Fully substituted pyranones via quasi-heterogeneous genuinely ligand-free migita-stille coupling of iodoacrylates

Article abstract of DOI:10.1021/ol5035113

Migita-Stille coupling of (Z)-?2-iodoacrylates with (E)-?±-stannyl allylic alcohols to furnish 5-alkylidene-4-substituted-5,6-dihydro-2H-pyran-2-ones is efficiently catalyzed by 2% Pd black in DMF, while Pd(PPh₃)₄ is inactive. Heterogeneous Pd released in solution is most likely responsible for the catalysis. The reaction is applicable to other substrates, without having to resort to ligands, additives, and/or solid support for Pd. The resulting pyranones can be rearranged to fully functionalized pyranones in another single step.

Full text of DOI:10.1021/ol5035113

Letter
pubs.acs.org/OrgLett
Fully Substituted Pyranones via Quasi-Heterogeneous Genuinely
Ligand-Free Migita−Stille Coupling of Iodoacrylates
Jirí Kratochvíl,† Zdenek Novak,† Mukund Ghavre,† Lucie Novakova,‡ Ales Ruzicka,§ Jirí Kunes,†
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and Milan Pour*,†
†Department of Inorganic and Organic Chemistry and ‡Department of Analytical Chemistry, Faculty of Pharmacy, Charles University
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in Prague, Akademika Heyrovskeho 1203, Hradec Kralove 500 05, Czech Republic
§Department of General and Inorganic Chemistry, Faculty of Chemical Technology, University of Pardubice, Studentska
Pardubice 532 10, Czech Republic
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95,
S
* Supporting Information
ABSTRACT: Migita−Stille coupling of (Z)-β-iodoacrylates with
(E)-α-stannyl allylic alcohols to furnish 5-alkylidene-4-substituted-
5,6-dihydro-2H-pyran-2-ones is efficiently catalyzed by 2% Pd
black in DMF, while Pd(PPh3)4 is inactive. Heterogeneous Pd
released in solution is most likely responsible for the catalysis. The
reaction is applicable to other substrates, without having to resort
to ligands, additives, and/or solid support for Pd. The resulting
pyranones can be rearranged to fully functionalized pyranones in
another single step.
igita−Stille coupling continues to be a popular Pd-
Mcatalyzed cross-coupling reaction. The majority of
examples involve catalysis by a ligand-stabilized Pd0 species in
solution.1 On the other hand, the more attractive heterogeneous
protocols2 employing ligand-free Pd metal as the catalyst are
limited to a few examples that utilize Pd on a solid support.
Additionally, they suffer from several limitations. By way of
example, catalysis using Pd/C requires the presence of AsPh3/
cuprous iodide3 or other additives (fluorides, LiCl) to achieve
good yields,4 while Pd-doped KF/Al2O3 was subjected to MW
irradiation in solvent-free conditions to a single substrate5 and
Pd/CaCO3 was reportedly used in the presence of tributylphe-
nyltin only.6 An area of growing importance is Pd nanoparticles,7
which were prepared by the reduction of PdII salts and either
encapsulated in a polymer matrix8a,b or applied in an ionic
liquid8c when used in the Migita−Stille coupling.
followed by Migita−Stille coupling of resultant (E)-2-stannyl-2-
en-1-ols with (Z)-β-iodoacrylates should deliver 5-alkylidene-4-
substituted-5,6-dihydro-2H-pyran-2-ones in one pot (Scheme
1). Interestingly, coupling of β-iodoacrylates was reported only in
a few cases, possibly due to their basic- and temperature-sensitive
nature.11
Scheme 1. Designed One-Pot Pyranone Synthesis
Herein, we report a general cross-coupling catalyzed by
colloidal Pd particles released from Pd black (2%) in DMF using
(Z)-β-iodoacrylates. Interestingly, the reaction was inhibited by
the presence of a phosphine under homogeneous conditions.
The process allows an assembly of densely substituted pyranones
in one step, and is also applicable to other substrate types. To the
best of our knowledge, no reports of simple, unsupported
commercially available Pd in its metallic form being employed as
a catalyst in the Migita−Stille coupling have been published to
date. Furthermore, the resulting pyranones can subsequently be
converted to fully substituted heterocycles via PdL4-mediated
transfer of the substituent from the alkylidene group to C6.
Following our previous studies9 around the preparation of
natural product like10 5-alkylidenepyranone scaffolds, we
reasoned that a properly tuned protocol employing Pd(PPh3)4-
catalyzed hydrostannation of appropriate propargylic alcohols
After some experimentation using propargylic alcohol 1a and
ester 3a, where THF was replaced by DMF for the coupling step
in order to promote the reaction, it came as a surprise that the
coupling proceeded only when the mixture was accidentally
exposed to air prior to addition of the iodoacrylate. The mixture
turned black on account of formation of phosphine oxide and
ensuing Pd black formation (Ph3PO formation observed by 31
P
NMR). Upon workup, a mixture of the expected pyranone 4a
and its isomer 5a was obtained. Furthermore, exposure to a
stream of oxygen after hydrostannation resulted in complete
phosphine oxidation and suppressed the formation of 5a. Since a
Received: December 8, 2014
© XXXX American Chemical Society
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control experiment confirmed that pure stannane 2a did not
react with iodoacrylate 3a in the presence of freshly prepared
Pd(PPh3)4 (1.6%) under Ar, with other conditions being
identical, metallic Pd itself or a derived species must have acted
as the catalyst. As the stability of oxidative adduct formed from
iodoacrylates and Pd(PPh3)4 is well documented,12 a conclusion
can be drawn that its reactivity is insufficient for transmetalation
with the organotin component.
Table 1. Methodology Application: Lactones
Our next experiments were aimed at determining the activity
of commercial Pd black in the coupling step and its recyclability.
Coupling reactions performed in an NMR tube with varying
amounts of Pd black (10, 5, 1, and 0.5%) in DMF-d7 enabled us
to determine the optimal amount of the catalyst and temperature
(2% and 70 °C, respectively; see the Supporting Information).
Then, stannane 2a and acrylate 3a were coupled in different
solvents on a milimolar scale. DMF was the solvent of choice, and
importantly, the absence of phosphine again resulted in no
formation of 5a (Scheme 2). Reuse of the recovered catalyst in
the same reaction (5 times) led to comparable yields and
marginally higher reaction time (see the Supporting Informa-
tion).
Scheme 2. Solvent Optimization
Application of the optimized conditions to variously
substituted derivatives of 2 and 3 (Table 1) showed that the
reaction was tolerant of a wide range of functionalities (aryl,
heteroaryl, alkyl, substituted alkyl) in both R1 and R2, with high
isolated yields (80−95%) achieved in most cases. Basic groups
(4n and 4o) were protected in order to prevent dehydroiodi-
nation of the acrylate (t-Boc group was used). Such compounds
could be easily deprotected once the ring was constructed (4n).
In order to ascertain possible limitation of this methodology to
relatively reactive (Z)-β-iodoacrylates, we performed series of
experiments employing various types of stannanes and halides.
The results showed that these conditions are generally applicable
(Table 2). Again, a variety of functionalities were tolerated and
the coupling proceeded even with aryl iodides bearing electron-
donating substituents (11 and 12) and aryl bromides bearing
electron-withdrawing substituents (14 and 16), although higher
reaction temperatures were required in these cases.
In an attempt to improve the yield for substrates bearing
electron-donating substituents, we briefly investigated the effect
of additives (LiCl, LiF, TBAF; see the Supporting Information).
Lithium chloride had a positive impact both on the yield and
reaction time (Table 3).4,13 Moreover, the coupling of aryl
chloride bearing an electron-withdrawing substituent was
successfully performed. While we cannot strictly exclude Cl−
coordination to Pd in our system, it appears more likely that,
given the amount of LiCl needed for significant rate enhance-
ment and the heterogeneous conditions, Cl− ions may act simply
by increasing the polarity of the reaction mixture. A similar effect
has been observed by Roy and Hartwig for Br− ions in Kumada
couplings and aminations.14
a
b
Performed in gram scale. Ethyl ester used as starting material.
c
Overall yield (coupling and deprotection).
Nature of the catalysis was addressed as follows: First, Pd black
was suspended in DMF, and the suspension was stirred for 3 h at
70 °C and subsequently filtered through a 100 nm filter to give a
clear solution. The same filtration process was performed with
the reaction mixture after the acrylate was consumed in coupling
reaction, and both solutions were analyzed for the presence of Pd
metal. Pd contents were determined by ICP-MS as 15 and
99 ppm of Pd, respectively. Hence, the presence of substrate gave
rise to a significantly higher proportion of active Pd particles
(<100 nm in diameter) in the mixture, the formation of which
was very likely accelerated by oxidative addition.
Second, upon monitoring the reaction progress by NMR (see
the Supporting Information), all curves showed an induction
period independent of the amount of Pd black used, which
indicates that the bulk metal is merely a precatalyst.15
Third, HPLC monitoring experiments were conducted (see
the Supporting Information). Here the mixture was divided into
4 aliquots at approximately 50% conversion. The first aliquot was
filtered through a 100 nm filter, a droplet of Hg was added to the
second, the third was filtered and Hg then added, and the fourth
was used as control. The HPLC analyses showed rapid
termination of the cross-coupling process in both aliquots
B
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Table 2. Methodology Application: General
Table 3. Influence of LiCl
a
b
c
d
70 °C. Iodide was used as starting material. 90 °C. 110 °C.
e
f
g
100 °C. Bromide was used as starting material. 4% of Pd black was
h
i
used. 140 °C. Chloride was used as starting material.
molecular Tsuji−Trost reaction,16 when some PdL4 catalyst
remained in the mixture after incomplete phosphine oxidation.
Indeed, when pyranone 4q was exposed to Pd(PPh3)4, partial
conversion to 5b took place. The reaction proceeded under even
milder conditions when Pd(TFP)4 (TFP = tris-2-furylphos-
phine) was employed. While the experiment with 13C-labeled 4q
(Scheme 3) supports the mechanism involving the formation of a
Scheme 3. Mechanistic Proposal for the Observed Tsuji−
Trost Reaction
η3-allylic Pd complex that can be reattacked by the liberated
carboxylate, the geometry of such compounds ignores stereo-
electronic requirements for this process since alignment of the π
orbitals of the double bond with the σ orbital of the leaving group
is a prerequisite for the allylic substitution to occur.17 Following
the X-ray study of the analogous derivative 4e, the σ orbital of the
C−O bond is far from any alignment in both structural
conformations present (calculated angles are 42,28° and
80,19°; see the Supporting Information).
a
b
c
d
90 °C. 110 °C. After 21 h, temperature was raised to 90 °C. Aryl
e
bromide was used as starting material. Trimethylphenyltin was used
as starting material. 100 °C.
f
containing Hg; the amount of Pd after the filtration dropped to
2.5 ppm. This is supportive for the heterogeneous catalysis.
Furthermore, the kinetic curve of filtered experiment compared
to control is essentially the same. Hence, particles larger than
100 nm in size can be excluded from the catalysis once the
induction period is over, the presence of which again supports
the hypothesis that there is an interaction between the Pd particle
surface and the substrates.15
On the basis of these observations, a tentative conclusion can
be drawn that Pd black releases colloidal particles smaller than
100 nm, which are probably responsible for the catalysis, and the
formation of which is accelerated by the oxidative addition of the
substrate.
Importantly, compound 5b possesses a fully functionalized
pyranone core, capable of further elaboration into other
structural types.
To conclude, we have found that Migita−Stille coupling of
(Z)-β-iodoacrylates with (E)-α-stannyl allylic alcohols furnishes
substituted pyranones in one step and is catalyzed by commercial
Pd black most likely via the release of colloidal particles in
solution, whereas Pd(PPh3)4 under homogeneous conditions is
inactive. Since the process is also applicable to other types of
substrates, commercially available, recyclable Pd black may be
sufficient for a number of Migita−Stille cross-coupling cases,
without the need for ligands and/or other additives. Finally, the
Finally, the formation of pyranone of structural type 5 was
investigated in a greater detail. We hypothesized that the
compound was formed from lactone pattern 4 via an intra-
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(15) For related observations, see: Widegren, J. A.; Finke, R. J. J. Mol.
Catal. A: Chem. 2003, 198, 317−341.
pyranones obtained can be further converted to synthetically
versatile, fully substituted pyranones by a PdL4 type of catalyst.
(16) For reviews on this topic, see: (a) Trost, B. M.; Crawley, M. L.
Chem. Rev. 2003, 103, 2921−2944. (b) Lu, Z.; Ma, S. Angew. Chem., Int.
Ed. 2008, 47, 258−297.
ASSOCIATED CONTENT
* Supporting Information
■
S
(17) Farthing, C. N.; Koco
6672.
̌
vsky, P. J. Am. Chem. Soc. 1998, 120, 6661−
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Experimental procedures, characterization data, and copies of
NMR for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*Email: pour@faf.cuni.cz.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Charles University in Prague
(Project Nos. GAUK 1176213 and SVV 260062), Czech Science
Foundation (Project No. 15-07332S), and European Social Fund
and the state budget of the Czech Republic (Project No.
CZ.1.07/2.3.00/30.0061).
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