Rhodium-Catalyzed Tandem Reaction of Isocyanides with Azides and

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Article Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

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Rhodium-Catalyzed Tandem Reaction of Isocyanides with Azides and Oxygen Nucleophiles: Synthesis of Isoureas Xiu-Bin Bu,† Zhi-Xin Zhang,† Qin-Qin Peng,† Xianxiu Xu,‡ and Yu-Long Zhao*,† †

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Jilin Province Key Laboratory of Organic Functional Molecular Design & Synthesis, Faculty of Chemistry, Northeast Normal University, Changchun 130024, China ‡ College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong, Key Laboratory of Molecular and Nano Probes, Ministry of Education, Institute of Molecular and Nano Science, Shandong Normal University, Jinan 250014, China S Supporting Information *

ABSTRACT: A novel rhodium-catalyzed tandem reaction of isocyanides with azides and various oxygen nucleophiles has been developed. The reaction provides a simple and highly efficient one-pot synthesis of various N-sulfonyl/acylisoureas with broad substrate scope in an atom-economical manner from readily available starting materials in a highly stereoselective manner.



INTRODUCTION The isourea skeleton is present in various agrochemicals and pharmacologically active substances.1 Additionally, isoureas have many applications, including not only the utilization as key precursors for constructing various important compounds2 but also usage as alkylating and guanylating agents.3 Therefore, many methods for the synthesis of isoureas have been developed, starting from ureas, carbodiimides, chloroformamidines, cyanamides, organic cyanates, and isocyanides.4−8 However, most of methods are focused on the preparation of O-alkylisoureas.4 In stark contrast, methods to access Oarylisourea derivatives are very limited.5−8 The history of the preparation of O-arylisoureas can be traced back to the nucleophilic addition of phenols to carbodiimides.5 These reactions use an excess of the phenol, but common to all is the use of high reaction concentrations at high temperature. In 2008, Rozas and co-workers reported the synthesis of Oarylisoureas via the HgCl2-promoted coupling reaction of N,N′-bis(tert-butoxycarbonyl)thiourea with phenols.6 Recently, a simple and efficient method for the synthesis of Oarylisoureas was developed via actinide-catalyzed intermolecular addition of phenols to carbodiimides.7 In 2018, an elegant alkali-metal-catalyzed addition of phenols to carbodiimides to afford O-arylisoureas was reported by Cantat and co-workers.8 Thus, the development of an efficient and new method for the synthesis of various isoureas, especially O-arylisoureas, which are not based on carbodiimides, is highly desired. Over the past decades, rhodium-catalyzed transformations have received increasing attention because of the versatility and wide application range of rhodium catalysis.9 In this field, rhodium-catalyzed coupling reactions of nitrene precursors with σ-donor/π-acceptor ligands have become a convenient and promising approach for the synthesis of N-containing compounds.10 Recently, Zhang and co-workers developed a © XXXX American Chemical Society

novel strategy to access functionalized amidines via a rhodiumcatalyzed tandem reaction of isocyanides with azides and boronic acids using carbodiimide species as key intermediate (Scheme 1, a).11 As part of our continuing research on Scheme 1. Rhodium-Catalyzed Tandem Reaction of Isocyanides and Azides with Nucleophiles

carbon−carbon and carbon−nitrogen bond formation reactions,12 herein we report a rhodium(I)-catalyzed tandem coupling of isocyanides and azides with oxygen nucleophiles (Scheme 1, b). The reaction works with a broad range of oxygen nucleophiles and provides a simple and efficient method for the construction of various N-sulfonyl/acylisoureas in good to high yields in a single step.



RESULTS AND DISCUSSION Initially, the three-component reaction of 4-isocyanobipheny 1a, sulfonyl azide 2a, and methanol 3a was investigated to optimize the reaction conditions in the presence of rhodium catalysts. As a result, we found that the tandem reaction of 1a (0.2 mmol), Ts-N3 2a (0.3 mmol), and CH3OH (0.3 mmol) proceeded smoothly to give the desired (E)-O-alkylisourea 4aa in 70% yield in the presence of [Cp*RhCl2]2 (2 mol %) in Received: July 18, 2018

A

DOI: 10.1021/acs.joc.8b01842 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Table 2. Synthesis of O-Alkylisoureas 4aa−la,b

toluene at room temperature for 1 h under N2 atmosphere (Table 1, entry 1). The yield of 4aa was raised to 87% by Table 1. Optimization of Reaction Conditionsa,b

entry

catalyst (mol %)

temp (°C)

solvent

yieldb (%)

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

[Cp*RhCl2]2 (2) [Cp*RhCl2]2 (2) [Cp*RhCl2]2 (2) [Cp*RhCl2]2 (2) [Cp*RhCl2]2 (5) [Rh(COD)Cl]2(2) Rh(PPh3)3Cl (2) Rh2(OAc)4 (2) [Rh(nbd)Cl]2(2) [Cp*RhCl2]2 (2) [Cp*RhCl2]2 (2) [Cp*RhCl2]2 (2)

rt 50 100 130 130 130 130 130 130 130 130 130

toluene toluene toluene toluene toluene toluene toluene toluene toluene DCE THF DMF

70 81 82 87c 70 51 30 44 67 50 47 −

a

Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3a−l (0.3 mmol), [Cp*RhCl2]2 (0.004 mmol), at 130 °C in toluene for 1−3 h in a sealed tube. bIsolated yield.

a

Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3a (0.3 mmol), Rh catalyst (0.004−0.01 mmol), solvent (2.0 mL), at rt to 130 °C for 1 h in a sealed tube. [Cp*RhCl2]2 = bis[(pentamethylcyclopentadienyl)dichloro-rhodium], [Rh(COD)Cl]2= chloro(1,5-cyclooctadiene)rhodium(I) dimer, [Rh(nbd)Cl]2 = bicyclo[2.2.1]hepta-2,5-diene-rhodium(I) chloride dimer. bEstimated by 1H NMR spectroscopy using dimethyl phthalate as an internal standard. cIsolated yield.

Table 3. Synthesis of O-Arylisoureas 4am−ra,b

increasing the temperature to 130 °C (entry 4). Other rhodium catalysts, such as [Rh(COD)Cl]2, Rh(PPh3)3Cl, Rh2(OAc)4, and [Rh(nbd)Cl]2 were less effective (entries 6−9). Among the solvents tested, toluene seemed to be the best choice. Other solvents, such as DCE and THF gave lower product yields (entries 10 and 11). No desired product 4aa was observed (TLC) when the reaction was performed in DMF (entry 12). With the optimized reaction conditions in hand, the scope of the reaction was examined and the results are summarized in Table 2. It is obvious that the tandem reaction showed broad tolerance for alcohols. Various primary alcohols, even including the sterically hindered 2,2,2-trifluoroethanol, reacted smoothly with 4-isocyanobiphenyl 1a and sulfonyl azide 2a to give the corresponding (E)-O-alkylisoureas 4aa−h in high yields. Noticeably, a variety of functional groups were tolerated in this process, including alkyl, trifluoromethyl, alkenyl, heteroaryl, and benzyl groups. In addition to primary alcohols, secondary alcohols such as propan-2-ol and cyclohexanol also proved to be efficient partners, and the desired products 4ai and 4aj were produced in 81% and 84% yields, respectively. More importantly, even using 2-isopropyl-5-methylcyclohexanol 3k as nucleophile, the three-component reaction also worked well, providing the desired product 4ak in 78% yield. However, no reaction was observed when tert-butyl alcohol was used as partner. To further explore the generality of this reaction for oxygen nucleophiles, along with the significance of O-arylisoureas,5−8 the rhodium-catalyzed tandem reactions of isocyanide 1a with sulfonyl azide 2a and various phenols 3m−r were investigated. As described in Table 3, various phenols, such as phenols with electron-rich, electron-neutral, or electron-deficient groups and β-naphthol, could react with 1a and 2a to give the

a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), 3m−r (0.3 mmol), [Cp*RhCl2]2 (0.004 mmol), at 130 °C in toluene for 1−3 h in a sealed tube. bIsolated yield.

corresponding (E)-O-arylisoureas 4am−r in high yields (3). It is noteworthy that the tandem reaction also tolerates orthomonosubstituted phenol, indicating that the transformation exhibits good tolerance of steric hindrance (3). The above result not only demonstrates the wide applicability of the current protocol but also provides a simple and efficient onestep access to O-arylisourea derivatives. Next we turned to extend the scope of the reaction with respect to the isocyanides, and the results are summarized in Table 4. It was found that various aromatic isocyanides 1b−h, bearing either electron-withdrawing or electron-donating groups, reacted with sulfonyl azide 2a and methanol 3a to give the corresponding (E)-O-alkylisoureas 4b−ga in good to high yields (Table 4). Similarly, when p-cresol was employed as oxygen nucleophile, (E)-O-arylisoureas 4cm and 4dm were obtained in 82% and 79% yields, respectively (Table 4). However, no reaction was observed when tert-butyl isocyanide was used as a partner (Table 4). Besides functionalized N-sulfonyl azides, this rhodiumcatalyzed tandem reaction could also be applied to general acyl azides (Table 5). Benzoyl azides 2c−e with electron-rich, B

DOI: 10.1021/acs.joc.8b01842 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Table 4. Synthesis of O-Aryl/Alkylisoureas 4a,b

Scheme 2. Control Experiments for Mechanistic Studies

Scheme 3. Proposed Mechanisms for the Formation of 4

a Reaction conditions: 1b−h (0.2 mmol), 2a (0.3 mmol), 3 (0.3 mmol), [Cp*RhCl2]2 (0.004 mmol), at 130 °C in toluene for 1−6 h in a sealed tube. bIsolated yield.

Table 5. Synthesis of O-Alkylisoureas 4as−xa,b

On the basis of the above experimental results together with related reports,9−11 a possible mechanism for the formation of 4 is proposed in Scheme 3. Initially, under the assistance of rhodium catalysts, 1 reacts with 2 to generate the intermediate A. Subsequently, intermediate B, generated by the extrusion of N2 from intermediate A, undergoes reductive elimination to give the carbodiimide intermediate C. Finally, oxygen nucleophiles attack carbodiimide intermediate C to produce the corresponding products 4 (Scheme 3). In conclusion, we have developed a novel strategy for the rapid and efficient synthesis of various O-aryl/alkylisourea derivatives through rhodium-catalyzed tandem reaction of isocyanides, azides, and various oxygen nucleophiles. These reactions feature readily available starting materials, a threecomponent, one-pot procedure, good to high yields, broad substrate scope, good functional group tolerance, and excellent stereoselectivity. Further investigations of rhodium-catalyzed coupling reactions of nitrene precursors with σ-donor/πacceptor ligands are in progress.

a Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), 3a (0.3 mmol), [Cp*RhCl2]2 (0.004 mmol), at 130 °C in toluene for 1−3 h in a sealed tube. bIsolated yield.



EXPERIMENTAL SECTION

Chromatography was carried on flash silica gel (300−400 mesh). All reactions were monitored by TLC, which was performed on precoated aluminum sheets of silica gel 60 (F254). Melting points were uncorrected. Unless noted, the 1H NMR spectra were recorded at 400 MHz, 500 MHz, or 600 MHz in CDCl3, and the 13C NMR spectra were recorded at 126 MHz or 151 MHz in CDCl3 with TMS as internal standard. All coupling constants (J values) are reported in hertz (Hz). High-resolution mass spectra (HRMS) were obtained using a Bruker micro TOF II focus spectrometer (ESI). General Procedure for the Construction of 4. To a solution of 1a (35.8 mg, 0.2 mmol) in toluene (2.0 mL) were added (Cp*RhCl2)2 (3.1 mg, 0.004 mmol), 2a (12.1 μL, 0.3 mmol), and 3a (66.1 μL, 0.3 mmol) under a N2 atmosphere. Then the mixture was stirred for 60 min at 130 °C. After the complete consumption of 1a (TLC), the mixture was treated with brine (50 mL) and extracted with DCM (3 × 15 mL). The combined organic layer was dried over MgSO4 and evaporated under reduced pressure to remove the solvent. Then the given residue was purified by silica gel column chromatography (EtOAc/petroleum ether = 1:50−1:30, V/V) to afford 4aa (66.1 mg, 87% yield) as a yellow solid.

electron-neutral, or electron-deficient groups on the benzene ring were tolerated, giving the corresponding (E)-Oalkylisoureas 4at−v in moderate to high yields (Table 5). Notably, cinnamoyl azide 2f also efficiently yielded the desired product 4aw in 63% yield. However, no reaction was observed when azidobenzene 2g was used as a partner (Table 4). To further probe the reaction mechanisms, some control experiments were performed (Scheme 2). We found that the nucleophilic addition reaction of carbodiimide 5a with methanol 3a can smoothly proceed to give the desired product 4ha in 76% yield under the optimal reaction conditions (Scheme 2, a), implying that carbodiimide should be the intermediate in the tandem reaction. Similarly, when carbodiimide 5b was treated with methanol 3a, N-arylisourea 4ay was obtained in 77% yield (Scheme 2, b). These results indicate that it is the reductive elimination step with loss of N2 that does not work when alkyl azide 2g was employed (Scheme 3). C

DOI: 10.1021/acs.joc.8b01842 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry Methyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4aa). Yellow solid (66.1 mg, 87%), mp 116−118 °C; 1H NMR (600 MHz, CDCl3): δ 9.39 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 7.8 Hz, 4H), 7.43 (t, J = 7.8 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.31−7.27 (m, 4H), 3.89 (s, 3H), 2.42 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 156.3, 143.1, 140.1, 139.7, 138.8, 134.8, 129.5, 128.9, 127.8, 127.5, 126.9, 126.3, 123.1, 55.9, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C21H20N2NaO3S+: 403.1087, found: 403.1092. Ethyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ab). Yellow solid (64.6 mg, 82%), mp 124−126 °C; 1H NMR (600 MHz, CDCl3): δ 9.41 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.57−7.55 (m, 4H), 7.45−7.42 (m, 2H), 7.36−7.33 (m, 1H), 7.30−7.28 (m, 4H), 4.37 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ 155.7, 142.9, 140.1, 139.8, 138.5, 135.1, 129.5, 128.9, 127.7, 127.5, 126.9, 126.2, 122.8, 65.5, 21.6, 14.2; HRMS (ESITOF): [M + Na]+ calculated for C22H22N2NaO3S+: 417.1243, found: 417.1251. Propyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ac). Yellow solid (67.8 mg, 83%), mp 137−139 °C; 1H NMR (600 MHz, CDCl3): δ 9.42 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.60−7.53 (m, 4H), 7.43 (t, J = 7.7 Hz, 2H), 7.37−7.32 (m, 1H), 7.32−7.27 (m, 4H), 4.27 (t, J = 6.7 Hz, 2H), 2.42 (s, 3H), 1.73−1.67 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ 155.9, 142.9, 140.1, 139.8, 138.5, 135.1, 129.5, 128.9, 127.7, 127.5, 126.9, 126.2, 122.8, 71.0, 21.8, 21.6, 10.4; HRMS (ESI-TOF): [M + Na]+ calculated for C23H24N2NaO3S+: 431.1400, found: 431.1405. Butyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ad). Yellow solid (70.9 mg, 84%), mp 152−154 °C; 1H NMR (600 MHz, CDCl3): δ 9.42 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.60−7.54 (m, 4H), 7.43 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.29 (t, J = 8.2 Hz, 4H), 4.31 (t, J = 6.7 Hz, 2H), 2.42 (s, 3H), 1.71−1.59 (m, 2H), 1.37−1.33 (m, 2H), 0.89 (t, J = 7.4 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ 155.9, 142.9, 140.1, 139.8, 138.5, 135.1, 129.5, 128.9, 127.7, 127.5, 126.9, 126.2, 122.8, 69.3, 30.4, 21.6, 19.1, 13.7; HRMS [ESI-TOF]: [M + Na]+ calculated for C24H26N2NaO3S+: 445.1556, found: 445.1577. 2,2,2-Trifluoroethyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ae). Yellow solid (67.2 mg, 75%), mp 143−145 °C; 1H NMR (500 MHz, CDCl3): δ 9.45 (s, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.59 (t, J = 8.5 Hz, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.37 (d, J = 7.5 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H), 4.65 (q, JFH = 8.0 Hz, 2H), 2.45 (s, 3H); 13C NMR (126 MHz, CDCl3): δ 153.9, 143.5, 139.8, 139.3, 138.8, 133.9, 129.5, 128.8, 127.8, 127.5, 126.9, 126.3, 123.4 (q, JFC = 190.4 Hz), 123.1, 63.7 (q, JFC = 37.3 Hz), 21.5; HRMS (ESI-TOF): [M + Na]+ calculated for C22H19F3N2NaO3S+: 471.0961, found: 471.0968. Allyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4af). Yellow solid (67.4 mg, 83%), mp 144−146 °C; 1H NMR (600 MHz, CDCl3): δ 9.41 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.3 Hz, 4H), 7.44 (t, J = 7.2 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 7.32− 7.28 (m, 4H), 5.90 (ddt, J = 16.3, 11.4, 5.8 Hz, 1H), 5.32−5.21 (m, 2H), 4.79 (d, J = 5.4 Hz, 2H), 2.42 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 155.4, 143.1, 140.1, 139.6, 138.7, 134.9, 130.9, 129.5, 128.9, 127.8, 127.5, 126.9, 126.3, 123.0, 119.6, 69.6, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C23H22N2NaO3S+: 429.1243, found: 429.1253. 2-(Thiophen-2-yl)ethyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ag). White solid (82.8 mg, 87%), mp 147−149 °C; 1H NMR (600 MHz, CDCl3): δ 9.38 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.58−7.54 (m, 2H), 7.52−7.48 (m, 2H), 7.45−7.42 (m, 2H), 7.37− 7.32 (m, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.17−7.11 (m, 3H), 6.90 (dd, J = 5.1, 3.4 Hz, 1H), 6.77−6.73 (m, 1H), 4.52 (t, J = 6.6 Hz, 2H), 3.17 (t, J = 6.5 Hz, 2H), 2.42 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 155.5, 143.1, 140.1, 139.7, 139.1, 138.7, 134.7, 129.5, 128.9, 127.7, 127.5, 127.0, 126.9, 126.3, 125.9, 124.3, 123.2, 69.3, 29.1, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C26H24N2NaO3S2+: 499.1121, found: 499.1125. Benzyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ah). White solid (64.8 mg, 71%), mp 153−155 °C; 1H NMR (600 MHz, CDCl3): δ 9.44 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.57−7.50 (m, 4H),

7.42 (t, J = 7.7 Hz, 2H), 7.38−7.31 (m, 1H), 7.31−7.25 (m, 9H), 5.34 (s, 2H), 2.42 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 155.5, 143.0, 140.0, 139.6, 138.7, 134.9, 134.7, 129.5, 128.9, 128.7, 128.6, 128.3, 127.8, 127.5, 126.9, 126.2, 122.9, 70.6, 21.6; HRMS (ESITOF): [M + Na]+ calculated for C27H24N2NaO3S+: 479.1400, found: 479.1389. Isopropyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ai). White solid (66.1 mg, 81%), mp 112−114 °C; 1H NMR (600 MHz, CDCl3): δ 9.42 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.60− 7.52 (m, 4H), 7.43 (t, J = 7.7 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.29 (dd, J = 8.1, 5.7 Hz, 4H), 5.26 (p, J = 6.2 Hz, 1H), 2.41 (s, 3H), 1.29 (d, J = 6.3 Hz, 6H); 13C NMR (151 MHz, CDCl3): δ 155.2, 142.9, 140.1, 139.9, 138.3, 135.2, 129.5, 128.9, 127.7, 127.5, 126.9, 126.2, 122.6, 73.8, 21.8, 21.6; HRMS (ESI-TOF): [M + H]+ calculated for C23H25N2O3S+: 409.1580, found: 409.1607. Cyclohexyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4aj). White solid (75.3 mg, 84%), mp 119−121 °C; 1H NMR (600 MHz, CDCl3): δ 9.44 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.56 (t, J = 7.1 Hz, 4H), 7.43 (t, J = 7.6 Hz, 2H), 7.34 (t, J = 7.4 Hz, 1H), 7.29 (dd, J = 8.4, 2.3 Hz, 4H), 5.07 (tt, J = 8.1, 3.5 Hz, 1H), 2.41 (s, 3H), 1.87−1.86 (m, 2H), 1.69−1.62 (m, 2H), 1.57−1.46 (m, 3H), 1.40−1.34 (m, 2H), 1.32−1.24 (m, 1H); 13C NMR (151 MHz, CDCl3): δ 155.2, 142.8, 140.1, 139.9, 138.3, 135.2, 129.4, 128.9, 127.7, 127.5, 126.9, 126.1, 122.6, 78.1, 31.3, 25.2, 23.4, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C26H28N2NaO3S+: 471.1713, found: 471.1710. 2-Isopropyl-5-methylcyclohexyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′tosylcarbamimidate (4ak). Yellow solid (78.6 mg, 78%), mp 135− 137 °C; 1H NMR (400 MHz, CDCl3): δ 9.39 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.49−7.46 (m, 4H), 7.35 (t, J = 7.6 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.19 (d, J = 8.4 Hz, 4H), 4.95−4.89 (m, 1H), 2.32 (s, 3H), 1.96 (d, J = 11.6 Hz,1H), 1.72−1.70 (m, 1H), 1.57 (d, J = 11.2 Hz, 2H), 1.39−1.33 (m, 2H), 0.98−0.88 (m, 2H), 0.79−0.74 (m, 7H), 0.53 (d, J = 6.8 Hz, 3H); 13C NMR (151 MHz, CDCl3): δ 155.7, 142.8, 140.1, 139.9, 138.3, 135.3, 129.4, 128.9, 127.7, 127.5, 126.9, 126.1, 122.6, 79.9, 47.2, 40.7, 33.9, 31.3, 26.4, 23.3, 21.9, 21.5, 20.8, 16.3; HRMS [ESI-TOF]: [M + Na] + calculated for C30H36N2NaO3S+: 527.2339, found: 527.2335. 4-Methoxyphenyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4am). White solid (84.0 mg, 89%), mp 178−180 °C; 1H NMR (600 MHz, CDCl3): δ 9.52 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.62−7.53 (m, 4H), 7.44 (t, J = 7.7 Hz, 2H), 7.42−7.38 (m, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.25 (d, J = 7.3 Hz, 2H), 6.99−6.92 (m, 2H), 6.86−6.81 (m, 2H), 3.79 (s, 3H), 2.40 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 157.6, 155.4, 144.4, 143.0, 140.0, 139.4, 139.1, 134.7, 129.4, 128.9, 127.9, 127.6, 126.9, 126.1, 123.3, 122.4, 114.4, 55.7, 21.6; HRMS (ESI-TOF): [M + Na] + calculated for C27H24N2NaO4S+: 495.1349, found: 495.1357. p-Tolyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4an). White solid (78.5 mg, 86%), mp 156−158 °C; 1H NMR (600 MHz, CDCl3): δ 9.54 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.57 (ddd, J = 9.2, 7.3, 1.3 Hz, 4H), 7.45−7.38 (m, 4H), 7.35 (dd, J = 9.0, 4.2 Hz, 1H), 7.26−7.24 (m, 2H), 7.12 (d, J = 8.2 Hz, 2H), 6.92−6.91 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 155.3, 148.7, 142.9, 140.0, 139.4, 139.1, 136.1, 134.7, 129.9, 129.4, 128.9, 127.9, 127.6, 126.9, 126.2, 123.3, 121.2, 21.6, 20.9; HRMS (ESITOF): [M + Na]+ calculated for C27H24N2NaO3S+: 479.1400, found: 479.1406. 4-Bromophenyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ao). Yellow solid (84.2 mg, 81%), mp 201−203 °C; 1H NMR (600 MHz, CDCl3): δ 9.53 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.61−7.56 (m, 2H), 7.56 (dd, J = 8.2, 1.1 Hz, 2H), 7.46−7.43 (m, 4H), 7.40−7.37 (m, 2H), 7.36−7.35 (m, 1H), 7.27 (d, J = 8.0 Hz, 2H), 6.94−6.91 (m, 2H), 2.42 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 154.7, 149.9, 143.3, 139.9, 139.4, 139.1, 134.4, 132.5, 129.5, 128.9, 127.9, 127.7, 126.9, 126.2, 123.5, 123.4, 119.6, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C26H21BrN2NaO3S+: 543.0348, found: 543.0352. 2-Bromophenyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ap). Yellow solid (81.1 mg, 78% yield), mp 194−196 °C; D

DOI: 10.1021/acs.joc.8b01842 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry H NMR (600 MHz, CDCl3): δ 9.58 (s, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.62−7.60 (m, 2H), 7.58−7.56 (m, 2H), 7.54−7.50 (m, 3H), 7.45−7.42 (m, 2H), 7.37−7.34 (m, 1H), 7.29 (td, J = 7.9, 1.5 Hz, 1H), 7.25−7.23 (m, 2H), 7.13−7.10 (m, 2H), 2.40 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 154.8, 148.3, 143.1, 140.0, 139.5, 139.0, 134.4, 133.2, 129.3, 128.9, 128.6, 127.9, 127.8, 127.6, 127.0, 126.4, 124.0, 123.9, 116.0, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C26H21BrN2NaO3S+: 543.0348, found: 543.0351. 2-Iodophenyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4aq). White solid (85.2 mg, 75%), mp 208−210 °C; 1H NMR (600 MHz, CDCl3): δ 9.61 (s, 1H), 7.75−7.71 (m, 3H), 7.62−7.60 (m, 2H), 7.58−7.57 (m, 2H), 7.54 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 7.7 Hz, 2H), 7.36−7.31 (m, 2H), 7.25−7.24 (m, 2H), 7.07 (dd, J = 8.1, 1.3 Hz, 1H), 6.97 (td, J = 7.8, 1.4 Hz, 1H), 2.40 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 154.7, 151.3, 143.1, 140.0, 139.4, 139.3, 139.1, 134.5, 129.6, 129.3, 128.9, 128.1, 127.9, 127.6, 127.0, 126.5, 124.0, 123.4, 90.1, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C26H21IN2NaO3S+: 591.0210, found: 591.0218. Naphthalen-2-yl-N-([1,1′-Biphenyl]-4-yl)-N′-tosylcarbamimidate (4ar). White solid (82.7 mg, 84%), mp 172−174 °C; 1H NMR (600 MHz, CDCl3): δ 9.59 (s, 1H), 7.84−7.82 (m, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.74−7.69 (m, 3H), 7.63−7.59 (m, 2H), 7.59−7.55 (m, 2H), 7.50−7.45 (m, 4H), 7.46−7.41 (m, 3H), 7.35 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 7.17 (dd, J = 8.9, 2.4 Hz, 1H), 2.39 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 155.2, 148.5, 143.1, 139.9, 139.3, 139.2, 134.7, 133.6, 131.7, 129.5, 129.4, 128.9, 127.9, 127.8, 127.7, 127.6, 127.0, 126.8, 126.2, 126.1, 123.4, 120.9, 118.6, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C30H24N2NaO3S+: 515.1400, found: 515.1418. Methyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-(phenylsulfonyl)carbamimidate (4as). White solid (54.2 mg, 74%), mp 163−165 °C; 1H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.42−7.34 (m, 7H), 7.29 (t, J = 7.2 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 3.75 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 156.5, 142.5, 140.1, 138.9, 134.8, 132.4, 128.9, 127.8, 127.6, 126.9, 126.2, 123.2, 55.9, one carbon is not visible due to overlapping peaks; HRMS (ESI-TOF): [M + Na]+ calculated for C20H18N2NaO3S+: 389.0930, found: 389.0936. Methyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-benzoylcarbamimidate (4at). White solid (45.6 mg, 69%), mp 107−109 °C; 1H NMR (400 MHz, CDCl3): δ 12.14 (s, 1H), 8.32−8.30 (m, 2H), 7.58 (d, J = 8.4 Hz, 4H), 7.54−7.50 (m, 1H), 7.47−7.40 (m, 6H), 7.34 (d, J = 7.2 Hz, 1H), 4.14 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 177.9, 161.1, 140.3, 138.1, 137.4, 135.6, 132.2, 129.5, 128.9, 128.1, 127.8, 127.4, 126.9, 122.5, 55.1; HRMS (ESI-TOF): [M + Na]+ calculated for C21H18N2NaO2+: 353.1260, found: 353.1262. Methyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-(4-chlorobenzoyl)carbamimidate (4au). White solid (56.1 mg, 77%), mp 140−142 °C; 1H NMR (400 MHz, CDCl3): δ 12.08 (s, 1H), 8.24 (d, J = 8.8 Hz, 2H),7.59 (m, 4H), 7.46−7.40 (m, 6H), 7.37−7.33 (m, 1H), 4.14 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 176.8, 161.1, 140.2, 138.4, 138.3, 135.8, 135.4, 130.8, 128.9, 128.4, 127.8, 127.4, 126.9, 122.6, 55.2; HRMS (ESI-TOF): [M + Na] + calculated for C21H17ClN2NaO2+: 387.0871, found: 387.0879. Methyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-(4-methoxybenzoyl)carbamimidate (4av). White solid (33.1 mg, 46%), mp 151−153 °C; 1H NMR (400 MHz, CDCl3): δ 12.03 (s, 1H), 8.19 (d, J = 9.2 Hz, 2H), 7.50−7.48 (m, 4H), 7.37−7.31 (m, 4H), 7.25 (t, J = 7.2 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 4.05 (s, 3H), 3.78 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 177.4, 162.9, 160.7, 140.3, 137.9, 135.7, 131.5, 130.1, 128.8, 127.7, 127.3, 126.9, 122.4, 113.3, 55.4, 54.9; HRMS (ESI-TOF): [M + Na]+ calculated for C22H20N2NaO3+: 383.1366, found: 383.1357. Methyl (E)-N-([1,1′-Biphenyl]-4-yl)-N′-cinnamoylcarbamimidate (4aw). White solid (44.9 mg, 63%), mp 118−120 °C; 1H NMR (400 MHz, CDCl3): δ 11.95 (s, 1H), 7.69 (d, J = 16.0 Hz, 1H), 7.45−7.43 (m, 6H), 7.32−7.21 (m, 8H), 6.59 (d, J = 16.0 Hz, 1H), 3.95 (s, 3H); 13 C NMR (151 MHz, CDCl3): δ 178.5, 160.7, 142.3, 140.3, 138.0, 135.6, 135.4, 129.7, 128.9, 128.8, 128.2, 127.7, 127.4, 127.3, 126.9,

122.5, 55.0; HRMS (ESI-TOF): [M + Na]+ calculated for C23H20N2NaO2+: 379.1417, found: 379.1416. Methyl (E)-N-tert-Butyl-N′-phenylcarbamimidate (4ay). Colorless liquid (31.7 mg, 77%); 1H NMR (600 MHz, CDCl3): δ 7.28 (t, J = 7.8 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.2 Hz, 2H), 3.88 (s, 1H), 3.86 (s, 3H), 1.22 (s, 9H); 13C NMR (151 MHz, CDCl3): δ 154.5, 148.9, 129.5, 122.9, 122.3, 53.1, 50.9, 30.2; HRMS (ESI-TOF): [M + H]+ calculated for C12H19N2O+: 207.1492, found: 207.1500. Methyl (E)-N-(4-Methoxyphenyl)-N′-tosylcarbamimidate (4ba). White solid (57.5 mg, 86% yield), mp 174−176 °C; 1H NMR (600 MHz, CDCl3): δ 9.12 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 3.80 (s, 3H), 2.43 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 157.9, 156.8, 142.9, 139.8, 129.4, 128.3, 126.2, 125.3, 114.3, 55.7, 55.5, 21.5; HRMS (ESI-TOF): [M + Na] + calculated for C16H18N2NaO4S+: 357.0879, found: 357.0889. Methyl (E)-N-(p-Tolyl)-N′-tosylcarbamimidate (4ca). White solid (56.6 mg, 89%), mp 166−168 °C; 1H NMR (600 MHz, CDCl3): δ 9.22 (s, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 7.14 (d, J = 7.8 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 3.84 (s, 3H), 2.42 (s, 3H), 2.33 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 156.5, 142.9, 139.8, 135.9, 132.9, 129.7, 129.4, 126.2, 123.2, 55.7, 21.5, 20.9; HRMS (ESI-TOF): [M + Na]+ calculated for C16H18N2NaO3S+: 341.0930, found: 341.0922. Methyl (E)-N-Mesityl-N′-tosylcarbamimidate (4da). White solid (53.3 mg, 77%), mp 178−180 °C; 1H NMR (500 MHz, CDCl3): δ 8.62 (s, 1H), 7.88 (d, J = 8.4, 2H), 7.30 (d, J = 7.8 Hz, 2H), 6.89 (s, 2H), 3.76 (s, 3H), 2.43 (s, 3H), 2.28 (s, 3H), 2.11 (s, 6H); 13C NMR (151 MHz, CDCl3): δ 157.8, 142.9, 139.9, 137.8, 135.3, 130.3, 129.4, 129.0, 126.3, 55.8, 21.5, 20.9, 18.0; HRMS (ESI-TOF): [M + Na]+ calculated for C18H22N2NaO3S+: 369.1243, found: 369.1247. Methyl (E)-N′-(4-Chlorophenyl)-N-tosylcarbamimidate (4ea). Yellow solid (55.4 mg, 82%), mp 153−155 °C; 1H NMR (500 MHz, CDCl3): δ 9.32 (s, 1H), 7.86−7.84 (m, 2H), 7.31−7.30 (m, 4H), 7.16−7.14 (m, 2H), 3.87 (s, 3H), 2.43 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 156.1, 143.2, 139.5, 134.2, 131.4, 129.5, 129.3, 126.3, 124.2, 55.9, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C15H15ClN2NaO3S+: 361.0384, found: 361.0377. Methyl (E)-N′-(4-Bromophenyl)-N-tosylcarbamimidate (4fa). Yellow solid (58.8 mg, 77%), mp 194−196 °C; 1H NMR (600 MHz, CDCl3): δ 9.32 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 3.87 (s, 3H), 2.43 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 156.0, 143.2, 139.5, 134.7, 132.2, 129.5, 126.3, 124.5, 119.0, 55.9, 21.6; HRMS (ESI-TOF): [M + Na}+calculated for C15H15BrN2NaO3S+: 404.9879, found: 404.9870. Methyl (E)-N-(4-Chloro-2-iodophenyl)-N′-tosylcarbamimidate (4ga). White solid (62.2 mg, 67%), mp 185−187 °C; 1H NMR (600 MHz, CDCl3): δ 9.24 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 1.6 Hz, 1H), 7.33−7.30 (m, 3H), 7.26 (d, J = 8.4 Hz, 1H), 3.82 (s, 3H), 2.43 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 155.9, 143.2, 139.4, 138.7, 136.5, 132.8, 129.5, 129.1, 127.0, 126.5, 95.4, 55.9, 21.6; HRMS (ESI-TOF): [M + Na]+ calculated for C15H14ClIN2NaO3S+: 486.9351, found: 486.9373. Methyl (E)-N-tert-Butyl-N′-tosylcarbamimidate (4ha). White solid (43.2 mg, 76%), mp 74−75 °C; 1H NMR (600 MHz, CDCl3): δ 7.78 (d, J = 8.4 Hz, 2H), 7.43 (s, 1H), 7.27 (d, J = 7.8 Hz, 2H), 3.81 (s, 3H), 2.41 (s, 3H), 1.31 (s, 9H); 13C NMR (151 MHz, CDCl3): δ 158.3, 142.5, 140.2, 129.2, 126.0, 55.1, 52.7, 29.5, 21.5; HRMS (ESI-TOF): [M + Na] + calculated for C13H20N2NaO3S+: 307.1087, found: 307.1088. p-Tolyl (E)-N-(p-Tolyl)-N′-tosylcarbamimidate (4cm). Yellow solid (64.6 mg, 82%), mp 151−153 °C; 1H NMR (600 MHz, CDCl3): δ 9.38 (s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 2.39 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H); 13C NMR (151 MHz, CDCl3): δ 155.5, 148.8, 142.9, 139.5, 137.7, 136.2, 135.9, 132.9, 129.8, 129.3, 126.1, 123.3, 121.2, 21.5, 20.9, 20.8, one carbon is not visible due to overlapping peaks; HRMS

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DOI: 10.1021/acs.joc.8b01842 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry (ESI-TOF): [M + Na]+ calculated for C22H22N2NaO3S+: 417.1243, found: 417.1251. p-Tolyl (E)-N-Mesityl-N′-tosylcarbamimidate (4dm). Yellow solid (66.7 mg, 79%), mp 163−165 °C; 1H NMR (600 MHz, CDCl3): δ 8.79 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 6.90 (s, 2H), 6.76 (d, J = 8.4 Hz, 2H), 2.41 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H), 2.23 (s, 6H); 13C NMR (151 MHz, CDCl3): δ 157.1, 148.9, 142.8, 139.6, 137.9, 135.7, 135.3, 130.3, 129.7, 129.3, 129.1, 126.2, 121.2, 21.5, 20.9, 20.8, 18.2; HRMS (ESITOF): [M + Na]+ calculated for C24H26N2NaO3S+: 445.1556, found: 445.1559.



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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.8b01842. Copies of 1H and 13C NMR spectra of the products (PDF)



AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Xianxiu Xu: 0000-0001-7435-7449 Yu-Long Zhao: 0000-0001-6577-1074 Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS Financial support of this research by the National Natural Sciences Foundation of China (21472017 and 21871044) is greatly acknowledged.



REFERENCES

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DOI: 10.1021/acs.joc.8b01842 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

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DOI: 10.1021/acs.joc.8b01842 J. Org. Chem. XXXX, XXX, XXX−XXX