Highly enantioselective copper(I)-catalyzed conjugate addition of terminal alkynes to 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones: New ester/amide surrogates in asymmetric catalysis

Article abstract of DOI:10.1002/chem.201303920

A highly enantioselective copper-catalyzed conjugate alkynylation of monoactivated enones, namely 1,1-difluoro-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 β-alkynylated difluoro(phenylsulfonyl) ketones can be converted into the corresponding β-alkynylated difluoro- and trifluoromethyl ketones, esters and amides. This is the first example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2- ones as substrates in an enantioselective reaction, which have been shown to be new ester/amide surrogates. Copyright

Full text of DOI:10.1002/chem.201303920

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-2-
ones: New Ester/Amide Surrogates in Asymmetric Catalysis
Amparo Sanz-Marco, Andrea Garcꢀa-Ortiz, Gonzalo Blay,* Isabel Fernꢁndez, and
Josꢂ 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]
Abstract: A highly enantioselective copper-catalyzed con-
catalysts. Despite these advances, there are still some limita-
tions regarding the enantioselectivity and the substrate or
alkyne scope. In particular, the possibility to chemically manip-
ulate 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 inter-
mediate copper–alkynylides. In fact, alkynyl substituents have
been used as dummy ligands in mixed organocuprates, per-
mitting 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 over-
come by the use of doubly activated alkenes, namely Meldrum
acid derivatives (Scheme 1a),[4] or by the use of unsaturated
jugate alkynylation of monoactivated enones, namely 1,1-
difluoro-1-(phenylsulfonyl)-3-en-2-ones, is described. The
reaction products are obtained with good yields and ex-
cellent enantioselectivities (from 92 to 99% ee). The b-al-
kynylated difluoro(phenylsulfonyl) ketones can be convert-
ed into the corresponding b-alkynylated difluoro- and tri-
fluoromethyl ketones, esters and amides. This is the first
example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3-
en-2-ones as substrates in an enantioselective reaction,
which have been shown to be new ester/amide surro-
gates.
The interest in the chemistry of alkynes has experienced a pro-
gressive growth in the last years.[1,2] The asymmetric conjugate
addition of terminal alkynes to electrophilic double bonds con-
jugated with electron-withdrawing functional groups, especial-
ly in b-substituted a,b-unsaturated carbonyl and related com-
pounds, 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 proce-
dures for the alkynylation of enones and related compounds
have been carried out by using preformed alkynyl organome-
tallic 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 cata-
lytic 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. Garcꢀa-Ortiz, Prof. Dr. G. Blay, I. Fernꢁndez,
Prof. Dr. J. R. Pedro
thioamides that are especially designed to simultaneously acti-
vate the alkyne and the double bond through soft Lewis acid/
hard Brønsted base cooperative catalysis (Scheme 1b).[5]
Department de Quꢀmica Orgꢂnica-Facultat de Quꢀmica
Universitat de Valꢃncia
C/Dr. Moliner 50, 46100 Burjassot (Valꢃncia) (Spain)
Fax: (+34)963544328
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 inter-
esting, because simple unsaturated esters and amides have
E-mail: gonzalo.blay@uv.es
jose.r.pedro@uv.es
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303920.
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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, im-
proved coordination to the chiral catalyst, and easy replace-
ment by other groups.
Table 1. Screening of ligands in the reaction between phenylacetylene
(2a) and 1a to give 3aa.[a]
Entry
L
L–CuI
[mol%]
2a
[equiv]
t
[h]
Yield
[%]
ee
[%][b]
1
2
3
4
5
6
7
8[c]
9
L1
L2
L3
L4
L5
L6
L7
L7
L7
L7
L7
20
20
20
20
20
20
20
20
10
5
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
–
59
–
66
34
51
62
80
78
71
62
70
54
55
38
40
98
93
96
94
97
Following our interest on enantioselective alkynyla-
tions,[3 g,h,12] we have studied the copper-catalyzed conjugate
alkynylation
of
1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones
(Scheme 1c). These compounds are readily prepared by treat-
ment of the appropriate a,b-unsaturated methyl esters with di-
fluoromethyl phenyl sulfone and lithium hexamethyl disilazide
(LHMDS).[13] We envisioned that the presence of two strong
electronegative fluorine atoms and a sulfone electron-with-
drawing group next to the carbonyl group would largely en-
hance 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, im-
proving 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 indus-
try.[16] Herein, we will show for the first time that the 1,1-di-
fluoro-1-(phenylsulfonyl)-2-one moiety can be easily trans-
formed into ester or amide groups under very mild conditions.
In initial investigations, we examined the copper(I)-catalyzed
addition of phenylacetylene (2a) to (E)-1,1-difluoro-4-phenyl-1-
(phenylsulfonyl)but-3-en-2-one (1a) in the presence of [Cu-
(CH3CN)4][BF4], a variety of phosphane ligands and triethyl-
10
11
20
[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].
the number of alkyne equivalents can be diminished without
any effect on the enantiomeric excess of compound 3aa, al-
though the reaction rate and the yield slightly decreases (en-
tries 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 substi-
tuted 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-(phenyl-
sulfonyl)-3-en-2-ones.[a]
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 Ph
2a Ph
2a Ph
2a Ph
2a Ph
48 3aa 80
24 3ba 90
48 3ca 80
48 3da 75
72 3ea 77
96 3ea 70
48 3 fa 82
96 3 fa 83
48 3ga 77
98
99
97
97
96
94
99
98
97
95
–
98
97
97
99
97
94
98
92
1b 2-BrC6H4
1c 3-BrC6H4
1d 4-BrC6H4
1e 4-MeOC6H4 2a Ph
1e 4-MeOC6H4 2a Ph
1 f 2-MeC6H4
1 f 2-MeC6H4
1g 4-MeC6H4
1h 2-naphthyl 2a Ph
1j cyclohexyl 2a Ph
1a Ph
1a Ph
1a Ph
1a Ph
1g 4-MeC6H4
1g 4-MeC6H4
1a Ph
2a Ph
2a Ph
2a Ph
72 3ha 50
[d]
–
3ja
–
2b 4-MeOC6H4 72 3ab 86
2b 4-MeOC6H4 96 3ab 67
2c 4-FC6H4
2d 4-ClC6H4
2b 4-MeOC6H4 48 3gb 84
2c 4-FC6H4
2e 3-thienyl
Scheme 2. Copper(I)-catalyzed conjugate addition of phenylacetylene (2a)
to compound 1a and ligands used in this study.
72 3ac 69
48 3ad 90
72 3gc 69
72 3ae 70
amine (Scheme 2, Table 1). The best results were obtained with
biphenylphosphane L7 that provided the expected compound
3aa 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 3aa being obtained with 78% yield
and 93% ee (entry 8). On the other hand, the catalyst load or
1a Ph
2 f cyclopropyl 96 3af
82
[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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substituted with either electron-withdrawing or electron-do-
nating groups attached to different positions. For a same sub-
stituent, slightly higher yields and enantioselectivities were
found for ortho- and meta- substituted phenyl rings with re-
spect 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 Car-
reira with Meldrum’s acid derivatives.[4] The reaction allowed
also a bulky 2-naphthyl substituent, but in this case the alkyny-
lated product 3ha was obtained with lower yield (50%) al-
though with excellent enantioselectivity (entry 10). The enan-
tioselectivities obtained with these substrates (95–99% ee),
were higher than those obtained for the addition of phenyl-
acetylene to Meldrum’s acid derivatives bearing aromatic rings
removal of the THF, treatment of the enol ether with Select-
fluor 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 CÀS bond in compound 3aa we dis-
covered that the whole difluoro(phenylsulfonyl)methyl moiety
was replaced by a methoxy group upon treatment with mag-
nesium in methanol to give methyl ester 6. After some optimi-
zation, ester 6 could be obtained in 93% yield upon treatment
of 3aa with MeOH in THF at 08C 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 3aa with benzylamine in
THF that gave amide 7 in 73% yield (Scheme 4). These trans-
in the
b
position with the biphasic pinap-CuI system
(Scheme 1a, R1 =Ar, 64–87% yield, 83–90% ee)[4] and similar to
those obtained with the CuI-catalyzed addition of phenylacety-
lene to aromatic thioamides (Scheme 1b, R1 =Ar, 72–98%
yield, 94–98% ee).[5a] Unfortunately, the reaction did not take
place with the aliphatic compound 1j, bearing a cyclohexyl
group (entry 11). We attribute this lack of reactivity to deproto-
nation 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 re-
acted with compounds 1a and 1g with excellent enantioselec-
tivities (entries 12–17). 3-Thienylacetylene (2e) reacted with 1a
to give compound 3ae with 70% yield an 98% ee (entry 18),
while cyclopropylacetylene (2 f) reacted with 1a to give 3af
with a remarkable 82% yield and 92% ee (entry 19). Finally, al-
though 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).
Scheme 4. Synthesis of b-alkynylated esters and amides from compound
3aa.
formations demonstrate the potential use of 1,1-difluoro-1-
(phenylsulfonyl)-3-en-2-ones as unsaturated ester/amide surro-
gates in asymmetric catalysis, which is an important issue since
simple esters and amides are difficult substrates in relay asym-
metric 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.
To show the synthetic versatility of the difluoro(phenylsulfo-
nyl)methyl moiety, we carried out different modifications of
this moiety in compound 3aa. Given the importance of fluori-
nated compounds as pharmaceuticals and agrochemicals, we
studied the substitution of the phenylsulfonyl group by a hy-
drogen or a fluorine atom to give the corresponding b-alkyny-
lated difluoromethyl and trifluoromethyl ketones (Scheme 3).
Thus treatment of compound 3aa with Mg and TMSCl in THF
provided an intermediate enol ether.[13b] Quenching of this re-
action mixture with aqueous HF gave the corresponding di-
fluoromethyl ketone 4 in 83% yield. On the other hand, after
The determination of the absolute stereochemistry of com-
pound 3aa was carried out by chemical correlation with com-
Scheme 3. Synthesis of b-alkynylated difluoromethyl and trifluoromethyl ke-
tones from compound 3aa.
Scheme 5. Determination of the absolute stereochemistry of compound
3aa.
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Communication
pound 9 of known stereochemistry (Scheme 5).[18] A sample of
ester 6 (91% ee), prepared from compound 3aa of the same
optical purity, was hydrogenated over Pd/C to give the saturat-
ed 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 ob-
tained 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 3aa are of R
configuration at the stereogenic center. For the rest of com-
pounds 3, the stereochemistry was assigned upon the assump-
tion of a common stereochemical mechanism.
Keywords: alkynes
addition · enones · fluorine compounds
·
asymmetric catalysis
·
conjugate
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In summary, we have developed a highly enantioselective
copper-catalyzed conjugate alkynylation of monoactivated a,b-
unsaturated ketones, namely 1,1-difluoro-1-(phenylsulfonyl)-3-
en-2-ones. The addition of phenylacetylene derivatives, 3-thie-
nylacetylene 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 enan-
tioselectivities. The resulting products are synthetic precursors
of b-alkynylated difluoromethyl and trifluoromethyl ketones.
On the other hand, the alkynylated products can be conven-
iently transformed into b-alkynylated ester or amides by treat-
ment with an alcohol or an amine, respectively. This is the first
example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-
ones as substrates in an enantioselective reaction. New appli-
cations of these substrates as ester/amide surrogates in asym-
metric catalysis are underway.
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Experimental Section
General procedure for the enantioselective alkynylation re-
action
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[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 triethyl-
amine (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 (2ꢄ
15 mL), washed with brine (15 mL), dried over MgSO4, and concen-
trated under reduced pressure. Purification by flash chromatogra-
phy on silica gel eluting with hexane/CH2Cl2 mixtures afforded
compound 3.
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Acknowledgements
Financial support from the Ministerio de Economꢀa y Competi-
tividad (Gobierno de EspaÇa) and FEDER (European Union)
[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.
(CTQ2009–13083)
and
from
Generalitat
Valenciana
[14] For some examples on the use of a’-sulfonyl enones as chelating sub-
strates in metal-catalyzed reactions, see: a) E. Wada, H. Yasuoka, S. Kane-
masa, 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.
(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.
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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.
19F NMR (282 MHz, CDCl3) d=À109.7 ppm (s, 2F); IR (neat): n˜ =3485,
1449, 1334, 1147 cmÀ1; HRMS (ESI): m/z calcd for C16H15F2O3S: 327.0861;
found: 327.0860 [MÀH+] (see the Supporting Information).
[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. Mꢆller, C. Faeh, F. Diederich, Science 2007, 317, 1881.
[17] Compound 1j 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
1j, was obtained after column chromatography eluting with hexane/
EtOAc. 1H NMR (300 MHz, CDCl3) d=8.07–8.00 (m, 2H), 7.78–7.71 (m,
1H), 7.66–7.56 (m, 2H), 6.36 (d, J=
[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 com-
pound 9, measured by chiral HPLC (Chiralcel OD-H), with those de-
scribed in the literature (ref. [18]), we established that the major enan-
tiomer was R (91% ee). However, our material showed the opposite op-
tical 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 com-
pound 9 (see the Supporting Information), we relied on the HPLC data
to assess the absolute stereochemistry of compound 9.
5.9 Hz, 1H), 5.85 (d, J=5.9 Hz, 1H),
4.29 (s, 1H), 1.77–1.55 (m, 3H), 1.55–
1.30 ppm
(m,
7H);
13C NMR
(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);
Received: October 7, 2013
Published online on December 12, 2013
Chem. Eur. J. 2014, 20, 668 – 672
www.chemeurj.org
672
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