Regiocontrolled palladium-catalyzed arylative cyclizations of alkynols

Article abstract of DOI:10.1021/ja5029028

Tuning the reactivity of arylpalladium intermediates enables control of catalytic arylative 5-exo and 6-endo cyclizations of alkynols. The two modes of cyclizations represent a rare example of controllable, regioselective difunctionalization of alkynes. T

Full text of DOI:10.1021/ja5029028

Communication
pubs.acs.org/JACS
Regiocontrolled Palladium-Catalyzed Arylative Cyclizations of
Alkynols
Daishi Fujino,† Hideki Yorimitsu,*,†,‡ and Atsuhiro Osuka†
†Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan
‡ACT-C, JST, Sakyo-ku, Kyoto 606-8502, Japan
S
* Supporting Information
Scheme 1. Pd-Catalyzed anti-5-exo-Selective Cyclization
ABSTRACT: Tuning the reactivity of arylpalladium
intermediates enables control of catalytic arylative 5-exo
and 6-endo cyclizations of alkynols. The two modes of
cyclizations represent a rare example of controllable,
regioselective difunctionalization of alkynes. The cycliza-
tions are useful in offering a divergent synthesis of oxygen-
containing heterocycles, which is of synthetic use for
further derivatization. Formal synthesis of an hNK-1
receptor antagonist also showcases the utility of our
arylative cyclization.
favored 5-exo cyclization changed to a 6-endo mode, not by
substrate structures but largely by catalysts. Therefore, the
present synthetic protocols can be regarded as catalyst-
controlled oxyarylations of alkyne,10 leading to highly function-
alized tetrasubstituted alkenes in regiocontrolled manners.11
Such controllable difunctionalizations of alkynes by a metal
catalyst are still rare despite persistent interest.12
he prevalence of oxygen heterocycles in bioactive
Tcompounds and natural products has led to the
development of a number of cyclization reactions. A particularly
attractive method to synthesize cyclic ethers is metal-catalyzed
intramolecular addition of an O−H nucleophile across an
unsaturated carbon−carbon bond.1 These reactions are
regarded as a part of hydrofunctionalization, in which
numerous efforts have been devoted to the development of
controllable, regioselective reactions by tuning a metal
catalyst.1,2 For instance, W-, Rh-, and Ru-catalyzed cyclizations
of 4-alkyn-1-ols bearing a terminal alkyne provide 6-endo cyclic
products via distinct metal-vinylidene intermediates3 while
other metals usually give kinetically favorable 5-exo products.
However, both modes of cyclizations commonly resulted in
protonation, which lacks the divergence of products.4
Palladium catalysts are often employed for difunctionaliza-
tion of unsaturated bonds due to their remarkable ability to
create new carbon−carbon or carbon−heteroatom bonds.5
Particularly, difunctionalization that involves intramolecular
cyclization should offer regio- and stereoselective approaches to
complex cyclic skeletons in a single operation.5−7 However, the
regioselectivity of cyclization heavily depends on the substrate
structure in most cases, which severely limits the diversity of the
products available by this methodology.6 For instance,
palladium-catalyzed cyclization of alcohol A proceeds in an
anti-5-exo mode selectively to afford tetrahydrofuran derivative
B and avoids the formation of dihydropyran C in a kinetically
disfavored 6-endo fashion (Scheme 1).8
Our attempt began with alcohol 1a bearing an ynamide
moiety since ynamides display attractive reactivities and enable
installation of an amino group in products.13,14 Table S1 shows
the effect of ligands on phenylative cyclizations of 1a with
phenyl triflate (see Supporting Information (SI)). Employment
of PPh3, DPPF, XPhos, and PCy3 gave exo cyclic compound
3aa as a major product with concomitant formation of endo
cyclic compound 2aa (Table S1, entries 1−4).15 To our
surprise, X-ray crystal structure analysis revealed that exo cyclic
product 3aa is a syn adduct, which represents the first
palladium-catalyzed intramolecular syn-oxyarylation of al-
kynes.6,16 Further ligand screening revealed oxygen-linked
bidentate ligands such as DPEphos and Xantphos were
exceptionally effective for conventionally unfavorable 6-endo
cyclization (entries 5 and 6). It is in stark contrast to the fact
that ynamides usually react with transition metal complexes,
except for gold,17 to place the metal center at the α-position
owing to the directing effect of the amido group.18
The scope of aryl sources in this unusual endo-selective
cyclization was investigated as shown in Table 1. Chloro, fluoro,
and methylthio groups were compatible with the reaction (2ac,
2ad, and 2ae). The use of bulky o-tolyl triflate provided 2af in
good yield. Electron-rich aryl triflates also participated in the
cyclization (2ag and 2ah) although 1,3-benzodioxolyl triflate
gave slightly lower selectivity. Electron-deficient aryl groups
were introduced to 6-endo products 2ai and 2aj by using the
corresponding bromides, since the use of the corresponding
triflates resulted in the formation of complex mixtures.
Recently, our group became interested in developing new
palladium-catalyzed arylative cyclization reactions of unsatu-
rated compounds bearing a nucleophilic moiety.9 Along this
line, we disclose herein controllable, regioselective arylative
cyclization reactions of alkynols, leading to the divergent
formations of exo and endo cyclic products. Thus, kinetically
Received: March 22, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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Journal of the American Chemical Society
Communication
a
eventually allowed us to use electron-deficient aryl bromides
with the aid of Pd2(dba)3/P(2-furyl)3/NaOH, avoiding
concomitant formation of the endo cyclic products (3ak and
3al). Additionally, alkenyl bromide could be used for exo
cyclization (3am).
Table 1. Scope of Aryl Sources for endo Cyclization
The regioselectivity of cyclization was independent of the
substrate structures, which often determined the mode of
cyclization (Table 3).6 An alcohol bearing a bulky cyclohexyl
a
Table 3. Scope of Alkynols
a
Endo/exo ratios were determined by 1H NMR. Isolated yield.
Reaction was carried out at 100 °C. 5.0 mol % of Pd2(dba)3, 10 mol
b
c
% Xantphos, and 3.0 equiv of 2-chloropyridine were used.
Furthermore, heteroaryl groups could be installed into endo
cyclic products (2ak and 2al).
a
Conditions A and B correspond to the conditions in Tables 1 and 2,
1
respectively. Endo/exo ratios were determined by H NMR. Isolated
yield. Reaction was carried out at 80 °C. The products as well as the
starting material are diastereomeric mixtures (trans/cis = 70:30).
b
c
Next, we focused on developing a new syn-5-exo cyclization
by adjusting the reactivity of palladium catalysts. After extensive
screening, conditions employing XPhos as a ligand and aryl
bromides as an aryl source realized expected exo-selective
cyclization (Table 2). The scope of aryl bromides is wide,
except for electron-deficient aryl bromides that lead to 6-endo
cyclization. Further optimization of reaction conditions
group or a dimethyl group gave the corresponding 6-endo and
syn-5-exo products with high regioselectivity depending on the
conditions (2ba/3ba and 2ca/3ca). tert-Butyldimethylsilyl
ether was tolerated under the reaction conditions without
conceivable decomposition (2da/3da). Notably, conditions A
could be used for the synthesis of amino-substituted glycal19
derivative 2ea while conditions B afforded exo cyclic product
3ea.
a
Table 2. Scope of Aryl Bromides for syn-5-exo Cyclization
Our reaction conditions for endo cyclization could be
extended to the synthesis of the other frameworks. Benzene-
fused substrate 4 was converted to isochromene derivative 5 in
good yield (eq 1). We also found 5-endo cyclization of 6
afforded amino-substituted dihydrofuran 7 in high yield (eq 2).
The 6-endo cyclization of (+)-8 bearing a camphor sultam
chiral auxiliary was successful to afford (+)-9 (Scheme 2).
Although hydrogenation of a tetrasubstituted double bond is
difficult due to its steric hindrance, we were pleased to
accomplish the highly diastereoselective hydrogenation of
(+)-9 with Pd/C under atmospheric hydrogen to yield
a
Endo/exo ratios were determined by 1H NMR. Isolated yield.
b
c
Reaction was carried out at 100 °C. 20 mol % of P(2-furyl)3 was
d
used. 2.0 equiv of NaOH were used.
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(XPhos)] would have a preferential affinity for a hydroxy group
Scheme 2. Transformation of Optically Active endo Cyclic
Products
24
whereas the other intermediate [ArPd(Xantphos)]+OTf−
would not have such an apparent affinity but interacts with
an ynamide moiety. Thus, Lewis acidic cationic [ArPd-
(Xantphos)]+OTf− would be coordinated by the ynamide
moiety, thereby efficiently activating the triple bond to develop
a positive charge at the α-position ready for the 6-endo
cyclization. As for the 5-exo cyclization, preferential coordina-
tion of the hydroxy group to [ArPdBr(XPhos)] followed by
base-mediated alkoxide formation might lead to syn-insertion of
the alkyne moiety to the oxygen−palladium bond.25
In conclusion, we have disclosed the first catalyst-dependent
6-endo/syn-5-exo regioselective arylative cyclization of alkynols.
Coordination environments around the palladium centers of
arylpalladium intermediates, rather than substrate structures,
precisely dictate the regioselectivity. The present reactions
afford a variety of five- and six-membered heterocycles from
simple common substrates. The 6-endo products are useful
building blocks in organic synthesis, as specially exemplified in
the preparation of a key intermediate for the synthesis of an
hNK-1 receptor antagonist.
(+)-10.20,21 The present transformation offers a new route to
optically active cyclic N,O-acetals, which are often found in a
number of bioactive and naturally occurring products.22
The endo-selective arylative cyclization was also applied to
the formal synthesis of a potent hNK-1 receptor antagonist
(Scheme 3 and SI).23 Readily available chiral alkynol 11 was
Scheme 3. Formal Synthesis of Potent hNK-1 Receptor
Antagonist
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure, spectroscopic data, 1H/13C NMR
spectra, and X-ray crystallographic analysis. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
yori@kuchem.kyoto-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid from MEXT (Nos.:
24106721 “Reaction Integration” and 25107002 “Science of
Atomic Layers”) and from JSPS (Nos.: 25220802 (Scientific
Research (S)), 24685007 (Young Scientists (A)), 23655037
(Exploratory Research)). D.F. acknowledges a JSPS Fellowship
for Young Scientists.
smoothly converted to endo cyclic product 12, which was
hydrolyzed into lactone 13, a key synthetic intermediate of the
antagonist.
We also developed some other useful transformations of the
ketene N,O-acetal product (see SI). Thus, the endo cyclic
products could be used for a variety of arylated oxacycles.
We performed careful NMR experiments (see SI for details)
to account for the selectivity control and propose a plausible
mechanism in Scheme 4. According to the implication of the
NMR analysis, initially formed oxidative adduct [ArPdBr-
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