Diastereoselective synthesis of 2-fluoroaziridine-2-carboxylates by Reformatsky-type aza-Darzens reaction.

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 CH3CN 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.

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. Among them, fluorinated amino acids and the peptides derived from them have been attracting much attention in medicinal field.(c), 2 On the other hand, aziridine compounds have been used in many fields. For example, these compounds are used as building blocks to form α- and β-amino acids by ring-opening reaction. Further, aziridine-2-carboxylates themselves have been applied to antibacterial agents and SARS-CoV protease inhibitor.

Recently, we reported that the Reformatsky-type reaction of ethyl dibromofluoroacetate (1) with imines (2) using Et2Zn gave syn-α-bromo-α-fluoro-β-lactams (3) in good yields (Scheme 1 ). 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.

Scheme 1

Diastereoselective Reformatsky-type synthesis of α-bromo-α-fluoro-β-lactams.

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 α-fluoro-α-ethoxycarbonylcarbene to a CN double bond and in the other by addition of a nitrene to an α-fluoro-α,β-unsaturated ester. 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 Et2Zn-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.

Our previous results 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.

Scheme 2

The Reformatsky-type aza-Darzens reaction of 1 with imines.

Using our previous condition, the reaction of 1 with benzylidenebenzylamine (2a) and Et2Zn in Et2O at −10 °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 CH3CN (entry 2). Conventional Reformatsky condition using activated Zn metal also led to selective formation of 4a (entry 3). Interestingly, unactivated 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 19F NMR spectroscopy. In all cases, noncyclized ethyl 3-benzylamino-2-bromo-2-fluoro-3-phenylpropionate (5a), the usual Reformatsky adduct, was not obtained.

Table 1

Screening of reaction condition of Reformatsky-type aza-Darzens reaction

Entry	Solv.	Zn source	Time (h)	Yield of 3aa (%)	Dr of 3ab (syn:anti)	19F NMR yield of 4a (%)	Dr of 4ab (syn:anti)	Yield of 5a (%)
1	Et2O	Et2Zn	1	76	100:0	8	0:100	ND
2	CH3CN	Et2Zn	6	ND	—	91	82:18	ND
3	CH3CN	Activated Zn powder	6	ND	—	95	85:15	ND
4	CH3CN	Unactivated Zn powder	6	ND	—	Quant.	85:15	ND

Isolated yields.

Determined by 19F NMR.

As shown above, we achieved chemoselective formation of 4a by using CH3CN 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 1−6). In the cases of aliphatic aldimine (2g) and ketimine (2h), the corresponding fluoroaziridine products were not observed by 19F NMR spectroscopy (entries 7 and 8). The substituents on the nitrogen (R1) did not affect this reaction essentially (entries 9−12). 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.

Table 2

Scope and limitations of Reformatsky-type aza-Darzens reaction

Entry	2				19F NMR yield of 4 (%)	Dr of 4a (syn:anti)
	R1	R2	R3
1	Bn–	Ph–	H–	2a	Quant.	85:15
2	Bn–	4-Cl–C6H4–	H–	2b	91	85:15
3	Bn–	4-CF3–C6H4–	H–	2c	94	83:17
4	Bn–	4-MeOCO–C6H4–	H–	2d	94	81:19
5	Bn–	4-MeO–C6H4–	H–	2e	Quant.	87:13
6	Bn–	4-Me–C6H4–	H–	2f	93	83:17
7	Bn–	PhCH2CH2–	H–	2g	ND	—
8	Bn–	Ph–	Me–	2h	ND	—
9b	Me–	Ph–	H–	2i	70	72:28
10	Benzhydryl–	Ph–	H–	2j	28	84:16
11c	Benzhydryl–	Ph–	H–	2j	60	83:17
12	Ph–	Ph–	H–	2k	85	100:0

Determined by 19F NMR.

The reaction was carried out for 28 h.

The reaction was carried out for 48 h.

However, these fluorinated aziridine compounds (4) were not so stable as that reported for fluorinated epoxides. So 4 must be stored at −30 °C to avoid their decomposition. Especially, syn-isomers 4 were less stable than anti-isomers. Therefore their yields and diastereoratios were determined by 19F 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 α-bromo-α-fluoro-β-lactams by Et2Zn-promoted Reformatsky-type reaction of 1 with imine in Et2O. 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 Et2O 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. On the other hand, the strongly coordinating solvent, CH3CN, 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 solvent 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 Et2Zn and Et2O as a solvent in the presence of PPh3 which must be a better monovalent ligand than CH3CN. 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.

Figure 1

Tentative mechanism for the diastereoselective outcome.

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 CH3CN. Now, we are planning the synthesis of bioactive compounds with fluorinated aziridine ring and the ring-opening reaction of 4 for the synthesis of α-fluoro-α- or β-amino acids.