Table of Contents
Organic Chemistry International
Volume 2010 (2010), Article ID 452956, 3 pages
Research Article

Directed Metalation of Heterocycles, 5-Methoxy-2-phenyloxazol-4-yllithium: An Approach to , -Dehydroamino Acids

Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India

Received 1 July 2009; Accepted 16 September 2009

Academic Editor: Kirpal Bisht

Copyright © 2010 Sosale Chandrasekhar and Malempati Srimannarayana. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


5-Methoxy-2-phenyloxazole was deprotonated at (by -BuLi or LDA, in THF at −78 ). The resulting anion was generally unreactive to alkylation (except methylation with MeI-TMEDA) but added to PhCHO and CHCHO. The alcohols thus produced dehydrated and ring opened in acid, to the corresponding , -dehydroamino acids in moderate overall yields.

1. Introduction

Directed metalation (sometimes also “ortho-metalation’’) is now firmly established as an important synthetic strategy in aromatic chemistry [1]. This involves deprotonation at a site ortho to a directing group such as OMe or NMe2; this is assisted either by coordination of the counterion of the attacking base with the heteroatom lone pairs, or by electron withdrawal by the heteroatoms (or both). Thus, the formation of the anionic product is facilitated both kinetically and thermodynamically, with its subsequent electrophilic reactions leading to products not easily accessed otherwise.

Interestingly, however, heteroaromatic examples of directed metalation have been relatively scarce [2]. In particular, we have been interested in the possibility that the analogous reaction in the case of 5-methoxy-2-phenyloxazole (1 → I, Scheme 1) would define a novel approach to α-amino acids, via hydrolysis of the resulting substituted derivatives (Scheme 1). The 5-methoxy group would then not only function as a directing group but also maintain as a masked carboxyl centre. We report in what follows preliminary results from our study.

Scheme 1: The directed metalation strategy as applied to 5-methoxy-2-phenyloxazole (1), shown reacting with n-BuLi to form the oxazolyllithium I; this reacted with D2O to form 2a (R = D, 88%) and with MeI-TMEDA to form 2b (R = Me, 63%).

2. Results and Discussion

5-Methoxy-2-phenyloxazole (1) [3, 4] was treated with an equivalent of n-butyllithium (n-BuLi) in THF at for 3 hours, and the reaction mixture quenched with D2O. 1H NMR showed evidence of deuterium incorporation (88%), as seen by the disappearance of the H resonance at δ 5.80 (cf. 2a). When the deprotonation was followed by treatment with methyl iodide, no reaction was observed; however, when the methylation was conducted in the presence of one equivalent of N,N, , -tetramethylethylenediamine (TMEDA, to /3 h), 5-methoxy-4-methyloxazole (2b) was formed in 63% yield. These reactions also occurred in lower yields with lithium diisopropylamide (LDA, vide infra) as base [5].

These results clearly indicate the formation and intermediacy of 5-methoxy-2-phenyloxazol-4-yllithium (I). Intriguingly, however, this did not react with longer chain alkylating agents, for example, n-BuI, n-C7H15Br, PhCH2Br, and allyl bromide. (I could also be generated with LDA and methylated with MeI and added hexamethylphosphoramide (HMPA).) It seems likely that TMEDA and HMPA act by chelating the lithium counterion of I, thus breaking down aggregates into more reactive monomeric and dimeric forms.

However, the oxazolyllithium I was found to add to benzaldehyde and iso-butyraldehyde to furnish the expected alcohols 3, in moderate yields (Scheme 2). Interestingly, 3 underwent rearrangement with ring cleavage and hydrolysis in dilute acid, to form the corresponding N-benzoyl α,β-dehydroamino acids 5 in fair yields [5].

Scheme 2: Addition of the oxazolyllithium I to benzaldehyde and iso-butyraldehyde to form the alcohols 3, and their acid catalyzed rearrangement, ring cleavage, and hydrolysis to furnish the corresponding N-benzoyl dehydroamino acids 5.

A probable mechanism is shown, with the double bond geometry in 5 being known to be variable [6, 7]. (The corresponding esters 4 were isolated and characterized spectrally. 4-Alkylideneoxazol-5-ones reportedly fragment similarly [8].) Dehydroamino acids have gained importance in recent times, particularly as immediate precursors for homochiral amino acids [9, 10].

2.1. Experimental: General Remarks

are in cm-1 and are in Hz; were recorded at 300 MHz and at 75 MHz. Metalation and methylation of oxazole 1. A stirred mixture of n-BuLi (1.6 mmol in 1.0 mL hexane) and TMEDA (1.6 mmol) at was treated dropwise with a solution of the oxazole [3, 4] (1 mmol in 3.0 mL THF). After 3 hours the mixture was warmed to , treated with MeI (1.6 mmol), and allowed to reach room temperature. Work-up with EtOAc and satd. NH4Cl, followed by chromatography (SiO2 eluting with 20% EtOAc-hexane), led to the 4-Me derivative 1b (63%); 1663; 2.12 (s, 3H), 3.99 (s, 3H), 7.37–7.44 (m, 3H), 7.89–7.93 (m, 2H); 10.1, 61.1, 113.1, 125.3, 127.7, 128.6, 129.4, 152.0, 155.0; HRMS 190.0856 (Calcd. for C11H11NO2 + H 190.0868). iso-Butyraldehyde adduct 3b: 3410, 2957, 1654; 0.88 (d, 3H, J 6.6), 1.07 (d, 3H, J 6.6), 2.09–2.16 (m, 1H), 2.53–2.55 (m, 1H), 4.00 (s, 3H), 4.26–4.31 (m, 1H), 7.38–7.41 (m, 3H), 7.89–7.91 (m, 2H); 18.3, 18.8, 33.6, 60.8, 71.4, 118.3, 125.5, 128.6, 129.6, 152.2, 154.7; HRMS 270.1110 (Calcd. for C14H17NO3 + Na 270.1106). N-Benzoyl 2-amino-4-methylpent-2-enoic acid (5b): 3267, 1697, 1640; 1.09 (d, 6H, J 6.6), 2.60–2.80 (m, 1H), 6.73 (d, 1H, J 10.5), 7.44–7.54 (m, 3H), 7.79–7.87 (m, 2H); 21.5, 28.4, 122.8, 127.4, 128.6, 132.0, 132.2, 133.8, 147.2, 166.4, 168.9, 170.8; HRMS 256.0960 (Calcd. for C13H15NO3 + Na 256.0950).

3. Conclusions

We have demonstrated the feasibility of the directed metalation strategy in the case of a heterocycle that is a potential amino acid synthon. The resulting carbanion is generally unreactive towards several alkylating agents (except MeI). However, addition to aldehydes, followed by rearrangement and hydrolysis in acid, led to α,β-dehydroamino acids in fair yields in two cases.


The authors are grateful to CSIR (New Delhi) for generous fellowship support to the second author.


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