Catalytic asymmetric conjugate addition of terminal alkynes to β-trifluoromethyl α,β-enones

Article abstract of DOI:10.1039/c3cc48508k

The first enantioselective conjugate alkynylation of β-trifluoromethyl α,β-enones using terminal alkynes and a taniaphos-Cu(I) complex as catalyst is described. Ketones bearing a trifluoromethylated propargylic chiral centre in the β-position were obtained with good yields and high enantiomeric excesses (up to 99%). The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc48508k

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Catalytic asymmetric conjugate addition of
terminal alkynes to b-trifluoromethyl a,b-enones†
Cite this: Chem. Commun., 2014,
50, 2275
Amparo Sanz-Marco, Andrea Garcıa-Ortiz, Gonzalo Blay* and Jose R. Pedro*
´
´
Received 7th November 2013,
Accepted 27th December 2013
DOI: 10.1039/c3cc48508k
www.rsc.org/chemcomm
The first enantioselective conjugate alkynylation of b-trifluoromethyl
a,b-enones using terminal alkynes and a taniaphos–Cu(I) complex as
catalyst is described. Ketones bearing a trifluoromethylated propargylic
chiral centre in the b-position were obtained with good yields and high
enantiomeric excesses (up to 99%).
Scheme 1 Conjugate alkynylation of b-trifluoromethyl enones.
In recent years the stereoselective introduction of perfluoroalkyl
substituents1 into organic molecules has attracted great attention strategy (ii) we envisioned that this kind of chiral centre may be
in the field of medicinal, agricultural and material chemistry, mainly created by asymmetric conjugate alkynylation of b-trifluoromethyl
due to the significant changes in the physical, chemical, and a,b-unsaturated carbonyl compounds, i.e. enones (Scheme 1).
biological properties that the introduction of fluorine atoms causes
The enantioselective conjugate alkynylation of a,b-unsaturated
in the parent molecules.2 In this context, molecules containing carbonyl compounds has been carried out by using pre-formed
chiral centres bearing a trifluoromethyl substituent3 have attracted metal alkynylides,13 or, more conveniently, by direct alkynylation
special interest due to the increasing occurrence of this motif in with terminal alkynes using Cu,14 Rh,15 Co,16 Zn,17 Ru (one example
biologically active compounds,4 but also in chiral reagents5 or in with 82% ee)18 and Pd (two examples with 39% and 38% ee)19
materials for optoelectronic devices.6 This kind of chiral centre has catalysts. However, none of these procedures has been applied with
been constructed by following two general approaches: (i) the direct fluorinated substrates.
trifluoromethylation of prochiral carbons and (ii) the functionaliza-
In this communication we describe the first example of enantio-
tion of trifluoromethylated prochiral carbons. Although straight- selective alkynylation of b-trifluoromethyl a,b-unsaturated ketones with
forward, there are few enantioselective examples using the first terminal alkynes, using copper(I)-complexes as catalysts. Although
approach7 and the second one has been more often preferred for convenient from the economic and environmental point of view, the
the construction of chiral centres bearing a trifluoromethyl group in use of copper catalysis in conjugate alkynylation is hampered by the low
an enantioselective fashion.3,8 On the other hand, chiral trifluoro- nucleophilicity of the intermediate copper alkynylides. In fact, the
methylated propargylic carbons are present in a number of bioactive copper(I)-catalyzed conjugated alkynylation of a,b-unsaturated carbonyl
compounds such as the HIV reverse transcriptase inhibitor efavirenz compounds has been only possible with highly activated substrates,
and its analogues.9 Recently some enantioselective procedures for i.e. Meldrum’s acid derivatives14a with two carbonyl groups on the
the synthesis of trifluoromethylated propargylic carbons having double bond a-carbon, or by the use of unsaturated thioamides
heteroatoms by trifluoromethylation of ynones,10 and alkynylation specially designed to simultaneously activate the alkyne and the double
of ketones11 or imines12 have been reported in the literature. bond via a soft Lewis acid/hard Brønsted base cooperative catalysis.14b–d
However, a catalytic procedure for the enantioselective synthesis of Despite these limitations, we believed that the presence of the strong
trifluoromethylated propargylic carbons without heteroatoms has electron-withdrawing trifluoromethyl group should increase the electro-
not been reported yet, to the best of our knowledge. By following philicity of the double bond by lowering the LUMO energy level,20 thus
allowing the reaction to take place.
In the onset of our investigation we studied the addition of
´
`
´
`
phenylacetylene (1a, R1 = Ph) to enone 2a (R2 = Ph) in the
presence of [Cu(CH3CN)4]BF4, a variety of ferrocene-based
phosphane ligands (Fig. 1) and triethylamine in toluene at 60 1C
(Table 1, entries 1–5).‡ The best result was obtained with ligand L4
Departament de Quımica Organica, Facultat de Quımica, Universitat de Valencia,
C/ Dr. Moliner 50, 46100-Burjassot, Spain. E-mail: jose.r.pedro@uv.es,
gonzalo.blay@uv.es; Fax: +34-963544328; Tel: +34-962544336
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization of all new compounds. See DOI: 10.1039/c3cc48508k
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Table 2 Enantioselective conjugate alkynylation of enones 2 with alkynes 1.
Scope of the reactiona
Entry
1
R1
2
R2
3
Yield (%) eeb (%)
1
2
3
4
5
6
7
8
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1b 4-MeOC6H4
1c 4-FC6H4
1d 4-ClC6H4
1b 4-MeOC6H4
1c 4-FC6H4
1d 4-ClC6H4
1e 2-MeOC6H4
1f 3-FC6H4
2a Ph
2b 4-MeC6H4
2c 4-MeOC6H4 3ac 64
2d 4-ClC6H4 3ad 94
2e 4-NO2C6H4 3ae 54
2f 2-Naphthyl 3af 87
2g 2-Thienyl
2a Ph
2a Ph
3aa 70
3ab 66
85
80
80
80
70
84
90
83
80
77
93
90
84
98
99
86
88
92
79
82
—
3ag 99
3ba 90
3ca 77
3da 60
3bg 96
3cg 99
3dg 81
3eg 86
3fg 97
3gg 68
3hg 80
3ig 51c
9
Fig. 1 Ligands tested in the addition of phenylacetylene (1a, R1 = Ph), to
trifluoromethyl enone 2a (R2 = Ph).
10
11
12
13
14
15
16
17
18
19d
20d
21d
2a Ph
2g 2-Thienyl
2g 2-Thienyl
2g 2-Thienyl
2g 2-Thienyl
2g 2-Thienyl
Table 1 Enantioselective conjugate addition of phenylacetylene (1a, R1 = Ph)
to trifluoromethyl enone 2a (R2 = Ph). Screening of ligands and conditionsa
1g 3,5-(MeO)2C6H3 2g 2-Thienyl
1h 3-Thienyl
1i PhCH2CH2
1a Ph
1b 4-MeOC6H4
1a Ph
2g 2-Thienyl
2g 2-Thienyl
Entry Ligand T (1C) Solvent
Time (h) Yield (%) eeb (%)
2h PhCH2CH2 3ah 30e
1
2
3
4
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
L4
L4
60
60
60
60
60
60
40
rt
40
40
40
40
40
40
Toluene 72
Toluene 72
Toluene 48
Toluene 72
Toluene 72
Toluene 72
Toluene 72
Toluene 96
Toluene 96
26
45
93
64
47
30
64
53
40
40
56
20
70
26
14
10
42
78
75
78
80
80
76
73
81
79
85
81
2h PhCH2CH2 3bh 28 f
2i n-Bu
3ai
—
a
1 (7.5 equiv.), 2 (1.0 equiv.), Et3N (1.0 equiv.), [Cu(CH3CN)4]BF4
5
b
6c
7
(0.2 equiv.), L4 (0.2 equiv.), THF, 40 1C, 72 h. Determined by HPLC.
c
Starting material 2g (17%) was recovered. d Reaction carried out for 90 h.
e Starting material 2h (51%) was recovered. f Starting material 2h (50%) was
8
9d
10
11
12
13
14
recovered.
PhNO2
Anisole
TBME
THF
96
96
96
72
heteroaromatic ring substrates were also applicable, giving
the expected products with good results (entries 6 and 7).
Remarkably, the presence of the thienyl ring enhanced both the
reactivity and enantioselectivity, product 3ag being obtained quanti-
tatively with 90% ee (entry 7). The reaction also allowed variation in
the alkyne. Substituted phenylacetylenes bearing electron-donating
or electron-withdrawing groups at different positions (entries 8–16)
Dioxane 96
a
1a (7.5 equiv.), 2a (1.0 equiv.), Et3N (1.0 equiv.), [Cu(CH3CN)4]BF4 (0.2 equiv.),
ligand (0.2 equiv.), unless if otherwise stated. b Determined by HPLC.
c [(CuOTf)2Tol] instead of [Cu(CH3CN)4]BF4. d iPr2NH instead of Et3N.
(taniaphos 1) that provided compound 3aa (R1 = R2 = Ph) in reacted with enones 2a and 2g to give the alkynylation products with
64% yield and 78% ee. The use of [(CuOTf)2Tol] instead of good yields and enantioselectivities, with nearly 100% ee for the
[Cu(CH3CN)4]BF4 resulted in a decrease of the reaction yield addition of 2-methoxyphenylacetylene and 3-fluorophenylacetylene
(entry 4 vs. entry 6). Changing the base to diisopropylamine (entries 14 and 15, respectively). Again the 2-thienyl derived enones
decreased both the yield and enantioselectivity (entry 4 vs. entry 9). showed higher enantioselectivity with respect to the phenyl enone.
Next, we examined the effect of the temperature. When the The reaction could be carried out also with heterocyclic alkynes
reaction was carried out at 40 1C a slight increase of the ee was such as 3-ethynylthiophene (1h) that reacted with enone 2g
obtained (entry 7). However, a further decrease of the temperature to give compound 3hg with good yield and excellent enantio-
to rt was detrimental for the yield without improving the enantio- selectivity (entry 17). Finally, the reaction also worked with
selectivity (entry 8). Finally, we tested several solvents. The best aliphatic alkynes such as 4-phenyl-1-butyne (1i), although in
results were observed in THF, which allowed obtaining compound this case the reaction was slow and the alkynylation product 3ig
3aa in 70% yield and 85% ee (entry 13).
(entry 18) was obtained in moderate yield after 72 h but with
Under the optimal reaction conditions§ (Table 1, entry 13) excellent enantioselectivity (92% ee).
various b-trifluoromethyl aryl enones 2 and alkynes 1 were screened
Enones bearing an aliphatic group R2 attached to the
(Table 2). Noteworthily, the electronic nature of the substituent carbonyl group were also tested, which were less reactive than
at the phenyl ring of the enones 2 had little influence on the the aromatic ones. Thus, enone 2h (R2 = PhCH2CH2) reacted
enantioselectivity of the reaction (entries 1–4), although the slowly with phenylacetylene (1a) and p-methoxyphenylacetylene
presence of a very strong electron-withdrawing nitro group (1b) to give the corresponding products 3ah and 3bh with low
brought about an appreciable decrease of both reactivity yields, although with good enantioselectivities (entries 19 and 20),
and enantioselectivity (entry 5). Moreover, fused ring and after 90 h. However, the reaction of phenylacetylene (1a) with
2276 | Chem. Commun., 2014, 50, 2275--2278
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alkynes in the presence of a Cu(I)–taniaphos complex to give
ketones having a trifluoromethylated propargylic stereogenic
centre in b to the carbonyl group with good yields and high
enantiomeric excesses. These compounds have been shown to be
building blocks for the synthesis of chiral trifluoromethylated hetero-
cycles such as 4-trifluoromethyl-4H-pyrans upon iodocyclisation.
Research toward the extension of this procedure to other
perhalogenated substrates and new applications of the resulting
products are underway in our laboratory.
´
Financial support from the Ministerio de Economıa y
˜
Competitividad (Gobierno de Espana) 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. We thank
Professor Tsutomu Konno, Kyoto Institute of Technology, for sending
us complete characterization data of compound (E,R)-5.
Scheme 2 Determination of the absolute stereochemistry of compound
3aa.
enone 2i (R2 = n-Bu) did not show any appreciable advance after a
similar time (entry 21).
The absolute stereochemistry of compound 3aa was determined
by chemical correlation with compound 5 of known stereochemistry
(Scheme 2). Hydroalumination of the triple bond of a 80% ee sample
of compound 3aa with LiAlH4 under THF reflux took place with
concomitant reduction of the ketone to give, after hydrolysis, a
mixture of two epimeric E-allylic alcohols 4, which were oxidized
with pyridinium chlorochromate (PCC) to the E-enone 5.8g,h Com-
pound 5 prepared in this way showed opposite optical rotation sign
and elution times in chiral HPLC (Chiralpak AD-H) to (E,R)-5,
indicating that our compound 5 and, therefore, compound 3aa
were both of S-configuration at the stereogenic centre. For the rest of
the compounds 3, the stereochemistry was assigned upon the
assumption of a common stereogenic mechanism.
Some synthetic modifications of compound 3aa that shows the
synthetic potential of the b-alkynyl-b-trifluoromethyl ketones are
presented in Scheme 3. Thus, further to the trans hydrogenation of
the triple bond shown in Scheme 1, hydrogenation over the Lindlar
catalyst yields compound 6, having a trifluoromethylated allylic
carbon with the Z-double bond. More interestingly, iodine in basic
medium promotes the cyclisation of compound 3aa to give the
highly substituted chiral 4-trifluoromethyl-4H-pyran 7 without any
lost of optical purity.
Notes and references
‡ We also tested some catalysts based on pyBOX-Cu(I) complexes which
were inactive.
§ Typical procedure for the enantioselective alkynylation: [Cu(CH3CN)4]BF4
(5.7 mg, 0.018 mmol) and L4 (12.4 mg, 0.018 mmol) were placed in a dry
round bottom flask which was purged with nitrogen. THF (0.2 mL) was
added and the mixture was stirred for 1.5 h at room temperature. Then, a
solution of b-trifluoromethyl-a,b-enone 2 (0.090 mmol) in dry THF (1.0 mL)
was added via a syringe, followed by triethylamine (12.5 mL, 0.090 mmol). The
solution was placed in a bath at 40 1C. After 10 min, alkyne 1 (0.675 mmol)
was added and the solution was stirred at 40 1C under nitrogen until the
reaction was complete (TLC). The reaction mixture was quenched with 20%
aqueous NH4Cl (1.0 mL), extracted with CH2Cl2 (2 Â 15 mL), washed
with brine (15 mL), dried over MgSO4 and concentrated under reduced
pressure. Purification by flash chromatography on a silica gel eluting with
hexane : diethyl ether mixtures afforded compound 3.
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Scheme 3 Synthetic modifications of compound 3aa.
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