C-C Activation by Retro-Aldol Reaction of Two β-Hydroxy Carbonyl Compounds: Synergy with Pd-Catalyzed Cross-Coupling to Access Mono-α-arylated Ketones and Esters

Article abstract of DOI:10.1021/acs.joc.5b02098

A retro-aldol reaction of two β-hydroxy compounds in synergy with Pd-catalyzed cross-coupling of aryl halides is reported herein, which produces selectively mono-α-arylated ketones and esters in good yields. This reaction is compatible with a broad range of aryl iodides, bromides, chlorides, and triflates and can tolerate an array of functional groups on the aromatic ring. Ready scale-up of this reaction to gram level is applicable without an appreciable decrease in the reaction yield. Furthermore, concise syntheses of biologically active isocoumarin and indole derivatives have been achieved to greatly demonstrate the synthetic value of this retro-aldol reaction. Finally, the reaction mechanism has been discussed on the basis of experimental observations and DFT computational results. A regulated six-membered-ring transition structure has been located for the key retro-aldol C-C cleavage, which constitutes the rate-determining step of a full catalytic cycle. The concept of C-C activation by retro-aldol reaction may also find applications in other fundamental reactions.

Full text of DOI:10.1021/acs.joc.5b02098

Article
pubs.acs.org/joc
C−C Activation by Retro-Aldol Reaction of Two β‑Hydroxy Carbonyl
Compounds: Synergy with Pd-Catalyzed Cross-Coupling To Access
Mono-α-arylated Ketones and Esters
Song-Lin Zhang* and Ze-Long Yu
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering,
Jiangnan University, Lihu Road 1800, Wuxi, Jiangsu 214122, China
S
* Supporting Information
ABSTRACT: A retro-aldol reaction of two β-hydroxy compounds
in synergy with Pd-catalyzed cross-coupling of aryl halides is
reported herein, which produces selectively mono-α-arylated ketones
and esters in good yields. This reaction is compatible with a broad
range of aryl iodides, bromides, chlorides, and triflates and can
tolerate an array of functional groups on the aromatic ring. Ready
scale-up of this reaction to gram level is applicable without an
appreciable decrease in the reaction yield. Furthermore, concise
syntheses of biologically active isocoumarin and indole derivatives
have been achieved to greatly demonstrate the synthetic value of this
retro-aldol reaction. Finally, the reaction mechanism has been
discussed on the basis of experimental observations and DFT
computational results. A regulated six-membered-ring transition structure has been located for the key retro-aldol C−C cleavage,
which constitutes the rate-determining step of a full catalytic cycle. The concept of C−C activation by retro-aldol reaction may
also find applications in other fundamental reactions.
with the release of a ketone byproduct and undergo further
reactions. To stabilize the M−C intermediates and avoid
possible decomposition pathways resulting from β-H elimi-
nation, typically aryl, heteroaryl, and allyl groups have been
reported for the carbon-centered group in the literature.
However, harsh reaction conditions such as high temperatures
and long reaction times are still required for many of the
reactions reported. We hypothesized that in the key transition
state TS, the presence of an additional pendant group in the
alcohol that can coordinate to the metal center should
effectively assist in stabilizing the key transition state (TSNu
in Scheme 1b) and therefore may promote C−C activation in
the alcohol.
To explore the feasibility of this hypothesis, a carbonyl
pendant group was initially considered. Thus, a β-hydroxy
ketone substrate was studied for the activation of the Cα−Cβ
bond, which is the microscopic reverse process of the classic
aldol reaction. Because of the keto−enol tautomerization of the
carbonyl group, a potential conformationally regulated six-
membered-ring transition state TSretro‑aldol, reminiscent of the
chairlike conformation of cyclohexanes, can be favorably
generated in principle (Scheme 1c). Thus, by synergy of this
retro-aldol strategy with classic Pd-catalyzed cross-coupling of
aryl halides, key aryl-Pd(II) enolate intermediates could be
1. INTRODUCTION
The integral connection of C−C bonds constitutes the
backbone of a diversity of compounds ranging from simple
hydrocarbons and basic functionalized organic molecules to
more complicated natural products and biologically active
compounds and further to tremendous supramolecular
assemblies and polymeric materials. Therefore, the formation
and activation of C−C bonds are two kinds of transformations
that are of fundamental significance to organic chemistry.
However, compared with C−C bond formation reactions,
which have witnessed great progress and form the foundation
of organic chemistry,1 the reverse process of C−C bond
activation has received far less attention. This is largely due to
the inertness of C−C bonds and the ensuing difficulty in
achieving efficient and practical C−C activation reactions.
However, in recent years C−C activation reactions, particularly
those promoted by transition metal complexes, have begun to
attract increasingly more attention of chemists from across the
world.2 Significant progress has been achieved through the wise
implementation of effective promoting strategies, including the
release of ring strain,3 chelation assistance,4 β-C elimination,
etc.5
Alcohols are a preferred and versatile class of substrates that
are greatly utilized in transition-metal-mediated C−C activation
reactions.6,7 A mechanism of β-C elimination has often been
invoked for the key C−C bond cleavage of alcohols, which
involves a typical four-membered-ring transition state (Scheme
1a).8 Organometallic M−C intermediates are thus generated
Received: September 7, 2015
© XXXX American Chemical Society
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Scheme 1. Transition-Metal-Promoted C−C Activation of
Alcohols
2. RESULTS AND DISCUSSION
2.1. Reaction Development. Our study commenced with
reaction of 1a with 2a to produce 3a via C−C bond cleavage in
2a to transfer the acetonyl group to the aryl ring (Table 1).
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
ligand
base
solvent
yield (%)
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
−
P(p-tolyl)3
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
45
56
30
37
32
0
3
PCy3
4
XantPhos
XPhos
BINAP
DPPE
PPh3
5
6
7
0
c
8
45
c
9
XantPhos
PPh3
20
10
11
12
13
14
15
16
17
18
19
20
21
<10
0
PPh3
PPh3
NMP
0
PPh3
DMA
0
PPh3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
17
0
PPh3
NaOtBu
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
obtained, which are known to undergo reductive elimination to
deliver α-arylated ketones (Scheme 1c).9
PPh3
0
d
PPh3
60
e
α-Arylated ketones are important synthetic intermediates for
biologically active compounds. Therefore, α-arylation of
carbonyl compounds has been intensively studied in the past
decades by Pd-catalyzed cross-coupling of aryl halides with
carbonyl compounds in the presence of a base.10 Notably in
this area, Buchwald, Hartwig, and Miura independently
reported elegant pioneering work on the α-arylation of ketones
with aryl halides.11 Following these seminal reports, numerous
studies concerning the development and application of α-
arylation of ketones,12,13 aldehydes,14 esters,15 amides,16
nitriles,17 etc. have been described. However, these reactions
are often troubled by over-α-arylation due to the presence of
excess α-hydrogens and the higher reactivity of monoarylated
carbonyl compounds compared with their parent counterparts.
Selective mono-α-arylation of ketones in the presence of
additional active hydrogen atoms represents a challenging task.
Additionally, the quest for other novel ways to generate metal
enolates in a mild and controllable manner would clearly be
valuable to the development of new α-arylation chemistry.
In this report, we describe in detail the novel retro-aldol
strategy to generate the key Pd enolate intermediate, which in
synergy with Pd-catalyzed cross-coupling18 provides an
alternative and efficient method for selective access to mono-
α-arylated ketones and esters (Scheme 1c). Because of the
stronger acidity of the alcohol than the monoarylated ketone
product,19 overarylation of the monoarylation product can be
effectively avoided, and thus, the mono-α-arylation product is
selectively obtained with high efficiency. Furthermore, a broad
range of aryl electrophiles with diverse electronic properties are
compatible with the reaction conditions. The reaction develop-
ment, substrate scope, and mechanism are elucidated along
with applications to the synthesis of biologically active
compounds that show the great promise of this reaction for
practical applications in organic synthesis.
PPh3
80
e
PPh3
82
e
PPh3
0
ef
,
Pd(OAc)2
PPh3
76
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst (0.025
mmol), ligand (0.1 mmol), base (0.75 mmol), and solvent (3 mL)
were stirred at 120 °C (oil bath) for 5 h under N2. Isolated yields
after silica gel column chromatography. Ligand (0.05 mmol). 2a (2.0
b
c
d
e
f
mmol). 2a (3.0 mmol). At 90 °C.
Initial intensive screening of the ancillary ligand (entries 1−7)
indicated that P(p-tolyl)3 and PPh3 are efficient for this task
with 5 mol % Pd(OAc)2 as the catalyst in toluene, giving the
desired 3a in isolated yields of 45% and 56% (entries 1 and 2).
Notably, the use of 20 mol % phosphine ligand (4 equiv relative
to the Pd(OAc)2 catalyst) is preferred. When 10 mol %
phosphine ligand was used, the reaction yield decreased
significantly (entries 8 and 9). It is possible that excess
phosphine is needed for reduction of the Pd(OAc)2 precursor
to the Pd(0) active catalyst, which reacts with aryl halides to
initiate the reaction.
Next, the solvent effect was studied by examining a series of
common organic solvents other than toluene, such as DMSO,
DMF, NMP, and DMA. These solvents gave the desired
product 3a in less than 10% yield or led to no reaction at all
(entries 10−13). Furthermore, a number of bases other than
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Cs2CO3 were also examined, including K3PO4, NaOtBu, and
Na2CO3, but gave considerably lower yields compared with
Cs2CO3 (entries 2 and 14−16). Notably, the amount of 2a has
a great impact on the reaction yield. The reaction of 4 equiv of
2a with 1a produced 3a in a little higher yield of 60% (entry
17). When 6 equiv of 2a was used, the reaction yield increased
greatly to 80% (entry 18). These results suggest that reversible
deprotonation of 2a may be involved before or in the rate-
determining step of the catalytic cycle.
No reaction occurred in the absence of Pd catalyst (entry
20). This confirmed the crucial role of the Pd salt in this
reaction and makes the SNAr mechanism of direct attack of the
enolate on the aromatic ring unlikely. Additionally, a Pd(0)
catalyst gave similar results as Pd(OAc)2 (entry 19), which also
supports the hypothesis that the reaction proceeds via initial
oxidative addition of the aryl halide to a Pd(0) active catalyst.
Finally, the reaction temperature has a substantial effect on the
reaction yield. When the reaction was conducted at 90 °C, a
yield of 76% was obtained, which was a little lower than the
yield at 120 °C (entry 21).
α-H atoms of esters are much less acidic than those of ketones
(e.g., the pKa values for the α-H atoms of ethyl acetate and
acetone are 29.5 and 26.5, respectively19). This means that the
reaction should occur directly via retro-aldol reaction of the β-
hydroxy ester to generate the Pd enolate of the ester.
Furthermore, this also indicates that the generation of the Pd
enolate by retro-aldol C−C cleavage is kinetically much faster
than the potential generation of acetone enolate by
deprotonation of acetone. Otherwise, the acetone α-arylation
product should be formed significantly. All of these results
strongly indicate that it is the β-hydroxy carbonyl compound
that directly participates in the coupling reaction with the aryl
halide through Cα−Cβ bond cleavage and the attachment of the
α-carbon of the β-hydroxy carbonyl compound to the aromatic
ring. Finally, the reaction of 2c with 1a under the optimized
conditions led to no reaction at all (Scheme 2c), which
underscores the indispensable presence of coordinating carbon-
yl group to effectively promote this reaction via the concerted
six-membered-ring transition structure TSretro‑aldol (Scheme 1c).
2.2. Substrate Scope. With the optimized reaction
conditions in hand, we next studied the substrate scope for
this retro-aldol reaction to evaluate its synthetic capability
(Table 2). Various substituted aryl bromides were compatible
Because of the equilibrium of 2a with acetone under basic
conditions, the reaction may proceed by the direct reaction of
acetone with the aryl halide to deliver the α-arylated product
3a.13 To clarify this issue, additional experiments were done as
shown in Scheme 2. If the reaction of 1a and 2a proceeds via
Table 2. Pd-Catalyzed Retro-Aldol Reaction of β-Hydroxy
ab
,
Ketone 2a with Various Aryl Bromides and Iodides
Scheme 2. Reactions of Other β-Hydroxy Carbonyl
Compounds and Acetone with 1a
acetone α-arylation, then the direct reaction of 1a with excess
acetone under otherwise identical conditions should produce
3a in a higher yield or at least a similar yield. However, the fact
is against this deduction, as the reaction of 1a with 4 equiv of
acetone under the optimized conditions gave 3a in a much
lower yield of 35% (Scheme 2a). Therefore, 2a should be more
reactive than acetone and represent the major reactant for the
formation of 3a. The observation of the ineffectiveness of
Xantphos and BINAP (Table 1, entries 4 and 6) also implies
that acetone should not be the major active coupling substrate
because previous studies showed that Xantphos and BINAP are
very good ligands for promoting the coupling of acetone with
aryl halides and sulfonates under similar conditions.13b
Furthermore, the analogous β-hydroxy ester 2b reacted in a
similar way with 1a to give mono-α-arylated acetic ester 4a in
60% yield (Scheme 2b). The yield could further be improved to
71% by using the Pd(TFA)2/PCy3 catalyst system in xylene.
The byproduct arising from acetone α-arylation was not
observed in an appreciable amount (<7%). It is known that the
a
Reaction conditions: 1 (0.5 mmol), 2a (3.0 mmol), Pd(OAc)2 (0.025
mmol), Cs2CO3 (0.75 mmol), PPh3 (0.1 mmol), and toluene (3 mL)
were stirred at 120 °C (oil bath) for 5 h under N2. Isolated yields
using silica gel column chromatography are shown.
b
with the optimized reaction conditions. Aryl bromides with
alkyl, methoxy, nitro, phenyl, acetyl, aldehyde, and trifluor-
omethyl groups at the ortho, meta, and para positions were able
to give the desired mono-α-arylated ketones in good yields.
Notably, the reaction of 4-bromobenzaldehyde bearing a highly
reactive aldehyde with 2a gave the desired product 3k in 50%
yield with the aldehyde group intact. Some multiply substituted
aryl bromides were also good substrates for this reaction (3c−
e). Additionally, naphthyl and biphenyl bromide also gave the
desired products in good yields (3f and 3g).
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Aryl iodides reacted with reactivity similar to that of aryl
bromides (Table 2). All of the o-, m-, and p-nitro aryl iodides
reacted with 2a to produce the desired α-arylated products in
good to satisfying yields (3a, 3b, and 3m). 1-Naphthyl, 2-
biphenyl, and p-acetylphenyl iodide reacted with 2a to give
good yields comparable to those for the corresponding
bromides (3f, 3g, and 3j). Heteroaryl iodides such as 2-pyridyl
iodide and 2-thiophenyl iodide were also examined but did not
give the desired α-arylated products.
In addition to 2a, 2b was also studied to react with aryl
halides to give α-aryl acetic esters in good yields (Table 4). The
Table 4. Pd-Catalyzed Retro-Aldol Reaction of β-Hydroxy
a b
,
Ester 2b with Aryl Halides
In addition, aryl chlorides, which have been shown to be
more challenging in ketone α-arylation reactions and other
types of cross-coupling reactions, are also compatible with the
optimized reaction conditions (Table 3). Good yields were
Table 3. Pd-Catalyzed Retro-Aldol Reaction of β-Hydroxy
a b
,
Ketone 2a with Various Aryl Chlorides and Triflates
a
Reaction conditions: 1 (0.5 mmol), 2b (1.5 mmol), Pd(TFA)2 (0.025
mmol), Cs2CO3 (0.75 mmol), PCy3 (0.05 mmol), and xylene (3 mL)
b
were stirred at 120 °C (oil bath) for 15 h under N2. Isolated yields
using silica gel column chromatography are shown.
reactions were found to perform better using the Pd(TFA)2/
PCy3 catalyst system compared with the Pd(OAc)2/PPh3
system. These mono-α-arylated esters are also important
synthetic intermediates for biologically active compounds. No
appreciable amounts of overarylation products were observed,
as evidenced by TLC analyses of the crude product mixtures.
Additionally, the byproducts arising from acetone α-arylation
were also negligible in all cases, which strongly supports the
retro-aldol mechanism proposed in this study.
a
Reaction conditions: 1 (0.5 mmol), 2a (3.0 mmol), Pd(OAc)2 (0.025
mmol), Cs2CO3 (0.75 mmol), PPh3 (0.1 mmol), and toluene (3 mL)
were stirred at 120 °C (oil bath) for 5 h under N2. Isolated yields
using silica gel column chromatography are shown.
b
2.3. Applications. The general compatibility of this
reaction with various aryl iodides, bromides, chlorides, and
triflates and the tolerance of a range of functional groups make
this reaction very attractive for organic synthesis. The robust
nature of the reaction conditions (which are not sensitive to
adventitious moisture or air) further enhances the synthetic
value of this retro-aldol reaction. Here we will show the
usefulness of this reaction by three additional examples
(Schemes 3−5).
generally obtained for the production of 3 from various
chlorides. It is noteworthy that o-nitrophenyl chloride reacted
with 2a to give a reaction yield similar to those for the
corresponding bromide and iodide (please compare the results
for 3a in Tables 2 and 3). Other chlorides gave a little lower
yields than the corresponding bromides and iodides. To further
expand the substrate scope, aryl triflates were also subjected to
the optimized reaction conditions and found to exhibit good
reactivity, comparable to those of aryl bromides and iodides. p-
Nitro- and p-acetylphenyl triflates gave the desired products 3b
and 3j in 71% and 60% yield, respectively, which are
comparable to or even higher than the yields for the aryl
halide counterparts.
As shown in Scheme 3, this reaction could be easily scaled up
to gram level. The reaction of 8 mmol of chloro derivative 1r
Scheme 3. Scale-Up of This Reaction to Gram Level
To summarize, the reactivity of various aryl electrophiles with
2a generally follows the trend of ArI ∼ ArBr ∼ ArOTf, all of
which are a little more reactive than ArCl. This suggests that
aryl halide activation is unlikely to be the rate-limiting step of
the catalytic cycle. Additionally, it seems that both electronic
and steric effects of the substituents play a role in this reaction.
It is possible that the steric effect of the substituents influences
the approaching and subsequent coordination of the β-hydroxy
carbonyl to the Ar−Pd(II)−X intermediate generated from
oxidative addition of the aryl halide to Pd(0). Electronic effects
could be explained as influencing both the oxidative addition
and retro-aldol C−C cleavage steps where aryl group is
involved.
with an excess amount of 2a delivered the desired product 3a in
76% yield (1.101 g). It is worth pointing out that the scale-up
of this reaction did not reduce the reaction yield appreciably
(76% in this case vs 77% in Table 3). This feature is particularly
important for practical large-scale applications given the fact
that many academic reactions have performed poorly when
scaled up.
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As an interesting special case of this retro-aldol reaction, 1h
with an o-ester group directly gave 3-methylisocoumarin (3h)
in 70% yield (Scheme 4). It is possible that the initially formed
Scheme 6. Plausible Mechanism for This Retro-Aldol
Reaction
Scheme 4. One-Step Synthesis of a Biologically Active
Isocoumarin
α-arylated ketone undergoes subsequent intramolecular
nucleophilic substitution at the ester carbonyl group to deliver
the annulated product. Coumarin derivatives are important
biologically active compounds that are widely used as drug
intermediates, luminescent fluorophores, and agrochemicals.
To further showcase the significance of this reaction, it was
applied to the concise synthesis of indole derivatives (Scheme
5), which represent a key structural motif in many naturally
of the alcohol are achieved in the presence of base, resulting in
the formation of the key aryl-Pd(II) alkoxide intermediate 2.
This ligand exchange step may possibly be reversible and is
therefore promoted in the presence of excess alcohol substrate.
The key retro-aldol step occurs from 2 to generate aryl-Pd(II)
enolate intermediate 3 with the release of acetone byproduct,
which was confirmed by GC analysis of the crude reaction
mixture.25 A concerted transition structure TS is proposed for
this step featuring concurrent C−C bond cleavage and Pd−O
bond formation. This retro-aldol C−C cleavage step should be
the rate-determining step of the catalytic cycle. Finally,
reductive elimination of 3 delivers the desired α-arylated
carbonyl product and regenerates the active Pd(0) catalyst.
To provide further evidence supporting this mechanistic
proposal, DFT computational studies were conducted in order
to locate the key intermediates proposed and to construct a full
catalytic cycle of this reaction.26 As summarized in Figure 1, the
catalytic cycle is proposed to comprise three key stages:
oxidative addition, retro-aldol C−C cleavage, and reductive
elimination. Oxidative addition of the aryl halide to the Pd(0)
catalyst is relatively facile, with an activation barrier of 19.2
kcal/mol (TS1 in Figure 1), leading to the formation of trans
intermediate CP1-trans. Subsequent deprotonation of the
alcohol by CP1-trans in the presence of base is reversible
and forms CP2, which is endergonic by 11.9 kcal/mol. This is
consistent with the experimental observations that excess
alcohol benefits the reaction outcome and our hypothesis.
For the retro-aldol reaction to occur, a free coordination site in
CP2 is required, and therefore, a PPh3 ligand dissociates. This
leads to the generation of CP3 with the stabilizing coordination
of carbonyl group. From CP3, the key retro-aldol reaction
occurs to cleave the Cα−Cβ bond, producing the critical
(Ar)PdII(enolate) intermediate CP5 with concurrent release of
acetone. The key transition structure for this step, TS2, is
shown in Figure 1. It features a six-membered ring, and the
geometric parameters are consistent with the electronic
structure assigned. In CP5, there is stabilizing π coordination
of the double bond of the enolate to the Pd(II) center, forming
a Pd(II)−oxyallyl-type structure. This retro-aldol C−C cleavage
step has an overall activation barrier of 26.2 kcal/mol as
calculated from the free energies of low-lying CP1-trans and
high-lying TS2. Finally, reductive elimination from CP5
delivers the desired product and regenerates the active Pd(0)
catalyst. This step is quite facile, with an activation free energy
Scheme 5. Concise Two-Step Synthesis of 2-Methylindole
occurring compounds, pharmaceuticals, and biologically active
molecules.20 Typical methods for the synthesis of indole
derivatives are the intramolecular hydroamination of o-
alkynylanilines21 and transition-metal-catalyzed multistep tan-
dem reactions starting from o-haloanilines or o-haloarylal-
kynes.22 These methods are limited by either the expensive and
uncommon reagents or the multistep complex procedures.
Here, by means of the retro-aldol reaction developed in this
study, the synthesis of 2-methylindole (6) was readily achieved
in only two steps from readily available and cheap aryl bromide
1a and alcohol 2a (Scheme 5). The reaction of 1a with 2a to
give 3a in 80% yield was followed by a one-pot tandem
reduction of the o-nitro group by Zn/HOAc and intramolecular
condensation at room temperature for 90 min.23 This resulted
in the formation of 6 in a total yield of 36% in only two steps,
which is a streamlined and operationally convenient route from
cheap and readily available starting materials. Notably,
introducing a simple methyl group into biologically active
compounds imparts significant changes in the properties such
as conformation and bioavailibility of the resulting methylated
targets and represents an important and challenging task for
drug development.24
2.4. DFT Insights into the Reaction Mechanism. On the
basis of the observations in section 2.1 and mechanistic
proposals for related α-arylation reactions and alcohol C−C
activation,2,8,10 a plausible mechanism for this reaction is
suggested as shown in Scheme 6. Oxidative addition of the aryl
halide to the Pd(0) active catalyst leads to the formation of
intermediate 1. Subsequent ligand exchange and deprotonation
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Figure 1. Catalytic cycle calculated for this retro-aldol reaction at the M06/SDD-6-311+G(d,p) level. Values in parentheses are relative free energies
in kcal/mol in toluene.
of only 13.4 kcal/mol, and is significantly exergonic by 39.5
kcal/mol.
expansion of the substrate scope and the application of this
retro-aldol reaction are ongoing in our group.27
As shown in Figure 1, retro-aldol C−C cleavage is the rate-
determining step in the full catalytic cycle, with an apparent
activation barrier of 26.2 kcal/mol, the magnitude of which is in
good agreement with the experimental conditions that the
reactions were conducted in refluxing toluene. This relatively
large activation barrier is contributed mainly by two
components: the energy required for deprotonation of the
alcohol and the activation energy for the retro-aldol C−C
cleavage. These computational results not only provide strong
evidence supporting the mechanistic proposal shown in
Scheme 6 but also reveal more detailed mechanistic insights
into this reaction, including the structures and energetics of the
key intermediates and transition states along the reaction
coordinate.
EXPERIMENTAL SECTION
■
General Information. All of the reactants and reagents were used
as received from commercial suppliers without further purification. All
of the reactions were performed under an atmosphere of N2 using
conventional evacuation/backfill techniques. NMR spectra were
recorded on a 400 MHz spectrometer using TMS as the internal
standard. GC analyses were performed by comparison with authentic
samples.
General Procedure for the Retro-Aldol Reaction of β-
Hydroxy Ketone 2a with Aryl Halides or Triflates. Palladium
acetate (6.0 mg, 0.025 mmol), PPh3 (26 mg, 0.10 mmol), aryl halide or
triflate 1 (0.5 mmol), and cesium carbonate (244 mg, 0.75 mmol)
were added to an oven-dried Schlenk tube equipped with a stir bar.
The tube was then sealed, evacuated, and backfilled with nitrogen
three times using standard Schlenk techniques. Toluene (3.0 mL) and
4-hydroxy-4-methyl-2-pentanone (2a) (348 mg, 3.0 mmol) were
sequentially added by syringe at ambient temperature. The resulting
mixture was vigorously stirred and heated at 120 °C (oil bath) for 5 h.
After the mixture was cooled to room temperature, water (20 mL) was
added. The resulting mixture was extracted with ethyl acetate (5 mL ×
3). The combined organic layers were then washed with brine, dried
over Na2SO4, and concentrated in vacuum. The residue was purified
by column chromatography on silica gel (eluting with 10:1−5:1 (v/v)
petroleum ether/ethyl acetate) to provide the desired product 3.13,28
1-(2-Nitrophenyl)propan-2-one (3a). Yield: 72 mg, 80%. Brown
3. CONCLUSIONS
A general and efficient Pd-catalyzed coupling of two β-hydroxy
ketone or ester compounds with aryl halides and triflates to
produce mono-α-arylated ketones and esters in good yields has
been reported. This reaction is compatible with various aryl
iodides, bromides, chlorides, and triflates and can tolerate an
array of useful functional groups on the aromatic ring. It can be
readily scaled up to produce the desired α-arylated ketones on a
gram level without a significant decrease in the reaction yield.
By means of this reaction, biologically active isocoumarin and
indole derivatives could be readily prepared from readily
available alcohols and aryl halides, which demonstrates the
synthetic potential of this reaction. Finally, the mechanism of
this reaction has been discussed on the basis of experimental
observations and DFT computational studies. The retro-aldol
C−C cleavage of β-hydroxy carbonyls is proposed to be the
rate-determining step in a full catalytic cycle and involves a key
regulated six-membered transition structure to produce the key
aryl-Pd(II) enolate intermediate. Further studies on the
1
oil. H NMR (400 MHz, CDCl3): δ 8.14 (dd, J = 8.2, 1.3 Hz, 1H),
7.62 (td, J = 7.5, 1.3 Hz, 1H), 7.53−7.44 (m, 1H), 7.30 (dd, J = 7.6,
1.1 Hz, 1H), 4.14 (s, 2H), 2.35 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 203.5, 148.6, 133.6, 133.5, 130.4, 128.4, 125.2, 48.5, 30.0.
Anal. Calcd for C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C,
60.51; H, 5.10; N, 7.72.
1-(4-Nitrophenyl)propan-2-one (3b). Yield: 58 mg, 65%. Yellow
liquid. 1H NMR (400 MHz, CDCl3): δ 8.21 (d, J = 8.7 Hz, 2H), 7.38
(d, J = 8.7 Hz, 2H), 3.87 (s, 2H), 2.26 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 204.0, 147.2, 141.4, 130.5, 123.8, 50.1, 29.9. Anal. Calcd for
C9H9NO3: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.58; H, 5.16; N,
7.70.
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1-(4-Methyl-2-nitrophenyl)propan-2-one (3c). Yield: 80 mg,
83%. Brown oil. H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H), 7.41
backfilled with nitrogen three times using standard Schlenk techniques.
Xylene (3.0 mL) and 2b (219 mg, 1.5 mmol) were sequentially added
by syringe at ambient temperature. The resulting mixture was
vigorously stirred and heated at 120 °C (oil bath) for 15 h. After
the mixture was cooled to room temperature, water (20 mL) was
added. The resulting mixture was extracted with ethyl acetate (5 mL ×
3). The combined organic layers were then washed with brine, dried
over Na2SO4, and concentrated in vacuum. The residue was purified
by column chromatography on silica gel (eluting with 20:1 (v/v)
petroleum ether/ethyl acetate) to provide the desired product 4.15,29
Ethyl 2-(2-Nitrophenyl)acetate (4a). Yield: 74 mg, 71%. Brown
1
(dd, J = 7.7, 1.1 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 4.08 (s, 2H), 2.45
(s, 3H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 203.8, 148.4,
138.9, 134.3, 133.3, 127.4, 125.6, 48.2, 29.9, 20.8. Anal. Calcd for
C10H11NO3: C, 62.17; H, 5.74; N, 7.25. Found: C, 62.25; H, 5.78; N,
7.22.
1-(2-Nitro-4-trifluoromethylphenyl)propan-2-one (3d). Yield:
79 mg, 64%. Brown oil. 1H NMR (400 MHz, CDCl3): δ 8.41 (s, 1H),
7.86 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 4.24 (s, 2H), 2.38
(s, 3H). 13C NMR (101 MHz, CDCl3): δ 202.4, 148.7, 134.4, 134.2,
131.4, 131.0, 129.9, 124.1, 122.6, 121.4, 48.4, 30.1. Anal. Calcd for
C10H8F3NO3: C, 48.59; H, 3.26; N, 5.67. Found: C, 48.66; H, 3.29; N,
5.64.
1
oil. H NMR (400 MHz, CDCl3): δ 8.13 (dd, J = 8.2, 1.2 Hz, 1H),
7.62 (td, J = 7.5, 1.3 Hz, 1H), 7.50 (td, J = 8.1, 1.4 Hz, 1H), 7.38 (dd, J
= 7.5, 0.9 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 4.04 (s, 2H), 1.28 (t, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 169.9, 148.9, 133.5,
133.3, 129.9, 128.5, 125.3, 61.3, 39.8, 14.1. Anal. Calcd for
C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found: C, 57.60; H, 5.38;
N, 6.56.
1-(4-Methoxy-2-nitrophenyl)propan-2-one (3e). Yield: 80 mg,
1
76%. Brown oil. H NMR (400 MHz, CDCl3): δ 7.67 (d, J = 2.5 Hz,
1H), 7.23−7.12 (m, 2H), 4.06 (s, 2H), 3.90 (s, 3H), 2.33 (s, 3H). 13C
NMR (101 MHz, CDCl3): δ 204.0, 159.2, 149.0, 134.4, 134.2, 130.0,
128.0, 122.3, 120.3, 109.9, 55.9, 47.9, 29.9. Anal. Calcd for
C10H11NO4: C, 57.41; H, 5.30; N, 6.70. Found: C, 57.68; H, 5.42;
N, 6.56.
Ethyl 2-(Naphthalen-1-yl)acetate (4b). Yield: 76 mg, 71%.
1
Light-yellow liquid. H NMR (400 MHz, CDCl3): δ 7.44−7.33 (m,
7H), 4.11 (q, J = 7.1 Hz, 2H), 3.62 (s, 2H), 1.22 (t, J = 7.1 Hz, 3H).
13C NMR (101 MHz, CDCl3): δ 171.9, 142.5, 141.2, 131.9, 130.3,
130.2, 129.3, 128.2, 127.5, 127.1, 60.7, 39.0, 14.1. Anal. Calcd for
C14H14O2: C, 78.48; H, 6.59. Found: C, 78.80; H, 6.65.
1-(1-Naphthyl)propan-2-one (3f). Yield: 65 mg, 71%. Light-
yellow liquid. 1H NMR (400 MHz, CDCl3): δ 7.91 (ddd, J = 6.9, 3.6,
1.8 Hz, 2H), 7.84 (d, J = 8.2 Hz, 1H), 7.54 (ddd, J = 7.2, 3.9, 1.7 Hz,
2H), 7.51−7.45 (m, 1H), 7.42 (d, J = 6.9 Hz, 1H), 4.18 (s, 2H), 2.14
(s, 3H). 13C NMR (101 MHz, CDCl3): δ 206.8, 133.9, 132.2, 131.1,
128.8, 128.2, 128.1, 126.6, 125.9, 125.6, 123.8, 49.2, 28.9. Anal. Calcd
for C13H12O: C, 84.75; H, 6.57. Found: C, 84.84; H, 6.60.
1-(2-Phenylphenyl)propan-2-one (3g). Yield: 69 mg, 66%.
Yellow liquid. 1H NMR (400 MHz, DMSO-d6): δ 7.49−7.16 (m, 9H),
3.72 (s, 2H), 1.96 (s, 3H). 13C NMR (101 MHz, DMSO-d6): δ 206.5,
142.4, 141.4, 133.1, 131.5, 130.1, 129.2, 128.8, 127.8, 127.6, 127.3,
48.1, 30.1. Anal. Calcd for C15H14O: C, 85.68; H, 6.71. Found: C,
85.74; H, 6.73.
Ethyl 2-(4-Methyl-2-nitrophenyl)acetate (4c). Yield: 70 mg,
64%. Brown oil. 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.41 (d,
J = 7.7 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H),
3.98 (s, 2H), 2.45 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (101
MHz, CDCl3): δ 170.1, 148.6, 139.0, 134.2, 133.1, 126.9, 125.6, 61.2,
39.5, 20.8, 14.1. Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87; N,
6.27. Found: C, 59.30; H, 5.92; N, 6.16.
Methyl 2-(2-Ethoxy-2-oxoethyl)benzoate (4d). Yield: 42 mg,
38%. Light-yellow liquid. 1H NMR (400 MHz, CDCl3): δ 8.03 (dd, J =
7.8, 1.3 Hz, 1H), 7.50 (td, J = 7.5, 1.5 Hz, 1H), 7.38 (td, J = 7.7, 1.3
Hz, 1H), 7.28 (dd, J = 7.1, 1.1 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.03
(s, 2H), 3.89 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 171.5, 167.6, 136.0, 134.7, 132.3, 132.2, 131.0, 127.3, 60.7,
52.0, 40.7, 14.2. Anal. Calcd for C12H14O4: C, 64.85; H, 6.35. Found:
C, 65.12; H, 6.08.
Procedure for the Synthesis of 6. Zinc dust (0.131 g, 2 mmol)
and glacial acetic acid (0.240 g, 4 mmol) were added to a reaction
tube. MeOH (2 mL) and 3a (0.090 g, 0.5 mmol) were sequentially
added by syringe at ambient temperature. The mixture was stirred at
room temperature for 90 min. Water (20 mL) was then added to the
reaction mixture, and the resulting mixture was extracted with ethyl
acetate (3 × 10 mL). The combined organic layers were then washed
with brine, dried over Na2SO4, and concentrated in vacuum. The
residue was purified by column chromatography on silica gel (eluting
with 10:1 (v/v) petroleum ether/ethyl acetate) to provide 2-methyl-
1H-indole (6) as a white solid in 45% yield (0.030 g, 0.227 mmol).
2-Methyl-1H-indole (6). Yield: 30 mg, 45%. White solid. 1H
NMR (400 MHz, CDCl3): δ 7.79 (s, 1H), 7.58 (d, J = 7.4 Hz, 1H),
7.31 (d, J = 7.6 Hz, 1H), 7.21−7.10 (m, 2H), 6.27 (s, 1H), 2.47 (s,
3H). 13C NMR (101 MHz, CDCl3): δ 136.1, 135.1, 129.1, 120.9,
119.7, 110.2, 100.4, 13.7. Anal. Calcd for C9H9N: C, 82.41; H, 6.92; N,
10.68. Found: C, 82.56; H, 6.94; N, 10.50.
3-Methyl-1H-isochromen-1-one (3h). Yield: 55 mg, 70%. White
1
solid. H NMR (400 MHz, CDCl3): δ 8.27 (d, J = 8.5 Hz, 1H), 7.69
(td, J = 7.7, 1.3 Hz, 1H), 7.46 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 7.9 Hz,
1H), 6.28 (s, 1H), 2.30 (s, 3H). 13C NMR (101 MHz, CDCl3): δ
162.9, 154.6, 137.7, 134.7, 129.5, 127.5, 124.8, 120.0, 103.5, 19.6. Anal.
Calcd for C10H8O2: C, 74.99; H, 5.03. Found: C, 75.06; H, 5.05.
1-(3-Acetylphenyl)propan-2-one (3i). Yield: 36 mg, 41%.
1
Yellow liquid. H NMR (400 MHz, CDCl3): δ 7.88 (dt, J = 7.4, 1.5
Hz, 1H), 7.81 (s, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.44−7.40 (m, 1H),
3.80 (s, 2H), 2.62 (s, 3H), 2.22 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 205.5, 197.9, 137.5, 134.7, 134.2, 129.2, 128.9, 127.2, 50.4,
29.6, 26.7. Anal. Calcd for C11H12O2: C, 74.98; H, 6.86. Found: C,
75.18; H, 6.95. ESI-MS m/z: [M + H]+ calcd 177.1, found 177.1.
1-(4-Acetylphenyl)propan-2-one (3j). Yield: 53 mg, 60%.
1
Yellow liquid. H NMR (400 MHz, CDCl3): δ 7.94 (d, J = 8.2 Hz,
2H), 7.31 (d, J = 8.2 Hz, 2H), 3.79 (s, 2H), 2.60 (s, 3H), 2.20 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 205.1, 197.6, 139.5, 136.0, 129.7,
128.7, 50.6, 29.6, 26.6. Anal. Calcd for C11H12O2: C, 74.98; H, 6.86.
Found: C, 75.10; H, 6.92.
1-(4-Formylphenyl)propan-2-one (3k). Yield: 40 mg, 50%.
Yellow liquid. 1H NMR (400 MHz, CDCl3): δ 10.02 (s, 1H), 7.88 (d,
J = 8.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 3.83 (s, 2H), 2.23 (s, 3H).
13C NMR (101 MHz, CDCl3): δ 204.8, 191.8, 141.0, 135.3, 130.2,
130.1, 50.8, 29.7. Anal. Calcd for C10H10O2: C, 74.06; H, 6.21. Found:
C, 74.28; H, 6.35. ESI-MS m/z: [M + Na]+ calcd 185.1, found 185.1.
1-(3-Nitrophenyl)propan-2-one (3m). Yield: 48 mg, 54%.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b02098.
Yellow liquid. H NMR (400 MHz, CDCl3): δ 8.20−8.12 (m, 1H),
8.08 (s, 1H), 7.55−7.52 (m, 2H), 3.88 (s, 2H), 2.28 (s, 3H). 13C NMR
(101 MHz, CDCl3): δ 204.3, 148.4, 135.9, 135.8, 129.5, 124.5, 122.2,
49.7, 29.8. Anal. Calcd for C9H9NO3: C, 60.33; H, 5.06; N, 7.82.
Found: C, 60.60; H, 5.18; N, 7.68.
1H and 13C NMR spectra for all of the products and
DFT computational results (PDF)
General Procedure for the Retro-Aldol Reaction of β-
Hydroxy Acetic Ester 2b with Aryl Halides. Pd(TFA)2 (8.0 mg,
0.025 mmol), PCy3 (14 mg, 0.05 mmol), aryl halide 1 (0.5 mmol), and
Cs2CO3 (244 mg, 0.75 mmol) were added into an oven-dried Schlenk
tube equipped with a stir bar. The tube was then sealed, evacuated, and
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: slzhang@jiangnan.edu.cn.
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DOI: 10.1021/acs.joc.5b02098
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169. (c) Yu, H.; Wang, C.; Yang, Y.; Dang, Z.-M. Chem. - Eur. J. 2014,
20, 3839. (d) Masarwa, A.; Weber, M.; Sarpong, R. J. Am. Chem. Soc.
2015, 137, 6327. (e) Xue, L.; Ng, K. C.; Lin, Z. Dalton Trans. 2009,
5841.
(9) For the reductive elimination reactivity of aryl-Pd(II) enolates,
see: (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816.
(b) Wolkowski, J. P.; Hartwig, J. F. Angew. Chem., Int. Ed. 2002, 41,
4289.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported by the National Natural Science
Foundation of China (21472068 and 21202062) and the
Natural Science Foundation of Jiangsu Province (BK2012108).
(10) For reviews of α-arylation, see: (a) Culkin, D. A.; Hartwig, J. F.
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(26) DFT calculations were performed using the M06 functional, the
SDD basis set for Pd and the 6-311+G(d,p) basis set for C, H, O, Br,
and P, and the SMD solvation model (toluene). For more detailed
information about the DFT studies, please see the Supporting
Information.
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in synergy with other basic organic transformations, such as addition
to unsaturated bonds, and initial success has been achieved.
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