Ruthenium-catalyzed transfer oxygenative cyclization of α,ω-diynes: Unprecedented [2 + 2 + 1] route to bicyclic furans via ruthenacyclopentatriene

Article abstract of DOI:10.1021/ja302868s

A novel oxygen-atom-transfer process enables the catalytic [2 + 2 + 1] synthesis of bicyclic furans from α,ω-diynes with DMSO. [CpRu(AN)₃]PF₆ catalyzed the transfer oxygenative cyclization of diynes with aryl terminal groups, while t

Full text of DOI:10.1021/ja302868s

Communication
pubs.acs.org/JACS
Ruthenium-Catalyzed Transfer Oxygenative Cyclization of α,ω-
Diynes: Unprecedented [2 + 2 + 1] Route to Bicyclic Furans via
Ruthenacyclopentatriene
Ken Yamashita,† Yoshihiko Yamamoto,*,‡ and Hisao Nishiyama†
†Department of Applied Chemistry, Graduate School of Engineering, and ‡Department of Basic Medicinal Sciences, Graduate School
of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan
S
* Supporting Information
to the above precedents, two alkyne molecules are simultaneously
ABSTRACT: A novel oxygen-atom-transfer process en-
ables the catalytic [2 + 2 + 1] synthesis of bicyclic furans
from α,ω-diynes with DMSO. [CpRu(AN)3]PF6 catalyzed
the transfer oxygenative cyclization of diynes with aryl
terminal groups, while those of diynes with alkyl terminal
groups were effectively promoted by the corresponding
Cp* complex. A mechanism for bicyclic furan formation
via a ruthenacyclopentatriene was proposed on the basis of
both experimental and theoretical studies.
activated by a single metal center to produce bis(carbenoid) species,
and two C−O bonds and one C−C bond are formed in a single
transfer oxygenation process. In addition to the mechanistic
novelty, this method is an atom-economical and straightforward
route to bicyclic furans under neutral conditions.
Previously, Beller, Dixneuf, and co-workers reported that
dienyl ethers formed via Ru-catalyzed alkoxylative dimerization
of phenylacetylenes undergo cyclization in the presence of a
Cu(II) catalyst and TsOH in air to afford diphenylfurans
(Scheme 2a).5 A similar transformation of diphenylacetylenes
ransition-metal-catalyzed transfer oxygenation of alkynes
Scheme 2. Previous Syntheses of Furans from Arylalkynes
T
is an effective method for synthesizing carbonyl
compounds. Transfer oxygenation of gold-activated alkynes
with N-oxides, sulfoxides, and epoxides has emerged as a
powerful method to produce α-oxo gold carbene species
(Scheme 1a).1 Since the pioneering studies carried out by
Scheme 1. Transfer Oxygenation of Alkynes Relevant to
Carbene Complexes
into tetraphenylfurans has been achieved using a Pd catalyst
and zinc Lewis acids under an oxygen atmosphere.6 The scope of
these furan formations was almost limited to aryl-substituted
monoalkynes; only one example of a 1,6-diyne with aryl terminals
resulted in a lower yield (32%) under the Pd-catalyzed
conditions.6b In addition, Muller’s group has shown that bicyclic
̈
furans can be obtained in low yields by the oxidation of
preformed rhodacyclopentadienes (Scheme 2b).7 In contrast to
these precedents, our method catalytically converts a wide variety
of 1,6- and 1,7-diyne substrates having both aryl and alkyl
terminals into bicyclic furans in moderate to high yields. Here we
report the preliminary results of our investigation of this novel
oxidative cyclization reaction of α,ω-diynes to produce bicyclic
furans. We also propose a possible mechanism for this process
on the basis of our experimental and theoretical studies on
ruthenacyclopentatrienes.
At the outset, the reaction conditions were optimized for the
cyclization of diyne 2a using Ru catalysts 1 (Table 1).8 First, we
used the pentamethylcyclopentadienyl (Cp*) complex
[Cp*RuCl(cod)] (1a; cod = 1,5-cyclooctadiene) for the
Toste,1a Zhang,1b and others, fascinating cascade processes
initiated by transfer oxygenation have been studied extensively.2
In contrast, catalytic transfer oxygenation of carbene complexes
derived from alkynes has almost been neglected. Trost and
Rhee synthesized lactones via Ru-catalyzed oxidative cyclization
of alkynols (Scheme 1b).3 The transfer oxygenation of transient
Ru−carbene species with N-hydroxysuccinimide is the key step
in performing this transformation successfully.
In our recent efforts to develop a new mode of Ru-catalyzed
cyclization of 1,6-diynes,4 we found that the O atom is
transferred from dimethyl sulfoxide (DMSO) to the diyne
substrates with concomitant cyclization, resulting in the
catalytic formation of bicyclic furans (Scheme 1c). In contrast
Received: March 24, 2012
Published: April 20, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
cyclization conditions were used to study the substrate scope:
catalyst 1c, DMSO (5 equiv), DMF solvent, 140 °C.
Table 1. Optimization of the Reaction Conditions
Various 1,6-diynes with aryl terminal groups were subjected
to the optimal cyclization conditions (Table 2). Diynes 2b−d
with quaternary carbon tethers and tosylamide 2e underwent
furan annulation with 5 mol % catalyst, affording the
corresponding bicyclic furans in ∼90% yields (runs 1−4). On
the other hand, sulfone 2f required 10 mol % catalyst because
a
run
cat (mol %)
conditions
products (yield/%)
a
Table 2. Scope of Diynes with Aryl Terminal Groups
b
c
c
1
1a (10)
THF, 70 °C, 12 h
THF, 70 °C, 12 h
THF, 70 °C, 3.5 h
THF, 70 °C, 24 h
THF, 70 °C, 24 h
THF, 70 °C, 24 h
DMF, 70 °C, 24 h
DMF, 100 °C, 10 h
DMF, 140 °C, 4 h
3a (4), 4 (36)
b
d
c
c
2
1a (10)
3a (46), 4 (3)
e
d
3
1a (10)
3a (71), 4 (trace)
e
c
4
1b (10)
1c (10)
1c (10)
1c (5)
1c (5)
1c (3)
3a (19)
e
c
5
3a (50)
f
c
6
3a (40)
e
7
3a (73)
3a (79)
3a (90)
e
8
e
9
a
b
Isolated yields based on 0.3 mmol of 2a. DMSO (10 equiv) and
c
solvent (1.5 mL). Yield determined by 1H NMR analysis of the crude
products; 2a was returned in 37, 9, 57, 30, and 35% yield for runs 1, 2,
d
e
and 4−6, respectively. MsOH (20 mol %) was added. DMSO (5
f
equiv) and solvent (3 mL). DMSO (1.2 equiv) and solvent (3 mL).
cyclization of 2a in the presence of 10 mol % catalyst and 10
equiv of DMSO in refluxing THF for 12 h (run 1). The
1
formation of bicyclic furan 3a was confirmed by H NMR
analysis of the crude products, although 37% of 2a remained
intact. In addition, the [2 + 2 + 2] self-cycloaddition product 4
was found. Since this reaction was presumed to proceed via a
ruthenacyclopentatriene intermediate (see below), methane-
sulfonic acid (MsOH) (20 mol %) was added to enhance the
electrophilicity of the ruthenacycle via protonation.9 Gratify-
ingly, this increased the conversion rate of 2a and afforded the
desired 3a in a higher yield (run 2). Using a reduced amount of
DMSO (5 equiv) dramatically increased the reaction rate, and
3a was isolated in 71% yield (run 3). In contrast to DMSO,
pyridine N-oxide and PhIO proved to be much less efficient as
O-atom donors. The reactions using these reagents immedi-
ately yielded black precipitates, and <10% yield of 3a was
detected in the crude reaction mixtures.
Electron-deficient ruthenacycle intermediates produced from
cationic Ru complexes were also expected to enhance the
reaction rate. In addition, the undesirable self-cycloaddition of
the diyne was expected to be suppressed by the use of cationic
complexes. In fact, no trace of 4 was detected in the crude
products when the cationic complex [Cp*Ru(AN)3]PF6 (1b;
AN = acetonitrile) was used as the catalyst (run 4). However,
the reaction was sluggish, and 3a was formed in a low yield.
Next, instead of 1b, the corresponding cyclopentadienyl (Cp)
complex 1c was investigated as a catalyst, as Cp is less electron-
donating than Cp*. As a result, the yield of 3a improved to 50%
under the same conditions (run 5). The product yield was
significantly decreased by the use of 1.2 equiv of DMSO (run
6). Finally, to improve the yield of 3a further, different solvents
such as acetone, N,N-dimethylformamide (DMF), N,N-
dimethylacetamide, and 1,3-dimethyltetrahydropyrimidin-
2(1H)-one were studied. DMF gave the best results (run 7):
the reaction was almost completed with a reduced catalyst
loading (5 mol %), and 3a was isolated in 73% yield. At higher
temperatures, the reaction time and the catalyst loading were
reduced (runs 8 and 9). Therefore, the following optimal
a
1c [5 mol % (10 mol % for runs 5, 12−14, and 16; 20 mol % for runs
11 and 15)], 2 (0.3 mmol), DMSO (5 equiv), DMF (3 mL), 140 °C.
b
c
Isolated yields. Yields of recovered starting materials were
determined by 1H NMR analyses: 6% for run 13 and 22% for run 15.
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Communication
the reaction was sluggish (run 5). The desired 3f was obtained
in 87% yield, and its X-ray structure was determined [see the
Supporting Information (SI)]. These results indicate that the
Ru-catalyzed transfer oxygenative cyclization tolerates esters,
ketones, nitriles, and sulfones.
efficiently underwent oxygenative cyclization with 5 mol % 1b,
affording 3s in 74% yield. Ether derivative 2t featuring bulky
cyclopentyl groups required a higher catalyst loading (15 mol
%) and gave the desired bicyclic furan 3t in 61% yield. The
cyclization of diyne 2u with both alkyl and aryl terminals was
carried out using 1c as the catalyst in DMF at 140 °C to obtain
3u in 81% yield. In contrast, diynes with terminal alkynes were
not compatible with this method.
Our intramolecular [2 + 2 + 1] cyclization has several
synthetic advantages. The synthesis of oligoarylenes such as 6
via previous monocyclic furan annulations is difficult, but 6 can
be selectively constructed in 87% yield from tetrayne 5 via the
Ru-catalyzed double transfer oxygenative cyclization (Scheme
4). Such furan-containing oligoaryls are reported to be efficient
hole-transporting materials.10
Next, the influence of the terminal aryl moieties was
investigated. Diynes 2g−j, which have electron-donating
methoxy or electron-withdrawing halogen substituents or
both, were cleanly converted to 3g−j in yields of >90% (runs
6−9). When substrates with strongly electron-withdrawing
fluorine substituents were used, the reaction times were notably
shortened (runs 7 and 9). Diyne 2k with thiophene terminal
groups underwent cyclization without any difficulty, giving a
90% yield of the interesting product 3k having a thiophene−
furan−thiophene sequence (run 10). The sluggish reaction of
2l with ferrocenyl (Fc) terminal moieties required a 1c loading
of 20 mol % and gave the expected bis(ferrocenyl)furan 3l in a
moderate yield (run 11).
Scheme 4. Double Transfer Oxygenative Cyclization of
Tetraynes
Moreover, 1,7-diynes also participated in the transfer
oxygenative cyclization, albeit with increased catalyst loadings.
Diyne 2m with four ester substituents on the tether efficiently
underwent oxygenative cyclization with a 10 mol % catalyst
loading, affording 3m with a fused six-membered ring in 84%
yield (run 12). The corresponding diester 2n and diol
derivative 2o were also subjected to similar conditions (runs
13 and 14); although these reactions were less efficient, the
corresponding furans 3n and 3o were obtained in good yields
(64 and 70%, respectively). Because the reaction of the parent
2p with no substituent on the tether was very sluggish, the
catalyst loading was increased to 20 mol %, which furnished 3p
in a moderate 51% yield. Furthermore, the desired tricyclic
furan 3q was obtained in a high yield (85%) because of the
favorable conformational rigidity of the phenylene tether. These
results imply that conformational restraint by the tether
substituents is significant for the cyclization of 1,7-diynes. In
contrast, 1,8-diynes failed to undergo transfer oxygenative
cyclization under the optimal conditions.
In regard to the mechanism of furan formation, the previous
catalytic methods involve ketonic intermediates such as β,γ-
unsaturated ketones and unsaturated 1,4-diketones that under-
go subsequent cyclization under the influence of Cu(II) or Zn
salts, respectively. In contrast, in our Ru-catalyzed reaction,
furan ring formation is presumed to occur via ruthenacycle
intermediates without extra metal catalysts or Brønsted/Lewis
acids. To gain insight into this mechanism, we reacted isolated
ruthenacyclopentatriene 7 with DMSO (2.0 equiv) in the
presence of AgPF6 (1.1 equiv) in THF at 25 °C for 0.5 h and
obtained bicyclic furan 3a in 65% NMR yield (Scheme 5).
However, in the absence of the Ag salt, 3a was scarcely formed
within 1 h under the same conditions.
Next, 1,6-diynes with terminal alkyl groups were examined as
substrates (Scheme 3). Malonate-derived diyne 2r was
Scheme 5. Reaction of Ruthenacycle 7 with DMSO
Scheme 3. Synthesis of Furans from Diynes with Alkyl
Terminal Groups
These results imply that the reaction proceeds via cationic
ruthenacycle intermediates (Figure 1a). A possible catalytic
cycle starts with oxidative cyclization of diyne complex 8 to give
bicyclic biscarbene 9 with an O-bound DMSO, which then
undergoes rate-determining transfer oxygenation to produce
keto carbene intermediate 10. A related transfer oxygenation of
a Fischer-type carbene complex with DMSO was reported by
Casey and co-workers.11 Subsequent cyclization of 10 involving
the ketone carbonyl group and the remaining carbene carbon
generates bicyclic furan complex 11. Similar cyclizations of
oxadienyl carbene complexes yielding furans have been
proposed for different types of furan ring formations.12
The proposed mechanism was supported by preliminary
density functional theory (DFT) calculations on a model
system (Figure 1b and Figures S2 and S3 in the SI). The
reaction starts with a delocalized ruthenacyclopentatriene
complex with an O-bound DMSO (A). O-atom transfer from
subjected to the above optimal reaction conditions, but the
desired furan was obtained in a poor yield, probably because of
the poor electron-donating ability of the [CpRu]+ fragment
toward the diyne bearing electron-donating methyl terminal
groups. After reoptimization of the reaction conditions, we
eventually found that the reaction with a 3 mol % loading of the
more electron-rich complex 1b in THF at 70 °C for 1 h
afforded 3r in 90% yield. This improvement is presumably due
to the enhancement of oxidative cyclization of diyne 2r with the
electron-rich catalyst 1b. Similarly, tosylamide analogue 2s
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Communication
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, compound characterization data, a CIF
file, and NMR spectra of the products. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
yamamoto-yoshi@ps.nagoya-u.ac.jp
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was partially supported by the MEXT, Grant-in-
Aid for Scientific Research (B) (20350045), a JSPS Research
Fellowship for Young Scientists (K.Y., 10438), and the Global
COE Program (Nagoya University).
REFERENCES
■
(1) (a) Shapiro, N. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129,
4160. (b) Li, G.; Zhang, L. Angew. Chem., Int. Ed. 2007, 46, 5156.
(2) For an excellent review, see: Xiao, J.; Li, X. Angew. Chem., Int. Ed.
2011, 50, 7226. For selected recent examples, see: (a) Davies, P. W.;
Cremonesi, A.; Martin, N. Chem. Commun. 2011, 47, 379. (b) Yeom,
H.-S.; So, E.; Shin, S. Chem.Eur. J. 2011, 17, 1764. (c) Jeong, J.;
Yeom, H.-S.; Kwon, O.; Shin, S. Chem.Asian J. 2011, 6, 1977.
(d) Ye, L.; He, W.; Zhang, L. Angew. Chem., Int. Ed. 2011, 50, 3236.
(e) He, W.; Li, C.; Zhang, L. J. Am. Chem. Soc. 2011, 133, 8482.
(f) Vasu, D.; Hung, H.-H.; Bhunia, S.; Gawade, S. A.; Das, A.; Liu, R.-
S. Angew. Chem., Int. Ed. 2011, 50, 6911. (g) Patel, P.; Ramana, C. V.
Org. Biomol. Chem. 2011, 9, 7327. (h) Song, G.; Chen, D.; Su, Y.; Han,
K.; Pan, C.-L.; Jia, A.; Li, X. Angew. Chem., Int. Ed. 2011, 50, 7791.
(i) Chen, D.; Song, G.; Jia, A.; Li, X. J. Org. Chem. 2011, 76, 8488.
(3) (a) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2002, 124, 2528.
For cycloisomerization of alkynols, see: (b) McDonald, F. E. Chem.
Figure 1. (a) Proposed mechanism. (b) Calculated energy surface with
relative Gibbs free energies ΔG (kcal/mol) at 298 K.
Eur. J. 1999, 5, 3103. (b) Weyershausen, B.; Dotz, K. H. Eur. J. Inorg.
̈
Chem. 1999, 1057.
DMSO to the carbene carbon of the ruthenacycle to give
oxaruthenacyclohexatriene complex B with a DMS ligand
occurs in a concerted manner (transition state TS-AB) with an
activation barrier of ΔG⧧ = 18.3 kcal/mol, which is larger than
that of the oxidative cyclization step (ΔG⧧ = 14.1 kcal/mol;
Figure S3). After this rate-determining step, which is expected
to be highly exergonic (ΔG = −51.3 kcal/mol), extrusion of the
DMS ligand produces C, which is 12.4 kcal/mol higher in
energy. Subsequent isomerization of C generates γ-keto
carbene complex D via transition state TS-CD with a small
barrier of ΔG⧧ = 3.0 kcal/mol. The final furan ring closure from
D is expected to proceed via TS-DE with a similarly small
activation barrier of ΔG⧧ = 4.5 kcal/mol. The formation of η5-
furan complex E (with Ru−O, Ru−Cα, and Ru−Cβ distances
of 2.39, 2.35, and 2.32 Å, respectively) from A is highly
exergonic (ΔG = −57.9 kcal/mol).
In summary, we have successfully developed a novel transfer
oxygenative cyclization of diynes with DMSO catalyzed by
cationic Ru complexes. For diynes with terminal aryl groups,
[CpRu(AN)3]PF6 was the optimal catalyst, while those with
terminal alkyl groups were effectively catalyzed by the
corresponding Cp* complex. A mechanism for the formation
of bicyclic furans was proposed on the basis of the results
obtained by carrying out the stoichiometric reaction of a
ruthenacyclopentatriene complex with DMSO and by perform-
ing DFT calculations of model ruthenacycles. This novel
method is highly useful for the synthesis of bicyclic furans and
is complementary to previous monocyclic furan formations.
(4) (a) Yamamoto, Y.; Yamashita, K.; Nishiyama, H. Chem. Commun.
2011, 47, 1556. (b) Yamashita, K.; Nagashima, Y.; Yamamoto, Y.;
Nishiyama, H. Chem. Commun. 2011, 47, 11552.
(5) Zhang, M.; Jiang, H.-F.; Neumann, H.; Beller, M.; Dixneuf, P. H.
Angew. Chem., Int. Ed. 2009, 48, 1681.
(6) (a) Wang, A.; Jiang, H.; Xu, Q. Synlett 2009, 929. (b) Wen, Y.;
Zhu, S.; Jiang, H.; Wang, A.; Chen, Z. Synlett 2011, 1023.
(7) Muller, E. Synthesis 1974, 761.
̈
(8) For reviews of catalytic reactions using [Cp′RuLn] complexes,
see: (a) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. Rev. 2001,
́
101, 2067. (b) Derien, S.; Dixneuf, P. H. J. Organomet. Chem. 2004,
689, 1382. (c) Schmid, R.; Kirchner, K. Eur. J. Inorg. Chem. 2004,
2609. (d) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew. Chem.,
Int. Ed. 2005, 44, 6630. (e) Varela, J. A.; Saa,
2009, 694, 143.
́
C. J. Organomet. Chem.
(9) The enhancement of a relevant reaction by addition of a protic
acid has been evidenced. See: (a) Zhang, M.; Jiang, H.; Dixneuf, P. H.
Adv. Synth. Catal. 2009, 351, 1488. Protonated ruthenacycles have
been analyzed by DFT calculations. See: (b) Le Paih, J.; Monnier, F.;
Derien, S.; Dixneuf, P. H.; Clot, E.; Eisenstein, O. J. Am. Chem. Soc.
́
2003, 125, 11964.
(10) Zhang, L.-Z.; Chen, C.-W.; Lee, C.-F.; Wu, C.-C.; Luh, T.-Y.
Chem. Commun. 2002, 2336.
(11) Casey, C. P.; Burkhardt, T. J.; Bunnell, C. A.; Calabrese, J. C. J.
Am. Chem. Soc. 1977, 99, 2127.
(12) Similar cyclizations of oxadienyl carbene complexes to give
furans were proposed: (a) Herndon, J. W.; Wang, H. J. Org. Chem.
1998, 63, 4564. (b) Chen, J.; Ma, S. Chem.Asian J. 2010, 5, 2415.
7663
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