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: [email protected] 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. Koyama et al.: Umpolung reactions of α-imino esters

Table 1 Tandem N-alkylation-addition reaction.

O N R RnAlCl3-n OMe AcCl DMAP Et PMP PMP N N (1.5 equiv.), (5.0 equiv.), (1.2 equiv.) (10 equiv.), (20 mol%) R EtO C EtO C 2 MeCN, -45 to -30 °C, 6 h 30 °C, 3.5 h 2 5 7 OAc

Entry Aluminum reagent R 7 (%)a anti : syn

1 Et2AlCl 4-ClC6H4 a: 75 89:11

2 Et2AlCl C6H5 b: 64 90:10

3 Et2AlCl 2-ClC6H4 c: 61 74:26

4 Et2AlCl 4-O2NC6H4 d: 46 80:20

5 Et2AlCl 4-MeOC6H4 e: 50 > 99:1

6 Et2AlCl 4-MeC6H4 f: 61 89:11

7 Et2AlCl 2-thienyl g: 62 84:16

8 Et2AlCl Ph-C≡C h: 42 62:38

9 Et2AlCl (E)-MeCH = CH i: 50 74:26

10 Et2AlCl n-C6H13 j: 38 63:37 b c,d 11 n-Oct3Al 4-ClC6H4 k: 10 78:22

12 n-Oct2AlCl 4-ClC6H4 k: 0 -:- b c 13 n-Oct2AlCl 4-ClC6H4 k: 3 > 99:1 b c 14 i-Bu2AlCl 4-ClC6H4 l: 6 > 99:1 c 15 i-Bu2AlCl 4-ClC6H4 l: 6 > 99:1 aIsolated yields. bn-Hexane was used as a solvent. c1,2-Diamine products arising form N-alkylation followed by addition to the parent imine were obtained in yields ranging from 24 to 46 %. dIsolated as the unprotected alcohol prior to acetylation.

PMP N

EtO2C Mixing Mixer 5 (0.25 M) Et PMPCl Et AlCl N O 2 EtO C 0.05 mL / min 2 OH

X MeCN, rt O PMP (0.375 M) N 20 cm EtO C Cl 2 Et2AlCl or n-Oct3Al (1.25 M) AcCl (10 equiv.), DMAP (20 mol %), MeCN, 30 °C, 3.5 h PMP Et Cl Et PMP Et PMP n-Oct PMP N N N NO2 N Cl EtO C EtO2C 2 EtO2CEtO2C OAc OAc OAc OAc 7a 70 % 7b 54 % 7d 48 % 7k 48 % anti : syn = 67 : 33 anti : syn = 72 : 28 anti : syn = 71 : 29 anti : syn = 84 : 16

Scheme 6 Tandem addition using a connected micromixer

Synthesis of indolin-3-ones and tetrahydro-4-quinolones

Heterocyclic compounds possessing indolin-3-one and tetrahydro-4-quinolone skeletons have received a considerable amount of attention because of the widespread existence of naturally occurring bioactive materials containing these heterocycles. When the α-imino ester 8 was treated with bis(trimethylsilyl)alu- minum chloride in propionitrile at room temperature for 2 h, followed by work-up with saturated aqueous KF, indolin-3-one 9 was obtained. Under these conditions, a variety of indolin-3-one were synthesized (Table 2) [6]. Of the R2 groups examined, the methoxy group showed the best result (entry 1). Regarding the R1 substitu- ent, the 2-thienyl, 4-chlorophenyl, ethoxycarbonyl, phenylethynyl, and phenylethenyl groups gave moderate to good results (entries 5, 6, 8, 9, and 10), whereas the 4-methoxyphenyl-substituted imino ester gave a poor K. Koyama et al.: Umpolung reactions of α-imino esters 759

Table 2 Indolin-3-one formation.

O R1 2 R (TMS)2AlCl (2.0 eq) sat. aq. KF N EtCN (0.030 M) N CO2Et O H 1 rt, 2 h R CO2Et 8 9

Entry R1 R2 Yield (%) Entry R1 R2 Yield (%) Entry R1 R2 Yield (%)

a 1 Ph OMe 65 5 2-thieny OMe 67 8 EtO2C OMe 61

2 Ph OPh 62 6 4-ClC6H4 OMe 59 9 OMe 66 Ph 3 Ph SEt 62 7 4-MeC H OMe 18 10 OMe 49 6 4 Ph 4 Ph STol 42 aIn the presence of MS 4A.

yield of the cyclized product 9 (entry 7). These results indicate that the ability to induce the aza-Brook rear- rangement [7] or N-silylation together with that to attack the ester carbonyl of the benzoate moiety reflect the efficiency of the present tactics. On the basis of the above results, the reaction pathways shown in Scheme 7 are proposed. There are two possible sites for the attack of the trimethylsilyl anion. In path a, the initial attack of the trimethylsilyl anion to the imino carbon generates the C-silylated species, which in turn undergoes a 1,2-aza- Brook rearrangement to generate the aluminum enolate, whereas in path b, addition of the trimethylsilyl anion to the imino nitrogen atom generates the aluminum enolate. The subsequent Dieckmann condensa- tion gives the indolin-3-one 9. Although we examined several systems for trapping the intermediary C- or N-silylated species with acetyl chloride, trifluoroacetic anhydride, trialkylsilyl triflate, and so on, only the cyclized product 9 was obtained together with the reduction of the imino functional group. 1,3-Aza-Brook rearrangement/cyclization was next discovered (Table 3). In the aryl- or ethynyl-substituted cases, the cyclized tetrahydro-4-quinolones 10 were obtained in low yields (entries 1–4), whereas the arylethenyl derivatives afforded the products in moderate yields with the cis-isomers predominating (entries 5–8). Stereoselctive formation of the cis-isomer is explained in terms of kinetic protonation of the intermediary lithium enolate from the less hindered site. On the basis of these results, the reaction pathways shown in Scheme 8 are proposed. The initial addition of the lithium enolate of ethyl trimethylsilylacetate gives the C-adduct, which under- goes a 1,3-aza-Brook rearrangement to yield an intermediate lithium enolate. Cyclization of this enolate leads to the formation of the tetrahydro-4-quinolone 10.

X2Al N Path a CO2Me

R CO2Et TMS N CO Me (TMS) AlCl 2 2 1,2-Aza-Brook Rearrangement R CO Et 2 O 8 O O Path b TMS OMe N TMS R sat. aq. KF R CO2Me N OEt CO Et R CO Et OEt N N 2 2 R O H X Al TMS AlX3 2 O 9 AlX2

Scheme 7 Possible pathways for the formation of indolin-3-one. 760 K. Koyama et al.: Umpolung reactions of α-imino esters

Table 3 Trahydro-4-quinolone formation

O TMS OEt , LDA O (1.5 eq) (2.0 eq) sat. aq. KF CO Et OMe 2 N CO2Et O DME / EtCN (1 / 3, 0.025 M) 1 1 N R R CO2Et 8 -60 °C to rt, 7 h 10 H

Entry R1 Yield (%) Entry R1 Yield (%) Entry R1 Yield (%) (cis/trans) (cis/trans) (cis/trans)

1 Ph 12 (100/0) 4 31 (70/30) 7 53 (81/19) Ph Cl Ph 2 4-ClC6H4 18 (100/0) 5 50 (100/0) 8 59 (100/0) Cl Cl S 3 13 (100/0) 6 49 (81/19) MeO

O TMS TMS OEt Li Li CO Me N 2 N LDA CO Me N CO2Me N 2 Me Si CO2Et CO2Me 3 R CO Et R CO Et R 2 R CO Et 2 OEt 2 TMS CO Et 2 CO2Et O 8 Li Li Lithium Enolate O O O O CO2Et CO Et Base OEt sat. aq. KF 2 CO2Et CO Et CO2Et 2 N R N R N R TMS H TMS 10

Scheme 8 Possible pathways for the trahydro-4-quinolone formation.

Regioselective tandem N-alkylation/C-acylation of β,γ-alkynyl α-imino esters

A new synthesis of α-quaternary alkynyl amino esters and allenoates was developed utilizing umpol- ung N-addition to β,γ-alkynyl α-imino esters followed by regioselective acylation. The reaction exhib- its broad substrate generality and unique regioselectivity. Moreover, synthesis of α-quaternary alkynyl amino esters was also carried out via oxidation of the intermediary enolate followed by alkylation (Scheme 9) [8].

R3 PMP N

2 3 PMP R3 PMP CO2R R PMP R3 PMP N N + α-addition 1 E N - N R3 M E R Nu 2 OM 2 CO R 3 CO R 2 2 2 CO2R 1 N-alkylation R PMP C-addition Nu R R1 OR2 N R1 R1 γ-addition 1 2 R CO2R E [O]

Scheme 9 Tandem reactions with β,γ-alkynyl α-imino esters. K. Koyama et al.: Umpolung reactions of α-imino esters 761

Table 4 Tandem N-alkylation/α-acylation.

O

PMP R2MgBr R3 Cl R2 PMP N N (1.1 equiv), (5.0 equiv) CO Et CO Et 2 THF, -78 °C to rt, 30 min 2 R1 R1 O R3 11 12

Entry R1 R2 R3 Product Yield (%)a

1 Ph Et Me 12a 79 2b Ph Et Me 12a 56 3 Ph Et Et 12b 78 4 Ph Et iPr 12c 32 5 Ph Et tBu 12d 0 6 Ph Et Ph 12e 75 7 Ph Et 2-furyl 12f 54 8 Ph Et OEt 12g 80

9 Ph Et CH3CH = CH- 12h 92

10 3-FC6H4- Et Me 12i 80

11 4-ClC6H4- Et Me 12j 83 12 1-cyclohexeny Et Me 12k 76 13 TIPS Et Me 12l 85 14 TIPS Et Ph 12m 88 15 TIPS Et 2-thienyl 12n 98 16 TES Et Ph 12o 87 17 TES Et 2-thienyl 12p quant 18 2-thienyl Et OEt 12q 70 19 Ph Me Me 12r 73 20 Ph Bn Me 12s 41 aIsolated yield. bAcetyl bromide was used instead of acetyl chloride.

As shown in Table 4, acyl chlorides having linear aliphatic groups such as acetyl and propionyl chlo- rides underwent the desired reaction to give the products 12a,b in high yields (entries 1 and 3), while those having branched aliphatic groups such as isobutyryl and pivaloyl chlorides decreased the yield or gave no product, presumably because of the steric hindrance (entries 4 and 5). Aromatic and heteroaro- matic acid chlorides also afforded the desired products 12e,f in moderate to high yields (entries 6 and 7). The substrates having aromatic substituents with electron-withdrawing groups or an aliphatic substitu- ent afforded the desired products 12i–k in high yields (entries 10–12). Silyl substituents were efficient for this reaction to give the products 12l-p in high yields (entries 13–17). In addition to ethyl Grignard reagent, methyl- and benzylmagnesium bromides also gave the products in moderate to good yields (entries 19 and 20).

Regarding the γ-acylation with acyl chlorides, MgBr2 was an appropriate Lewis acid to promote γ-addition, and the combined use of THF and MgBr2 gave the best result. Under the conditions A or B a variety of γ-addition products were obtained. Aromatic and heteroaromatic acyl chlorides afforded the desired products 13a, b, f, k in good to high yields (entries 1, 3, 9, and 15). When aliphatic acyl chlorides were used, the γ-products 13c, d were not obtained at all (entries 4 and 6). As compared with the results obtained under the conditions A, the yields of 13a, f, k decreased under the conditions B (entries 2, 10, 16), while the γ-products 13c, d were obtained in moderate yields under the conditions B (entries 5 and 7). These results indicate that when benzoyl chloride was used, the Lewis acidity of MgBr2 was suitable for the in situ formation of an acylium ion, whereas the use of BF3·OEt2 led to decomposition of the product, perhaps due to an increased Lewis acidity. When ali- phatic acid chlorides were used, relatively slow formation of acylium ions by MgBr2 would reflect the results. 762 K. Koyama et al.: Umpolung reactions of α-imino esters

It should be noted that silyl substituted imino esters gave the α-adducts exclusively in high yields (entries 18–20). Sequential N-alkylation/oxidation/nucleophilic addition to β,γ-alkynyl-α-imino ester gave the products 14a, b, c, d in a maximum 49 % yield (Scheme 10). Among the substrates examined, the one with the terminal silyl group gave the desired product 14e in good yield. A proposed reaction mechanism is shown in Scheme 11. First, N-ethylation of the imino ester 11 gen- erates the magnesium enolate A. Under basic conditions, the enolate reacts with an electrophile at the

Table 5 Tandem N-alkylation/γ-acylation

O Conditions A: 2 Et PMP PMP EtMgBr MgBr2 R Cl N N (1.1 equiv), (2.0 equiv), (2.0 equiv), THF, -78 °C to rt, 30 min R1 CO Et CO Et 2 2 Conditions B: O 1 R 2 2 O R EtMgBr BF3·OEt2 R Cl 11 (1.1 equiv), (2.0 equiv), (5.0 equiv), toluene, -78 °C to rt, 30 min 13

Entry R1 R2 Conditions Product Yield (%)a

1 Ph Ph A 13a 82 2c Ph Ph B 13a 54 3 Ph 2-thienyl A 13b 86 4b,c Ph Me A 13c 0 5 Ph Me B 13c 54 6 Ph Et A 13d 0 7 Ph Et B 13d 42 d 8 Ph CH3CH = CH- B 13e 40 9e 2-thienyl Ph A 13f 82 10d 2-thienyl Ph B 13f 46 11d 2-thienyl 2-thienyl B 13g 42

12 3-FC6H4- Me B 13h 28 f 13 3-FC6H4- Ph B 13i 36

14 4-ClC6H4- Me B 13j 13 15 1-cyclohexenyl Ph A 13k 63 16g 1-cyclohexenyl Ph B 13k 50 17 1-cyclohexenyl Me B 13l 36 18 TES Ph A 12mg 83 19 TIPS Ph A 12ng 86 20 TIPS 2-thienyl A 12og 85 aIsolated yield. bAcyl chloride (5.0 equiv) was used. cToluene was used as a solvent. dTHF was used as a solvent. eReaction was carried out in the absence of Lewis acid. fAcyl chloride (2.0 equiv) was used. gα-Addition product.

PMP 1. EtMgBr (3.0 equiv), THF, -78 °C to rt, 20 min Et PMP N N 2.DBDMH (1.5 equiv), rt, 10 min CO Et CO Et 2 3. EtMgBr (3.0 equiv), -78 °C to rt, 1 h Et 2 R1 R1 11 DBDMH = 1,3-dibromo-5,5-dimethylhydantoin 14

Et PMP Et PMP Et PMP Et PMP Et PMP N N N N N

CO Et CO Et CO Et CO Et CO Et Et 2 Et 2 F Et 2 Et 2 Et 2 TIPS

14a 49% 14b 39% 14c 45% Cl 14d 46% 14e 73%

Scheme 10 Tandem addition via an iminium salt. K. Koyama et al.: Umpolung reactions of α-imino esters 763

PMP Et PMPp Et 3 N N O R PMP PMP PMPp Et Et N O N Br PMP α-addition MgBr CO Et Mg N MgBr 1 2 DBDMH 1 2 EtMgBr N R Cl (basic) CO R R OEt 1 Br O 2 A R CO2Et O R1 O R1 O 1 OMgBr R 1 Br Br R1 OEt R OEt 12 N N Br N N 11 A γ-addition 3 R PMP O (acidic) N O 1 2 R CO2R Br 1 PMPp Et O O R N PMPp Et LA O 13 EtMgBr N R1 Cl R1 CO Et 2 CO Et R1 Et 2 R1 B Et–MgBr 14

Scheme 11 Possible reaction pathways.

α-position to give the alkynyl amino ester 12, while under Lewis acidic conditions, the enolate reacts with the acylium ion derived from acyl chloride with a Lewis acid at the γ-position through orbital control to provide the allenyl esters 13. In the cases with DBDMH as an oxidant, the enolate A is oxidized to give an iminium salt as intermediate B, which reacts with another equivalent of EtMgBr to give the alkynyl amino ester 14.

Conclusion

Integrated sequential reactions of α-imino esters described here offer a useful strategy for the synthesis of various amino esters. Tandem N-ethylation/Mannich reaction gave a rapid access to aspartic acid deriva- tives in a diastereo-controlled manner, while N-alkylation/addition reaction afforded important 1,2-amino alcohols via the aluminum enolate addition to aldehydes. The latter reaction could be carried out even at room temperature when a connected micro mixer was used as a reaction medium. An interesting 1,2- or 1,3-aza-Brook type rearrangement was observed upon addition of bis(trimethylsilyl)aluminum chloride or the lithium enolate from ethyl trimethylsilylacetate as a nucleophile, leading to the synthesis of indolin-3-ones or tetrahydro-4-quinolones, respectively. A regioselective tandem N-alkylation /C-acylation of β,γ-alkynyl α-imino esters is of interest in terms of controlled regisoselectivity on an addition to acyl chlorides. Thus, the use of α-imino esters has broadened the utility of this class of compounds as useful substrates for the synthe- sis of the amino ester derivatives which are not readily accessible by other methods.

Acknowledgments: We would like to thank our coworkers for their intellectual and experimental contribu- tions to the present project. This work was supported by Grants-in-Aid for Scientific Research from the Min- istry of Education, Science, Sports, and Culture, of the Japanese Government, and a grant from the Japan Science and Technology Agency is also gratefully acknowledged.

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