C-C bond formation via copper-catalyzed conjugate addition reactions to enones in water at room temperature

Article abstract of DOI:10.1021/ja309409e

Conjugate addition reactions to enones can now be done in water at room temperature with in situ generated organocopper reagents. Mixing an enone, zinc powder, TMEDA, and an alkyl halide in a micellar environemnt containing catalytic amounts of Cu(I), Ag(I), and Au(III) leads to 1,4-adducts in good isolated yields: no organometallic precursor need be formed.

Full text of DOI:10.1021/ja309409e

Communication
pubs.acs.org/JACS
C−C Bond Formation via Copper-Catalyzed Conjugate Addition
Reactions to Enones in Water at Room Temperature
Bruce H. Lipshutz,*,‡ Shenlin Huang,‡,# Wendy Wen Yi Leong,†,# Guofu Zhong,§ and Nicholas A. Isley‡
‡Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106, United States
†Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 637371
§College of Materials, Chemistry, & Chemical Engineering, Hangzhou Normal University, Hangzhou 310036, Zhejiang, China
S
* Supporting Information
ABSTRACT: Conjugate addition reactions to enones can
now be done in water at room temperature with in situ
generated organocopper reagents. Mixing an enone, zinc
powder, TMEDA, and an alkyl halide in a micellar
environemnt containing catalytic amounts of Cu(I), Ag(I),
and Au(III) leads to 1,4-adducts in good isolated yields: no
organometallic precursor need be formed.
Figure 1. Structure for polyoxyethanyl-α-tocopheryl succinate (TPGS-
750-M).
he origins of organocopper chemistry in synthesis date
1
Tback to the late 1940s and early 1950s when Kharasch
and Gilman2 first disclosed the preparation of Grignard- and
organolithium-derived organocuprates, respectively. These
fundamental reagents are generally scribed as “R2CuMgX”
and “R2CuLi”, the hallmark of each being their ability to deliver
both Csp and Csp residues from copper to carbon,3 most
notably in a conjugate addition sense.4 Indeed, such species and
their reactions with Michael acceptors are standard entries in
textbooks on basic organic chemistry. But along with such
instruction comes an appreciation for the incompatibility of
organocopper reagents of almost all varieties with water; hence,
practitioners must go to considerable lengths to ensure use of
dry copper salt precursors, dry organic, aprotic solvents, and
proper handling of organometallic precursors, whether
obtained as items of commerce or freshly prepared prior to
use.5 And while alternative inroads to organocopper reagents
have been devised over time (e.g., transmetalations, etc.6), the
overall level of tolerance to moisture, in general, is essentially
nil. In this report, as counterintuitive as it may seem, new
technology for achieving organocopper-mediated 1,4-additions
is reported that not only is tolerant of moisture but also, in fact,
is performed entirely in water as the gross reaction medium
3
2
Figure 2. Distinctions between intermediates in Pd- vs Cu-catalyzed
reactions.
(Scheme 1). Moreover, unlike most conjugate additions (e.g.,
to enones) that occur best at lower temperatures,3 these
proceed smoothly at ambient temperature. Hence, no invest-
ment of energy beyond that provided at room temperature
need be made.
There is no true precedent for Cu-catalyzed conjugate
additions of alkyl (or alkenyl, or aryl) groups to enones in
aqueous media, with the exception of alkynyl conjugate
additions by Carreira.7a Early work by Luche demonstrated
promising results using a Zn/Cu couple in aqueous media,
using copper or NH4Cl to activate zinc under ultrasonication
leading to a radical pathway.7b−d
Scheme 1. Comparison Approaches: Traditional vs Micellar
Catalysis
Related methodology developed by Fleming performed
preferentially on silica applies solely to unsaturated nitriles,8
partners that, while excellent radical acceptors,9 are typically not
ready participants toward copper-mediated 1,4-additions.3b As
Received: September 25, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja309409e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Conjugate Additions of Alkyl Halides to Enones
yield of 1
b
entry
1
conditions
(%)
Cu(OAc)2·H2O (5 mol%), Zn powder (4 equiv), TMEDA
54
67
78
87
93
50
2
(5 equiv)
2
3
4
Cu(OAc)2·H2O (5 mol%), Zn powder (4 equiv), TMEDA
(2 equiv)
Cu(OAc)2·H2O (5 mol%), LiClO4 (5 mol%), Zn powder
(4 equiv), TMEDA (2 equiv)
Cu(OAc)2·H2O (5 mol%), AuCl3 (5 mol%), Zn powder
(4 equiv), TMEDA (2 equiv)
c
5
Cu(OAc)2·H2O (5 mol%), AuCl3 (5 mol%), Zn powder
(4 equiv), TMEDA (2 equiv)
d
6
Cu(OAc)2·H2O (5 mol%), AuCl3 (5 mol%), Zn powder
(4 equiv), TMEDA (2 equiv)
7
AuCl3 (5 mol%), Zn powder (4 equiv), TMEDA
(2 equiv)
a
b
For details, see Supporting Information. Determined by GC on
c
crude material. Iodobutane and zinc were added in two portions: t = 0
h, 1.5 equiv; t = 6 h, 1.5 equiv. Water only was used as the medium
d
(no surfactant).
such, excessive amounts of alkyl halide (8 equiv) and Zn (6
equiv) are needed. More recently, Loh and co-workers
described the use of indium/copper leading to conjugate
additions of unactivated (mainly secondary) alkyl iodides (and
not bromides) to α,β-unsaturated compounds in water, also via
a proposed radical mechanism.10
We recently disclosed highly moisture-sensitive Negishi-like
cross-couplings that could be carried out in water using either
alkyliodides11a or bromides.11b This methodology is enabled by
small amounts of commercially available amphiphiles (e.g., 2 wt
% TPGS-750-M; Figure 1)12 that form nanomicelles in water
within which the coupling occurs, where the precursor halides
are used directly in the presence of Zn metal; i.e., no prior
formation of RZnX is required.11a,13
If conditions could be found such that transmetalation to
copper, rather than palladium, takes place, in this case, in the
presence of a Michael acceptor, 1,4-addition might ensue.
However, there is a key distinguishing feature between these
two types of reactions, one that suggests that a process
involving organocopper species is potentially far more
demanding. That is, transmetalation from Zn to Pd would
provide a moisture-tolerant intermediate, while in situ
generated organozinc and organocopper reagents are both
highly moisture-sensitive (Figure 2).
a
Conditions: alkyl-X (3 equiv), Zn powder (X = I) or Zn dust (X =
Br) (4 equiv), TMEDA (2 equiv), 3−5 mol% [Cu], 5 mol% AuCl3, 0.5
mL 2 wt% TPGS-750-M/H2O, rt, 24 h. Isolated, chromatographically
purified. Zinc dust used.
b
c
Initially, the combination of 5-phenylcyclohexenone and 1-
iodobutane was studied in aqueous TPGS-750-M as a
representative substrate pair, in the presence of Cu(OAc)2·H2O
(5 mol%) and excess zinc powder and TMEDA (Table 1).
Only moderate yields of the desired product 1 (as a mixture of
cis/trans isomers) were obtained due to a significant amount of
unreacted starting material (>40%), along with lesser quantities
(ca. 5%) of reduced enone (entry 1). A drop in the level of
TMEDA led to a rise in conversion, with two equivalents being
optimal (entry 2).
by complexation of lithium with the enone.14 Other salts (e.g.,
Li halides, NiCl2, Sc(OTf)3) were screened, but ultimately
AuCl3 was found to be the most effective (entry 4). By adding
the alkyl halide and zinc in two portions, the yield could be
further increased to 93% (entry 5). A control reaction carried
out “on water”15 (i.e., in the absence of TPGS-750-M)
confirmed the importance of micellar catalysis in facilitating
conjugate additions in aqueous media (entry 6). Attempts to
vary the surfactant, including trials with Brij 30 and 35, Triton
X-100, cremophor EL, and solutol HS (see Supporting
Addition of a catalytic amount of a Lewis acid (e.g., LiClO4;
entry 3) further increased the level of conversion, presumably
B
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Journal of the American Chemical Society
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Table 3. Conjugate Addition Reactions of Secondary Alkyl
Halides to Enones
Scheme 3. The Coinage Metal Triad as Catalysts
a
of secondary centers was observed, unlike those known to
occur in related reactions, presumably due to β-hydride
elimination.17
a
Conditions: alkyl-X (3 equiv), Zn powder (X = I) or Zn dust (X =
Br) (4 equiv), TMEDA (2 equiv), 3 mol% [Cu], 5 mol% AuCl3, 0.5
mL 2 wt% TPGS-750-M/H2O, rt, 24 h. Isolated, chromatographically
purified. Tetraethyl analogue of TMEDA used.
b
Studies on the potential for recycling of both the aqueous
medium containing the surfactant and the gold catalyst show
considerable potential. In-flask recycling was achieved using
minimum amounts of hexanes as the extraction solvent
(Scheme 2, study 1). Each recycle, without the addition of
fresh surfactant or AuCl3, showed a minimal decrease in
reaction rate, as well as minimal competitive enone reduction
(see Supporting Information for details). Moreover, different
substrate combinations can be used in each recycle, further
broadening the utility of TPGS-750-M/H2O as a reaction
medium (Scheme 2, study 2).
c
Scheme 2. In-Flask Recycling of TPGS-750-M and AuCl3
In an effort to further enhance the rate of these copper-
catalyzed conjugate addition reactions, the Lewis acidity of
AuCl3 was modified by introduction of an equimolar (catalytic)
amount of AgBF4, a ploy oftentimes used in gold catalyzed
reactions.18 Remarkably, in the presence of this additive, the
amounts of alkyl halide, Zn, and AuCl3 needed were reduced
dramatically, as were reaction times. As the examples in Scheme 3
illustrate, the overall efficiency remains high.
a
b
c
Reduced enone. Reaction time 32 h. Isolated as a mix of cis/trans
isomers.
In summary, the first green methodology for effecting water-
sensitive copper-catalyzed 1,4-additions in a totally aqueous
environment has been developed. It takes advantage of micellar
catalysis leveraged by use of a “designer” surfactant that forms
nanoreactors of a favored size and within which organozinc
reagents are formed in situ at the metal surface. The resulting
organozinc species then undergo transmetalation to copper
and, ultimately, conjugate addition to unsaturated ketones,
giving good yields of the desired 1,4-adducts. A broad substrate
scope has been demonstrated indicative of considerable
generality, including tolerance to a wide range of functionality.
Neither organic solvents nor energy in the form of applied heat
or cooling need be invested. Further work on developing an
Information), led in all cases to significantly lower yields of the
1,4-adduct. The absence of a copper salt results in almost no
formation of the product, suggesting that both Cu(OAc)2·H2O
and AuCl3, along with the proper choice of amphiphile, are
essential for realization of a synthetically useful process based
on organocopper chemistry (entry 7).
Several enones and alkyl halides bearing functional groups
can be utilized, given the mildness of the reaction conditions
and the functional group tolerance for which organozinc
reagents are well-known (Table 2).16
Secondary iodides and bromides also work well under these
standard conditions (Table 3). Remarkably, no rearrangement
C
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Journal of the American Chemical Society
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Organocopper Compounds, Part 2; Rappoport, Z., Marek, I., Ed.; John
Wiley & Sons Ltd.: Chichester, 2009; pp 443−525.
enantioselective version of this process, as well as other
coupling reactions involving organocopper complexes in water,
is currently underway.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, analytical and spectral data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
lipshutz@chem.ucsb.edu
■
Author Contributions
#S.H. and W.W.Y.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support provided by the NIH (GM 86485) and NSF
(CHE 0948479) is gratefully acknowledged. Fellowship
support to W.W.Y.L. was provided by Nanyang Technological
University (Research Scholarship).
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