Tandem ruthenium-catalyzed transfer-hydrogenative cyclization/ intramolecular diels-alder reaction of enediynes affording dihydrocoumarin-fused polycycles

Article abstract of DOI:10.1021/ol500548x

A tandem transfer-hydrogenative cyclization/intramolecular Diels-Alder reaction of enediyne substrates, containing 1,6-diyne, acrylate dienophile, and phenol tether moieties, was successfully accomplished using the combination of a cationic ruthenium complex, [CpRu(AN)₃]PF₆ (1b, Cp = ?⁵-C₅H₅, AN = MeCN), as the catalyst and a Hantzsch ester as the H₂ surrogate to afford interesting dihydrocoumarin-fused polycyclic products as single diastereomers.

Full text of DOI:10.1021/ol500548x

Letter
pubs.acs.org/OrgLett
Tandem Ruthenium-Catalyzed Transfer-Hydrogenative Cyclization/
Intramolecular Diels−Alder Reaction of Enediynes Affording
Dihydrocoumarin-Fused Polycycles
Yoshihiko Yamamoto,* Kazuma Matsui, and Masatoshi Shibuya
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya 464-8601,
Japan
S
* Supporting Information
ABSTRACT: A tandem transfer-hydrogenative cyclization/
intramolecular Diels−Alder reaction of enediyne substrates,
containing 1,6-diyne, acrylate dienophile, and phenol tether
moieties, was successfully accomplished using the combination
of a cationic ruthenium complex, [CpRu(AN)3]PF6 (1b, Cp =
η5-C5H5, AN = MeCN), as the catalyst and a Hantzsch ester as
the H2 surrogate to afford interesting dihydrocoumarin-fused
polycyclic products as single diastereomers.
ransition-metal-catalyzed carbocyclizations have been
Trecognized as efficient methods to synthesize valuable
cyclic products with increasing complexity from simple acyclic
precursors.1 Among them, the hydrogenative cyclization of α,ω-
diynes is a powerful route to exocyclic 1,3-dienes, which are
useful synthetic intermediates, via carbon−carbon bond
formation with concomitant hydrogenation.2 This fascinating
catalytic process was first pioneered by Trost and Lee, who
used a palladium catalyst with acetic acid and hydrosilanes as
the proton and hydride sources, respectively.3 Recently, several
research groups have also reported that rhodium, iron, or
platinum catalysts enable the direct use of molecular hydrogen
for the hydrogenative cyclization of α,ω-diynes, even though
the platinum-catalyzed reaction selectively afforded cyclo-
alkenes instead of exocyclic 1,3-dienes.4
exocyclic 1,3-dienes from 1,6-diynes possessing terminal aryl
groups. In contrast, when a 1,6-diyne possessing terminal
methyl groups was used as the substrate, [2 + 2 + 2]
cyclodimerization rather than transfer-hydrogenative cyclization
occurred. Thus, we used cationic ruthenium complexes,
[CpRu(AN)3]PF6 (1b, Cp = η5-C5H5, AN = MeCN) and
[Cp*Ru(AN)3]PF6 (1c), as the catalysts, which enabled the
transfer-hydrogenative cyclization of various 1,6-diynes possess-
ing terminal aryl, alkenyl, or alkyl groups using a Hantzsch ester
(HE, 2) as an alternative H2 surrogate (Scheme 1).7 However,
1,6-diynes possessing terminal alkyl groups were selectively
converted into cycloalkenes via the 1,4-hydrogenation of the
corresponding exocyclic 1,3-diene intermediates.
We also demonstrated that the exocyclic 1,3-diene products
efficiently underwent Diels−Alder reaction with highly electro-
philic dienophiles such as N-phenylmaleimide, 4-phenyl-1,2,4-
triazoline-3,5-dione, or dimethyl acetylenedicarboxylate.7 Re-
cently, various tandem processes comprising catalytic 1,3-diene
formations and subsequent Diels−Alder reactions have been
developed for the rapid and diversity-oriented syntheses of
complex polycyclic molecules.8,9 Therefore, we also attempted
the tandem ruthenium-catalyzed transfer-hydrogenative cycliza-
tion/Diels−Alder reaction of a 1,6-diyne in the presence of HE
2 and N-phenylmaleimide. However, this one-pot process was
hampered by the undesirable hydrogenation of the dien-
ophile.10 As a continuation of our study, we then carried out a
tandem process including an intramolecular Diels−Alder
reaction because such an intramolecular setting would facilitate
the [4 + 2] cycloaddition step. Therefore, a less electrophilic
dienophile such as an acrylate can be used, thereby suppressing
the undesirable hydrogenation of the dienophile. In addition,
Our group has independently developed the transfer-
hydrogenative cyclization of 1,6-diynes using a ruthenium
catalyst, Cp*RuCl(cod) (1a, Cp* = η5-Me5C5, cod = 1,5-
cyclooctadiene, Scheme 1).5,6 Notably, we used methanol as an
inexpensive and safe H2 surrogate, selectively affording
Scheme 1. Ruthenium-Catalyzed Transfer-Hydrogenative
Cyclization of 1,6-Diynes
Received: February 19, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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the newly developed tandem process would afford complex
polycyclic products from simple acyclic precursors in a single
operation. For this purpose, we designed a new enediyne
substrate (3) consisting of a pendant acrylate dienophile
attached to a 1,6-diyne moiety through an o-phenol tether.
Representative enediyne 3a was readily obtained by the
Sonogashira coupling of monophenylated propargyl ether
with tert-butyldimethylsilyl (TBS)-protected o-iodophenol and
subsequent deprotection, followed by condensation with acrylic
acid (Scheme 2). Because of the modular nature of this scheme,
diverse enediyne substrates were also obtained by replacing the
1,6-diyne and acrylic acid.
Scheme 4. Cyclization of 3a in the Presence of 1b and HE 2
Scheme 5. Stepwise Synthesis of 7a from 4
Scheme 2. Modular Synthesis of Enediyne Substrate 6a
cyclization, affording exocyclic 1,3-diene 8 in 95% yield. Using
similar procedures for the synthesis of 3a, 8 was converted into
9a, which underwent the intramolecular Diels−Alder reaction
in DMF at 70 °C for 5 h to afford 7a in 70% yield. Therefore,
7a was unambiguously confirmed as the thermal [4 + 2]
cycloadduct obtained from exocyclic 1,3-diene 9a with the
pendant acrylate dienophile. It was confirmed that the
cycloaddition of 3,4-dibenzylidenetetrahydrofuran with ethyl
acrylate did not take place in DMF at 100 °C within 5 h. It was
also shown that 7a was not an intermediate for the formation of
5a and 6a: the isolated 7a was subjected to the transfer-
hydrogenative cyclization conditions using catalyst 1a and
MeOH, yielding neither 5a nor 6a.
At the outset, the reaction of 3a was examined under the
previously optimized conditions using catalyst 1a and MeOH as
the H2 surrogate (Scheme 3). In the presence of 5 mol % 1a, 3a
Scheme 3. Cyclization of Enediyne 3a in the Presence of 1a
and MeOH
The substrate scope of the tandem process was further
investigated with various enediynes (Table 1). First, the effect
of the diyne moiety was examined. Enediynes possessing an
electron-donating methoxy or electron-withdrawing fluoro
substituent at the para position of the terminal phenyl groups,
3b and 3c, were converted into the corresponding tetracyclic
products 7b and 7c in comparable yields. In the previous study,
electron-donating substituents decreased the reaction rates of
the transfer-hydrogenative cyclization of 1,6-diynes.7 However,
no such effect was observed for this tandem process, because
the second intramolecular Diels−Alder reaction is the rate-
determining step. In addition to the phenyl groups, the 2-
thienyl group of 3d was tolerated, affording 7d in 75% yield.
The terminal aryl group was essential for the tandem process;
enediyne 10 possessing a terminal methyl group was subjected
to the transfer-hydrogenative cyclization conditions (5 mol %
1b, 2.0 equiv of 2, DMF, 70 °C, 17 h), affording intractable
materials along with unreacted substrate 10. The use of an
alternative catalyst 1c in THF afforded a similar result.
was refluxed in THF for 14 h to afford two new products 5a
and 6a. According to 1H and 13C NMR, IR, and high-resolution
mass analyses (see Supporting Information), 5a and 6a could
be assigned as the cyclohexadiene and phthalan derivatives,
respectively, which are probably formed via the intramolecular
[2 + 2 + 2] cycloaddition,11 followed by alkene isomerization or
aromatization rather than the expected tandem process. These
characterizations are also in good agreement with the fact that
5a gradually underwent aromatization upon exposure to air,
affording 6a.
These results indicate that the intramolecular [2 + 2 + 2]
cycloaddition is preferred over transfer-hydrogenative cycliza-
tion when catalyst 1a was used with MeOH. Then, the reaction
of 3a under alternative transfer-hydrogenative cyclization
conditions was examined using cationic catalyst 1b and HE
(2) as the H2 surrogate (Scheme 4). In the presence of 1 mol %
1b and 2 equiv of 2, 3a was heated in DMF at 70 °C for 5 h,
affording the desired tandem reaction product 7a as the sole
product. The structural assignment of 7a was corroborated by
an alternative stepwise synthesis of 7a from diyne 4, which is
the precursor of 3a (Scheme 5). In the presence of 1a and
MeOH, 4 uneventfully underwent the transfer-hydrogenative
The effect of the diyne tether was then examined for p-
toluenesulfonamide derivative 3e and malonate derivative 3f.
The tandem reaction of 3e proceeded under the same
conditions to afford the expected 3-pyrroline-fused product
7e in a similar yield (70%). In contrast, the tandem reaction of
3f was sluggish under the same conditions. Thus, 3f was
subjected to the reaction using an increased loading of 1b (10
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Furthermore, interesting pentacyclic compound 7j was also
obtained, albeit in a moderate yield (56%), from enediyne 3j
possessing the cyclopentenecarboxylate dienophile. In this case,
a prolonged reaction time of 16 h was required although
transfer-hydrogenative cyclization proceeded smoothly under
the standard conditions. Therefore, the substitution of the β-
position to the ester detrimentally effected the efficiency of the
Diels−Alder step.12 This is also true of enediyne 3k possessing
the methacrylate dienophile; this substrate afforded polymeric
materials at an elevated temperature of 120 °C, even though its
transfer-hydrogenative cyclization under the standard con-
ditions (1 mol % 1b, 2.0 equiv of 2, DMF, 70 °C, 1 h) afforded
exocyclic 1,3-diene 9k without difficulty in a high yield. The
Diels−Alder reaction of isolated 9k was also unsuccessful under
thermal conditions. Finally, enediyne 3l was examined as the
substrate bearing a doubly activated dienophile. Consequently,
the tandem reaction proceeded at 70 °C. However, the desired
7l was isolated in a moderate yield (42%) because of complex
side reactions.
Table 1. Scope of Tandem Process
All the polycyclic products were obtained as single
diastereomers by this tandem process. The relative stereo-
chemistry of these products was determined by NOE analyses
of representative products 7b and 7g and was also
unambiguously confirmed by a single-crystal X-ray diffraction
study of compound 7l (Figure 1). These data indicate that the
Figure 1. NOE data for 7b and 7g and ORTEP drawing of 7l.
intramolecular Diels−Alder reactions of the exocyclic 1,3-diene
intermediates possessing the pendant acrylate dienophiles
proceeded via endo transition states. In contrast, previously
reported reactions of closely related compounds 11 at higher
reaction temperatures (110 °C for R = H and 180 °C for R =
Me) afforded two stereoisomers 12 and 13 in a ca. 3:7 ratio
(Scheme 6).13 The formations of 12 and 13 were correlated to
Scheme 6. Previously Reported Intramolecular Diels−Alder
Reactions of 11
mol %) and 2 (3.0 equiv) for 7 h to afford the desired
cyclopentene-fused product 7f, albeit in a moderate yield
(60%). Subsequently, the effect of the dienophile on the
reaction efficiency was examined (Table 1). The reaction of
enediyne 3g possessing the crotonate moiety was attempted
under the standard conditions (1 mol % 1b, 2.0 equiv of 2,
DMF, 70 °C, 5 h); however, the 1H NMR analysis of the crude
reaction mixture indicated that the second intramolecular
Diels−Alder step did not proceed. Therefore, the reaction
temperature was raised to 120 °C, after transfer-hydrogenative
cyclization was carried out at 70 °C for 1 h. Consequently, the
desired tetracyclic product 7g was obtained in 77% yield.
Enediynes 3h and 3i, which possess sorbate or 3-(2-
furyl)acrylate as the dienophiles, were successfully converted
to the corresponding products 7h and 7i in similar yields.
the endo and exo transition states, respectively, based on density
functional theory (DFT) calculations. Therefore, the major
pathways of the Diels−Alder reactions of 11 were inferred to be
via the exo transition states. To gain more insights, we analyzed
the transition states for the intramolecular Diels−Alder
reactions of exocyclic 1,3-diene intermediate 9g corresponding
to enediyne 3g, using DFT calculations (Figure S2). The endo
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(6) The rhodium-catalyzed transfer-hydrogenative cyclization of 1,6-
enynes with ethanol as a H2 surrogate has been reported; see: (a) Parj,
J. H.; Kim, S. M.; Chung, Y. K. Chem.Eur. J. 2011, 17, 10852−
10856. The catalytic transfer-hydrogenative cyclization of a single ω-
alkynylaldehyde by using formic acid as a H2 surrogate has been
reported; see: Patman, R. L.; Chaulagain, M. R.; Williams, V. M.;
Krische, M. J. J. Am. Chem. Soc. 2009, 131, 2066−2067.
transition state was found to be 2.2 kcal/mol lower in energy
than the corresponding exo transition state. This energy
difference corresponds to an endo/exo selectivity of ca. 96:4.
Therefore, this theoretical prediction that the endo pathway is
kinetically favorable is qualitatively in good agreement with the
experimental results of the exclusive formation of endo
cycloadducts 7 from 3. The difference in stereoselectivity
between 11 and our system such as 9 can be ascribed to the
rigid exocyclic 1,3-diene moiety as well as the aryl terminal
group, although the details are unclear at this stage.
In conclusion, we have successfully developed a new tandem
process comprising a transfer-hydrogenative cyclization and
subsequent intramolecular Diels−Alder reaction. The use of
our previously reported catalyst system with a cationic
ruthenium catalyst, [CpRu(AN)3]PF6, and a Hantzsch ester
as the H2 surrogate in DMF effectively converted enediyne
substrates containing 1,6-diyne, acrylate dienophile, and phenol
tether moieties into dihydrocoumarin-fused polycyclic prod-
ucts. The relative stereochemistry of the tandem reaction
products was confirmed by NOE as well as X-ray
crystallography. Furthermore, based on DFT calculations, it
was reasoned that the intramolecular Diels−Alder reactions of
exocyclic 1,3-diene intermediates proceed via endo transition
states.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yamamoto-yoshi@ps.nagoya-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(12) Bae, H. W.; Han, J.-S.; Jung, S.; Cheong, M.; Kim, H. S.; Lee, J.
S. Appl. Catal., A 2007, 331, 34−38.
(13) Pearson, E. L.; Kwan, L. C. H.; Turner, C. I.; Jones, G. A.; Willis,
A. C.; Paddon-Row, M. N.; Sherburn, M. S. J. Org. Chem. 2006, 71,
6099−6109.
This work was partially supported by Platform for Drug
Discovery, Informatics, and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan, and by the Naito Foundation.
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