Integrated reactions based on the sequential addition to α-imino esters

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-quinolone 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, 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).

Scheme 1

Tandem N,C-dialkylation reaction.

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.

Scheme 2

Addition of various Li-enolates.

Scheme 3

Diastereoselective addition of various Li-enolates.

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).

Scheme 4

Possible reaction pathways

(E)- and (Z)-Ketene silyl acetals in place of their lithium enolates work equally well in this addition reaction, and the (E)- ketene silyl acetals or their (Z)-counterparts gave anti- or syn-adducts, respectively in an excellent diastereoselective manner.

N-alkylation/addition reaction

1,2-Amino alcohol moieties have often been found in many biologically important compounds. Several synthetic 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 methodology 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].

Scheme 5

n-Alkylation/addition reaction

Among the additives examined the presence of N,N-dimethyl-2-methoxyethylamine prevented the formation 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 consisting 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-addition 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).

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-quinoloneskeletons 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)aluminum 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].

Table 2

Indolin-3-one formation.

Entry	R1	R2	Yield (%)	Entry	R1	R2	Yield (%)	Entry	R1	R2	Yield (%)
1	Ph	OMe	65	5	2-thieny	OMe	67	8	EtO2C	OMe	61a
2	Ph	OPh	62	6	4-ClC6H4	OMe	59	9		OMe	66
3	Ph	SEt	62	7	4-MeC6H4	OMe	18	10		OMe	49
4	Ph	STol	42

^aIn the presence of MS 4A.

Of the R² groups examined, the methoxy group showed the best result (entry 1). Regarding the R¹ substituent, 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 yield of the cyclized product 9 (entry 7). These results indicate that the ability to induce the aza-Brook rearrangement [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.

Scheme 7

Possible pathways for the formation of indolin-3-one.

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 condensation 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).

Table 3

Trahydro-4-quinolone formation

Entry	R1	Yield (%) (cis/trans)	Entry	R1	Yield (%) (cis/trans)	Entry	R1	Yield (%) (cis/trans)
1	Ph	12 (100/0)	4		31 (70/30)	7		53 (81/19)
2	4-ClC6H4	18 (100/0)	5		50 (100/0)	8		59 (100/0)
3		13 (100/0)	6		49 (81/19)

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.

Scheme 8

Possible pathways for the trahydro-4-quinolone formation.

The initial addition of the lithium enolate of ethyl trimethylsilylacetate gives the C-adduct, which undergoes 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.

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 umpolung N-addition to β,γ-alkynyl α-imino esters followed by regioselective acylation. The reaction exhibits 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].

Scheme 9

Tandem reactions with β,γ-alkynyl α-imino esters.

As shown in Table 4, acyl chlorides having linear aliphatic groups such as acetyl and propionyl chlorides 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 heteroaromatic 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 substituent 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 MgBr₂was 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 aliphatic acid chlorides were used, relatively slow formation of acylium ions by MgBr₂would reflect the results. 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.

Scheme 10

Tandem addition via an iminium salt.

A proposed reaction mechanism is shown in Scheme 11. First, N-ethylation of the imino ester 11 generates the magnesium enolate A. Under basic conditions, the enolate reacts with an electrophile at the 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.

Scheme 11

Possible reaction pathways.

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 derivatives 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 synthesis of the amino ester derivatives which are not readily accessible by other methods.