Synthesis of α,β-Unsaturated Amidines through Gold-Catalyzed Intermolecular Reaction of Azides with Ynamides

Article abstract of DOI:10.1021/acs.joc.7b01689

A concise and flexible synthesis of α,β-unsaturated amidines via gold-catalyzed intermolecular ynamide amination/carbene 1,2-shift between ynamides and benzylic azides has been developed. Under mild reaction conditions, various α,β-unsaturated amidines were obtained in mostly good yields, thus providing an efficient and atom-economic way for the construction of valuable α,β-unsaturated amidines.

Full text of DOI:10.1021/acs.joc.7b01689

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Article
Synthesis of #,#-Unsaturated Amidines through Gold-
Catalyzed Intermolecular Reaction of Azides with Ynamides
Peng-Peng Ruan, Hang-Hao Li, Xin Liu, Te Zhang, Shao-Xuan Zuo, Chunyin Zhu, and Long-Wu Ye
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01689 • Publication Date (Web): 10 Aug 2017
Downloaded from http://pubs.acs.org on August 10, 2017
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Synthesis of α,β-Unsaturated Amidines through Gold-
Catalyzed Intermolecular Reaction of Azides with
Ynamides
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Peng-Peng Ruan,† Hang-Hao Li,† Xin Liu,† Te Zhang,‡ Shao-Xuan Zuo,† Chunyin Zhu,*, ‡ and Long-
Wu Ye*,†,§
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† State Key Laboratory of Physical Chemistry of Solid Surfaces & Key Laboratory for Chemical Biology
of Fujian Province, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, China
‡ School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, China
§ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences Shanghai 200032, China
longwuye@xmu.edu.cn; zhucycn@gmail.com
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ABSTRACT: A concise and flexible synthesis of α,β-unsaturated amidines via gold-catalyzed
intermolecular ynamide amination/carbene 1,2-shift between ynamides and benzylic azides has
been developed. Under mild reaction conditions, various α,β-unsaturated amidines were
obtained in mostly good yields, thus providing an efficient and atom-economic way for the
construction of valuable α,β-unsaturated amidines.
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Introduction
α,β-Unsaturated amidines are important structural motifs found in a variety of pharmacologically
active molecules,1 and they are also widely employed as versatile building blocks in organic synthesis,
especially as pivotal intermediates for the construction of valuable amidines.2 It is surprising, however,
that only a few preparative methods have been reported to date.3 Consequently, the development of
novel methods for the preparation of α,β-unsaturated amidines is highly desirable, especially those based
on assembling structures directly from readily available and easily diversified precursors.
Recently, the generation of α-imino gold carbenes4 through gold-catalyzed alkyne amination has
gained significant attention, as this chemistry offers easy access to an incredible variety of useful
complex nitrogen-containing molecules.5-7 Compared with intramolecular alkyne amination,6 the
intermolecular approach offers much more flexibility, and therefore it is more synthetically useful.7 For
examples, Zhang and co-workers demonstrated an elegant protocol for the gold-catalyzed intermolecular
alkyne amination for the synthesis of α,β-unsaturated amidines by employing iminopyridium ylides as
nitrene-transfer reagents (Scheme 1a).7g In our recent study on the ynamide chemistry,8,9 we first
disclosed that benzyl azides could serve as efficient nitrene transfer reagents to react with ynamides for
the intermolecular generation of α-imino gold carbenes, thus leading to the efficient synthesis of
versatile 2-aminoindoles and 3-amino-β-carbolines.10a Importantly, this protocol provides a strategically
novel, atom-economic route to the generation of α-imino gold carbenes. On the basis of this work, we
further developed the relevant gold-catalyzed intermolecular ynamide amination initiated aza-Nazarov
cyclization10b,11 and C−H functionalization,10c which afforded highly functionalized 2-aminopyrroles
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and 2-aza-1,3-butadienes, respectively. Herein, we would like to communicate a gold-catalyzed
intermolecular alkyne amination/carbene 1,2-shift by employing benzyl azides as nitrene-transfer
reagents, allowing the efficient synthesis of various α,β-unsaturated amidines under mild reaction
conditions, particularly in an atom- and step- economic manner (Scheme 1b).
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Scheme 1. Synthesis of α,β-Unsaturated Amidines through Gold-Catalyzed Intermolecular Alkyne
Amination Reaction.
Results and Discussion
At the outset, ynamide 1a and benzyl azide 2a were chosen as the model substrates for our initial
study and some of the results are listed in Table 1. To our delight, it was found that the reaction of
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ynamide 1a and benzyl azide 2a in the presence of IPrAuNTf2 and 3 Å MS in DCE under 80 C could
afford the desired α,β-unsaturated amidine 3a in 49% yield with good E/Z selectivity (Table 1, entry 1).
Then, the screening of various gold catalysts bearing different ligands showed that Ph3PAuNTf2 and
XPhosAuNTf2 were not effective in promoting this reaction, while Cy-JohnPhosAuNTf2 and
BrettPhosAuNTf2 could hardly work for the reaction (Table 1, entries 2-5). Notably molecular sieves
were found to be indispensible for the reaction as confirmed by the control experiment (Table 1, entry 6),
and 3 Å MS was found to be superior to 4 Å MS and 5 Å MS (entry 1 vs entries 7-8). Notably, other
solvents such as toluene and PhCl failed to produce the desired product (Table 1, entries 9-10).
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Increasing the equivalents of 2a could enhance the reaction (Table 1, entries 11-12), and the reaction
with 4 equivalents of 2a gave a yield of 81% (Table 1, entry 12). Further investigation revealed that the
reaction also proceeded at lower temperature, but resulting in a slightly decreased yield (Table 1, entry
13).
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Table 1. Optimization of Reaction Conditionsa
With the optimized reaction conditions in hand (Table 1, entry 12), we set out to probe the scope of
this novel transformation and the results are summarized in Table 2. Besides ynamide 1a, the reaction
also worked for methyl and cyclopropyl ynamides, affording the desired α,β-unsaturated amidines 3 in
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good yields (Table 2, entries 2, 15-16). Then benzyl azides with different groups at the benzene ring
were also examined, and the desired products 3c–h could be formed in 66-84% yields (Table 2, entries
3-8). Besides, the variation of alkyl groups on the triple bond was also possible, and the reaction
proceeded well for ynamides with different linear, branched, and cyclic alkyl groups, leading to the
corresponding products 3i–l in good yields (Table 2, entries 9-12). In addition, various functional groups
including OBoc and OAc were found to be well tolerated under this reaction (Table 2, entries 13-14). Of
note, a longer reaction time was needed in some cases (Table 2, entries 2, 10, 13-16). Finally, it should
be mentioned that high E/Z selectivity was achieved in all cases, which is better than observed in
Zhang’s protocol7g and our previous result in the relevant alkyne oxidation reaction.12 While the exact
reason for the observed high E/Z selectivity here remains unclear, we suspect that it should be attributed
to thermodynamic factors, and further studies on theoretical calculations to elucidate it will be pursued.
Thus, this protocol provides a highly convenient and atom-economic route for the construction of
synthetically useful α,β-unsaturated amidines, which may find practical applications in organic
synthesis.2,3
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Table 2. Reaction Scope Studya
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Table 2. (Continued)
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We then considered the possibility of extending the reaction to the conjugated N-sulfonyl ynamide.
However, as depicted in eq 1, only 2-aminopyrrole 4a formation was observed under the above
optimized reaction conditions presumably via a gold-catalyzed tandem ynamide amination/aza-Nazarov
cyclization.10b Of note, this is distinctively different from the relevant ynamide oxidation reaction, where
the corresponding α,β,γ,δ-unsaturated N-sulfonyl imide was formed.12 In addition, it should be
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mentioned that other types of azides such as alkyl azides and phenyl azides were not effective substrates
for this reaction (<10% 1H NMR yield), which is in accordance with our previous work.10
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These α,β-unsaturated amidines are potentially useful in organic synthesis,2 as depicted in Scheme 2.
For α,β-unsaturated amidine 3a, it could be readily converted into the corresponding α,β-unsaturated
amide 5a and amidine 6a in in 63% and 65%yield, respectively.3a
Scheme 2. Synthetic Applications
Based on the above experimental observations and our previous results,10 the catalytic pathway for the
formation of 3 is considered to proceed as illustrated in Scheme 3. Taking substrates 1a and 2a for
example, similarly, the transformation possibly starts with the nucleophilic attack of benzyl azide 2a to
the Au-ligated alkyne of ynamide 1a to give the vinyl gold intermediate A, which is further transformed
into the α-imino gold carbene intermediate B. Subsequent carbene 1,2-shift is expected to generate the
desired product 3a.13
Scheme 3. Plausible Reaction Mechanism
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Conclusion
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In summary, we have developed an efficient, flexible, and viable alternative strategy for the
preparation of synthetically useful α,β-unsaturated amidines through gold-catalyzed intermolecular
ynamide amination/carbene 1,2-shift of ynamides with azides. Compared to the previously reported
protocol, this strategy provides an atom- and step- economic way for the construction of functionalized
α,β-unsaturated amidines. Other notable features of this method include widespread availability of the
substrates, compatibility with broad functional groups, simple procedure and mild reaction conditions.
Further synthetic applications of this chemistry are in progress in our laboratory.
Experimental Section
General Information. Ethyl acetate (ACS grade), hexanes (ACS grade) and anhydrous 1,2-
dichloroethane (ACS grade) were obtained commercially and used without further purification.
Methylene chloride, tetrahydrofuran and diethyl ether were purified according to standard methods
unless otherwise noted. Commercially available reagents were used without further purification. High-
resolution mass spectra were obtained using electrospray ionization using an ICR analyzer (ESI-MS).
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1H NMR spectra were recorded in chloroform-d3. Chemical shifts are reported in ppm with the
internal TMS signal at 0.0 ppm as a standard. The data are being reported as (s = singlet, d = doublet, t =
triplet, m = multiplet or unresolved, brs = broad singlet, coupling constant(s) in Hz, integration).
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13C NMR spectra were recorded in chloroform-d3. Chemical shifts are reported in ppm with the
internal chloroform signal at 77.0 ppm as a standard.
Representative Synthetic Procedures for the Preparation of Ynamides 1.14 Alkynyl bromide (1.1
mmol) was added to a stirred solution of amide (1.0 mmol), K2CO3 (2.0 mmol, 276.4 mg), CuSO4·5H2O
(0.1 mmol, 25.0 mg), 1,10-phenthroline (0.2 mmol, 36.0 mg) and toluene (2 mL) under air, and the
resulting mixture was stirred at 80 °C for 8-32 h. The suspension was filtered, and the residue was
washed with diethyl ether (3 × 10 mL). The purification of products was achieved by flash
chromatography (eluent: hexanes/ethyl acetate = 10/1) to afford the desired ynamide 1.
N-benzyl-N-(hex-1-yn-1-yl)methanesulfonamide (1a). Pale yellow oil (201.4mg, 75%). This
compound is known and the spectroscopic data match those reported.10c 1H NMR (400 MHz, CDCl3) δ
7.47 – 7.31 (m, 5H), 4.56 (s, 2H), 2.86 (s, 3H), 2.26 (t, J = 6.8 Hz, 2H), 1.53 – 1.41 (m, 2H), 1.40 – 1.26
(m, 2H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 134.8, 128.9, 128.6, 128.5, 72.9, 71.3,
55.6, 38.2, 30.8, 21.8, 18.1, 13.5.
N-(hex-1-yn-1-yl)-N-methylmethanesulfonamide (1b). Pale yellow oil (147.4 mg, 78%). This
compound is known and the spectroscopic data match those reported.7c 1H NMR (400 MHz, CDCl3) δ
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3.15 (s, 3H), 3.03 (s, 3H), 2.28 (t, J = 6.8 Hz, 2H), 1.52 – 1.31 (m, 4H), 0.89 (t, J = 7.2 Hz, 3H); C
NMR (100 MHz, CDCl3) δ 74.1, 68.9, 39.0, 35.6, 30.8, 21.7, 17.8, 13.4.
N-benzyl-N-(oct-1-yn-1-yl)methanesulfonamide (1c). Pale yellow oil (237.3 mg, 81%). This
compound is known and the spectroscopic data match those reported.15 1H NMR (400 MHz, CDCl3) δ
7.36 – 7.22 (m, 5H), 4.46 (s, 2H), 2.76 (s, 3H), 2.15 (t, J = 6.8 Hz, 2H), 1.42 – 1.31 (m, 2H), 1.26 – 1.10
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(m, 6H), 0.76 (t, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 134.6, 128.7, 128.5, 128.3, 72.8, 71.1,
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55.4, 38.0, 31.1, 28.6, 28.2, 22.4, 18.2, 13.9.
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N-benzyl-N-(5-methylhex-1-yn-1-yl)methanesulfonamide (1d). Pale yellow oil (203.7 mg, 73%). H
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NMR (400 MHz, CDCl3) δ 7.45 – 7.33 (m, 5H), 4.56 (s, 2H), 2.86 (s, 3H), 2.26 (t, J = 7.2 Hz, 2H), 1.62
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– 1.52 (m, 1H), 1.38 – 1.32 (m, 2H), 0.86 (d, J = 6.8 Hz, 6H); C NMR (100 MHz, CDCl3) δ 134.7,
128.8, 128.6, 128.4, 77.3, 71.3, 55.5, 38.1, 37.6, 27.0, 22.0, 16.4; IR (neat): 2956, 2931, 2252, 1358,
1163, 583, 514; HRESIMS Calcd for [C15H21NNaO2S]+ (M + Na+) 302.1185, found 302.1189.
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N-benzyl-N-(3-methylbut-1-yn-1-yl)methanesulfonamide (1e). Pale yellow oil (165.8 mg, 66%). H
NMR (500 MHz, CDCl3) δ 7.46 – 7.31 (m, 5H), 4.55 (s, 2H), 2.85 (s, 3H), 2.69 – 2.56 (m, 1H), 1.13 (d,
J = 6.5 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 134.7, 128.9, 128.5, 128.4, 76.6, 72.5, 55.6, 38.0, 23.0,
20.3; IR (neat): 2967, 2918, 2251, 1356, 1163, 582, 513; HRESIMS Calcd for [C13H17NNaO2S]+ (M +
Na+) 274.0872, found 274.0870.
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N-benzyl-N-(cyclohexylethynyl)methanesulfonamide (1f). Pale yellow oil (218.3 mg, 75%). H NMR
(400 MHz, CDCl3) δ 7.46 – 7.31 (m, 5H), 4.56 (s, 2H), 2.85 (s, 3H), 2.52 – 2.42 (m, 1H), 1.79 – 1.68 (m,
2H), 1.67 – 1.56 (m, 2H), 1.52 – 1.20 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 134.8, 129.0, 128.6,
128.5, 75.4, 73.3, 55.6, 38.1, 32.7, 28.7, 25.8, 24.6; IR (neat): 2929, 2852, 2247, 1358, 1163, 585, 514;
HRESIMS Calcd for [C16H21NNaO2S]+ (M + Na+) 314.1185, found 314.1188.
5-(N-benzylmethylsulfonamido)pent-4-yn-1-yl tert-butyl carbonate (1g). Pale yellow oil (121.1 mg,
33%). 1H NMR (400 MHz, CDCl3) δ 7.45 – 7.29 (m, 5H), 4.55 (s, 2H), 4.06 (t, J = 6.4 Hz, 2H), 2.87 (s,
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2H), 2.37 (t, J = 7.2 Hz, 2H), 1.84 – 1.75 (m, 2H), 1.48 (s, 9H); C NMR (100 MHz, CDCl3) δ 153.2,
134.5, 128.6, 128.5, 128.3, 81.7, 73.5, 69.6, 65.2, 55.3, 38.1, 27.8, 27.5, 14.9; IR (neat): 2979, 2933,
2255, 1740 (s), 1359, 1163, 583, 515; HRESIMS Calcd for [C18H25NNaO5S]+ (M + Na+) 390.1346,
found 390.1347.
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5-(N-benzylmethylsulfonamido)pent-4-yn-1-yl acetate (1h). Pale yellow oil (108.2 mg, 35%). H
NMR (500 MHz, CDCl3) δ 7.44 – 7.31 (m, 5H), 4.56 (s, 2H), 4.07 (t, J = 6.4 Hz, 2H), 2.88 (s, 3H), 2.35
(t, J = 7.0 Hz, 2H), 2.03 (s, 3H), 1.81 – 1.74 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 170.7, 134.5,
128.7, 128.5, 128.4, 73.5, 69.7, 62.7, 55.3, 38.2, 27.7, 20.7, 15.0; IR (neat): 2925, 2254, 1738 (s), 1357,
1162, 582, 514; HRESIMS Calcd for [C15H19NNaO4S]+ (M + Na+) 332.0927, found 332.0929.
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N-cyclopropyl-N-(hex-1-yn-1-yl)methanesulfonamide (1i). Pale yellow oil (118.4 mg, 55%). 1H NMR
(400 MHz, CDCl3) δ 3.06 (s, 3H), 3.00 – 2.91 (m, 1H), 2.29 (t, J = 6.8 Hz, 2H), 1.55 – 1.34 (m, 4H),
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0.97 – 0.79 (m, 7H); C NMR (100 MHz, CDCl3) δ 71.5, 70.8, 36.6, 32.6, 30.9, 21.8, 18.0, 13.5, 6.2;
IR (neat): 2958, 2933, 2252, 1360, 1167, 758, 514; HRESIMS Calcd for [C10H17NNaO2S]+ (M + Na+)
238.0872, found 238.0874.
N-benzyl- N-(cyclohex-1-en-1-ylethynyl)methanesulfonamide (1j). Pale yellow oil (216.8 mg, 75%).
1H NMR (400 MHz, CDCl3) δ 7.47 – 7.32 (m, 5H), 6.03 – 5.99 (m, 1H), 4.60 (s, 2H), 2.85 (s, 3H), 2.10
– 2.03 (m, 4H), 1.65 – 1.50 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 134.5, 134.3, 128.8, 128.6, 128.4,
119.5, 79.4, 72.9, 55.6, 38.3, 29.2, 25.5, 22.1, 21.3; IR (neat): 2930, 2859, 2228, 1359, 1163, 703, 514;
HRESIMS Calcd for [C16H19NNaO2S]+ (M + Na+) 312.1029, found 312.1026.
General Procedure of the Synthesis of α,β-Unsaturated Amidine 3 from Ynamide 1. A solution
of ynamide 1 (0.2 mmol) and benzyl azide 2 (0.8 mmol) in dry DCE (4 mL) was added into the
mixture of IPrAuNTf2 (17.3 mg, 0.02 mmol) and 3 Å MS (40 mg) in 10 mL Schlenk flask under N2 at
room temperature. The reaction mixture was stirred at 80 oC and the progress of the reaction was
monitored by TLC. The reaction typically took 24 h. Upon completion, the mixture was then diluted
with DCM, filtered, concentrated and the residue was purified by chromatography on silicagel (eluent:
hexanes/ethyl acetate = 10/1) to afford the desired α,β-unsaturated amidine 3.
(1E,2E)-N,N'-dibenzyl-N-(methylsulfonyl)hex-2-enimidamide (3a). Pale yellow oil (56.4 mg, 76%). 1H
NMR (400 MHz, CDCl3) δ 7.36 – 7.22 (m, 10H), 6.46 (dt, J = 15.5, 7.0 Hz, 1H), 6.11 (dt, J = 15.4, 1.5
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Hz, 1H), 4.72 (s, 2H), 4.65 (s, 2H), 2.99 (s, 3H), 2.16 – 2.08 (m, 2H), 1.42 – 1.32 (m, 2H), 0.85 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.8, 146.5, 139.5, 135.9, 129.1, 128.4, 127.8, 127.4,
126.7, 119.5, 54.0, 52.6, 39.9, 34.7, 21.5, 13.6; IR (neat): 3030, 2959, 2931, 1650 (s), 1613, 1344, 1152,
964, 699, 516; HRESIMS Calcd for [C21H26N2NaO2S]+ (M + Na+) 393.1607, found 393.1608.
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(1E,2E)-N'-benzyl-N-methyl-N-(methylsulfonyl)hex-2-enimidamide (3b). Pale yellow oil (40.6 mg,
69%). 1H NMR (400 MHz, CDCl3) δ 7.38 – 7.22 (m, 5H), 6.64 (dt, J = 15.3, 7.0 Hz, 1H), 6.17 (dt, J =
15.4, 1.4 Hz, 1H), 4.66 (s, 2H), 3.12 (s, 3H), 3.11 (s, 3H), 2.29 – 2.19 (m, 2H), 1.56 – 1.47 (m, 2H), 0.95
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.6, 146.2, 139.6, 128.4, 127.3, 126.8, 118.6, 53.8,
38.0, 36.3, 34.8, 21.6, 13.7; IR (neat): 3028, 2960, 2930, 1650 (s), 1615, 1343, 1148, 966, 699, 517;
HRESIMS Calcd for [C15H22N2NaO2S]+ (M + Na+) 317.1294, found 317.1299.
(1E,2E)-N-benzyl-N'-(4-methylbenzyl)-N-(methylsulfonyl)hex-2-enimidamide (3c). Pale yellow oil
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(63.7 mg, 83%). H NMR (400 MHz, CDCl3) δ 7.30 – 7.26 (m, 5H), 7.24 – 7.12 (m, 4H), 6.50 – 6.40
(m, 1H), 6.14 – 6.07 (m, 1H), 4.71 (s, 2H), 4.60 (s, 2H), 2.98 (s, 3H), 2.34 (s, 3H), 2.15 – 2.07 (m, 2H),
1.43 – 1.32 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7, 146.4, 136.5, 136.3,
136.0, 129.2, 129.1, 128.4, 127.8, 127.4, 119.6, 53.8, 52.7, 39.9, 34.7, 21.5, 21.1, 13.6; IR (neat): 3030,
2959, 2929, 1647 (s), 1613, 1344, 1153, 965, 700, 516; HRESIMS Calcd for [C22H28N2NaO2S]+ (M +
Na+) 407.1764, found 407.1772.
(1E,2E)-N-benzyl-N'-(3-methylbenzyl)-N-(methylsulfonyl)hex-2-enimidamide (3d). Pale yellow oil
(58.4 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.34 – 7.18 (m, 7H), 7.11 – 7.03 (m, 2H), 6.45 (dt, J =
15.4, 7.0 Hz, 1H), 6.12 (dt, J = 15.4, 1.5 Hz, 1H), 4.72 (s, 2H), 4.62 (s, 2H), 2.99 (s, 3H), 2.35 (s, 3H),
2.16 – 2.08 (m, 2H), 1.43 – 1.31 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7,
146.5, 139.5, 138.0, 135.9, 129.2, 128.4, 128.3, 128.2, 127.8, 127.5, 124.5, 119.5, 54.0, 52.6, 39.9, 34.7,
21.5, 21.4, 13.6; IR (neat): 3030, 2959, 2929, 1647 (s), 1609, 1343, 1153, 965, 699, 516; HRESIMS
Calcd for [C22H28N2NaO2S]+ (M + Na+) 407.1764, found 407.1771.
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(1E,2E)-N-benzyl-N'-(2-methylbenzyl)-N-(methylsulfonyl)hex-2-enimidamide (3e). Pale yellow oil
(50.7 mg, 66%). 1H NMR (400 MHz, CDCl3) δ 7.27 – 7.25 (m, 5H), 7.23 – 7.14 (m, 4H), 6.46 (dt, J =
15.5, 7.1 Hz, 1H), 6.12 (dt, J = 15.4, 1.5 Hz, 1H), 4.71 (s, 2H), 4.59 (s, 2H), 2.98 (s, 3H), 2.29 (s, 3H),
2.16 –2.08 (m, 2H), 1.44 – 1.33 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7,
146.4, 137.6, 135.9, 135.8, 130.1, 129.2, 128.4, 127.8, 127.6, 126.8, 126.0, 119.5, 52.6, 52.1, 40.0, 34.7,
21.5, 19.2, 13.6; IR (neat): 3030, 2959, 2929, 1646 (s), 1605, 1343, 1152, 964, 700, 516; HRESIMS
Calcd for [C22H28N2NaO2S]+ (M + Na+) 407.1764, found 407.1768.
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(1E,2E)-N-benzyl-N'-(4-methoxybenzyl)-N-(methylsulfonyl)hex-2-enimidamide (3f). Pale yellow oil
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(67.2 mg, 84%). H NMR (400 MHz, CDCl3) δ 7.30 – 7.26 (m, 5H), 7.20 – 7.14 (m, 2H), 6.90 – 6.84
(m, 2H), 6.46 (dt, J = 15.5, 7.0 Hz, 1H), 6.11 (dt, J = 15.5, 1.5 Hz, 1H), 4.71 (s, 2H), 4.59 (s, 2H), 3.80
(s, 3H), 2.98 (s, 3H), 2.15 – 2.08 (m, 2H), 1.44 – 1.32 (m, 2H), 0.84 (t, J = 7.2 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 158.5, 156.5, 146.3, 136.0, 131.7, 129.2, 128.5, 128.4, 127.8, 119.6, 113.8, 55.3, 53.5,
52.6, 39.9, 34.7, 21.5, 13.6; IR (neat): 3031, 2959, 2931, 1647 (s), 1611, 1342, 1152, 964, 703, 516;
HRESIMS Calcd for [C22H28N2NaO3S]+ (M + Na+) 423.1713, found 423.1715.
(1E,2E)-N-benzyl-N'-(4-bromobenzyl)-N-(methylsulfonyl)hex-2-enimidamide (3g). Pale yellow oil
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(63.6 mg, 71%). H NMR (400 MHz, CDCl3) δ 7.46 – 7.41 (m, 2H), 7.31 – 7.24 (m, 5H), 7.15 – 7.10
(m, 2H), 6.46 (dt, J = 15.5, 7.0 Hz, 1H), 6.07 (dt, J = 15.5, 1.5 Hz, 1H), 4.73 (s, 2H), 4.58 (s, 2H), 2.98
(s, 3H), 2.16 –2.08 (m, 2H), 1.44 – 1.33 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 157.1, 146.7, 138.7, 135.9, 131.5, 129.2, 129.1, 128.5, 127.9, 120.5, 119.5, 53.4, 52.5, 40.3, 34.7, 21.5,
13.6; IR (neat): 3031, 2959, 2929, 1647 (s), 1613, 1343, 1153, 966, 700, 517; HRESIMS Calcd for
[C21H25BrN2NaO2S]+ (M + Na+) 471.0712, found 471.0719.
(1E,2E)-N-benzyl-N'-(3-bromobenzyl)-N-(methylsulfonyl)hex-2-enimidamide (3h). Pale yellow oil
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(59.2 mg, 67%). H NMR (400 MHz, CDCl3) δ 7.45 – 7.42 (m, 1H), 7.41 – 7.36 (m, 1H), 7.34 – 7.24
(m, 5H), 7.21 – 7.17 (m, 2H), 6.47 (dt, J = 15.5, 7.1 Hz, 1H), 6.07 (dt, J = 15.4, 1.5 Hz, 1H), 4.74 (s,
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2H), 4.60 (s, 2H), 2.99 (s, 3H), 2.18 – 2.10 (m, 2H), 1.44 – 1.34 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H); C
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NMR (100 MHz, CDCl3) δ 157.1, 146.8, 142.0, 135.8, 130.5, 130.0, 129.8, 129.0, 128.5, 127.9, 126.0,
122.5, 119.4, 53.3, 52.5, 40.3, 34.7, 21.5, 13.6; IR (neat): 3031, 2959, 2929, 1647 (s), 1613, 1343, 1152,
964, 700, 517; HRESIMS Calcd for [C21H25BrN2NaO2S]+ (M + Na+) 471.0712, found 471.0718.
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(1E,2E)-N-benzyl-N'-(4-methylbenzyl)-N-(methylsulfonyl)oct-2-enimidamide (3i). Pale yellow oil (53.6
mg, 65%). 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.26 (m, 5H), 7.14 (s, 4H), 6.46 (dt, J = 15.4, 7.0 Hz,
1H), 6.10 (dt, J = 15.4, 1.6 Hz, 1H), 4.71 (s, 2H), 4.61 (s, 2H), 2.98 (s, 3H), 2.35 (s, 3H), 2.17 – 2.07 (m,
2H), 1.39 – 1.13 (m, 6H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7, 146.8, 136.5,
136.3, 136.0, 129.2, 129.1, 128.4, 127.8, 127.4, 119.4, 53.8, 52.7, 39.8, 32.7, 31.2, 28.0, 22.4, 21.1, 13.9;
IR (neat): 3030, 2956, 2927, 1646(s), 1613, 1344, 1153, 962, 700, 516; HRESIMS Calcd for
[C24H32N2NaO2S]+ (M + Na+) 435.2077, found 435.2081.
(1E,2E)-N-benzyl-5-methyl-N'-(4-methylbenzyl)-N-(methylsulfonyl)hex-2-enimidamide
(3j).
Pale
yellow oil (58.9 mg, 74%). 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.26 (m, 5H), 7.14 (s, 4H), 6.46 (dt, J
= 15.2, 7.5 Hz, 1H), 6.11 (dt, J = 15.3, 1.4 Hz, 1H), 4.71 (s, 2H), 4.61 (s, 2H), 2.98 (s, 3H), 2.35 (s, 3H),
2.05 – 1.99 (m, 2H), 1.68 – 1.57 (m, 1H), 0.82 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 156.6,
145.6, 136.4, 136.3, 135.9, 129.2, 129.1, 128.4, 127.8, 127.4, 120.5, 53.7, 52.7, 42.0, 39.5, 27.9, 22.3,
21.1; IR (neat): 3030, 2955, 2926, 1646 (s), 1612, 1344, 1153, 965, 700, 518; HRESIMS Calcd for
[C23H30N2NaO2S]+ (M + Na+) 421.1920, found 421.1918.
(E)-N-benzyl-3-methyl-N'-(4-methylbenzyl)-N-(methylsulfonyl)but-2-enimidamide (3k). Pale yellow oil
(55.5 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.32 – 7.23 (m, 5H), 7.18 – 7.08 (m, 4H), 5.60 (s, 1H),
4.90 (s, 2H), 4.47 (s, 2H), 3.10 (s, 3H), 2.32 (s, 3H), 1.83 (d, J = 1.2 Hz, 3H), 1.61 (d, J = 1.2 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 155.3, 144.5, 137.5, 137.2, 135.9, 128.9, 128.5, 128.0, 127.4, 127.2,
116.4, 54.1, 50.0, 43.4, 25.0, 21.0, 20.3; IR (neat): 3030, 2920, 1638 (s), 1341, 1152, 960, 701, 515;
HRESIMS Calcd for [C21H26N2NaO2S]+ (M + Na+) 393.1607, found 393.1608.
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(E)-N-benzyl-2-cyclohexylidene-N'-(4-methylbenzyl)-N-(methylsulfonyl)acetimidamide
(3l).
Pale
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yellow oil (64.0 mg, 78%). H NMR (400 MHz, CDCl3) δ 7.33 – 7.23 (m, 5H), 7.19 – 7.08 (m, 4H),
5.49 (s, 1H), 4.93 (s, 2H), 4.49 (s, 2H), 3.12 (s, 3H), 2.32 (s, 3H), 2.18 (t, J = 5.6 Hz, 2H), 2.05 (t, J =
6.4 Hz, 2H), 1.63 – 1.39 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 155.2, 151.5, 137.6, 137.3, 135.9,
128.9, 128.5, 127.8, 127.4, 127.2, 112.9, 54.4, 50.1, 43.4, 36.1, 30.9, 28.1, 26.8, 25.9, 21.0; IR (neat):
3030, 2929, 2855, 1638 (s), 1342, 1153, 960, 701, 516; HRESIMS Calcd for [C24H30N2NaO2S]+ (M +
Na+) 433.1920, found 433.1923.
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(3E,5E)-5-(N-benzylmethylsulfonamido)-5-((4-methylbenzyl)imino)pent-3-en-1-yl tert-butyl carbonate
(3m). Pale yellow oil (70.0 mg, 72%). 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.26 (m, 5H), 7.13 (s, 4H),
6.36 (dt, J = 15.5, 6.9 Hz, 1H), 6.19 (dt, J = 15.6, 1.5 Hz, 1H), 4.72 (s, 2H), 4.60 (s, 2H), 4.03 (t, J = 6.4
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Hz, 2H), 2.99 (s, 3H), 2.53 – 2.46 (m, 2H), 2.34 (s, 3H), 1.46 (s, 9H); C NMR (100 MHz, CDCl3) δ
156.0, 153.3, 140.4, 136.4, 136.3, 135.9, 129.2, 129.1, 128.5, 127.9, 127.3, 121.9, 82.2, 64.9, 53.9, 52.5,
40.3, 31.9, 27.7, 21.1; IR (neat): 2977, 2926, 1740 (s), 1650, 1615, 1343, 1154, 963, 701, 516; RESIMS
Calcd for [C26H34N2NaO5S]+ (M + Na+) 509.2081, found 509.2091.
(3E,5E)-5-(N-benzylmethylsulfonamido)-5-((4-methylbenzyl)imino)pent-3-en-1-yl acetate (3n). Pale
yellow oil (43.7 mg, 51%). 1H NMR (500 MHz, CDCl3) δ 7.29 – 7.26 (m, 5H), 7.13 (s, 4H), 6.37 (dt, J
= 15.5, 6.9 Hz, 1H), 6.19 (dt, J = 15.5, 1.5 Hz, 1H), 4.71 (s, 2H), 4.61 (s, 2H), 4.03 (t, J = 5.2 Hz, 2H),
2.99 (s, 3H), 2.49 – 2.42 (m, 2H), 2.35 (s, 3H), 2.01 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.8,
156.1, 141.0, 136.4, 136.2, 135.8, 129.2, 129.1, 128.4, 127.9, 127.3, 121.8, 62.5, 53.9, 52.6, 39.8, 31.9,
21.1, 20.9; IR (neat): 3024, 2924, 2854, 1738 (s), 1650, 1614, 1341, 1152, 963, 700, 515; HRESIMS
Calcd for [C23H28N2NaO4S]+ (M + Na+) 451.1662, found 451.1668.
(1E,2E)-N-methyl-N'-(4-methylbenzyl)-N-(methylsulfonyl)hex-2-enimidamide (3o). Pale yellow oil
(44.4 mg, 62%). 1H NMR (400 MHz, CDCl3) δ 7.21 – 7.17 (m, 2H), 7.16 – 7.12 (m, 2H), 6.63 (dt, J =
15.4, 7.0 Hz, 1H), 6.17 (dt, J = 15.4, 1.5 Hz, 1H), 4.61 (s, 2H), 3.10 (s, 6H), 2.34 (s, 3H), 2.27 – 2.19 (m,
2H), 1.56 – 1.46 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 157.5, 146.1, 136.6,
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136.4, 129.1, 127.3, 118.6, 53.6, 38.0, 36.3, 34.8, 21.6, 21.1, 13.7; IR (neat): 2958, 2925, 1649 (s), 1615,
1342, 1148, 967, 771, 518; HRESIMS Calcd for [C16H24N2NaO2S]+ (M + Na+) 331.1451, found
331.1453.
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(1E,2E)-N-cyclopropyl-N'-(4-methylbenzyl)-N-(methylsulfonyl)hex-2-enimidamide (3p). Pale yellow
oil (50.1 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.22 – 7.11 (m, 4H), 6.60 (dt, J = 15.2, 7.0 Hz, 1H),
6.31 (dt, J = 15.1, 1.5 Hz, 1H), 4.65 (s, 2H), 3.13 (s, 3H), 2.92 – 2.85 (m, 1H), 2.34 (s, 3H), 2.26 – 2.17
(m, 2H), 1.56 – 1.44 (m, 2H), 0.93 (t, J = 7.6 Hz, 3H), 0.84 – 0.74 (m, 4H); 13C NMR (100 MHz, CDCl3)
δ 157.8, 146.5, 136.4, 136.3, 129.1, 127.3, 120.3, 53.6, 38.4, 34.7, 30.4, 21.6, 21.1, 13.7, 7.0; IR (neat):
3016, 2959, 2928, 1647 (s), 1613, 1344, 1156, 966, 760, 522; HRESIMS Calcd for [C18H26N2NaO2S]+
(M + Na+) 357.1607, found 357.1608.
N-benzyl-N-(1-(4-methylbenzyl)-4,5,6,7-tetrahydro-1H-indol-2-yl)methanesulfonamide (4a). Pale
yellow oil (50.8 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.29 – 7.21 (m, 5H), 7.01 (d, J = 8.0 Hz, 2H),
6.71 (d, J = 8.0 Hz, 2H), 5.74 (s, 1H), 5.09 (s, 1H), 4.76 (s, 1H), 4.53 (s, 1H), 4.13 (s, 1H), 2.77 (s, 3H),
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2.50 – 2.43 (t, J = 6.4 Hz, 2H), 2.28 (s, 3H), 2.27 – 2.10 (m, 2H), 1.77 – 1.65 (m, 4H); C NMR (100
MHz, CDCl3) δ 136.3, 135.8, 135.5, 129.7, 129.1, 128.4, 128.1, 127.8, 126.2, 125.2, 116.0, 104.9, 56.4,
45.7, 37.9, 23.4, 23.1, 22.9, 22.2, 21.0; IR (neat): 2926, 2852, 1340, 1154, 913, 748, 700; HRESIMS
Calcd for [C24H28N2NaO2S]+ (M + Na+) 431.1764, found 431.1765.
(E)-N-benzyl-N-(methylsulfonyl)hex-2-enamide (5a). Compound 5a (0.2 mmol scale) was prepared
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according to the known procedures.3a Pale yellow oil (35.5 mg, 63%). H NMR (400 MHz, CDCl3) δ
7.37 – 7.30 (m, 4H), 7.31 – 7.26 (m, 1H), 7.14 (dt, J = 15.2, 7.2 Hz, 1H), 6.49 (dt, J = 15.2, 1.6 Hz, 1H),
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5.05 (s, 2H), 3.14 (s, 3H), 2.23 – 2.17 (m, 2H), 1.51 – 1.42 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H); C NMR
(100 MHz, CDCl3) δ 166.6, 152.4, 136.5, 128.8, 127.9, 127.6, 120.7, 48.9, 43.1, 34.7, 21.2, 13.6; IR
(neat): 2924, 2848, 1681 (s), 1632, 1536, 1495, 1453, 1353, 1179, 1159, 962, 700; HRESIMS Calcd for
[C14H19NNaO3S]+ (M + Na+) 304.0978, found 304.0981.
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(E)-N,N'-dibenzyl-N-(methylsulfonyl)hexanimidamide (6a). Compound 6a (0.2 mmol scale) was
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prepared according to the known procedures.3a Pale yellow oil (48.4 mg, 65%). H NMR (400 MHz,
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CDCl3) δ 7.35 – 7.24 (m, 10H), 4.80 (s, 2H), 4.57 (s, 2H), 3.05 (s, 3H), 2.45 (t, J = 8.0 Hz, 2H), 1.33 –
1.28 (m, 2H), 1.18 – 1.11 (m, 4H), 0.79 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.8,
139.6, 136.7, 128.7, 128.5, 128.4, 127.7, 127.4, 126.8, 53.8, 51.1, 40.3, 31.5, 30.6, 25.2, 22.2, 13.8; IR
(neat): 2925, 2855, 1652, 1558. 1496, 1455, 1341, 1150, 1076, 1027, 961, 698, 517; HRESIMS Calcd
for [C21H28N2NaO2S]+ (M + Na+) 395.1764, found 395.1765.
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ASSOCIATED CONTENT
1
Supporting Information Available. H and 13C NMR spectra for all described compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
Author Contributions. P.-P.R. and H.-H.L. contributed equally to this work.
ORCID
Chunyin Zhu: 0000-0001-5759-8232
Long-Wu Ye: 0000-0003-3108-2611
Notes
The authors declare no competing financial interest.
Acknowledgment. We are grateful for financial support from the National Natural Science
Foundation of China (21622204 and 21572186), the Natural Science Foundation of Fujian Province for
Distinguished Young Scholars (No. 2015J06003), Qing Lan Project of Jiangsu Province and Jiangsu
University Foundation (No. 13JDG059), NFFTBS (No. J1310024), the President Research Funds from
Xiamen University (20720150045), XMU Undergraduate Innovation and Entrepreneurship Training
Programs (201510384008).
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