Practical Direct α-Arylation of Cyclopentanones by Palladium/Enamine Cooperative Catalysis

Article abstract of DOI:10.1002/anie.201510638

Direct arylation of cyclopentanones has been a long-standing challenge because of competitive self-aldol condensation and multiple arylations. Reported herein is a direct mono-α-C-H arylation of cyclopentanones with aryl bromides which is enabled by palla

Full text of DOI:10.1002/anie.201510638

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International Edition: DOI: 10.1002/anie.201510638
German Edition: DOI: 10.1002/ange.201510638
Synthetic Methods
Practical Direct a-Arylation of Cyclopentanones by Palladium/
Enamine Cooperative Catalysis
Yan Xu, Tianshun Su, Zhongxing Huang, and Guangbin Dong*
Abstract: Direct arylation of cyclopentanones has been a long-
standing challenge because of competitive self-aldol conden-
sation and multiple arylations. Reported herein is a direct
À
mono-a-C H arylation of cyclopentanones with aryl bromides
which is enabled by palladium/amine cooperative catalysis.
This method is scalable and chemoselective with broad func-
tional-group tolerance. Application to controlled sequential
arylation of cyclopentanones has been also demonstrated.
T
he Buchwald–Hartwig–Miura (BHM) arylation represents
a cornerstone in functionalizing carbonyl compounds through
transition metal catalyzed cross-coupling with aryl halides.[1,2]
While broad substrate scope has been established for this
transformation, simple or less substituted cyclopentanones
have been known as problematic substrates[3] despite a-
arylated cyclopentanones being widely found in pharmaceut-
icals and bioactive compounds (Figure 1). The challenge is
attributed to the side reactions of the cyclopentanones, for
example, self-aldol condensation[3a,c] and multiarylation,[3b]
which result from the basic reaction media and more acidic
a-hydrogen atoms in singly arylated products (Scheme 1a).[4]
Scheme 1. a-Functionalization of ketones. DG=donating group.
Consequently, only few examples[5] have been reported
wherein either excess[6] or specialized cyclopentanones are
used.[3a,7] More often, indirect multistep approaches are
employed to access a-arylated cyclopentanones.[8–10] Thus,
a general solution to the cyclopentanone arylation problem
remains to be discovered. Complementary to the BHM
À
reaction, herein, a direct a-C H arylation strategy between
readily available aryl bromides and normal cyclopentanones
is described using palladium/enamine cooperative catalysis.
This method is highly selective for monoarylation, operation-
ally simple, and exceptionally chemoselective.
Figure 1. Representative examples of bioactive a-arylated cyclopenta-
nones.
Merging transition-metal and enamine catalysis has
À
enabled a number of powerful C C bond-forming trans-
formations at the a-position of carbonyl compounds.[11,12] The
mode of activation generally includes 1) nucleophilic attack
of enamines on metal-activated allyl, benzylic, propargyl, and
alkynyl electrophiles; 2) 1,2- or 1,4-addition to polar p bonds
activated by Lewis-acidic metals (Scheme 1b).[11e] In addition,
[*] Y. Xu, Z. Huang, Prof. Dr. G. Dong
Department of Chemistry, University of Texas at Austin
100 East 24th street, Austin, TX 78712 (USA)
E-mail: gbdong@cm.utexas.edu
Homepage: http://gbdong.cm.utexas.edu/
À
we recently reported a directed C H insertion/metalation
T. Su
approach for ketone a-alkylation[13a–c] and alkenylation[13d]
with olefins and alkynes. Moreover, through combining
enamine and copper catalysis, elegant trifluoromethyla-
tion,[14a] arylation,[14b] and vinylation[14c] of more reactive
Department of Chemistry, University of Science and Technology of
China (USTC), Hefei, Anhui 230026 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510638.
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Table 1: Selected optimization studies.
aldehyde substrates were reported by MacMillan and co-
workers using hypervalent iodonium salts. However, to the
best of our knowledge, direct catalytic ketone a-arylation by
transition metal/enamine catalysis has not been reported to
date (Scheme 1c).
To address the challenge of the a-arylation of cyclo-
pentanones, a palladium/enamine cooperative catalysis strat-
egy was conceived (Figure 2). Starting with a secondary amine
and a palladium(0) catalyst, an enamine and a X-PdII-aryl
species can be formed, respectively, with cyclopentanone and
Entry
Variation on the reaction conditions given above
Yield [%][a]
1
2
3
none
no pyrrolidine
no Pd(OAc)2
75
0
0
À
4
5
6
7
8
9
10
11
12
13
14
15
no P(o-tol)3
9
the aryl halide (steps A and B). Subsequently, C H metal-
PPh3 instead of P(o-tol)3
P(1-naphthyl)3 instead of P(o-tol)3
P(tBu)3 instead of P(o-tol)3
P(iPr)3 instead of P(o-tol)3
[Pd0{P(o-tol)3}2] instead of Pd(OAc)2/P(o-tol)3
no amine 4
48
58
73
0
77
59
54
27
57
52
67
ation of the enamine would afford an enaminyl aryl–
palladium(II) intermediate (steps C and D),[15] which can
undergo reductive elimination and hydrolysis to provide the
arylated ketone and regenerate the catalysts (step E). This
strategy avoids the use of strong bases (or acids), thus self-
aldol reactions should be less favorable. In addition, over
arylation can be minimized because enamine formation is
highly sensitive to the sterics of the ketone substrate.
Furthermore, because of the redox-neutral and mild pH
conditions, high chemoselectivity and broad functional-group
tolerance are expected.
NEt3 instead of 4
no NaOAc
NaHCO3 instead of NaOAc
Na2CO3 instead of NaOAc
4 (1 equiv)/PivOH (1 equiv)
instead of 4 (30 mol%)/NaOAc (1 equiv)
808C, 26 h[b]
608C, 48 h, with P(tBu)3
with 5 mol% Pd(OAc)2/10 mol% P(o-tol)3
with 2.5 mol% Pd(OAc)2/5 mol% P(o-tol)3
16
17
18
19
20
21
22
23
75
60
79
82
85 (80)
80
74
[b]
[b]
with 2.5 mol% Pd(OAc)2/5 mol% P(o-tol)3
PhBr (1 equiv)[c]
H2O (1 equiv) was added[c]
under air[c]
50
[a] Determined by GC analysis using dodecane as the internal standard.
[b] 30 mol% pyrrolidine was used. [c] Change was made based on
entry 20.
and both pyrrolidine[22] and Pd(OAc)2 were found to be
pivotal (entries 2 and 3). Among various ligands, P(o-tol)3
proved to be excellent, although P(tBu)3 worked almost
equally as well (entries 4–8). The amine 4 was found to be an
important additive, although its role remains to be defined
(entries 10 and 11).[13b] One equivalent of a weak base is
required to neutralize the HBr generated from the reaction
(see step F in Figure 2). While NaOAc proved to be optimal,
other weak bases, such as NaHCO3, were also effective
(Table 1, entries 12–14). Note that near-neutral conditions
can be adopted when NaOAc is replaced with a 1:1 4/PivOH
buffer (entry 15). Lower temperatures are also possible but
longer reaction times are required (entries 16 and 17). In
addition, 1 equivalent of PhBr can be used without significant
loss of yield (entry 20). Finally, high compatibility with water
(entry 22) and moderate tolerance of air (entry 23) were
observed.
The substrate scope was subsequently examined (Table 2).
Various aryl bromides having different electronic properties
were efficiently coupled in good to excellent yields. Substi-
tutions at the ortho-, meta-, or para-positions were all
tolerated. Functional groups (FGs), such as aryl chlorides
(3j), fluorides (3n), esters (3g and 3h), nitriles (3o), amides
(3i, 3q and 3u), thioethers (3d), and even a tocopherol
moiety (3y), were compatible. Substrates bearing enolizable
protons, such as methyl sulfones (3r), or FGs which are
Figure 2. Proposed strategy.
Nevertheless, the challenges of the proposed strategy are
twofold: 1) In palladium catalysis, amines are known to either
reduce aryl halides to arenes[16] or cross-couple to form
anilines,[17] thus, the compatibility between the two catalytic
processes would be one concern. 2) The kinetics of forming
the enamine and X-PdII-aryl species need to match each
other. Otherwise, known side reactions, such as enamine-
aldol,[18] ketone dehydrogenation,[19] and aryl dimerization[20]
can compete. Hence, to test the feasibility of this strategy,
cyclopentanone and PhBr were employed as model sub-
strates. After investigating various reaction parameters, using
pyrrolidine as the amine catalyst and Pd(OAc)2/P(o-tol)3
provided the desired monoarylation product in 75% yield
(Table 1).[21] Interestingly, lowering the palladium loading
(down to 2.5 mol%) increased the yield up to 85%
(entries 18–20). Control experiments were then conducted,
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Table 2: Scope with respect to the aryl bromide.
Table 3: Scope with respect to the cyclopentanones.
Yields shown are those of the isolated product. The d.r. and r.r. values
were determined by NMR analysis of the crude reaction mixture. [a] With
10 mol% Pd(OAc)2, 20 mol% P(o-tol)3 and 50 mol% of pyrrolidine.
[b] 18 h. [c] Without 4, 24 h. Ts=4-toluenesulfonyl.
(6a). For substrates with an existing stereocenter, moderate
to good diastereoselectivity was observed. The thermody-
namically more stable isomers were favored, which is likely
controlled by the rapid keto–enol tautomerization under the
reaction conditions.
Yields shown are those of the isolated product. [a] With 10 mol%
Pd(OAc)2, 20 mol% P(o-tol)3. [b] 24 h. [c] With 2 equiv of ArBr, 18 h.
pin=pinacol.
A
gram-scale preparation was demonstrated using
sensitive to nucleophiles, for example, benzophenones (3t)
and Weinreb amides (3q), all worked well. Remarkably, free
carboxylic acids (3p) and alcohols (3x) remained intact. In
addition, this transformation is highly chemoselective for
cyclopentanones. For example, the methyl aryl ketone 3s was
well tolerated, and is likely attributed to the rate difference in
enamine formation.[23] Encouragingly, aryl silanes (3w) and
boronic esters (3v), well known partners for palladium-
catalyzed cross couplings, remained untouched because of the
lack of strong bases. Furthermore, both electron-rich and
electron-deficient heteroarenes and polyarenes, such as
unprotected indole (5a), pyridine (5b), benzothiophene
(5c) and naphthalene (5d) can also be introduced. Alto-
gether, this arylation method offers distinct and complemen-
tary features to those of the BHM reaction.
1 mol% palladium (Scheme 2a). Given the relatively low
costs of each reagent used and the tolerance of moisture/air,
this protocol is expected to be practical for larger scales.
Further applications were illustrated in the synthesis of
multiarylated cyclopentanones (Scheme 2b), which are chal-
lenging to prepare by other methods. While the previous
attempt only offered the bis(aryl)ated product in spite of
using excess cyclopentanone,[4] under the current reaction
conditions the monoarylated product was smoothly obtained.
Further conversion into the 2,2-diarylated product 9 was
achieved with a regular BHM reaction. In contrast, by using
our previously developed b-arylation methods,[25] followed by
the current a-arylation protocol, the 2,4-diarylated compound
11 was rapidly synthesized in two steps from cyclopentanones.
In conclusion, the long-standing challenge of mono-a-
arylation of cyclopentanones is addressed by palladium/
enamine cooperative catalysis. The unique mode of activation
should have further implications on developing other ketone
a-functionalization reactions. Efforts on elucidating detailed
reaction mechanism are ongoing.
Cyclopentanones with different substitution patterns were
tested (Table 3).[24] Substitutions at a- or b-positions, includ-
ing alkyl, aryl, and carbonyl groups, were all tolerated. Both
bridged (6b) and fused cycles (6c) are suitable substrates.
Interestingly, tertiary alcohol moiety was also competent
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Scheme 2. Synthetic applications. dba=dibenzylideneacetone, TFA=
trifluoroacetate.
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We thank CPRIT and the Welch Foundation (F 1781) for
research grants. USTC is acknowledged for a fellowship to
T.S. We thank Dr. M. C. Young for X-ray crystallographic
analysis, and D. E. Alonso for preparing aryl bromides.
Johnson Matthey is thanked for a donation of palladium salts.
Keywords: arylation · homogeneous catalysis · ketones ·
palladium · synthetic methods
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2559–2563
Angew. Chem. 2016, 128, 2605–2609
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[21] The diarylated product was only observed in a trace amount (ca.
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[22] Attempts to use various chiral secondary amines resulted in no
enantiomeric induction, and is likely attributed to the rapid
Received: November 16, 2015
Published online: January 14, 2016
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