Catalytic intermolecular C-alkylation of 1,2-diketones with simple olefins: A recyclable directing group strategy

Article abstract of DOI:10.1021/ja306123m

We describe the first example of Rh-catalyzed intermolecular C-alkylation of cyclic 1,2-diketones using simple terminal olefins as alkylating agents. Aminopyridine is employed as a recyclable directing group. First, it reacts with ketones to give enamines and delivers Rh to activate the vinyl C-H bonds in the same pot; second, it can be cleaved off and recovered via hydrolysis. A broad range of olefins can be utilized as substrates, including aliphatic, aromatic olefins and vinyl esters. The efficiency of this method is also demonstrated in the synthesis of a natural flavoring compound, 3-ethyl-5-methyl-1,2- cyclopentadione (one-pot 53% yield vs a previous four-step route 16% yield from the same starting material). This work is expected to serve as a seminal study toward catalytic ketone α-alkylation with unactivated olefins.

Full text of DOI:10.1021/ja306123m

Communication
pubs.acs.org/JACS
Catalytic Intermolecular C‑Alkylation of 1,2-Diketones with Simple
Olefins: A Recyclable Directing Group Strategy
Zhiqian Wang, Brandon J. Reinus, and Guangbin Dong*
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: We describe the first example of Rh-
catalyzed intermolecular C-alkylation of cyclic 1,2-
diketones using simple terminal olefins as alkylating
agents. Aminopyridine is employed as a recyclable
directing group. First, it reacts with ketones to give
enamines and delivers Rh to activate the vinyl C−H bonds
in the same pot; second, it can be cleaved off and
recovered via hydrolysis. A broad range of olefins can be
utilized as substrates, including aliphatic, aromatic olefins
and vinyl esters. The efficiency of this method is also
Figure 1. C-Alkylation of cyclic 1,2-diketones using simple olefins.
demonstrated in the synthesis of a natural flavoring
compound, 3-ethyl-5-methyl-1,2-cyclopentadione (one-pot
53% yield vs a previous four-step route 16% yield from the
reactions with olefins provide β-alkylated products (Scheme
same starting material). This work is expected to serve as a
1b).1d−f Addition of α C−H bonds of ketones across
seminal study toward catalytic ketone α-alkylation with
unactivated olefins would afford formal enolate-alkylation
unactivated olefins.
products but in a more atom-economical3 and “greener” fashion
compared to the typical enolate alkylation, because this catalytic
process would eliminate the need for stoichiometric amounts of
a strong base and relatively expensive and/or toxic alkylating
ransition-metal-catalyzed addition of C−H bonds across
Tolefins represents a powerful and economical way to
agents. However, general strategies for such transformations
construct C−C bonds;1 in particular, carbonyl-involved C−H
addition reactions are very attractive due to the pivotal role of
the carbonyl group in organic synthesis. For example, aldehydes
or imines can be catalytically transformed to functionalized
ketones via oxidative addition of the C−H bonds (Scheme
1a).2 The β C−H bonds in aryl ketones or enones are known
to undergo carbonyl or imine-directed metalation, and addition
remain underdeveloped.4−6 The challenges are likely due to the
inert nature of the α C−H bonds (sp3 vs sp2 for aldehyde and
enone C−H bonds) and lack of suitable directing groups
(DGs).
To address these challenges, we envisaged that enamine
formation would convert the ketone sp3 α C−H bonds to sp2 bonds,
thus enhancing their reactivity toward oxidative addition by a low-
valent transition metal (Scheme 1c).7 Meanwhile, if a proper
DG is incorporated with the amine agent, metalation would be
directed to the α C−H bonds upon enamine formation.8
Subsequent olefin insertion−reductive elimination and enamine
hydrolysis would lead to the desired α-alkylation product. Here,
serving as an important proof of principle, we examine the
feasibility of such a transformation in a 1,2-diketone system.
Cyclic 1,2-diketones represent an important structural motif
in various natural products,9 such as bruceantin (anticancer)10
and terpestacin (anti-HIV),11 and are also widely used as
perfumery and flavoring materials in cosmetics and food
industries respectively.12 This functional group possesses
unique reactivity where one of the ketones often exists in
enol form. However, their usage as synthetic building blocks
has received limited attention, likely because direct and
regioselective alkylation to form C−C bonds is difficult and
O-alkylation is generally favored under normal alkylation
Scheme 1. Carbonyl-Involved C−H Additions Across
Olefins
Received: June 23, 2012
Published: August 13, 2012
© 2012 American Chemical Society
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Table 1. Investigation of the C−H/Olefin Coupling Step
Table 2. Selected Optimization of the Tandem Enamine
Formation/C−H Olefin Coupling Reaction
b
entry
variation from the “standard” conditions
yield
1
2
3
4
5
6
7
8
9
none
65%
7%
no alumina
c
4 Å MS, instead of alumina
half the amount of alumina
no Rh(PPh3)3Cl
0%
37%
0%
d
d
e
Rh(PPh3)3Cl (5 mol %)
48%
<1%
39%
0%
[Rh(coe)2Cl]2 (5 mol %), instead of Rh(PPh3)3Cl
toluene, instead of 1,4-dioxane
aniline (1 equiv), instead of 2
a
Standard conditions: 1a (0.2 mmol, 1 equiv), 2 (0.2 mmol, 1 equiv),
3,3-dimethyl-1-butene (2 mmol, 10 equiv), neutral alumina (200 mg),
Rh(PPh3)3Cl (0.02 mmol, 10 mol %) in 1,4-dioxane (0.4 mL), 130 °C
b
c
d
in a sealed vial. Isolated yield. 1a remained unreacted. Enamine 3a
e
was the major product. Only enamine formation and no alkylation
products were observed.
common five-membered ones (see Scheme 1a,b). Subse-
quently, the C-alkylation product would be generated via
migratory insertion of an olefin and reductive elimination.
Finally, the aminopyridine DG would be cleaved off and
recycled via acid-mediated hydrolysis.
Given that the C−H/olefin coupling is the key to the success
of the proposed strategy, we investigated the viability of this
step directly using enamine adducts (3a−c) as substrates
(Table 1). After optimizing the reaction conditions, we found
the vinyl C−H bonds of the enamines were effectively coupled
with a broad range of terminal olefins, providing adducts 4a−s
in good to excellent yields.17 Wilkinson’s catalyst (5 mol %)
proved to be most effective for aliphatic olefins, including both
sterically hindered olefins, such as tert-butyl ethylene and vinyl
silanes, and less hindered ones, such as 1-hexene and ethylene
gas (entries 1−9, Table 1). Both the alkylation product (4a)
and its starting material (3a) were unambiguously identified by
1H and 13C NMR, IR, HRMS, and X-ray crystallography (see
Supporting Information). Notably, Michael acceptors, such as
methyl acrylate, also serve as a good substrate (entry 9, Table
1). Although aromatic olefins also react under the same
reaction conditions, [Rh(coe)2Cl]2 (coe = cyclooctene) was
found to be a more efficient catalyst (entry 10). Para-, meta-,
and ortho-substituted styrenes coupled smoothly (entries 11−
16, Table 1).18 In addition, a number of functional groups are
tolerated under the C−H/olefin coupling conditions, including
silanes, ethers, silyl ethers, aryl chlorides, aryl fluorides, and
esters. Importantly, all these reactions proceeded with excellent
regioselectivity offering only the linear products likely due to
the preference of formation of the less hindered Rh-alkyl
species (see Figure 1),1e,f while the potential branched products
were not observed.
a
General reaction conditions: 3a−c (1 equiv), olefin (10 equiv), Rh
catalyst (5 mol %) in 1,4-dioxane (0.4 M), 130 °C in a sealed vial.
TIPS, triisopropylsilyl. Py, pyridyl group. Catalyst A: Rh(PPh3)3Cl 5
mol %, Catalyst B: [Rh(coe)2Cl]2 2.5 mol %. Isolated yields of the
C−H functionalization step; the number in parentheses represents the
yield based on recovered starting material (brsm). 5 equiv of the
olefin are used. 2 equiv of the olefin are used.
b
c
d
e
conditions.13−15 In this communication, we report the first
example of a Rh-catalyzed intermolecular C-alkylation of cyclic
1,2-diketones using simple terminal olefins as alkylating agents.
Our strategy is depicted in Figure 1. 2-Aminopyridine is
employed as a DG for selective activation of the less hindered α
C−H bond of cyclic 1,2-diketones.16 It would first generate the
enamine with the less hindered ketone and then deliver Rh
insertion into the resulting vinyl C−H bond. Note that a six-
membered metallocycle is expected in contrast to the more
With the success of the Rh-catalyzed α-alkylation reaction,
we then attempted to combine the enamine formation and C−
H activation into one pot. Toward this end, the optimal
conditions were discovered: when tert-butyl ethylene was used
as the olefin partner, alkylation product 4c was isolated in 65%
yield (entry 1, Table 2). Subsequently, we examined the role of
each reactant through a series of control experiments. Neutral
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a
Table 3. Direct Alkylation with Cyclic 1,2-Diketones
Scheme 2. Cleavage and Recovery of Aminopyridine DG
By properly choosing the Rh catalysts, both aliphatic and
aromatic olefins reacted and provided good yields of substituted
enamines.20 The six-membered diketones (1b and 1c) are more
challenging substrates for this tandem reaction, likely caused by
their tendency to decompose to aromatic compounds during
the enamine-formation step (entries 14−16, Table 3),21 as their
yields are much higher when using the corresponding enamines
as the starting materials (entries 17−19, Table 1). Note that
only monoalkylation was observed with nonsubstituted
cyclcohexan-1,2-dione (1c) (entry 16, Table 3).
With success of the tandem enamine formation/C−H olefin
coupling, we continued to explore the feasibility to remove and
recycle the aminopyridine auxiliary. Preliminary hydrolytic-
cleavage experiments were conducted: treatment with acetic
acid and HCl at elevated temperatures provided the alkylated
1,2-diketones in high yields, which exist as enol tautomers
(Scheme 2a).22 In addition, the pyridine was recovered in 77−
78% yield. Further study suggested that the enamine formation,
C−H/olefin coupling, and enamine cleavage can all be
operated in one pot! Reaction of diketone 1a with ethylene
gas at ca. 1 atm pressure followed by hydrolysis afforded
diketone 5a in 53% yield along with enamine 4a in 33% yield
(Scheme 2b). Notably, 3-ethyl-5-methyl-1,2-cyclopentadione
(5a) is a natural flavoring compound isolated in a trace amount
a
General reaction conditions: 1a (0.2 mmol, 1 equiv), 2 (0.2 mmol, 1
equiv), olefins (2 mmol, 10 equiv), neutral alumina (200 mg), Rh
catalyst (0.02 mmol, 10 mol %) in 1,4-dioxane (0.4 mL), 130 °C in a
b
sealed vial. Catalyst A: Rh(PPh3)3Cl, 10 mol %; Catalyst B:
c
d
[Rh(coe)2Cl]2 5 mol %. Isolated yield. 2 equiv of 2 were used.
from roasted coffee and cigarette smoke condensate.23,24
A
e
No alumina is used.
previous synthetic route required four steps from diketone 1a
and provided 5a in 16% yield.24 Our method prepared the same
compound in 53% yield via a one-pot procedure from the same
diketone intermediate using ethylene gas as the alkylating agent.
In summary, we developed the first Rh-catalyzed intermo-
lecular α-alkylation of cyclic 1,2-diketones via coupling with
simple olefins. This reaction exhibits excellent regioselectivity
to give linear products. Aminopyridine was employed as a
recyclable DG for this transformation, and a broad range of
terminal olefins can be coupled in good to excellent yields. This
preliminary work should have broad implications and serve as a
seminal study toward catalytic ketone alkylation with
unactivated olefins. Future work will focus on achieving milder
cleavage and catalytic turnover of the DG through its structural
modification and expanding the scope of C−H donors, such as
1,3-diketones, enones, and regular ketones, as well as the scope
of C−H acceptors, such as alkynes, allenes, and dienes. In
addition, mechanistic studies and development of the related
intramolecular reactions are currently ongoing.
alumina was found to promote the enamine formation
effectively; in contrast, only a 7% yield was obtained in the
absence of alumina (entry 2, Table 2). Use of 4 Å molecule
sieves did not lead to enamine formation (entry 3, Table 2). No
alkylation occurred without Wilkinson’s catalyst, while a 48%
yield was obtained with a 5 mol % catalyst loading. Use of
[Rh(coe)2Cl]2 as a catalyst proved to be inefficient for tert-butyl
ethylene insertion (entry 7, Table 2). 1,4-Dioxane served as a
more effective solvent than toluene (entry 8, Table 2). Finally,
replacement of aminopyridine with aniline led only to enamine
formation; however, no alkylation product was observed,
suggesting a critical role for the pyridine group as a DG for
C−H activation.19
Next, we investigated the scope of the tandem enamine
formation/alkylation reaction (Table 3). Similar to the C−H/
olefin coupling with preformed enamines, a broad scope of
olefins can be coupled under the tandem-reaction conditions.
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Journal of the American Chemical Society
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(11) Oka, M.; Iimura, S.; Tenmyo, O.; Sawada, Y.; Sugawara, M.;
Ohkusa, H.; Yamamoto, H.; Kawano, K.; Hu, S. L.; Fukagawa, Y.; Oki,
T. J. Antibiot. 1993, 46, 367.
(12) Strunz, G. M. J. Agric. Food Chem. 1983, 31, 185.
(13) For examples of O-alkylation and Claisen rearrangement of
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3866. (b) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 2000, 122,
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(14) For a dianion strategy to alkylate cyclic 1,2-diketones, see:
(a) Kende, A. S.; Eilerman, R. G. Tetrahedron Lett. 1973, 697.
(b) Utaka, M.; Hojo, M.; Takeda, A. Chem. Lett. 1984, 445.
(15) For a CAN-mediated oxidative coupling of cyclic 1,2-diketones
with electron-rich olefins, see: Miura, M.; Arai, N.; Narasaka, K. Bull.
Chem. Soc. Jpn. 1998, 71, 1437.
ASSOCIATED CONTENT
■
S
* Supporting Information
Complete experimental procedures, spectral data for new
compounds, and crystallographic data (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
gbdong@cm.utexas.edu
Notes
The authors declare no competing financial interest.
(16) Aminopyridines have been used in the aldehyde C−H
activation; for a seminal work, see: (a) Suggs, J. W. J. Am. Chem.
Soc. 1979, 101, 489. For reviews, see refs 2c and 2e. Use of 2-
carboxamide-pyridine as a DG in the Pd-catalyzed C−H functionaliza-
tion was recently developed by Daugulis and Chen, for seminal works;
see: (b) Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156.
(c) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192.
(17) Excess olefins were generally used in this study to enhance the
reaction rate because they are often volatile under these reaction
conditions; however, when 2 equiv of vinyl trimethylsilane reacted
with enamine 3a, an 87% yield was obtained (see SI).
ACKNOWLEDGMENTS
■
Dedicated to Prof. Robert G. Bergman on the occasion of his
70th birthday. We thank UT Austin and CPRIT for a start-up
fund and thank the Welch Foundation and Frasch Foundation
for research grants. G.D. thanks ORAU for a new faculty
enhancement award. We also thank faculty members from the
organic division at UT Austin for their generous support. Dr.
Lynch is acknowledged for X-ray crystallography. We thank
Mrs. Spangenberg and Mr. Sorey for their NMR advice.
Johnson Matthew is thanked for their generous donation of Rh
salts.
(18) 1,1-Disubstituted styrenes, cyclohexene, and cyclopentene do
not react under current reaction conditions.
(19) Further control experiments were conducted: using the aniline-
derived enamine with added pyridine (either 10 mol% or 1 equiv)
under the standard reaction conditions (5 mol% catalyst) did not
provide any coupling products.
(20) Two challenging substrates: (a) Reaction with TIPS-protected
4-penten-1-ol proceeded sluggishly under the tandem conditions and
provided the alkylated enamine product in 12% yield. (b) Reaction
with methyl acrylate gave a complex mixture, likely due to the
background reaction between methyl acrylate (Michael acceptor) and
the diketones (OH as the nucleophile).
(21) For example, condensation between six-membered diketone 1b
and 2 in the presence of alumina generated a significant amount of
aromatic oligomers (see SI), while use of five-membered diketone 1a
experiences no such problem.
(22) Enamine hydrolysis has been attempted with substrates 4b and
4i; unfortunately, the silane and ester groups are not tolerated under
the aqueous acidic conditions: protodesilylation and ester hydrolysis
were observed.
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