Palladium-catalyzed dehydrogenative β′-arylation of β-keto esters under aerobic conditions: Interplay of metal and Bronsted acids

Article abstract of DOI:10.1002/chem.201201988

The Bronsted aids: The first dehydrogenative arylation of β-keto esters with arenes under ambient aerobic conditions is described (see scheme). Under a Pd^II/Bronsted acid co-catalytic system, regioselective arylations with alkoxylated arenes an

Full text of DOI:10.1002/chem.201201988

COMMUNICATION
DOI: 10.1002/chem.201201988
Palladium-Catalyzed Dehydrogenative b’-Arylation of b-Keto Esters under
Aerobic Conditions: Interplay of Metal and Brønsted Acids
Kai-Tai Yip, Roshan Y. Nimje, Mikko V. Leskinen, and Petri M. Pihko*[a]
In chemical synthesis, methods that enable the rapid build
Table 1. Screen of Brønsted acid additive and solvent.[a]
up of complexity from simple precursors are highly valuable
from an atom and redox economic point of view. In this
regard, catalytic dehydrogenative cross-couplings between
two different molecules are particularly attractive, since
they do not require any pre-functionalization of the sub-
strate.[1,2] The challenges associated with such processes are
formidable—the catalysts will need to activate both compo-
[b]
Entry
Brønsted
acid
pKa
ACTHNUGRTNE(NUG H2O)
Yield [%]
Yield [%]
of 3a[c]
of 4a[c]
nents chemo- and regioselectively, while avoiding potential
homocoupling reactions between either of the two coupling
partners. For example, electron-rich arenes and phenols are
known to undergo oxidative homocoupling reactions under
catalytic oxidative conditions.[3,4] Another serious problem
associated with these reactions is the potential for further
oxidation of the product, especially when prolonged reac-
tion times and/or forcing conditions, such as heating, are re-
quired to promote the reactions.
Here we show that by a careful choice of Pd catalyst and
a Brønsted acid co-catalyst,[5] electron-rich arenes and a va-
riety of phenols can undergo a highly regioselective cross-
dehydrogenative coupling at room temperature with b-keto
esters in the b’-position, overcoming problems associated
with the overoxidation or degradation of the product. Previ-
ously, regioselective arylation in the b-position of esters has
been successful only with prefunctionalized aryl halides.[6]
In contrast to our recently reported cross-dehydrogenative
b’-functionalization of b-keto esters with indoles,[7] in our in-
itial screens with electron-rich arenes we encountered signif-
icant challenges associated with expanding the scope of the
reaction, including the generally lower reactivity of arenes
compared to indoles, and the competing overoxidation or
degradation of the product. In our initial screens with 1,3,5-
trimethoxybenzene (2a) and b-keto ester 1a (Table 1), the
reaction was feasible only at elevated temperatures (808C)
when tert-butyl perbenzoate (tBuOOBz) was used as the ox-
idant. Owing to the inherent hazards associated with pro-
longed heating of high concentrations of peroxides, we
turned to oxygen gas as a mild alternative.[8] Although [Pd-
1[d]
2[e,f,g]
3[f,h]
4[h]
–
–
–
–
8
44
17
40
0
29
15
15
TFA (excess)
TFA (excess)
TsOH·H2O
Cl3CCOOH
HIO3
À0.3
À0.3
ca. À3
0.7
0.8
ca. 1
1.3
2.2
2.9
3.4
2.4
5[d]
complex mixture
6[e]
42
37
0
<3
5 (3)[i]
5
<3
6
7[e]
8[d]
(PhO)2P(O)OH
82 (87)[i]
74
9[e]
Cl2CHCOOH
o-NO2-BzOH
ClCH2COOH
p-NO2-BzOH
IBX
10[e]
11[e]
12[d]
13[e]
13
19
N.D.[j]
<3
complex mixture
[a] Reaction conditions: 1a (0.6 mmol), 2a (0.4 mmol), acid additive
(0.08 mmol), Pd(OAc)2 (0.04 mmol) in 0.5 mL solvent under an oxygen-
filled balloon at 258C for 24 h. [b] For a comparison of pKa values, see
Supporting Information. [c] Determined by 1H NMR spectroscopy using
an internal standard. [d] 4:1 AcOH/DCE. [e] 1:1 AcOH/DCE.
AHCTUNGTRENNUNG
[f] 10 mol% of [PdACHTNUGTRENNUG(tfa)2] were used instead of PdACHTUNTGERN(NUGN OAc)2. [g] At 508C.
[h] TFA/DCE (4:1) as solvent. [i] Isolated yield; 50 mol% diphenyl phos-
phate used. [j] N.D.=not detected.
AHCTUNGRTEG(NUNN tfa)2] (tfa=trifluoroacetate) was an active catalyst at 508C,
its use also resulted in significant overoxidation to enones
4a and also 6a (enone derived from 1a) when O2 was used
as the terminal oxidant.
Instead of trying to control the reaction by limiting the
oxygen supply, we observed that the activity of a milder cat-
alyst, PdACHTUNGRTNENG(U OAc)2, could be boosted by the addition of catalyt-
ic amounts of acids,[9] especially when acetic acid was also
used as a co-solvent.[10] A survey of different acid co-cata-
lysts revealed that diphenyl phosphate was particularly ef-
fective, affording the desired product 3a in 82% yield and
minimizing the formation of overoxidation product 4a
(entry 8). When 50 mol% diphenyl phosphate was used, 3a
was isolated in 87% yield. The rate of b-arylation in the
presence of 50 mol% (PhO)2P(O)OH was approximately
14-fold faster when compared to the rate without the acid
additive (Scheme 1).
[a] K.-T. Yip, R. Y. Nimje, M. V. Leskinen, P. M. Pihko
Department of Chemistry and Nanoscience Center
University of Jyvꢀskylꢀ
P. O. B. 35, F40014 JYU (Finland)
E-mail: Petri.Pihko@jyu.fi
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201988.
Chem. Eur. J. 2012, 00, 0 – 0
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Scheme 1. Diphenyl phosphate accelerated PdII-catalyzed dehydrogena-
tive coupling.
With the optimized conditions in hand, the scope of the
coupling between different arenes and b-keto esters was
then explored (Scheme 2). Among cyclic b-keto esters ex-
plored, 5-membered cyclic b-keto esters system furnishes
coupling products (3a–e) with 2a in high yields (75–87%)
regardless of the steric bulkiness of ester group. Even a
moderately diastereoselective arylation (3e of d.r. 2.3:1) can
be achieved by (À)-menthyl ester. Seven-membered rings
(3 f) and g-lactones (3g) are also viable partners for the b-
arylation, and variations in substituent and substitution pat-
tern of the aryl component can also be tolerated. For exam-
ple, coupling of 1a with triethoxylated arene yielded 3h in
72% yield. Interestingly, some regioselectivity in the aryla-
tion process can be achieved by altering the arene substitu-
ent. For instance, a bulky TIPS-substituted arene led to se-
lective formation of para-regioisomer of 3i of 2.3:1 ratio,
while the use of benzylated arene resulted in the reverse
ratio in the formation of 3j (para/ortho=1:2.2). Further-
more, the coupling of 1a with 1,2,3-trimethoxybenzene,
under modified conditions, afforded 3k as the exclusive
isomer. Finally, acyclic b-keto ester-derived products can
also be obtained by slow addition of the b-keto ester (3l).
Although arenes bearing two donor groups, such as 1,3-di-
methoxybenzene, were insufficiently reactive, we were de-
lighted to find that unprotected phenols can be successfully
used as the reaction partners when the reaction is conducted
under modified conditions.[10] The scope of these reactions is
summarized in Scheme 3. In general, b-arylation reactions
are highly para-selective to phenolic systems, even in the
case of simple phenol (3m and 3n), which is known to be
reactive at both para- and ortho-positions.[11] In addition, the
reactions are remarkably tolerant to the steric crowding
from the substitution(s) at the ortho-position(s) (3o–u). In
particular, product 3q can be efficiently obtained from the
coupling with 2,6-di-tert-butylphenol. An electronically de-
activated phenol can also be used, although with somewhat
reduced yield (3u). Besides the cyclic b-keto esters, phenols
are also capable of b-coupling to a b-keto lactone system
(3v–x) without a competitive ring opening. Finally, success-
ful dehydrogenative coupling between an a-methyl-b-keto
ester and either an electron-rich arene (to give 3l in
Scheme 2) or unprotected phenols (to give 3y–3za in
Scheme 3) demonstrates that oxidative coupling can be used
as an alternative disconnection to the conventional benzyla-
tion of b-keto esters.
Scheme 2. Scope of diphenyl phosphate/PdII co-catalyzed dehydrogena-
tive coupling of 1 with different aromatics. Yields of isolated products
are reported. Reaction conditions, unless otherwise indicated:
(0.6 mmol, 1.5 equiv), (0.4 mmol, 1.0 equiv), diphenyl phosphate
(50 mol%), Pd(OAc)2 (10 mol%), AcOH/DCE (DCE=dichloroethane;
1
2
AHCTUNGTRENNUNG
4:1, 0.5 mL) under an oxygen-filled balloon at 258C. [a] X-ray structure
of 3a is available [CCDC 879905], see the Supporting Information.[17]
[b] 1 (1.33 g, 1.4 equiv),
2 (1.00 g, 1.0 equiv), diphenyl phosphate
(25 mol%), Pd(OAc)2 (5 mol%), AcOH/DCE (4:1, 15 mL) under an
AHCTUNGTRENNUNG
oxygen-filled balloon at 258C. [c] 1.2 equiv of 1e used. [d] Isomeric ratio
1
determined by H NMR spectroscopy from a crude mixture. [e] Single re-
gioisomer obtained exclusively. [f] 10 mol% of [Pd
(4:1, 0.5 mL) were used instead of Pd(OAc)2 in AcOH/DCE. [g] In the
absence of diphenyl phosphate. [h] 10 mol% of [Pd(tfa)2] were used in-
stead of Pd(OAc)2. [i] Slow addition of b-keto ester 1 over 10 h.
ACHTUNGRTEN(NGNU tfa)2] in TFA/DCE
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
The practicability of dehydrogenative b’-arylation was
also demonstrated by the gram-scale syntheses of 3a
(Scheme 2) and 3s (Scheme 3) with a reduced loading
(5 mol%) of PdII catalyst and oxygen gas as the sole oxi-
dant.
In line with the previously reported b’-arylation of b-keto
esters with indoles,[7] two major mechanistic pathways for
the reaction can be presented (Scheme 4): an “early-aryla-
tion” pathway in which the arene is palladated prior to its
engagement with the b-keto ester, and a “late-arylation”
pathway in which the b-keto ester is first oxidized to an
enone species and then undergoes a conjugate addition-type
process with the arene. The early arene pathway might in-
volve migratory insertion to give D-1/D-2 and subsequent
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Palladium-Catalyzed Dehydrogenative Arylation
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(4.3ꢂ10À5 mminÀ1; <6% conversion to enone 6a after
13 h).[12] Conducting the same experiment in the presence of
50 mol% (PhO)2P(O)OH reveals that the rate of formation
of enone is similarly slow (6.6ꢂ10À5 mminÀ1; 2% conversion
to enone 6a after 3.5 h, after which time the concentration
of 6a remains essentially constant). However, control ex-
periments with preformed enone 6b and arene 2a indicate
that conversion to the product 3b is essentially complete in
30 min with diphenyl phosphate (50 mol%), and the rate is
independent of the presence of 10 mol% PdACTHNURGTNEUNG(OAc)2. As
such, although the “late-arylation” pathway is feasible if
enough enone is available, the slow formation of enone may
limit the overall reaction rate.[13] The higher observed rate
of the overall reaction (6.7ꢂ10À4 mminÀ1, Scheme 1)[14] may
be more consistent with the “early-arylation” pathway in
which the dehydrogenation of the b-keto ester 1a takes
place with the involvement of the aryl–Pd species B. Impor-
tantly, our preliminary studies revealed that PdII-catalyzed
dehydrogenation of 1a can be accelerated by the presence
of electron-rich carbon ligands [Eq. (1)],[15] pointing towards
early involvement of the electron-rich arene in the reaction
pathway.
Scheme 3. Scope of PdII-catalyzed dehydrogenative coupling of 1 with
different phenols. Yields of isolated products are reported. Reaction con-
ditions:
(10 mol%), TFA/DCE (4:1, 0.5 mL) under an oxygen-filled balloon at
20–258C. [a] 1 (2.34 g, 1.4 equiv), (1.08 g, 1.0 equiv), [Pd(tfa)2]
1 (0.6 mmol, 1.5 equiv), 2 (0.4 mmol, 1.0 equiv), [PdACTHUGNTREN(NUGN tfa)2]
2
ACHTUNGTRENNUNG
(5 mol%), TFA/DCE (4:1, 12.5 mL) under an oxygen-filled balloon at
208C. [b] X-ray structure of 3v is available [CCDC 880392], see the Sup-
porting Information.[17]
À
reductive elimination that results in the formation of the C
C bond at the b’-position.
In view of the above, the role of acid co-catalyst (diaryl
phosphate) in these reactions most likely is to promote the
formation of the arylpalladium species B. Previously, Fuji-
wara and co-workers have reported the use of acids, such as
In control experiments with tBuOOBz (130 mol%) and
ACHTUNGTRENNUNG(OAc)2 (10 mol%) but without arene 2a, the enone 6a
derived from b-keto ester 1a is generated only very slowly
Pd
Scheme 4. Plausible reaction mechanism of dehydrogenative b-arylation of 1a with 2a.
Chem. Eur. J. 2012, 00, 0 – 0
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P. M. Pihko et al.
mann, Chem. Asian J. 2010, 5, 436; c) C.-J. Li, Acc. Chem. Res. 2009,
42, 335.
trifluoroacetic acid as solvent in promoting electrophilic pal-
ladation of arenes at room temperature.[9] Alternatively, the
acid co-catalyst might promote the conjugate addition step
in the “late-arylation” scenario. However, no enantioselec-
tivity could be obtained when a variety of sterically bulky
chiral diaryl phosphates were screened instead of diphenyl
phosphate.[10] Of course, such a result does not completely
rule out the “late-arylation” pathway, since the stereochem-
istry could already be set in the planar-chiral complex A
À
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À
before the C C bond formation. In the “early-arylation”
scenario, the chiral Brønsted acid might be dissociated
before the engagement of 1a to generate complex C, thus
leading to racemic product.
Although we cannot fully exclude either mechanism with
these experiments, we have nevertheless obtained additional
indirect evidence for the feasibility of the “early-arylation”
pathway in a control experiment with iodobenzene.[16] The
reaction proceeds with the use of AgOAc as the iodide scav-
enger to give direct b-arylation product 3zb in 55% yield
under acidic and phosphine-free conditions [Eq. (2)].
In conclusion, we have developed a PdII/Brønsted acid co-
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catalyzed dehydrogenative b’-arylation of b-keto esters with
arenes and phenols at room temperature using molecular
oxygen (1 atm) as the sole oxidant. Notable features of the
reaction include 1) mild, ambient reaction conditions, 2) tol-
erance of different substituent patterns, and 3) high regiose-
lectivity. A possible mechanism involving acid-assisted palla-
dation of arene and subsequent engagement of the b-keto
ester is proposed on the basis of control experiments. The
tunability and cooperativity of PdII/Brønsted acid system
should play a pivotal role to broaden the scope of this trans-
formation even further.
ˇ
ˇ
ˇ
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Acknowledgements
We thank Mr. Esa Haapaniemi and Ms. Mirja Lahtiperꢀ for NMR and
mass spectrometric assistance, and Prof. Kari Rissanen and Mr. Antti
Neuvonen for assistance with the X-ray studies. Financial support has
been provided by Tekes, Orion, CABB, Hormos Medical, PCAS Finland,
Fermion, Pharmatory and AB Enzymes (all under the auspices of the
Pharma program of Tekes) and the Academy of Finland (Projects 138854
and 139046).
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dat, E. Clot, O. Baudoin, Chem. Eur. J. 2012, 18, 1932.
À
C H
Keywords: arylation
functionalization · oxidation · palladium catalysis
·
Brønsted
acids
·
[7] M. V. Leskinen, K.-T. Yip, A. Valkonen, P. M. Pihko, J. Am. Chem.
Soc. 2012, 134, 5750.
[1] For recent reviews on dehydrogenative cross-coupling, see: a) C. S.
[8] For recent reviews, see: a) A. N. Campbell, S. S. Stahl, Acc. Chem.
Res. 2012, 45, 851; b) Z. Shi, C. Zhang, C. Tang, N. Jiao, Chem. Soc.
Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215; b) C. J. Scheuer-
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Palladium-Catalyzed Dehydrogenative Arylation
COMMUNICATION
Rev. 2012, 41, 3381; c) T. Punniyamurthy, S. Velusamy, J. Iqbal,
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[13] It should be noted that the “early- and late-arylation” pathways are
not necessarily exclusive.
[14] Due to the instability of enone derived from 1a and the proton–deu-
terium exchange of arene 2a in [D4]acetic acid, the kinetics of
enone formation experiments and dehydrogenative couplings were
studied under slightly different, but comparable conditions.
[15] Detailed studies and the mechanistic implications of the accelerated
effect of dehydrogenation of 1a will be reported in due course.
[16] These reactions would take place via oxidative addition pathways, as
in reference [6].
[17] CCDC-879905 (3a) and CCDC-880392 (3v) contain the supplemen-
tary crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[9] For a pioneering study on the effect of acidic medium on PdII-cata-
lyzed arene functionalization reactions, see: a) C. Jia, T. Kitamura,
Y. Fujiwara, Acc. Chem. Res. 2001, 34, 633; b) C. Jia, D. Piao, J.
Oyamada, W. Lu, T. Kitamura, Y. Fujiwara, Science 2000, 287, 1992.
[10] See the Supporting Information for detailed screens.
[11] a) X. Guo, R. Yu, H. Li, Z. Li, J. Am. Chem. Soc. 2009, 131, 17387;
b) K. M. Bogle, D. J. Hirst, D. J. Dixon, Org. Lett. 2007, 9, 4901;
c) R. B. Bedford, S. J. Coles, M. B. Hursthouse, M. E. Limmert,
Angew. Chem. 2003, 115, 116; Angew. Chem. Int. Ed. 2003, 42, 112;
d) K. Kobayashi, M. Arisawa, M. Yamaguchi, J. Am. Chem. Soc.
2002, 124, 8528.
Received: June 5, 2012
Published online: && &&, 0000
[12] See Supporting Information for details.
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P. M. Pihko et al.
Arylation
K.-T. Yip, R. Y. Nimje, M. V. Leskinen,
P. M. Pihko* .................. &&&& — &&&&
Palladium-Catalyzed Dehydrogenative
b’-Arylation of b-Keto Esters under
Aerobic Conditions: Interplay of
Metal and Brønsted Acids
The Brønsted aids: The first dehydro-
genative arylation of b-keto esters with
arenes under ambient aerobic condi-
tions was described (see scheme).
system, regioselective arylations with
alkoxylated arenes and phenols were
achieved in good yields, even in gram-
scale conditions.
Under a PdII/Brønsted acid co-catalytic
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