Terminal Alkyne-Assisted One-Pot Synthesis of ... - ACS Publications

Subscriber access provided by Nottingham Trent University

Article

Terminal Alkyne-Assisted One-Pot Synthesis of Arylamidines: Carbon Source of Amidine Group from Oxime Chlorides Fengping Yi, Qihui Sun, Jing Sun, Chao Fu, and Weiyin Yi J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00538 • Publication Date (Web): 10 May 2019 Downloaded from http://pubs.acs.org on May 10, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Journal of Organic Chemistry

Terminal Alkyne-Assisted One-Pot Synthesis of Arylamidines: Carbon Source of Amidine Group from Oxime Chlorides Fengping Yi, Qihui Sun, Jing Sun, Chao Fu and Weiyin Yi* School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, P. R. China Cl + catalytic amount

R2SO2N3 2

R =aryl, alkyl

N

+ R3

OH

CuI, TEA DCM/H2O, rt,12h

R

3

one-pot green fashion mild condition cheap/easily accessible substrates cleavage of multiple bonds (C-N, C-O, N-O et al)

R2 S NH2 O O 32 examples 68-92% yields N

ABSTRACT: A terminal alkyne-assisted protocol for the one-pot formation of a diverse range of arylamidines from a novel cascade reaction of in situ generated nitrile oxides, sulfonyl azides, terminal alkynes and water by [3+2] cycloaddition and ring opening sequence was developed. The use of aryl oxime chlorides as the carbon source of amidine group and the addition of water proved to be critical for the reaction. Moreover, terminal alkynes, which can lead to high yields of products by employing less amount, may play a catalytic role in the reaction. A broader range of substrates was investigated. INTRODUCTION Amidines are of great importance on account of their many important applications in the field of organic synthesis, which, as synthetic precursor, were frequently used to prepare various heterocyclic ring systems such as quinazolines,1 quinazolinones,2 pyrimidines,3 triazoles,4 and benzimidazoles.5 Meanwhile, the compounds containing amidine structural motif also exhibited excellent bioactivity in the area of pharmaceuticals. For example, the amidine functional group was found in a wide range of biologically active molecules, which have been shown to have a wide range of interesting biological activities including antimicrobial agents,6 ASIC inhibitors,7 muscarinic against for the treatment of Alzheimer’s disease,8 platelet aggregation inhibitors,9 and serine protease inhibitors.10 Consequently, various research groups are engaging themselves to access amidines via new and convenient protocols. Conventionly, the typical methodologies for the synthesis of amidine and its derivatives involve the nucleophilic addition of amines or ammonia equivalents to nitriles under forcing conditions or the direct condensation of amines or ammonia equivalents with suitably activated carboxylate equivalents, such as imidoyl chlorides, imidoyl benzotriazoles, imidates, and thioimidates under harsh conditions.11 In recent years, in order to further expand the desirable molecular library of amidines for the high-throught

ACS Paragon Plus Environment

The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 19

screening of pharmaceutically active compounds, many efficient protocols to amidine and its derivatives have also been further developed. For example, a series of Pdcatalyzed reactions to synthesize amidine and its derivatives from ynamides,11c aryltrifluoroborates,12a amidoximes,12b aryl halides,12c-e were reported. More recently, synthetic methodologies employing the reaction of arynes with thioureas or Ntosylacetimidates/acetimidamides under certain conditions have also been exploited for constructing amidines by Greaney13 and Chandrasekhar14. Every above-mentioned method has its advantages and disadvantages, therefore, it is still highly desirable to further develop more convenient, efficient and economical methods for the generation of amidines under mild conditions. In 2005, Chang’s group first devised a highly efficient copper-catalyzed multicomponent reactions (MCRs), in which sulfonyl azides react with a series of terminal alkynes and amines to give amidines under fairly mild conditions (Scheme 1a).15a It was presumed that the environment-friendly reaction was proposed to proceed via active sulfonylketenimine intermediates generated from sulfonyl azides and terminal alkynes under Cu (I) and base. Subsequently, a series of similar MCRs for the synthesis of amidines (alkyl amidines only!) were also investigated (Scheme 1a).15 In contrast to other synthetic methods, these reactions to furnish amidines are convenient and mild, but the carbon source of amidine functional group were from terminal alkynes. However, it is generally known that terminal alkynes are more expensive. As a result, this factor will limit the wide application of this methodology. To address the problem of this methodology, a further synthetic idea to furnish amidines by utilizing such MCRs, in which the carbon source of amidine functional group is from available substrates rather than expensive terminal alkynes, is conceived. Therefore, the appropriate choices of other easily accessible substrates or reagents, which will be able to participate in the reaction and alter the reaction route under certain condition to access the desired results, are of tremendous significance. a) Previous works on the synthesis of amidines from sulfonyl azides, terminal alkynes and amines + R2SO2N3 + HNR4R5 Cu(I), base

R1 b) this work R1

Cl 2

+ R SO2N3

+

R3

N

OH + H2O

R1

ref 15

NR4R5 O R2 N S O

Cu(I), base

NH2 O R2 S 3 N O R

Scheme 1. Previous works on the synthesis of amidines from sulfonyl azides, terminal alkynes and amines and this work. Nitrile oxides from cheap/easily accessible oxime halides under bases are frequently employed as excellent synthons for the preparation of a wide variety of important heterocycles compounds with biological activities by cycloaddition reaction with unsaturated organic molecules.16 In view of the unsaturated nature of sulfonylketenimine intermediates, the cycloaddition reaction of in situ generated nitrile oxide with active sulfonylketenimine intermediate will also occur. Therefore, herein,


Page 3 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


we disclosed a Cu(I)-catalyzed protocol for the formation of amidines from the reaction of aryl oxime chlorides, terminal alkynes, sulfonyl azides with water by cycloaddition and ring opening sequence, in which the carbon source of amidines were from nitrile oxides rather than terminal alkynes (Scheme 1b, this work). RESULTS AND DISCUSSION Preliminary investigation of the reaction of alkyne 1a, tosyl azide 2a, oxime halide 3a, and water 4 in the presence of Cu (I) salt and triethylamine (Et3N or TEA) in dichloromethane (DCM) at room temperature for 12h under open air revealed that the results of reaction strongly depended on the common Cu (I) salt used. As shown in Table 1 (Table 1, entries 1-4), It was found that CuI turned out to be the best catalyst in improving the yield of MCRs (entry 4, 87%), but Cu2O would be not able to afford any the desired products we wanted (entry 2). 5a had been confirmed by 1H NMR, 13C NMR, and HRMS. Meanwhile, the amount of Table 1. Optimization of the reaction conditionsa) Cl N

+ TsN3 + 1a

2a

3a

OH

+ H 2O

condition

N

S NH2 O O 5a

4

Entry

Catalyst

Base

Solvent

Temp(℃)

Yieldd)(%)

1

CuBr

Et3N

DCM

rt

65

2

Cu2O

Et3N

DCM

rt

ndb)

3

CuCl

Et3N

DCM

rt

63

4

CuI

Et3N

DCM

rt

87

5

CuI

Et3N

DCM

rt

87

6

CuI

Et3N

DCM

rt

86

7

CuI

Et3N

DCM

rt

71

8

CuI

Et3N

DCM

40

81

9

CuI

Et3N

DCM

60

78

10

CuI

Et3N

CHCl3

rt

53

11

CuI

Et3N

MeCN

rt

83

12

CuI

Et3N

THF

rt

17

13

CuI

Et3N

Dioxane

rt

37

14

CuI

Et3N

DMSO

rt

80

15

CuI

K2CO3

DCM

rt

22

16

CuI

Cs2CO3

DCM

rt

20

17

CuI

tBuOK

DCM

rt

Trace



Page 4 of 19

18

CuI

DBU

DCM

rt

Trace

19c)

CuI

Et3N

DCM

rt

72

a) Reaction

conditions: entries 1-4, 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), 4 (0.5 mmol), Cu catalyst (0.1 mmol), base (1 mmol) in solvent (2 mL), stired at rt for 12h under open air; entry 5, 1a:2a:3a:4 = 0.4:1:1:1, the amount of other reagents are unchanged; entries 6, 8-19 1a:2a:3a:4 = 0.2:1:1:1, the amount of other reagents are unchanged; entries 7, 1a:2a:3a:4 = 0.1:1:1:1, the amount of other reagents are unchanged. b) n.d. = not detected. c) Reaction carried out for 8h. d) Isolated yields of 5a are given, 3a as reference. reaction substrates, which would change the chemical yields of the desired products, were also investigated. To our surprise, the results indicated that a change in the amount of reaction substrates, especially phenylacetylene, did not affected obviously the yield of the reaction (Table 1, entries 4-7). In contrast to the stoichiometry of phenylacetylene (87%, entry 4), lower amount can also afford almost equal yield of 5a. For example, when MCRs were carried out according to the 0.2:1:1:1 ratio of 1a:2a:3a:4 under above-mentioned optimal condition, 5a would be also achieved in 86% yield (entry 6). Therefore, phenylacetylene may act as a catalyst in the reaction. We also observed that the temperature had little effect on this novel transformation, but the lower temperature was more favorable to increase the yield of the reaction (Table 1, entry 6, entries 8-9). We, subsequently, attempted to perform the reaction in various commonly used solvents. It was shown that DCM was best for this tandem reaction in term of the yields of product 5a (Table 1, entry 6, entries 1014). Among the evaluation of bases, Et3N was found to be the best base, whereas K2CO3 and Cs2CO3 just provided the desired products in 22% and 20% yields, respectively (Table 1, entries 15-16). However, for KOtBu and DBU, only a trace amount of product 5a was detected (Table 1, entries 17-18). In addition, it was noteworthy that the longer reaction time was required for the formation of 5a (Table 1, entry 6, entry19). Therefore, according to the results, it was determined that the MCRs reaction system with the ratio of 0.2:1:1:1(1a:2a:3a:4) at rt in dichloromethane for 12h under CuI in the presence of Et3N (2eq, 3a as reference) were the optimal reaction conditions Subsequently, we evaluated the generality of MCRs to prompt the generation of 5 by varying the scopes of various substrates other than terminal alkynes under the optimized conditions. As depicted in Table 2, all tested substrates were cleanly transformed into their corresponding products (5a-5ag) with good to excellent yields, reflecting wide scope of this MCRs. The structure of product 5a was also confirmed by single-crystal X-ray diffraction, as also shown in Table 2. Moreover, it was found that the substituent groups on various substrates had no obvious influence on the chemical yields of the corresponding products 5, only the substrates bearing electron-withdrawing groups furnish a slightly lower yields (for example 5p in Table 2) than those with other substituents. Because of the mild reaction conditions and convenience of the procedure,


Page 5 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


therefore, in order to verify the practicability of this reaction, we carried out a Table 2. Substrate scopes of MCRs for the formation of 5a)



Cl 2

R SO2N3

+ 1a

+

R

3

N

2

OH

CuI, TEA

+ H 2O

R3

R2 S NH2 O O 5 N

DCM, rt,12h

4

3

Page 6 of 19

NO2 N

N

S NH2O O

N

S

S NH2O O

NH2O O

5a 86%b) for phenylacetylene CCDC: 1855635 73% for p-Tolyacetylene 23% for p-Ethynylchlorobenzene

5b 89%

5c 81%

NO2 N

N

S NH2O O

N

NH2O O 5e 88%

5d 85%

N

S NH2O O

S

S NH2O O

5f 87%

5g 80%

O N

N

S

N

S

NH2O O

NH2O O 5h 83% O

NO2

O N

N

5p 68%

Cl

S NH2O O

N

NO2 Cl

Br N

S NH2O O

NH2O O 5t 85%

N

S

5v 92%

5w 90%

Cl

NO2 Br N

S NH2O O

NH2O O

5u 88%

Br

S NH2O O 5s 89%

Br N

S

N

S

NH2O O 5r 91%

5q 72%

Cl

5o 83%

Cl Cl

N

S

S NH2O O

NH2O O 5x 88%

N

S NH2O O

5y 86%

Cl

5z 88%

Cl NO2 N

N

S NH2O O 5ab 87% Br

S NH2O O

Cl

5n 84%

N

S

NH2O O

N

S

NH2O O

Cl

5m 80% NO2 Cl

N

Cl

S

NH2O O

5l 79%

Cl

5k 77%

Cl

NH2O O

N

S NH2O O

5j 81%

S

Cl

N

S

NH2O O

5i 87%

N

O

Cl N

S

S NH2O O

NH2O O 5ac 79% Br

5ad 84% Br NO2

N

S NH2O O 5ae 81%

N

S NH2O O 5af 82%


N

S NH2O O 5ag 73%

Page 7 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


a) Optimal reaction conditions: 1a (0.1 mmol), 2 (0.5 mmol), 3 (0.5 mmol), 4 (0.5mmol), CuI (0.1 mmol), Et3N (1 mmol) in DCM (2 mL), stired at rt for 12h under open air. b) Isolated yields of 5 are given, 3 as reference. scale-up experiment on substrate 3a under the optimized conditions according the procedure (Scheme 2). It was found that the reaction of 1.56 g (10 mmol) of substrate 3a afforded 2.19 g of 5a in 77% yield, indicating that a large-scale synthesis of α-arylamidine is practical using this method. Cl N3

+ 1a

2a

S O O

+

N

OH +

3a (1.56 g, 10mmol)

H 2O

CuI, TEA DCM, rt,12h

4

N

S NH2 O O 5a (2.11g, 77%)

Scheme 2 Ampliﬁcation Reaction for the synthesis of 5a When the other terminal alkynes rather than phenyl acetylene as the substrate, for example p-tolyacetylene and p-ethynylchlorobenzene, were selected to apply this model strategy under the optimized conditions, the corresponding amidines containing p-tolyl and p-chlorophenyl were not observed. However, to our surprise, only the same product 5a was furnished in 73% and 23% yield, respectively (Table 2 (5a) and Scheme 3 eq 1). The results prompted us to speculate that the terminal alkynes might not incorporate into the reaction. To gain better insight into the reaction mechanism, a series of control experiments were conducted in accordance with the optimal conditions. (Scheme 3). However, when the reactions were carried out according to eq 2-4 in Scheme 3 under the standard reaction conditions or even strict anhydrous standard reaction conditions, the desired product 5a was not isolated. These results indicated that the participation of terminal alkynes and water was essential for the successful completion of the reaction. As a consequence, the investigations also further confirmed that terminal alkynes might play a catalytic role in the reaction. Meanwhile, to clarify whether compound 6 as an intermediate achieved from the reaction of 3a with H2O in this reaction system in advance are involved in this reaction, the reactions 5-6 were investigated (Scheme 3). Unfortunately, the product 5a was not afforded as well. The results suggested that compound 6 was not the intermediate of the mechanistic process. In order to confirm the carbon source of amidine functional group, the reaction 7 was performed under standard reaction conditions (Scheme 3, eq 7). Pleasingly, the product 5r was furnished in 91% yield. Therefore, we can conclude that the carbon source comes from oxime chloride 3f. According to these results and previous reports,15 we are able to propose the tentative mechanism of the reactions, as shown in Scheme 4. Taking the reaction of eq 7 in Scheme 3 for the formation of 5r as example, phenyl acetylene 1a first reacts readily with tosyl azide 2a to give a ketenimine intermediate A in the presence of CuI and Et3N, which then undergo a formal [3+2]



Page 8 of 19

Cl R1 1

OH + H 2O

N

+ TsN3 + 2a

CuI, TEA

S NH2 O O 5a

4

3a

R1 = phenyl R1 = p-tolyl R1 = p-chlorophenyl

86% 73% 23%

Cl N

TsN3 + 2a

OH

CuI, TEA

+ H 2O

3a

S NH2 O O 5a

4

1a

N

+

2a

OH

CuI, TEA

S NH2 O O 5a

Cl TsN3

N

+

OH

CuI, TEA

S NH2 O O 5a

3a O N H

+ TsN3 + H2O + 2a

1a

OH

CuI, TEA DCM, rt, 12h

6

4

(4)

N

DCM, rt, 12h

2a

(3)

N

DCM, rt, 12h strict anhydrous condition

3a

(2)

N

DCM, rt, 12h

Cl + TsN3

(1)

N

DCM, rt, 12h

N

S NH2 O O 5a

(5)

O N H

+ TsN3 + 2a

1a

OH

CuI, TEA DCM, rt, 12h

6 Cl N

+ TsN3 +

OH + H 2O

Cl 1a

2a

3f

Cl CuI, TEA DCM, rt, 12h

4

N

S NH2 O O 5a

N

(6)

(7)

S NH2 O O 5r, 91%

Scheme 3. Control experiments cycloaddition reaction with in situ generated nitrile oxide B from oxime halide 3f under Et3N to offer intermediate C (HRMS: calcd. for C or D [M+H] + 425.07212; found 425.07270 ， see SI).17 Subsequently, electronic ring opening of intermediate C occurs in the help of H2O (or OH-) under such reaction conditions,18 leading to the formation of intermediate D. Intermediate E will be generated by the reaction of OH- (or H2O ) with intermediate D accompanied by the formation of phenyl acetylene, which will be further recycled. And then, intermediate E will transformed into the desired isomer amidine 5r’ with the release of O2 in the presence of OH- (or H2O). Finally, 5r’ will further isomerize into 5r. Therefore,


Page 9 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


the role of added water in the whole reaction may promote the cleavage of bonds (C-O and N-O) and provide the proton source15f and OH- anion under such reaction conditions (OH- anion may be afforded from the reaction of Et3N and H2O),18 resulting in the generation of the desired product. NH Et3N

H 2O

+

Cl

Et3N . H+ + OH -

NHTs

5r'

Cl 3f HCl

N

.

OH

A

TEA

Cl

Cl CuI, TEA

N2

5r

H N

1a

NTs

H 2O 4

NTs

NTs

O2

H 2O

TsN3 2a

Cl

NH2

Cl

H OH

OH O H O E

Cl H N

[3+2]

N O B

H OH O

NTs

Cl Ts N

H

N O H OH C

OH

D

OH

H 2O HRMS: calcd: for C or D [M+1] 425.07212 found: [M+1] 425.07270

Scheme 4. Proposed mechanistic pathway for the formation of 5r CONCLUSION In conclusion, we have developed a robust protocol for the one-pot formation of a diverse range of arylamidines from a novel cascade reaction of in situ generated nitrile oxides, sulfonyl azides, terminal alkynes and water by [3+2] cycloaddition and ring opening sequence. In combination with previous reports15 that can only get alkyl amidines by MCRs, the present strategy, which is an important supplement to those methods, can provide a powerful tool to the synthesis of various amidines using easily accessible substrates under very mild conditions. Importantly, the reaction, which is devoid of various terminal alkynes as substrates, can also lead to the generation of corresponding arylamidines only by using the catalytic amount of phenyl acetylene. Furthermore, the use of oxime chlorides as the carbon source of amidine group and the addition of water proved to be critical for the reaction. The methodology further gave an excellent example that the use of appropriate substrates would alter the typical product composition by changing the mechanistic process. We anticipate that the methodology will continue to expand an evergrowing toolbox of synthetic tools for medicinal chemists. EXPERIMENTAL SECTION General Remarks: All reagents were purchased from commercial suppliers, and were used without further purification. All solvents were treated according to standard procedures. The progress of reactions was monitored by TLC. For chromatographic



purifications, 200–300 mesh silica gel was used. 1H (500 MHz) and 13C (126 MHz) NMR spectra were recorded with tetramethylsilane as an internal standard. HRMS measurements were carried out using the ESI ionization technique with an FT-ICR analyzer. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz) and integration. Procedure for generation of hydroximoyl chlorides 3: Hydroximoyl chlorides 3a-c was prepared as reported in the literature19-21 according to the reaction equation (see SI part). Other hydroximoyl chlorides 3 are commercially available, and their spectroscopic data are also consistent with the reported literatures.22-24 N

OH Cl

3a

(Z)-N-hydroxybenzimidoyl chloride 3a. 1H NMR (501 MHz, Chloroform-d) δ 8.72 (s, 1H), 7.87 (d, J = 7.3 Hz, 2H), 7.46 (dt, J = 14.7, 7.0 Hz, 3H). N

OH Cl

3b

(Z)-N-hydroxy-4-methylbenzimidoyl chloride 3b. 1H NMR (501 MHz, Chloroformd) δ 9.57 (s, 1H), 7.76 (s, 2H), 7.25 (s, 2H), 2.41 (s, 3H). N

OH Cl

Cl

Cl 3c

(Z)-2,4-dichloro-N-hydroxybenzimidoyl chloride 3c. 1H NMR (501 MHz, Chloroform-d) δ 9.61 (s, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H). General Procedure for the synthesis of (5): To a stirred mixture of alkynes 1 (0.1 mmol), azides 2 (0.5 mmol), and CuI (0.1 mmol) in dry DCM (2 mL) was slowly added triethylamine (1 mmol) at room temperature, stired at rt for 1-2h under open air. And then, hydroximoyl chlorides 3 (0.5 mmol) and water 4 (0.5 mmol) were added into the stirred reaction, the reaction mixture continued to react for 12 hours. After the reaction was completed, which was monitored with TLC, the reaction mixture was diluted by adding CH2Cl2 (6 mL) and aqueous NH4Cl solution (9 mL). The mixture was stirred for an additional 30min and two layers were separated. The aqueous layer was extracted with CH2Cl2 (9 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column


Page 10 of 19

Page 11 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


chromatograph with an appropriate eluting solvent system. Gram synthesis method on 5a mmol scale: To a stirred mixture of phenylacetylene 1a (2 mmol), azide 2a (10 mmol), and CuI (1 mmol) in dry DCM (30 mL) was slowly added triethylamine (20 mmol) at room temperature, stired at rt for 1-2h under open air. And then, hydroximoyl chloride 3a (10 mmol) and water 4 (10 mmol) were added into the stirred reaction, the reaction mixture continued to react for 12 hours at rt. After the reaction was completed, which was monitored by TLC, the reaction mixture was diluted by adding CH2Cl2 (60 mL) and aqueous NH4Cl solution (200 mL). The mixture was stirred for an additional 30min and two layers were separated. The aqueous layer was extracted with CH2Cl2 (30 mL x 3). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatograph using petroleum ether/ethyl acetate as the eluent to afford 2.11 g product 5a, 77% yield. Characterization data for 5. (Z)-N'-tosylbenzimidamide(5a). A Light yellow solid. Yield: 86% (118 mg). mp

147−149 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.30 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 7.36 (t, J = 7.7 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 6.97 (s, 1H), 2.40 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.1, 143.1, 139.3, 133.1, 132.7, 129.4, 128.7, 127.5, 126.4, 21.5. HRMS: calcd. for C14H14N2O2S [M+H]+ 275.0848; found 275.0830. (Z)-N'-(phenylsulfonyl)benzimidamide(5b). A Light yellow solid. Yield: 89% (116 mg). mp 149−151 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.02 (d, J = 7.6 Hz, 2H), 7.81 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 5.9 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 7.7 Hz, 2H), 6.67 (s, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.1, 142.1, 133.2, 132.8, 132.4, 128.8, 127.4, 126.4. HRMS: calcd. for C13H13N2O2S [M+H]+ 261.0692; found 261.0693. (Z)-N'-((4-nitrophenyl)sulfonyl)benzimidamide(5c). A Light yellow solid. Yield: 81% (124 mg). mp 176−178°C. 1H NMR (500 MHz, DMSO-d6) δ 9.30 (s, 1H), 8.45 (s, 1H), 8.41 (dd, J = 16.1, 8.7 Hz, 3H), 8.20 (d, J = 8.6 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d ) δ 163.8, 149.9, 148.4, 133.4, 133.2, 129.0, 128.5, 6 128.1, 127.7, 124.9, 124.8. HRMS: calcd. for C13H12N3O4S [M+H]+ 306.0543; found 306.0543. (Z)-N'-(methylsulfonyl)benzimidamide(5d). A yellow solid. Yield: 85% (85 mg). mp 122−124°C. 1H NMR (500 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.83 (dd, J = 8.4, 1.2 Hz, 2H), 7.59 – 7.52 (m, 1H), 7.45 (t, J = 7.8 Hz, 2H), 6.75 (s, 1H), 3.09 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.1 , 133.2 , 132.8 , 128.8 , 127.4 , 42.2 .HRMS: calcd. for C8H11N2O2S [M+H]+ 199.0535; found 199.0534. (Z)-4-methyl-N'-tosylbenzimidamide(5e). A yellow solid. Yield: 88% (127 mg). mp 103−105 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.28 (s, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 7.8 Hz, 2H), 6.75 (s, 1H), 2.41 (s, 3H), 2.37 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 162.7,



143.5, 142.9, 130.4, 129.4, 129.3, 127.4, 126.42 21.5. HRMS: calcd. for C15H16N2O2S [M+H]+ 289.1005; found 289.1033. (Z)-4-methyl-N'-(phenylsulfonyl)benzimidamide(5f). A Light yellow solid. Yield: 87% (120 mg). mp 141−143 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.32 (s, 1H), 8.03 – 7.99 (m, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.57 – 7.54 (m, 1H), 7.50 (t, J = 7.5 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 6.59 (s, 1H), 2.39 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.0, 143.7, 142.3 132.2, 130.2, 129.5, 128.8, 127.4, 126.4, 21.5. HRMS: calcd. for C14H15N2O2S [M+H]+ 275.0848; found 275.0849. (Z)-4-methyl-N'-((4-nitrophenyl)sulfonyl)benzimidamide(5g). A Light yellow solid. Yield: 80% (128 mg). mp 145−147 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.33 (s, 1H), 8.19 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.70 (s, 1H), 2.41 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.6, 149.8, 147.9, 144.4, 129.7, 127.8, 127.7, 127.4, 124.3, 124.1, 21.6. HRMS: calcd. for C14H14N3O4S [M+H]+ 320.0699; found 320.0699. (Z)-4-methyl-N'-(methylsulfonyl)benzimidamide(5h). A yellow solid. Yield: 83% (88 mg). mp 139−141 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H), 6.69 (s, 1H), 3.07 (s, 3H), 2.40 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.0, 143.6, 130.3, 129.5, 127.4, 42.2, 21.5. HRMS: calcd. for C9H13N2O2S [M+H]+ 213.0692; found 213.0690. (Z)-3-methyl-N'-tosylbenzimidamide(5i). A Light yellow solid. Yield: 87% (126 mg). mp 110−112 °C. 1H NMR (501 MHz, Chloroform-d) δ 8.27 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.4 Hz, 3H), 7.06 (s, 1H), 2.38 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (126 MHz, Chloroformd) δ 178.2, 163.3, 143.0, 143.0, 139.4, 139.3, 139.2, 139.2, 138.6, 133.1, 130.0, 129.2, 129.0, 128.9, 128.8, 128.8, 127.9, 127.6, 127.1, 127.0, 125.8, 125.7, 125.6, 125.2, 123.9, 22.0, 21.9, 21.0. HRMS: calcd. for C15H17N2O2S [M+H]+ 289.1005; found 289.1007. (Z)-4-methoxy-N'-tosylbenzimidamide(5j). A Light yellow solid. Yield: 81% (124mg). mp 148−150 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.24 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 6.82 (s, 1H), 3.80 (s, 3H), 2.40 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.3, 162.4, 142.8, 129.5, 129.3, 126.4, 114.0, 55.5, 21.5. HRMS: calcd. for C15H16N2O3S [M+H]+ 305.0954; found 305.0971. (Z)-4-methoxy-N'-(phenylsulfonyl)benzimidamide(5k). A Light yellow solid. Yield: 77% (112 mg). mp 146−148 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.29 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.55 (t, J = 6.9 Hz, 1H), 7.49 (t, J = 7.3 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.62 (s, 1H), 3.83 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.4, 162.6, 132.2, 129.5, 128.8, 126.3, 124.9, 114.0, 55.5. HRMS: calcd. for C14H15N2O3S [M+H]+ 291.0797; found 291.0799. (Z)-4-methoxy-N'-((4-nitrophenyl)sulfonyl)benzimidamide(5l). A yellow solid. Yield: 79% (133 mg). mp 155−157 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.34 (d, J = 8.8 Hz, 2H), 8.31 (s, 1H), 8.19 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 8.9 Hz, 2H), 6.60 (s, 1H), 3.87 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.9, 162.9, 149.8, 148.1, 129.4, 127.7, 124.4, 124.1, 114.3, 55.6. HRMS: calcd. for C14H14N3O5S [M+H]+ 336.0648; found 336.0649.


Page 12 of 19

Page 13 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(Z)-4-methoxy-N'-(methylsulfonyl)benzimidamide(5m). A Light yellow solid. Yield: 80% (92 mg). mp 151−153 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.82 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 6.43 (s, 1H), 3.87 (s, 3H), 3.10 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 163.4, 162.3, 129.3, 128.6, 128.5, 125.1, 114.1, 55.5, 42.3. HRMS: calcd.for C9H13N2O3S [M+H]+ 229.06414; found 229.0640. (Z)-2,4-dichloro-N'-tosylbenzimidamide(5n). A Light yellow solid. Yield: 84% (144mg). mp 153−154 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.49 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.32 – 7.29 (m, 2H), 6.48 (s, 1H), 2.44 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 143.5, 137.6, 132.2, 131.5, 130.3, 129.7, 129.4, 127.6, 126.6, 126.4, 21.5 .HRMS: calcd. for C14H13Cl2N2O2S [M+H]+ 343.0069; found 343.0070. (Z)-2,4-dichloro-N'-(phenylsulfonyl)benzimidamide(5o). A Light yellow solid. Yield: 83% (136 mg). mp 155−157 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.46 (s, 1H), 7.97 (d, J = 7.4 Hz, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.54 – 7.49 (m, 3H), 7.39 (d, J = 1.9 Hz, 1H), 7.29 – 7.26 (m, 1H), 6.66 (s, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 161.7, 141.4, 132.7, 132.2, 131.7, 131.5, 130.3, 129.1, 128.8, 127.6, 126.5, 126.3. HRMS: calcd. For C13H11Cl2N2O2S[M+H]+ 328.9912; found 328.9915. (Z)-2,4-dichloro-N'-((4-nitrophenyl)sulfonyl)benzimidamide(5p). A Light yellow solid. Yield: 68% (127 mg). mp 139−141 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.52 (s, 1H), 8.39 – 8.36 (m, 1H), 8.34 – 8.31 (m, 1H), 8.20 – 8.18 (m, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 6.68 (s, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 167.7, 136.42 134.7, 131.4, 130.5, 129.6, 128.2, 127.7, 124.7. HRMS: calcd. for C13H10Cl2N3O4S [M+H]+ 373.9763; found 373.9762. (Z)-2,4-dichloro-N'-(methylsulfonyl)benzimidamide(5q). A Light yellow solid. Yield: 72% (96 mg). mp 133−135 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.23 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 8.3, 2.0 Hz, 1H), 6.42 (s, 1H), 3.10 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 161.4, 137.9, 132.2, 131.8, 131.7, 131.5, 130.5, 130.2, 127.7, 127.6, 42.2. HRMS: calcd. for C8H9Cl2N2O2S [M+H]+ 266.9756; found 266.9758. (Z)-4-chloro-N'-tosylbenzimidamide(5r). A Light yellow solid. Yield: 91% (141 mg). mp 151−153 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.30 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.75 (s, 1H), 7.74 (s, 1H), 7.34 (s, 1H), 7.32 (s, 1H), 7.28 (d, J = 8.0 Hz, 2H), 6.97 (s, 1H), 2.42 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 161.9, 143.3, 139.1, 131.6, 129.7, 129.47, 129.0, 128.9, 126.4, 21.5. HRMS: calcd. for C14H14ClN2O2S [M+H]+ 309.0459; found 309.0460. (Z)-4-chloro-N'-(phenylsulfonyl)benzimidamide(5s). A Light yellow solid. Yield: 89% (131 mg). mp 161−163 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.32 (s, 1H), 7.99 – 7.94 (m, 2H), 7.77 – 7.73 (m, 2H), 7.59 – 7.54 (m, 1H), 7.52 – 7.47 (m, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.17 (s, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 162.2, 141.8, 139.2, 132.5, 131.4, 129.1, 129.0, 128.9, 126.3. HRMS: calcd. for C13H12ClN2O2S [M+H]+ 295.0302; found 295.0304.



(Z)-4-chloro-N'-((4-nitrophenyl)sulfonyl)benzimidamide(5t). A Light yellow solid. Yield: 85% (145 mg). mp 160−162 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.50 (s, 1H), 8.41 (ddd, J = 9.4, 7.0, 1.9 Hz, 2H), 8.21 – 8.19 (m, 1H), 8.11 – 8.05 (m, 2H), 7.90 – 7.87 (m, 1H), 7.75 (s, 2H), 7.56 (d, J = 8.6 Hz, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 162.7, 149.9, 149.87, 149.6, 132.1, 130.4, 129.0, 128.1, 127.7, 124.9, 124.8. HRMS: calcd. for C13H11ClN3O4S [M+H]+ 340.0153; found 340.0153. (Z)-4-chloro-N'-(methylsulfonyl)benzimidamide(5u). A Light yellow solid. Yield: 88% (103 mg). mp 140−142 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 6.63 (s, 1H), 3.11 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 161.8, 139.20 131.6, 129.1, 128.8, 42.3. HRMS: calcd. for C8H10ClN2O2S [M+H]+ 233.0146; found 233.0145. (Z)-4-bromo-N'-tosylbenzimidamide(5v). A Light yellow solid. Yield: 92% (162 mg). mp 159−161 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.30 (s, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.68 (s, 1H), 7.66 (d, J = 2.0 Hz, 1H), 7.50 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.29 (s, 1H), 7.27 (s, 1H), 6.96 (s, 1H), 2.42 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 161.9, 143.2, 138.9, 131.9, 129.6, 129.4, 129.1, 127.6, 126.4, 126.3, 21.5. HRMS: calcd. for C14H14BrN2O2S [M+H]+ 352.9953, found 352.9957. (Z)-4-bromo-N'-(phenylsulfonyl)benzimidamide(5w). A Light yellow solid. Yield: 90% (153mg). mp 169−171 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.34 (s, 1H), 7.97 – 7.95 (m, 1H), 7.86 (dd, J = 7.8, 1.6 Hz, 1H), 7.82 – 7.80 (m, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.68 (s, 1H), 7.65 – 7.60 (m, 1H), 7.59 – 7.56 (m, 2H), 7.38 (s, 1H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 162.2, 142.8, 132.9, 132.7, 132.2, 131.9, 130.4, 129.4, 129.3, 126.8, 126.5, 126.0. HRMS: calcd. for C13H12BrN2O2S [M+H]+ 338.9797; found 338.9799. (Z)-4-bromo-N'-((4-nitrophenyl)sulfonyl)benzimidamide(5x). A Light yellow solid. Yield: 88% (169 mg). mp 164−166 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.50 (s, 1H), 8.44 – 8.41 (m, 1H), 8.40 – 8.38 (m, 1H), 8.21 – 8.19 (m, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.75 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 162.8, 149.9, 149.6, 148.2, 132.5, 132.0, 130.5, 128.1, 127.7, 127.0, 124.9, 124.8. HRMS: calcd. for C13H11BrN3O4S [M+H]+ 383.9648; found 383.9643. (Z)-4-bromo-N'-(methylsulfonyl)benzimidamide(5y). A Light yellow solid. Yield: 86% (119 mg). mp 149−151 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.74 – 7.69 (m, 2H), 7.63 – 7.59 (m, 2H), 6.58 (s, 1H), 3.11 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 161.9, 132.1, 132.1, 128.9, 127.7, 42.3. HRMS: calcd. for C8H10BrN2O2S [M+H]+ 276.9640; found 276.9644. (Z)-3-chloro-N'-tosylbenzimidamide(5z). A Light yellow solid. Yield: 88% (136 mg). mp 150−152 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.32 (s, 1H), 7.90 – 7.83 (m, 2H), 7.74 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.8 Hz, 2H), 7.31 (s, 1H), 2.36 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 161.5, 143.0, 139.8, 135.7, 133.7, 132.6, 130.8, 129.8, 129.7, 128.0, 127.0, 126.6, 126.1, 21.4, 21.3. HRMS: calcd. for C14H14ClN2O2S [M+H]+ 309.0459; found 309.0459.


Page 14 of 19

Page 15 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(Z)-3-chloro-N'-(phenylsulfonyl)benzimidamide(5ab). A yellow solid. Yield: 87% (128 mg). mp 137−139 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.99 (d, J = 7.5 Hz, 2H), 7.81 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.57 (t, J = 7.4 Hz, 2H), 7.50 (s, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.02 (s, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 161.8, 141.7, 134.96, 134.9, 132.7, 132.5, 130.0, 129.1, 128.8, 127.8, 126.4, 126.3, 125.5. HRMS: calcd. for C13H12ClN2O2S [M+H]+ 295.0302; found 295.0305. (Z)-3-chloro-N'-((4-nitrophenyl)sulfonyl)benzimidamide(5ac). A yellow solid. Yield: 77% (131 mg). mp 163−164 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.36 (d, J = 8.9 Hz, 2H), 8.20 (d, J = 8.9 Hz, 2H), 7.85 (t, J = 1.9 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.54 (dd, J = 8.0, 1.1 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.13 (s, 1H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 162.3, 149.9, 147.5, 135.1, 134.4, 133.1, 130.2, 127.9, 127.8, 125.5, 124.5. HRMS: calcd. for C13H11ClN3O4S [M+H]+ 340.0153; found 340.0154. (Z)-3-chloro-N'-(methylsulfonyl)benzimidamide(5ad). A Light yellow solid. Yield: 84% (98 mg). mp 135−137 °C. 1H NMR (500 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.86 (t, J = 1.9 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 6.63 (s, 1H), 3.12 (s, 3H). 13C{1H} NMR (126 MHz, Chloroform-d) δ 161.5, 135.1, 132.7, 132.1, 130.1, 129.9, 127.8, 127.7, 125.4, 125.3, 42.3. HRMS: calcd. for C8H10ClN2O2S [M+H]+ 233.0146; found 233.0145. (Z)-3-bromo-N'-tosylbenzimidamide(5ae). A Light yellow solid. Yield: 81% (143 mg). mp 157−159 °C. 1H NMR (500 MHz, DMSO-d6) δ 8.97 (s, 1H), 8.46 (s, 0.5H), 7.73 (d, J = 8.2 Hz, 2H), 7.37 (t, J = 7.7 Hz, 4H), 7.29 (s, 2H), 2.38 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 164.5, 142.7, 142.3, 141.8, 139.9, 137.1, 133.0, 131.8, 129.7, 129.6, 129.6, 127.9, 126.8, 126.1, 119.8, 21.4. HRMS: calcd. for C14H14BrN2O2S [M+H]+ 352.9953; found 352.9959. (Z)-3-bromo-N'-(phenylsulfonyl)benzimidamide(5af). A yellow solid. Yield: 82% (139 mg). mp 138−140 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.49 (s, 1H), 7.83 (s, 2H), 7.58 (d, J = 7.5 Hz, 4H), 7.38 (s, 3H). 13C{1H} NMR (126 MHz, DMSOd6) δ 169.8, 164.9, 144.4, 142.4, 136.9, 133.2, 133.1, 132.7, 132.4, 131.9, 131.2, 129.5, 129.4, 129.3, 128.9, 128.0, 127.9, 126.7, 126.0. HRMS: calcd. for C13H12BrN2O2S [M+H]+ 338.9797; found 338.9799. (Z)-3-bromo-N'-((4-nitrophenyl)sulfonyl)benzimidamide(5ag). A Light yellow solid. Yield: 73% (140 mg). mp 111−113 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.80 (s, 1H), 8.38 (d, J = 8.9 Hz, 2H), 8.06 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 7.9, 3.4 Hz, 1H), 7.46 – 7.37 (m, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 169.5, 165.7, 149.8, 148.2, 136.7, 133.2, 133.0, 131.9, 131.1, 129.6, 129.0, 128.3, 127.9, 127.9, 124.7, 119.8. HRMS: calcd. for C13H11BrN3O4S [M+H]+ 383.9648; found 383.9648. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc. 1H

NMR, 13C NMR and X-ray spectra of final products (PDF)



AUTHOR INFORMATION Corresponding Authors *E-mail for W. Y.: [email protected] ORCID Weiyin Yi: 0000-0003-4480-7407 Notes The authors declare no competing financial interest. Additional supporting research data, CCDC-1855635 (5a), containing the supplementary crystallographic data for this article may be accessed free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ request/cif. ACKNOWLEDGMENTS This research was supported by the Horizontal Projects of Shanghai Institute of Technology (J2017-150, J2017-202). REFERENCES (1) Ohta, Y.; Tokimizu, Y.; Oishi, S.; Fujii, N.; Ohno, H. Direct synthesis of quinazolines through copper-catalyzed reaction of aniline-derived benzamidines. Org. Lett. 2010, 12, 3963-3965. (2) Ma, B.; Wang, Y.; Peng, J. L.; Zhu, Q. Synthesis of quinazolin-4(3H)-ones via Pd (II)-catalyzed intramolecular C(sp2)–H carboxamidation of N-arylamidines. J. Org. Chem. 2011, 76, 6362-6366. (3) (a) Anderson, E. D.; Boger, D. L. Inverse electron demand Diels–Alder reactionsof 1,2,3-triazines: pronounced substituent effects on reactivity and cycloaddition scope. J. Am. Chem. Soc. 2011, 133, 12285-12292. (b) Anderson, E. D.; Boger, D. L. Scope of the inverse electron demand Diels–Alder reactions of 1,2,3-triazine. Org. Lett. 2011, 13, 2492-2494. (4) Castanedo, G. M.; Seng, P. S.; Blaquiere, N.; Trapp, S.; Staben,S. T. Rapid synthesis of 1,3,5-substituted 1,2,4-triazoles from carboxylic acids, amidines, and hydrazines. J. Org. Chem. 2011, 76, 1177-1179. (5) Peng, J. S.; Ye, M.; Zong, C. J.; Hu, F. Y.; Feng, L. T.; Wang, X. Y.; Wang, Y. F.; Chen, C. X. Copper-catalyzed intramolecular C−N bond formation: a straightforward synthesis of benzimidazole derivatives in water J. Org. Chem. 2011, 76, 716-719. (6) (a) Tidwell, R. R.; Boykin, D. W. Dicationic DNA minor groove binders as antimicrobial agents, in small molecule DNA and RNA binders: from synthesis to nucleic acid complexes., Vol. 2; Demeunynck, M.; Bailly, C.; Wilson, W. D., Eds.; Wiley-VCH: New York, 2003, 416-460. (b) Weidner-Wells, M. A.; Ohemeng, K. A.; Nguyen, V. N.; Frago-Spano, S.; Macielag, M. J.; Werblood, H. M.; Foleno, B. D.; Webb, G. C.; Barrett, J. F.; Hlasta, D. J. Amidino benzimidazole inhibitors of bacterial


Page 16 of 19

Page 17 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


two-component systems Bioorg. Med. Chem. Lett. 2001, 11, 1545-1548. (c) Boykin, D. W.; Kumar, A.; Spychala, J. M.; Zhou, M.; Lombardy, R. J.; Wilson, W. D.; Dykstra, C. C.; Jones, S. K.; Hall, J. E.; Tidwell, R. R.; Laughton, C.; Nunn, C. M.; Neidle, S. Dicationic diarylfurans as anti-pneumocystis carinii agents. J. Med. Chem. 1995, 38, 912-946. (7) Chen, X. M.; Orser, B. A.; MacDonald, J. F. Design and screening of ASIC inhibitors based on aromatic diamidines for combating neurological disorders Eur. J. Pharmacol. 2010, 648, 15-23. (8) Ojo, B.; Dunbar, P. G.; Durant, G. J.; Nagy, P. I.; Huzl, J. J.; Periyasamy, S.; Ngur, D. O.; ElAssadi, A. A.; Hoss, W. P.; Messer, W. S. Synthesis and biochemical activity of novel amidine derivatives as m1 muscarinic receptor agonists. Bioorg. Med. Chem. 1996, 4, 1605-1615. (9) Cannon, C. P. Oral platelet glycoprotein IIb/IIIa receptor inhibitors part II Clin. Cardiol. 2003, 26, 401-406. (10) Fevig, J. M.; Pinto, D. J.; Han, Q.; Quan, M. L.; Pruitt, J. R.; Jacobson, I. C.; Galemmo, R. A. Jr.; Wang, S.; Orwat, M. J.; Bostrom, L. L.; Knabb, R. M.; Wong, P. C.; Lam, P. Y. S.; Wexler, R. R. Synthesis and SAR of benzamidine factor Xa inhibitors containing a vicinally-substituted heterocyclic core. Bioorg. Med. Chem. Lett. 2001, 11, 641-645. (11) Selectives literatures for the synthesis of amidines according to strategies (a) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. A facile access to N-Sulfonylimidates and their synthetic utility for the transformation to amidines and amides. Org. Lett. 2006, 8, 1347-1350. (b) Katritzky, A. R.; Cai, C. M.; Singh, S. K. Efficient microwave access to polysubstituted amidines from imidoylbenzotriazoles. J. Org. Chem. 2006, 71, 33753380. (c) DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai, H. F.; Deng, J.; Lohse, A. G.; Zhang, Y. S. N-Allyl-N-sulfonyl ynamides as synthetic precursors to amidines and vinylogous amidines. an unexpected N-to-C 1,3-sulfonyl shift in nitrile synthesis. J. Org. Chem. 2011, 76, 5092-5103. (12) (a) Sävmarker, J.; Rydfjord, J.; Gising, J.; Odell, L. R.; Larhed, M. Direct Palladium (II)-catalyzed synthesis of arylamidines from aryltrifluoroborates. Org. Lett. 2012, 14, 2394-2397. (b) Anbazhagan, M.; Boykin, D. W.; Stephens, C. E. Direct conversion of amidoximes to amidines via transfer hydrogenation. Synthesis 2003, 2467-2469. (c) Saluste, C. G,; Whitby, R. J.; Furber, M. A Palladium-catalyzed synthesis of amidines from aryl halides. Angew. Chem. Int. Ed. 2000, 39, 4156-4158. (d) Saluste, C. G.; Whitby, R. J.; Furber, M. Palladium-catalysed synthesis of imidates, thioimidates and amidines from aryl halides. Tetrahedron Lett. 2001, 42, 6191-6194. (e) Tetala, K. K. R.; Whitby, R. J.; Light, M. E.; Hurtshouse, M. B. Palladium-catalysed three component synthesis of α, β-unsaturated amidines and imidates. Tetrahedron Lett. 2004, 45, 6991-6994 and the cited references. (13) Biswas, K.; Greaney, M. F. Insertion of arynes into thioureas: a new amidine synthesis. Org. Lett. 2012, 14, 2394-2397. (14) Kranthikumar, R.; Chegondi, R.; Chandrasekhar, S. Insertion of N-tosylacet imidates/acetimidamides onto arynes via [2 + 2] cycloaddition. J. Org. Chem. 2016, 81, 2451-2459.



(15) Selective literatures for the Synthesis of amidines by Cu-catalyzed MCRs. (a) Bae, I.; Han, H.; Chang, S. Highly efficient one-pot synthesis of N-sulfonyl -amidines by Cu-catalyzed three-gomponent coupling of sulfonyl azide, alkyne, and amine. J. Am. Chem. Soc. 2005, 127, 2038-2039. (b) Cui, S. L.; Wang, J.; Wang, Y. G. Coppercatalyzed multicomponent reaction: facile access to novel phosphorus amidines. Org. Lett. 2008, 10, 1267-1269. (c) Wang, J. J.; Lu, P.; Wang, Y. G. Copper-catalyzed multicomponent synthesis of acrylamidines and benzoimidazoles. Org. Chem. Front. 2015, 2, 1346-1351. (d) Huang, Y.; Yi, W. Y.; Sun, Q. H.; Yi, F. P. Copper-catalyzed onepot approach to α-aryl amidines via Truce-Smiles rearrangement. Adv. Synth. Catal. 2018, 360, 3074-3082. (e) Chauhan, D. P.; Varma, S. J.; Vijeta, A.; Banerjee, P.; Talukdar, P. A 1,3-amino group migration route to form acrylamidines. Chem. Commun. 2014, 50, 323-325. (f) Zhang, D.; Nakamura, I.; Terada, M. Copper-catalyzed cascade transformation of O-propargylic oximes with sulfonyl azides to α, β-unsaturated Nacylamidines. Org. Lett. 2014, 16, 5184−5187. (g) Choi, W.; Kim, J.; Ryu, T.; Kim, K. B.; Lee, P. H. Synthesis of N-imidoyl and N-oxoimidoyl sulfoximines from 1alkynes, N-sulfonyl azides, and sulfoximines. Org. Lett. 2015, 17, 3330-3333. (h) Wang, J. J.; Liu, J. Y.; Ding, H. L.; Wang, J.; Lu, P.; Wang, Y. G. Construction of multifunctional 3-amino-2-carbamimido-ylacry- lamides and their crystalline channeltype inclusion complexes. J. Org. Chem. 2015, 80, 5842-5850. (i) Kim, J.; Lee, Y.; Lee, J.; Do, Y.; Chang, S. Synthetic utility of ammonium salts in a Cu-catalyzed threecomponent reaction as a facile coupling partner. J. Org. Chem. 2008, 73, 9454-9457 and the cited references. (16) Selective literatures for cycloaddition reaction of nitrile oxides. (a) Shang, X. Y.; Liu, K.; Zhang, Z. Y.; Xu, X. H.; Li, P. F.; Li, W. J. Direct access to spirobiisoxazoline via the double 1,3-dipolar cycloaddition of nitrile oxide with allenoate Org. Biomol. Chem. 2018, 16, 895-898. (b) Slagbrand, T.; Kervefors, G.; Tinnis, F.; Adolfsson, H. An efficient one-pot procedure for the direct preparation of 4,5-dihydroisoxazoles from amides Adv. Synth. Catal. 2017, 359, 1990-1995. (c) Bhat, S. V.; Robinson, D.; Moses, J. E.; Sharma, P. Synthesis of oxadiazol-5-imines via the cyclizative capture of in situ generated cyanamide ions and nitrile Oxides. Org. Lett. 2016, 18, 1100-1103 and the cited references. (17) Namitharan, K.; Pitchumani, K. Copper(I)-catalyzed three component reaction of sulfonyl azide, alkyne, and nitrone cycloaddition/rearrangement cascades: a novel onestep synthesis of imidazolidin-4-ones. Org. Lett. 2011, 13, 5728-5731. (18) (a) Reddy, R. J.; Kumari, A. H.; Kumar, J. J.; Nanubolub, J. B. Cs2CO3-mediated vicinal thiosulfonylation of 1,1-dibromo-1-alkenes with thiosulfonates: an expedient synthesis of (E)-1,2-thiosulfonylethenes. Adv. Synth. Catal. 2019, 361, 1587-1591. (b) Anitha, M.; Shankar, M.; Swamy, K. C. K. Reactivity of epoxy-ynamides with metal halides: nucleophile (Br/Cl/OH)-assisted tandem intramolecular 5-exo-dig or 6-endo-dig cyclisation and AgF2-promoted oxidation. Org. Chem. Front. 2019, 6, 1133–1139. (19) Slagbrand, T.; Kervefors, G.; Tinnis, F.; Adolfssona, H. An efficient one-pot procedure for the direct preparation of 4,5-dihydroisoxazoles from amides. Adv. Synth. Catal. 2017, 359, 1990-1995.


Page 18 of 19

Page 19 of 19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(20) Sanders, B. C.; Friscourt, F.; Ledin, P. A.; Mbua, N. E.; Arumugam, S.; Guo, J.; Boltje, T. J.; Popik, V. V.; Boons, G. J. Metal-free sequential [3+2]-dipolar cycloadditions using cyclooctynes and 1,3-dipoles of different reactivity. J. Am. Chem. Soc. 2011, 133, 949-957. (21) Kelly, D. R.; Baker, S. C.; King, D. S.; de Silva, D. S.; Lord, G.; Taylor, J. P. Studies of nitrile oxide cycloadditions, and the phenolic oxidative coupling of vanillin aldoxime by Geobacillus sp. DDS012 from Italian rye grass silage. Org. Biomol. Chem. 2008, 6, 787-796. (22) Dubrovskiy, A. V.; Larock, R. C. Synthesis of benzisoxazoles by the [3+2] cycloaddition of in situ generated nitrile oxides and arynes. Org. Lett. 2010, 12, 11801183. (23) Lemercier, B. C.; Pierce, J. G. Synthesis of thiohydroxamic acids and thiohydroximic acid derivatives. J. Org. Chem. 2014, 79, 2321-2330. (24) Kuma, V.; Kaushik, M. P.; Kumar, V.; Kaushik, M. P. A novel one-pot synthesis of hydroximoyl chlorides and 2-isoxazolines using N-tert-butyl-N-chlorocyanamide. Tetrahedron Lett. 2006, 47, 1457-1460.


Terminal Alkyne-Assisted One-Pot Synthesis of ... - ACS Publications

Recommend Documents