English

• 1.   Introduction

  Effectively scissoring carbon-carbon bond represents one of the most important tools in current organic synthesis because of the ubiquitous presence of carbon-carbon bond in both saturated and unsaturated forms in nature.^[1] The past decades have witnessed spectacular advances in synthetic organic reactions based on the key functionalization or activation of carbon-carbon bonds. Among the numerous known donors of reactive carbon-carbon bond, ^[2] the enaminones have been identified as a class of promising substrates in the designation of practical organic reactions by cleaving the C＝C double bond in recent years.^[3] As typical stable enamine species, the C＝C double bonds in enaminones have been found to be capable of decomposing via the formation and reorganization of 1, 2-dioxetane^[4]/1, 2-oxathietane intermediate, ^[5] free radical-based bond cleavage via DMF release, ^[6] ring opening and reconstruction of cyclopropane intermediate resulting from carbene cycloaddition, ^[7] and Pd-catalyzed tandem enamine hydrolysis and decarbonylation.^[8]

  On the other hand, as a typical transformation, the cycloaddition of the in situ formed unstable enamine intermediate and azide has been found as highly important route to cleave the carbon-carbon bond via the decomposition of the resulted triazoline ring, which provides effective accesses to amidines.^[9] Accordingly, the employment of stable enamines such as enaminones has also received concerns in the development of synthetic method toward amidine scaffolds. Early in 1963, Fusco and co-workers^[10] have observed the formation of N-sulfonyl amidines in the reactions of aryl stabilized N, N-disubstituted α-aminostyrene with tosyl azide. Later efforts in similar reactions, unexceptionally, can be used only for the synthesis of N-sulfonyl amidines featured with N, N-disubstituted substructure because only N, N-disubstituted α-aminostyrenes are the tolerable enamine substrates.^[11] Clearly, such synthetic methods suffer from rigid restriction in the synthesis of amidine products with diversified amino functionalization, thus reflects the urgent requirement in developing new synthetic approaches allowing the synthesis of other amino group, such as free NH₂-functionalized amidines.

  Over past decade, an array of different tactics have been devised for the synthesis amidines. For instance, the condensation of amines with amide acetals or in situ activated amides, ^[12] the decomposition of in situ generated 1, 2, 3-triazoline ring given by copper-catalyzed alkyne-azide dipolar cycloaddition, ^[13] the activation of terminal alkynes, ^[14] catalytic C＝N bond formation from the thioamide C＝S bond^[15] etc have been disclosed as useful methods. Amazingly, regardless the availability of these important synthetic routes, ^[16] most of them are limited in the synthesis of N, N-disubstituted or N-substituted amidines. Only rather a few transition-metal-catalyzed protocols, on the contrary, can be used for the synthesis of amidines bearing free NH₂-group.^{[9c, 17]} The synthesis of NH₂-free amidines under transition-metal-free conditions, however, has not yet been realized. In combination of the urgent requirement to find transition-metal-free NH₂-amidine synthesis and the highly versatile application of enaminone platform synthons in the synthesis of diversified organic products, ^[18] we thought that NH₂-functionalized enaminones might be used as proper precursors to achieve such expected synthesis. Herein, we report the first metal-free method for the synthesis of NH₂-featured N-sulfonyl amidines via the reactions of NH₂-functionalized enaminones and sulfonyl azides, which significantly expands the frontiers of enaminones in the synthesis of structurally diverse amidines and sulfonylated scaffolds.^[19]

  2.   Results and discussion

  Originally, the readily available enaminone 1a and tosyl azide 2a were selected as substrates to probe practical reaction conditions. As presented in Table 1, by stirring in DMF at room temperature, the reaction of the two substrates in the presence of t-BuONa gave the target amidine product 3a with 21% yield, and 3a was not observed without using any additive (Entries 1, 2, Table 1). Following these results, a series of different base additives, including organic and inorganic ones, were then screened. Based on the in hand data, 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU) was identified as amongst the best additive by assisting the formation of 3a with 46% yield (Entries 3~7, Table 1). Heightening the reaction temperature led to inferior result (Entry 8, Table 1). Later on, this reaction was conducted independently in different media such as water, MeCN, toluene, EtOH, dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF) (Entries 9~14, Table 1). However, DMF was yet the best medium. In further study, prolonging the reaction time to 12 h was found to improve the yield of the target product (Entries 15~16, Table 1). On the other hand, increasing the amount of tosyl azide 2a could also help in enhancing the product yield (Entries 17, 18, Table 1). Finally, when the loading of DBU was increased to 5 equiv., the target product was obtained with 91% yield (Entries 19, 20, Table 1).

  Table 1

  

  Table 1.  Optimization on reaction conditions^a

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  Entry	Additive	Solvent	Yieldb/%
  1	t-BuONa	DMF	21
  2	—	DMF	0
  3	NaHCO3	DMF	20
  4	NaOH	DMF	19
  5	DBU	DMF	46
  6	DMAP	DMF	17
  7	2, 6-Lutidine	DMF	12
  8c	DBU	DMF	26
  9	DBU	H2O	38
  10	DBU	MeCN	35
  11	DBU	Toluene	38
  12	DBU	EtOH	37
  13	DBU	DMSO	34
  14	DBU	THF	28
  15d	DBU	DMF	61
  16e	DBU	DMF	48
  17d, f	DBU	DMF	52
  18d, g	DBU	DMF	67
  19d, g, h	DBU	DMF	81
  20d, g, i	DBU	DMF	91
  a General conditions: 1a (0.2 mmol), 2a (0.5 mmol), additive (0.4 mmol) in 2 mL of solvent, stirred at r.t. for 6 h. b Yield of isolated product based on 1a. c Reaction at 60 ℃. d Stirred for 12 h. e Stirred for 24 h. f With 0.3 mmol of 2a. g With 1.0 mmol of 2a. h With 0.8 mmol of DBU. I With 1.0 mmol of DBU.

  With the optimized reaction conditions, the application scope of this C＝C bond cleavage reaction in the synthesis of NH₂-functionalized N-sulfonyl amidines was systematically investigated (Table 2). Firstly, the enaminone 1a was employed to react with a plethora of aryl sulfonyl azides, respectively. As expected, the reaction displayed broad tolerance to the aryl substructure. Azides functionalized with phenyl containing electron donating (3a~3b) and withdrawing (3c~3d) group in the para-position, the phenyls with ortho- and meta-substituent (3e~3g) and polysubstituted phenyl (3h), as well as naphthyl/heteroaryl (3i~3j) were all transformed into the target products with good to excellent yields. On the other hand, enaminones 1 with alkyl (3k~3n), alkoxyl (3o~3p), halogen (3q) substituted β-phenyl also participated the reaction to provide the products with satisfactory results. Furthermore, equivalent enaminones featured with heteroaryl (3r) and fuse aryl (3s) were also practical substrates. Finally, employing methyl sulfonyl azide to react with enaminone 1a did not provide the expected amidine product under the standard conditions.

  Table 2

  

  Table 2.  Scope on the enaminone-based synthesis of N-sulfonyl amidines^{a, b}

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  Encouraged by the successful synthesis of the diverse amidine products, the gram scale reaction for the synthesis of 3a was then performed. We were delighted to find that authentically practical result was provided by the scale-up synthesis with up to 78% yield of 3a (Eq. 1).

  (1)

  Later on, for the sake of probing the reaction mechanism, several control experiments were then designed and conducted. First, the model reaction for 3a synthesis was conducted in the presence of free radical scavenger 2, 2, 6, 6-Tetramethylpiperidinooxy (TEMPO) and 2, 6-di-t-butyl-p-cresol (BHT), respectively. Both scavengers, however, exhibited no inhibition effect to the reaction even at the loading of 4 equiv. (Eqs. 2, 3), suggesting against the formation of any free radical intermediate in the reaction. In addition, the reaction of ¹⁵N-labelled enaminone and tosyl azide 2a gave ¹⁵N-labelled product ¹⁵N-3a, confirming that the amino group in the enaminone substrate was retained during the reaction process (Eq. 4).

  (2)

  (3)

  (4)

  On the basis of the results obtained in hand, a plausible mechanism for the reaction is proposed. As outlined in Scheme 1, initially, the enaminone and sulfonyl azide couples provide 1, 2, 3-triazoline intermediate 4 via the well documented dipolar cycloaddition. The possible transformation of this intermediate to 1, 2, 3-triazole 7 by eliminating ammonium can be inhibited by the presence of DBU. Instead, the other transformation route of ring decomposition providing amidine 5 and the diazoketone 6 is favored under the present reaction conditions. The tautomerization of 5 then yields the final amidine products 3.

  Scheme 1

  

  Scheme 1.  Proposed reaction mechanism

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  3.   Conclusions

  In conclusion, by employing NH₂-functionalized enaminone esters as the C＝C bond donors, we have successfully established the first metal-free protocol toward the synthesis of free NH₂-featured N-sulfonyl amidines by cleaving C＝C double bond. Besides the metal-free operation, the ambient reaction conditions as well as the practical scale-up synthesis constitute also notable advantages of this work.

  4.   Experimental section

  4.1   General experimental information

  All experiments were carried out under air atmosphere. Enaminones 1^[20] and tosyl azides 2 (except the commercially available 2a)^[21] were synthesized following literature processes. All other chemicals and solvents used in the experiments were obtained from commercial sources and used directly without further treatment. ¹H NMR and ¹³C NMR spectra were recorded in 400 MHz apparatus and the frequencies for ¹H NMR and ¹³C NMR test are 400 MHz and 100 MHz, respectively. The chemical shifts were reported with TMS as internal standard. Melting points were tested in an X-4A instrument without correcting temperature and the HRMS were obtained under ESI model in a mass spectrometer equipped with TOF analyzer.

  4.2   General procedure for the synthesis of amidines 3

  To a 25 mL round-bottom flask were added enaminone 1 (0.2 mmol), sulfonyl azide 2 (1.0 mmol), DBU (1.0 mmol) and DMF (2.0 mL). Then the mixture was stirred at the room temperature for 12 h (TLC). Upon completion, 5 mL of water was added, and the resulting mixture was extracted with ethyl acetate (8 mL×3). The organic phases were combined and washed with small amount of water for three times. After drying with anhydrous Na₂SO₄, the solid was filtered and the solvent in the acquired solution was removed under reduced pressure. The resulting residue was subjected to flash silica gel column chromatography to provide pure products with the elution of mixed petroleum ether/ethyl acetate (V:V＝5:1 or 3:1).

  N-Tosylbenzimidamide (3a):^[22] 49.8 mg, 91% yield. White solid, m.p. 153~155 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.30 (s, 1H), 7.86 (d, J＝8.4 Hz, 2H), 7.78 (d, J＝7.6 Hz, 2H), 7.49 (t, J＝7.4 Hz, 1H), 7.37 (t, J＝7.8 Hz, 2H), 7.26 (d, J＝8.0 Hz, 2H), 6.68 (s, 1H), 2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.8, 143.0, 139.3, 133.3, 132.7, 129.4, 128.7, 127.4, 126.4, 21.5.

  N-(4-Methoxyphenylsulfonyl)benzimidamide (3b): 49.0 mg, 84% yield. White solid, m.p. 109~111 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.26 (s, 1H), 7.90 (d, J＝8.8 Hz, 2H), 7.78 (d, J＝7.6 Hz, 2H), 7.48 (t, J＝7.4 Hz, 1H), 7.36 (t, J＝7.4 Hz, 2H), 6.92 (d, J＝8.8 Hz, 2H), 6.88 (s, 1H), 3.82 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.7, 134.1, 133.3, 132.7, 128.7, 128.5, 128.5, 127.5, 114.0, 55.6; ESI-HRMS calcd for C₁₄H₁₅N₂O₃S [M+H]⁺ 291.0798, found 291.0799.

  N-(4-Chlorophenylsulfonyl)benzimidamide (3c): 46.1 mg, 78% yield. White solid, m.p. 98~100 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.29 (s, 1H), 7.90 (d, J＝8.8 Hz, 2H), 7.78 (d, J＝7.6 Hz, 2H), 7.51 (t, J＝7.4 Hz, 1H), 7.46~7.35 (m, 4 H), 6.80 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 140.6, 138.7, 133.0, 132.9, 129.1, 128.8, 127.9, 127.5; ESI-HRMS calcd for C₁₃H₁₂ClN₂O₂S [M+H]⁺ 295.0303, found 295.0304.

  N-(4-Bromophenylsulfonyl)benzimidamide (3d): 49.9 mg, 74% yield. White solid, m.p. 102~103 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.29 (s, 1H), 7.83 (d, J＝8.4 Hz, 2H), 7.77 (d, J＝7.2 Hz, 2H), 7.59 (d, J＝8.4 Hz, 2H), 7.52 (t, J＝7.4 Hz, 1H), 7.39 (t, J＝7.6 Hz, 2H), 6.85 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.3, 141.2, 133.0, 132.9, 132.1, 128.8, 128.0, 127.5, 127.2; ESI-HRMS calcd for C₁₃H₁₂BrN₂O₂S [M+H]⁺ 338.9797, found 338.9798.

  N-(o-Tolylsulfonyl)benzimidamide (3e): 40.0 mg, 73% yield. White solid, m.p. 68~70 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.25 (s, 1H), 8.06 (d, J＝8.0 Hz, 1H), 7.79 (d, J＝7.2 Hz, 2H), 7.50 (t, J＝7.4 Hz, 1H), 7.45~7.35 (m, 3H), 7.29 (d, J＝7.2 Hz, 2H), 6.63 (s, 1H), 2.75 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.8, 140.2, 137.6, 133.3, 132.7, 132.4, 132.3, 128.8, 127.7, 127.4, 125.8, 20.4; ESI-HRMS calcd for C₁₄H₁₅N₂O₂S [M+H]⁺ 275.0849, found 275.0852.

  N-(2-Chlorophenylsulfonyl)benzimidamide (3f): 38.4 mg, 65% yield. White solid, m.p. 91~92 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.43 (s, 1H), 8.20 (dd, J＝7.8, 1.4 Hz, 1H), 7.79 (d, J＝7.2 Hz, 2H), 7.56~7.43 (m, 3H), 7.39 (d, J＝7.6 Hz, 3H), 6.73 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 164.1, 139.4, 133.3, 133.2, 132.8, 132.6, 131.6, 129.7, 128.8, 127.5, 126.9; ESI-HRMS calcd for C₁₃H₁₂Cl-N₂O₂S [M+H]⁺ 295.0303, found 295.0305.

  N-(3-Chlorophenylsulfonyl)benzimidamide (3g): 41.3 mg, 70% yield. White solid, m.p. 79~80 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.33 (s, 1H), 7.97 (s, 1H), 7.88 (d, J＝7.2 Hz, 1H), 7.80 (d, J＝7.2 Hz, 2H), 7.60~7.47 (m, 2H), 7.43 (t, J＝7.4 Hz, 3H), 6.64 (s, 1H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.3, 143.8, 134.9, 133.1, 132.9, 132.5, 130.2, 128.9, 127.5, 126.6, 124.6; ESI-HRMS calcd for C₁₃H₁₂ClN₂O₂S [M+H]⁺ 295.0303, found 295.0302.

  N-(Mesitylsulfonyl)benzimidamide (3h): 49.3 mg, 82% yield. White solid, m.p. 90~92 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.17 (s, 1H), 7.76 (d, J＝7.6 Hz, 2H), 7.49 (t, J＝7.4 Hz, 1H), 7.39 (t, J＝7.6 Hz, 2H), 6.92 (s, 2H), 6.40 (s, 1H), 2.71 (s, 6 H), 2.28 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.8, 141.6, 138.7, 136.4, 133.6, 132.5, 131.6, 128.8, 127.3, 22.7, 20.9; ESI-HRMS calcd for C₁₆H₁₉N₂-O₂S [M+H]⁺ 303.1162, found 303.1166.

  N-(Naphthalen-2-ylsulfonyl)benzimidamide (3i). 49.7 mg, 80% yield. White solid, m.p. 103~105 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.52 (s, 1H), 8.38 (s, 1H), 7.97 (d, J＝8.4 Hz, 1H), 7.90 (t, J＝8.4 Hz, 2H), 7.85 (d, J＝8.0 Hz, 1H), 7.68 (d, J＝8.0 Hz, 2H), 7.61~7.51 (m, 2H), 7.13 (d, J＝8.0 Hz, 2H), 6.74 (s, 1H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.1, 143.7, 139.1, 134.7, 132.1, 130.2, 129.4, 129.3, 129.1, 128.5, 127.8, 127.5, 127.3, 127.1, 122.4, 21.5; ESI-HRMS calcd for C₁₇H₁₅-N₂O₂S [M+H]⁺ 311.0849, found 311.0850.

  N-(Quinolin-8-ylsulfonyl)benzimidamide (3j): 45.2 mg, 73% yield. White solid, m.p. 107~109 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.18 (s, 1H), 8.98 (s, 1H), 8.77 (s, 1H), 8.55~8.42 (m, 2H), 8.26 (d, J＝8.0 Hz, 1H), 7.91~7.71 (m, 3H), 7.70~7.60 (m, 1H), 7.58~7.49 (m, 1H), 7.48~7.38 (m, 2H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 164.0, 151.4, 144.0, 139.6, 137.3, 134.3, 133.7, 132.6, 130.4, 129.0, 128.9, 128.2, 126.1, 122.7; ESI-HRMS calcd for C₁₆H₁₄N₃O₂S [M+H]⁺ 312.0801, found 312.0803.

  4-Methyl-N-tosylbenzimidamide (3k): 50.7 mg, 88% yield. White solid, m.p. 167~168 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.27 (s, 1H), 7.86 (d, J＝8.0 Hz, 2H), 7.68 (d, J＝8.0 Hz, 2H), 7.26 (d, J＝8.0 Hz, 2H), 7.18 (d, J＝8.0 Hz, 2H), 6.53 (s, 1H), 2.39 (s, 3H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 162.7, 143.5, 142.9, 139.5, 130.4, 129.4, 129.3, 127.4, 126.4, 21.5; ESI-HRMS calcd for C₁₅H₁₇N₂O₂S [M+H]⁺ 289.1005, found 289.1008.

  N-(4-Chlorophenylsulfonyl)-4-methylbenzimidamide(3l): 46.0 mg, 75% yield. White solid, m.p. 151~152 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.27 (s, 1H), 7.90 (d, J＝8.4 Hz, 2H), 7.68 (d, J＝8.4 Hz, 2H), 7.43 (d, J＝8.8 Hz, 2H), 7.19 (d, J＝8.0 Hz, 2H), 6.69 (s, 1H), 2.37 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.2, 143.9, 140.8, 138.6, 130.0, 129.5, 129.0, 127.9, 127.5, 21.5; ESI-HRMS calcd for C₁₄H₁₄ClN₂O₂S [M+H]⁺ 309.0459, found 309.0460.

  4-Methyl-N-(naphthalen-2-ylsulfonyl)benzimidamide(3m): 50.6 mg, 78% yield. White solid, m.p. 160~162 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.52 (s, 1H), 8.38 (s, 1H), 7.97 (d, J＝8.4 Hz, 1H), 7.90 (t, J＝8.4 Hz, 2H), 7.85 (d, J＝8.0 Hz, 1H), 7.68 (d, J＝8.0 Hz, 2H), 7.61~7.49 (m, 2H), 7.13 (d, J＝8.0 Hz, 2H), 6.74 (s, 1H), 2.30 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.1, 143.7, 139.1, 134.7, 132.1, 130.2, 129.4, 129.3, 129.1, 128.5, 127.8, 127.5, 127.3, 127.1, 122.4, 21.5; ESI-HRMS calcd for C₁₈H₁₇N₂O₂S [M+H]⁺ 325.1005, found 325.1006.

  4-Methyl-N-(quinolin-8-ylsulfonyl)benzimidamide (3n): 45.0 mg, 69% yield. White solid, m.p. 164~166 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 8.22 (s, 1H), 8.05 (d, J＝2.8 Hz, 1H), 7.84 (s, 1H), 7.62~7.50 (m, 2H), 7.34 (d, J＝8.0 Hz, 1H), 6.88~6.78 (m, 3H), 6.73 (q, J＝4.0 Hz, 1H), 6.32 (d, J＝8.0 Hz, 2H), 1.40 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 163.8, 151.4, 144.0, 143.0, 139.7, 137.2, 133.6, 131.4, 130.3, 129.4, 129.0, 128.3, 126.1, 122.7, 21.4; ESI-HRMS calcd for C₁₇H₁₆N₃O₂S [M+H]⁺ 326.0958, found 326.0961.

  4-Methoxy-N-tosylbenzimidamide (3o): 48.8 mg, 80% yield. White solid, m.p. 164~166 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.24 (s, 1H), 7.86 (d, J＝8.0 Hz, 2H), 7.77 (d, J＝8.8 Hz, 2H), 7.26 (d, J＝8.0 Hz, 2H), 6.87 (d, J＝9.2 Hz, 2H), 6.54 (s, 1H), 3.82 (s, 3H), 2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.4, 162.2, 142.8, 139.6, 129.4, 129.3, 126.4, 125.2, 114.0, 55.5, 21.5; ESI-HRMS calcd for C₁₅H₁₇N₂O₃S [M+H]⁺ 305.0954, found 305.0958.

  N-(4-Chlorophenylsulfonyl)-4-methoxybenzimidamide(3p): 46.6 mg, 72% yield. White solid, m.p. 72~74 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.23 (s, 1H), 7.90 (d, J＝8.4 Hz, 2H), 7.77 (d, J＝8.8 Hz, 2H), 7.43 (d, J＝8.4 Hz, 2H), 6.87 (d, J＝8.8 Hz, 2H), 6.69 (s, 1H), 3.82 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 163.5, 162.7, 141.0, 138.5, 129.5, 129.0, 127.9, 124.8, 114.1, 55.5; ESI-HRMS calcd for C₁₄H₁₄ClN₂O₃S [M+H]⁺ 325.0408, found 325.0409.

  4-Chloro-N-tosylbenzimidamide (3q): 47.5 mg, 77% yield. White solid, m.p. 108~109 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.30 (s, 1H), 7.85 (d, J＝8.4 Hz, 2H), 7.72 (d, J＝8.4 Hz, 2H), 7.34 (d, J＝8.8 Hz, 2H), 7.28 (d, J＝10.0 Hz, 2H), 6.67 (s, 1H), 2.41 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 161.7, 143.3, 139.1, 131.6, 129.7, 129.5, 129.0, 128.9, 126.4, 21.5; ESI-HRMS calcd for C₁₄H₁₄Cl-N₂O₂S [M+H]⁺ 309.0459, found 309.0456.

  N-Tosylfuran-2-carboximidamide (3r): 38.0 mg, 72% yield. White solid, m.p. 145~146 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.19 (s, 1H), 7.85 (d, J＝8.0 Hz, 2H), 7.51 (s, 1H), 7.26 (d, J＝8.0 Hz, 2H), 7.22 (d, J＝3.2 Hz, 1H), 6.73 (s, 1H), 6.53~6.45 (m, 1H), 2.39 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 153.2, 146.5, 146.0, 143.0, 139.3, 129.4, 126.4, 116.9, 113.0, 21.5; ESI-HRMS calcd for C₁₂H₁₃N₂O₃S [M+H]⁺ 265.0641, found 265.0642.

  N-Tosyl-2-naphthimidamide (3s): 55.0 mg, 85% yield. White solid, m.p. 181~183 ℃; ¹H NMR (400 MHz, DMSO-d₆) δ: 9.21 (s, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.04 (d, J＝7.6 Hz, 1H), 8.02~7.96 (m, 2H), 7.93~7.87 (m, 3H), 7.69~7.57 (m, 2H), 7.38 (d, J＝8.0 Hz, 2H), 2.37 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆) δ: 163.1, 142.9, 140.2, 135.1, 132.4, 131.1, 129.9, 129.5, 129.2, 128.7, 128.5, 128.1, 127.4, 126.6, 124.6, 21.4; ESI-HRMS calcd for C₁₈H₁₇N₂O₂S [M+H]⁺ 325.1005, found 325.1007.

  Supporting Information The ¹H NMR and ¹³C NMR spectra of all products, the HRMS spectrum of ¹⁵N-3a. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn/.

  
  
• 1. [1]

     For selected reviews, see:
     (a) Kim, D.-S.; Park, W.-J.; Jun, C.-H. Chem. Rev. 2017, 117, 8977.
     (b) Souillart, L.; Cramer, N. Chem. Rev. 2015, 115, 9410.
     (c) Ruhland, K. Eur. J. Org. Chem. 2012, 2683。
     (d) Liang, Y.-F.; Jiao, N. Acc. Chem. Res. 2017, 50, 1640.
     (e) Wu, X.; Zhu, C. Chem. Rec. 2018, 18, 587.
     (f) Wan, J.-P.; Gao, Y.; Wei, L. Chem. Asian J. 2016, 11, 2092.

  2. [2]

     For selected examples, see:
     (a) Roque, J. B.; Kuroda, Y.; Göttemann, L. T.; Sarpong, R. Science 2018, 361, 171.
     (b) He, C.; Guo, S.; Huang, L.; Lei, A. J. Am. Chem. Soc. 2010, 132, 8273.
     (c) Ren, R.; Wu, Z.; Zhu, C. Chem. Commun. 2016, 52, 8160.
     (d) Dieskau, A. P.; Holzwarth, M. S.; Plietker, B. J. Am. Chem. Soc. 2012, 134, 5048.
     (e) Souillart, L.; Parker, E.; Cramer, N. Angew. Chem. Int. Ed. 2014, 53, 3001.

  3. [3]

     For selected reviews in enaminone-based synthesis, see:
     (a) Fu, L.; Wan, J.-P. Asian J. Org. Chem. 2019, 8, 767.
     (b) Wan, J.-P.; Gao, Y. Chem. Rec. 2016, 16, 1164.
     (c) Elassar, A.-Z. A.; El-Khair, A. A. Tetrahedron 2003, 59, 8463.
     (d) Greenhill, J. V. Chem. Soc. Rev. 1977, 277.

  4. [4]

     (a) Wasserman, H. H.; Ives, J. L. J. Am. Chem. Soc. 1976, 98, 7868.
     (b) Cao, S.; Zhong, S.; Xin, L.; Wan, J.-P.; Wen, C. ChemCatChem 2015, 7, 1478.
     (c) Yu, Q.; Zhang, Y.; Wan, J.-P. Green Chem. 2019, 21, 3436.
     (d) Wan, J.-P.; Lin, Y.; Cao, X.; Liu, Y.; Wei, L. Chem. Commun. 2016, 52, 1270.
     (e) Yang, Y.; Zhong, G.; Fan, J.; Liu, Y. Eur. J. Org. Chem. 2019, 4422.

  5. [5]

     Gan, L.; Gao, Y.; Wan, J.-P. J. Org. Chem. 2019, 84, 1064. doi: 10.1021/acs.joc.8b02670

  6. [6]

     (a) Zhou, P.; Hu, B.; Li, L.; Rao, K.; Yang, J.; Yu, F. J. Org. Chem. 2017, 82, 13268.
     (b) Tian, L.; Guo, Y.; Wei, L.; Wan, J.-P.; Shou, S. Asian J. Org. Chem. 2019, 8, 1484.
     (c) Liu, Y.; Xiong, J.; Wei, L.; Wan, J.-P. Adv. Synth. Catal. 2020, 362, 877.

  7. [7]

     (a) Ni, M.; Zhang, J.; Liang, X.; Jiang, Y.; Loh, T.-P. Chem. Commun. 2017, 53, 12286.
     (b) Chen, J.; Guo, P.; Zhang, J.; Rong, J.; Sun, W.; Jiang, Y.; Luo, T.-P. Angew. Chem. Int. Ed. 2019, 58, 12674.

  8. [8]

     Hu, W.; Zheng, J.; Li, M.; Wu, W.; Liu, H.; Jiang, H. Chin. J. Chem. 2018, 36, 712. doi: 10.1002/cjoc.201800127

  9. [9]

     (a) Chang, S.; Lee, M.; Jung, D. Y.; Yoo, E. J.; Cho, S. H.; Han, S. K. J. Am. Chem. Soc. 2006, 128, 12366.
     (b) Xu, X.; Li, X.; Ma, L.; Ye, N.; Weng, B. J. Am. Chem. Soc. 2008, 130, 14084.
     (c) Ding, R.; Chen, H.; Xu, Y.-L.; Tang, H.-T.; Chen, Y.-M.; Pan, Y.-M. Adv. Synth. Catal. 2019, 361, 3656.
     (d) Zheng, X.; Wan, J.-P. Adv. Synth. Catal. 2019, 361, 5690.

  10. [10]

      Fusco, R.; Bianchetti, G.; Pocar, D.; Ugo, R. Chem. Ber. 1963, 96, 802. doi: 10.1002/cber.19630960321

  11. [11]

      (a) Kato, N.; Hamada, Y.; Shioiri, T. Chem. Pharm. Bull. 1984, 32, 2496.
      (b) Gao, T.; Zhao, M.; Meng, X.; Li, C.; Chen, B. Synlett 2011, 1281.
      (c) Efimov, I.; Beliaev, N.; Beryozkina, T.; Slepukhin, P.; Bakulev, V. Tetrahedron Lett. 2016, 57, 1949.
      (d) Bakulev, V. A.; Beryozkina, T.; Thomas, J.; Dehaen, W. Eur. J. Org. Chem. 2018, 262.

  12. [12]

      (a) Chandna, N.; Chandak, N.; Kumar, P.; Kapoor, J. K.; Sharma, P. K. Green Chem. 2013, 15, 2294.
      (b) Chen, S.; Xu, Y.; Wan, X. Org. Lett. 2011, 13, 6152.
      (c) Yang, W.; Huang, D.; Zeng, X.; Luo, D.; Wang, X.; Hu, Y. Chem. Commun. 2018, 54, 8222.
      (d) Chen, J.; Long, W.; Fang, S.; Yang, Y.; Wan, X. Chem. Commun. 2017, 53, 13256.

  13. [13]

      (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.
      (b) Yao, B.; Shen, C.; Liang, Z.; Zhang, Y. J. Org. Chem. 2014, 79, 936.
      (c) Murugavel, G.; Punniyamurthy, T. J. Org. Chem. 2015, 80, 6291.
      (d) Shang, Y.; He, X.; Hu, J.; Wu, J.; Zhang, M.; Yu, S.; Zhang, Q. Adv. Synth. Catal. 2009, 351, 2709.

  14. [14]

      (a) van Vliet, K. M.; Polak, L. H.; Siegler, M. A.; van der Vlugt, J. I.; Guerra, C. F.; de Bruin, B. J. Am. Chem. Soc. 2019, 141, 15240.
      (b) Liu, B.; Ning, Y.; Virelli, M.; Zanoni, G.; Anderson, E. A.; Bi, X. J. Am. Chem. Soc. 2019, 141, 1593.

  15. [15]

      (a) Aswad, M.; Chiba, J.; Tomohiro, T.; Hatanaka, Y. Chem. Commun. 2013, 49, 10242.
      (b) Hajibabaei, K.; Boeini, H. Synlett 2014, 2044.

  16. [16]

      For other known methods, see:
      (a) Mo, D.-L.; Pecak, W. H.; Zhao, M.; Wink, D. J.; Anderson, L. L. Org. Lett. 2014, 16, 3696.
      (b) Zhou, M.; Li, J.; Tian, C.; Sun, X.; Zhu, X.; Cheng, Y.; An, G.; Li, G. J. Org. Chem. 2019, 84, 1015.
      (c) Kim, J.; Stahl, S. S. J. Org. Chem. 2015, 80, 2448.

  17. [17]

      Yi, F.; Sun, Q.; Sun, J.; Fu, C.; Yi, W. J. Org. Chem. 2019, 84, 6780. doi: 10.1021/acs.joc.9b00538

  18. [18]

      (a) Shang, Z.; Chen, Q.; Xing, L.; Zhang, Y.; Wait, L.; Du, Y. Adv. Synth. Catal. 2019, 361, 4926.
      (b) Wu, M.; Jiang, Y.; An, Z.; Qi, Z.; Yan, R. Adv. Synth. Catal. 2018, 360, 4236.
      (c) Guo, Y.; Xiang, Y.; Wei, L.; Wan, J.-P. Org. Lett. 2018, 20, 3971.
      (d) Wan, J.-P.; Cao, S.; Liu, Y. Org. Lett. 2016, 18, 6034.
      (e) Cheng, D.; Deng, Z.; Yan, X.; Wang, M.; Xu, X.; Yan, J. Adv. Synth. Catal. 2019, 361, 5025.
      (f) Wan, J.-P.; Tu, Z.; Wang, Y. Chem.-Eur. J. 2019, 25, 6907.
      (g) Luo, T.; Xu, H.; Liu, Y. ChemistrySelect 2019, 4, 10621.
      (h) Yang, L.; Wei, L.; Wan, J.-P. Chem. Commun. 2018, 54, 7475.
      (i) Yan, R.; Li, X.; Yang, X.; Kang, X.; Xiang, L.; Huang, G. Chem. Commun. 2015, 51, 2573.
      (j) Zhao, Q.; Xiang, H.; Xiao, J.-A.; Xia, P.-J.; Wang, J.-J.; Chen, X.; Yang, H. J. Org. Chem. 2017, 82, 9837.
      (k) Bai F.; Hu, D.; Liu, Y.; Wei, L. Chin. J. Org. Chem. 2018, 38, 2054 (in Chinese).
      (白飞成, 胡德庆, 刘云云, 韦丽, 有机化学, 2018, 38, 2054.)
      (l) Fu, L.; Cao, X.; Wan, J.-P.; Liu, Y. Chin. J. Chem. 2020, 38, 254.

  19. [19]

      (a) Xie, L.-Y.; Fang, T.-G.; Tan, J.-X.; Bang, B.; Cao, Z.; Yang, L.-H.; He, W.-M. Green Chem. 2019, 21, 3858.
      (b) Wan, J.-P.; Zhong, S.; Guo, Y.; Wei, L. Eur. J. Org. Chem. 2017, 4401.
      (c) Yu, H.; Bao, P.; Wang, L.; Lv, X.; Yang, D.; Wang, H.; Wei, W. Chin. J. Org. Chem. 2019, 39, 463 (in Chinese).
      (岳会兰, 鲍鹏丽, 王雷雷, 吕晓霞, 杨道山, 王桦, 魏伟, 有机化学, 2019, 39, 463.)
      (d) Du, Y.; Wei, L.; Liu, Y. Heteroatom Chem. 2017, 28, e21401.
      (e) Dong, D.; Chen, W.; Chen, D.; Li, L.; Li, G.; Wang, Z.; Deng, Q.; Long, S. Chin. J. Org. Chem. 2019, 39, 3190 (in Chinese).
      (董道青, 陈文静, 陈德茂, 李丽霞, 李光辉, 王祖利, 邓企, 龙姝, 有机化学, 2019, 39, 3190.)

  20. [20]

      Zhu, Z.; Tang, X.; Li, J.; Li, X.; Wu, W.; Deng, G.; Jiang, H. Chem. Commun. 2017, 53, 3228. doi: 10.1039/C7CC00260B

  21. [21]

      Chandna, N.; Kaur, F.; Kumar, S.; Jain, N. Green Chem. 2017, 19, 4268. doi: 10.1039/C7GC01593C

  22. [22]

      Baeten, M.; Maes, B. U. W. Adv. Synth. Catal. 2016, 358, 826. doi: 10.1002/adsc.201501146

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  Scheme 1  Proposed reaction mechanism

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization on reaction conditions^a

  Entry	Additive	Solvent	Yieldb/%
  1	t-BuONa	DMF	21
  2	—	DMF	0
  3	NaHCO3	DMF	20
  4	NaOH	DMF	19
  5	DBU	DMF	46
  6	DMAP	DMF	17
  7	2, 6-Lutidine	DMF	12
  8c	DBU	DMF	26
  9	DBU	H2O	38
  10	DBU	MeCN	35
  11	DBU	Toluene	38
  12	DBU	EtOH	37
  13	DBU	DMSO	34
  14	DBU	THF	28
  15d	DBU	DMF	61
  16e	DBU	DMF	48
  17d, f	DBU	DMF	52
  18d, g	DBU	DMF	67
  19d, g, h	DBU	DMF	81
  20d, g, i	DBU	DMF	91
  a General conditions: 1a (0.2 mmol), 2a (0.5 mmol), additive (0.4 mmol) in 2 mL of solvent, stirred at r.t. for 6 h. b Yield of isolated product based on 1a. c Reaction at 60 ℃. d Stirred for 12 h. e Stirred for 24 h. f With 0.3 mmol of 2a. g With 1.0 mmol of 2a. h With 0.8 mmol of DBU. I With 1.0 mmol of DBU.

  下载: 导出CSV

  Table 2.  Scope on the enaminone-based synthesis of N-sulfonyl amidines^{a, b}

  下载: 导出CSV
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