Synergistic palladium/enamine catalysis for asymmetric hydrocarbon functionalization of unactivated alkenes with ketones

Article abstract of DOI:10.1039/c9ob01165j

Synergistic palladium and enamine catalysis was explored to promote ketone addition to unactivated olefins. A secondary amine-based organocatalyst was identified as the optimal co-catalyst for the directed Pd-catalyzed alkene activation. Furthermore, asymmetric hydrocarbon functionalization of unactivated alkenes was also achieved with good to excellent yield (up to 96% yields) and stereoselectivity (up to 96% ee). This strategy presented an efficient approach to prepare α-branched ketone derivatives under mild conditions.

Full text of DOI:10.1039/c9ob01165j

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Takeharu Haino et al.
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Paper
Synergistic Palladium/Enamine Catalysis for Asymmetric
Hydrocarbon Functionalization of Unactivated Alkenes with
Ketones
Received 00th January 20xx,
Accepted 00th January 20xx
Chiyu Wei,a Xiaohan Ye ,a Qingyu Xing,a Yong Hu,c Yan Xie,*b and Xiaodong Shi*a
DOI: 10.1039/x0xx00000x
Synergistic palladium and enamine catalysis were explored to promote ketone addition to unactivated olefin. Secondary
amine-based organocatalyst was identified as the optimal co-catalyst for the directed Pd-catalyzed alkene activation.
Furthermore, asymmetric hydrocarbon functionalization of unactivated alkenes was also achieved with good to excellent
yield (up to 96% yields) and stereoselectivity (up to 96% ee). This strategy presented an efficient approach to prepare
branched ketone derivatives under mild conditions.
Introduction
Synergistic metal/organo catalysis has flourished over the past
decade, enabling a combination of the orthogonal reactivity
between transition metal chemistry and organocatalysis.1 In
particular, combining palladium and enamine chemistry offered
a powerful toolbox for C-C bonds construction.2 A general
reaction pattern is employing enamine as a nucleophile to react
with a Pd-activated carbon electrophile. One type of this well-
explored electrophile is -allyl complex, which is often
generated in-situ via Pd addition/oxidation toward allyl or
allene moieties (Scheme 1A).3
Although this protocol
represents an efficient approach for a C-C bond construction, it
suffers from several limitations, including limited substrate
scope and lack of effective stereochemistry control.4 This is
mainly due to A) the requirement of a pre-functionalized alkene
to form Pd -allyl complex and B) problematic reversible -H
elimination involved. Therefore, developing new reaction
partners that can facilitate transformations under this dual-
catalysis mode will not only offer practical synthetic utility but
also foster mechanistic insight to further advance this intriguing
reaction pattern.
Scheme 1. Combining organo and Pd catalysis for alkene functionalization
The intrinsic reactivity of C-C double bonds allows alkene
to own a privileged position in the organic synthesis.5 Lewis
acid catalyzed nucleophilic addition of alkenes have become a
powerful synthetic approach for C-C and C-X bond
construction.6 However, palladium is considered as a weak -
acid towards alkene activation, therefore, a strong nucleophile
is required to attack the Pd-activated alkene.7 Moreover, the
resulting Pd-C intermediate could undergo fast -H elimination,
giving alkene products and other potential undesired side
reactions. To overcome this problem, in 2016, Engle and
coworkers first reported the application of bidentate directing
group (DG) strategy to enhance the reactivity of Pd, allowing un-
activated alkene to be readily attacked by soft carbon
nucleophiles.8 More importantly, with a more sterically
constrained Pd intermediate, the -H elimination was
a. Department of Chemistry, University of South Florida, Tampa, FL 33620, United
State.
b. College of Chemistry and Materials Engineering, Quzhou University, Quzhou
324000, China
c. Department of Neonatology, Shanghai Children’s Hospital, Shanghai Jiao Tong
University, Shanghai, Shanghai 200040, China.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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successfully inhibited (Scheme 1B).
This seminal work
As expected, without the addition of amine, no desired
product was observed in all the cases, which highlighted the
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DOI: 10.1039/C9OB01165J
highlighted the advantage of applying the bidentate DGs in A)
improve the reactivity of Pd(II) cation and B) secure olefin
hydrocarbofunctionalization through protodemetallation.
Although a wide range of carbon nucleophiles, including 1,3-
dicarbonyls, aryl carbonyls, and electron-rich arenes, have been
successfully applied for this transformation, ketones and
aldehydes remained problematic. Also, only few examples have
been reported for enantioselective addition to unactivated alkene
using this strategy.9 Inspired by these findings, we envisioned
that the combination of Pd-catalyzed directed alkene activation
with enamine addition could offer a valid strategy to further
extend reaction scope to ketone derivatives. More importantly,
the adoption of a chiral amine catalysts will provide an effective
stereochemistry control to achieve asymmetric -alkylation of
a ketone.
challenge of applying acetophenone as a nucleophile toward
Pd-activated alkene. Fortunately, when L-proline was applied
as the co-catalyst with 8-aminoquinoline (AQ) as the directing
group, the reaction successfully gave the desired addition
product 3a in 60% NMR yield. Interestingly, other directing
groups could not promote this transformation even with the
addition of proline, emphasizing the unique roles of AQ in this
reaction. After a series of conditions screening, pyrrolidine was
identified as the optimal co-catalyst with toluene as the solvent.
The reaction proceeded smoothly at 80 oC with nearly
quantitative yield.
Inspired by this result, we then turned our attention into
more challenging asymmetric addition with the assistant of
chiral amines.
Representative conditions screened are
summarized in Table 2.
It is important to note here that as we were working on this
idea independently， one paper with similar design from the
Gong group was published, in which they reported the
alkylation of substituted cyclic ketones through enamine
activation.10, The desired -alkylation was obtained in good
yields and ee. We herein report our efforts on this novel
transformation with alternative reaction conditions. We are
able to extend the substrate scope to various of acetophenones,
as well as -keto-esters. It is our hope to offer another
perspective on how we achieved this transformation from a
different approach.
Table 2. Optimization of amines for palladium/enamine catalysisa
[Pd] cat. 10%
[Amine] cat. 30%
AcOH 1 eq.
O
O
O
AQ
N
H
+
AQ
Solvent (0.5 M), 80 o
C
N
AQ
O
1a
2b
4a
Entry
[Pd]
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
Pd(CH3CN)2Cl2
[Amine]
n/a
A1
A2 or A3
A4
A4
A5
A6
A7
A8
A9
A9
A9
Sol.
MeCN
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Tol
Conv.b
<5%
100%
<20%
62%
Yieldb
<5%
95%
<20%
54%
77%
90%
91%
57%
96%
97%
97%
55%
ee%c
-
-
1d
2
3
4
5
6
7
8
9
0
11%
15%
33%
63%
<5%
65%
71%
<5%
93%
88%
79%
100%
100%
100%
100%
100%
100%
60%
Results and discussion
10 Pd(CH3CN)2Cl2
11e Pd(CH3CN)2Cl2
12f Pd(CH3CN)2Cl2
13f Pd(CH3CN)2Cl2
Considering that the directing group is crucial for increasing
the reactivity of Pd catalyst, we first screened some common
used directing groups (1a-1e) under Engle’s condition (HOAc,
MeCN, 120 oC). The results are summarized in Table 1.
A9
neat
100%
99% (95%)g
Table 1. Screening directing groupsa
a Reaction conditions: [Pd] cat. (10 mol%), [amine] cat. (30 mol%), AcOH (1 eq.),
solvent (0.5 M), under 80 oC, 24 hours. b Conversion and yield were determined by
c
1H NMR using 1,3,5-trimethoxybenzene as internal standard.
ee value was
determined by HPLC. d 120 oC, 36 hours. e 72 h. f 60 oC, 24 hours. g Isolated yield.
DGs
Conditions
MeCN, 120 oC
Conv.b
<5%
Yieldb
<5%
1a-1e
As expected, treating 1a with cyclohexanone 2b under
Pd/pyrrolidine conditions gave 4a in 95% yield, as expected
(entry 2). Various chiral amine catalysts were then tested for
stereoselectivity. The Macmillan catalysts were ineffective in
this system, which might due to the lack of reactivity towards
ketone.11 L-Proline gave a decreased conversion and yield with
11% ee of 4a. Clearly, a tight transition state with Pd and amine
is crucial for good stereoselectivity. To avoid competitive OAc
binding, Pd(CH3CN)2Cl2 was then employed. An increasing ee
1a
L-Proline 20%, MeCN, 120 oC
70%
60%
1b-1e
1a
L-Proline 20%, MeCN, 120 oC
Pyrrolidine 20%, Tol, 80 oC
<10%
100%
<10%
99%(94%c)
a Reaction conditions: 1a (1 eq.), 2a (3 eq.), Pd(OAc)2 (10 mol%), [amine] cat.
(20 mol%), AcOH (1 eq.), solvent (0.5 M), 36 hours. b Conversion and yield
were determined by 1H NMR using 1,3,5-trimethoxybenzene as internal
standard. c Isolated yield.
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(15%) was obtained with L-proline as co-catalyst (entry 5). compound 3a was synthesized in a gram scale, which indicated
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DOI: 10.1039/C9OB01165J
Finally, with Jorgensen catalyst A9, product 4a was obtained in its practical synthetic value.
97% yield with 71% ee (entry 10). It is important to note that
prolinol A8 gave the product in 65% ee, while the OMe
protected ligand A7 gave almost no stereoselectivity (<5% ee).
This result clearly suggested the importance of the hydroxyl
group in promoting the stereoselectivity of the transformation.
This is likely due to the coordination of OH with Pd
intermediate, which not only accelerates the overall reaction
rate by rendering the enamine addition into an intramolecular
fashion, but also provides a good stereochemistry control. One
challenge that prevents further improvement of the
enantioselectivity is the racemization of product 4a. Extending
reaction time resulted in a decreased ee value under the
reaction conditions (entry 11). To further fine-tuning the
reaction, we conducted the reaction at lower temperature (60
oC). Lower conversion (60%) and yield (55%) were observed,
though higher ee was received (93%). To increase the reaction
rate at a lower temperature, the neat condition was applied.
The reaction gave 100% conversion and 95% isolated yield with
88% ee of 4a. Notably, under Gong’s conditions, only 60% ee
was obtained, though with 93% yield. With this optimal
condition revealed, the reaction scope was evaluated.
Substrates 3 from methyl-ketone is shown in Table 3.
Exploration of asymmetric reaction performance with
cyclic ketones was also performed and summarized in Table 4.
Comparing with non-substituted cyclohexanone (4a), 4-
substituted cyclohexanone derivatives (4b-4d) required a
higher temperature (80 oC) to achieve the full conversion due to
increased hindrance. Interestingly, in these cases problematic
racemization was also inhibited, providing higher
enantioselectivity. On the other hand, modest dr value were
observed. Ketal derivative (4e) was also tolerated under this
acidic condition without deprotection, excellent yield and ee
were obtained. Next, both O and N containing cyclohexanone
(4f-4h) were tested. 4-oxotetrahydropyran (4f) provided 90%
yield and 88% ee, while 4-oxopiperidine (4g) failed to observe
any enantioselectivity possibly because of a quick epimerization.
By switching to Boc protection, 3-oxopiperidine (4h) was
achieved with modest ee, resulting from resonance of amide
group to lock the conformation. 1-Tetralone (4i) showed
excellent yields with 0% ee due to the more acidic -proton.
Smaller cyclic ketones such as cyclopentanone (4j) and
cyclobutanone (4k) gave excellent yields with no ee, which is
likely due to the presence of more acidic -proton, which
caused quick racemization of the formed product. As a result,
introduction of an ester on cyclobutanone (4l) to increase steric
bulkiness not only resulted in moderate enantioselectivity (45%
ee) but also delivered excellent dr value (> 20:1).
Table 3. Substrate scope of compound 3a,b
Table 4. Substrate scope for asymmetric ketone alkylationa,b,c
a Reaction conditions: Pd(OAc)2 (10 mol%), pyrrolidine (20 mol%), AcOH (1
eq.), solvent (0.5 M), 36 hours. b Isolated yield.
In general, over 90% yields were obtained with almost all
tested acetophenone derivatives. Both EDG (3b–3d) and EWG
(3e and 3f) modified ketones gave excellent yields. Slightly
reduced yields were obtained with the ortho-substituted
substrate (3j 89%, 3k, 82%) due to steric hindrance.
Interestingly, aryl halide substrates (3g, 3h, and 3i) worked very
well for this transformation without observation of Pd catalyzed
oxidative addition of C-X bond, revealing an orthogonal
reactivity compared with typical Pd(0) involved coupling
reactions. With 4'-Iodoacetophenone 3j, modest yield was
observed, due to the formation of heck type by-product in the
presence of more active C-I bond. Finally, amino acid modified
derivative (3o) was also suitable for this reaction, suggesting the
potential application of this method in bio-compatible
compound preparation. Internal alkene derivatives, (Z) and (E)-
N-(quinolin-8-yl)hex-3-enamide, were unreactive. Moreover,
a Reaction conditions: Pd(MeCN)2Cl2. (10 mol%), A9 (30 mol%), AcOH (1 eq.),
24 hours. b Isolated yield. c The dr and ee was determined by HPLC. d 80 oC.
In addition to cyclic ketones, other carbonyl substrates
were also explored (Scheme 2A). First, aldehyde was tested and
proved not suitable for this transformation due to the undesired
rapid aldol condensation side reaction. Other readily available
ketone derivatives such as 1,3-diketones and -keto-esters
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mixture was loaded on a silica gel column directly and purified
were also tested. In particular, we chose -substituted 1,3-
View Article Online
DOI: 10.1039/C9OB01165J
by flash chromatography to give desired product.
dicarbonyl compounds for further study because it could form
product with
a
quaternary stereocenter to prevent
General procedure to synthesize 4a-4l:
racemization. After the extensive screening of catalysts (see
details in SI), primary amine A10 was identified as an effective
catalyst in promoting condensation of -keto-ester with AQ-
modified olefin (Table 5A). Although all ketone esters (5a, 5b,
and 5c) showed excellent yield (95%), a regioselectivity issue
(linear vs branch selectivity) was revealed as well, due to the
formation of two possible enamine intermediates. All of these
three substrates gave similar regioselectivity ratio (from 53:47
to 48:52). With the increasing size of substituted group R, the
enantioselectivity would be increased from 63% to 74% ee. We
also demonstrated that AQ directing group could be removed
by a Boc protection-basic hydrolysis sequence, yielding the ε-
keto acids 6 with 86% yield over two steps (Table 5B).12
An oven-dried vial was charged with Pd(MeCN)2Cl2 (10 mol%,
0.02 mmol), HOAc (1 equiv., 0.2 mmol), ketone (4 equiv., 0.8
mmol) and A9 (30 mol%, 0.06 mmol). The vial was placed under
vacuum and charged with Ar. Alkene (1a) (1 equiv., 0.2 mmol)
was added into the vial sequentially under Ar atmosphere. The
reaction was run under 60 oC and monitored by TLC. Once the
reaction completed, the crude mixture was loaded on a silica gel
column directly and purified by flash chromatography to give
desired product.
General procedure to synthesize 5a-5c:
An oven-dried vial was charged with Pd(MeCN)2Cl2 (10 mol%,
0.02 mmol), HOAc (1 equiv., 0.2 mmol), ketone ester (3 equiv.,
0.6 mmol) and A10 (30 mol %, 0.6 mmol). The vial was placed
under vacuum and charged with Ar. Alkene (1a) (1 equiv., 0.2
mmol) was added into the vial sequentially under Ar
atmosphere. The reaction was run under 60 oC and monitored
by TLC. Once the reaction completed, the crude mixture was
loaded on a silica gel column directly and purified by flash
chromatography to give desired product.
Conflicts of interest
There are no conflicts to declare
Scheme 2. Substrate scope of compound 5 and the removal of AQ
Conclusions
Acknowledgements
We are grateful to the NSF (CHE-1665122), NIH
(1R01GM120240- 01) and NSFC (21228204) for financial
support.
In summary, we reported a synergistic palladium/enamine
catalyzed asymmetric addition of ketone to non-activated
alkene under mild conditions. Using this protocol, asymmetric
α-alkylation of ketone derivatives were successfully achieved by
combining the chiral enamine formation and directed Pd-
catalyzed alkene activation, which offered an efficient and
cooperative catalysis system. Furthermore, this study revealed
a novel approach towards -branched ketones derivatives,
highlighting its valuable synthetic utility.
Notes and references
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Experimental
General procedure to synthesize 3a-3n:
An oven-dried vial was charged with Pd(OAc)2 (10 mol%, 0.02
mmol), HOAc (1 equiv., 0.2 mmol), ketone (3 equiv., 0.6 mmol)
and pyrrolidine (20 mol%, 0.04 mmol). The vial was placed
under vacuum and charged with Ar. Alkene (1a) (1 equiv., 0.2
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sequentially under Ar atmosphere. The reaction was run under
80 oC and monitored by TLC. Once the reaction completed, the
solvent was removed under vacuum, and the resulting crude
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