Cu-Catalyzed Stereoselective γ-Alkylation of Enones

Article abstract of DOI:10.1021/jacs.6b02565

A general regio- and stereoselective γ-C-C bond formation is achieved using α-halocarbonyl compounds and dienol ethers via Cu(II) catalysis. This method constitutes a novel approach to the challenging 1,6-dioxygenation motif. A range of γ-substituted enones, including many bearing all-carbon quaternary centers, are available through a simple protocol under mild reaction conditions with superb functional group compatibility. Excellent stereoinduction is observed providing controlled access to challenging stereochemical arrays.

Full text of DOI:10.1021/jacs.6b02565

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Communication
Cu-Catalyzed Stereoselective #-Alkylation of Enones
Xiaohong Chen, Xiaoguang Liu, and Justin T Mohr
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b02565 • Publication Date (Web): 09 May 2016
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Cu-Catalyzed Stereoselective γ-Alkylation of Enones
Xiaohong Chen, Xiaoguang Liu, and Justin T. Mohr*
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Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
Supporting Information Placeholder
Scheme 1. Strategies for 1,6-dicarbonyl synthesis
ABSTRACT: A general regio- and stereoselective γ-C–C
bond formation is achieved using α-halocarbonyl com-
pounds and dienol ethers via Cu(II) catalysis. This method
constitutes a novel approach to the challenging 1,6-
dioxygenation motif. A range of γ-substituted enones, in-
cluding many bearing all-carbon quaternary centers, are
available through a simple protocol under mild reaction con-
ditions with superb functional group compatiblity. Excellent
stereoinduction is observed providing controlled access to
challenging stereochemical arrays.
A
α
α
O
conventional
disconnection
O
alkylation
favored
O
O
γ
O
(not generally
feasible)
O
1,6-dicarbonyl motif
α
antithetical
step
(limited
scope)
C
OTBS
O
α
B
radical
addition
to diene
OR
γ
OR
O
X
γ
O
(this work)
practical
feedstocks
through the γ-addition pathway. Seminal reports by Kim and
co-workers suggested the viability of this design using spe-
cialized substrates such as hydroxamic acids, but a general
application of this strategy to common ketone synthesis has
The carbonyl group is arguably the most important and
versatile functional group in synthetic chemistry. This moie-
ty is valuable not only for the useful electrophilic character of
the carbonyl carbon, but also due to the ability to manipulate
3h,i
not been reported. We have therefore sought a system to
resolve the significant and long-standing problem of γ-C–C
bond formation in simple enone systems. In this communi-
cation we disclose the first regio- and stereoselective γ-
alkylation protocol that enables direct synthesis of 1,6-
dicarbonyl compounds from simple enones and readily avail-
able α-halocarbonyl compounds using Cu catalysis.
1
the surrounding atoms to construct new bonds. Utilizing
these features of carbonyl reactivity in combination, powerful
strategies for synthesizing dicarbonyl compounds have been
developed. Claisen condensation, enolate alkylation with α-
halocarbonyl electrophiles, and Michael addition protocols
are robust classical platforms for generating 1,3-, 1,4-, and
1,5-dicarbonyl compounds. The homologous 1,6-dicarbonyl
motif is considerably more challenging, however. Dienolate
At the outset, we were attracted to recent reports of Cu
catalysts capable of activating α-haloesters toward addition to
5
π-systems. Although the mechanism of these
Table 1. Optimization of radical coupling conditionsa
2
derivatives of enones posit a potential solution, but such
hypothetical reactions are often complicated by the de-
creased electron density at the distant γ-site, and most elec-
trophiles are found to react preferentially at the more nucle-
O
OTBS
Cu catalyst
ligand
O
Br
3a
EtO
3
solvent
NaHCO3
80 °C, 24 h
ophilic α-C (Scheme 1, path A). As a result, it has been nec-
2a
1a
EtO2C
solvent
essary to rely on antithetical disconnections such as oxidative
cleavage of cyclohexenes, but these methods have substantial
scope limitations (path B). The need for a direct γ-C–C
bond formation technique is therefore quite significant.
Our research program has aimed to develop robust sys-
tems for bond formation at γ-sites that are directly applicable
to the synthesis of valuable target molecules bearing substitu-
entry
Cu catalyst (mol %)
ligand (mol %)
% yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
none
none
none
bipy (20)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH3CN
THF
0
0
0
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
CuI (10)
TMEDA (20)
PMDTA (20)
PMDTA (20)
PMDTA (20)
PMDTA (20)
PMDTA (20)
PMDTA (20)
PMDTA (20)
PMDTA (20)
PMDTA (20)
PMDTA (20)
PMDTA (15)
16
58
16
12
49
42
0
73
77
86
92
94
CuCl2 (10)
CuBr•SMe2 (10)
CuCO3 (10)
none
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (7.5)
4
tions at this location. One potential strategy involves the
addition of radical intermediates to dienol ethers which are,
in turn, readily available enone derivatives (Scheme 1, path
1,4-dioxane
DCE
DCE
4b,c
C). This design is based on the hypothesis that site selec-
a
Isolated yield from reaction of of dienol ether 1a (0.25
mmol), α-haloester 2a (1.5 equiv), NaHCO3 (1.0 equiv), Cu
catalyst, and ligand in 1 mL of solvent at 80 °C for 24 h.
tivity in bond formation will be controlled through a prefer-
ence for the stabilized oxyallyl radical that is only accessible
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When the enone precursor con-
4b,c
transformations have not been rigorously supported, we hy-
enolization techniques.
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2
3
4
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6
7
8
pothesized that a C-centered radical may be key intermediate
tained an α-substituent, we observed exceptional stereoselec-
tivity in the alkylation reaction, delivering the 1,6-dicarbonyl
products in high yield as a single detectable diastereomer
(entries 2–5). This stereoinduction was maintained with β-
substituted enones as well, delivering the anti stereodiads as a
single isolated diastereomer (entries 6–7). Dienols contain-
ing an exocyclic reactive site also proved to be very good sub-
strates for the coupling reaction (entries 8–10).
6
that is potentially useful in our proposed coupling. We se-
4b,c
lected readily available, stable TBS dienol ether 1a and
commercially available α-haloester 2a to examine the γ-
alkylation with a range of Cu catalysts in toluene solvent with
7
heterogeneous base (Table 1). We quickly learned that the
supporting ligand is critical to reactivity: unligated Cu(II)
and the bipy complex each fail to catalyze the coupling. Ter-
tiary amine Cu complexes are catalytically active, and com-
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Modification of the α-halocarbonyl coupling partner
Table 3. Scope of α-halo coupling partnera
mercially
available
pentamethyldiethylenetriamine
5
(PMDTA) is particularly effective (entries 1–5). Other Cu
salts were inferior to Cu(OTf)2 and Cu is necessary for reac-
tion to occur (entries 6–10). A solvent survey found 1,2-
dichloroethane (DCE) to be the optimal solvent (entries 11–
14). Reduction of the catalyst loading to 7.5 mol % resulted
O
OTBS
OTBS
O
7.5 mol% Cu(OTf)2
15 mol% PMDTA
X
3
Y
or
NaHCO3
DCE, 80 °C
R1 R2
R2
R1
O
1a
1k
2
8
Y
in isolation of the γ-alkylation product 3a in 94% yield.
entry siloxydiene
halocarbonyl
2b Y = OAllyl
product
% yield
We have observed that a variety of dienol ethers are viable
substrates for the γ-alkylation reaction (Table 2). These
dienol ethers are prepared by straightforward enoliza-
tion/silylation under basic conditions or through soft
Table 2. Scope of siloxydiene coupling partnera
O
1
1a
1a
1a
1a
1a
1a
3k 80
2
2c Y = OPropargyl
2d Y = OCH2CH2OH
2e Y = NEt2
3l
84
O
3
3m 93
3n 77
3o 97
3p 85
Br
Y
4
O
5b
2f Y = SC18H37
2g Y = H
Y
6
O
O
OTBS
7.5 mol% Cu(OTf)2
15 mol% PMDTA
O
7
1a
1a
2h R = CO2Et
2i R = H
3q 93
3r 90
EtO2C
Br
R
Br
3
R
EtO
NaHCO3
DCE, 80 °C
8c
R
R
EtO2C
EtO2C
1
2a
O
entry
siloxydiene
product
% yield
94
O
O
1
2
3
4
5
1a R = H
3a
9d
1a
2j
3s 82
Br
OTBS
MeO
R
1b R = Me
3b >20:1 dr 82
3c >20:1 dr 88
3d >20:1 dr 64
3e >20:1 dr 72
R
t-Bu
1c R = Bn
MeO2C
O
t-Bu
1d R = Allyl
1e R = CH2CO2t-Bu
O
OEt
EtO2C
O
OEt
O
10e
11e
12e
13e
1k
1k
1k
1k
1k
2k
2l
3t
74
OTBS
Br
Ph
O
Ph
O
6
7
1f
3f >20:1 dr 68
O
O
O
O
O
3u 65
3v 83
3w 57
EtO2C
Br
O
O
OTBS
O
1g
3g >20:1 dr 76
2m
2n
2o
Cl
O
CO2Et
CO2Et
OTBS
O
O
8b
1h
1i
3h
75
Br
O
OTBS
O
O
O
Ph
Ph
14e
3x 72
CO2Et
9b
3i
3j
71
64
Br
O
O
OTBS
10b
1j
O
O
N
15e,f
1k
2p
3y 85
Ph
Br
CO2Et
Ph
N
N
N
a
O
O
Isolated yield (average of two runs) from reaction of of
Ph
Ph
dienol ether 1a (0.25 mmol), α-haloester 2a (1.5 equiv), Na-
HCO3 (1.0 equiv), 7.5 mol% Cu(OTf)2, and 15 mol% PMDTA
in 1 mL of DCE at 80 °C for 24 h. b Isolated yield over two steps
from the corresponding enone.
a Isolated yields. See Table 2 for reaction conditions. b Reac-
c
d
e
tion in EtOH solvent. 1:1 dr. 1.4:1 dr. Isolated yield over
two steps from the corresponding enone. f Reaction at 22 °C.
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provided a test of functional group tolerance (Table 3). We In further examining the scope of the halocarbonyl com-
1
2
3
4
5
6
7
8
were delighted to discover that alkenes, alkynes, unprotected
hydroxyl groups, amides, thioesters, and even aldehydes are
compatible with our protocol (entries 1–6). Use of an α-
bromomalonate, an α-bromopropionate, a neopentyl bro-
mide, or a benzylic bromide each provided excellent results,
indicating both steric and electronic flexibility in the halide
component (entries 7–10). Isophorone-derived dienol ether
1k was readily alkylated with either cyclic or acyclic α-
halocarbonyls to generate tertiary or all-carbon quaternary
centers in high isolated yields (entries 10–15). Notably, α-
chlorocyclohexanone (2m) performed well under our stand-
ard conditions and the use of a brominated derivative of the
commercialized antiinflammatory agent phenylbutazone
(2p) delivered the coupling product in very good yield when
the reaction was conducted at 22 °C.
ponent, we observed that ethyl trichloroacetate (2q, Table 4,
entry 1) furnished the coupled product 3z in excellent yield.
Adjustment of reagent stoichiometry led to formation of the
2:1 coupling product 3aa as the major product, although the
final chloride proved reluctant to couple further even under
forcing conditions (entry 2). In addition to chlorinated
compounds, ethyl bromodifluoroacetate (2r) was found to
provide desirable difluoracetate derivatives efficiently (en-
tries 3–5). The exceptional diastereoselectivity was main-
tained with these less sterically demanding substrates.
Although primary α-halo compounds were unreactive un-
der our standard reactions conditions, we discovered that
dihalocarbonyl compounds served as viable synthons for the
parent coupling partners. α,α-Dichloroacetophenone (2s)
coupled with dienol ether 1a in 80% yield, and the initial
coupling product was readily reduced with Zn0 in AcOH to
enone 5 in 84% yield (Scheme 2a). Alternatively, the initial
coupling product (3ae) eliminates under basic conditions to
furnish the formal α-arylation product 6 in 95% yield.
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Seeking to test the limits of our method for preparing ste-
rically congested systems, we examined γ-alkylated dienol
ether 1l (eq 1). Although this substrate was unreactive with
O
OTBS
7.5 mol% Cu(OTf)2
15 mol% PMDTA
O
To explore the prospect of heterocycle synthesis, we em-
ployed haloacetoacetate 2t in our transformation and ob-
tained hexahydrobenzofuran 7, the product of a formal
Br
4
EtO
(1)
NaHCO3
DCE, 80 °C
54% yield,1.3:1 dr
EtO2C
1l
2i
4c
[3+2] cycloaddition, in excellent yield (Scheme 2b). To-
tertiary α-halo esters (e.g., 2a), vicinal quaternary and ter-
tiary carbon centers could be accessed using ethyl 2-
bromopropionate (2i) under our standard conditions, there-
by demonstrating the ability to generate sterically challeng-
ing C–C bonds with relative ease.
ward N-heterocycles, we employed propionimide 2u in our
coupling and after cleavage of the Boc group and acid-
catalyzed conjugate addition, lactam 8 was formed in 71%
Scheme 2. Synthetic applications of coupling products
Table 4. α-Polyhalo coupling partnersa
a)
O
Zn
(1 equiv)
AcOH
O
OTBS
O
TBSO
Ph
7.5 mol% Cu(OTf)2
O
15 mol% PMDTA
O
1a
5 (84%)
6 (95%)
O
Cu cat.
X2
R
R
DBU
THF
3
% yield
88
EtO
O
Ph
NaHCO3
DCE, 80 °C
OH
X1 X1
O
Cl
Cl
X1
X1
Ph
1
EtO2C
2
3ae
(80%, 1.1:1 dr)
Ph
2s Cl
entry
siloxydiene
TBSO
α-halo compound
product
b)
O
O
OTBS
O
O
O
7
91%
single
diastereomer
Cu cat.
H
Cl
1
1a
2q
3z
EtO
EtO
O
Cl
H
Cl Cl
Cl
Cl
1a
2t
EtO2C
EtO2C
c)
O
O
O
OTBS
1. TFA
CH2Cl2
O
1a
8
71%
overall
1:1 dr
Cu cat.
2
3
1a
(3.05 equiv)
2q
3aa 59
3.9:1 dr
H
Cl
Cl Cl
EtO
O
2. TsOH
PhH, ∆
Boc
NBn
NBn
H
Br
O
EtO2C
NBn
Boc
Cl
O
2u
3af
O
O
TBSO
d)
O
OTBS
O
R
1a R = H
2r
3ab
90
71
1. MeLi
THF
0 → 22 °C
wine
lactone
(9)
37%
R
Br
1a
EtO
Cu cat.
H
4
1c R = Bn
F
F
2r
3ac
>20:1 dr
O
Cl
2. 2 N HCl
F
3ag
H
EtO2C
overall
F
CO2Me
OH
CO2Me
2v
O
O
TBSO
e)
OH
O
H
N
1k
O
Br
5
1f
2r
3ad
>20:1 dr
63
H
N
EtO
O
TBSO
F
F
Cu(OTf)2 (7.5%)
PMDTA (15%)
O2N
HO
O
F
EtO2C
O2N
HO
Cl
Cl
F
NaHCO3
EtOH, 80 °C, 6h;
DBU, 20 min
10
(82%)
a Isolated yields. See Table 2 for reaction conditions.
Chloramphenicol (2w)
antibiotic
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3. For selected examples of γ-functionalization of carbonyl compounds,
overall yield (Scheme 2c). Through a similar strategy, dienol
ether 1a was coupled with propionate 2v and after subse-
quent chemoselective addition of MeLi and acid treatment,
the natural product wine lactone (9) was isolated in 37%
overall yield (Scheme 2d). As a final application, the unpro-
tected broad-spectrum antibiotic chloramphenicol (2w) was
coupled to dienol ether 1k with concomitant elimination to
acrylamide 10 in high overall yield (Scheme 2e).
To conclude, we have developed a robust, general, Cu-
catalyzed technology for γ-alkylation of enones via readily
available dienol ether derivatives and α-halo compounds.
The transformation proceeds in excellent yield, exhibits
complete regiocontrol, tolerates sterically demanding cou-
pling partners, and is highly diastereoselective. This method
enables the synthesis of 1,6-dicarbonyl compounds that have
largely eluded conventional bond formation strategies. The
excellent functional group compatibility of this transfor-
mation ensures broad applicability to a variety of highly func-
tionalized target molecules.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures and characterization data (PDF)
Copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: jtmohr@uic.edu
ACKNOWLEDGMENT
Funding was provided by the UIC Department of Chemistry.
We thank Profs. Vladimir Gevorgyan, Duncan Wardrop, Tom
Driver, Laura Anderson, Daesung Lee, and Neal Mankad (UIC)
for helpful discussions and use of reagents and equipment.
REFERENCES
1. (a) Stoltz, B. M.; Mohr, J. T. Protonation, Alkylation, Arylation, and
Vinylation of Enolates. In Science of Synthesis; De Vries, J. G., Molander,
G. A., Evans, P. A., Eds.; Thieme: Stuttgart, Germany, 2011; Vol. 3, pp
615–674. (b) MacMillan, D. W. C.; Watson, A. J. B. α-Functionalization of
Carbonyl Compounds. In Science of Synthesis; De Vries, J. G., Molander,
G. A., Evans, P. A., Eds.; Thieme: Stuttgart, Germany, 2011; Vol. 3, pp
675–745. (c) Nguyen, B. N.; Hii, K. K.; Szymanski, W.; Janssen, D. B.
Conjugate Addition Reactions. In Science of Synthesis; De Vries, J. G.,
Molander, G. A., Evans, P. A., Eds.; Thieme: Stuttgart, Germany, 2011;
Vol. 1, pp 571–688.
7. The base is important to overall reactivity, although several bases were
found to be competent. See the Supporting Information for details.
8. The reaction proceeds with lower catalyst loadings but achieving high
yield requires long reaction time. A reaction with 1 mol % Cu(OTf)2 for 48
h delivered 77% yield although conversion was incomplete.
2. The γ-dienolate is lower in energy than the isomeric α-dienolate, see:
Bartmess, J. E.; Kiplinger, J. P. J. Org. Chem. 1986, 51, 2173–2176.
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OTBS
O
R1
– new γ-C–C bond
– regioselective
– stereoselective
–1,6-dicarbonyl moiety
– quaternary centers
– functional group tolerant
– 36 examples
γ
Cu-catalyzed
α,γ-coupling
R1
α
Br
O
α
γ
R3
R2
practical
feedstocks
O
R3
R2
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