Domino gold-catalyzed rearrangement and fluorination of propargyl acetates

Article abstract of DOI:10.1039/c002679d

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,

Full text of DOI:10.1039/c002679d

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Domino gold-catalyzed rearrangement and fluorination of propargyl
acetatesw
Teresa de Haro and Cristina Nevado*
Received 10th February 2010, Accepted 28th May 2010
DOI: 10.1039/c002679d
A combination of IPrAuNTf2 as catalyst in the presence of
Selectfluor has been successfully used for the high yielding
synthesis of a-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.
Table 1 Study of the reaction scopea
Yield
(%)b
Entry Substrate
1
Product
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 a-fluoroenones. Despite their synthetic potential
as Michael acceptors or as precursors of peptidomimetics,7a
only a few methods to prepare a-fluoroenones are known.7b–c
Acetate 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)).
1a
1b
2a
2b
77
2
84c
3
4
5
1c (n = 1)
1d (n = 2)
1e (n = 3)
2c (n = 1)
2d (n = 2)
2e (n = 3)
82
71
87
6
1f (R = nHex)
2f (R = nHex) 79
1g (R =
1-cyclopropyl)
1h (R = Ph)
2g (R =
57
7
8
1-cyclopropyl)
2h (R = Ph) 81
9
5a
5b
6a
6b
71d,e
10
72d,e
a
Standard reaction conditions: IPrAuNTf2 (5 mol%), Selectfluor
(2 eq.), 20 : 1 CH3CN–H2O as solvent (substrate concentration
b
0.02 M), 80 1C, 20 min. Isolated yield after column chromato-
graphy. 1.5 : 1 E : Z ratio. As standard conditions but stirred for
c
d
e
2 h, substrate concentration 0.1 M. 4 : 1 E : Z ratio.
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
a-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).
ð1Þ
We then decided to explore the scope of this transformation.
First, we focused on propargyl acetates derived from ketones,
Organic Chemistry Institute, University of Zurich, Winterthurerstrasse
¨
190 Switzerland. E-mail: nevado@oci.uzh.ch; Tel: +41 4463 53975
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of products. See DOI: 10.1039/
c002679d
ꢀc
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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 propargyl
acetate 5c afforded not only the isomeric a-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 Ca of the ketone (II) through the
Csp3–Au bond.
of V could deliver a,b-unsaturated ketones (VIII), or trans-
metallation 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.
In summary, we present here a novel and efficient method to
synthesize a-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.
2 (a) K. L. Hull, W. Q. Anani and M. S. Sanford, J. Am. Chem. Soc.,
2006, 128, 7134; (b) T. Furuya, H. M. Kaiser and T. Ritter, Angew.
Chem., Int. Ed., 2008, 47, 5993; (c) D. A. Watson, M. Su,
G. Teverovskiy, Y. Zhang, J. Garcı
S. L. Buchwald, Science, 2009, 325, 1661.
´
a-Fortanet, T. Kinzel and
ð2Þ
3 J. A. Akana, K. X. Bhattacharyya, P. Muller and J. P. Sadighi,
¨
J. Am. Chem. Soc., 2007, 129, 7736.
Our mechanistic proposal for the formation of a-fluoroenones
has been outlined in Scheme 1. Upon gold coordination, the
complex III undergoes a [3,3]-sigmatropic rearrangement of
the acyloxy moiety affording allene IV, which according to
previously reported DFT calculations, features gold coordinated
to the external double bond of the allene.11 Hydrolysis 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
a-fluorenones VII.13 As competing pathways, protonolysis
4 M. Schuler, F. Silva, C. Bobbio, A. Tessier and V. Gouverneur,
Angew. Chem., Int. Ed., 2008, 47, 7927.
5 (a) S. F. Kirsch, J. T. Binder, B. Crone, A. Duschek, T. T. Haug,
C. Liebert and H. Menz, Angew. Chem., Int. Ed., 2007, 46, 2310;
´
(b) A. Buzas and F. Gagosz, Org. Lett., 2006, 8, 515; (c) M. Yu,
G. Zhang and L. Zhang, Org. Lett., 2007, 9, 2147; (d) M. Yu,
G. Zhang and L. Zhang, Tetrahedron, 2009, 65, 1846; (e) Z. Shi
and C. He, J. Am. Chem. Soc., 2004, 126, 13596.
6 (a) X. Huang, T. De Haro and C. Nevado, Chem.–Eur. J., 2009,
15, 5904; (b) Y. Zou, D. Garayalde, Q. Wang, C. Nevado and
A. Goeke, Angew. Chem., Int. Ed., 2008, 47, 10110.
7 (a) G. Dutheuil, S. Couve-Bonnaire and X. Pannecoucke, Angew.
Chem., Int. Ed., 2007, 46, 1290; (b) Dutheuil, S. Couve-Bonnaire
and X. Pannecoucke, Tetrahedron, 2009, 65, 6034 and references
therein; (c) A. K. Ghosh, S. Banerjee, S. Sinha, S. B. Kang and
B. Zajc, J. Org. Chem., 2009, 74, 3689.
8 For full experimental details, see the ESIw.
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. Lemiere, A. Hours, L. Fensterbank and
M. Malacria, Angew. Chem., Int. Ed., 2008, 47, 7534;
(c) D. Garayalde, E. Gomez-Bengoa, X. Huang, A. Goeke 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. Muniz, 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 E 5 kcal molꢁ1, with the
Z isomer being the thermodynamically more stable.
Scheme 1 Proposed mechanistic pathway.
ꢀc
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 248–249 | 249