SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2015, 26, 0271–0272 spotlight
Syn lett
271
Spotlight
A. Sanz-Marco
β-Trifluoromethyl-α,β-unsaturated Ketones Departament de Química Orgànica, Facultat de Química, Universitat de València, C/ Dr. Moliner 50, 46100 Burjassot, Spain
[email protected] Published online: 22.12.2014 DOI: 10.1055/s-0034-1379776; Art ID: st-2014-v0503-v
Amparo Sanz-Marco was born in Valencia, Spain, in 1986. She obtained her B.Sc. and M.Sc. degrees in chemistry from the University of Valencia, where she is currently pursuing her Ph.D. under the supervision of Prof. José Ramón Pedro and Prof. Gonzalo Blay. She has carried out a pre-doctoral stay at Boston College, Massachusetts, USA, with Prof. James P. Morken. Her Ph.D. research is focused on asymmetric conjugate alkynylation.
Introduction
Preparation
β-Trifluoromethyl enones are important synthetic precursors of molecules containing chiral centers with a trifluoromethyl substituent, a structural motif which is present in biologically active compounds, chiral reagents and in materials for optoelectronic devices.1 The presence of the strong electron-withdrawing β-trifluoromethyl group increases the electrophilicity of the double bond expediting the conjugate nucleophilic additions.
β-Trifluoromethyl-α,β-unsaturated ketones can be prepared by different methods.2 Among them, one of the most general applications is the aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with a ketone followed by dehydratation. OEt
O
F3C
OH
R
1
OH
pyrrolidine, AcOH
+
O
F3C
PhMe
2
O
PTSA R
F3C
R
3
4
Scheme 1 Synthesis of β-Trifluoromethyl-α,β-unsaturated ketones
Table 1 Use of β-Trifluoromethyl-α,β-unsaturated Ketones (A) Arylation The enantioselective conjugate arylation of β-trifluoromethyl-α,βunsaturated ketones was carried out by treatment with arylboronic acids 5 under catalysis with the Rh(I)-BINAP (L1) complex. The products 6 were obtained in high yields and enantioselectivities with a variety of arylboronic acids.3 (B) Friedel–Crafts Alkylation Pedro and co-workers reported the first example of enantioselective Friedel–Crafts alkylation of indoles 7 with β-trifluoromethyl-α,βunsaturated ketones, using a chiral Zr(IV)–BINOL (L2) complex as catalyst. Functionalized indoles 8 bearing a stereogenic tertiary center attached to a trifluoromethyl group were afforded with good yields and high enantiomeric excesses.4a A similar reaction was described later by Feng and co-workers using an yttrium(III) complex.4b
L1 (6 mol%) CF3 O [Rh(C8H12)2]BF4 (5 mol%) + R2B(OH)2 R2 R1 PhMe–H2O, reflux 5 6
O R1
F3C
4 R1 = Ph, OEt, NMe2 2 R = allyl, Ar
PPh2 PPh2
3–96%, 9–94% ee
L1
F3C L2-Zr(Ot-Bu)4 (20 mol%)
O R1
F3C
2 + R
7
4
N H
CH2Cl2, r.t.
R1 O
R2 N H
R1 = Ar R2 = H, Me, OMe, Br
8
30–97%, 64–97% ee Br OH OH Br L2
(C) Epoxidation The asymmetric epoxidation of α,β-unsaturated carbonyl compounds using a chiral Sc(III)–N,N′-dioxide (L3) complex was achieved by Feng and co-workers. The authors describe several examples with β-trifluoromethyl-α,β-unsaturated ketones giving the corresponding epoxides 10 in excellent yields and enantioselectivities under mild conditions.5
O F3C
R 4 R = Ar
+ H2O2
L3-[Sc(OTf)3] (5 mol%) THF, 35 °C
9
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 271–272
O F3C
O N
R 10
91–99%, 97–99% ee
N
N
O
O
O
O
H
H
N Ar
Ar Ar = 2,6-i-Pr2C6H3 L3
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Amparo Sanz-Marco
272
Spotlight
A. Sanz-Marco
(D) Haloamination The enantioselective haloamination of β-trifluoromethyl enones 4 was achieved upon treatment with TsNH2 and the electrophilic halogen source 11 in the presence of a catalytic amount of a complex of Sc(OTf) with the N,N′-dioxide ligand L4. NIS, NBS and TsNCl2 were used as halogen sources to provide the desired haloaminated products 12 in excellent yields, diastereo- and enantioselectivities.6
O F3C
L4-[Sc(OTf)3] (0.5 mol%) TsNH2 (0.6–1.1 equiv)
N–X source
Ph
NHTs O F3C
4 Å MS, CH2Cl2, r.t.
Ph X
4
11
12
X = Cl, Br, I
93–96%, 93–98% ee dr > 95:5
N O
N H N
O
1. L5 (10 mol%) Cs2CO3
O R1
F3C
OR2
13
4
CO2R2 N
CPME, –20 °C
+ Ph2C N
R1 = Ar R2 = 1-adamantyl
Ph
L4
Ph
(E) Michael Addition: Synthesis of β-Trifluoromethyl-pyrroline Carboxylates Shibata and co-workers carried out the conjugate addition of glycinate imine 13 to 4 under PTC conditions with a cinchona alkaloid derived catalyst L5. Pyrroline carboxylates 14 were obtained with excellent yields, diastereo- and enantioselectivities after a deprotection–cyclization–dehydration sequence.7a Enantioenriched β-trifluoromethyl pyrrolines were also obtained via organocatalytic conjugate addition of nitromethane to enones 4 followed by a nitroreduction–cyclization–dehydration sequence.7b
O
O
O N H
2. concd HCl CH2Cl2, r.t.
CF3
R1 14
72–96%, 72–88% ee dr > 98:2
CPME = MeOC5H9
HO –Br
N N
t-Bu L5 t-Bu
(F) Alkynylation The enantioselective conjugate addition of terminal alkynes 15 to β-trifluoromethyl-α,β-unsaturated ketones 4 catalyzed by a chiral Cu(I)–taniaphos (L6) complex afforded ketones bearing a trifluoromethylated propargylic chiral center in β-position. The alkynylation products 16 were obtained with good yields and high enantiomeric excesses. Iodocyclisation of 16 furnished access to 4-trifluoromethyl-4H-pyrans without any loss of optical purity.8
O R1
F3C 4
2
H
+ R
15
R1 = Alk, Ar R2 = Alk, Ar
CF3
L6-[Cu(MeCN)4]BF4 (20 mol%) Et3N, THF, 40 °C
O R1
R2
16 51–99%, 77–99% ee PPh2 Fe
PPh2
NH L6
References (1) (a) Zhang, N.; Ayral-Kaloustian, S.; Nguyen, T.; Afragola, J.; Hernandez, R.; Lucas, J.; Gibbons, J.; Beyer, C. J. Med. Chem. 2007, 50, 319. (b) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2543. (c) Mikami, K.; Yajima, T.; Terada, M.; Suzuki, Y.; Kobayashi, I. Chem. Commun. 1997, 57. (2) (a) Yamazaki, T.; Mizutani, K.; Kitazume, T. J. Org. Chem. 1995, 60, 6046. (b) Zhang, F.; Peng, Y.; Liao, S.; Gong, Y. Tetrahedron 2007, 63, 4636. (c) Yamazaki, T.; Kawasaki-Takasuda, T.; Furuta, A.; Sakamoto, S. Tetrahedron 2009, 65, 5945. (d) Marrec, O.; Borrini, J.; Billard, T.; Langlois, B. R. Synlett 2009, 1241. (3) (a) Konno, T.; Tanaka, T.; Miyabe, T.; Morigaki, A.; Ishihara, T. Tetrahedron Lett. 2008, 49, 2106. (b) Morigaki, A.; Tanaka, T.; Miyabe, T.; Ishihara, T.; Konno, T. Org. Biomol. Chem. 2013, 11, 586.
(4) (a) Blay, G.; Fernández, I.; Muñoz, M. C.; Pedro, J. R.; Vila, C. Chem. Eur. J. 2010, 16, 9117. (b) Wang, W.; Lian, X.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2011, 47, 7821. (5) Chu, Y.; Liu, X.; Li, W.; Hu, X.; Lin, L.; Feng, X. Chem. Sci. 2012, 3, 1996. (6) Cai, Y.; Liu, X.; Li, J.; Chen, W.; Wang, W.; Lin, L.; Feng, X. Chem. Eur. J. 2011, 17, 14916. (7) (a) Kawai, H.; Sugita, Y.; Tokunaga, E.; Sato, H.; Shiro, M.; Shibata, N. Chem. Commun. 2012, 48, 3632. (b) Kawai, H.; Kitayama, T.; Tokunaga, E.; Matsumoto, T.; Sato, H.; Shiro, M.; Shibata, N. Chem. Commun. 2012, 48, 4067. (8) Sanz-Marco, A.; García-Ortiz, A.; Blay, G.; Pedro, J. R. Chem. Commun. 2014, 50, 2275.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 271–272
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