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Imino Esters DOI 10.1515/pac-2013-1105 Pure Appl. Chem. 2014; 86(5): 755–764 Conference paper Kaichiro Koyama, Isao Mizota and Makoto Shimizu* Integrated reactions based on the sequential addition to α-imino esters Abstract: This article summarizes integrated sequential reactions with α-imino esters, where the umpolung addition reaction to the imino nitrogen followed by the second addition or oxidation is the crucial step. The following four types of reactions are discussed: (1) tandem N-ethylation/Mannich reaction; (2) N-alkylation/ addition reaction; (3) synthesis of indolin-3-ones and tetrahydro-4-quinolones; (4) regioselective tandem N-alkylation/ C-acylation of β,γ-alkynyl α-imino esters. Keywords: alkoxycarbonyl iminium salt; α-imino ester; indolin-3-one; N-alkylation; NMS-IX; tetrahydro- 4-quinolone; umpolung. *Corresponding author: Makoto Shimizu, Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan, e-mail: mshimizu@chem.mie-u.ac.jp Kaichiro Koyama and Isao Mizota: Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507, Japan Article note: Paper based on a presentation at the 9th International Symposium on Novel Materials and their Synthesis (NMS-IX) and the 23rd International Symposium on Fine Chemistry and Functional Polymers (FCFP-XXIII), Shanghai, China, 17–22 October 2013. This paper is dedicated to the memory of Prof. Yingyan Jiang. Introduction Synthetic methods for the preparation of nitrogen-containing esters are of utmost interest and importance because these structures are the key components of natural and unnatural biologically active compounds and functionalized materials. The most straightforward approach to synthesize amino esters involves chemoselective nucleophilic additions to the imino groups of imino esters, and many examples have been reported in which various nucleophiles add to imines in a 1,2-fashion. However, α-imino esters behave as acceptors of nucleophiles at their nitrogen atoms in an “umpolung” manner, when appropriate nucleophiles are used [1]. This kind of reactivity of α-imino esters is of interest, and several intriguing features have already been discovered [2]. The addition reaction was also carried out using a micro-flow system, with which the transformation could be conducted even at room temperature to give the three components coupling products in moderate yields. When the α-imino ester derived from 2-aminobenzoate and glyoxylate was treated with bis(trimethylsilyl) aluminum chloride or the lithium enolate from ethyl trimethylsilylacetate, indolin-3-one or tetrahydro-4-qui- nolone was respectively obtained via a cyclization reaction of the resulting enolates. Tandem N-ethylation/Mannich reaction The construction of quaternary centers of amino acids in a stereoselective manner is becoming increasingly important in connection with the need to create new biologically interesting molecules. For this purpose, © 2014 IUPAC & De Gruyter 756 K. Koyama et al.: Umpolung reactions of α-imino esters we have already discovered a useful method for the double introduction of nucleophiles across the imino groups. The method involves umpolung addition of the first nucleophile at the imino nitrogen followed by oxidation of the resulting enolate to the alkoxy iminium salt, and addition of the second nucleophile to this salt (Scheme 1). For the preparation of aspartic acid derivatives, the addition of ester enolates to the iminium salt of this type offers a straightforward strategy [3]. High diastereocontrol is achieved in the addition reaction to the iminium salts using the lithium enolates and/or ketene silyl acetals. When the reaction was carried out in DME with 1.5 equiv of the enolate, the desired adduct 4 was obtained in yields ranging from 29 to 97 % (Scheme 2). Use of trisubstituted lithium enolates offers very high diastereoselectivities for all the examples examined except for the ortho-methoxy derivative. The ‘(E)’-lithium enolate gave the syn-adducts exclusively in good yields, whereas its ‘(Z)’-counterpart effected the formation of the anti-adducts in a stereospecific manner (Scheme 3). This is the first example in which such high diastereoselectivities have been observed in a Mannich reaction by using either the ‘(E)’- or ‘(Z)’-lithium ester enolate. The present high diastereoselectivity may be rationalized using the following models. N-Ethylation of the imino ester 1a generates the aluminum enolate A, which is oxidized with benzoyl peroxide (BPO) to give the intermediary iminium salt C. In the cases with the ‘(E)’-Li enolate, the chelation of the lithium metal between ester oxygen atoms would give rise to a seven-membered transition state D, leading to the formation of the syn-adduct. Regarding the ‘(Z)’-Li enolate, a similar seven-membered transition state E would account for the preferred formation of the anti-adduct (Scheme 4). (E)- and (Z)-Ketene silyl acetals in place of their lithium enolates work equally well in this addition reac- tion, and the (E)- ketene silyl acetals or their (Z)-counterparts gave anti- or syn-adducts, respectively in an excellent diastereoselective manner. Nu1 PMP PhCO2 PMP Nu1 PMP N Nu1 PMP N Nu1 PMP N N Nu2- N Nu1- BPO OAlX Ph CO2Et Ph 2 Ph CO Et Ph CO2Et O O Ph CO2Et 2 OEt Nu2 1a PMP = p-MeC6H4 Ph 2 3 Scheme 1 Tandem N,C-dialkylation reaction. 1) Et AlCl (1 equiv), EtAlCl (1 equiv) PMP 2 2 Et PMP R1 = Ph, p-MeOC H , m-MeOC H , N BPO (1 equiv), DME, rt, 10 min N 6 4 6 4 3 o-MeOC6H4, p-ClC6H4 2 CO2R 1 2) R OLi EtO2C R CO Et 1 2-Naphthyl, 1-Naphthyl, or Cy 2 R 2 2 THF, -78°C, 10 min R R R2 = Me or H R2 OR3 1 29 to 97 % yield 4 R3 = Me, Et, i-Pr, or t-Bu (1.5 equiv) Scheme 2 Addition of various Li-enolates. OLi E/Z = >99/1 PMP Et R = Ph: 94 % (>99:1) N Me t (1.5 eq) R = p-MeOC6H4: 95 % (>99:1) O Bu t CO Bu R = p-ClC6H4: 90 % (>99:1) BPO (1 eq) R 2 THF, -78 , 10 min R = m-MeOC6H4: 95 % (>99:1) Et AlCl in hex (1 eq) EtO C Me R =Cy: 84 % (>99:1) PMP 2 2 N EtAlCl2 in hex (1 eq) anti Me OLi DME, rt, 10 min E/Z = 1/>99 R = Ph: 91 % (1:>99) R CO2Et PMP Et N R = p-MeOC H : 95 % (1:>99) 1 OtBu ( 1.5 eq) 6 4 CO tBu R = p-ClC H : 92 % (1:>99) R 2 6 4 THF , -78 , 10 min R = m-MeOC6H4: 95 % (1:>99) EtO C Me 2 R =Cy: 92 % (1:>99) syn Scheme 3 Diastereoselective addition of various Li-enolates. K. Koyama et al.: Umpolung reactions of α-imino esters 757 PhCO Et PMP Et PMP 2 PMP N N Et PMP N Et2AlCl BPO Et PMP Li Enolate N OAlX N t 2 Ph CO2Et CO2 Bu EtAlCl Ph O EtO2C Ph CO2Et 2 O Ph CO Et OEt 2 Ph Me Ph 1a A B C 4a Et PMP Et PMP N N PhCO Et PMP PhCO Et PMP Me 2 N Me 2 N t CO tBu OEt CO2 Bu OEt EtO C 2 Ph EtO2C Ph 2 O O O Ph Me O O O Ph Me tBu Li syn-4a tBu Li anti-4a '(E )'-Enolate (D) '(Z )'-Enolate (E) Scheme 4 Possible reaction pathways N-alkylation/addition reaction 1,2-Amino alcohol moieties have often been found in many biologically important compounds. Several syn- thetic 1,2-amino alcohol derivatives have also been employed as drugs for therapeutic purpose as well as chiral auxiliaries or metal ligands in catalytic asymmetric synthesis. We have recently introduced a useful method for the N-alkylation of α-imino esters, and this methodol- ogy makes possible an integrated addition reaction to form 1,2-diamines (eq 1 in Scheme 5). We focussed on the direct use of the aluminum enolates derived from α-aldimino esters for the addition of aldehydes, and have found that the N-alkylation followed by addition reaction proceeds well to give 1,2-amino alcohols in the presence of a certain additive (eq 2) [4a]. Among the additives examined the presence of N,N-dimethyl-2-methoxyethylamine prevented the forma- tion of by-products such as that derived from C-alkylation. As shown in Table 1, use of aromatic aldehydes gave good yields of the tandem addition products (entries 1–7), whereas α,β-unsaturated and aliphatic derivatives recorded moderate yields of the desired products. When n-octyl- and iso-butylaluminum reagents were used, N-alkylation followed by addition to the starting imine 5 as previously reported was observed to give the 1,2-diamines [4b] in yields ranging from 24 to 46 % as major products, which were not suppressed under various conditions attempted (entries 11–15). Further application of this type of tandem addition to a flow synthesis [5] leads to a useful system consist- ing of connected micromixers for the N-octylation-addition reaction conducted at room temperature. Using a connected micromixer with an acetylation process, a variety of the tandem addition products were obtained in moderate yields even at room temperature (Scheme 6). It is noteworthy that the tandem N-octylation-addi- tion product 7k was obtained in 48 % yield, making a strong contrast to that obtained using a conventional batch reaction (see, Table 1, entries 11–13). 2 Organo- PMP R PMP PMP R PMP R PMP N N N aluminum 1 N 1) R2 AlCl 1 N 1) R CHO 2 1 CO R Reagent 1 2 (1) EtO + R (2) R1O C R O2C EtO2C 2) H EtO C 2 2) AcCl N 2 OAl OH PMP Ac 5 6 Scheme 5 n-Alkylation/addition reaction 758 K.
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