DOI: 10.1002/chem.201303920
Communication
& Asymmetric Synthesis
Highly Enantioselective Copper(I)-Catalyzed Conjugate Addition of Terminal Alkynes to 1,1-Difluoro-1-(phenylsulfonyl)-3-en-2ones: New Ester/Amide Surrogates in Asymmetric Catalysis Amparo Sanz-Marco, Andrea Garca-Ortiz, Gonzalo Blay,* Isabel Fernndez, and Jos R. Pedro*[a] have been reported by using Cu,[5] Rh,[6] Co,[7] Ru (one example with 82 % ee),[8] and Pd (two examples with 39 and 38 % ee)[9] catalysts. Despite these advances, there are still some limitations regarding the enantioselectivity and the substrate or alkyne scope. In particular, the possibility to chemically manipulate the electron-withdrawing group that activates the double bond would be very convenient. Moreover, in the case of the less toxic and less expensive copper metal, the reaction is further hampered by the low nucleophilicity of the intermediate copper–alkynylides. In fact, alkynyl substituents have been used as dummy ligands in mixed organocuprates, permitting the selective transfer of alkyl or alkenyl groups in the course of conjugate addition reactions.[10] This limitation for the copper-catalyzed conjugate alkynylation has been overcome by the use of doubly activated alkenes, namely Meldrum acid derivatives (Scheme 1 a),[4] or by the use of unsaturated
Abstract: A highly enantioselective copper-catalyzed conjugate alkynylation of monoactivated enones, namely 1,1difluoro-1-(phenylsulfonyl)-3-en-2-ones, is described. The reaction products are obtained with good yields and excellent enantioselectivities (from 92 to 99% ee). The b-alkynylated difluoro(phenylsulfonyl) ketones can be converted into the corresponding b-alkynylated difluoro- and trifluoromethyl ketones, esters and amides. This is the first example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3en-2-ones as substrates in an enantioselective reaction, which have been shown to be new ester/amide surrogates.
The interest in the chemistry of alkynes has experienced a progressive growth in the last years.[1, 2] The asymmetric conjugate addition of terminal alkynes to electrophilic double bonds conjugated with electron-withdrawing functional groups, especially in b-substituted a,b-unsaturated carbonyl and related compounds, is a highly efficient method to obtain internal alkynes bearing a stereogenic center at the propargylic position. The resulting products are very versatile chiral building blocks in view of the potential modification of the triple bond and/or the carbonyl-related functional group. Enantioselective procedures for the alkynylation of enones and related compounds have been carried out by using preformed alkynyl organometallic reagents and different catalysts or chiral auxiliaries,[3] which unavoidably yield significant amounts of metallic waste. A more convenient approach from the environmental and atom-economic point of view would be the generation of the reactive alkynyl–metal species from terminal alkynes and a catalytic amount of a chiral metal complex. Since the first report by Carreira[4] on copper-catalyzed reactions of terminal alkynes with derivatives of Meldrum’s acid, several successful examples
Scheme 1. Strategies for the enantioselective copper-catalyzed conjugate addition of terminal alkynes.
[a] A. Sanz-Marco, A. Garca-Ortiz, Prof. Dr. G. Blay, I. Fernndez, Prof. Dr. J. R. Pedro Department de Qumica Orgnica-Facultat de Qumica Universitat de Valncia C/Dr. Moliner 50, 46100 Burjassot (Valncia) (Spain) Fax: (+ 34) 963544328 E-mail: [email protected] [email protected]
thioamides that are especially designed to simultaneously activate the alkyne and the double bond through soft Lewis acid/ hard Brønsted base cooperative catalysis (Scheme 1 b).[5] An important requirement of the alkene activating groups is the possibility of further synthetic transformation. In particular, their conversion into ester or amide moieties is especially interesting, because simple unsaturated esters and amides have
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303920. Chem. Eur. J. 2014, 20, 668 – 672
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Communication proven to be difficult substrates in relay asymmetric catalysis. Therefore, the use of activated ester/amide surrogates has become a convenient strategy to encounter this problem.[11] Ideally, these surrogates should meet certain requirements, that is, enhanced electrophilic activation of the substrate, improved coordination to the chiral catalyst, and easy replacement by other groups. Following our interest on enantioselective alkynylations,[3 g, h, 12] we have studied the copper-catalyzed conjugate alkynylation of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones (Scheme 1 c). These compounds are readily prepared by treatment of the appropriate a,b-unsaturated methyl esters with difluoromethyl phenyl sulfone and lithium hexamethyl disilazide (LHMDS).[13] We envisioned that the presence of two strong electronegative fluorine atoms and a sulfone electron-withdrawing group next to the carbonyl group would largely enhance the electrophilicity of the double bond. Additionally, the a-sulfonyl carbonyl moiety may act in certain reactions as a chelating scaffold or as a double hydrogen-bond donor, improving the coordination of the substrate to the catalyst.[14, 15] Moreover, the difluoro(phenylsulfonyl)methyl group can be transformed into different fluorinated groups, that is, CF3 or CF2H, which are of great interest owing to their prevalence in molecules used in the pharmaceutical and agrochemical industry.[16] Herein, we will show for the first time that the 1,1-difluoro-1-(phenylsulfonyl)-2-one moiety can be easily transformed into ester or amide groups under very mild conditions. In initial investigations, we examined the copper(I)-catalyzed addition of phenylacetylene (2 a) to (E)-1,1-difluoro-4-phenyl-1(phenylsulfonyl)but-3-en-2-one (1 a) in the presence of [Cu(CH3CN)4][BF4], a variety of phosphane ligands and triethyl-
Table 1. Screening of ligands in the reaction between phenylacetylene (2 a) and 1 a to give 3 aa.[a] L–CuI [mol %]
2a [equiv]
t [h]
Yield [%]
ee [%][b]
1 2 3 4 5 6 7 8[c] 9 10 11
L1 L2 L3 L4 L5 L6 L7 L7 L7 L7 L7
20 20 20 20 20 20 20 20 10 5 20
7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 5
48 – 96 120 120 120 48 72 96 120 72
96 – 66 34 51 62 80 78 71 62 70
59 – 54 55 38 40 98 93 96 94 97
the number of alkyne equivalents can be diminished without any effect on the enantiomeric excess of compound 3 aa, although the reaction rate and the yield slightly decreases (entries 9–11). The scope of the reaction was then examined (Table 2). First, we carried out the addition of phenylacetylene to a number of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones 1 differently substituted at the b carbon of the double bond (entries 1–11). The group R1 was amenable to variation allowing aromatic groups
Table 2. Enantioselective conjugate alkynylation of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones.[a]
amine (Scheme 2, Table 1). The best results were obtained with biphenylphosphane L7 that provided the expected compound 3 aa in 80 % yield and 98 % ee (Entry 7). [(CuOTf)2Tol] could be also used although it gave slightly lower results than [Cu(CH3CN)4][BF4], compound 3 aa being obtained with 78 % yield and 93 % ee (entry 8). On the other hand, the catalyst load or www.chemeurj.org
L
[a] Reactions carried out in the presence of Et3N (1 equiv) and ligand–[Cu(CH3CN)4][BF4] (1:1) in toluene at RT. [b] Determined by HPLC using chiral stationary phases. [c] [(CuOTf)2Tol] was used instead of [Cu(CH3CN)4][BF4].
Scheme 2. Copper(I)-catalyzed conjugate addition of phenylacetylene (2 a) to compound 1 a and ligands used in this study.
Chem. Eur. J. 2014, 20, 668 – 672
Entry
Entry
1
R1
2
R2
t [h]
3
Yield [%]
ee [%][b]
1 2 3 4 5 6[c] 7 8[c] 9 10 11 12 13[c] 14 15 16 17 18 19
1a 1b 1c 1d 1e 1e 1f 1f 1g 1h 1j 1a 1a 1a 1a 1g 1g 1a 1a
Ph 2-BrC6H4 3-BrC6H4 4-BrC6H4 4-MeOC6H4 4-MeOC6H4 2-MeC6H4 2-MeC6H4 4-MeC6H4 2-naphthyl cyclohexyl Ph Ph Ph Ph 4-MeC6H4 4-MeC6H4 Ph Ph
2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b 2c 2d 2b 2c 2e 2f
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-MeOC6H4 4-MeOC6H4 4-FC6H4 4-ClC6H4 4-MeOC6H4 4-FC6H4 3-thienyl cyclopropyl
48 24 48 48 72 96 48 96 48 72 –[d] 72 96 72 48 48 72 72 96
3 aa 3 ba 3 ca 3 da 3 ea 3 ea 3 fa 3 fa 3 ga 3 ha 3 ja 3 ab 3 ab 3 ac 3 ad 3 gb 3 gc 3 ae 3 af
80 90 80 75 77 70 82 83 77 50 – 86 67 69 90 84 69 70 82
98 99 97 97 96 94 99 98 97 95 – 98 97 97 99 97 94 98 92
[a] 1 (1 equiv), 2 (7.5 equiv), Et3N (1 equiv), [Cu(CH3CN)4][BF4] (0.2 equiv), L7 (0.2 equiv), unless otherwise stated. [b] Determined by HPLC using chiral stationary phases. [c] 0.1 equiv of L7 and CuI salt were used. [d] No advance observed.
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Communication substituted with either electron-withdrawing or electron-donating groups attached to different positions. For a same substituent, slightly higher yields and enantioselectivities were found for ortho- and meta- substituted phenyl rings with respect to the para-substituted one (entries 2 and 3 vs. entry 4 and entry 7 vs. entry 9), in a similar way as observed by Carreira with Meldrum’s acid derivatives.[4] The reaction allowed also a bulky 2-naphthyl substituent, but in this case the alkynylated product 3 ha was obtained with lower yield (50 %) although with excellent enantioselectivity (entry 10). The enantioselectivities obtained with these substrates (95–99 % ee), were higher than those obtained for the addition of phenylacetylene to Meldrum’s acid derivatives bearing aromatic rings in the b position with the biphasic pinap-CuI system (Scheme 1 a, R1 = Ar, 64–87 % yield, 83–90 % ee)[4] and similar to those obtained with the CuI-catalyzed addition of phenylacetylene to aromatic thioamides (Scheme 1 b, R1 = Ar, 72–98 % yield, 94–98 % ee).[5a] Unfortunately, the reaction did not take place with the aliphatic compound 1 j, bearing a cyclohexyl group (entry 11). We attribute this lack of reactivity to deprotonation of the g carbon to form an enolate under the reaction conditions.[17] We examined also the addition of other alkynes. Substituted phenylacetylenes bearing electron-donating (MeO) or electron-withdrawing groups (Cl, F) on the phenyl group reacted with compounds 1 a and 1 g with excellent enantioselectivities (entries 12–17). 3-Thienylacetylene (2 e) reacted with 1 a to give compound 3 ae with 70 % yield an 98 % ee (entry 18), while cyclopropylacetylene (2 f) reacted with 1 a to give 3 af with a remarkable 82 % yield and 92 % ee (entry 19). Finally, although most of the examples have been carried out with 20 mol % of catalyst load, this can be lowered to 10 mol % with only a minor decrease on the yield and without appreciable effect on the enantioselectivity (entries 6, 8, and 13). To show the synthetic versatility of the difluoro(phenylsulfonyl)methyl moiety, we carried out different modifications of this moiety in compound 3 aa. Given the importance of fluorinated compounds as pharmaceuticals and agrochemicals, we studied the substitution of the phenylsulfonyl group by a hydrogen or a fluorine atom to give the corresponding b-alkynylated difluoromethyl and trifluoromethyl ketones (Scheme 3). Thus treatment of compound 3 aa with Mg and TMSCl in THF provided an intermediate enol ether.[13b] Quenching of this reaction mixture with aqueous HF gave the corresponding difluoromethyl ketone 4 in 83 % yield. On the other hand, after
removal of the THF, treatment of the enol ether with Selectfluor in acetonitrile gave trifluoromethyl ketone 5 in 60 % yield. In both cases, the optical purity of the starting material was maintained in the final products. On the other hand, during the studies addressed to achieve the hydrogenolysis of the C S bond in compound 3 aa we discovered that the whole difluoro(phenylsulfonyl)methyl moiety was replaced by a methoxy group upon treatment with magnesium in methanol to give methyl ester 6. After some optimization, ester 6 could be obtained in 93 % yield upon treatment of 3 aa with MeOH in THF at 0 8C without the need for Mg. This result indicates that the 1,1-difluoro-1-(phenylsulfonyl)methyl-2-one moiety can be considered as an equivalent of an activated carboxyl group, with the difluoro(phenylsulfonyl)methyl group acting as a leaving group. According to this, we studied the reaction of compound 3 aa with benzylamine in THF that gave amide 7 in 73 % yield (Scheme 4). These trans-
Scheme 4. Synthesis of b-alkynylated esters and amides from compound 3 aa.
formations demonstrate the potential use of 1,1-difluoro-1(phenylsulfonyl)-3-en-2-ones as unsaturated ester/amide surrogates in asymmetric catalysis, which is an important issue since simple esters and amides are difficult substrates in relay asymmetric catalysis, specially by metal complexes. It is worth to mention that this ester/amide synthesis does not requires other additional reagents than an alcohol/amine and that the only by-product is difluoromethyl phenyl sulfone, which is used for the initial preparation of the starting materials 1, and that can be recovered from the reaction mixture upon column chromatography. The determination of the absolute stereochemistry of compound 3 aa was carried out by chemical correlation with com-
Scheme 3. Synthesis of b-alkynylated difluoromethyl and trifluoromethyl ketones from compound 3 aa. Chem. Eur. J. 2014, 20, 668 – 672
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Scheme 5. Determination of the absolute stereochemistry of compound 3 aa.
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Communication pound 9 of known stereochemistry (Scheme 5).[18] A sample of ester 6 (91 % ee), prepared from compound 3 aa of the same optical purity, was hydrogenated over Pd/C to give the saturated ester 8 in 89 % yield. Reduction of the methyl ester group with LiAlH4 yielded 95 % of alcohol 9. By comparison of the chiral chromatography retention times[19] of compound 9 obtained in this way with those described in the literature for the R-enantiomer of compound 9,[18a] we could establish that our prepared compounds 6–9 as well as compound 3 aa are of R configuration at the stereogenic center. For the rest of compounds 3, the stereochemistry was assigned upon the assumption of a common stereochemical mechanism. In summary, we have developed a highly enantioselective copper-catalyzed conjugate alkynylation of monoactivated a,bunsaturated ketones, namely 1,1-difluoro-1-(phenylsulfonyl)-3en-2-ones. The addition of phenylacetylene derivatives, 3-thienylacetylene and cyclopropylacetylene to this group of enones bearing different aromatic groups at the b carbon of the double bond takes place with good yields and excellent enantioselectivities. The resulting products are synthetic precursors of b-alkynylated difluoromethyl and trifluoromethyl ketones. On the other hand, the alkynylated products can be conveniently transformed into b-alkynylated ester or amides by treatment with an alcohol or an amine, respectively. This is the first example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2ones as substrates in an enantioselective reaction. New applications of these substrates as ester/amide surrogates in asymmetric catalysis are underway.
Keywords: alkynes · asymmetric catalysis addition · enones · fluorine compounds
General procedure for the enantioselective alkynylation reaction [Cu(CH3CN)4][BF4] (5.7 mg, 0.018 mmol) and (R)-L7 (20.7 mg, 0.018 mmol) were introduced into a round-bottom flask that was purged with nitrogen. Toluene (0.5 mL) was added via a syringe and the mixture was stirred for 1.5 h at room temperature. Then, a solution of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-one 1 (0.090 mmol) in toluene (1.0 mL) was added, followed by triethylamine (12.5 mL, 0.090). The solution was stirred for 10 min at room temperature. Then, the alkyne 2 (0.675 mmol) was added and the solution was stirred at room temperature under nitrogen until the reaction was complete (TLC). The reaction mixture was quenched with aqueous NH4Cl (20 %, 1.0 mL), extracted with CH2Cl2 (2 15 mL), washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with hexane/CH2Cl2 mixtures afforded compound 3.
Acknowledgements Financial support from the Ministerio de Economa y Competitividad (Gobierno de EspaÇa) and FEDER (European Union) (CTQ2009–13083) and from Generalitat Valenciana (ACOMP2012–212 and ISIC2012/001) is acknowledged. A. S-M. thanks the MEC for a pre-doctoral grant (FPI). We thank the Solvias company for the donation of a university ligand kit. www.chemeurj.org
conjugate
[1] For reviews, see: a) Comprehensive Organic Synthesis, Vol. 4 and 5 (Ed.: B. M. Trost), Pergamon Press, Oxford, 1990; b) C. Oger, L. Balas, T. Durand, J. Galano, Chem. Rev. 2013, 113, 1313; c) B. Godoi, R. F. Schumacher, G. Zeni, Chem. Rev. 2011, 111, 2937; d) M. C. Willis, Chem. Rev. 2010, 110, 725; e) Y. Yamamoto, I. D. Gridnev, N. T. Patil, T. Jin, Chem. Commun. 2009, 5075; f) M. Meldal, C. W. Tornøe, Chem. Rev. 2008, 108, 2952; g) Z. Li, C. Brouwer, C. He, Chem. Rev. 2008, 108, 3239; h) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180; i) F. Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2004, 104, 3079; j) R. Chinchilla, C. Njera, Chem. Rev. 2013, DOI: 10.1021/cr400133p. [2] For some recent examples, see: a) I. N. Michaelides, D. J. Dixon, Angew. Chem. 2013, 125, 836; Angew. Chem. Int. Ed. 2013, 52, 806; b) Y. Minami, H. Yoshiyasu, Y. Nakao, T. Hiyama, Angew. Chem. 2013, 125, 917; Angew. Chem. Int. Ed. 2013, 52, 883; c) L. Wang, J. Huang, S. Peng, H. Liu, X. Jiang, J. Wang, Angew. Chem. 2013, 125, 1812; Angew. Chem. Int. Ed. 2013, 52, 1768; d) G. Kang, Q. Wu, M. Liu, Q. Xu, Z. Chen, W. Chen, Y. Luo, W. Ye, J. Jiang, H. Wu, Adv. Synth. Catal. 2013, 355, 315; e) H. Wang, Y. Luo, B Zhu, J. Wu, Chem. Commun. 2012, 48, 5581; f) S. Li, Z. Li, Y. Yuan, Y. Li, L. Zhang, Y. Wu, Chem. Eur. J. 2013, 19, 1496; g) Q. Tang, D. Xia, X. Jin, Q. Zhang, X.-Q. Sun, C. Wang, J. Am. Chem. Soc. 2013, 135, 4628; h) B. Zhou, H. Chen, C. Wang, J. Am. Chem. Soc. 2013, 135, 1264; i) B. Panda, T. K. Sarkar, J. Org. Chem. 2013, 78, 2413; j) F. Huber, S. F. Kirsch, J. Org. Chem. 2013, 78, 2780; k) A. Monlen, G. Blay, M. C. MuÇoz, L. R. Domingo, J. R. Pedro, Chem. Eur. J. 2013, 19, 14852. [3] Boron reagents: a) J. M. Chong, L. Shen, N. J. Taylor, J. Am. Chem. Soc. 2000, 122, 1822; b) T. R. Wu, J. M. Chong, J. Am. Chem. Soc. 2005, 127, 3244; aluminum reagents: c) Y.-S. Kwak, E. J. Corey, Org. Lett. 2004, 6, 3385; d) O. V. Larionov, E. Corey, J. Org. Lett. 2010, 12, 300; grignard reagents: e) S. Cui, S. D. Walker, J. C. S. Woo, C. J. Borths, H. Mukherjee, M. J. Chen, M. M. Faul, J. Am. Chem. Soc. 2010, 132, 436; f) J. C. S. Woo, S. Cui, S. D. Walker, M. M. Faul, Tetrahedron 2010, 66, 4730; zinc reagents: g) G. Blay, L. Cardona, J. R. Pedro, A. Sanz-Marco, Chem. Eur. J. 2012, 18, 12966; h) G. Blay, M. C. MuÇoz, J. R. Pedro, A. Sanz-Marco, Adv. Synth. Catal. 2013, 355, 1071. [4] T. F. Knçpfel, P. Zarotti, T. Ichikawa, E. M. Carreira, J. Am. Chem. Soc. 2005, 127, 9682. [5] a) R. Yazaki, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2010, 132, 10275; b) R. Yazaki, N. Kumagai, M. Shibasaki, Org. Lett. 2011, 13, 952; c) R. Yazaki, N. Kumagai, M. Shibasaki, Chem. Asian J. 2011, 6, 1778. [6] a) T. Nishimura, X.-X. Guo, N. Uchiyama, T. Katoh, T. Hayashi, J. Am. Chem. Soc. 2008, 130, 1576; b) T. Nishimura, T. Sawano, T. Hayashi, Angew. Chem. 2009, 121, 8201; Angew. Chem. Int. Ed. 2009, 48, 8057; c) T. Nishimura, S. Tokuji, T. Sawano, T. Hayashi, Org. Lett. 2009, 11, 3222; d) E. Fillion, A. K. Zorzitto, J. Am. Chem. Soc. 2009, 131, 14608. [7] T. Nishimura, T. Sawano, K. Ou, T. Hayashi, Chem. Commun. 2011, 47, 10142. [8] J. Ito, K. Fujii, H. Nishiyama, Chem. Eur. J. 2013, 19, 601. [9] L. Villarino, R. Garca-FandiÇo, F. Lpez, J. L. MascareÇas, Org. Lett. 2012, 14, 2996. [10] E. J. Corey, D. J. Beames, J. Am. Chem. Soc. 1972, 94, 7210. [11] H. Jiang, M. W. Paix¼o, D. Monge, K. A. Jørgensen, J. Am. Chem. Soc. 2010, 132, 2775. [12] a) G. Blay, I. Fernndez, A. Marco-Aleixandre, J. R. Pedro, J. Org. Chem. 2006, 71, 6674; b) G. Blay, L. Cardona, E. Climent, J. R. Pedro, Angew. Chem. 2008, 120, 5675; Angew. Chem. Int. Ed. 2008, 47, 5593; c) G. Blay, L. Cardona, I. Fernndez, A. Marco-Aleixandre, M. C. MuÇoz, J. R. Pedro, Org. Biomol. Chem. 2009, 7, 4301; d) G. Blay, E. Ceballos, A. Monlen, J. R. Pedro, Tetrahedron 2012, 68, 2128; e) G. Blay, A. Brines, A. Monlen, J. R. Pedro, Chem. Eur. J. 2012, 18, 2440. [13] a) C. Ni, L. Zhang, J. Hu, J. Org. Chem. 2008, 73, 5699; b) C. Ni, L. Zhang, J. Hu, J. Org. Chem. 2009, 74, 3767. [14] For some examples on the use of a’-sulfonyl enones as chelating substrates in metal-catalyzed reactions, see: a) E. Wada, H. Yasuoka, S. Kanemasa, Chem. Lett. 1994, 1637; b) E. Wada, W. Pei, H. Yasuoka, U. Chin, S. Kanemasa, Tetrahedron 1996, 52, 1205; c) S. Barroso, G. Blay, L. Al-Midfa, M. C. MuÇoz, J. R. Pedro, J. Org. Chem. 2008, 73, 6389.
Experimental Section
Chem. Eur. J. 2014, 20, 668 – 672
·
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Communication [15] Given the reduced coordination number of the CuI ion, it is not likely that this chelating mechanism operates in the CuI-catalyzed conjugate alkynylation. [16] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320; b) V. D. Romanenko, V. P. Kukhar, Tetrahedron 2008, 64, 6153; c) K. Mller, C. Faeh, F. Diederich, Science 2007, 317, 1881. [17] Compound 1 j was subjected to the general procedure of the conjugate alkynylation with phenylacetylene. After 3 days and the habitual work up, compound 10, which was identified as the enol form of compound 1 j, was obtained after column chromatography eluting with hexane/ EtOAc. 1H NMR (300 MHz, CDCl3) d = 8.07–8.00 (m, 2 H), 7.78–7.71 (m, 1 H), 7.66–7.56 (m, 2 H), 6.36 (d, J = 5.9 Hz, 1 H), 5.85 (d, J = 5.9 Hz, 1 H), 4.29 (s, 1 H), 1.77–1.55 (m, 3 H), 1.55– 13 C NMR 1.30 ppm (m, 7 H); (75.5 MHz, CDCl3) d = 142.5 (CH), 135.2 (CH), 134.4 (C), 130.8 (2CH), 129.0 (2CH), 122.3 (CH), 117.7 (t, JC,F = 298.9 Hz, C), 108.1 (t, J = 26.6 Hz, C), 93.6 (C), 37.9 (CH2), 35.7 (CH2), 24.9 (CH2), 23.0 (CH2), 22.7 ppm (CH2);
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19
F NMR (282 MHz, CDCl3) d = 109.7 ppm (s, 2F); IR (neat): n˜ = 3485, 1449, 1334, 1147 cm 1; HRMS (ESI): m/z calcd for C16H15F2O3S: 327.0861; found: 327.0860 [M H + ] (see the Supporting Information). [18] a) M. Yoshida, H. Ohmiya, M. Sawamura, J. Am. Chem. Soc. 2012, 134, 11896; b) K. Sasaki, T. Hayashi, Angew. Chem. 2010, 122, 8321; Angew. Chem. Int. Ed. 2010, 49, 8145. [19] By comparison of the elution order of both enantiomers of our compound 9, measured by chiral HPLC (Chiralcel OD-H), with those described in the literature (ref. [18]), we established that the major enantiomer was R (91 % ee). However, our material showed the opposite optical rotation sign to that reported for the R enantiomer in the literature (ref. [18a]). We do not have an explanation for this discrepancy, but given the low absolute value of specific optical rotation shown by compound 9 (see the Supporting Information), we relied on the HPLC data to assess the absolute stereochemistry of compound 9.
Received: October 7, 2013 Published online on December 12, 2013
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Communication
& Asymmetric Synthesis
Highly Enantioselective Copper(I)-Catalyzed Conjugate Addition of Terminal Alkynes to 1,1-Difluoro-1-(phenylsulfonyl)-3-en-2ones: New Ester/Amide Surrogates in Asymmetric Catalysis Amparo Sanz-Marco, Andrea Garca-Ortiz, Gonzalo Blay,* Isabel Fernndez, and Jos R. Pedro*[a] have been reported by using Cu,[5] Rh,[6] Co,[7] Ru (one example with 82 % ee),[8] and Pd (two examples with 39 and 38 % ee)[9] catalysts. Despite these advances, there are still some limitations regarding the enantioselectivity and the substrate or alkyne scope. In particular, the possibility to chemically manipulate the electron-withdrawing group that activates the double bond would be very convenient. Moreover, in the case of the less toxic and less expensive copper metal, the reaction is further hampered by the low nucleophilicity of the intermediate copper–alkynylides. In fact, alkynyl substituents have been used as dummy ligands in mixed organocuprates, permitting the selective transfer of alkyl or alkenyl groups in the course of conjugate addition reactions.[10] This limitation for the copper-catalyzed conjugate alkynylation has been overcome by the use of doubly activated alkenes, namely Meldrum acid derivatives (Scheme 1 a),[4] or by the use of unsaturated
Abstract: A highly enantioselective copper-catalyzed conjugate alkynylation of monoactivated enones, namely 1,1difluoro-1-(phenylsulfonyl)-3-en-2-ones, is described. The reaction products are obtained with good yields and excellent enantioselectivities (from 92 to 99% ee). The b-alkynylated difluoro(phenylsulfonyl) ketones can be converted into the corresponding b-alkynylated difluoro- and trifluoromethyl ketones, esters and amides. This is the first example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3en-2-ones as substrates in an enantioselective reaction, which have been shown to be new ester/amide surrogates.
The interest in the chemistry of alkynes has experienced a progressive growth in the last years.[1, 2] The asymmetric conjugate addition of terminal alkynes to electrophilic double bonds conjugated with electron-withdrawing functional groups, especially in b-substituted a,b-unsaturated carbonyl and related compounds, is a highly efficient method to obtain internal alkynes bearing a stereogenic center at the propargylic position. The resulting products are very versatile chiral building blocks in view of the potential modification of the triple bond and/or the carbonyl-related functional group. Enantioselective procedures for the alkynylation of enones and related compounds have been carried out by using preformed alkynyl organometallic reagents and different catalysts or chiral auxiliaries,[3] which unavoidably yield significant amounts of metallic waste. A more convenient approach from the environmental and atom-economic point of view would be the generation of the reactive alkynyl–metal species from terminal alkynes and a catalytic amount of a chiral metal complex. Since the first report by Carreira[4] on copper-catalyzed reactions of terminal alkynes with derivatives of Meldrum’s acid, several successful examples
Scheme 1. Strategies for the enantioselective copper-catalyzed conjugate addition of terminal alkynes.
[a] A. Sanz-Marco, A. Garca-Ortiz, Prof. Dr. G. Blay, I. Fernndez, Prof. Dr. J. R. Pedro Department de Qumica Orgnica-Facultat de Qumica Universitat de Valncia C/Dr. Moliner 50, 46100 Burjassot (Valncia) (Spain) Fax: (+ 34) 963544328 E-mail: [email protected] [email protected]
thioamides that are especially designed to simultaneously activate the alkyne and the double bond through soft Lewis acid/ hard Brønsted base cooperative catalysis (Scheme 1 b).[5] An important requirement of the alkene activating groups is the possibility of further synthetic transformation. In particular, their conversion into ester or amide moieties is especially interesting, because simple unsaturated esters and amides have
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303920. Chem. Eur. J. 2014, 20, 668 – 672
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Communication proven to be difficult substrates in relay asymmetric catalysis. Therefore, the use of activated ester/amide surrogates has become a convenient strategy to encounter this problem.[11] Ideally, these surrogates should meet certain requirements, that is, enhanced electrophilic activation of the substrate, improved coordination to the chiral catalyst, and easy replacement by other groups. Following our interest on enantioselective alkynylations,[3 g, h, 12] we have studied the copper-catalyzed conjugate alkynylation of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones (Scheme 1 c). These compounds are readily prepared by treatment of the appropriate a,b-unsaturated methyl esters with difluoromethyl phenyl sulfone and lithium hexamethyl disilazide (LHMDS).[13] We envisioned that the presence of two strong electronegative fluorine atoms and a sulfone electron-withdrawing group next to the carbonyl group would largely enhance the electrophilicity of the double bond. Additionally, the a-sulfonyl carbonyl moiety may act in certain reactions as a chelating scaffold or as a double hydrogen-bond donor, improving the coordination of the substrate to the catalyst.[14, 15] Moreover, the difluoro(phenylsulfonyl)methyl group can be transformed into different fluorinated groups, that is, CF3 or CF2H, which are of great interest owing to their prevalence in molecules used in the pharmaceutical and agrochemical industry.[16] Herein, we will show for the first time that the 1,1-difluoro-1-(phenylsulfonyl)-2-one moiety can be easily transformed into ester or amide groups under very mild conditions. In initial investigations, we examined the copper(I)-catalyzed addition of phenylacetylene (2 a) to (E)-1,1-difluoro-4-phenyl-1(phenylsulfonyl)but-3-en-2-one (1 a) in the presence of [Cu(CH3CN)4][BF4], a variety of phosphane ligands and triethyl-
Table 1. Screening of ligands in the reaction between phenylacetylene (2 a) and 1 a to give 3 aa.[a] L–CuI [mol %]
2a [equiv]
t [h]
Yield [%]
ee [%][b]
1 2 3 4 5 6 7 8[c] 9 10 11
L1 L2 L3 L4 L5 L6 L7 L7 L7 L7 L7
20 20 20 20 20 20 20 20 10 5 20
7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 7.5 5
48 – 96 120 120 120 48 72 96 120 72
96 – 66 34 51 62 80 78 71 62 70
59 – 54 55 38 40 98 93 96 94 97
the number of alkyne equivalents can be diminished without any effect on the enantiomeric excess of compound 3 aa, although the reaction rate and the yield slightly decreases (entries 9–11). The scope of the reaction was then examined (Table 2). First, we carried out the addition of phenylacetylene to a number of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones 1 differently substituted at the b carbon of the double bond (entries 1–11). The group R1 was amenable to variation allowing aromatic groups
Table 2. Enantioselective conjugate alkynylation of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones.[a]
amine (Scheme 2, Table 1). The best results were obtained with biphenylphosphane L7 that provided the expected compound 3 aa in 80 % yield and 98 % ee (Entry 7). [(CuOTf)2Tol] could be also used although it gave slightly lower results than [Cu(CH3CN)4][BF4], compound 3 aa being obtained with 78 % yield and 93 % ee (entry 8). On the other hand, the catalyst load or www.chemeurj.org
L
[a] Reactions carried out in the presence of Et3N (1 equiv) and ligand–[Cu(CH3CN)4][BF4] (1:1) in toluene at RT. [b] Determined by HPLC using chiral stationary phases. [c] [(CuOTf)2Tol] was used instead of [Cu(CH3CN)4][BF4].
Scheme 2. Copper(I)-catalyzed conjugate addition of phenylacetylene (2 a) to compound 1 a and ligands used in this study.
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Entry
Entry
1
R1
2
R2
t [h]
3
Yield [%]
ee [%][b]
1 2 3 4 5 6[c] 7 8[c] 9 10 11 12 13[c] 14 15 16 17 18 19
1a 1b 1c 1d 1e 1e 1f 1f 1g 1h 1j 1a 1a 1a 1a 1g 1g 1a 1a
Ph 2-BrC6H4 3-BrC6H4 4-BrC6H4 4-MeOC6H4 4-MeOC6H4 2-MeC6H4 2-MeC6H4 4-MeC6H4 2-naphthyl cyclohexyl Ph Ph Ph Ph 4-MeC6H4 4-MeC6H4 Ph Ph
2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2b 2c 2d 2b 2c 2e 2f
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 4-MeOC6H4 4-MeOC6H4 4-FC6H4 4-ClC6H4 4-MeOC6H4 4-FC6H4 3-thienyl cyclopropyl
48 24 48 48 72 96 48 96 48 72 –[d] 72 96 72 48 48 72 72 96
3 aa 3 ba 3 ca 3 da 3 ea 3 ea 3 fa 3 fa 3 ga 3 ha 3 ja 3 ab 3 ab 3 ac 3 ad 3 gb 3 gc 3 ae 3 af
80 90 80 75 77 70 82 83 77 50 – 86 67 69 90 84 69 70 82
98 99 97 97 96 94 99 98 97 95 – 98 97 97 99 97 94 98 92
[a] 1 (1 equiv), 2 (7.5 equiv), Et3N (1 equiv), [Cu(CH3CN)4][BF4] (0.2 equiv), L7 (0.2 equiv), unless otherwise stated. [b] Determined by HPLC using chiral stationary phases. [c] 0.1 equiv of L7 and CuI salt were used. [d] No advance observed.
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Communication substituted with either electron-withdrawing or electron-donating groups attached to different positions. For a same substituent, slightly higher yields and enantioselectivities were found for ortho- and meta- substituted phenyl rings with respect to the para-substituted one (entries 2 and 3 vs. entry 4 and entry 7 vs. entry 9), in a similar way as observed by Carreira with Meldrum’s acid derivatives.[4] The reaction allowed also a bulky 2-naphthyl substituent, but in this case the alkynylated product 3 ha was obtained with lower yield (50 %) although with excellent enantioselectivity (entry 10). The enantioselectivities obtained with these substrates (95–99 % ee), were higher than those obtained for the addition of phenylacetylene to Meldrum’s acid derivatives bearing aromatic rings in the b position with the biphasic pinap-CuI system (Scheme 1 a, R1 = Ar, 64–87 % yield, 83–90 % ee)[4] and similar to those obtained with the CuI-catalyzed addition of phenylacetylene to aromatic thioamides (Scheme 1 b, R1 = Ar, 72–98 % yield, 94–98 % ee).[5a] Unfortunately, the reaction did not take place with the aliphatic compound 1 j, bearing a cyclohexyl group (entry 11). We attribute this lack of reactivity to deprotonation of the g carbon to form an enolate under the reaction conditions.[17] We examined also the addition of other alkynes. Substituted phenylacetylenes bearing electron-donating (MeO) or electron-withdrawing groups (Cl, F) on the phenyl group reacted with compounds 1 a and 1 g with excellent enantioselectivities (entries 12–17). 3-Thienylacetylene (2 e) reacted with 1 a to give compound 3 ae with 70 % yield an 98 % ee (entry 18), while cyclopropylacetylene (2 f) reacted with 1 a to give 3 af with a remarkable 82 % yield and 92 % ee (entry 19). Finally, although most of the examples have been carried out with 20 mol % of catalyst load, this can be lowered to 10 mol % with only a minor decrease on the yield and without appreciable effect on the enantioselectivity (entries 6, 8, and 13). To show the synthetic versatility of the difluoro(phenylsulfonyl)methyl moiety, we carried out different modifications of this moiety in compound 3 aa. Given the importance of fluorinated compounds as pharmaceuticals and agrochemicals, we studied the substitution of the phenylsulfonyl group by a hydrogen or a fluorine atom to give the corresponding b-alkynylated difluoromethyl and trifluoromethyl ketones (Scheme 3). Thus treatment of compound 3 aa with Mg and TMSCl in THF provided an intermediate enol ether.[13b] Quenching of this reaction mixture with aqueous HF gave the corresponding difluoromethyl ketone 4 in 83 % yield. On the other hand, after
removal of the THF, treatment of the enol ether with Selectfluor in acetonitrile gave trifluoromethyl ketone 5 in 60 % yield. In both cases, the optical purity of the starting material was maintained in the final products. On the other hand, during the studies addressed to achieve the hydrogenolysis of the C S bond in compound 3 aa we discovered that the whole difluoro(phenylsulfonyl)methyl moiety was replaced by a methoxy group upon treatment with magnesium in methanol to give methyl ester 6. After some optimization, ester 6 could be obtained in 93 % yield upon treatment of 3 aa with MeOH in THF at 0 8C without the need for Mg. This result indicates that the 1,1-difluoro-1-(phenylsulfonyl)methyl-2-one moiety can be considered as an equivalent of an activated carboxyl group, with the difluoro(phenylsulfonyl)methyl group acting as a leaving group. According to this, we studied the reaction of compound 3 aa with benzylamine in THF that gave amide 7 in 73 % yield (Scheme 4). These trans-
Scheme 4. Synthesis of b-alkynylated esters and amides from compound 3 aa.
formations demonstrate the potential use of 1,1-difluoro-1(phenylsulfonyl)-3-en-2-ones as unsaturated ester/amide surrogates in asymmetric catalysis, which is an important issue since simple esters and amides are difficult substrates in relay asymmetric catalysis, specially by metal complexes. It is worth to mention that this ester/amide synthesis does not requires other additional reagents than an alcohol/amine and that the only by-product is difluoromethyl phenyl sulfone, which is used for the initial preparation of the starting materials 1, and that can be recovered from the reaction mixture upon column chromatography. The determination of the absolute stereochemistry of compound 3 aa was carried out by chemical correlation with com-
Scheme 3. Synthesis of b-alkynylated difluoromethyl and trifluoromethyl ketones from compound 3 aa. Chem. Eur. J. 2014, 20, 668 – 672
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Scheme 5. Determination of the absolute stereochemistry of compound 3 aa.
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Communication pound 9 of known stereochemistry (Scheme 5).[18] A sample of ester 6 (91 % ee), prepared from compound 3 aa of the same optical purity, was hydrogenated over Pd/C to give the saturated ester 8 in 89 % yield. Reduction of the methyl ester group with LiAlH4 yielded 95 % of alcohol 9. By comparison of the chiral chromatography retention times[19] of compound 9 obtained in this way with those described in the literature for the R-enantiomer of compound 9,[18a] we could establish that our prepared compounds 6–9 as well as compound 3 aa are of R configuration at the stereogenic center. For the rest of compounds 3, the stereochemistry was assigned upon the assumption of a common stereochemical mechanism. In summary, we have developed a highly enantioselective copper-catalyzed conjugate alkynylation of monoactivated a,bunsaturated ketones, namely 1,1-difluoro-1-(phenylsulfonyl)-3en-2-ones. The addition of phenylacetylene derivatives, 3-thienylacetylene and cyclopropylacetylene to this group of enones bearing different aromatic groups at the b carbon of the double bond takes place with good yields and excellent enantioselectivities. The resulting products are synthetic precursors of b-alkynylated difluoromethyl and trifluoromethyl ketones. On the other hand, the alkynylated products can be conveniently transformed into b-alkynylated ester or amides by treatment with an alcohol or an amine, respectively. This is the first example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2ones as substrates in an enantioselective reaction. New applications of these substrates as ester/amide surrogates in asymmetric catalysis are underway.
Keywords: alkynes · asymmetric catalysis addition · enones · fluorine compounds
General procedure for the enantioselective alkynylation reaction [Cu(CH3CN)4][BF4] (5.7 mg, 0.018 mmol) and (R)-L7 (20.7 mg, 0.018 mmol) were introduced into a round-bottom flask that was purged with nitrogen. Toluene (0.5 mL) was added via a syringe and the mixture was stirred for 1.5 h at room temperature. Then, a solution of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-one 1 (0.090 mmol) in toluene (1.0 mL) was added, followed by triethylamine (12.5 mL, 0.090). The solution was stirred for 10 min at room temperature. Then, the alkyne 2 (0.675 mmol) was added and the solution was stirred at room temperature under nitrogen until the reaction was complete (TLC). The reaction mixture was quenched with aqueous NH4Cl (20 %, 1.0 mL), extracted with CH2Cl2 (2 15 mL), washed with brine (15 mL), dried over MgSO4, and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with hexane/CH2Cl2 mixtures afforded compound 3.
Acknowledgements Financial support from the Ministerio de Economa y Competitividad (Gobierno de EspaÇa) and FEDER (European Union) (CTQ2009–13083) and from Generalitat Valenciana (ACOMP2012–212 and ISIC2012/001) is acknowledged. A. S-M. thanks the MEC for a pre-doctoral grant (FPI). We thank the Solvias company for the donation of a university ligand kit. www.chemeurj.org
conjugate
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Experimental Section
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Communication [15] Given the reduced coordination number of the CuI ion, it is not likely that this chelating mechanism operates in the CuI-catalyzed conjugate alkynylation. [16] a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320; b) V. D. Romanenko, V. P. Kukhar, Tetrahedron 2008, 64, 6153; c) K. Mller, C. Faeh, F. Diederich, Science 2007, 317, 1881. [17] Compound 1 j was subjected to the general procedure of the conjugate alkynylation with phenylacetylene. After 3 days and the habitual work up, compound 10, which was identified as the enol form of compound 1 j, was obtained after column chromatography eluting with hexane/ EtOAc. 1H NMR (300 MHz, CDCl3) d = 8.07–8.00 (m, 2 H), 7.78–7.71 (m, 1 H), 7.66–7.56 (m, 2 H), 6.36 (d, J = 5.9 Hz, 1 H), 5.85 (d, J = 5.9 Hz, 1 H), 4.29 (s, 1 H), 1.77–1.55 (m, 3 H), 1.55– 13 C NMR 1.30 ppm (m, 7 H); (75.5 MHz, CDCl3) d = 142.5 (CH), 135.2 (CH), 134.4 (C), 130.8 (2CH), 129.0 (2CH), 122.3 (CH), 117.7 (t, JC,F = 298.9 Hz, C), 108.1 (t, J = 26.6 Hz, C), 93.6 (C), 37.9 (CH2), 35.7 (CH2), 24.9 (CH2), 23.0 (CH2), 22.7 ppm (CH2);
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19
F NMR (282 MHz, CDCl3) d = 109.7 ppm (s, 2F); IR (neat): n˜ = 3485, 1449, 1334, 1147 cm 1; HRMS (ESI): m/z calcd for C16H15F2O3S: 327.0861; found: 327.0860 [M H + ] (see the Supporting Information). [18] a) M. Yoshida, H. Ohmiya, M. Sawamura, J. Am. Chem. Soc. 2012, 134, 11896; b) K. Sasaki, T. Hayashi, Angew. Chem. 2010, 122, 8321; Angew. Chem. Int. Ed. 2010, 49, 8145. [19] By comparison of the elution order of both enantiomers of our compound 9, measured by chiral HPLC (Chiralcel OD-H), with those described in the literature (ref. [18]), we established that the major enantiomer was R (91 % ee). However, our material showed the opposite optical rotation sign to that reported for the R enantiomer in the literature (ref. [18a]). We do not have an explanation for this discrepancy, but given the low absolute value of specific optical rotation shown by compound 9 (see the Supporting Information), we relied on the HPLC data to assess the absolute stereochemistry of compound 9.
Received: October 7, 2013 Published online on December 12, 2013
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