Umpolung Reactions of α-Tosyloximino Esters in a Flow System

Abstract

An umpolung reaction of α-tosyloximino esters in a flow system is disclosed. Tandem N,N-dialkylations with two different Grignard reagents gave the desired N,N-dialkylated products in moderate to good yields. In addition, a tandem N,N,C-trialkylation of an α-tosyloximino ester with three different Grignard reagents has been successfully achieved to afford the desired N,N,C-trialkylated product in moderate yield.

Key words

umpolung - tosyloximino esters - tandem - alkylation - Grignard­ reagents - flow reactor

Publication History

Received: 20 July 2020

Accepted after revision: 03 August 2020

Article published online:
03 September 2020

• References and Notes


For reviews on α,α-disubstituted α-amino acids and their ­peptides, see:
• 1a Venkatraman J, Shankaramma SC, Balaram P. Chem. Rev. 2001; 101: 3131
• 1b Tanaka M. Chem. Pharm. Bull. 2007; 55: 349
• 1c Vogt H, Bräse S. Org. Biomol. Chem. 2007; 5: 406
• 2 For a review on recent advances in applications of α-imino esters in organic synthesis, see: Eftekhari-Sis B, Zirak M. Chem. Rev. 2017; 117: 8326

For representative N-alkylations of α-imino esters by our group, see:
• 3a Shimizu M, Niwa Y. Tetrahedron Lett. 2001; 42: 2829
• 3b Niwa Y, Takayama K, Shimizu M. Tetrahedron Lett. 2001; 42: 5473
• 3c Niwa Y, Takayama K, Shimizu M. Bull. Chem. Soc. Jpn. 2002; 75: 1819
• 3d Niwa Y, Shimizu M. J. Am. Chem. Soc. 2003; 125: 3720
• 3e Mizota I, Tanaka K, Shimizu M. Tetrahedron Lett. 2012; 53: 1847
• 3f Shimizu M, Takao Y, Katsurayama H, Mizota I. Asian J. Org. Chem. 2013; 2: 130
• 3g Shimizu M, Kurita D, Mizota I. Asian J. Org. Chem. 2013; 2: 208
• 3h Mizota I, Matsuda Y, Kamimura S, Tanaka H, Shimizu M. Org. Lett. 2013; 15: 4206
• 3i Tanaka H, Mizota I, Shimizu M. Org. Lett. 2014; 16: 2276
• 3j Tanaka T, Mizota I, Umezu K, Ito A, Shimizu M. Heterocycles 2017; 95: 830
• 3k Kawanishi M, Mizota I, Aratake K, Tanaka H, Nakahama K, Shimizu M. Bull. Chem. Soc. Jpn. 2017; 90: 395
• 3l Mizota I, Nakajima Y, Higashino A, Shimizu M. Arabian J. Sci. Eng. 2017; 42: 4249
• 3m Nakahama K, Suzuki M, Ozako M, Mizota I, Shimizu M. Asian J. Org. Chem. 2018; 7: 910
• 3n Mizota I, Tadano Y, Nakamura Y, Haramiishi T, Hotta M, Shimizu M. Org. Lett. 2019; 21: 2663
• 3o Shimizu M, Mushika M, Mizota I, Zhu Y. RSC Adv. 2019; 9: 23400
• 4 Hata S, Maeda T, Shimizu M. Bull. Chem. Soc. Jpn. 2012; 85: 1203
• 5 Mizota I, Maeda T, Shimizu M. Tetrahedron 2015; 71: 5793

For representative reviews on flow-microreactor syntheses, see:
• 6a Mason BP, Price KE, Steinbacher JL, Bogdan AR, McQuade DT. Chem. Rev. 2007; 107: 2300
• 6b Ahmed-Omer B, Brandt JC, Wirth T. Org. Biomol. Chem. 2007; 5: 733
• 6c Watts P, Wiles C. Chem. Commun. 2007; 443
• 6d Fukuyama T, Rahman MT, Sato M, Ryu I. Synlett 2008; 151
• 6e Hartman RL, Jensen KF. Lab Chip 2009; 9: 2495
• 6f McMullen JP, Jensen KF. Annu. Rev. Anal. Chem. 2010; 3: 19
• 6g Yoshida J.-i, Kim H, Nagaki A. ChemSusChem 2011; 4: 331
• 6h Wiles C, Watts P. Green Chem. 2012; 14: 38
• 6i Kirschning A, Kupracz L, Hartwig J. Chem. Lett. 2012; 41: 562
• 6j McQuade DT, Seeberger PH. J. Org. Chem. 2013; 78: 6384
• 6k Elvira KS, Casdevall i Solvas X, Wootton RC. R, deMello AJ. Nat. Chem. 2013; 5: 905
• 6l Pastre JC, Browne DL, Ley SV. Chem. Soc. Rev. 2013; 42: 8849
• 6m Baxendale IR. J. Chem. Technol. Biotechnol. 2013; 88: 519
• 6n Fukuyama T, Totoki T, Ryu I. Green Chem. 2014; 16: 2042
• 6o Gemoets HP. L, Su Y, Shang M, Hessel V, Luque R, Noël T. Chem. Soc. Rev. 2016; 45: 83
• 6p Cambié D, Bottecchia C, Straathof NJ. W, Hessel V, Noël T. Chem. Rev. 2016; 116: 10276
• 6q Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
• 6r Gutmann B, Kappe CO. J. Flow Chem. 2017; 7: 65

For some selected recent examples of flow-microreactor syntheses, see:
• 7a Fuse S, Mifune Y, Takahashi T. Angew. Chem. Int. Ed. 2014; 53: 851
• 7b He Z, Jamison TF. Angew. Chem. Int. Ed. 2014; 53: 3353
• 7c Nagaki A, Takahashi Y, Yoshida J.-i. Chem. Eur. J. 2014; 20: 7931
• 7d Chen M, Ichikawa S, Buchwald SL. Angew. Chem. Int. Ed. 2015; 54: 263
• 7e Fuse S, Mifune Y, Nakamura H, Tanaka H. Nat. Commun. 2016; 7: 13491
• 7f Nagaki A, Takahashi Y, Yoshida J.-i. Angew. Chem. Int. Ed. 2016; 55: 5327
• 7g Seo H, Katcher MH, Jamison TF. Nat. Chem. 2017; 9: 453
• 7h Mambrini A, Gori D, Kouklovsky C, Kim H, Yoshida J.-i, Alezra V. Eur. J. Org. Chem. 2018; 6754
• 7i Nagaki A, Sasatsuki K, Ishiuchi S, Miuchi N, Takumi M, Yoshida J.-i. Chem. Eur. J. 2019; 25: 4946
• 7j Nagaki A, Yamashita H, Tsuchihashi Y, Hirose K, Takumi M, Yoshida J.-i. Chem. Eur. J. 2019; 25: 13719
• 7k Fuse S, Masuda K, Otake Y, Nakamura H. Chem. Eur. J. 2019; 25: 15008
• 7l Sugisawa N, Otake YN, Nakamura H, Fuse S. Chem. Asian J. 2020; 15: 79
• 7m Alexandre Baralle A, Inukai T, Yanagi T, Nogi K, Osuka A, Nagaki A, Yoshida J.-i, Yorimitsu H. Chem. Lett. 2020; 49: 160
• 7n Sugisawa N, Nakamura H, Fuse S. Chem. Commun. 2020; 56: 4527

For representative examples of flow-microreactor syntheses using Comet X-01, see:
• 8a Tanaka K, Fukase K. Synlett 2007; 164
• 8b Tanaka K, Motomatsu S, Koyama K, Tanaka S.-i, Fukase K. Org. Lett. 2007; 9: 299
• 8c Tanaka K, Motomatsu S, Koyama K, Fukase K. Tetrahedron Lett. 2008; 49: 2010
• 8d Tanaka K, Mori Y, Fukase K. J. Carbohydr. Chem. 2009; 28: 1
• 8e Brandt J, Elmore S, Robinson R, Wirth T. Synlett 2010; 3099
• 8f Ishikawa H, Bondzic BP, Hayashi Y. Eur. J. Org. Chem. 2011; 6020
• 8g Uchinashi Y, Nagasaki M, Zhou J, Tanaka K, Fukase K. Org. Biomol. Chem. 2011; 9: 7243
• 8h Sano T, Mizota I, Shimizu M. Chem. Lett. 2013; 42: 995
• 8i Uchinashi Y, Tanaka K, Manabe Y, Fujimoto Y, Fukase K. J. Carbohydr. Chem. 2014; 33: 55
• 8j Pradipta AR, Tsutsui A, Ogura A, Hanashima S, Yamaguchi Y, Kurbangalieva A, Tanaka K. Synlett 2014; 25: 2442
• 8k Doi T, Otaka H, Umeda K, Yoshida M. Tetrahedron 2015; 71: 6463
• 8l Konishi N, Shirahata T, Yokoyama M, Katsumi T, Ito Y, Hirata N, Nishino T, Makino K, Sato N, Nagai T, Kiyohara H, Yamada H, Kaji E, Kobayashi Y. J. Org. Chem. 2017; 82: 6703
• 8m Ikawa T, Masuda S, Akai S. Chem. Pharm. Bull. 2018; 66: 1153
• 8n Myachin IV, Orlova AV, Kononov LO. Russ. Chem. Bull. 2019; 68: 2126
• 8o Arakawa Y, Ueta S, Okamoto T, Minagawa K, Imada Y. Synlett 2020; 31: 866
• 9 See the Supporting Information for details.
• 10 Results with other acids as additives are summarized in Table S1 of the Supporting Information.
• 11 Ethyl [Ethyl(propyl)amino](phenyl)acetate (3b) ⁴; Typical ProcedureA flow-microreactor system consisting of two connected Comet X-01 micromixers (M1), a Comet X-01 micromixer (M2), two pre-cooling units (P1: inner diameter = 2000 μm, length = 100 cm; P2: inner diameter: 2 mm, length = 100 cm), and two Teflon tube reactors (R1: inner diameter = 2 mm, length = 5 cm; R2: inner diameter = 2 mm, length = 20 cm) was used. The first flow-microreactor system consisting of the two connected Comet X-01 micromixers together with P1 and P2 was immersed in a magnetically stirred constant-temperature bath at –40 °C. The remainder of the system was at rt. A solution of α-tosyloxyimino ester 1a (0.02 M) and BzOH (0.01 M) in toluene (9.5 mL/min) [prepared from α-tosyloximino ester (E)-1a (138.9 mg, 0.40 mmol), BzOH (24.4 mg, 0.20 mmol), and toluene (20 mL)] was introduced into M1 by using a syringe pump. A 0.04 M solution of EtMgBr in toluene–Et₂O (9.5 mL/min) [prepared from a 0.93 M solution of EtMgBr (0.86 mL, 0.80 mmol) in Et₂O and toluene (19.14 mL)] was also introduced into M1 by using a syringe pump, and the mixed solution was passed through R1. A 0.04 M solution of PrMgBr in DME–Et₂O (9.5 mL/min), prepared from a 0.82 M solution of PrMgBr (0.98 mL, 0.80 mmol) in Et₂O and DME (19.02 mL), was introduced into M2 by using a syringe pump, and the resulting solution was passed through R2. Once a steady state was reached, the resulting solution (30 mL) was poured into sat. aq NaHCO₃ (10 mL) to quench the reaction. The resulting mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (15 mL), dried (Na₂SO₄), and filtered. The solvents were evaporated in vacuo, and the residue was purified by preparative TLC [silica gel, hexane–Et₂O (20:1)] three times to give the desired product 3b [yield: 35.5 mg (71%)], together with the N,N-diethyl product 3a [yield: 3.0 mg (6%)].3bYellow oil. IR (neat): 1737, 1453, 1372, 1154, 1067 1029, 728, 696 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.42–7.40 (m, 2 H), 7.34–7.25 (m, 3 H), 4.51 (s, 1 H), 4.25–4.13 (m, 2 H), 2.63 (q, J = 7.3 Hz, 2 H), 2.55–2.44 (m, 2 H), 1.52–1.35 (m, 2 H), 1.24 (t, J = 7.3 Hz, 3 H), 0.98 (t, J = 7.3 Hz, 3 H), 0.81 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃) δ = 172.4, 137.4, 128.7, 128.2, 127.7, 69.1, 60.4, 52.0, 44.3, 20.4, 14.2, 12.3, 11.7. HRMS (EI): m/z [M – C₃H₅O₂]⁺ calcd for C₁₂H₁₈N: 176.1434; found: 176.1434.