Decarboxylative Csp3-Csp3 coupling for benzylation of unstable ketone enolates: Synthesis of: P -(acylethyl)phenols

Article abstract of DOI:10.1039/c6cc03835b

A new decarboxylative C_sp3-C_sp3 coupling approach for the benzylation of ketone enolates has been developed. A variety of raspberry ketone derivatives were conveniently synthesized in good to excellent yields under mild conditions. A crossover reaction shed light on the mechanism of this tandem reaction.

Full text of DOI:10.1039/c6cc03835b

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Decarboxylative Csp -Csp3 Coupling for Benzylation of Unstabilized
Ketone Enolates: Synthesis of p-(Acylethyl)phenols
Sasa Wang,† Xinzheng Chen,† Qiaoqiao Ao,$ Huifei Wang,*,† and Hongbin Zhai*,†,‡,
Received 00th January 20xx,
Accepted 00th January 20xx
⊥
DOI: 10.1039/x0xx00000x
www.rsc.org/
3
3
A new decarboxylative Csp
−
Csp coupling approach for the in transition-metal-catalyzed decarboxylative benzylations, we
ketoester might be a
of raspberry ketone derivatives were conveniently synthesized suitable precursor for the decarboxylative benzylation reaction
benzylation of ketone enolates has been developed. A variety speculate that a para-siloxybenzyl
β−
3
in good to excellent yields under mild conditions. A crossover (Scheme 1c). First, cleavage of the benzylic Csp
−
O bond
followed by decarboxylation might be initiated upon removal
of the silyl group. Second, p-quinone methide (p-QMs), formed
reaction shed light on the mechanism of this tandem reaction.
3
Decarboxylation has garnered tremendous attention as
upon cleavage of the benzylic Csp −O bond, could serve as a
highly reactive electrophilic benzylating species to enable the
subsequent benzylation reaction.9 Herein, we disclose our
important synthetic methods for the carbon−carbon bond
formation due to its high efficiency in generating a nucleophile
in situ under mild conditions.1 In particular, as one of the most
efficient ways to capture the ketone enolates, palladium-
findings regarding TBAF−induced decarboxylative benzylation
3
of ketone enolates for the Csp3-Csp bond formation which
provides an efficient approach to a series of synthetically
useful p-(acylethyl)phenols such as raspberry ketone,
vanillylacetone, and their derivatives under mild conditions.10
catalyzed decarboxylative allylation of
β−
ketoesters2 has
attracted considerable attention since the early discoveries
reported by Tsuji3 and Saegusa4 (Scheme 1a). Compared with a
great wealth of studies on the decarboxylative allylation of
ketone enolates, the corresponding benzylation reactions
were much less investigated and more challenging, mainly due
to transient loss of aromaticity upon π−benzyl formation.5
Catalytic benzylation becomes more difficult for the
Previous studies:
a) Metal-catalyzed decarboxylative allylation of ketones
(very common in the literatures)
O
O
O
O
R3
R2
O
O
M
R1
O
R1
unstabilized nucleophiles,6 though the corresponding reactions
of stabilized nucleophiles work well.5f Only few examples
R2
R3
R2
R3
M
CO2
i,7
R1
−
b) Metal-catalyzed decarboxylative benzylations of ketones
(ralely reported and only specificcases worked )
involving unstabilized ketone enolates have recently been
reported (Scheme 1b).8 In 2010, Tunge reported Pd-catalyzed
M
O
O
R4
O
O
R4
R3
R4
O
O
M
R3
R2
decarboxylative benzylation of
β
−
ketoesters to access a broad
polyaromatic benzyl ketones. Recently, Hu
Cu catalyzed decarboxylative propargylic
R1
O
Ar
R1
Ar
R2
R3
R2
range of
developed
α
−
a
CO2
R1
This work:
−
c) TBAF-induced decarboxylative benzylations of ketones
alkylation which allowed access to a series of benzyl ketones
R2
O
bearing −ethynyl. So decarboxylative benzylation reactions
are still in their infancy.
β
O
O
R2
O
R2
O
O
R1
R1
R3
TBAF
R4
O
R4
R1
R3
R3
Given the difficulty in generating the π−benzyl-metal species
R4
CO2
OH
OR
1
2
O
Scheme 1 Decarboxylative benzylation of ketone enolates
To test the feasibility of our hypothesis, para-siloxybenzyl
−ketoester 1a was selected as a model substrate to evaluate
the benzylation of ketone enolates (Table 1). To our
excitement, the desired reaction proceeded smoothly in THF
at room temperature, giving the expected ketone 2a in 37%
yield in less than 5 min (entry 1). Solvent screening revealed
that toluene delivered a slightly improved yield (entries 2-8).
β
‡The State Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, China
$College of Science, Northwest A&F University, Xi’an 712100, China
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The reaction was then performed at different temperatures. It pattern at the both positions ortho to the (acyloxy)methyl or
was found that increasing or decreasing the temperature did the siloxy group (2h-i). Notably, substrate 1h generated the
not improve the reaction (entries 9-11). Application of desired product in
a high yield of 95%. In addition,
powdered 4 Å molecular sieves rendered the products in polysubstituted substrate proved to be amenable to the
similar yields (entry 12). Next, the effect of acids was process as well, albeit somewhat reluctantly, furnishing the
examined. When HOAc was added, the reaction could hardly corresponding product in 51% yield after a three-day reaction
proceed (entry 13). As for the role of Lewis acids, Co(C5H7O2)3,
Ni(OAc)2·4H2O, and CuSO4·5H2O had little impact on the
product yields (entries 15, 17, and 18), and MgCl2 led to a poor
yield (18%), while FeCl3 completely shut down the reaction
(entries 14 and 16). To our delight, in the presence of ZnCl2,
the yield of the product was increased to 82% (entry 19). By
contrast, ZnBr2 and ZnI2 did not perform as well as ZnCl2
(entries 20 and 21). ZnCl2 promoted the reaction presumably
by its stabilization effect on the enolate generated in situ. It
was noteworthy that one or two side-products were formed in
some cases, which were determined to be 4-
(hydroxymethyl)phenol and/or the corresponding desilylation
product.
(2j).
Table 2 Substrate scope studiesa
Table 1 Optimization of the decarboxylaive benzylation reaction conditionsa
time
entry
solvent
T (oC)
additiveb
yield (%)
(min)
< 5
45
45
45
45
45
45
45
120
45
45
45
45
4 d
45
45
90
90
1
2
3
4
5
6
7
8
9
10
11
12 c
13
14
15
16
17
18
19
20
21
THF
toluene
ACN
CH2Cl2
1,4ꢀdioxane
xylene
rt
rt
rt
rt
rt
rt
rt
rt
0
50
100
rt
rt
rt
rt
rt
rt
rt
/
/
/
/
/
/
/
/
37
57
46
48
54
55
55
56
41
53
44
56
trace
18
49
0
Et2O
nꢀhexane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
/
/
/
aReaction conditions: 1a-x (1 equiv), TBAF (1 equiv), ZnCl2 (1 equiv) in
toluene, rt; 1g (0.2 mmol), TBAF (0.3 mmol), ZnCl2 (0.2 mmol), isolated
yield. bRatios were determined by 1H NMR analysis of the crude mixture.
4 Å MS
CH3COOH
MgCl2
Co(C5H7O2)3
FeCl3
Ni(OAc)2·4H2O
CuSO4·5H2O
ZnCl2
The substituent effect of the β-keto acyl moieties was
examined subsequently. Substituents at the benzyl position
were compatible with the reaction conditions and the
expected products were obtained in good to excellent yield (2k
and 2l). It is noteworthy that this method could be used to
construct hindered tertiary carbon centers with high efficiency
62
58
82d
66
12
rt
rt
rt
45
4 d
45
ZnBr2
ZnI2
aDetermined by 1H NMR analysis of purified reaction mixtures using 1,3,5ꢀ
(
2m
with the substrates containing a five-, six- or seven
cycloalkanone ring (2o ). Moreover, various alkyl substituents
attached to the terminal residue had little effect on the
,
2n and 2v). To our delight, the reaction also worked well
trimethoxybenzene as an internal standard, TBAF (tetra-n butylammonium
−
membered
b
c
fluoride, 1M in THF) is used. 1.0 equiv of additive was employed. 100 wt
% of 4 Å MS was used. dIsolated yield.
-q
With the optimized reaction conditions identified, we reaction yields, presumably because the terminal groups were
started to investigate the scope of this tandem reaction. As remote to the reactive site (2r-t). The presence of a terminal
demonstrated in Table 2, the substituents on aromatic ring phenyl group was also well-tolerated, as demonstrated by the
were first studied. Substrates bearing electron-deficient fact that phenyl ketone 1u reacted to afford 2u in 81% yield,
substituents (F, Cl, Br, CO2Me) or electron-rich substituents (2- yet taking a prolonged reaction period (2u). Substrates 1w and
OMe, 3-OMe) underwent the reaction smoothly, giving the 1x, bearing two stereocenters, reacted to afford the expected
corresponding products in moderate to good yields (2b-g). products 2w and 2x in good yields with moderate
Gratifyingly, the reaction accommodated the disubstitution diastereoselectivities.11
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Substrates bearing different silyl groups (TBS and TIPS) led
to the formation of products 2a in the yields of 66% and 56%,
respectively (Scheme 2).
O
O
O
TBAF, ZnCl2
(1)
O
toluene, rt
45 min, 66%
TBSO
HO
HO
1a1
2a
2a
O
O
O
O
(2)
TBAF, ZnCl2
Scheme 4 Crossover reaction experiment
toluene, rt
3 h, 70%
TIPSO
1a2
A
tentative mechanism is proposed for the current
Scheme 2 Substrate scope studies: different silyl groups
decarboxylative benzylation process (Scheme 5).2b First, the
reaction is triggered by the attack of TBAF to the silyl group to
Several additional substrates
(
5a, 1a, 1aa
-
1ad) were
cleave the Si
unstable p-QM
both path a and path b should be possible. In path a, facile
decarboxylation occurs first to give enolate , 1,6 conjugated
addition of which with p-QM affords raspberry ketone 2a
For path b, tautomerization of
generate . Subsequently, 1,6
−
O bond, resulting in the formation of the
examined to gain certain insights into the reaction mechanism
(Scheme 3). ortho-Silylated phenolic benzyl ketoester 5a
6
and the keto carboxylate . In principle,
β
−
7
β
−
underwent the transformation smoothly under the optimized
reaction conditions, giving a mixture of the expected ketone
5b and the corresponding hemiacetal 5c in a ratio of 2.1:1 (eq
3). If the substrate was lacking a β-keto moiety (e.g., in
substrate 1aa), only desilylation was effected (eq 4). A fluoride
source was necessary to trigger the reaction since no reaction
took place in the absence of TBAF (eq 5). Moreover, no
reaction was observed with 1ab or 1ac (eq 6) either. Thus, the
desilylation step proved to be crucial for the overall reaction
outcome. Finally, treatment of the α,α-disubstituted reactant
1ad with TBAF and ZnCl2 led only to a trace amount of ketone
2ad (eq 7).
9
−
6
.
β
−
keto carboxylate
7
may
8
−
addition of
8
with p-QM
6
renders intermediate 10, decarboxylation and protonation of
which furnishes raspberry ketone 2a. Since the reaction of 1ad
only produced a trace amount of 2ad (Scheme 3, eq 7), path b
might represent the dominant reaction pathway. However, the
possibility of path a could not be ruled out completely at
present.
Scheme 5 Proposed reaction pathways
p-(Acylethyl)phenols prepared by this current protocol could
be used as versatile building blocks in synthetically useful
transformations (Scheme 6). For instance, p-(acylethyl)phenol
2a was converted into phenol triflate 2af, which was reduced
to deliver benzylacetone 2ag or functionalized via Sonogashira
reaction to give alkyne 2ah. Additionally, they have been
reported in the previous literatures12 as important starting
materials for the synthesis of bioactive natural products and
pharmaceuticals, such as (+)-Ces-B, cephalosporolides C, E, F,
and G, and tyrosinase inhibitor 2ai. These representative
applications have convincingly demonstrated the versatilities
of p-(acylethyl)phenols in organic synthesis.
Scheme 3 Experiments of mechanistic significance
Furthermore, a crossover reaction with a 1:1 mixture of
β
−
ketoesters 1h and 1m was conducted (Scheme 4). Based
upon the HRMS and GC MS analyses, two crossover products
2a and 2v) were also formed in addition to 2h and 2m
−
(
,
demonstrating that the reaction involves an intermolecular
process.
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Scheme 6 Further transformations of p-(acylethyl)phenol 2a
7
8
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In conclusion, we have developed a novel TBAF−induced
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J. A. Tunge, J. Am. Chem. Soc., 2010, 132, 9280. (b) F.-L. Zhu,
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3
which efficiently forms a Csp3-Csp bond. The method tolerates
a broad range of substrates and functionalized raspberry
ketone derivatives were obtained in good to excellent yields.
This discovery represents a significant expansion of the
existing decarboxylative benzylation strategies. Further
development of benzylation involving other unstabilized
nucleophiles is under investigation.
9
We thank NSFC (21272105; 21290183; 21472072), Shenzhen
127, 13915. For selective reviews on dearomatization
Science
and
Technology
Innovation
Committee
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Zarrinmayeh, S. A. Munk, P. A. Kitos and O. Suntornwat, J.
Am. Chem. Soc., 1990, 112, 8961. (e) F. R. Petronijevic and P.
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(JCYJ20150529153646078), Program for Changjiang Scholars
and Innovative Research Team in University (PCSIRT:
IRT_15R28), and “111” Program of MOE for financial support.
We are grateful to Dr. David Zhigang Wang for enlightening
discussions.
10 For selected reviews on raspberry ketone, see: (a) C.
Morimoto, Y. Satoh, M. Hara, S. Inoue, T. Tsujita and H.
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11 The stereochemistry of the major diastereomer is
determined by an X-ray analysis of compound 2aj, the
derivative of the major diastereomer of 2x. The crystal
structure of 2aj was deposited at the Cambridge
Crystallographic Data Centre (tracking number: 1486135).
See the Supporting Information for more details.
Notes and references
1
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4 | J. Name., 2012, 00, 1-3
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