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DOI: 10.1055/s-0040-1707265
Umpolung Reactions of α-Tosyloximino Esters in a Flow System
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant No. JP18H04402 in Middle Molecular Strategy and JP17K05860.
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.
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Natural products, pharmaceuticals, and the basic skeletons of other important biologically active compounds frequently include nitrogen-containing organic moieties. Among nitrogen-containing compounds, α-amino acids and their derivatives, including amino esters and amino alcohols, have attracted considerable attention. Consequently, there has been a considerable desire to develop reactions that efficiently synthesize compounds with various substituents on both the nitrogen and the carbon atoms at the α-positions of α-amino acid moieties. α-Imino esters are among the most useful nitrogen-containing starting materials for the synthesis of various natural and nonnatural α-amino acid derivatives.[1] [2]
We have previously reported that the N-alkylation reaction of α-imino esters with Grignard reagents proceeds smoothly to give the N-alkylated products,[3] and that N,N-dialkylations and N,N,C-trialkylations of α-sulfoximino esters give the corresponding α-amino acid derivatives.[4] There are some limitations on these reactions; for example, the use of an (E)-nosyloximino ester was needed for the synthesis of N,N-dialkylated α-amino acid derivatives having two different substituents on the amino nitrogen. However, when reaction was conducted at the extremely low temperature of –78 °C problems were encountered in introducing a second substituent onto the imino nitrogen atom to give an N,N-dialkylated amino ester (Scheme [1a]). In N,N,C-trialkylations of (Z)-tosyloximino esters, N,N,C-trialkylated α-amino acid derivatives with two identical substituents on the amino nitrogen were obtained (Scheme [1b]). In 2015, we reported that N,N,C-trialkylated α-amino acid derivatives with two different alkyl substituents on the nitrogen atom could be synthesized by using α-N-p-toluoyloximino esters as highly efficient starting α-imino esters (Scheme [1c]).[5]
Flow systems can provide conditions different from those of batch processes conducted in flasks. A reaction field in micro-space can increase the efficiency of heat exchange, permitting better control of the reaction temperature than in a batch reaction. In addition, because tandem reactions can be easily carried out, it becomes possible to use unstable intermediates and to synthesize products efficiently and rapidly.[6] [7] Here, we report N,N-dialkylation, and N,N,C-trialkylation reactions of α-tosyloximino esters in a flow system; this has such advantages as high efficiency and rapid heat transfer compared with conventional batch reactions (Scheme [2]).
First, we screened the reaction conditions for N-monoethylation of the α-tosyloximino ester (E)-1a by using a Comet X-01 micromixer (Figure S1).[8] [9] The results are summarized in Table [1]. A solution of (E)-1a in toluene and a solution of ethylmagnesium bromide (EtMgBr) in toluene–diethyl ether were mixed by using the Comet X-01 at various temperatures. When the reaction was carried out at room temperature, the desired N-monoethylated product 2 was obtained in 37% yield, accompanied by the diethylated product 3a in 18% yield (Table [1], entry 1). Lower reaction temperatures gave better yields (entries 2–5). Although the best yield (70%) was obtained at –78 °C, we continued to examine the effects of various concentrations of EtMgBr at the milder temperature of –40 °C (entries 6–10). The use of 1.4 equivalents of EtMgBr slightly improved the yield (entry 7). The use of the isomer (Z)-1a was then examined under several reaction conditions, but the desired monoethylated product 2 was not obtained (entries 11–13).
Because the starting material (E)-1a was recovered in some cases, we next examined the use of two connected Comet X-01 micromixers to increase the mixing efficiency (Figure [1]).
The results are summarized in Table [2]. The formation of the diethylated product 3a increased and (E)-1a was not recovered (entries 2–6). Benzoic acid (BzOH) was examined as an additive to quench excess EtMgBr and to activate (E)-1a. A solution of (E)-1a containing BzOH in toluene and a solution of EtMgBr in toluene–diethyl ether were mixed by using the two connected Comet X-01 micromixers. The use of 2.0 equivalents of EtMgBr and 0.5 equivalents of BzOH gave the desired N-monoethylated product 2 in the best yield of 69% (entry 9).[9]
Tandem N,N-dialkylations with two different Grignard reagents were next examined. The reaction conditions were screened by using ethyl and propyl Grignard reagents. The results are summarized in Table [3]. The use of 2.0 equivalents of EtMgBr, 0.5 equivalents of BzOH, and 2.0 equivalents of PrMgBr gave the desired N-ethyl N-propyl product 3b in the best yield of 71% (entry 3).[10] [11]
With the optimized reaction conditions in hand, we used a variety of second Grignard reagents and α-tosyloximino esters 1 in the tandem N,N-dialkylation (Scheme [3]). Methyl Grignard reagent as the second nucleophile did not give the desired product 3d, as previously reported.[3] The use of primary benzyl Grignard reagent afforded the product 3e in 52% yield. Secondary alkyl (isopropyl and cyclohexyl) Grignard reagents gave the corresponding products 3f and 3g in yields of 60 and 46%, respectively. The use of tert-butyl Grignard reagent afforded product 3h in a lower yield of 21% as a result of steric hindrance. The scope of the aromatic group was next examined. α-Tosyloximino esters (E)-1b–d containing tolyl groups gave the desired products 3i–k in moderate yields. α-Tosyloximino esters (E)-1e and 1f, with electron-withdrawing and electron-donating groups respectively, gave the corresponding products 3l and 3m in yields of 63 and 43%, respectively.
Finally, we examined the tandem N,N,C-trialkylation of α-tosyloximino ester 1a with three different Grignard reagents. Effects of the number of equivalents of 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) as an oxidant and of BnMgBr as the third nucleophile were examined (see Supporting Information, Figure S2).[9] The results are summarized in Table [4]. The use of 1.2 equivalents of DBDMH and 2.5 equivalents of BnMgBr afforded the desired N-ethyl N-propyl C-benzyl product 4 in the best yield of 57% (entry 6).
a Yield previously obtained under batch conditions.[5]
Based on our previous study,[5] a plausible reaction mechanism for the N-mono-, N,N-di-, and N,N,C-trialkylations of α-tosyloximino ester (E)-1a is shown in Scheme [4]. The addition of the first Grignard reagent gives (Z)-2 through either an addition–elimination reaction (path a) or an SN2 reaction (path b). With regard to the role of benzoic acid, we presume that it coordinates to the tosyloxy group of intermediate A or B to facilitate its elimination. (Z)-2 might isomerize to (E)-2 in the presence of benzoic acid or bromomagnesium tosylate. The addition of the second Grignard reagent gives the magnesium enolate D via the five-membered intermediate C. The magnesium enolate D is hydrolyzed to afford the N,N-dialkylated product 3. Oxidation of the magnesium enolate D with DBDMH generates the iminium salt E, which undergoes an addition reaction with the third Grignard reagent to give the N,N,C-trialkylated product 4.
In conclusion, we have investigated the umpolung reaction of α-tosyloximino esters in a flow system. Tandem N,N-dialkylations with two different Grignard reagents gave the desired N,N-dialkylated products in moderate to good yields. In addition, the tandem N,N,C-trialkylation of an α-tosyloximino ester with three different Grignard reagents proceeded successfully to afford the desired N,N,C-trialkylated product in moderate yield. The present flow system is an attractive because one step can be eliminated by simultaneous introduction of benzoic acid. Moreover, the N,N-dialkylated and N,N,C-trialkylated products are useful intermediates for syntheses of biologically active compounds, and they can be synthesized at the less extreme temperature of –40 °C in a shorter time in comparison with the previously reported batch conditions.
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Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1707265.
- Supporting Information
-
References and Notes
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- 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
- 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
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- 6a Mason BP, Price KE, Steinbacher JL, Bogdan AR, McQuade DT. Chem. Rev. 2007; 107: 2300
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- 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
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- 8e Brandt J, Elmore S, Robinson R, Wirth T. Synlett 2010; 3099
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- 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
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- 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.
For reviews on α,α-disubstituted α-amino acids and their peptides, see:
For representative N-alkylations of α-imino esters by our group, see:
For representative reviews on flow-microreactor syntheses, see:
For some selected recent examples of flow-microreactor syntheses, see:
For representative examples of flow-microreactor syntheses using Comet X-01, see:
Corresponding Author
Publication History
Received: 20 July 2020
Accepted after revision: 03 August 2020
Article published online:
03 September 2020
© 2020. Thieme. All rights reserved
Georg Thieme Verlag KG
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References and Notes
- 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
- 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
- 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
- 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
- 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.
For reviews on α,α-disubstituted α-amino acids and their peptides, see:
For representative N-alkylations of α-imino esters by our group, see:
For representative reviews on flow-microreactor syntheses, see:
For some selected recent examples of flow-microreactor syntheses, see:
For representative examples of flow-microreactor syntheses using Comet X-01, see:
