Microwave-assisted rhodium-complex-catalyzed cascade decarbonylation and asymmetric Pauson-Khand-type cyclizations

Article abstract of DOI:10.1002/ejoc.200800272

Microwave-assisted Rh-diphosphane-complex-catalyzed dual catalysis is reported. This cooperative process provides [2+2+1] cycloadducts by sequential decarbonylation of aldehyde or formate and carbonylation of enynes within a short period of time. Various

Full text of DOI:10.1002/ejoc.200800272

FULL PAPER
DOI: 10.1002/ejoc.200800272
Microwave-Assisted Rhodium-Complex-Catalyzed Cascade Decarbonylation
and Asymmetric Pauson–Khand-Type Cyclizations
Hang Wai Lee,[a] Lai Na Lee,[a] Albert S. C. Chan,[a] and Fuk Yee Kwong*[a]
Keywords: Microwave / Rhodium / Asymmetric catalysis / Cyclization
Microwave-assisted
Rh–diphosphane-complex-catalyzed
The first enantioselective version of this microwave-ac-
celerated cascade cyclization was realized. In the presence
of chiral Rh-(S)-bisbenzodioxanPhos complex, the cyclopen-
tenone products were achieved with ee values up to 90%.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
dual catalysis is reported. This cooperative process provides
[2+2+1] cycloadducts by sequential decarbonylation of alde-
hyde or formate and carbonylation of enynes within a short
period of time. Various O-, N-, and C-tethered enynes were
transformed into the corresponding products in good yields.
stoichiometric to catalytic Pauson–Khand-type reactions.[9]
The reaction conditions for catalytic PKRs usually require
elevated temperatures to carry out the reaction successfully.
In view of the efficient heat-energy transfer, microwave irra-
diation would be an alternative energy source for this type
of reaction. Nevertheless, microwave-promoted PKRs re-
main sporadically studied.[10] In continuing our cycload-
dition study,[11] we herein report the first example of Rh-
catalyzed a tandem decarbonylation–Pauson–Khand-type
cyclization process under microwave conditions. This versa-
tile protocol accelerates the carbonylative reaction to fur-
nish the desired cycloadducts in minutes and can be ren-
dered enantioselective with suitable choice of chiral diphos-
phane supporting ligands.
Introduction
Microwave heating has penetrated many different areas
of chemical research in the last decade and is set to revolu-
tionize the foremost way that chemists will carry out trans-
formations in the near future.[1] Since the pioneering reports
on microwave-accelerated organic transformations by the
groups of Gedye and Giguere/Majetich in 1986,[2] the appli-
cation of microwave dielectric heating to microwave-assisted
organic synthesis (MAOS) has attracted considerable
amount of attention in recent years.[3] Advantages to micro-
wave irradiation include minimization of thermal decompo-
sition of reagents and products by eliminating potential
temperature gradients and localized overheating, which are
common to conventional heating methods. Moreover, mi-
crowave irradiation also greatly accelerates reaction rates
and typically provides better yields with fewer byproducts.[4]
Inspired by the previous successful examples in MAOS,[5]
we were intrigued to investigate whether the influence of
microwave irradiation could reduce the prolonged reaction
periods, as well as side-product formation, in catalytic Pau-
son–Khand-type processes. In fact, cobalt-mediated
[2+2+1] carbonylative cyclization of an alkyne, alkene, and
carbon monoxide (i.e., the Pauson–Khand reaction,
PKR)[6] is a versatile protocol for the construction of vari-
ous bicyclic cyclopentenones.[7] These valuable scaffolds are
of particular interest in targeting a variety of synthetically
useful and pharmaceutically attractive compounds.[8] Con-
siderable advancements have been recently achieved from
Results and Discussions
The feasibility of the Rh-catalyzed decarbonylation of al-
dehyde under microwave conditions was examined in our
initial studies.[12]
A
stoichiometric amount of the
[Rh(COD)Cl]2/dppp complex and cinnamaldehyde were
placed in the microwave reactor at 100 °C for 10 min. Sty-
rene (Ͼ90% from GC–MS, by decarbonylation of cinnam-
aldehyde) and (carbonyl)(dppp)–rhodium(I) chloride were
observed. These preliminary results showed the potential
for catalytic decarbonylation under microwave-assisted re-
action conditions.
We were not only focused on the decarbonylation reac-
tion, but we also targeted the efficacy of dual catalysis (de-
carbonylation and subsequent carbonylative cyclization).
Commercially available phosphane ligands were tested in
the model reaction and oxygen-tethered enyne 1a was cho-
sen as the prototypical substrate (Table 1). Control experi-
ments revealed that a phosphane ligand was necessary for
the successful tandem transformation (Table 1, Entries 1–
[a] Open Laboratory of Chirotechnology of the Institute of Molec-
ular Technology for Drug Discovery and Synthesis and the De-
partment of Applied Biology and Chemical Technology, The
Hong Kong Polytechnic University,
Hong Kong, China
E-mail: bcfyk@inet.polyu.edu.hk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 3403–3406
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. W. Lee, L. N. Lee, A. S. C. Chan, F. Y. Kwong
FULL PAPER
4). Diphosphane ligands (e.g. dppp) were found to be supe- Table 2. Microwave-assisted Rh-catalyzed cascade Pauson–Khand-
type reaction.[a]
rior to monophosphane ligands (Table 1, Entries 3 and 5).
It is interesting to show that the CO surrogates (aldehydes)
were even better than gaseous CO as the CO source in these
microwave-assisted carbonylative reactions (Table 1, En-
tries 6–10), and α,β-unsaturated aldehydes gave the best re-
sults (Table 1, Entry 3). Though the decarbonylation of ali-
phatic aldehyde was observed, the efficiency was inferior to
that found in aromatic aldehydes (Table 1, Entry 10).
Table 1. Investigations on ligand and CO source effects in the mi-
crowave-assisted cascade PKR.[a]
Entry
Ligand
CO source
% Yield[b]
1
2
3
4
5
6
7
8
9
10
no ligand
dppe
dppp
dppf
cinnamaldehyde
cinnamaldehyde
cinnamaldehyde
cinnamaldehyde
cinnamaldehyde
CO gas[c]
p-ClC6H4CHO
C6H4CHO
p-OMeC6H4CHO
n-nonylaldehyde
trace
22
75
12
Ͻ5
15
44
55
48
36
Ph3P
dppp
dppp
dppp
dppp
dppp
[a] Reaction conditions: [Rh(COD)Cl]2 (3 mol-%), ligand (6 mol-
%), enyne (0.3 mmol), aldehyde (0.45 mmol), and tert-amyl alcohol
(1.0 mL) were placed in microwave-proof vials under an atmo-
sphere of nitrogen, and the reaction mixture was heated at 120 °C
for 45 min under microwave irradiation. [b] Isolated yield. [c] A CO
pressure of 1 atm was applied.
To further probe the effectiveness of microwave-assisted
dual catalysis, we examined various oxygen-tethered 1,6-en-
ynes for the Pauson–Khand-type cyclization (Table 2). Elec-
tronically different aromatic enynes were found to be com-
patible under these reaction conditions to furnish the corre-
sponding cyclopentenones (Table 2, Entries 1–7). Sterically
hindered ortho-substituted aromatic enynes afforded low
yields of the product; presumably, the ortho-methyl group
hindered the coordination of the yne moiety to the Rh cen-
ter (Table 2, Entry 8). Particularly noteworthy is that we
firstly demonstrated the successful transformation of het-
erocyclic thienyl–enyne to the desired product under micro-
wave-assisted conditions (Table 2, Entry 9). In contrast,
only trace amounts of the product were obtained under
[a] Reaction conditions: [Rh(COD)Cl]2 (3 mol-%), ligand (6.6 mol-
%), enyne (0.3 mmol), cinnamaldehyde (0.45 mmol), and tert-amyl
alcohol (1.0 mL) were placed in microwave-proof vials under an
atmosphere of nitrogen, and the reaction mixture was heated at
120 °C for 45 min under microwave irradiation. [b] Isolated yields.
[c] Reactions were performed under conventional heating at 120 °C
for 36 h.
conventional oil-bath heating (Table 2, Entry 10); moreover, were successfully transformed into the corresponding cyclo-
a significant amount of substrate decomposition was ob- pentenones with better enantioselectivities (up to 90%ee;
served by GC–MS analysis. The 1,8-enyne substrate was Table 3).
unsuccessful in this transformation, and ca. 80% of the
starting material was recovered (Table 2, Entry 14).
In order to determine the origin of carbonyl group in
the microwave-promoted CO transfer process, we used 13C-
Apart from achiral tandem catalysis, we were attracted labeled benzaldehyde for the decarbonylation–carbon-
by the possibility to achieve the first enantioselective ver- ylation sequence (Scheme 1).[12f] When the reactions were
sion of microwave-assisted cascade transformation. Com- placed under either a nitrogen or CO atmosphere, over 99%
monly used chiral diphosphane ligands were examined in of the corresponding 13C-cyclopentenone was obtained, as
place of dppp. (S)-BisbenzodioxanPhos provided the best judged by MS and NMR spectroscopy. These informative
results in terms of product yield and enantioselectivity.[13] results indicate that the CO moiety for carbonylative coup-
Various substrates including O-, N-, and C-tethered enynes ling is mainly provided by the decarbonylation of aldehyde.
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Eur. J. Org. Chem. 2008, 3403–3406

Cascade Decarbonylation and Asymmetric Pauson–Khand-Type Cyclizations
Table 3. Microwave-assisted asymmetric Rh-catalyzed cascade Pau- was thus carried out (Scheme 2). The reaction was success-
son–Khand-type reaction.[a]
ful, and the advantages of our newly developed reaction
conditions, including a shortened reaction time (3 d vs.
45 min), resulted in better product yield (43% vs. 62%)
(Scheme 2).
Scheme 2. Microwave-assisted cascade decarbonylation–Pauson–
Khand-type reaction with the use of formate as a CO surrogate;
under conventional oil-bath heating, 3 d were required for comple-
tion of the reaction with 43% isolated yield.
Conclusions
We reported the first successful microwave-assisted coop-
erative process. The microwave energy considerably increase
the rate of reaction in both decarbonylation and carbon-
ylative cyclization. Substrates such as thienyl enyne signifi-
cantly showed better yields under microwave conditions.
Notably, the reaction conditions in this sequential process
can be rendered enantioselective. Higher enantioselectivities
were observed than conventional heating with product ee
values up to 90%. In addition to aldehyde as the CO surro-
gate, we succeeded in showing that formate ester can be
used as the condensed CO source in microwave-accelerated
CO-transfer processes.
[a] Reaction conditions: [Rh(COD)Cl]2 (3 mol-%), ligand (6.6 mol-
%), enyne (0.3 mmol), cinnamaldehyde (0.45 mmol), and tert-amyl
alcohol (1.0 mL) were placed in microwave-proof vials under an
atmosphere of nitrogen, and the reaction was heated at 100 °C for
Experimental Section
45 min under microwave irradiation. [b] Isolated yields. [c] Average
of two runs from chiral HPLC analysis by using Daicel Chiracel
AS-H and AD-H columns (0.46 cmϫ25 cm). [d] Reactions were
performed under conventional heating at 100 °C for 36 h.
General: Unless otherwise noted, all reagents were purchased from
commercial suppliers and used without further purification. All air-
sensitive reactions were performed in Rotaflo (England) resealable
screw-cap Schlenk flasks (approx. 10-mL volume) or Teflon-lined
screw cap vials (approx. 2-mL volume) in the presence of Teflon-
coated magnetic stirrer bar (3 mmϫ10 mm). Toluene and tetra-
hydrofuran (THF) were distilled from sodium and sodium benzo-
phenone ketyl under an atmosphere of nitrogen, respectively. Al-
lylamine and triethylamine were distilled from CaH2 prior to use.
Formate esters (liquid form at room temp.) were distilled under
reduced pressure and stored in screw-capped vials. NaH (60% in
mineral oil) was washed with dry hexane prior to use (Caution:
This procedure should be performed under a relatively dry atmo-
sphere with adequate shielding). Shiny-orange [Rh(COD)Cl]2 crys-
talline solid and (S)-SYNPHOS (BisbenzodioxanPhos) were pur-
chased from Strem Chemicals. Thin-layer chromatography was per-
Scheme 1. Labeling experiment for microwave-assisted sequential
CO-transfer process.
There has been considerable interest in recent years in formed on Merck precoated silica gel 60 F254 plates. Silica gel
the chemistry of formate esters.[14] Particularly, the conver-
sion of methyl formate into methanol and carbon monoxide
is desirable in the generation of an easily handled “CO”
(Merck or MN, 230–400 mesh) was used for flash-column
chromatography. Melting points were recorded with a Büchi Melt-
ing Point B-545 instrument and are uncorrected. 1H NMR spectra
were recorded with a Varian (500 MHz) spectrometer. Spectra were
moiety. Nevertheless, drastic reaction conditions are usually
referenced internally to the residual proton resonance in CDCl3 (δ
employed (e.g. Ͼ180 °C and/or Ͼ1 atm pressure).[15] It
= 7.26 ppm) or with tetramethylsilane (TMS, δ = 0.00 ppm) as the
seemed conceivable to us that the decarbonylation of for-
internal standard. Commercially available CDCl3 was stored under
anhydrous K2CO3 granules with 4-Å molecular sieves in desicca-
mates could be attained under mild reaction conditions
with the suitable choice of mixed-metal complexes.[16]
tors. Chemical shifts (δ) were reported as part per million (ppm) in
δ scale downfield from TMS. 13C NMR spectra were recorded with
Attempts to study the first microwave-accelerated CO-
transfer process by using formate ester as the CO surrogate a Varian 500 spectrometer and referenced to CDCl3 (δ = 77.0 ppm).
Eur. J. Org. Chem. 2008, 3403–3406
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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H. W. Lee, L. N. Lee, A. S. C. Chan, F. Y. Kwong
FULL PAPER
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Coupling constants (J) were reported in Hertz (Hz). Mass spectra
(EI and FAB) were recorded with an HP 5989B Mass Spectrometer.
High-resolution mass spectra (HRMS) were obtained with a
Bruker APEX 47e FT-ICR mass spectrometer (ESI). HPLC analy-
ses were performed with an HP-1100 system by using Chiralcel AS-
H, AD-H, and OD-H (0.46 cmϫ25 cm) columns. Racemic bicyclic
cyclopentenone products (for chiral HPLC analysis calibration)
were obtained from the same PKR representative procedure except
dppp ligand was used. GC–MS analysis was conducted with an HP
6890 system with an HP 5973N mass-selective detector by using an
HP5MS column (30 m 0.25 mm). Microwave-assisted reactions
were performed with a Milestone MicroSynth Combichem micro-
wave reactor.
[8]
General Procedures for Microwave-Assisted Catalytic Pauson–
Khand Cyclization: [Rh(COD)Cl]2 (4.4 mg, 9.0 µmol) and dppp
(7.4 mg, 19.8 µmol) were charged into the reaction vial on a bench
top at room temperature. The reaction vial was then transferred
into the dry box before being evacuated and backfilled with nitro-
gen (3cycles). tert-Amyl alcohol (0.2 mL), cinnamaldehyde (59 mg,
0.45 mmol, 1.5 equiv. with respected to enyne) and enynes (57 mg,
0.3 mmol) were charged into the reaction vial. The vial was air
tightened by a special designed lid and transferred to the microwave
oven. The reaction mixtures were heated to 120 °C by microwave
irradiation with power of 500 watts for 45 min. The vials were al-
lowed to reach room temperature. Diethyl ether or ethyl acetate
(ca. 2 mL) was added. The crude reaction mixtures were directly
purified by column chromatography on silica gel (hexane/ethyl ace-
tate) to afford bicyclic cyclopentenones. Note: for the asymmetric
Pauson–Khand-type cyclization, the enantiomeric excess values of
the products were determined by chiral HPLC analysis by using
Chiralcel columns.
[9]
[10]
[11]
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, preparation of enyne sub-
strates, initial screening results, compound characterization data
and copies of 1H and 13C NMR spectra and chiral HPLC chroma-
tograms.
[12]
Acknowledgments
We thank the Research Grants Council of Hong Kong (CERG:
PolyU5008/06P) and the University Grants Committee Areas of
Excellence Scheme (AoE/P-10/01) for financial support.
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Received: February 11, 2008
Published Online: May 9, 2008
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Eur. J. Org. Chem. 2008, 3403–3406