Palladium-catalyzed carbonylative cyclization of aryl alkenes/alkenols: A new reaction mode for the synthesis of electron-rich chromanes

Article abstract of DOI:10.1021/acs.orglett.5b00214

The Pd(II)-catalyzed intramolecular carbonylative cyclization reaction of aryl alkenes and aryl alkenols is reported for the synthesis of structurally diverse chromanes. PdCl₂(CH₃CN)₂ was used as the catalyst and CuCl₂ as the oxidant under the balloon pressure of CO. The reaction is conducted under mild conditions, and chromane-type esters and lactones can be generated in a highly regio- and stereoselective manner.

Full text of DOI:10.1021/acs.orglett.5b00214

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Carbonylative Cyclization of Aryl Alkenes/
Alkenols: A New Reaction Mode for the Synthesis of Electron-Rich
Chromanes
Shuang Li,† Fuzhuo Li,† Jianxian Gong,*,† and Zhen Yang*,†,‡,§
†Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School,
Shenzhen 518055, China
‡Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for
Molecular Science (BNLMS), and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
§Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5
Yushan Road, Qingdao 266003, China
S
* Supporting Information
ABSTRACT: The Pd(II)-catalyzed intramolecular carbonylative cyclization reaction of aryl alkenes and aryl alkenols is reported
for the synthesis of structurally diverse chromanes. PdCl2(CH3CN)2 was used as the catalyst and CuCl2 as the oxidant under the
balloon pressure of CO. The reaction is conducted under mild conditions, and chromane-type esters and lactones can be
generated in a highly regio- and stereoselective manner.
and products D, E, G, and H are frequently obtained.
Furthermore, the ratio of products D, E, G, and H depends
on different reaction conditions, such as the CO pressure,
reaction temperature, and solvent.3a,b
ransition metal catalyzed carbonylation reactions are a
Tpowerful method to realize the direct fixation of carbon
monoxide and produce various carbonyl compounds.1 The
palladium catalyzed Heck-type carbonylation reactions have
been extensively studied by chemists in the past decades.2 The
insertion of CO into an aryl-palladium bond leads to the
formation of an acylpalladium complex, and subsequent
reaction of this complex with various nucleophiles is used to
prepare aryl carbonyl compounds. The intramolecular version
of this reaction, in which a carbon−carbon double bond is
tethered to an aryl halide, has been well studied (Scheme 1).3
However, this type of reaction usually gives multiple products,
Hence, the direct Pd-catalyzed carbonylative cyclization of a
carbon nucleophile and a carbonyl group across the CC
bond of an unactivated olefin would be an ideal way to make
functionalized polycyclic aryl derivatives from simple alkenyl
arenes in terms of atom and step economy. In 2004,
Widenhoefer et al. reported the Pd-catalyzed carbonylative
cyclization reaction of an indole-linked alkene to give polycyclic
indole derivatives (Scheme 2, eq 1).4 In this reaction, the
electron-rich C3 and C2 of indole were used as carbon
nucleophiles.
Scheme 1. Palladium-Catalyzed Heck-Type Carbonylation
Chromane scaffolds are privileged structural motifs in natural
products and pharmaceuticals. Examples include anthopogo-
chromane,5 catiguanins A,6 and myristinin B.7,8 We envisioned
that this Pd-catalyzed carbonylative cyclization to afford an
aromatic carbonyl compound would be useful (Scheme 2, eq
2). Furthermore, when Y in I is a hydroxyl group, lactone K
could be made in one step.9 If developed, this methodology
would provide straightforward access to a variety of densely
functionalized multisubstituted chromanes.10
Reaction of Ar−X
Received: January 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00214
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Organic Letters
Letter
However, changing the catalyst to PdCl2 and Pd(OAc)2, or
replacing CuCl2 with Cu(OAc)2 and benzoquinone, resulted in
low yields (Table 1, entries 9−12).
The substrate scope was then investigated (Scheme 3).
Various electron-rich aryl alkenes 4b−4p were prepared and
Scheme 2. Palladium-Catalyzed Carbonylative Cyclization
Reactions of Ar−H
Scheme 3. Pd(II)-Catalyzed Carbonylative Cyclization of
a
Aryl Alkenes
Aryl alkene 4a was then selected as a model to explore the
scope of this reaction. Initially, PdCl2(CH3CN)2 was used as
the catalyst and CuCl2 as the oxidant, with a balloon of CO at
room temperature in THF and MeOH;11 no desired annulation
product was observed (Table 1, entries 1 and 2). This could be
because the Pd(II)-based cationic active species12 is extenuated
when exposed to oxygen-containing solvents.
a
Table 1. Screening of the Reaction Conditions
MeOH
(equiv)
yield
b
entry solvent
catalyst
oxidant (equiv) (%)
1
THF
MeOH
DCM
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
10
−
10
10
50
5
PdCl2(CH3CN)2 CuCl2 (2.5)
PdCl2(CH3CN)2 CuCl2 (2.5)
PdCl2(CH3CN)2 CuCl2 (2.5)
PdCl2(CH3CN)2 CuCl2 (2.5)
PdCl2(CH3CN)2 CuCl2 (2.5)
PdCl2(CH3CN)2 CuCl2 (2.5)
PdCl2(CH3CN)2 CuCl2 (3.5)
PdCl2(CH3CN)2 CuCl2 (3.5)
0
0
2
3
55
68
40
75
90
70
82
60
0
4
5
6
a
7
5
Isolated yield. For products 5i, 5j, 5k, and L, the reaction time is 36 h.
c
8
5
9
5
PdCl2
CuCl2 (3.5)
CuCl2 (3.5)
annulated under the optimized conditions. The following
observations were made from the results: (1) the alkoxyl
substituted electron-rich aryl alkenes 4b−4h gave annulated
products 5b−5h in good yields, and a strong para-directing
effect was observed; (2) aryl alkene 4i with two methyl groups,
and the naphthalene-based aryl alkene 4j gave desired products
5i−5j in moderate yields, although a longer reaction time was
required; (3) substituted alkenes 4k−4l with methyl groups at
R2 and R3 were used as substrates to undergo the expected
annulation; however, the yields were relatively low and a
significant amount of starting material remained after 36 h; (4)
substitution with methyl and phenyl groups at the C2 and C3
positions gave desired products 5m−5o in good yields with a
predominant cis-relationship at the newly generated chiral
center; (5) substrate 4p with gem-diester substitution at the C2
position gave the desired tetrahydronaphthalene product 5p in
good yield.
10
11
5
Pd(OAc)2
5
PdCl2(CH3CN)2 benzoquinone
(3.5)
12
DCE
5
PdCl2(CH3CN)2 Cu(OAc)2 (3.5)
0
a
Reaction conditions: 4a (0.2 mmol), palladium catalyst (10 mol %),
solvent (5 mL), oxidant (0.5 or 0.7 mmol), CO (1 atm pressure), 0 °C
for 2 h then rt for another 22 h. Isolated yield. Palladium catalyst (5
mol %).
b
c
Dichloromethane (DCM) and dichloroethane (DCE) were
selected as alternative solvents and used with MeOH (10
equiv). The desired product 5a was then obtained in 55% and
68% yield, respectively (Table 1, entries 3−4). The yield was
reduced to 40% on addition of MeOH (50 equiv) (Table 1,
entry 5). It was then improved to 90% yield when
PdCl2(CH3CN)2 (10 mol %) and CuCl2 (3.5 equiv) were
used in DCE and MeOH (5 equiv) (Table 1, entry 7).
B
DOI: 10.1021/acs.orglett.5b00214
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Organic Letters
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The effect of alcohols was then examined. Scheme 4 shows
that the primary and secondary alcohol based nucleophiles gave
Scheme 5. Pd(II)-Catalyzed Carbonylative Cyclization of
Aryl Alkenols
a
Scheme 4. Pd(II)-Catalyzed Carbonylative Cyclization of
a
Aryl Alkene 4a with Alcohols
a
Isolated yield.
a
Isolated yield.
the annulated products 6a−6f in good yields. In the case of
tertiary alcohol 6g, the yield decreased dramatically, indicating
that steric hindrance played an important role in this reaction.
Interestingly, when alcohol was replaced with water, no
carboxylic acid was formed, indicating the nucleophilicity of
the hydroxyl group is critical.
Scheme 6. Proposed Mechanism for the Pd-Catalyzed
Carbonylativa Cyclization of Aryl Alkenols
To extend the synthetic scope of this Pd-catalyzed reaction,
we intended to explore its potential application to the synthesis
of the chromane lactone core.13 Encouraged by early work on
Pd-catalyzed alkoxycarbonylative cyclization reactions,14 we
hypothesized that the synthesis of chromane lactones from aryl
alkenol substrates could be achieved by using our newly
developed Pd-catalyzed carbonylative cyclization methodology.
To validate this hypothesis, nine electron-rich aryl alkenols
were prepared and annulated under the optimized reaction
conditions (see Supporting Information for details). The results
are listed in Scheme 5, and the following conclusions can be
made: (1) Substrates with two or more methoxy groups on the
phenyl ring gave the desired products 8b−8i in reasonable
yields; however, when a single methoxy group was present on
the phenyl ring, only 18% annulated product 8a was obtained,
presumably because when the nucleophilicity of the aryls
reduced, decomposition reactions will be prominent under the
Pd(II)-catalyzed reaction conditions; (2) substrates with a
tertiary allylic alcohol gave the desired lactones 8f and 8g; (3)
the carbon-tethered substrates were converted to their
corresponding lactones 8h and 8i in acceptable yields; (4)
excellent diastereoselectivity was observed for this reaction to
give cis-chromane lactone as a single diastereomer. The
structure of 8b was determined with X-ray analysis.15
undergo reductive elimination to stereoselectively produce
lactone 8 and palladium(0). The palladium(0) would then be
oxidized with CuCl2, and chelation with CO would occur to
give palladium(II) complex A and complete the cycle.
In conclusion, we have developed a novel synthetic route to
highly substituted and electron-rich chromanes. Unlike the
previous Pd-catalyzed carbonylation of halo-aryl alkenes, our
newly developed reaction mode of the Pd-catalyzed carbon-
ylative cyclization allows for the synthesis of the structurally
diverse chromanes in a highly regio- and stereoselective manner
from simple aryl alkenes and aryl alkenols. Further application
of this method for the total synthesis of biologically active
natural products is currently underway in our laboratories.
A plausible mechanism was proposed to account for this
transformation (Scheme 6). We envisioned that the allylic
alcohol in substrate 7 could react with the palladium carbonyl
complex A to generate complex B,16 which would undergo an
intramolecular nucleopalladation to afford a cis-configured
palladocyclic intermediate C. Following migratory insertion of
CO into the alkyl-Pd bond, the resultant complex D would
C
DOI: 10.1021/acs.orglett.5b00214
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectral and other characterization
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: gongjx@pku.edu.cn.
*E-mail: zyang@pku.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSF of China (Grant Nos.
21372016 and 21402002), National 863 Program
(2013AA090203), 973 Program (2012CB722602), and
NSFC-Shandong Joint Fund for Marine Science Research
Centers (U1406402).
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DOI: 10.1021/acs.orglett.5b00214
Org. Lett. XXXX, XXX, XXX−XXX