Domino gold-catalyzed rearrangement and fluorination of propargyl acetates

Abstract

A combination of IPrAuNTf₂ as catalyst in the presence of Selectfluor has been successfully used for the high yielding synthesis of α-fluoroenones via 1,3-acyloxy rearrangement of propargyl acetates followed by Csp²–F bond formation, likely involving a redox Au(I)/Au(III) catalytic cycle.

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The efficient formation of C–F bonds represents a major challenge in organic and organometallic chemistry.¹ In recent years catalytic methods have been developed, usually involving electrophilic fluorinating reagents and/or specific directing groups in the substrate with Pd as catalyst.² Gold-complexes have also been used in catalytic fluorinations, as independently reported by the groups of Sadighi and Governeur. While Sadighi’s group has focused on the hydrofluorination of alkynes,³ Governeur has used the fluorodeauration of vinyl gold species to create new Csp²–F bonds, although the competitive formation of Csp²–H bonds could not be avoided.⁴ Additionally, vinyl-gold species have proved to efficiently form Csp²–Br and Csp²–I bonds in a catalytic fashion.⁵ Based on our previous experience in the gold-catalyzed rearrangement of propargyl acetates,⁶ we decided to explore the reactivity of these motifs in the presence of different fluorinating agents combining the “alkynophilicity” of Au(I) complexes with a redox Au(I)/Au(III) catalytic cycle to establish a new C–F bond upon acyloxy migration to give α-fluoroenones. Despite their synthetic potential as Michael acceptors or as precursors of peptidomimetics,^7a only a few methods to prepare α-fluoroenones are known.^7b–cAcetate 1a was prepared and used as the benchmark substrate. After some optimization,⁸ we found that the ligand bound to gold plays a key role in the formation of the undesired homocoupling (3a)⁹ and/or protonated products (4a). In contrast to Ph₃P, the use of a bulky N-heterocyclic ligand such as 1,3-bis(2,6-diiso-propylphenyl)-imidazol-2-ylide, afforded the fluorinated product 2a with complete conversion and excellent selectivity (eqn (1)).We then decided to explore the scope of this transformation. First, we focused on propargyl acetates derived from ketones, as summarized in Table 1. Under the previously optimized conditions, 1a afforded the desired fluorinated product (2a) in 77% isolated yield (Table 1, entry 1). The substrate derived from acetophenone (1b) delivered the corresponding α-fluoroenone 2b in 84% yield as a 1.5 : 1 mixture of E : Z isomers (Table 1, entry 2).⁸ Substrates derived from cyclic ketones such as 1c, 1d and 1e reacted smoothly in the presence of IPrAuNTf₂ delivering the correponding fluorinated products (2c–e) in 82, 71 and 87% yield, respectively (Table 1, entries 3–5). We also explored the substitution pattern in the alkyne moiety. A longer alkylic chain (1f) was well accommodated under these conditions (Table 1, entry 6). The presence of a cyclopropyl group (1g) was also tolerated, although partial decomposition of 2g could not be avoided during the purification process (Table 1, entry 7). Phenyl substituted alkyne 1h smoothly reacted to give fluorinated ketone 2h in 81% yield (Table 1, entry 8). Secondary acetates (5a, 5b) reacted efficiently by increasing the concentration and the reaction time (Table 1, entries 9 and 10). In these cases, the E isomer was the major product detected in the reaction mixtures. Interestingly, p-methoxyphenyl substituted propargylacetate 5c afforded not only the isomeric α-fluoroenones 6c (2 : 1 Z : E ratio), but also bis-fluorinated compound 7 isolated in 26% yield (eqn (2)).^4,10 Reactivation of the double bond in 6c by Au(I) or Au(III) present in the reaction mixture could trigger the nucleophilic attack of water (I), followed by fluorination at the C_α of the ketone (II) through the Csp³–Au bond.

Table 1 Study of the reaction scope^a

Entry	Substrate		Product		Yield(%)^b
a Standard reaction conditions: IPrAuNTf2 (5 mol%), Selectfluor (2 eq.), 20 : 1 CH3CN–H2O as solvent (substrate concentration 0.02 M), 80 °C, 20 min. b Isolated yield after column chromatography. c 1.5 : 1 E : Z ratio. d As standard conditions but stirred for 2 h, substrate concentration 0.1 M. e 4 : 1 E : Z ratio.
1		1a		2a	77
2		1b		2b	84^c
3		1c (n = 1)		2c (n = 1)	82
4		1d (n = 2)		2d (n = 2)	71
5		1e (n = 3)		2e (n = 3)	87
6		1f (R = nHex)		2f (R = nHex)	79
7		1g (R = 1-cyclopropyl)		2g (R = 1-cyclopropyl)	57
8		1h (R = Ph)		2h (R = Ph)	81
9		5a		6a	71^d^,^e
10		5b		6b	72^d^,^e

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Our mechanistic proposal for the formation of α-fluoroenones has been outlined in Scheme 1. Upon gold coordination, the complex III undergoes a [3,3]-sigmatropic rearrangement of the acyloxy moiety affording alleneIV, which according to previously reported DFT calculations, features gold coordinated to the external double bond of the allene.¹¹Hydrolysis of the acetoxy moiety in the aqueous media will deliver vinyl-gold(I) species V while releasing acetic acid, which can be neutralized in the presence of base (NaHCO₃). In the presence of a strong oxidant such as Selectfluor, oxidation of Au(I) to Au(III) can occur, affording complex VI.¹² Reductive elimination in VI will deliver the new Csp²–F bond and the observed α-fluorenones VII.¹³ As competing pathways, protonolysis of V could deliver α,β-unsaturated ketones (VIII), or transmetallation between V and VI could afford the homocoupling products IX (Scheme 1, green pathways).⁹ Under the standard reaction conditions, E-6a,6b did not isomerize to the thermodynamically more stable Z-isomers,¹⁴ thus indicating that the step defining the stereochemistry of the enone must be under kinetic control.

Scheme 1 Proposed mechanistic pathway.

In summary, we present here a novel and efficient method to synthesize α-fluoroenones based on a domino gold-catalyzed process starting from easily available propargyl acetates. The known tendency of Au(I)-complexes to activate alkynes triggers the 1,3-migration of the acyloxy moiety onto the triple bond delivering vinyl-Au(I) intermediates, which can be oxidized in the presence of Selectfluor to form Au(III) species prone to reductive elimination to give Csp²–F bonds. Further studies on the reaction mechanism and applications of this method to other substrates are currently ongoing.

Notes and references

1. (a) Modern Fluoroorganic Chemistry: Synthesis Reactivity Applications, Wiley-VCH, Weinheim, 2004; (b) Organo-Fluorine Compounds. Methods of Organic Chemistry, Houben-Weyl, E10, Thieme Verlag, Stuttgart, 1999.
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3. J. A. Akana, K. X. Bhattacharyya, P. Müller and J. P. Sadighi, J. Am. Chem. Soc., 2007, 129, 7736.
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8. For full experimental details, see the ESI†.
9. L. Cui, G. Zhang and L. Zhang, Bioorg. Med. Chem. Lett., 2009, 19, 3884.
10. Under the standard reaction conditions 6c was quantitatively transformed in 7.
11. For an in depth computational study on similar intermediates, see: (a) A. Correa, N. Marion, L. Fensterbank, M. Malacria, S. P. Nolan and L. Cavallo, Angew. Chem., Int. Ed., 2008, 47, 718; (b) V. Gandon, G. Lemière, A. Hours, L. Fensterbank and M. Malacria, Angew. Chem., Int. Ed., 2008, 47, 7534; (c) D. Garayalde, E. Gómez-Bengoa, X. Huang, A. Göeke and C. Nevado, J. Am. Chem. Soc., 2010, 132, 4720.
12. (a) H. A. Wegner, S. Ahles and M. Neuenburg, Chem.–Eur. J., 2008, 14, 11310; (b) G. Zhang, Y. Peng, L. Cui and L. Zhang, Angew. Chem., Int. Ed., 2009, 48, 3112; (c) G. Zhang, L. Cui, Y. Wang and L. Zhang, J. Am. Chem. Soc., 2010, 132, 1474; (d) A. Iglesias and K. Muñiz, Chem.–Eur. J., 2009, 48, 9346.
13. Fluorodeauration of the vinylic Csp²–Au(I) bond in the presence of “F⁺” can not be ruled out.
14. Semiempirical calculations (PM3 level), showed an energy difference between the E and Z isomers ≈ 5 kcal mol⁻¹, with the Z isomer being the thermodynamically more stable.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization of products. See DOI: 10.1039/c002679d

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