Highly enantioselective copper(i)-catalyzed conjugate addition of 1,3-diynes to α,β-unsaturated trifluoromethyl ketones

Article abstract of DOI:10.1039/c5cc01676b

The conjugate diynylation of α,β-unsaturated trifluoromethyl ketones is carried out in the presence of a low catalytic load (2.5 mol%) of a copper(i)-MeOBIPHEP complex, triethylamine and a terminal 1,3-diyne. Pre-metalation of the terminal 1,3-diyne with stoichiometric or higher amounts of dialkylzinc reagent is not required. The corresponding internal diynes bearing a propargylic stereogenic center are obtained with good yields and excellent enantioselectivities. This journal is

Full text of DOI:10.1039/c5cc01676b

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DOI: 10.1039/C5CC01676B
Journal Name
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COMMUNICATION
Highly Enantioselective Copper(I)ꢀCatalyzed
Conjugate Addition of 1,3ꢀDiynes to α,βꢀUnsaturated
Trifluoromethyl Ketones
Cite this: DOI: 10.1039/x0xx00000x
†
Amparo SanzꢀMarco,a Gonzalo Blay,*a M. Carmen Muñoz,b and José R. Pedro*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
The conjugate diynylation of α,βꢀunsaturated trifluoromethyl addition of 1,3ꢀdiynes to aldehydes using
ketones is carried out in the presence of a low catalytic load ProPhenol/zinc catalyst. Later on, Pu,10 Tykwinski11 and
(2.5 mol %) of
copper(I)ꢀMeOBIPHEP complex, Wang12 developed their own versions of the asymmetric zincꢀ
a dinuclear
a
triethylamine and a terminal 1,3ꢀdiyne. Preꢀmetalation of the catalyzed addition of 1,3 diynes to aldehydes by using
terminal 1,3ꢀdiyne with stoichiometric or higher amounts of combinations of dialkylzinc with amino alcohol11,12 or
dialkylzinc reagent is not required. The corresponding binaphtholꢀtype10 ligands. In 2011, Ma described the
internal diynes bearing a propargylic stereogenic center are enantioselective addition of 1,3ꢀdiynylzinc reagents, generated
obtained with good yields and excellent enantioselectivities.
in situ from Me2Zn and terminal diynes, to aromatic ketones in
the presence of a Cu(II)ꢀhydroxycamphorꢀsulfonamide complex
and Me2Zn.13 On the other hand, the diynylation of different
kind of aldimines14 and fluorinated ketimines15 has been
reported by the same group using terminal diynes, Me2Zn and
The 1,3ꢀdiyne moiety is present in a large number of natural
and artificial molecules.1 Naturally occurring diynes are found
as metabolites in a variety of fungi, higher plants and marine
organisms, and many of them have important biological and
pharmacological properties ranging from antifungal to
anticancer activities.2 Diynes and oligoynes also have interest a
as probes of extended πꢀconjugation and can serve as active
components in optoelectronic devices.3 Furthermore, conjugate
diynes are intriguing building blocks due to the unique behavior
of alkynes, especially in transition metalꢀcatalyzed processes.4
In recent years the nucleophilic addition of terminal alkynes
to prochiral electrophiles has emerged as one of the most
efficient procedures for the synthesis of internal alkynes
bearing a propargylic stereogenic center. Thus considerable
success has been obtained in the enantioselective alkynylation
of carbonyl compounds5 and imines,6 and, more recently, in the
conjugate alkynylation of electrophilic double bonds.7
However, studies on enantioselective additions of 1,3ꢀdiynes
are more limited, and all the examples reported in the literature
involve the activation of terminal 1,3ꢀdiynes as diynylzinc
reagents, which requires in most of the cases the use of
stoichiometric or larger amounts of expensive dialkylzinc
reagents. Thus, after the pioneering work by Carreira in 2003,8
binaphtholꢀtype ligands. However,
a procedure for the
enantioselective addition of 1,3ꢀdiynes to electrophilic CꢀC
double bonds, i.e. enones, has not been reported so far.
Following our research interest in the conjugate
alkynylation reaction,7d,e,I,j we report in this communication our
results on the enantioselective copperꢀcatalyzed conjugate
addition of terminal 1,3ꢀdiynes to enones, a reaction without
any precedent in the literature. In our study, we have chosen
α,βꢀunsaturated trifluoromethyl ketones (Scheme 1) as
electrophiles because of the significance of fluorinated
compounds in medicinal chemistry.15 Trifluoromethyl
enones16,17 are a particularly challenging class of substrates for
conjugate asymmetric transformations since the presence of the
strongly electronꢀwithdrawing trifluoromethyl group not only
activates the alkene but also renders the ketone functionality
highly reactive making the control over regioselectivity
difficult. In fact, only two examples of alkynylation of
trifluoromethyl enones have been reported so far, both taking
place regioselectively on the carbonyl group.17a,18
on the use of 4 equivalents of Zn(OTf)2/Nꢀmethylephedrine to
achieve the addition of a terminal 1,3ꢀdiyne to an aliphatic
aldehyde, Trost9 reported in 2010 a catalytic enantioselective
This journal is © The Royal Society of Chemistry 2012
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DOI: 10.1039/C5CC01676B
all the studied ligands, only biarylphosphine L1 provided a
catalytic complex sufficiently active to promote the reaction
with this low catalytic load. The use of copper(I) triflate (Table
1, entry 12) provided similar results as [Cu(CH3CN)4]BF4,
whereas other solvents such as THF or CH2Cl2 decreased the
reaction rate, compound 3aa being obtained in lower yields
than in toluene, although still with good enantioselectivities
(Table 1, entries 13,14). Diethyl ether performed better than
THF, but with lower yield and ee than toluene (Table 1, entry
15). The use of other bases such as DIPEA did not improve the
results obtained with Et3N (Table 1, entry 16).
Table 2. Enantioselective conjugate addition of terminal 1,3ꢀdiynes 2 to
enones 1. Scope of the reaction.a
R1
2
R2
3
Yield
(%)
73
94
55
56
76
55
69
41
59
50
53
50
50
68
89
65
72
41
50
61
50
62
ee
(%)b
93
94
93
92
94
92
94
92
92
84
87
88
90
92
92
91
94
93
95
93
85
92
Scheme 1. Conjugate diynylation of α,βꢀunsaturated trifluoromethyl ketones and
ligands used in this study.
Entry
1
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
2a
2a
2a
2a
2a
2a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3ꢀFC6H4
4ꢀFC6H4
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ab
3ac
2ꢀMeC6H4
3ꢀMeC6H4
4ꢀMeC6H4
2ꢀBrC6H4
4ꢀ BrC6H4
2ꢀMeOC6H4 2a
4ꢀMeOC6H4 2a
2ꢀnaphthyl
PhCH2CH2
CH3(CH2)3
Table 1. Conjugate addition of phenylbutaꢀ1,3ꢀdiyne (1a) to enone 2a.
Screening of ligands and reaction conditions.
Entry
L
LꢀCu
1a
Et3N
solvent
t
Yield [%]
ee
(%)a
93
93
93
93
93
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(mol %) (equiv) (equiv)
(h)
1
2
3
4
5
6
7
8
9
L1
L1
L1
L1
L1
L1
L2
L3
L4
20
10
5
7.4
5
3
1.0
1.0
1.0
0.1
0.1
0
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1c
toluene 18
toluene 18
toluene 18
toluene 18
toluene 18
toluene 18
toluene 18
toluene 18
toluene 18
toluene 18
toluene 18
toluene 18
82
70
73
75
73
n.r.
n.r.
n.r.
n.r.
trace
trace
65
2a
2a
2a
10c
11c
12c
13
14
15
16
17
18
19
20
21
22d
1j
1k
5
3
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1.3
1l (CH3)2CHCH2 2a
1a
1a
1a
1a
1a
1a
1b
1a
1a
1a
Ph
Ph
Ph
Ph
2b
2c
2d 2ꢀMeOC6H4 3ad
2e 4ꢀMeOC6H4 3ae
10 L5
11 L6
12b L1
13 L1
14 L1
15 L1
16 L1
Ph
2f
2g
2g
2h
2i
3ꢀthienyl
PhCH2CH2 3ag
PhCH2CH2 3bg
6ꢀClC4H8
TIPS
3af
ꢀ
Ph
2ꢀMeC6H4
Ph
93
94
90
90
91
THF
CH2Cl2 48
Et2O 48
toluene 18
48
34
17
58
65
3ah
3ai
3aa
Ph
Ph
2a
Ph
a 1 (0.14 mmol), 2 (1.3 equiv), Et3N (0.1 equiv), [Cu(CH3CN)4]BF4 (2.5 mol
%), L6 (2.5 mol %), toluene, rt. b Determined by HPLC using chiral
stationary phases. c Reaction carried out with 10 mol % of catalyst.d Reaction
carried out with 0.6 mmol of 1a.
a Determined by HPLC using chiral stationary phases. b CuOTf·0.5 Tol was
used instead of [Cu(CH3CN)4]BF4. c DIPEA was used instead of Et3N.
In the onset of our investigation we studied the addition of
phenylꢀ1,3ꢀbutadiyne (1a, R1=Ph) to enone 2a (R2=Ph)
catalyzed by 20 mol % of [Cu(CH3CN)4]BF4 and (R)ꢀ
Under the best reaction conditions available (Table 1, entry 5)
we studied the scope of the reaction with various enones
1 and
diynes 2.‡ First, we conducted the addition of diyne 2a with
several trifluoromethyl enones bearing different substituents at
the β position of the double bond. The results are gathered in
Table 2. Good results were obtained with a variety of enones
bearing a substituted aromatic ring at this position. Good
enantiomeric excesses were obtained for enones bearing an
MeOBIPHEP 2 (L1) in toluene (Scheme 1, Table 1, entry 1).
Pleasantly, compound 3aa was obtained in 82% yield and 93%
ee under these reaction conditions. No products arising from
1,2ꢀaddition to the carbonyl group were observed. Further
studies with this catalytic system (Table 1, entries 2ꢀ6) showed
that the catalyst load could be reduced as low as 2.5 mol % and
the amount of base decreased to subꢀstoichiometric 0.1 equiv
aromatic ring substituted at either the ortho, metha or para
without
Furthermore, the amount of diyne was also reduced to only 1.3
equivalents with respect to enone. Other phosphine ligands L2
a significant effect on the reaction outcome.
positions (Table 2, entries 2ꢀ4). Aromatic rings bearing
electronꢀwithdrawing (Table 2, entries 5, 6) or electronꢀ
donating (Table 2, entries 7, 8) substituents were also tolerated
yielding the expected products with enantiomeric excesses
ꢀ
L6 were also tested (Table 1, entries 7ꢀ11). Surprisingly, from
2 | J. Name., 2012, 00, 1-3
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above 90%. Enone 1i bearing a bulky 2ꢀnaphthyl group also enantioselectivities. The reaction is broad in scope for a wide
reacted under the optimized conditions to give the diynylated range of trifluoromethyl ketones19 allowing variation of
product 3ia with good yield and high ee. Remarkably, the substituents on the enone βꢀcarbon as well as on the diyne. It
reaction could also be carried out with enones, featuring should be remarked that, unlike in other enantioselective
aliphatic groups on the βꢀcarbon, providing the corresponding diynylations of carbonyl compounds and imines previously
products 3jaꢀ3la with moderated yields but high enantiomeric reported in the literature, preꢀmetalation of the terminal diyne
excesses (84ꢀ88%, Table 2, entries 10ꢀ12), although a higher with stoichiometric amounts of a dialkylzinc reagent is not
catalytic load (10 mol %) was required in these cases.
required. Our results show that the transient diynylꢀcopper
Next, we tested the diyne scope (Table 2, entries 13ꢀ21). species formed from the terminal diyne and the copper(I)
Substituted phenylꢀ1,3ꢀbutadiynes bearing electronꢀdonating complex in the presence of an amine are sufficiently
(MeO) or electronꢀwithdrawing groups (F) on the phenyl group nucleophilic to react even with weak electrophiles. This may
reacted with compound 1a with variable yields but excellent anticipate the possibility of other enantioselective diynylation
enantioselectivities (Table 2, entries 13ꢀ16). The heterocyclic 3ꢀ reactions not requiring preꢀmetalation of terminal diynes with
thienylꢀ1,3ꢀbutadiyne (2f) reacted with 1a to give compound stoichiometric amounts of organometallic reagents in the future.
3af with 72% yield and 94% ee (Table 2, entry 17). Next, we
Ph
O
examined the reaction with aliphatic diynes, which reacted
similarly to aromatic diynes. 6ꢀPhenylꢀ1,3ꢀhexadiyne reacted
with enones 1a and 1b to give the corresponding chiral diynes
3ag and 3bg, respectively, with moderate yield but high
enantioselectivity (Table 2, entries 18ꢀ19). 8ꢀChloroꢀ1,3ꢀ
octadiyne (2h) reacted in a similar way to give compound 3ah
in 61% yield and 93% ee (Table 2, entry 20). These results
contrast with those observed in the copperꢀcatalyzed conjugate
alkynylation of βꢀtrifluoromethyl enones with terminal
monoynes where aliphatic alkynes reacted with lower yields
and enantioselectivities than aromatic and heteroaromatic
ones.7d Finally, silyldiyne 2i, which is an equivalent of 1,3ꢀ
butadiyne, could be reacted with enone 1a to give the
diynylated product 3ai with 85% ee (Table 2, entry 21),
showing the broad scope of the reaction regarding the diyne
nucleophile. The reaction between enone 1a and diyne 2a was
also carried out at a fourfold scale with a small decrease of
yield but without noticeable effect on the enantioselectivity
(Table 2, entry 22).
Ph
O
H2, Pd/C
CF3
Ph(CH2)4
4 (ee = 92%)
CF3
EtOAc, RT
89%
Ph
3aa (ee = 93%)
Ph OH
CF3
Ph
O
MeMgCl
CF3
CH3
Et2OꢀTHF, 0 o
78%
C
Ph
Ph
5 (dr = 4.5:1)
3aa (ee = 93%)
H3C
O
1. AgOTf
THF, RT
CF3
Ph
2. Separation
60%
H
Ph
6 (ee = 92%)
Ph
O
Ph
O
TBAF, AcOH
CF3
CF3
THF, 0 o
70%
C
H
TIPS
7(ee = 85%)
3ai (ee = 85%)
The absolute sterochemistry of compound 3af (Table 2, entry
15) was elucidated by Xꢀray crystallographic analysis (see
Figure S2 in the SI),19 and for the rest of the products it was
assigned on the assumption of a uniform reaction mechanism.
Scheme 2. Examples of chemical transformations carried out on diynes 3.
Financial support from the Ministerio de Economía y
Competitividad (MINECOꢀGobierno de España) and FEDER
(EU) (CTQ2013ꢀ47494ꢀP), and from Generalitat Valenciana
(ISIC2012/001) is gratefully acknowledged. A. S.ꢀM. thanks
the MINECO for a predoctoral grant (FPI program). Access to
NMR and MS facilities from the Servei Central de Suport a la
Investigació Experimental (SCSIE)ꢀUV is also acknowledged.
Some synthetic modifications of diynes
3 are presented in
Scheme 2. Thus, full hydrogenation of both triple bonds in 3aa
could be carried out over 10% Pd/C in ethyl acetate to give
trifluoromethyl ketone without any loss of optical purity. On
the other hand,
a
chiral tetrahydrofuran bearing
a
trifluoromethylated quaternary stereocenter could be obtained
after diastereoselective addition of methylmagnesium chloride
to compound 3aa followed by silverꢀcatalyzed cyclization. We
have also performed the desilylation of compound 3ai (70%
Notes and references
a Departament de Química Orgànica, Facultat de Química, Universitat de
València, C/ Dr. Moliner 50, 46100ꢀBurjassot, Spain. Fax: +(34)963544328;
Tel:+(34)962544336; Eꢀmail: jose.r.pedro@uv.es; gonzalo.blay@uv.es
b
yield) to give the chiral terminal diyne
TBAF and acetic acid in THF.
7 upon treatment with
Departament de Física Aplicada, Universitat Politècnica de València,
Camí de Vera s/n, Eꢀ46022ꢀValència, Spain.
†
Electronic Supplementary Information (ESI) available: Experimental
In summary, we have reported the first example of
enantioselective conjugate diynylation of enones. The reaction
requires only a small excess (1.3 equiv) of a terminal diyne and
is carried out in the presence of a low catalytic load of a
copper(I)ꢀbiphosphine complex (0.025 equiv) and an amine
(0.1 equiv) to provide the corresponding internal diynes bearing
procedures and characterization data for new compounds. Xꢀray data and
ortep plot for compound 3af. See DOI: 10.1039/c000000x/
‡
General procedure for the enantioselective conjugate diynylation
reaction: [Cu(CH3CN)4]BF4 (1.1 mg, 0.0034 mmol) and (R)ꢀL1 (4.1 mg,
0.0034 mmol) were added to a dried round bottom flask which was
purged with nitrogen. Toluene (0.2 mL) was added via syringe and the
a
propargylic
stereogenic
center
with
excellent
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C5CC01676B
mixture was stirred for 1.5 h at room temperature under nitrogen
atmosphere. Then, a solution of α,βꢀunsaturated trifluoromethyl ketone
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1
(0.144 mmol) in toluene (1.0 mL) was added via syringe, followed of
triethylamine (2 µL, 0.0144 mmol). The solution was stirred for 10 min at
8
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room temperature. Then a solution of 1,3ꢀdiyne
2 (0.188 mmol) in
toluene (1.0 mL) was added via syringe and the solution was stirred at
room temperature until the reaction was complete (TLC). The reaction
mixture was quenched with 20 % aqueous NH4Cl (1.0 mL), extracted
with CH2Cl2 (2 x 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:ethyl acetate mixtures
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4 | J. Name., 2012, 00, 1-3
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