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Bromoform reaction of tertiary amines with N,N-dibromosulfonamides or NBS/sulfonamides† Jie Chen, Yu-Ping Guo, Ming-Hui Sun, Guo-Tao Fan and Ling Zhou*
Received 19th July 2014, Accepted 22nd August 2014 DOI: 10.1039/c4cc05578k www.rsc.org/chemcomm
A new bromoform reaction of tertiary amines with N,N-dibromosulfonamides or NBS/sulfonamides has been developed. A series of amidines were prepared with moderate to good yields via a Csp3–Csp3 bond cleavage.
Haloform reaction is one of the most fundamental transformations in organic chemistry, studies on it has a history of more than 100 years.1 As a classic textbook reaction, the haloform reaction was widely used to identify the structure of organic compounds before spectroscopic methods became available for structural elucidation.2 Presently, the reaction is used as an efficient method for the preparation of carboxylic acids with one less carbon atom.3 Yet, despite this rich history, the substrate scope of this reaction remains undeveloped. Only compounds containing the methyl ketone functional group or compounds that can be oxidized to methyl ketones by hypohalites are suitable for the transformation (Scheme 1, eqn (1)).4 During the course of our studies on the N,N-dibromosulfonamide promoted regioselective bromocyclization of unsaturated N-tosylcarbamates,5 we noticed that small amounts of amidine 3a were formed when triethylamine (TEA) was employed as a base (Scheme 1, eqn (2)). Amidine is the fundamental unit of natural products,6 bioactive molecules,7 organocatalysts,8 and metal complexation ligands.9 Amidine derivatives are key building blocks for the synthesis of various heterocyclic compounds and metal complexes.9,10 Many research endeavors have been dedicated to the development of efficient approaches to the synthesis of these compounds.11,12 For example, imidation of tertiary amines by using sulfonyl azides in the presence of diethyl azodicarboxylate or a metal catalyst has been explored.12 Herein we wish to describe a novel, efficient, and selective haloform reaction of tertiary amines using N,Ndibromosulfonamides or NBS/sulfonamides, leading to the formation of amidine derivatives and bromoform (Scheme 1, eqn (2)). Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an 710069, P. R. China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details, and spectroscopic and analytical data for new compounds. See DOI: 10.1039/c4cc05578k
This journal is © The Royal Society of Chemistry 2014
Scheme 1
Haloform reactions.
To the best of our knowledge, there is no report on such reactions, then we decided to study this unprecedented reaction on both of the mechanism and its scope. Simply mixing N,N-dibromo4-methylbenzenesulfonamide (TsNBr2) and TEA in CH2Cl2 gave 3a in 32% yield (Table 1, entry 1), indicating that the unsaturated N-tosylcarbamate substrate is unrelated to this reaction.
Table 1
Bromoform reaction of TEA with TsNBr2a
Entry
1a : 2a
1 2 3 4 5 6 7 8d 9d 10d 11 12 13 14 15e
1:1 1:1 1:1 1:1 1:1 1:1 1:2 2:1 1.5 : 1 1.2 : 1 1:1 1:1 1 : 2.5 1 : 2.5 1 : 2.5
Base (equiv.)
Solvent
Yieldb (%)
Pyridine (1.0) K2CO3 (3.0) DBU (1.0) DBU (1.5) DBU (1.5)
CH2Cl2 CHCl3 THF EtOAc ACN ACN EtOAc EtOAc EtOAc EtOAc ACN ACN ACN ACN ACN
32 19 16 41 42 43c 0 15 14 33 45 51 68 76 72
a Reactions were carried out with TEA (0.20 mmol), TsNBr2 in solvent (2 mL) at r.t. for 4 h. b Isolated yields. c Reaction temperature is 80 1C. d 0.20 mmol TsNBr2 was used. e 0.02 mmol BHT was used.
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Scheme 2
Table 2
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We hypothesized that this amidine product arose from a pathway in which the a, b Csp3–Csp3 bond of TEA is cleaved, and this reaction may follow a haloform-type reaction mechanism.13 As shown in Scheme 2, TEA first attacks TsNBr2 and forms a bromo ammonium intermediate I, next I releases an a proton with the assistance of a base to form an iminium intermediate II, which can be in equilibrium with enamine III. Then III attacks a bromine source to form a bromo iminium intermediate IV, a result similar to a secondary amine catalyzed a-bromination of aldehyde (or ketone).14 The process of II to IV was repeated to give an iminium intermediate V bearing a tribromomethyl group, to which is then added a tosyl amide ion to form an aminal
Proposed mechanism.
Bromoform reaction of tertiary amines with RNBr2a
Entry
Substrate
R
Product
Yieldb (%)
1 2 3
1a 1a 1a
Ts 4-NO2PhSO2 PhSO2
3a 3o 3l
77c 68 63
4
Ts
78d
5
Ts
65
6
Ts
7
Ts
66
8
Ts
26
9
Ts
10
Ts
11
Ts
12
Ts
3c
42
3a
45
Complex mixture
a Reactions were carried out on a 0.20 mmol scale, under the standard reaction conditions, see Table 1, entry 14. was conducted on a 10.0 mmol scale. d E : Z = 2 : 1, determined by 1H NMR analysis. e E : Z = 1 : 1.
12368 | Chem. Commun., 2014, 50, 12367--12370
b
Isolated yields. c The reaction
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intermediate VI. Finally, deprotonation of the sulfonamide group of VI and liberation of a tribromomethane result in the formation of amidine 3a. In a balanced equation (Scheme 2, eqn (4)), 2 mol TEA plus 2 mol TsNBr2 result in 1 mol amidine 3a, 1 mol CHBr3, 1 mol TsNH2 and 1 mol TEA–HBr. This means that TEA participates in the reaction not only as a substrate, but also as a base. To probe the mechanism and optimize the reaction, several experiments were conducted. Firstly, extensive screening of solvents was carried out with a mixture of TEA and TsNBr2 in a ratio of 1 : 1 (Table 1, entries 1–5). We found that both acetonitrile (ACN) and EtOAc are suitable solvents. Increasing the reaction temperature resulted in a slight effect on this reaction (Table 1, entry 6). Next, changing the ratio of the two reactants resulted in significant difference in the reaction yields. When the reaction was carried out in a ratio of 1 : 2 (TEA : TsNBr2), no desired product was detected (Table 1, entry 7); and a ratio of 2 : 1 also resulted in a clear decrease of the yield (Table 1, entry 8). These results indicate that TEA may participate in the reaction as both a substrate and a base, and excess TsNBr2 would be needed. Then external bases were employed, to our delight, the reaction yields increased clearly (Table 1, entries 11 and 12). Further optimization of this reaction using excess TsNBr2 returned amidine 3a in 76% yield in a ratio of 1 : 2.5 (TEA : TsNBr2) in the presence of 1.5 equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Table 1, entry 14). To gain more insight into this reaction, the reaction mixture was tested by 1H NMR and GC-MS. Indeed, both tribromomethane and TsNH2 were detected.15 Additionally, using 10 mol% of radical scavenger 2,6-di-tert-butyl-4-methylphenol (BHT) returned a comparable yield (Table 1, entries 15 vs. 14). These results demonstrated that this reaction may not follow a radical-type mechanism, further suggesting that the mechanism may follow our proposed cationic proposal. Under the optimized conditions, the reaction scalability and the substrate scope were investigated. As shown in Table 2, a 50-fold increase in the scale resulted in a small change in the yield (Table 2, entry 1). Besides TsNBr2, other N,N-dibromosulfonamides are also suitable for this reaction. N,N-Dibromo-4-nitro-benzenesulfonamide and N,N-dibromobenzenesulfonamide returned the desired amidines in 68% and 63% yields, respectively (Table 2, entries 2 and 3). N-Ethyl-N-methylethanamine 1b resulted in amidine 3b in 78% yield as a mixture (E : Z = 2 : 1). N,N-Dimethylethanamine 1c returned 3c in 65% yield. The cleavage of the Csp3–Csp3 bond of tertiary amine occurred in both cases no matter the substrates containing one or two ethyl groups (Table 2, entries 4 and 5). Meanwhile, trimethyl amine also resulted in amidine 3c in 42% yield (Table 2, entry 6).16 The high chemoselectivity may be attributed to the stability of the iminium intermediates. Surprisingly, the generally used bulky tertiary amine N,N-diisopropylethylamine also gave the desired amidine 3d in 66% yield as a sole product (Table 2, entry 7). Cyclic tertiary amine N-ethylpiperidine was a modest but encouraging substrate (Table 2, entry 8). In order to investigate the electronic effects of the substituents, tertiary amines 1f–h were examined. However, two reaction pathways with different chemoselectivity were observed (Table 2, entries 9–11). Wherein the electron rich substituents are prior to be cleaved, the reason
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Communication Table 3
Bromoform reaction of TEA with sulfonamides and NBSa
Entry
Sulfonamide
R
Product
Yieldb (%)
1 2c 3d 4 5 6 7 8 9 10 11 12 13
2a 2a 2a 2k 2l 2m 2n 2o 2p 2q 2r 2s 2t
4-Me-C6H4 4-Me-C6H4 4-Me-C6H4 4-Et-C6H4 Ph4-Cl-C6H4 4-Br-C6H4 4-NO2-C6H4 4-CF3O-C6H4 3-Me-C6H4 3-NO2-C6H4 2-Me-C6H4 2,4,6-Me3-C6H4
3a 3a 3a 3k 3l 3m 3n 3o 3p 3q 3r 3s 3t
79 36 Trace 91 76 80 95 91 94 87 81 68 72
a Reactions were carried out with TEA (0.20 mmol), RSO2NH2 (0.50 mmol), NBS (0.50 mmol) and DBU (0.30 mmol) in ACN (2 mL) at r.t. for 4 h. b Isolated yields. c NIS (0.50 mmol) was used. d NCS (0.50 mmol) was used.
may be ascribed to the fact that the nucleophilicity of the enamine intermediates is enhanced. Unfortunately, N,N-diethylaniline returned a complex mixture with aromatic brominated side products (Table 2, entry 12). In the proposed mechanism of this novel reaction, TsNBr2 acts as a bromine-oxidant, a proton scavenger and an amine source. We envisioned that the reaction can also be performed by using commercially available sulfonamides and halogen sources in the presence of a base. Thus, reaction of TEA with TsNH2 and NBS in the presence of DBU was conducted, as expected, the desired amidine 3a was obtained in 79% yield (Table 3, entry 1). However, NIS and NCS diminished the reaction (Table 3, entries 2 and 3). Other sulfonamides containing several functional groups such as alkyl, halo, and nitro could be well tolerated, and the desired amidines were obtained with good to excellent yields (Table 3, entries 4–13). In summary, we have developed a new haloform reaction of tertiary amines with N,N-dibromosulfonamides or NBS/sulfonamides for the first time. A series of amidines were prepared with moderate to good yields. The electron property plays an important role in the chemoselectivity. A multistep cationic mechanism for this novel reaction is proposed. Further investigations to better understand the mechanism and to develop new applications of this reaction are underway. We thank the National Natural Science Foundation of China (NSFC-21203148, 21302151), Science and Technology Department of Shaanxi Province (2013JQ2012), Education Department of Shaanxi Province (2013JK0644), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education, and the Northwest University for financial support.
Notes and references 1 (a) A. Lieben, Liebigs Ann. Chem., 1870, 7, 218; (b) R. C. Fuson and B. A. Bull, Chem. Rev., 1934, 15, 275; (c) B. F. Hrutfiord and A. R. Negri, Tappi J., 1990, 73(suppl.), 219.
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Communication 2 (a) R. N. Seelye and T. A. Turney, J. Chem. Educ., 1959, 36, 572; (b) B. Gillis, J. Org. Chem., 1959, 24, 1027. 3 (a) M. Ihara, T. Taniguchi, Y. Tokunaga and K. Fukumoto, J. Org. Chem., 1994, 59, 8092; (b) M. L. Bennasar, B. Vidal and J. Bosch, J. Org. Chem., 1996, 61, 1916; (c) J. P. Storm and C.-M. Andersson, J. Org. Chem., 2000, 65, 5264; (d) J. Xiao, G. Yuan, W. Huang, A. S. C. Chan and K. L. D. Lee, J. Org. Chem., 2000, 65, 5506; (e) J. Schmidt and C. B. W. Stark, J. Org. Chem., 2014, 79, 1920. 4 (a) G. I. Nikishin, M. N. Elinson and I. V. Makhova, Angew. Chem., Int. ´nez, M. P. Bosch and A. Guerrero, Ed. Engl., 1988, 27, 1716; (b) O. Jime ´ . Jime ´, O ´nez, J. Org. Chem., 2005, 70, 10883; (c) S. Olivella, A. Sole M. P. Bosch and A. Guerrero, J. Am. Chem. Soc., 2005, 127, 2620. 5 G.-T. Fan, M.-H. Sun, G. Gao, J. Chen and L. Zhou, Synlett, 2014, 25, 1921. 6 (a) R. G. S. Berlinck and M. H. Kossuga, Nat. Prod. Rep., 2005, 22, 516; (b) R. G. S. Berlinck, A. C. B. Burtoloso and M. H. Kossuga, Nat. Prod. Rep., 2008, 25, 919; (c) T. Kumamoto, in Superbases for Organic Synthesis: Guanidines, Amidines, Phosphazenes and Related Organoctalysts, ed. I. Ishikawa, John Wiley & Sons Press, West Sussex, UK, 2009, p. 295. 7 (a) L. De Luca, Curr. Med. Chem., 2006, 13, 1; (b) F. Bellina, S. Cauteruccio and R. Rossi, Tetrahedron, 2007, 63, 4571; (c) S. Arya, N. Kumar, P. Roy and S. M. Sondhi, Eur. J. Med. Chem., 2013, 59, 7. 8 (a) S. M. Ahmad, D. C. Braddock, G. Cansell, S. A. Hermitage, J. M. Redmond and A. J. P. White, Tetrahedron Lett., 2007, 48, 5948; (b) X. Li, H. Jiang, E. W. Uffman, L. Guo, Y. Zhang, X. Yang and V. B. Birman, J. Org. Chem., 2012, 77, 1722.
12370 | Chem. Commun., 2014, 50, 12367--12370
ChemComm 9 (a) F. T. Edelmann, Adv. Organomet. Chem., 2008, 57, 183; (b) W. Cho, H. Cho, C. S. Lee, B. Y. Lee, B. Moon and J. Kang, Organometallics, 2014, 33, 1617. 10 (a) G. V. Boyd, in The Chemistry of Amidines and Imidates, ed. S. Patai and Z. Rappoport, Wiley, New York, 1991, ch. 8, vol. 2; (b) J. Barker and M. Kilner, Coord. Chem. Rev., 1994, 133, 219; (c) H. Chen, S. Sanjaya, Y.-F. Wang and S. Chiba, Org. Lett., 2012, 15, 212. 11 (a) N. Kumagai, S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed., 2004, 43, 478; (b) I. Bae, H. Han and S. Chang, J. Am. Chem. Soc., 2005, 127, 2038; (c) J. Wang, F. Xu, T. Cai and Q. Shen, Org. Lett., 2008, 10, 445; (d) S. Chen, Y. Xu and X. Wan, Org. Lett., 2011, 13, 6152; (e) L. Zhou, J. Zhou, C. K. Tan, J. Chen and Y.-Y. Yeung, Org. Lett., 2011, 13, 2448; ( f ) K. Biswas and M. F. Greaney, Org. Lett., 2011, 13, 4946; ( g) N. Chandna, N. Chandak, P. Kumar, J. K. Kapoor and P. K. Sharma, Green Chem., 2013, 15, 2294. 12 (a) X. Xu, X. Li, L. Ma, N. Ye and B. Weng, J. Am. Chem. Soc., 2008, 130, 14048; (b) N. Liu, B.-Y. Tan, Y. Chen and L. He, Eur. J. Org. Chem., 2009, 2059; (c) S. Wang, Z. Wang and X. Zheng, Chem. Commun., 2009, 7372; (d) X. Xu, Z. Ge, D. Cheng, L. Ma, C. Lu, Q. Zhang, N. Yao and X. Li, Org. Lett., 2010, 12, 897; (e) S. Chen, Y. Xu and X. Wan, Org. Lett., 2011, 13, 6152; ( f ) L. Zhang, L. J.-H. Su, S. Wang, C. Wan, Z. Zha, J. Du and Z. Wang, Chem. Commun., 2011, 47, 5488. 13 (a) P. D. Bartlett, J. Am. Chem. Soc., 1934, 56, 967; (b) J. G. Aston, J. D. Newkirk, J. Dorsky and D. M. Jenkins, J. Am. Chem. Soc., 1942, 64, 1413. 14 M. Oestreich, Angew. Chem., Int. Ed., 2005, 44, 2324. 15 See ESI† for details. 16 3c may be generated directly by the addition of a tosyl amide ion to the corresponding iminium ion.
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Bromoform reaction of tertiary amines with N,N-dibromosulfonamides or NBS/sulfonamides† Jie Chen, Yu-Ping Guo, Ming-Hui Sun, Guo-Tao Fan and Ling Zhou*
Received 19th July 2014, Accepted 22nd August 2014 DOI: 10.1039/c4cc05578k www.rsc.org/chemcomm
A new bromoform reaction of tertiary amines with N,N-dibromosulfonamides or NBS/sulfonamides has been developed. A series of amidines were prepared with moderate to good yields via a Csp3–Csp3 bond cleavage.
Haloform reaction is one of the most fundamental transformations in organic chemistry, studies on it has a history of more than 100 years.1 As a classic textbook reaction, the haloform reaction was widely used to identify the structure of organic compounds before spectroscopic methods became available for structural elucidation.2 Presently, the reaction is used as an efficient method for the preparation of carboxylic acids with one less carbon atom.3 Yet, despite this rich history, the substrate scope of this reaction remains undeveloped. Only compounds containing the methyl ketone functional group or compounds that can be oxidized to methyl ketones by hypohalites are suitable for the transformation (Scheme 1, eqn (1)).4 During the course of our studies on the N,N-dibromosulfonamide promoted regioselective bromocyclization of unsaturated N-tosylcarbamates,5 we noticed that small amounts of amidine 3a were formed when triethylamine (TEA) was employed as a base (Scheme 1, eqn (2)). Amidine is the fundamental unit of natural products,6 bioactive molecules,7 organocatalysts,8 and metal complexation ligands.9 Amidine derivatives are key building blocks for the synthesis of various heterocyclic compounds and metal complexes.9,10 Many research endeavors have been dedicated to the development of efficient approaches to the synthesis of these compounds.11,12 For example, imidation of tertiary amines by using sulfonyl azides in the presence of diethyl azodicarboxylate or a metal catalyst has been explored.12 Herein we wish to describe a novel, efficient, and selective haloform reaction of tertiary amines using N,Ndibromosulfonamides or NBS/sulfonamides, leading to the formation of amidine derivatives and bromoform (Scheme 1, eqn (2)). Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an 710069, P. R. China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Experimental details, and spectroscopic and analytical data for new compounds. See DOI: 10.1039/c4cc05578k
This journal is © The Royal Society of Chemistry 2014
Scheme 1
Haloform reactions.
To the best of our knowledge, there is no report on such reactions, then we decided to study this unprecedented reaction on both of the mechanism and its scope. Simply mixing N,N-dibromo4-methylbenzenesulfonamide (TsNBr2) and TEA in CH2Cl2 gave 3a in 32% yield (Table 1, entry 1), indicating that the unsaturated N-tosylcarbamate substrate is unrelated to this reaction.
Table 1
Bromoform reaction of TEA with TsNBr2a
Entry
1a : 2a
1 2 3 4 5 6 7 8d 9d 10d 11 12 13 14 15e
1:1 1:1 1:1 1:1 1:1 1:1 1:2 2:1 1.5 : 1 1.2 : 1 1:1 1:1 1 : 2.5 1 : 2.5 1 : 2.5
Base (equiv.)
Solvent
Yieldb (%)
Pyridine (1.0) K2CO3 (3.0) DBU (1.0) DBU (1.5) DBU (1.5)
CH2Cl2 CHCl3 THF EtOAc ACN ACN EtOAc EtOAc EtOAc EtOAc ACN ACN ACN ACN ACN
32 19 16 41 42 43c 0 15 14 33 45 51 68 76 72
a Reactions were carried out with TEA (0.20 mmol), TsNBr2 in solvent (2 mL) at r.t. for 4 h. b Isolated yields. c Reaction temperature is 80 1C. d 0.20 mmol TsNBr2 was used. e 0.02 mmol BHT was used.
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Scheme 2
Table 2
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We hypothesized that this amidine product arose from a pathway in which the a, b Csp3–Csp3 bond of TEA is cleaved, and this reaction may follow a haloform-type reaction mechanism.13 As shown in Scheme 2, TEA first attacks TsNBr2 and forms a bromo ammonium intermediate I, next I releases an a proton with the assistance of a base to form an iminium intermediate II, which can be in equilibrium with enamine III. Then III attacks a bromine source to form a bromo iminium intermediate IV, a result similar to a secondary amine catalyzed a-bromination of aldehyde (or ketone).14 The process of II to IV was repeated to give an iminium intermediate V bearing a tribromomethyl group, to which is then added a tosyl amide ion to form an aminal
Proposed mechanism.
Bromoform reaction of tertiary amines with RNBr2a
Entry
Substrate
R
Product
Yieldb (%)
1 2 3
1a 1a 1a
Ts 4-NO2PhSO2 PhSO2
3a 3o 3l
77c 68 63
4
Ts
78d
5
Ts
65
6
Ts
7
Ts
66
8
Ts
26
9
Ts
10
Ts
11
Ts
12
Ts
3c
42
3a
45
Complex mixture
a Reactions were carried out on a 0.20 mmol scale, under the standard reaction conditions, see Table 1, entry 14. was conducted on a 10.0 mmol scale. d E : Z = 2 : 1, determined by 1H NMR analysis. e E : Z = 1 : 1.
12368 | Chem. Commun., 2014, 50, 12367--12370
b
Isolated yields. c The reaction
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intermediate VI. Finally, deprotonation of the sulfonamide group of VI and liberation of a tribromomethane result in the formation of amidine 3a. In a balanced equation (Scheme 2, eqn (4)), 2 mol TEA plus 2 mol TsNBr2 result in 1 mol amidine 3a, 1 mol CHBr3, 1 mol TsNH2 and 1 mol TEA–HBr. This means that TEA participates in the reaction not only as a substrate, but also as a base. To probe the mechanism and optimize the reaction, several experiments were conducted. Firstly, extensive screening of solvents was carried out with a mixture of TEA and TsNBr2 in a ratio of 1 : 1 (Table 1, entries 1–5). We found that both acetonitrile (ACN) and EtOAc are suitable solvents. Increasing the reaction temperature resulted in a slight effect on this reaction (Table 1, entry 6). Next, changing the ratio of the two reactants resulted in significant difference in the reaction yields. When the reaction was carried out in a ratio of 1 : 2 (TEA : TsNBr2), no desired product was detected (Table 1, entry 7); and a ratio of 2 : 1 also resulted in a clear decrease of the yield (Table 1, entry 8). These results indicate that TEA may participate in the reaction as both a substrate and a base, and excess TsNBr2 would be needed. Then external bases were employed, to our delight, the reaction yields increased clearly (Table 1, entries 11 and 12). Further optimization of this reaction using excess TsNBr2 returned amidine 3a in 76% yield in a ratio of 1 : 2.5 (TEA : TsNBr2) in the presence of 1.5 equiv. of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Table 1, entry 14). To gain more insight into this reaction, the reaction mixture was tested by 1H NMR and GC-MS. Indeed, both tribromomethane and TsNH2 were detected.15 Additionally, using 10 mol% of radical scavenger 2,6-di-tert-butyl-4-methylphenol (BHT) returned a comparable yield (Table 1, entries 15 vs. 14). These results demonstrated that this reaction may not follow a radical-type mechanism, further suggesting that the mechanism may follow our proposed cationic proposal. Under the optimized conditions, the reaction scalability and the substrate scope were investigated. As shown in Table 2, a 50-fold increase in the scale resulted in a small change in the yield (Table 2, entry 1). Besides TsNBr2, other N,N-dibromosulfonamides are also suitable for this reaction. N,N-Dibromo-4-nitro-benzenesulfonamide and N,N-dibromobenzenesulfonamide returned the desired amidines in 68% and 63% yields, respectively (Table 2, entries 2 and 3). N-Ethyl-N-methylethanamine 1b resulted in amidine 3b in 78% yield as a mixture (E : Z = 2 : 1). N,N-Dimethylethanamine 1c returned 3c in 65% yield. The cleavage of the Csp3–Csp3 bond of tertiary amine occurred in both cases no matter the substrates containing one or two ethyl groups (Table 2, entries 4 and 5). Meanwhile, trimethyl amine also resulted in amidine 3c in 42% yield (Table 2, entry 6).16 The high chemoselectivity may be attributed to the stability of the iminium intermediates. Surprisingly, the generally used bulky tertiary amine N,N-diisopropylethylamine also gave the desired amidine 3d in 66% yield as a sole product (Table 2, entry 7). Cyclic tertiary amine N-ethylpiperidine was a modest but encouraging substrate (Table 2, entry 8). In order to investigate the electronic effects of the substituents, tertiary amines 1f–h were examined. However, two reaction pathways with different chemoselectivity were observed (Table 2, entries 9–11). Wherein the electron rich substituents are prior to be cleaved, the reason
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Communication Table 3
Bromoform reaction of TEA with sulfonamides and NBSa
Entry
Sulfonamide
R
Product
Yieldb (%)
1 2c 3d 4 5 6 7 8 9 10 11 12 13
2a 2a 2a 2k 2l 2m 2n 2o 2p 2q 2r 2s 2t
4-Me-C6H4 4-Me-C6H4 4-Me-C6H4 4-Et-C6H4 Ph4-Cl-C6H4 4-Br-C6H4 4-NO2-C6H4 4-CF3O-C6H4 3-Me-C6H4 3-NO2-C6H4 2-Me-C6H4 2,4,6-Me3-C6H4
3a 3a 3a 3k 3l 3m 3n 3o 3p 3q 3r 3s 3t
79 36 Trace 91 76 80 95 91 94 87 81 68 72
a Reactions were carried out with TEA (0.20 mmol), RSO2NH2 (0.50 mmol), NBS (0.50 mmol) and DBU (0.30 mmol) in ACN (2 mL) at r.t. for 4 h. b Isolated yields. c NIS (0.50 mmol) was used. d NCS (0.50 mmol) was used.
may be ascribed to the fact that the nucleophilicity of the enamine intermediates is enhanced. Unfortunately, N,N-diethylaniline returned a complex mixture with aromatic brominated side products (Table 2, entry 12). In the proposed mechanism of this novel reaction, TsNBr2 acts as a bromine-oxidant, a proton scavenger and an amine source. We envisioned that the reaction can also be performed by using commercially available sulfonamides and halogen sources in the presence of a base. Thus, reaction of TEA with TsNH2 and NBS in the presence of DBU was conducted, as expected, the desired amidine 3a was obtained in 79% yield (Table 3, entry 1). However, NIS and NCS diminished the reaction (Table 3, entries 2 and 3). Other sulfonamides containing several functional groups such as alkyl, halo, and nitro could be well tolerated, and the desired amidines were obtained with good to excellent yields (Table 3, entries 4–13). In summary, we have developed a new haloform reaction of tertiary amines with N,N-dibromosulfonamides or NBS/sulfonamides for the first time. A series of amidines were prepared with moderate to good yields. The electron property plays an important role in the chemoselectivity. A multistep cationic mechanism for this novel reaction is proposed. Further investigations to better understand the mechanism and to develop new applications of this reaction are underway. We thank the National Natural Science Foundation of China (NSFC-21203148, 21302151), Science and Technology Department of Shaanxi Province (2013JQ2012), Education Department of Shaanxi Province (2013JK0644), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education, and the Northwest University for financial support.
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