakopoulos, P.; Soundararajan, M.; Burgy, G.; Durieu, E.; Cochet, C.; Schmid, R. S.; Lo, D. C.; Delhommel, F.; Oberholzer, A. E.; Pearl, L. H.; Carreaux, F.; Bazureau, J.-P.; Knapp, S.; Meijer, L. J. Med. Chem. 2012, 55, 9312. (10) (a) Zhang, W.-X.; Xu, L.; Xi, Z. Chem. Commun. 2015, 51, 254. (b) Alonso-Moreno, C.; Antinolo, A.; Carrillo-Hermosilla, F.; Otero, A. Chem. Soc. Rev. 2014, 43, 3406. (c) Kumar, S.; Singh, U.; Singh, L. Orient. J. Chem. 2007, 23, 541. (d) Katritzky, A. R.; Rogovoy, B. V. ARKIVOC 2005, 49. (e) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de los Santos, J. M. Tetrahedron 2007, 63, 523. (f) Alajarin, M.; Molina, P.; Sanchez-Andrada, P.; Concepción FocesFoces, M. J. Org. Chem. 1999, 64, 1121. (g) Molina, P.; Arques, A.; Alias, A. Tetrahedron Lett. 1991, 32, 2979.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01794. NMR spectra of all compounds, HPLC chromatogram of compound 4d, and 31P{1H} NMR spectra of the reaction toward 4a (PDF)

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

Mookda Pattarawarapan: 0000-0002-7484-122X Wong Phakhodee: 0000-0002-5489-9555 Notes

The authors declare no competing financial interest. 10339

DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340

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The Journal of Organic Chemistry (11) (a) Levallet, C.; Lerpiniere, J.; Ko, S. Y. Tetrahedron 1997, 53, 5291. (b) Cunha, S.; Costa, M. B.; Napolitano, H. B.; Lariucci, C.; Vencato, I. Tetrahedron 2001, 57, 1671. (c) Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Org. Chem. 2002, 67, 3138. (d) Zhang, J.; Shi, Y.; Stein, P.; Atwal, K.; Li, C. Tetrahedron Lett. 2002, 43, 57. (e) O’Donovan, D. H.; Rozas, I. Tetrahedron Lett. 2011, 52, 4117. (12) Ramadas, K.; Srinivasan, N. Tetrahedron Lett. 1995, 36, 2841. (13) Kelly, B.; Rozas, I. Tetrahedron Lett. 2013, 54, 3982. (14) Porcheddu, A.; De Luca, L.; Giacomelli, G. Synlett 2009, 2009, 3368. (15) Manimala, J. C.; Anslyn, E. V. Tetrahedron Lett. 2002, 43, 565. (16) (a) Shibanuma, T.; Shiono, M.; Mukaiyama, T. Chem. Lett. 1977, 6, 575. (b) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997, 62, 1540. (17) (a) Xu, S.; He, Z. RSC Adv. 2013, 3, 16885. (b) de Andrade, V. S. C.; de Mattos, M. C. S. Curr. Org. Synth. 2015, 12, 309. (c) Valentine, D. H., Jr.; Hillhouse, J. H. Synthesis 2003, 2003, 317. (18) Appel, R.; Kleinstueck, R.; Ziehn, K. D. Chem. Ber. 1971, 104, 1335. (19) Lukyanenko, N. G.; Kirichenko, T. I.; Limich, V. V. Synthesis 1986, 1986, 928. (20) (a) Han, M.; Hahn, H.-G. Bull. Korean Chem. Soc. 2012, 33, 1371. (b) Aburano, D.; Yoshida, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 6878. (c) Bayram, M.; Blaeser, D.; Woelper, C.; Schulz, S. Organometallics 2014, 33, 2080. (d) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 3262. (21) Mitsunobu, O.; Kato, K.; Tomari, M. Tetrahedron 1970, 26, 5731. (22) (a) Palomo, C.; Mestres, R. Synthesis 1981, 1981, 373. (b) Palomo, C.; Mestres, R. Bull. Soc. Chim. Fr. 1981, 361. (c) Lee, J. Y.; Park, S. J.; Park, S. J.; Lee, M. J.; Rhim, H.; Seo, S. H.; Kim, K.-S. Bioorg. Med. Chem. Lett. 2006, 16, 5014. (d) Lee, Y. S.; Lee, B. H.; Park, S. J.; Kang, S. B.; Rhim, H.; Park, J.-Y.; Lee, J.-H.; Jeong, S.-W.; Lee, J. Y. Bioorg. Med. Chem. Lett. 2004, 14, 3379. (e) Kennemur, J. G.; Clark, J. B.; Tian, G.; Novak, B. M. Macromolecules 2010, 43, 1867. (f) Heo, J. H.; Seo, H. N.; Choe, Y. J.; Kim, S.; Oh, C. R.; Kim, Y. D.; Rhim, H.; Choo, D. J.; Kim, J.; Lee, J. Y. Bioorg. Med. Chem. Lett. 2008, 18, 3899. (23) (a) Wangngae, S.; Pattarawarapan, M.; Phakhodee, W. Synlett 2016, 27, 1121. (b) Phakhodee, W.; Duangkamol, C.; Wangngae, S.; Pattarawarapan, M. Tetrahedron Lett. 2016, 57, 325. (c) Wangngae, S.; Duangkamol, C.; Pattarawarapan, M.; Phakhodee, W. RSC Adv. 2015, 5, 25789. (d) Duangkamol, C.; Wangngae, S.; Pattarawarapan, M.; Phakhodee, W. Eur. J. Org. Chem. 2014, 2014, 7109. (24) Appel, R. Angew. Chem. 1975, 87, 863. (25) (a) Shen, H.; Chan, H.-S.; Xie, Z. Organometallics 2006, 25, 5515. (b) Li, Q.; Wang, S.; Zhou, S.; Yang, G.; Zhu, X.; Liu, Y. J. Org. Chem. 2007, 72, 6763. (c) Du, Z.; Li, W.; Zhu, X.; Xu, F.; Shen, Q. J. Org. Chem. 2008, 73, 8966. (d) Li, D.; Guang, J.; Zhang, W.-X.; Wang, Y.; Xi, Z. Org. Biomol. Chem. 2010, 8, 1816. (e) Zhang, X.; Wang, C.; Qian, C.; Han, F.; Xu, F.; Shen, Q. Tetrahedron 2011, 67, 8790. (f) Li, Z.; Xue, M.; Yao, H.; Sun, H.; Zhang, Y.; Shen, Q. J. Organomet. Chem. 2012, 713, 27. (g) Pottabathula, S.; Royo, B. Tetrahedron Lett. 2012, 53, 5156. (h) Wei, Y.; Wang, S.; Zhou, S.; Feng, Z.; Guo, L.; Zhu, X.; Mu, X.; Yao, F. Organometallics 2015, 34, 1882. (26) Subtel’na, I.; Atamanyuk, D.; Szymanska, E.; Kiec-Kononowicz, K.; Zimenkovsky, B.; Vasylenko, O.; Gzella, A.; Lesyk, R. Bioorg. Med. Chem. 2010, 18, 5090. (27) Roue, M.; Domart-Coulon, I.; Ereskovsky, A.; Djediat, C.; Perez, T.; Bourguet-Kondracki, M.-L. J. Nat. Prod. 2010, 73, 1277. (28) (a) Ermoli, A.; Bargiotti, A.; Brasca, M. G.; Ciavolella, A.; Colombo, N.; Fachin, G.; Isacchi, A.; Menichincheri, M.; Molinari, A.; Montagnoli, A.; Pillan, A.; Rainoldi, S.; Sirtori, F. R.; Sola, F.; Thieffine, S.; Tibolla, M.; Valsasina, B.; Volpi, D.; Santocanale, C.; Vanotti, E. J. Med. Chem. 2009, 52, 4380. (b) Debdab, M.; Renault, S.; Lozach, O.; Meijer, L.; Paquin, L.; Carreaux, F.; Bazureau, J.-P. Eur. J. Med. Chem. 2010, 45, 805. (29) Sun, Z.-Y.; Kwon, C.-H.; Wurpel, J. N. D. J. Med. Chem. 1994, 37, 2841.

(30) Parmentier, J.-G.; Portevin, B.; Golsteyn, R. M.; Pierre, A.; Hickman, J.; Gloanec, P.; De Nanteuil, G. Bioorg. Med. Chem. Lett. 2009, 19, 841. (31) (a) Zhou, P.; Li, Y.; Fan, Y.; Wang, Z.; Chopra, R.; Olland, A.; Hu, Y.; Magolda, R. L.; Pangalos, M.; Reinhart, P. H.; Turner, M. J.; Bard, J.; Malamas, M. S.; Robichaud, A. J. Bioorg. Med. Chem. Lett. 2010, 20, 2326. (b) Egbertson, M.; McGaughey, G. B.; Pitzenberger, S. M.; Stauffer, S. R.; Coburn, C. A.; Stachel, S. J.; Yang, W.; Barrow, J. C.; Neilson, L. A.; McWherter, M.; Perlow, D.; Fahr, B.; Munshi, S.; Allison, T. J.; Holloway, K.; Selnick, H. G.; Yang, Z.; Swestock, J.; Simon, A. J.; Sankaranarayanan, S.; Colussi, D.; Tugusheva, K.; Lai, M.-T.; Pietrak, B.; Haugabook, S.; Jin, L.; Chen, I. W.; Holahan, M.; Stranieri-Michener, M.; Cook, J. J.; Vacca, J.; Graham, S. L. Bioorg. Med. Chem. Lett. 2015, 25, 4812. (c) Cumming, J. N.; Smith, E. M.; Wang, L.; Misiaszek, J.; Durkin, J.; Pan, J.; Iserloh, U.; Wu, Y.; Zhu, Z.; Strickland, C.; Voigt, J.; Chen, X.; Kennedy, M. E.; Kuvelkar, R.; Hyde, L. A.; Cox, K.; Favreau, L.; Czarniecki, M. F.; Greenlee, W. J.; McKittrick, B. A.; Parker, E. M.; Stamford, A. W. Bioorg. Med. Chem. Lett. 2012, 22, 2444. (d) Zhu, Z.; Sun, Z.-Y.; Ye, Y.; Voigt, J.; Strickland, C.; Smith, E. M.; Cumming, J.; Wang, L.; Wong, J.; Wang, Y.-S.; Wyss, D. F.; Chen, X.; Kuvelkar, R.; Kennedy, M. E.; Favreau, L.; Parker, E.; McKittrick, B. A.; Stamford, A.; Czarniecki, M.; Greenlee, W.; Hunter, J. C. J. Med. Chem. 2010, 53, 951. (32) (a) Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Comb. Chem. 2001, 3, 521. (b) Li, M.; Wilson, L. J. Tetrahedron Lett. 2001, 42, 1455. (c) Yu, Y.; Ostresh, J. M.; Houghten, R. A. Tetrahedron 2002, 58, 3349. (d) Drewry, D. H.; Ghiron, C. Tetrahedron Lett. 2000, 41, 6989. (e) Lange, U. E. W. Tetrahedron Lett. 2002, 43, 6857. (f) Gavrilyuk, J. I.; Evindar, G.; Batey, R. A. J. Comb. Chem. 2006, 8, 237. (g) Li, J.; Zhang, Z.; Fan, E. Tetrahedron Lett. 2004, 45, 1267. (h) Yang, K.; Lou, B.; Saneii, H. Tetrahedron Lett. 2002, 43, 4463. (i) Fu, M.; Fernandez, M.; Smith, M. L.; Flygare, J. A. Org. Lett. 1999, 1, 1351. (33) (a) Heras, M.; Ventura, M.; Linden, A.; Villalgordo, J. M. Tetrahedron 2001, 57, 4371. (b) Li, H.-X.; Sun, Y.; Ding, M.-W. Synth. Commun. 2008, 38, 4328. (c) Li, H.-X.; Xie, C.; Ding, M.-W.; Liu, Z.M.; Yang, G.-F. Synlett 2007, 2007, 2280. (d) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 1201. (e) Bepary, S.; Youn, I. K.; Lim, H.-J.; Lee, G. H. Eur. J. Org. Chem. 2012, 2012, 2542. (f) Bepary, S.; Youn, I. K.; Lim, H.-J.; Lee, G. H. Synth. Commun. 2014, 44, 1876. (g) Prabhu, G.; Santhosh, L.; Nagendra, G.; Panduranga, V.; Sureshbabu, V. V. ChemistrySelect 2017, 2, 1202. (h) Chi, Y.; Xu, L.; Du, S.; Yan, H.; Zhang, W.-X.; Xi, Z. Chem. - Eur. J. 2015, 21, 10369. (34) (a) Yavari, I.; Khalili, G.; Mirzaei, A. Helv. Chim. Acta 2010, 93, 72. (b) Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron 2002, 58, 1739. (35) Hayashi, M.; Matsuura, T.; Tanaka, I.; Ohta, H.; Watanabe, Y. Org. Lett. 2013, 15, 628. (36) (a) Krannich, L. K.; Kanjolia, R. K.; Watkins, C. L. Magn. Reson. Chem. 1987, 25, 320. (b) Maryasin, B.; Zipse, H. Phys. Chem. Chem. Phys. 2011, 13, 5150. (c) Albright, T. A.; Freeman, W. J.; Schweizer, E. E. J. Am. Chem. Soc. 1975, 97, 2946. (d) Godfrey, S. M.; McAuliffe, C. A.; Mushtaq, I.; Pritchard, R. G.; Sheffield, J. M. J. Chem. Soc., Dalton Trans. 1998, 3815. (37) Pattarawarapan, M.; Jaita, S.; Wangngae, S.; Phakhodee, W. Tetrahedron Lett. 2016, 57, 1354. (38) Yu, H.; Zhang, M.; Sun, W.; Li, Y.; Gao, R. Lett. Org. Chem. 2010, 7, 566. (39) Zhu, X.; Du, Z.; Xu, F.; Shen, Q. J. Org. Chem. 2009, 74, 6347. (40) Perricone, S. C.; Humphrey, S. J.; Skaletzky, L. L.; Graham, B. E.; Zandt, R. A.; Zins, G. R. J. Med. Chem. 1994, 37, 3693. (41) Baeten, M.; Maes, B. U. W. Adv. Synth. Catal. 2016, 358, 826.

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DOI: 10.1021/acs.joc.7b01794 J. Org. Chem. 2017, 82, 10331−10340