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Synthesis of fluorinated 3-aminobenzofurans via a tandem SNAr-cyclocondensation strategy

Synthesis of fluorinated 3-aminobenzofurans via a tandem SNAr-cyclocondensation strategy
Synthesis of fluorinated 3-aminobenzofurans via a tandem SNAr-cyclocondensation strategy

A small library of twenty-seven novel 3-amino-2,6-disubstituted-4,5,7-trifluorobenzofurans was successfully synthesized with the compounds formed in low to good yield using a tandem SNAr-cyclocondensation reaction of 4-substituted perfluorobenzonitriles with α-hydroxycarbonyl compounds employing DBU as base. The compounds were prepared as part of a medicinal chemistry project to develop novel fluorinated heterocyclic leads and were characterised by 1H and 19F NMR spectroscopy, IR spectroscopy, high resolution mass spectrometry and elemental analysis. The X-ray crystal structure of the 2-(4-methoxybenzoyl)-6-morpholino derivative was determined, which showed the benzoyl substituent to be coplanar with the benzofuran ring, and to form a hydrogen bond to the 3-amino group. Attempts to synthesise the corresponding 3-unsubstituted or 3-methyl analogues using 4-substituted perfluoro-benzaldehydes or acetophenones were unsuccessful, with cleavage of the carbonyl group occurring. A mechanistic study indicated that alkoxide ions attacked the carbonyl group, rather than effecting SNAr reaction at C-2, leading to loss of a perfluoroaryl anion which was trapped with D2O.

2046-2069
12843-12853
Tawell, Hugh W.
b01f9503-6673-4dbd-9abe-f937578a86a6
Robinson, William
70e92a47-f8cd-4d4c-b6f5-26bd53783705
Li, Yuqi
9d3ea352-22b9-4001-9300-b5665d2af7d5
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Bhambra, Avninder S.
9c6f085c-ccd8-42f7-b466-d5ddf1950659
Edgar, Mark
3269c739-ee0e-4e87-9129-c2e66e751297
Weaver, George W.
ef47d65f-d1fa-41c1-8d51-f3a48065ff6a
Tawell, Hugh W.
b01f9503-6673-4dbd-9abe-f937578a86a6
Robinson, William
70e92a47-f8cd-4d4c-b6f5-26bd53783705
Li, Yuqi
9d3ea352-22b9-4001-9300-b5665d2af7d5
Tizzard, Graham J.
8474c0fa-40df-43a6-a662-7f3c4722dbf2
Coles, Simon J.
3116f58b-c30c-48cf-bdd5-397d1c1fecf8
Bhambra, Avninder S.
9c6f085c-ccd8-42f7-b466-d5ddf1950659
Edgar, Mark
3269c739-ee0e-4e87-9129-c2e66e751297
Weaver, George W.
ef47d65f-d1fa-41c1-8d51-f3a48065ff6a

Tawell, Hugh W., Robinson, William, Li, Yuqi, Tizzard, Graham J., Coles, Simon J., Bhambra, Avninder S., Edgar, Mark and Weaver, George W. (2025) Synthesis of fluorinated 3-aminobenzofurans via a tandem SNAr-cyclocondensation strategy. RSC Advances, 15 (16), 12843-12853. (doi:10.1039/d5ra02024g).

Record type: Article

Abstract

A small library of twenty-seven novel 3-amino-2,6-disubstituted-4,5,7-trifluorobenzofurans was successfully synthesized with the compounds formed in low to good yield using a tandem SNAr-cyclocondensation reaction of 4-substituted perfluorobenzonitriles with α-hydroxycarbonyl compounds employing DBU as base. The compounds were prepared as part of a medicinal chemistry project to develop novel fluorinated heterocyclic leads and were characterised by 1H and 19F NMR spectroscopy, IR spectroscopy, high resolution mass spectrometry and elemental analysis. The X-ray crystal structure of the 2-(4-methoxybenzoyl)-6-morpholino derivative was determined, which showed the benzoyl substituent to be coplanar with the benzofuran ring, and to form a hydrogen bond to the 3-amino group. Attempts to synthesise the corresponding 3-unsubstituted or 3-methyl analogues using 4-substituted perfluoro-benzaldehydes or acetophenones were unsuccessful, with cleavage of the carbonyl group occurring. A mechanistic study indicated that alkoxide ions attacked the carbonyl group, rather than effecting SNAr reaction at C-2, leading to loss of a perfluoroaryl anion which was trapped with D2O.

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Accepted/In Press date: 11 April 2025
Published date: 22 April 2025

Identifiers

Local EPrints ID: 502079
URI: http://eprints.soton.ac.uk/id/eprint/502079
ISSN: 2046-2069
PURE UUID: 2a9c8d2e-99b5-47f3-b575-5731025f3574
ORCID for Graham J. Tizzard: ORCID iD orcid.org/0000-0002-1577-5779
ORCID for Simon J. Coles: ORCID iD orcid.org/0000-0001-8414-9272

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Date deposited: 16 Jun 2025 16:41
Last modified: 22 Aug 2025 01:48

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Contributors

Author: Hugh W. Tawell
Author: William Robinson
Author: Yuqi Li
Author: Simon J. Coles ORCID iD
Author: Avninder S. Bhambra
Author: Mark Edgar
Author: George W. Weaver

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