Copper(I) iodide dimethyl sulfide catalyzed 1,4-addition of alkenyl groups from alkenyl-alkylzincate reagents

Article abstract of DOI:10.1016/j.tetlet.2007.01.041

The presence of catalytic quantities of the copper(I) iodide dimethyl sulfide complex {(CuI)₄(SMe₂)₃} with alkenyl-alkylzincate reagents allows for the complete chemoselective 1,4-addition of various alkenyl groups to a nu

Full text of DOI:10.1016/j.tetlet.2007.01.041

Tetrahedron Letters 48 (2007) 1761–1765
Copper(I) iodide dimethyl sulfide catalyzed 1,4-addition
of alkenyl groups from alkenyl-alkylzincate reagents
Amer El-Batta and Mikael Bergdahl*
Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA 92182-1030, United States
Received 24 September 2006; revised 7 January 2007; accepted 9 January 2007
Available online 13 January 2007
Abstract—The presence of catalytic quantities of the copper(I) iodide dimethyl sulfide complex {(CuI)4(SMe2)3} with alkenyl-alkyl-
zincate reagents allows for the complete chemoselective 1,4-addition of various alkenyl groups to a number of a,b-unsaturated car-
bonyl compounds in CH2Cl2 at +35 °C. The 1,4-addition of the mixed vinylzincate reagent is more efficient than the corresponding
vinylzirconocene reagent in CH2Cl2 or THF. By employing CH2Cl2 as a medium, the asymmetric copper-catalyzed addition of the
vinyl groups to a,b-unsaturated imides is facilitated by the presence of TMSOTf to give excellent yields and up to 95:5 diastereo-
meric ratios (dr).
Ó 2007 Elsevier Ltd. All rights reserved.
The use of Schwartz’s reagent1a–c {Cp2Zr(H)Cl}1d in the
regioselective hydrozirconation of alkynes is a versatile
method for making synthetically useful organometallic
reagents. Although organozirconocenes have been used
in many applications in organic chemistry,2 the trans-
metalation from zirconium to zinc has been demon-
strated to be a more efficient subsequent procedure
toward the creation of carbon–carbon bonds.3 In a
sharp contrast to the more reactive organolithium or
Grignard reagents, the corresponding organozinc
reagents have distinguished themselves to be more
compatible with various functional groups.4 The process
to form such sufficiently nucleophilic alkenylzincate
intermediates and their subsequent 1,2-addition reac-
tions to aldehydes was introduced by Wipf,3g and more
recently the enantioselective 1,2-vinylation of ketones
was reported by Walsh.5
sary for the activation of the vinylzirconocene reagents
to be able to undergo conjugate addition reactions.
We recently reported7 the direct conjugate addition of
the vinyl group in high yields from the corresponding
alkenylzirconocene reagent in the presence of the
CuIÆ0.75DMS catalyst (DMS = dimethyl sulfide) in
THF conducted at 40 °C. We now report that the
CuIÆ0.75DMS complex is also a good catalyst for selec-
tive and high yield 1,4-additions of vinyl groups using
mixed alkenyl-alkylzincate reagents in CH2Cl2 at 35 °C.
The simple protocol reported herein is initiated by the
hydrozirconation of an alkyne using Cp2Zr(H)Cl in
CH2Cl2, followed by in situ transmetalation with Et2Zn
(Scheme 1).8 The corresponding alkenylzincate reagent
is subsequently exposed to 10 mol % of the
CuIÆ0.75DMS catalyst and the enone. The reaction of
the 1-hexenylzincate with benzalacetone utilizing the
CuIÆ0.75DMS complex to give the 1,4-product in 94%
illustrates the efficiency of this Cu(I) catalyst.9 Not only
is the formation of the 1,2-addition product completely
circumvented in this process, but also the 1,4-addition of
Copper(I) catalysis in promoting the 1,4-addition of
alkenyl groups is not only a very useful transformation
in synthetic chemistry,6 but it is also a complementary
resource to the use of more reactive discrete alkenyl-
cuprate reagents. Moreover, applying a stoichiometric
quantity of the copper(I) source makes the reaction less
appealing, particularly for scale-up. In order to maintain
the catalytic efficiency of Cu(I), reagents such as Me3Zn-
Li,2e Me2CuLi,2f or MeLi2g have been reported neces-
Et2Zn
"Cu"
ZrCp2Cl
ZnEt
R
R
CH2Cl2
10 mol%
Ph
O
Ph
R
O
94%; R =
n-Bu (1)
Me
Me
"Cu" = CuI•0.75DMS
35 °C, 6 h
Keywords: Copper catalyzed; Conjugate addition; 1,4-Addition.
*
Corresponding author. Tel.: +1 619 594 5865; fax: +1 619 594
4634; e-mail: bergdahl@sciences.sdsu.edu
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.041

1762
A. El-Batta, M. Bergdahl / Tetrahedron Letters 48 (2007) 1761–1765
the vinylzincate reagent is faster than the corresponding
vinylzirconocene reagent in CH2Cl2. Moreover, the cop-
per-catalyzed addition of vinylzincate reagent in CH2Cl2
is not only faster, but the yield of the 1,4-addition prod-
uct is higher than the corresponding copper-catalyzed
1,4-addition of vinylzirconocene reagents in THF.7
The unique efficiency of the dimethyl sulfide-containing
copper(I) iodide complex10 in the conjugate addition of
alkenylzinc reagents is demonstrated using a number of
enals and enones (Table 1). The results exemplify the
capability and the synthetic potential of this protocol.
It is important to note the efficiency of the Et2Zn reagent
Table 1. CuIÆ0.75DMS-catalyzed 1,4-additions of vinyl groups to enals and enones in CH2Cl2
Entry
Substrate
Alkynea
Reaction timeb
Product
Ph
Yieldc,d
82e 33f
O
Ph
O
1
6 h
2
Ph
Ph
Me
Me
Ph
O
2
3
4
6 h
6 h
6 h
89e 29f
BocHN
3
BocHN
Me
Ph
O
Et
82e
4
Et
Me
Et
Et
Ph
O
84e
5
TMS
TMS
O
Me
O
Me
5
6
7
8
2 h
2 h
67e,g 27f
Me
C4H9
6
C4H9
O
O
O
74e
Ph
7
8
Ph
2 h
83e 39f
C4H9
C4H9
Me
O
O
30 min
9
88e 41f
C4H9
C4H9
H
Me
H
Me
O
O
9
30 min
4 h
82e
10
12
BocHN
BocHN
H
Me
Ph
O
10
11
95e 39f
C4H9
C4H9
Et
Me
Ph
Et
Me
O
O
11
12
13
4 h
6 h
6 h
93e
BocHN
BocHN
Et
O
91e 51f
13
C4H9
Ph
C4H9
Ph
Ph
Ph
Ph
O
79e
14
Ph
a 1.0 equiv alkyne versus enone.
b 35 °C in CH2Cl2.
c Isolated and purified material (%).
d 10 mol % CuIÆ0.75DMS versus alkyne.
e Reaction conducted with vinylzincate reagent.
f Reaction conducted with vinylzirconocene reagent (absence of Et2Zn).
g Trans–cis ratio, ꢀ20:1.

A. El-Batta, M. Bergdahl / Tetrahedron Letters 48 (2007) 1761–1765
1763
in CH2Cl2. Attempts to conduct the reaction using the
vinylzirconocene intermediate directly in CH2Cl2, with-
out in situ transmetalation with the dialkylzinc reagent,
resulted in lower yields of the desired products and
recovered starting materials (e.g., entry 1). The Cu(I)
catalyst promotes the selective 1,4-addition transfer of
the vinyl group over the ethyl group11 from the mixed
alkenyl-alkylzinc reagent, which presumably is due to
the pre-formation of a more favorable sp2-hybridized
carbon to copper bond. Our results show that not only
terminal alkynes, but also internal alkynes are favored
in the 1,4-addition of vinyl groups. Functional groups
such as TMS and NHBoc, do not create drawbacks.
The fact that good chemical yields are obtained with en-
ones and enals implies that there is little, if any, oligo-
merization occurring. Normally, this is a common side
reaction between aldehydes and the enolates generated
from conventional Gilman type organocopper reagents.
worth mentioning that the CuIÆ0.75DMS catalyzed
1,4-addition of the vinylzincate reagent in solvents such
as THF or toluene gave at best 60% of the conjugate
product 1 after 6 h at 35 °C, while the yield is consider-
ably higher in CH2Cl2 using the same reaction
conditions.
Because of the increased efficiency of the mixed vinylzin-
cate reagent using CH2Cl2, we broadened the scope of
this copper-catalyzed reaction methodology to include
a,b-unsaturated imides. We found that the presence of
TMSOTf12 not only safeguards the efficiency of the
CuIÆ0.75DMS as a catalyst in 1,4-addition type reac-
tions of the vinyl group using the mixed alkenyl-alkyl-
zincates to the N-enoyl derived oxazolidinones,13–15
but TMSOTf also achieves 1,4-products in high yields
as well as diastereomeric ratios up to 95:5 (Table 3).
In the absence of TMSOTf, the reaction using the vinyl-
zincate reagents to the imides requires stoichiometric
quantities of the CuIÆ0.75DMS in order to sustain a
respectable yield of the 1,4-addition products. The re-
sults suggest that TMSOTf is a more efficient Lewis acid
with the imides than the corresponding vinylzincate
species. In the absence of Et2Zn, the intermediate vinyl-
zirconocene reagent is too unreactive to undergo Cu(I)-
catalyzed 1,4-transfer of the vinyl group to the imides
in THF, even in the presence of 1 equiv of TMSOTf (en-
tries 1, 3, and 6). Nor is the TMSOTf powerful enough
to assist in the 1,4-addition of the vinylzincate reagent16
in the absence of the CuIÆ0.75DMS catalyst, which then
underscores the crucial role of Cu(I) in these reactions.
The catalytic efficiency of the CuIÆ0.75DMS complex is
unique when it is compared to other complementary
copper(I) and copper(II) sources in the 1,4-addition of
a vinyl group utilizing a mixed vinylzincate reagent
(Table 2). It is not entirely surprising that the mixed
alkenyl-alkylzinc reagent displays both 1,4- and 1,2-
addition pathways with benzalacetone in CH2Cl2 in the
absence of a Cu(I) catalyst (entry 10), but it is unexpected
that both these reaction pathways are shut down in the
presence with most of the scrutinized copper catalysts.
Moreover, the amount of the diene coupling product
suggests that the Cu(I) species maintains its role as a
catalyst in those side reactions. On the other hand, the
presence of only 10 mol % of the CuIÆ0.75DMS complex
(entry 1) circumvents the formation of this ‘Glaser-type’
coupling product and provides in its place a high yield of
the conjugate addition product from benzalacetone.
Based on our previous work utilizing the same chiral N-
enoyl amides exposed to TMSOTf-promoted copper
reactions, the major diastereomer is formed via the
non-chelating conformational (anti-s-cis) transition state
(entry 3).17 The same major diastereomer obtained in
the absence of TMSOTf or Et2Zn (entry 3) suggests that
the zinc reagent is not acting as a chelating agent in these
reactions. The presence of powerful chelating agents
(e.g., MgBr2) influence the diastereomeric ratio in the
direction17b opposite to the TMSOTf-promoted 1,4-
additions of the alkenyl-alkylzinc reagents reported
herein. Thus, the anti-s-cis conformation is favored over
the chelated form (syn-s-cis) for the N-enoyl amides
(Scheme 2).
The CuIÆ0.75DMS catalyzed 1,4-addition of the alkenyl-
zincate reagent is more efficient compared to the corre-
sponding alkenylzirconocene using CH2Cl2 as
a
medium (Table 1). In terms of solvent efficiency, it is
Table 2. Influence of Cu and Ni additives on the 1,4-addition
C4H9
ZnEt
1) C4H9
O
H
"CuX"
35 °C, CH2Cl2, 6 h
2) H2O
O
Ph
Me
Ph
Me
Although the presence of TMSOTf was crucial to
achieve good results in the conjugate addition process,
its precise role remains uncertain. Even more elusive is
the role of the CuIÆ0.75DMS catalyst in the addition
of the vinyl groups. Since there is no evidence for the
formation of a discrete alkenylcopper species via the
zinc to copper transmetalation, it is proposed that the
reaction proceeds via an alkenyl-alkyl copper(III) inter-
mediate as indicated in Scheme 3.18,19 A subsequent
reductive elimination would then provide the zinc eno-
late of the 1,4-addition product and regeneration of
the essential Cu(I). We have previously rationalized
the greater efficiency of the CuIÆ0.75DMS complex in
comparison to the CuBrÆDMS complex in the conjugate
additions of vinyl groups from alkenyl zirconocenes.7
Also in the case for the alkenyl zincates, it appears as
1
Entrya
Additive
mol. equiv ‘CuX’
Yieldb
1
2
3
4
5
6
7
8
9
CulÆ0.75DMS
Culc
CuBrÆDMS
CuCl
CuOTfÆPhMe
CuCNÆ2LiCl
Cu(acac)2
Cu(OTf)2
Ni(acac)2
None
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
—
94 (0)
64 (30)
32 (60)
0 (95)
0 (95)
10 (85)
0 (95)
0 (95)
21 (70)
55d (0)
10
a 1.0 equiv alkyne versus substrate.
b Isolated and purified material. Recovered substrate in brackets (%).
c Aldrich ultrapure grade (99.999%).
d 24% of 1,2-addition product.

1764
A. El-Batta, M. Bergdahl / Tetrahedron Letters 48 (2007) 1761–1765
Table 3. TMSOTf-promoted Cu(I) catalyzed 1,4-additions of vinyl groups to a,b-unsaturated imides
Entry
1
Substrate
Alkynea
Reaction timeb (h)
Product
Yieldc,d
O
O
C4H9
N
N
10
92e (23)e,f
89g
C4H9
O
O 15
Me
Me
O
O
O
Ph
N
2
3
12
10
84e
Ph
O 16
Me
O
Ph
Ph
H
H
95:5
O
O
C4H9
86e (27)e,f
87g
N
N
C4H9
17
O
O
Me
Me
O
O
Ph
H
>9:1
O
Ph
N
4
5
12
12
89e
Ph
O 18
Me
O
O
O
C4H9
N
N
85e
C4H9
O
O 19
i-Pr
i-Pr
O
O
Me
Me
Me
Me
54e (0)e,f
C4H9
6
12
>3:1
C4H9
21
Me
N
O
N
S
S
O
O
O
O
Me
O
a 1.0 M ratio of alkyne:substrate:TMSOTf.
b 35 °C in CH2Cl2.
c Based on isolated and purified material (%).
d Diastereomeric ratio (dr) determined on the crude material using 1H NMR spectroscopy.
e 10 mol % CuIÆ0.75DMS versus alkyne.
f Reaction conducted with vinylzirconocene reagent (absence of Et2Zn).
g Without TMSOTf. 100 mol % CuIÆ0.75DMS versus alkyne.
R
R
of the distinct copper reagents or intermediates should
not be disregarded as important variables.
Zn
Cu
Ph
O
Ph
O
O
O
I
H
H
Me
N
Me
N
In conclusion, the experimentally convenient methodol-
ogy of in situ hydrozirconation–transmetalation to zinc
can be extended to the 1,4-addition of alkenyl groups to
various a,b-unsaturated carbonyl compounds. The un-
ique behavior of the CuIÆ0.75DMS complex and the role
of TMSOTf in asymmetric 1,4-additions are currently
being explored into further synthetic developments and
will be reported in due course.
anti-s-cis O
O
Scheme 2.
ZnEt
Zn
O
O
OZnEt
R
I
+ CuI•L
Cu
L
R
Acknowledgments
R
Cu
L
I
This work was funded by the Petroleum Research Fund
(Grant 41199-AC1), San Diego Foundation (Blasker)
and the San Diego State University Foundation. The
authors thank Dendreon Pharmaceuticals and Dr. Dave
Duncan (Corvas) for a substantial donation of chemi-
cals. The authors also wish to thank Dr. Leroy Lafferty,
Scheme 3.
the p-base complexation of the Zn-alkene to Cu(I) is
more favored with iodide present as a p-donor in com-
parison to the bromide. Obviously, solubility differences

A. El-Batta, M. Bergdahl / Tetrahedron Letters 48 (2007) 1761–1765
1765
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Supplementary data
Supplementary data (experimental procedures and spec-
tral data (1H, 13C NMR, IR, and MS/HRMS) for perti-
nent compounds) associated with this article can be
found, in the online version at doi:10.1016/
j.tetlet.2007.01.041.
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Org. Lett. 2004, 6, 107–110; (b) El-Batta, A.; Bergdahl, M.
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