[1772-43-6]  · C6H11NO  · 2,4,4-Trimethyl-2-oxazoline  · (MW 113.18)

(a masked ethyl acetate equivalent; generation of the anion with n-BuLi followed by treatment with electrophiles affords homologated acetic acids and esters, b-hydroxy esters, b-keto esters, a,b-unsaturated esters, and g-butyrolactones1)

Alternate Name: 4,5-dihydro-2,4,4-trimethyloxazole.

Physical Data: bp 112-113 °C.

Form Supplied in: commercially available.

Preparative Method: can be prepared by the thermal condensation (98-110 °C) of acetic acid and 2-amino-2-methyl-1-propanol in 73% yield (eq 1).2

Handling, Storage, and Precautions: no special precautions are warranted.

Preparation of Analogs.

Other 2-substituted oxazolines can be prepared in a similar fashion to the preparation of the title reagent, from the appropriate carboxylic acid. Substituted oxazolines can be formed under milder conditions by cyclocondensations with the corresponding orthoesters (DMF, 110 °C) or imino ether hydrochlorides (MeOH, 0 °C).3 2-Alkyl- and 2-aryl-4,4-dimethyl-2-oxazolines may also be prepared by rearrangement of N-acyl-2,2-dimethylaziridines.2b


Lithiation of the C-2 methyl group of the title compound occurs with n-Butyllithium. Treatment of the resulting anion with electrophiles forms substituted oxazolines (eq 2). One of the remaining methylene protons from the same position can be abstracted in a similar fashion and the resulting anion alkylated again. Subsequently, the mono- or dialkylated oxazoline can be easily transformed to the corresponding carboxylic acid or ethyl ester. Thus the title compound functions as an acetic acid synthon. Some illustrative examples of this methodology are listed in Table 1.3,5-8 This protocol has been used to synthesize radiolabelled amino acids.4

The initial 2-alkylated 4,4-dimethyl-2-oxazoline can also be prepared directly from homologs of acetic acid. a-Branching substituents can then be introduced by alkylation of the 2-alkyloxazoline. Thus n-butyric acid is converted to the desired oxazoline by condensation with 2-amino-2-methyl-1-propanol in 88% yield (eq 3).3 The standard protocol of metalation, electrophile addition, and oxazoline hydrolysis affords the 2-substituted butyric acid in 61% yield (eq 3).3 Since hydrolysis of the N-methylated heterocycle can be carried out under basic conditions, acid-labile groups such as the 1,3-dioxolane can be incorporated into the carboxylic acid product.

The stability of the anion of 2,4,4-trimethyl-2-oxazoline allows efficient alkylation with epoxides to form, after oxazoline hydrolysis, the corresponding g-butyrolactone or g-hydroxy acids (Table 2).9,10

Aldol Condensations.

The lithiated title reagent also adds cleanly to aldehydes and ketones. Acidic hydrolysis of the oxazoline gives a mixture of the a,b- and b,g-unsaturated acids or esters (eqs 4 and 5).3,5,11 When the hydrolysis is performed with lower concentrations of acid, it is possible to isolate the b-hydroxy ester (eq 4).5

The lithiated oxazoline can also be used as an enol acetate equivalent in the aldol reaction.12 The chiral sulfoxide (entry 5, Table 1), prepared from 2,4,4-trimethyl-2-oxazoline, has been used in the aldol reaction as an enol acetate equivalent, albeit with moderate enantiomeric enrichment (ee <= 53%).7

Acylation Reactions.

In addition, the lithium anion of 2,4,4-trimethyl-2-oxazoline undergoes C- and N-acylation with acid chlorides.13 Further alkylation leads to a stable enol, which is a masked b-keto acid or ester (eq 6). These oxazoline enols are also accessible from the reaction of 2-alkylated 4,4-dimethyl-2-oxazolines with acid anhydrides in the presence of AlCl3/Et3N/MeCN followed by treatment with KOH/MeOH.14

Addition of the lithio anion to nitriles forms the corresponding enamino oxazolines (eq 7).15,16

1,3-Dipolar Cycloadditions of Oxazoline N-oxides.

The N-oxide of 2,4,4-trimethyl-2-oxazoline has been utilized in [3 + 2] cycloadditions (eq 8).17

Asymmetric [3 + 2] cycloadditions have been accomplished by utilizing the N-oxides of chiral oxazolines.18

Carboxyl Protection.

2-Alkyl-2-oxazolines can also serve as protected forms of esters and carboxylic acids19 because they are resistant to attack by Grignard reagents5 and Lithium Aluminum Hydride.20 The oxazolines can be converted to ethyl esters (3 M HCl, EtOH) or carboxylic acids (MeI, 25 °C; 1 M NaOH, 25 °C).19

Related Reagents.

5,6-Dihydro-2,4,4,6-tetramethyl-1,3(4H)-oxazine; Dilithioacetate; Ethyl Lithioacetate; 2-(o-Methoxyphenyl)-4,4-dimethyl-2-oxazoline; Methoxy(phenylthio)trimethylsilylmethane; 2-Methylbenzothiazole; 2-Methyl-2-thiazoline; N,4,4-Trimethyl-2-oxazolinium Iodide.

1. (a) Gant, T. G.; Meyers, A. I. T 1994, 50, 2297. (b) Reuman, M.; Meyers, A. I. T 1985, 41, 837.
2. (a) Allen, P.; Ginos, J. JOC 1963, 28, 2759. (b) Meyers, A. I.; Temple, D. L., Jr.; Nolen, R. L.; Mihelich, E. D. JOC 1974, 39, 2778.
3. Meyers, A. I.; Knaus, G.; Kamata, K.; Ford, M. E. JACS 1976, 98, 567.
4. Yuan, S.-S. J. Labelled Comp. Radiopharm. 1983, 20, 173.
5. Meyers, A. I.; Temple, D. L., Jr. JACS 1970, 92, 6644.
6. Oehlschlager, A. C.; Wong, J. W.; Verigin, V. G.; Pierce, H. D. JOC 1983, 48, 5009.
7. Annunziata, R.; Cinquini, M.; Gilardi, A. S 1983, 1016.
8. Meyers, A. I.; Mihelich, E. D.; Kamata, K. CC 1974, 768.
9. Meyers, A. I.; Mihelich, E. D.; Nolen, R. L. JOC 1974, 39, 2783.
10. San Feliciano, A.; Medarde, M.; Caballero, E.; Hebrero, M. B.; Tome, F.; Prieto, P.; Montero, M. J. Eur. J. Med. Chem. 1990, 25, 413.
11. Shibata, S.; Matsushita, H.; Kato, K.; Kaneko, H.; Noguchi, M.; Saburi, M.; Yoshikawa, S. ABC 1981, 45, 315.
12. Meyers, A. I.; Walkup, R. D. T 1985, 41, 5089.
13. Tohda, Y.; Kawashima, T.; Ariga, M.; Akiyama, R.; Shudoh, H.; Mori, Y. BCJ 1984, 57, 2329.
14. Tohda, Y.; Morikawa, M.; Kawashima, T.; Ariga, M.; Mori, Y. CL 1986, 273.
15. Fustero, S.; Díaz, M. D.; Barluenga, J.; Aguilar, E. TL 1992, 33, 3801.
16. Poindexter, G. S.; Catt, J. D.; Sasse, P. A.; Kercher, M. A. H 1993, 36, 295.
17. (a) Ashburn, S. P.; Coates, R. M. JOC 1985, 50, 3076. (b) Kobayakawa, M.; Langlois, Y. TL 1992, 33, 2353. (c) Hisano, T.; Harano, K.; Matsuoka, T.; Watanabe, S.; Matsuzaki, T. CPB 1989, 37, 907.
18. Bérranger, T.; André-Barrès, C.; Kobayakawa, M.; Langlois, Y. TL 1993, 34, 5079.
19. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991; p 265-266.
20. Haidukewych, D.; Meyers, A. I. TL 1972, 3031.

Todd D. Nelson & Albert I. Meyers

Colorado State University, Fort Collins, CO, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.