Cooperative Palladium/Proline-Catalyzed Direct α-Allylic Alkylation of Ketones with Alkynes

Article abstract of DOI:10.1021/acs.orglett.6b02649

The cooperative palladium/l-proline-catalyzed direct α-allylic alkylation of ketones with alkynes is achieved. This reaction exhibits high atom economy since a leaving group is not liberated and a stoichiometric amount of extra oxidant is not needed. A br

Full text of DOI:10.1021/acs.orglett.6b02649

Letter
pubs.acs.org/OrgLett
Cooperative Palladium/Proline-Catalyzed Direct α‑Allylic Alkylation
of Ketones with Alkynes
Chi Yang, Kaifan Zhang, Zijun Wu, Hequan Yao, and Aijun Lin*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, P. R. China
*
S Supporting Information
ABSTRACT: The cooperative palladium/L-proline-catalyzed direct α-allylic alkylation of ketones with alkynes is achieved. This
reaction exhibits high atom economy since a leaving group is not liberated and a stoichiometric amount of extra oxidant is not
needed. A broad range of functional groups are tolerated, and the reaction scope could be further expanded to aldehydes.
nsaturated ketones, especially those bearing γ,δ-unsatu-
rated C−C double bonds, are important building blocks
Scheme 1. Strategies toward the Synthesis of γ,δ-
Unsaturated Ketones
U
existing in numerous biologically active compounds and natural
1
products. Moreover, they also serve as versatile synthetic
2
intermediates in natural products synthesis. Traditional
methods toward the synthesis of these precious structures
involve transition-metal-catalyzed C−C bond formation
3
between in situ formed metal enolates and allyl agents, while
stoichiometric strong metallic bases were a prerequisite and
corresponding stoichiometric metal salts were formed. In
addition, some competitive side reactions were unavoidable
(
e.g., Cannizzaro reactions).
Recently, transition-metal and organo-cooperative catalyses
4
5
have been widely investigated for the α-alkylation, α-
6
7
alkenylation, and α-arylation of ketones and aldehydes. In
006, Cordova and Ibrahem first reported a palladium and L-
proline co-catalyzed α-allylic alkylation of ketones with allylic
2
́
8a
acetate to access γ,δ-unsaturated ketones (Scheme 1a).
Subsequently, various allylic compounds such as allylic
alcohols,
8
b,c
8d
8e
allylic amines, and allylic ethers containing
leaving groups were validated to the construction of γ,δ-
unsaturated ketones. In 2014, Lei, Luo, and co-workers
developed a palladium/L-proline co-catalyzed oxidative cou-
pling reaction of ketones with allylic hydrocarbons employing
stoichiometric amount of p-benzoquinone (BQ) as oxidant
unsaturated ketones in a more succinct and highly efficient
manner (Scheme 1d).
We initiated our investigation with cyclohexanone 1a and 1-
phenyl-1-propyne 2a as model substrates, Pd(PPh ) as the
3
4
catalyst, and benzoic acid as an additive in toluene at 120 °C
under argon atmosphere. Gratifyingly, preliminary attempts
using pyrolidine (A1) as co-catalyst led to the allylic alkylated
product 3aa in 18% yield (Table 1, entry 1). Commercially
available L-proline (A2) showed good reactivity and afforded
3aa in 37% yield, while other amine catalysts such as
diphenyl(pyrrolidin-2-yl)methanol (A3), methyl L-prolinate
8
f
(Scheme 1b). Dong, Breit, and co-workers reported a Rh-
catalyzed decarboxylative reaction of β-keto acids and alkynes/
allenes to provide γ,δ-unsaturated ketones independently
9
(
Scheme 1c). Although many efforts have been devoted to
α-allylic alkylation of ketones, a brief and atom-efficient strategy
is still highly desirable. Combined with our previous work on
1
0
the functionalization of alkynes, herein we report a
palladium/L-proline co-catalyzed cross-coupling reaction be-
Received: September 3, 2016
11
tween ketones and internal methyl alkynes to construct γ,δ-
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02649
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a,b
Table 1. Screening of Reaction Conditions
Scheme 2. Substrate Scope of Ketones
a
Reaction conditions: 1a (0.25 mmol), 2a (0.44 mmol), Pd(PPh3)4
10 mol %), L-proline (30 mol %), TsOH·H O (15 mol %), and PPh
(
(
2
3
20 mol %) in toluene (2 mL) at 120 °C for 24 h under argon
b
c
atmosphere. Isolated yields. Diastereoisomeric ratio (dr) was
determined by H NMR analysis.
a
1
Reaction conditions: 1a (0.25 mmol), 2a (0.44 mmol), Pd(PPh3)4
(10 mol %), amines (30 mol %), additives (15 mol %), and ligands (20
mol %) in toluene (2 mL) at 120 °C for 24 h under argon atmosphere.
b
c
Isolated yields. Pd(PPh ) (5 mol %), L-proline (15 mol %), and
3
4
d
e
12
PPh (10 mol %) was used. Pd(PPh ) was removed. 80 °C, 39% ee.
detected, which indicated that the nucleophilic hydroxyl
3
3 4
group could be subjected to this reaction. It is noteworthy that
the acid-sensitive group ketal could also survive under the
standard conditions and provide 3fa in 75% yield. Tetrahy-
dropyran-4-one and tetrahydrothiopyran-4-one worked well
and gave 3ga in 66% yield and 3ha in 54% yield. Acyclic ketone
was also investigated, and acetone delivered 3ia in 55% yield.
Furthermore, in order to expand the substrate scope, cyclic and
acyclic aldehydes were also examined, and 3ja and 3ka were
obtained in 63% and 50% yield, respectively. These results
revealed that both ketones and aldehydes could be activated
efficiently with our catalyst system. Moreover, natural product
5α-cholestan-3-one 1l, containing a six-membered cyclic ketone
moiety, could also be alkylated at the less hindered site of the
ketone in 51% yield.
Next, we turned our attention to exploring the substrate
scope of alkynes, and the results are summarized in Scheme 3.
The 1-aryl-1-propynes with electron-donating groups, such as
methyl and methoxyl groups at the C4-position of the phenyl
ring, afforded 3ab and 3ac in 75% and 79% yields. Electron-
withdrawing groups on the C4-position showed slightly lower
reactivity and furnished 3ad and 3ae in 47% and 59% yields.
C3-Methyl- and C3,5-dimethyl-substituted 1-phenyl-1-pro-
pynes gave 3af in 64% yield and 3ah in 71% yield, while 3ag
with C2-methyl was obtained in 48% yield due to steric effects.
In addition, substrates with aryl substituents, such as biphenyl,
thienyl, and naphthyl groups, could also be compatible and
provided 3ai−al in 55−87% yields. Unfortunately, when but-1-
(
A4), and pyrrolidine-2-carboxamide (A5) exhibited inferior
performance (Table 1, entries 2−5). In order to improve the
reaction efficiency, both monodentate and bidentate phosphine
ligands were tested, and PPh could afford 3aa in 44% yield
3
(
Table 1, entries 6−9). A brief examination of additives
revealed that 3aa could be isolated in 80% yield when TsOH·
H O was used (Table 1, entry 15), while other acids such as
2
AcOH, CF COOH, PivOH, and TfOH delivered 3aa in lower
yields (Table 1, entries 11−14). Decreasing the loading amount
of Pd(PPh ) and L-proline led to an obvious drop of yield
3
3
4
(
Table 1, entry 16). Control experiments showed that
Pd(PPh ) , L-proline, and TsOH·H O were essential to this
3
4
2
reaction (Table 1, entries 17−19). Although optically active L-
proline was used, no ee value was detected under the standard
conditions due to the high reaction temperature. Decreasing
the temperature to 80 °C (Table 1, entry 20) led to a promising
3
9% enantioselectivity of 3aa, while only 17% yield was
obtained (see Table S1 for details).
With the optimized conditions in hand, we then explored the
substrate scope of ketones, and the results are shown in Scheme
2
alkylated cyclopentanone 3ba and cycloheptanone 3ca were
obtained in 76% and 44% yields. Cyclohexanone with methyl or
hydroxyl group at the C4-position reacted smoothly to afford
. The size of simple cyclic ketones was tested, and the α-allylic
3
da and 3ea in 72% and 84% yields. To our delight, the
intermolecular potential hydroalkoxylation of 2a was not
B
DOI: 10.1021/acs.orglett.6b02649
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 3. Substrate Scope of Alkynes
Scheme 5. Plausible Reaction Mechanism
generates a hydridopalladium species I. Syn-insertion of I into
alkyne 2a affords the intermediate II, which is followed by β-
hydrogen elimination to afford phenyl allene III. Insertion of
the intermediate I to phenyl allene III produces the π-
allylpalladium species IV. Simultaneously, the L-proline reacts
with the ketone 1a to generate the enamine intermediate VI. It
was reported that the formation of the intermediate VI could
enhance the nucleophilicity of the α-positon of 1a. According
to the screening of reaction conditions (Table 1, entries 1−5),
we suggest that the carboxylic acid of L-proline would be helpful
a
Reaction conditions: 1a (0.25 mmol), 2a (0.44 mmol), Pd(PPh3)4
(
(
10 mol %), L-proline (30 mol %), TsOH·H O (15 mol %), and PPh3
20 mol %) in toluene (2 mL) at 120 °C for 24 h under argon
2
b
atmosphere. Isolated yields.
8b
to the formation of intermediate V. Reductive elimination of
V delivers the iminium intermediate VII and regenerates the
Pd(0) catalyst. Hydrolysis of VII produces the allylic alkylated
product 3aa with the regeneration of L-proline to the next
catalytic cycle.
In conclusion, we have developed a cooperative palladium/L-
proline-catalyzed direct α-allylic alkylation of ketones with
alkynes. This reaction exhibits high atom economy since
neither a leaving group is liberated nor is a stoichiometric
amount of extra oxidant needed. A broad range of functional
groups are tolerated, and the substrate scope could be further
expanded to aldehydes. Further transformation of γ,δ-
unsaturated ketones and asymmetric study are ongoing in our
laboratory.
yn-1-ylbenzene 2m and prop-1-yne-1,3-diyldibenzene 2n were
employed, no corresponding products were obtained.
To gain more insight into the mechanism of this reaction,
deuterated-labeling experiments were conducted. Ketone 1a
reacted with 2a-d under the standard conditions (Scheme 4a),
3
a
Scheme 4. Deuterated-Labeling Experiments
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02649.
1
13
a
1
H and C NMR spectra for all new compounds (PDF)
The extent of deuterium incorporation was determined using H
NMR spectroscopy.
AUTHOR INFORMATION
Corresponding Author
E-mail: ajlin@cpu.edu.cn.
■
*
affording 3aa-d in 62% yield. The incorporation of hydrogen at
n
the γ-position of 3aa-d suggested that the procedure for the
n
insertion of the intermediate I to 2a-d3 and β-hydrogen
11g,h
Notes
elimination of the intermediate II was reversible.
When
TsOH·H O was replaced by 2.0 equiv of AcOD-d , the allylic
The authors declare no competing financial interest.
2
4
alkylated product 3aa-d was isolated in 46% yield (Scheme
x
ACKNOWLEDGMENTS
4b). The incorporation of deuterium at the β-position of 3aa-dx
■
in a 13% ratio suggested that the dissociation of the allene III
from the palladium center of the intermediate I occurred to
Generous financial support from the National Natural Science
Foundation of China (NSFC21572272 and NSFC21502232),
the Natural Science Foundation of Jiangsu Province
(BK20140655), and the Foundation of State Key Laboratory
of Natural Medicines (ZZJQ201306) is gratefully acknowl-
edged.
1
3
some extent after the β-hydrogen elimination.
On the basis of previous work
11,14
and our deuterated-
labeling experiments, a plausible catalytic cycle is proposed in
Scheme 5. First, oxidative addition of Pd(0) with TsOH·H O
2
C
DOI: 10.1021/acs.orglett.6b02649
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
11) For selected examples, see: (a) Kadota, I.; Shibuya, A.; Gyoung,
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DOI: 10.1021/acs.orglett.6b02649
Org. Lett. XXXX, XXX, XXX−XXX