key: cord-0858939-zeqdsyxt
authors: Tarui, Atsushi; Kawashima, Naoto; Sato, Kazuyuki; Omote, Masaaki; Ando, Akira
title: Diastereoselective synthesis of 2-fluoroaziridine-2-carboxylates by Reformatsky-type aza-Darzens reaction
date: 2010-08-11
journal: Tetrahedron Lett
DOI: 10.1016/j.tetlet.2010.06.030
sha: b1d2266989a1f3b180ec08869adb68cd2f19abeb
doc_id: 858939
cord_uid: zeqdsyxt

The reaction of ethyl dibromofluoroacetate with imines using zinc metal gave 2-fluoroaziridine-2-carboxylates via aza-Darzens reaction of the primary product of the Reformatsky reaction with high diastereoselectivity in excellent yields (quantitative yield and Dr = 85:15). This chemoselective formation of 2-fluoroaziridines was achieved by using CH(3)CN as a solvent. Interestingly, the reaction proceeded without activation of zinc metal, which was necessary for the Reformatsky reaction of bromodifluoroacetate. None of α-bromo-α-fluoro-β-lactams, four-membered cyclization products, and noncyclized 3-amino-2-bromo-2-fluorocarboxylic esters, usual Reformatsky adducts, were formed.

The reaction of ethyl dibromofluoroacetate with imines using zinc metal gave 2-fluoroaziridine-2-carboxylates via aza-Darzens reaction of the primary product of the Reformatsky reaction with high diastereoselectivity in excellent yields (quantitative yield and Dr = 85:15). This chemoselective formation of 2-fluoroaziridines was achieved by using CH 3 CN as a solvent. Interestingly, the reaction proceeded without activation of zinc metal, which was necessary for the Reformatsky reaction of bromodifluoroacetate.

None of a-bromo-a-fluoro-b-lactams, four-membered cyclization products, and noncyclized 3-amino-2bromo-2-fluorocarboxylic esters, usual Reformatsky adducts, were formed.

Ó 2010 Elsevier Ltd. All rights reserved.

Many methods were developed to introduce fluorine functional groups to various bioactive molecules, since the interesting effects of fluorine functional groups were brought about by putting them on a suitable position of bioactive compounds. 1 Among them, fluorinated amino acids and the peptides derived from them have been attracting much attention in medicinal field. 1c,2 On the other hand, aziridine compounds have been used in many fields. For example, these compounds are used as building blocks to form aand b-amino acids by ring-opening reaction. 3 Further, aziridine-2-carboxylates themselves have been applied to antibacterial agents 4 and SARS-CoV protease inhibitor. 5 Recently, we reported that the Reformatsky-type reaction of ethyl dibromofluoroacetate (1) with imines (2) using Et 2 Zn gave syn-a-bromo-a-fluoro-b-lactams (3) in good yields (Scheme 1). 6 The products were obtained with perfect diastereoselectivity and high chemoselectivity. In this reaction, a small amount of 2-fluoroaziridine-2-carboxylate (4) was isolated as a side product, which must be formed by the aza-Darzens reaction of the primary product. We call this side of reaction as the Reformatsky-type aza-Darzens reaction.

Surprisingly, only two methods for the synthesis of 2-fluoroaziridine-2-caboxylates (4) have been reported, in one of which the construction of fluorinated aziridine-2-carboxylate was achieved by addition of an a-fluoro-a-ethoxycarbonylcarbene to a C@N double bond 7 and in the other by addition of a nitrene to an a-fluoroa,b-unsaturated ester. 8 However, these reactions gave the products only in low yields. Further, it was troublesome to generate the nitrene or carbene species. Recently, Jubault and co-workers reported Et 2 Zn-promoted reactions of 1 with ketone in the presence of N,N-dimethylaminoethanol as an additive to give fluorinated glycidic esters via common Darzens reaction. 9 Our previous results 6 stimulated us to examine the Reformatsky-type aza-Darzens reaction of 1 with imines (2) in order to obtain 2-fluoroaziridine-2-carboxylate (4) selectively (Scheme 2). In this report, we wish to describe our recent results on the Zn-mediated chemo-and stereoselective formation of 4 by adjusting the reaction condition.

Using our previous condition, 6 the reaction of 1 with benzylidenebenzylamine (2a) and Et 2 Zn in Et 2 O at À10°C gave 3a as a main product with a small amount of 4a (Table 1 , entry 1). Depending on the reaction conditions, the ratio of products changed dramatically. The desired product 4a was obtained selectively in CH 3 CN (entry 2). Conventional Reformatsky condition using activated Zn metal also led to selective formation of 4a (entry 3). Interestingly, unac- 

Tetrahedron Letters j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / t e t l e t tivated Zn metal also gave 4a with high diastereoselectivity and in quantitative yield (entry 4). The configuration of the major diastereomer of 4a was determined to be syn by vicinal H-F coupling constant on 19 F NMR spectroscopy. 10 In all cases, noncyclized ethyl 3-benzylamino-2-bromo-2-fluoro-3-phenylpropionate (5a), the usual Reformatsky adduct, was not obtained. As shown above, we achieved chemoselective formation of 4a by using CH 3 CN as a reaction media and found that the yield of 4a was not affected by activation of zinc. 11, 12 Next, the scope and limitations of this Reformatsky-type aza-Darzens reaction were explored under the optimized reaction condition shown above ( Table 2 ). The imines from aromatic aldehydes gave the corresponding 2-fluoroaziridine-2-carboxylates in excellent yields regardless of the substituents on the phenyl ring (entries 1À6). In the cases of aliphatic aldimine (2g) and ketimine (2h), the corresponding fluoroaziridine products were not observed by 19 F NMR spectroscopy (entries 7 and 8). The substituents on the nitrogen (R 1 ) did not affect this reaction essentially (entries 9À12). In the case of imine (2j), the product was obtained in low yield probably due to the bulkiness of the N-substituent. The yield of 4j was improved by prolongation of the reaction time (entry 11). In all cases, the products (4) were obtained with high and similar diastereoselectivities.

However, these fluorinated aziridine compounds (4) were not so stable as that reported for fluorinated epoxides. 9 So 4 must be stored at À30°C to avoid their decomposition. Especially, syn-isomers 4 were less stable than anti-isomers. Therefore their yields and diastereoratios were determined by 19 F NMR spectroscopy of crude mixtures.

We propose the mechanism of this Reformatsky-type aza-Darzens reaction of 1 with imine (2a) as shown in Figure 1 . Recently, we reported the tentative mechanism for the formation of a-bromo-a-fluoro-b-lactams by Et 2 Zn-promoted Reformatsky-type reaction of 1 with imine in Et 2 O. 6 There, chemo-and diastereoselective formation of 3a was achieved by the addition of stable (Z)-zinc bromofluoroenolate (6) to imine, where low coordination power of Et 2 O makes the generation of chair-like transition state favorable. Intramolecular cyclization of intermediate (7) to ester carbonyl group was promoted by the intramolecular coordination of zinc to carbonyl moiety to give 3a. 6 On the other hand, the strongly coordinating solvent, CH 3 CN, could coordinate with Zn of the enolate 8 leading to reversible equilibrium of E/Z isomer of 8. And also the coordination could destroy the chair-like transition state to give another open-chain transition state (TS-1-TS-4). The Reformatsky adduct (9) gave the aziridine ring 4a via aza-Darzens-type intramolecular cyclization, where coordination of sol- vent to Zn of 9 seemed to disturb the activation of ester carbonyl moiety. This assumption was supported that the mixture of 3a and 4a was obtained by the reaction of 1 with imine (2a) using Et 2 Zn and Et 2 O as a solvent in the presence of PPh 3 which must be a better monovalent ligand than CH 3 CN. 13 In this transition model, the syn isomer is obtained mainly from TS-1, in which there is little steric repulsion. On the other hand, other transition states (TS-2-TS-4) have some steric repulsion between bromine and phenyl group and between phenyl group and the other functional group. Z-8 used for TS-1 might be provided from equilibrium of E-8 and Z-8. As a result, the selective generation of syn isomer was achieved by dynamic kinetic resolution.

In conclusion, we established a new methodology for 2-fluoroaziridine-2-carboxylates by chemo-and diastereoselective Reformatsky-type aza-Darzens reaction of ethyl dibromofluoroacetate with imines using Zn metal. The Reformatsky reagent of 1 was generated without any activation of zinc. This chemoselective reaction was achieved by carrying out in CH 3 CN. Now, we are planning the synthesis of bioactive compounds with fluorinated aziridine ring and the ring-opening reaction of 4 for the synthesis of a-fluoroaor b-amino acids. 1 mmol) was added at À10°C, and the resulting mixture was stirred at same temperature for 6 h. The reaction was quenched with saturated aqueous NaHCO 3 , and the mixture was filtered through Celite pad. The filtrate was extracted with AcOEt, and then the extract was washed with brine and dried over MgSO 4 . The solvent was removed in vacuo without heating and the residue was purified by column chromatography (SiO 2 , AcOEt/hexane = 5:95) to give the corresponding 2-fluoroaziridine-2-carboxylate (4a). The chemical yield was obtained from 19 F NMR of the crude mixture; benzotrifluoride (BTF) was used as an internal standard. 12. Spectroscopic data of 4a: syn-and anti-isomers were separated by column chromatography. Figure 1 . Tentative mechanism for the diastereoselective outcome.

Bioorganic and Medicinal Chemistry of Fluorine

Selective Fluorination in Organic and Bioorganic Chemistry

The relative configuration means that for H-F configuration. Relationship of stereoisomer and H-F coupling constant was described following book: Dorbier

mL, 3 mmol) was added to a suspension of Zn (196 mg, 3 mmol) in CH 3 CN (8 mL) at À10°C. The resulting mixture was stirred at same temperature for 1 h. To the yellow emulsion of mixture

MHz) d: À106.6 (1F, m)

MS m/z = 299 (M + )

HRMS (EI) Calcd for C 18 H 18 FNO 2 : 299.132 (M + )

The reaction gave syn-3a in 33% yield and the diastereomixture of 4a in 44% yield (syn/anti = 32%/12%). Total syn/anti ratio of product was 84/16