Palladium-catalyzed dehydrogenative β'-functionalization of β-keto esters with indoles at room temperature

Article abstract of DOI:10.1021/ja300684r

The dehydrogenative β'-functionalization of α-substituted β-keto esters with indoles proceeds with high regioselectivities (C3-selective for the indole partner and β′-selective for the β-keto ester) and good yields under mild palladium catalysis at room temperature with a variety of oxidants. Two possible mechanisms involving either late or early involvement of indole are presented.

Full text of DOI:10.1021/ja300684r

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Dehydrogenative β′-Functionalization of β-Keto
Esters with Indoles at Room Temperature
Mikko V. Leskinen, Kai-Tai Yip, Arto Valkonen, and Petri M. Pihko*
Department of Chemistry and NanoScience Center, University of Jyvaskyla, FI-40014 JYU, Finland
̈
̈
S
* Supporting Information
allow the union of indoles with tertiary amines, alkenes, arenes,
and heteroarenes.9,10 Herein we describe a simple protocol for
the oxidative coupling of α-substituted β-keto esters and indoles
at the remote β′ position of the β-keto ester (Scheme 2).
ABSTRACT: The dehydrogenative β′-functionalization of
α-substituted β-keto esters with indoles proceeds with high
regioselectivities (C3-selective for the indole partner and
β′-selective for the β-keto ester) and good yields under
mild palladium catalysis at room temperature with a variety
of oxidants. Two possible mechanisms involving either late
or early involvement of indole are presented.
Scheme 2. Regioselective Functionalization of β-Keto Esters
with Indoles
irect cross-coupling reactions where new carbon−carbon
D
bonds are generated via the oxidation of C−H bonds are
highly desirable transformations from the atom-economic point
of view. It is therefore not surprising that these reactions, also
called cross-dehydrogenative coupling (CDC) reactions, have
attracted significant attention in the past few years.1 The
selectivity challenges associated with such processes are
formidable, since the C−H functionalization could potentially
take place at several different sites.2 As an example,
regioselective coupling at the β-position of carbonyl com-
pounds would be a desirable alternative to the classical
conjugate addition reactions3 (Scheme 1) since saturated, less
We initiated our screen by examining the reaction of
N-methylindole (2a) with cyclic β-keto ester 1a (Table 1). With
Mn(OAc)2 and t-BuOOH as the oxidant, we obtained the
α-coupled product 4a in poor yield, and similar results were
obtained with Cu(OAc)2. However, the use of Pd(OAc)2 gave a
significantly improved yield, and more importantly, the site of
the coupling had switched to the β′ position to give 3a. Further
screens indicated that Pd(TFA)2 was a more active catalyst
than Pd(OAc)2 and that dioxane as well as the mixed solvent
2-propanol/AcOH were optimal solvents. With the i-PrOH/
AcOH solvent system,11 the undesired side reaction, homo-
coupling of 1a,12 could be minimized. Although a wide variety
of oxidants gave reasonable conversions at room temperature,
tert-butyl perbenzoate (t-BuOOBz) afforded superior results
(entry 18), and these conditions were then selected for further
exploration. It should be noted that in addition to peroxide
oxidants, MnO2, AgOAc, and oxygen were also synthetically
useful oxidants (entries 6, 9, and 12). Significantly, the
regioselectivity was excellent on both coupling partners, and
no 4a or no indole regioisomers could be detected in reactions
with PdII catalysts.
Scheme 1. Roadmap of β-Functionalization of Carbonyl
Derivatives
functionalized precursors would be required. However,
dehydrogenative β-functionalization reactions of carbonyl
compounds4 are rare and typically involve the use of directing
groups5 or auxiliary amine catalysts.6 In the case of esters,
amides, and β-dicarbonyl compounds, CDCs afford products
functionalized at the α-position instead of the β-position.7
Because of the central place of heterocycles, especially
indoles, in medicinal chemistry, we recently initiated a program
directed toward oxidative functionalizations of indoles and
β-keto esters. Indole is the third most popular ring system found
bioactive molecules8 and a common core of over 3000 natural
products.9 Known dehydrogenative coupling methods currently
Schemes 3 and 4 summarize the results obtained with a range
of indoles and β-keto esters. Both unsubstituted as well as
N-substituted indoles give good product yields (3a−h), and
the reaction is highly tolerant of substituents with different
Received: January 20, 2012
Published: March 16, 2012
© 2012 American Chemical Society
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Communication
a
Table 1. Optimization of Reaction Conditions
Scheme 4. Scope of Dehydrogenative Coupling with
a
Different β-Keto Esters
b
entry
catalyst
oxidizer
product (%)
c
d
1
Mn(OAc)2
Cu(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
t-BuOOH
4a (<10)
4a (12)
3a (43)
3a (67)
3a (46)
3a (64)
3a (<2)
3a (35)
3a (42)
3a (45)
3a (59)
3a (58)
3a (26)
3a (57)
3a (34)
3a (72)
3a (37)
3a (82)
c
d
2
t-BuOOH
3
t-BuOOH
t-BuOOH
H2O2
4
5
6
O2 (1 atm)
DDQ
7
8
oxone
9
AgOAc
10
11
12
13
14
15
16
17
18
19
Na2S2O8
K2S2O8
a
Isolated yields of pure products are reported. Conditions, unless
otherwise indicated: β-keto ester (1.5 equiv), indole (0.4 mmol, 1.0 equiv),
t-BuOOBz (1.3 equiv), Pd(TFA)2 (0.1 equiv), i-PrOH/AcOH (4:1, 0.5 mL)
MnO2
t-BuOOt-Bu
PhCMe2OOH
(PhCMe2O)2
t-BuOOAc
BzOOBz
t-BuOOBz
t-BuOOBz
b
c
at 25 °C. Slow addition of indole over 10 h. 4.5 equiv of 1r was used.
d
Opposite enantiomer shown.
electronic properties in the indole nucleus (3d−h) (Scheme 3),
allowing further opportunities for synthetic transformations.
Furthermore, β-keto esters with different steric demands (see
products 3i−l) are readily engaged in the coupling reaction
(Scheme 4). All cyclic products exhibited trans stereochemistry,13
and the use of an enantiopure menthyl-derived ester enables
the β-functionalization in a diastereoselective fashion (3m, dr =
3:1 for the two trans isomers). Other β-keto ester scaffolds,
including cycloheptanone (3n) and γ-butyrolactone (3o−p)
systems, are also compatible. Notably, a pendant olefinic unit in
3q remains intact, reflecting the mildness of the reaction con-
ditions and the orthogonal reactivity to Heck-type reactions.14
In addition, acyclic β-keto esters can also be β-functionalized
(3r and 3s).15
e
3a (66)
a
Unless otherwise indicated, reactions were carried out with 0.4 mmol
b
1
scale of 2a for 15−18 h. Determined by H NMR analysis using
dibenzyl ether as the internal standard. Neat at 70 °C. 5.3 M in iso-
octane. Addition of a polar cosolvent inhibited the reaction completely
(see the Supporting Information for further solvent screens). In 20%
c
d
e
AcOH/H2O.
Scheme 3. Scope of Dehydrogenative Coupling with
Different Indoles
a
Mechanistically, the β-arylation is likely to proceed via a Pd0/
PdII catalytic manifold instead of the oxidant-dependent PdII/
PdIV cycle16 because (1) the reaction could proceed with a
variety of oxidants (Table 1) and (2) a reasonable product yield
(66%) was obtained when the reaction was performed with a
stoichiometric amount of Pd(TFA)2 in the absence of an
external oxidant under an argon atmosphere.
To provide insight into the reaction mechanism, the fol-
lowing kinetic experiments were performed. The rate of the
dehydrogenative coupling between 1a and 2a displays a satu-
ration dependence on β-keto ester 1a.17 The effect of indole 2a
is more complex (Figure 1): at low [2a], the rate exhibits a
pseudo-first-order dependence (the rate rises to maximum at
1 equiv of 2a), while inhibition kinetics appears when [2a] is
increased from 1 to 8 equiv.17 Furthermore, the reaction rate is
not dependent on the oxidant concentration, and the reaction is
0.7th order with respect to [Pd(TFA)2].17
At least two different mechanistic scenarios are consistent
with the above data (Scheme 5). The first scenario involves a
Saegusa oxidation18 of 1a to enone intermediate A followed by
a Friedel−Crafts-type or Pd-catalyzed conjugate addition of
indole 2a. In this “late indole” mechanism, the pseudo-first-
order kinetics at low concentrations of 2a could be rationalized
a
Isolated yields of pure products are reported. Conditions, unless
otherwise indicated: 1 (1.5 equiv), 2 (0.4 mmol, 1.0 equiv), t-BuOOBz
(1.3 equiv), Pd(TFA)2 (0.1 equiv), i-PrOH/AcOH (4:1, 0.5 mL) at
25 °C. Opposite enantiomer shown.
b
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Journal of the American Chemical Society
Communication
alternative include the following: (a) indoles are known to
be palladated and homocoupled at C3;12 (b) α-arylpalladium
species derived from β-dicarbonyl compounds are known to
undergo slow reductive eliminations, suppressing the competing
α-arylation;20 and (c) a similar mechanism for the β-arylations
of preformed ester enolates with heteroaryl and aryl halides
was recently proposed on the basis of kinetic and computa-
tional studies.21
Further kinetic experiments with preformed enone 5i or
β-ketoester 1i did not fully resolve the issue. Under the standard
conditions, the reaction between 5i and 2a (eq 1a or 1b) was
Figure 1. Plot of the initial rate of dehydrogenative coupling of β-keto
ester 1a with varying concentrations of 1-methylindole 2a: [1a] =
0.484 M, [2a] = 0.0323−2.583 M, [Pd(TFA)2] = 0.032 M,
[t-BuOOBz] = 0.424 M at 25 °C. The inset displays a linear least-
squares fit for [2a] ranging from 0.0323 to 0.323 M.
Scheme 5. Plausible Mechanisms for PdII-Catalyzed
Dehydrogenative β′-Functionalization of β-Keto Esters
ca. 2−3 times faster than the standard reaction between 1i and
2a (eq 2). Under acid catalysis (20 mol % TFA) or with 4:1
i-PrOH/AcOH alone, the reaction between 5i and 2a was
significantly slower (initial rate of 0.003 or 0.001 M min−1,
respectively).17 These data suggest that if 5i is an intermediate
(Saegusa pathway), the conjugate addition step is unlikely to be
acid-catalyzed. Interestingly, in a control experiment with 1a
but without indole 2a, only very slow formation of enone was
observed (12% conversion to 5a after 14 h, rate of formation of
5a = 0.00025 M min−1).17 Therefore, although neither mechanistic
pathway can be completely ruled out at present, in practice the
reaction appears to require the presence of indole to engage the
β-keto ester partner fully.
In summary, we have presented a novel dehydrogenative
coupling method for constructing C(sp2)−C(sp3) bonds by
connecting the C3 position of indoles and the β′-position of
β-keto esters under mild reaction conditions and with excellent
regioselectivities. Two possible mechanisms have been presented: a
Saegusa-type mechanism (“late indole”) and an indole-assisted
dehydrogenation mechanism (“early indole”). Efforts to advance
the understanding of the reaction mechanism and generalize the
concept of dehydrogenative β′-functionalization are ongoing.
ASSOCIATED CONTENT
■
if the Saegusa oxidation is faster than the conjugate addition at
low [2a]. The catalytic cycle would be completed by the
regeneration of PdII from Pd0 in the presence of tert-butyl
perbenzoate.19
S
* Supporting Information
Experimental details and spectroscopic data for new com-
pounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
Alternatively, an “early indole” scenario in which a palladated
indole species B is involved in the dehydrogenation step could
also be envisioned. The reaction might then proceed via
intermediates C and D-1 or D-2. This mechanism would also
be consistent with the kinetic behavior of indole if the rate is
suppressed at high [2a] by the formation of Pd(indole)2
species. Literature precedents supporting this mechanistic
AUTHOR INFORMATION
■
Corresponding Author
Petri.Pihko@jyu.fi
Notes
The authors declare no competing financial interest.
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Journal of the American Chemical Society
Communication
(k) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J. Angew. Chem., Int. Ed.
2011, 50, 5365.
ACKNOWLEDGMENTS
■
We thank Mr. Esa Haapaniemi and Ms. Mirja Lahtipera for
̈
(11) The beneficial role of acetic acid is also attributed to its
assistance with palladium-catalyzed C−H bond functionalization of
arenes. See: (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res.
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Y.; Wang, W.-H.; Yang, S.-D.; Li, B.-J.; Feng, C.; Shi, Z.-J. Chem.
Commun. 2010, 46, 4553. (b) Liang, Z.; Zhao, J.; Zhang, Y. J. Org.
Chem. 2010, 75, 170. (c) Liu, Q.; Li, G.; Yi, H.; Wu, P.; Liu, J.; Lei, A.
Chem.Eur. J. 2011, 17, 2353.
NMR and mass spectrometric assistance and Prof. Kari
Rissanen and Mr. Antti Neuvonen for assistance with the
X-ray studies. Financial support was provided by Tekes, Orion,
CABB, Hormos Medical, PCAS Finland, Fermion, Pharmatory,
and AB Enzymes (all under the auspices of the Pharma
Program of Tekes). A.V. thanks Academy Professor Kari
Rissanen for funding through Academy of Finland (KR project
Nos. 130629, 122350, and 140718). We also thank the referees
for their constructive comments.
(13) The relative stereochemistry of the products was assigned on
the basis X-ray diffraction of 3b, 3n, and 3p as well as by comparison
3
of the 1H NMR JHα−Hβ′ coupling constants (see the Supporting
Information).
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