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. 2022 Jun 11;13(27):8080-8087.
doi: 10.1039/d2sc00046f. eCollection 2022 Jul 13.

An umpolung strategy for intermolecular [2 + 2 + 1] cycloaddition of aryl aldehydes and nitriles: a facile access to 2,4,5-trisubstituted oxazoles

Deevi Basavaiah  1 , Gangadhararao Golime  1 , Shivalal Banoth  1 , Saidulu Todeti  1
Affiliations

An umpolung strategy for intermolecular [2 + 2 + 1] cycloaddition of aryl aldehydes and nitriles: a facile access to 2,4,5-trisubstituted oxazoles

Deevi Basavaiah et al. Chem Sci. .

Abstract

We have described the first example of an umpolung strategy for intermolecular [2 + 2 + 1] cycloaddition between two aryl aldehydes and a nitrile under the influence of TMSOTf that proceeds through the formation of N-C, O-C and C-C bonds providing a simple synthetic protocol for obtaining 2,4,5-trisubstituted oxazoles.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1. Strategies for oxazoles via [2 + 2 + 1] cycloadditions.
Scheme 2
Scheme 2. Our hypothesis: competing cycloaddition reactions.
Scheme 3
Scheme 3. Synthesis of oxazoles (3): substrate scopea,b. aReaction conditions: all reactions were carried out with carboxaldehyde (1) (1 mmol), nitrile (2) (2 mmol), and TMSOTf (1.5 mmol) in n-PrOAc (2 mL) under reflux (oil bath temperature 120 °C) for 2–8 h. bIsolated yields (based on carboxaldehyde). cRemaining starting materials recovered. dThis reaction was performed with quinoline-2-carboxaldehyde.
Scheme 4
Scheme 4. 13C NMR carbonyl chemical shifts of 1a, 1e, pyridine-4-carboxaldehyde and benzaldehyde and their TMSOTf salts/complex.
Scheme 5
Scheme 5. Synthesis of mixed oxazoles (5): substrate scopea,b. aReaction conditions: all reactions were carried out with carboxaldehyde (1) (1 mmol), aryl aldehyde (4) (2 mmol), nitrile (2) (3 mmol), and TMSOTf (1.5 mmol) in n-PrOAc (2 mL) under reflux (oil bath temperature 120 °C) for 2–6 h. Other oxazoles (3) were not isolated as they were obtained in minor amounts (less than 10%). bIsolated yields [based on carboxaldehyde (1)]. cOther possible oxazoles (3) were not observed in these reactions.
Scheme 6
Scheme 6. Scope of aliphatic nitrilesa,b. aReaction conditions: all reactions were carried out with carboxaldehyde 1 (1 mmol). bIsolated yields (based on 1). cAcetonitrile was also used as a solvent (2 mL) under reflux (oil bath temperature 120 °C) for 24 h. dn-Propyl acetate was used as a solvent for the reaction of 1a with acetonitrile (4 mmol).
Scheme 7
Scheme 7. Scale up experiments. Reaction conditions are the same as Scheme 3 and 5, respectively.
Scheme 8
Scheme 8. HRMS mechanistic studies: observed intermediates. [obsd = observed, calcd = calculated].
Scheme 9
Scheme 9. Plausible mechanistic pathways for the formation of oxazoles 3 and 5.
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