Chapter Chapter Guanidine Catalyzed Enantioselective Desymmetrization of meso-Aziridines with Carbamodithioic Acids 59 Chapter 3.1 Introduction Dithiocarbamates (Figure 3.1) have received considerable biological and medical interest in recent time because they are ubiquitously found in a variety of biologically active compounds.1 They have also been used as agrochemicals,2 linkers in solid-phase organic synthesis,3 radical precursors,4 and recently in the synthesis of ionic liquids.5 Furthermore, dithiocarbamates are versatile classes of ligands with the ability to stabilize transition metals in a wide range of oxidation states.6 Therefore, the synthesis of dithiocarbamate derivatives with varied substitution patterns at the thiol chain has become a field of increasing interest in synthetic organic chemistry during the past few years. Figure 3.1 General structure of dithiocarbamate. General methods for the synthesis of dithiocarbamate derivatives involved the reactions of amines with costly and toxic reagents, such as thiophosgene and isothiocyanate.7 Recently, the preparation of dithiocarbamate derivatives by an one-pot reaction of an amine, inexpensive and readily available carbon disulfide, and a nucleophile acceptor was developed.8-15 Various amines reacted smoothly with carbon disulfide to in situ generate incipient carbamodithioic acids, which could subsequently undergo Michael additions to conjugated alkenes, condensations with alkyl halides, or ring opening reactions of epoxides to produce a variety of functionalized dithiocarbamates (Scheme 3.1). 60 Chapter Scheme 3.1 Synthesis of dithiocarbamates. The addition of carbamodithioic acids to epoxides provided a simple approach towards β-hydroxy dithiocarbamate derivatives. In 1993, Toda and co-workers12 reported the synthesis of a five-membered heterocyclic compound 2-thiazolidinethione from the reaction of N-substituded-2-aminomethyloxiane with CS2 as a heterocumulene (Scheme 3.2). The in situ generated carbamodithioic acid could undergo an intramolecular ring opening of epoxide to afford the corresponding β-hydroxy dithiocarbamate in a stereospecific manner. Scheme 3.2 Reaction of 2-aminomethyloxiranes with carbon disulfide. 61 Chapter Scheme 3.3 One-pot reaction of epoxides with amine/CS2. Saidi and co-workers13 reported the one-pot ring opening of epoxides with a variety of carbamodithioic acids generated in situ from structurally diverse amines and CS2 in water (Scheme 3.3, A). The reactions were catalyst- and organic-solventfree and complete within 1.5 hours. This was a clean, mild, efficient and neutral method for the preparation of β-hydroxy dithiocarbamate derivatives. Recently, Banerjee and co-workers14 observed a significant rate acceleration for the ring opening reaction by employing a simple and inexpensive ionic liquid 1-methyl3-pentylimidazolium bromide {[pmIm]Br} to in situ generate dithiocarbamate anions (Scheme 3.3, B). The reactions of different cyclic and open-chain amines proceeded smoothly at room temperature, affording β-hydroxy dithiocarbamate derivatives in high regio- and stereoselectivities. One-pot ring opening of epoxides with dithiocarbamate anions using inexpensive and readily available starting materials has been utilized to introduce carbodithioic acid moiety into fluoxetine (Figure 3.2). As shown in Scheme 3.4, S-[3-dialkylamino propan-2-ol] esters of fluoxetine carbodithioic acid were synthesized from the sodium salt of carbamodithioic acid derived from fluoxetine. In another modification, 62 Chapter fluoxetine was introduced as dialkylamine in propanolamino group, which was a side chain in carbamodithioic acid esters of different dialkylamines. These modifications at 3-amino terminus of fluoxetine led to compounds with better antifungal and anti-Trichomonas activities. Figure 3.2 Structure of fluoxetine. Scheme 3.4 Synthesis of carbodithioic acid esters of fluoxetine. 63 Chapter 3.2 Guanidine catalyzed enantioselective desymmetrization of meso-aziridines with in situ generated carbamodithioic acids As shown above, many examples of ring opening reactions of epoxides with in situ generated carbamodithioic acids have been realized. However, no variant with aziridines was reported. Herein we studied the ring opening reactions of mesoaziridines with various carbamodithioic acids, which were generated in situ from amines and CS2. As a starting point, several structurally diverse amines were subjected to the one-pot three-component ring opening reaction with N-tosyl azirdine 4a and CS2 in THF under catalyst-free condition (Scheme 3.5). The reactions for most of the primary and secondary amines proceeded smoothly to provide the trans βtosyl-amino dithiocarbamates as the sole products. It was observed that there was no reaction when aniline 94a was used. Secondary amines like N-methylaniline 94d and the more hindered dicyclohexylamine 94e also failed to produce the desired products. Scheme 3.5 Ring opening reaction of meso N-tosyl aziridine 4a with amines and CS2. 64 Chapter 3.2.1 Optimization studies on the enantioselective desymmetrization of meso-aziridines with in situ generated carbamodithioic acids Table 3.1 Chiral guanidine 79b catalyzed desymmetrization of meso N-tosyl aziridine 4a with various amines and CS2. a time /h conversion /%b ee /%c 40 80 55 40 80 50 40 100 50 40 100 36 40 90 51 40 90 52 36 100 47 entry amine 65 Chapter 48 90 67 40 100 68 10 40 100 69 a All reactions were performed with 0.02 mmol of aziridine, 0.04 mmol of amine and 0.04 mmol of CS2 in 0.4 mL of solvent. b Determined by TLC. c Determined by chiral HPLC. With the racemic reactions in hand, we embarked on the study of the chiral guanidine 79b catalyzed asymmetric desymmetrization of meso-aziridines with an amine and CS2. To reduce the effect of background reaction, which occurred at room temperature without any catalyst, the guanidine catalyzed reaction was studied at °C. With 10 mol% of 79b, this three component reaction was investigated with several primary and secondary amines (Table 3.1). Benzylamine and tert-butylamine provided the desired dithiocarbamates in 55% and 50% ee, respectively (entries 1-2). The cyclic secondary amine like piperidine gave 50% ee (entry 3), while pyrrolidine gave only 36% ee (entry 4). Increasing the size of cyclic amine slowed down the reaction rate without an improvement in enantioselectivity (entries 5-6). It was found that the open-chain secondary dibenzylamine provided the product with much higher ee value than that of dipropylamine (entries 7-8). With electron-donating methoxy substituents at either para- or meta- positions of dibenzylamine, slightly higher enantioselectivity was obtained with obvious reaction rate acceleration (entries 9-10). 66 Chapter Table 3.2 Chiral guanidine 79b catalyzed desymmetrization of meso N-acyl aziridine 12a with amines and CS2. a 12a:94:CS2 temp /°C time /h yield /%b ee /%c 5e 1:1.1:1.1 1:2:2 1:2:2 1:2:5 1:2:5 0 -20 0 48 48 48 40 48 60d 80d 60d 92 85 82 82 80 80 84 6e 1:2:5 1:2:5 1:2:5 1:1.2:2.4 -20 -50 -50 24 24 24 36 98 97 98 98 79 87 89 89 entry e 8e 9e amine a All reactions were performed with 0.02 mmol of aziridine in 1.0 mL of ether. Isolated yield. c Determined by chiral HPLC. d Conversion, determined by TLC. e Reaction was performed with 2.0 mL of ether. b meso N-3,5-dinitrobenzoyl aziridine 12a was also examined in the one-pot three component ring opening reaction with bis(3-methoxybenzyl)amine and CS2 (Table 3.2, entries 1-5). It was found that the mole ratio of aziridine, amine and CS2 had a significant influence on the reaction rate. When the equivalence ratios of amine and CS2 were increased from 1.1 to (entries 1-2), the reaction conversion was increased to 80% after 48 hours. With this mole ratio (1:2:2), lowering the temperature to -20 °C led to the decrease in both reaction rate and enantioselectivity (entry 3). Increasing the amount of CS2 was shown to be beneficial to the product output, albeit slightly lower 67 Chapter ee value (80%) was obtained (entry 4). Higher enantioselectivity (84% ee) was observed when the reaction concentration was diluted from 0.02 M to 0.01 M (entry 5). bis(2-Methoxybenzyl)amine was then employed under the same reaction conditions, affording the desired product in 98% yield and 79% ee with much faster reaction rate (entry 6). The ee value could be further improved to 89% by lowering the reaction temperature (entries 7-8). It was observed that the same level of enantioselectivity and yield could be obtained when the amounts of amine and CS2 were reduced (entry 9). 3.2.2 Highly enantioselective desymmetrization of meso N-acyl aziridines with in situ generated carbamodithioic acids The optimal reaction conditions were then applied to the desymmetrization of various meso N-3,5-dinitrobenzoyl aziridines (Table 3.3). Good enantioselectivities and yields of the ring-opened products were obtained for the six- and five-membered ring aziridines (entries 1-3). A bit lower ee and much lower yield were observed when the bulkier seven-membered ring aziridine 12f was used (entry 4). With 10 mol% of 79b as the catalyst, the acyclic meso-aziridine 12j provided the corresponding dithiocarbamate in 62% yield with 86% ee (entry 5). The use of 20 mol% catalyst was required for the reaction to complete, resulting in the formation of 96f in 91% yield with 90% ee. All ring-opened products 96b-f were obtained as solids, and their optical purity could be efficiently enhanced to excellent ee values (>90%) after a single recrystallization from CH2Cl2 and hexane. 68 Chapter Table 3.3 Chiral guanidine 79b catalyzed desymmetrization of various meso N-acyl aziridines 12 with amine and CS2. a 12 (R=3,5-dinitrobenzoyl) 96 x mol% time /h yield /%b ee /%c 1d 96b 10 36 98 89 (96) 96c 10 36 80 84 (95) 96d 10 36 98 85 (91) 96e 10 48 67 80 (90) 96f 10 20 48 44 62 91 86 (98) 90 (98) entry a All reactions were performed with 0.05 mmol of aziridine, 0.06 mmol of amine and 0.12 mmol of CS2 in mL of ether. b Isolated yield. c Determined by chiral HPLC; ees after recrystallization are reported in parentheses. d Reaction was performed at -50 °C. 3.3 Synthesis of chiral β-amino sulfonic acid Taurine analogues (2-amino sulfonic acids) are important naturally occurring amino acids16 that have been found in many mammalian tissues17, marine algae, fish and shellfish.18 They are also involved in various physiological processes.19 The 69 Chapter synthesis of structurally diverse substituted taurines has attracted increasing attention recently due to their high importance in the fields of biological and medicinal chemistry.20 To the best of our knowledge, there has been no efficient synthetic approach towards optically pure substituted taurines. We designed herein two pathways to synthesize chiral β-amino sulfonic acid 99 (Scheme 3.6). Scheme 3.6 Preparation of chiral β-amino sulfonic acid 99. In pathway A, the ring-opened product β-acylamino dithiocarbamate 96b was directly oxidized to the substituted taurine 97 with the pre-prepared performic acid, followed by hydrolysis in M hydrochloric acid under reflux condition. The desired zwitterionic β-amino sulfonic acid 99 was obtained in only 30% yield. In pathway B, dithiocarbamate 96b was first transformed into dithiocarbamate 98 in 78% yield without any loss in optical activity by Boc protection and the removal of the 70 Chapter 3,5-dinitrobenzoyl group with M aqueous NaOH. The subsequent oxidation of 98 with performic acid provided the desired product 99 in 92% yield. Thus pathway B was developed as a practical and efficient method for the synthesis of chiral β-amino sulfonic acid. 3.3 Conclusion In this chapter, we have discovered a highly enantioselective desymmetrization of meso-aziridines with carbamodithioic acid, which was generated in situ from an amine and CS2. This is the first time on the use of carbamodithioic acid as a nucleophile in the asymmetric ring opening of aziridines to form chiral dithiocarbamate derivatives. This method also provided a novel protocol for the synthesis of chiral substituted taurines. Although this one-pot three component reaction was a quite novel concept, the enantioselcitivity was still not excellent. Future efforts are still needed to improve the enantioselectivity and to explore the scope of the desymmetrization. 71 Chapter References: [1] (a) Erian, A.W.; Sherif, S. M. Tetrahedron 1999, 55, 7957. (b) Wood, T. F.; Gardner, J. H. J. Am. Chem. Soc. 1941, 63, 2741. (c) Bowden, K.; Chana, R. S. J. Chem. Soc., Perkin Trans. 1990, 2163. (d) Beji, M.; Sbihi, H.; Baklouti, A.; Cambon, A. J. Fluorine Chem. 1999, 99, 17. (e) Goel, A.; Mazur, S. J.; Fattah, R. J.; Hartman, T. L.; Turpin, J. A.; Huang, M.; Rice, W. G.; Appella, E.; Inman, J. K. Bioorg. Med. Chem. Lett. 2002, 12, 767. [2] (a) Chen, Y. S.; Schuphan, I.; Casida, J. E. J. Agric. Food Chem. 1979, 27, 709. (b) Rafin, C.; Veignie, E.; Sancholle, M.; Postal, D.; Len, C.; Villa, P.; Ronco, G. J. Agric. Food Chem. 2000, 48, 5283. (c) Len, C.; Postal, D.; Ronco, G.; Villa, P.; Goubert, C. Jeufrault, E.; Mathon, B.; Simon, H. J. Agric. Food Chem. 1997, 45, 3. [3] (a) Morf, P.; Raimondi, F.; Nothofer, H.-G.; Schnyder, B.; Yasuda, A.; Wessels, J. M.; Jung, T. A. Langmuir 2006, 22, 658. (b) McClain, A.; Hsieh, Y.-L. J. Appl. Polym. Sci. 2004, 92, 218. (c) Bongar, B. P.; Sadavarte, V. S.; Uppalla, L. S. J. Chem. Res. (S) 2004, 9, 450. (d) Dunn, A. D.; Rudorf, W.-D. Carbon Disulphide in Organic Chemistry; Ellis Horwood; Chichester, U.K., 1989; pp 226. [4] (a) Crich, D.; Quintero, L. Chem. Rev. 1989, 89, 1413. (b) Barton, D. H. R. Tetrahedron 1992, 48, 2529. (c) Zard, S. Z. Angew. Chem., Int. Ed. 1997, 36, 672. [5] Zhang, D.; Chen, J.; Liang, Y.; Zhou, H. Synth. Commun. 2005, 35, 521. 72 Chapter [6] Hogarth, G. Prog. Inorg. Chem. 2005, 53, 7. [7] (a) Tilles, H. J. Am. Chem. Soc. 1959, 81, 714. (b) Chin-Hsien, W. Synthesis 1981, 622. (c) Sugiyama, H. J. Synth. Org. Chem. Jpn. 1980, 38, 555. (d) Walter, W.; Bode, K.-D. Angew. Chem., Int. Ed. Engl. 1967, 6, 281. [8] Chaturvedi, D.; Ray, S. Tetrahedron Lett. 2006, 47, 1307. [9] Salvatore, R. N.; Sahab, S.; Jung, K. W. Tetrahedron Lett. 2001, 42, 2055. [10] Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi M. R. J. Org. Chem. 2006, 71, 3634. [11] Azizi, N.; Aryanasab, F.; Saidi M. R. Org. Lett. 2006, 8, 5275. [12] Karikomi, M.; Yamazaki, T.; Toda, T. Chem. Lett. 1993, 1965. [13] Ziyaei-Haimjani, A.; Saidi, M. R. Can. J. Chem. 2006, 84, 1515. [14] Ranu, B. C.; Saha, A.; Banerjee, S. Eur. J. Org. Chem. 2008, 519. [15] Kumar, S. K.; Kumar, L.; Sharma, V. L.; Jain, A.; Jain, R. K.; Maikhuri, J. P.; Kumar, M.; Shukla, P. K.; Gupta, G. Eur. J. Med. Chem. 2008, 43, 2247. [16] Xu, J. X. Chin. J. Org. Chem. 2003, 23, 1. [17] Timothy, C.; Birdsall, N. D. Alt. Med. Rev. 1998, 3, 128. [18] Wickberg, B. Acta Chem. Scand. 1957, 11, 506. [19] Huxtable, R. J. Physiol. Rev. 1992, 72, 101. [20] (a) Machetti, F.; Cacciarini, M.; Catrambone, F.; Cordero, F. M.; Romoli, S.; De Sarlo, F. J. Chem. Research (S), 2000, 120. (b) Cordero, F.; Cacciarini, M.; Machetti, F.; De Sarlo, F. Eur. J. Org. Chem. 2002, 1407. (c) Hu, L.; Zhu, H.; 73 Chapter Du D.-M.; Xu, J. J. Org. Chem. 2007, 72, 4543. (d) Zhang, W.; Wang, B.; Chen, N.; Du D.-M.; Xu, J. Synthesis 2008, 2, 197. Expeditious and Practical Synthesis of 74 [...]...Chapter 3 Table 3. 3 Chiral guanidine 79b catalyzed desymmetrization of various meso N-acyl aziridines 12 with amine and CS2 a 12 (R =3, 5-dinitrobenzoyl) 96 x mol% time /h yield /%b ee /%c 1d 96b 10 36 98 89 (96) 2 96c 10 36 80 84 (95) 3 96d 10 36 98 85 (91) 4 96e 10 48 67 80 (90) 5 96f 10 20 48 44 62 91 86 (98) 90 (98) entry a All reactions were performed with 0.05 mmol of aziridine, 0.06 mmol of amine... the removal of the 70 Chapter 3 3,5-dinitrobenzoyl group with 6 M aqueous NaOH The subsequent oxidation of 98 with performic acid provided the desired product 99 in 92% yield Thus pathway B was developed as a practical and efficient method for the synthesis of chiral β-amino sulfonic acid 3. 3 Conclusion In this chapter, we have discovered a highly enantioselective desymmetrization of meso- aziridines. .. Quintero, L Chem Rev 1989, 89, 14 13 (b) Barton, D H R Tetrahedron 1992, 48, 2529 (c) Zard, S Z Angew Chem., Int Ed 1997, 36 , 672 [5] Zhang, D.; Chen, J.; Liang, Y.; Zhou, H Synth Commun 2005, 35 , 521 72 Chapter 3 [6] Hogarth, G Prog Inorg Chem 2005, 53, 7 [7] (a) Tilles, H J Am Chem Soc 1959, 81, 714 (b) Chin-Hsien, W Synthesis 1981, 622 (c) Sugiyama, H J Synth Org Chem Jpn 1980, 38 , 555 (d) Walter, W.; Bode,... (98) 90 (98) entry a All reactions were performed with 0.05 mmol of aziridine, 0.06 mmol of amine and 0.12 mmol of CS2 in 5 mL of ether b Isolated yield c Determined by chiral HPLC; ees after recrystallization are reported in parentheses d Reaction was performed at -50 ° C 3. 3 Synthesis of chiral β-amino sulfonic acid Taurine analogues (2-amino sulfonic acids) are important naturally occurring amino... Future efforts are still needed to improve the enantioselectivity and to explore the scope of the desymmetrization 71 Chapter 3 References: [1] (a) Erian, A.W.; Sherif, S M Tetrahedron 1999, 55, 7957 (b) Wood, T F.; Gardner, J H J Am Chem Soc 1941, 63, 2741 (c) Bowden, K.; Chana, R S J Chem Soc., Perkin Trans 2 1990, 21 63 (d) Beji, M.; Sbihi, H.; Baklouti, A.; Cambon, A J Fluorine Chem 1999, 99, 17 (e) Goel,... Chapter 3 synthesis of structurally diverse substituted taurines has attracted increasing attention recently due to their high importance in the fields of biological and medicinal chemistry.20 To the best of our knowledge, there has been no efficient synthetic approach towards optically pure substituted taurines We designed herein two pathways to synthesize chiral β-amino sulfonic acid 99 (Scheme 3. 6)... Chaturvedi, D.; Ray, S Tetrahedron Lett 2006, 47, 130 7 [9] Salvatore, R N.; Sahab, S.; Jung, K W Tetrahedron Lett 2001, 42, 2055 [10] Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi M R J Org Chem 2006, 71, 36 34 [11] Azizi, N.; Aryanasab, F.; Saidi M R Org Lett 2006, 8, 5275 [12] Karikomi, M.; Yamazaki, T.; Toda, T Chem Lett 19 93, 1965 [ 13] Ziyaei-Haimjani, A.; Saidi, M R Can J Chem 2006,... carbamodithioic acid, which was generated in situ from an amine and CS2 This is the first time on the use of carbamodithioic acid as a nucleophile in the asymmetric ring opening of aziridines to form chiral dithiocarbamate derivatives This method also provided a novel protocol for the synthesis of chiral substituted taurines Although this one-pot three component reaction was a quite novel concept, the... 709 (b) Rafin, C.; Veignie, E.; Sancholle, M.; Postal, D.; Len, C.; Villa, P.; Ronco, G J Agric Food Chem 2000, 48, 52 83 (c) Len, C.; Postal, D.; Ronco, G.; Villa, P.; Goubert, C Jeufrault, E.; Mathon, B.; Simon, H J Agric Food Chem 1997, 45, 3 [3] (a) Morf, P.; Raimondi, F.; Nothofer, H.-G.; Schnyder, B.; Yasuda, A.; Wessels, J M.; Jung, T A Langmuir 2006, 22, 658 (b) McClain, A.; Hsieh, Y.-L J Appl... Chem 2008, 519 [15] Kumar, S K.; Kumar, L.; Sharma, V L.; Jain, A.; Jain, R K.; Maikhuri, J P.; Kumar, M.; Shukla, P K.; Gupta, G Eur J Med Chem 2008, 43, 2247 [16] Xu, J X Chin J Org Chem 20 03, 23, 1 [17] Timothy, C.; Birdsall, N D Alt Med Rev 1998, 3, 128 [18] Wickberg, B Acta Chem Scand 1957, 11, 506 [19] Huxtable, R J Physiol Rev 1992, 72, 101 [20] (a) Machetti, F.; Cacciarini, M.; Catrambone, F.; . Chapter 3 59 Chapter 3 Guanidine Catalyzed Enantioselective Desymmetrization of meso- Aziridines with Carbamodithioic Acids Chapter 3 60 3. 1 Introduction. fluoxetine. Chapter 3 64 3. 2 Guanidine catalyzed enantioselective desymmetrization of meso- aziridines with in situ generated carbamodithioic acids As shown above, many examples of ring opening. Scheme 3. 5 Ring opening reaction of meso N-tosyl aziridine 4a with amines and CS 2 . Chapter 3 65 3. 2.1 Optimization studies on the enantioselective desymmetrization of meso- aziridines