Ruthenium-Catalyzed Transfer Oxygenative [2 + 2 + 1] Cycloaddition of Silyldiynes Using Nitrones as Adjustable Oxygen Atom Donors. Synthesis of Bicyclic 2-Silylfurans

Article abstract of DOI:10.1021/acscatal.5b01855

The first example of the Ru-catalyzed transfer oxygenative [2 + 2 + 1] cycloaddition of silyldiynes to produce bicyclic 2-silylfurans is described. This cyclization process was realized using nitrones as readily available and adjustable oxygen atom donors

Full text of DOI:10.1021/acscatal.5b01855

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Letter
pubs.acs.org/acscatalysis
Ruthenium-Catalyzed Transfer Oxygenative [2 + 2 + 1] Cycloaddition
of Silyldiynes Using Nitrones as Adjustable Oxygen Atom Donors.
Synthesis of Bicyclic 2‑Silylfurans
Kazuma Matsui, Masatoshi Shibuya, and Yoshihiko Yamamoto*
Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Chikusa, Nagoya 464-8601,
Japan
S
* Supporting Information
ABSTRACT: The first example of the Ru-catalyzed transfer
oxygenative [2 + 2 + 1] cycloaddition of silyldiynes to produce
bicyclic 2-silylfurans is described. This cyclization process was
realized using nitrones as readily available and adjustable oxygen
atom donors. The bicyclic silylfuran products could be used as
platforms for a diverse range of functionalized furans.
KEYWORDS: cycloaddition, ruthenium, alkyne, furan, silane, nitrone
2-Silylfurans are useful building blocks in synthetic chemistry
because silyl groups are highly versatile synthetic handles owing
to their low toxicity and high abundance of silicon. Accordingly,
2-silylfurans have been transformed into various furan
derivatives via oxidation to furanones,1 homo and cross-
coupling reactions,2 halodesilylation,3 Friedel−Crafts type
reactions,4 and so on.5 Moreover, 2-silylfuran motifs are
commonly found in biologically active compounds and used
in functional materials (Figure 1).6,7
established. The de novo synthesis of 2-silylfurans is highly
important as complex 2-silylfuran frameworks can be assembled
in an atom- and step-economical manner via the transition-
metal-catalyzed cyclization of readily accessible acyclic
precursors.9 Therefore, we developed a novel synthetic
approach to bicyclic 2-silylfurans via the ruthenium-catalyzed
transfer oxygenative [2 + 2 + 1] cycloaddition of silyldiynes.
We previously reported the transfer oxygenative [2 + 2 + 1]
cycloaddition of α,ω-diynes to afford bicyclic furans.10,11 In this
study, dimethyl sulfoxide (DMSO) and cationic ruthenium
complexes, [Cp′Ru(MeCN)3]PF6 (1a: Cp′ = η5-C5H5, 1b: Cp′
= η5-C5Me5), were used as the oxygen atom donor and
catalysts, respectively (Figure 2). Although this process
provided a straightforward route to bicyclic furans under
neutral conditions, high reaction temperatures were required,
and the terminal groups of the α,ω-diyne substrates were
confined to aryl or alkyl groups. Therefore, we sought a more
flexible approach to diverse bicyclic furan products under
Figure 1. 2-Silylfuran motifs in functional molecules.
One of the simplest routes to 2-silylfurans is the silylation of
furans via 2-furyllithium intermediates. However, this method
has a limited functional group compatibility as strong bases are
required for the lithiation of furans. Recently, several
breakthrough studies have reported the direct C−H silylation
of aromatic compounds using hydrosilanes.8 Although direct
silylation methods avoid the use of a strong base, their
application has been confined to relatively simple furan
substrates, and thus, the scope has not yet been fully
Figure 2. Ruthenium catalysts and oxygen atom donors used in this
study.
Received: August 21, 2015
Revised: September 23, 2015
© XXXX American Chemical Society
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Letter
milder conditions. To this end, we selected nitrones as the
oxygen atom donors because nitrones with optimal oxygen
donor abilities could be readily prepared. Although the
transition-metal-catalyzed cycloaddition of nitrones has been
extensively studied,12 the transition-metal-catalyzed reactions of
α,ω-diynes with nitrones have rarely been investigated.13 To
the best of our knowledge, [2 + 2 + 1] cycloaddition using
nitrone oxygen atom donors to produce furans has not been
reported to date.
demanding silyl terminal groups hamper the approach of the
nitrone to the ruthenacycle in transition state B.
To establish a viable protocol for bissilylfuran formation,
reaction parameters were optimized using various nitrones
(Table 1 and Figure 2). In the presence of 3 mol % 1a, diyne 5a
Table 1. Reaction Optimization for Disilyldiyne 5a
We began our proof-of-concept study on transfer oxygenative
[2 + 2 + 1] cycloaddition with nitrones by revisiting the
reaction of ether-tethered 1,6-diyne 2 bearing terminal phenyl
groups (Scheme 1). Under previously optimized conditions
a
entry
1, mol %
4
conditions
6a yield/%
1
2
3
4
5
6
7
1a, 3
1a, 3
1a, 3
1a, 3
1a, 3
1a, 5
1a, 5
1a, 5
1b, 5
4a
4b
4b
4c
4d
4d
4e
4d
4d
DMF, 100 °C, 10 h
DMF, 100 °C, 10 h
DCE, reflux, 10 h
DCE, reflux, 10 h
DCE, reflux, 10 h
DCE, reflux, 10 h
DCE, reflux, 10 h
DCE, reflux, 8 h
DCE, reflux, 17 h
6
33
Scheme 1. Transfer Oxygenative [2 + 2 + 1] Cycloaddition
of Diynes 2 and 5a with DMSO or Nitrone 4a as Oxygen
Atom Donors
54
51
68 (64)
71 (69)
17
b
8
81 (75)
0
9
a
Yields were determined by 1H NMR using an internal standard.
b
Yields of isolated products are shown in parentheses. 1.1 equiv of 4d
was used.
and nitrone 4a (1.7 equiv) were heated in DMF at 100 °C for
using DMSO (5 equiv),10 diyne 2 was heated with 3 mol % 1a
in DMF at 140 °C for 4 h to afford the known furan 3 in 90%
yield. The reaction was then conducted using nitrone 4a (1.1
equiv) instead of DMSO, with the same catalyst loading of 1a.
Surprisingly, the reaction completed within 10 min at a lower
temperature (60 °C) to afford 3 in 94% yield. These results
demonstrate the exceptionally high oxygen donor ability of 4a.
We next focused on the use of bis(trimethylsilyl)diynes as
they would yield highly valuable bicyclic bissilylfurans.
However, such silyldiynes have proved to be challenging
substrates for transition-metal-catalyzed cycloaddition, and as
such, catalytic cycloaddition of bissilyldiynes is underdeveloped
compared to transformations using stoichiometric transition-
metal templates.14,15 In fact, several catalytic cycloadditions
using bis(trimethylsilyl)diynes totally failed in the recent
studies.16 Our original protocol using DMSO as the oxygen
atom donor and bis(trimethylsilyl)diyne 5a as the substrate also
did not yield the desired product after 3 h (Scheme 1). In a
plausible mechanism outlined in Scheme 2, the α-anion
stabilizing effect of the silyl groups dramatically reduces the
reactivity of key ruthenacycle intermediate A by decreasing
nucleophilicity of the α carbons. In addition, the sterically
10 h (entry 1). As a result, small amounts of the desired
1
product 6a was detected by H NMR analysis of the crude
reaction mixture, although 50% of 5a remained unreacted. The
use of nitrone 4b with an N-methyl substituent under the same
conditions improved the conversion of 5a, and the yield of 6a
increased to 33% (entry 2). The use of 1,2-dichloroethane
(DCE) as the solvent led to a further increase in conversion
(entry 3). Next, the electronic influence of the imine aryl group
on the reaction efficacy was investigated using nitrones 4c and
4d, containing an electron-withdrawing p-fluorophenyl sub-
stituent or an electron-donating p-methoxyphenyl substituent,
respectively. Although 4c showed a negligible effect on the yield
of 6a (entry 4), the use of 4d improved the yield (68%), but
11% of 5a remained unreacted (entry 5). Increasing the catalyst
loading of 1a (5 mol %) gave a slightly higher yield (entry 6).
In contrast, the product yield was considerably lowered using
nitrone 4e bearing a more electron-donating p-dimethylami-
nophenyl group. Finally, 5a was completely consumed when
the amount of 4d was reduced to 1.1 equiv (entry 8). As a
result, a maximum product yield of 81% was obtained, and 6a
was ultimately isolated in 75% yield by silica gel chromatog-
raphy. The use of complex 1b as the catalyst resulted in no
reaction after 17 h (entry 9). Thus, the conditions shown in
entry 8 are optimal.
Scheme 2. Plausible Catalytic Cycle of Transfer Oxygenative
[2 + 2 + 1] Cycloaddition
Thus, various bis(trimethylsilyl)diynes were subjected to the
optimal reaction conditions to demonstrate the general
applicability of this process (Table 2). Diynes with oxa or aza
tethers 5a−c facilely underwent [2 + 2 + 1] cycloaddition to
afford bicyclic bissilylfurans 6a−6c in high yields. The reaction
of amide-tethered diyne 5d completed within 2.5 h, affording
6d in a comparably high yield. In contrast, longer reaction times
and/or increased catalyst loadings were required for
bissilyldiynes containing all-carbon tethers. The formation of
malonate derivative 6e and 1,3-diketone derivative 6f required
prolonged reaction times of 24 and 20 h, respectively, although
the yields were excellent. Moreover, the yields of barbituric acid
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a
a
Table 2. Scope of Bissilyldiyne Substrates
Table 3. Scope of Monosilyldiyne Substrates
a
Standard conditions: 1a as the catalyst and nitrone 4d (1.1 equiv) in
b
DCE under reflux. Yields of isolated products were indicated.
A
solution of 4d (1.1 equiv) in DCE (1 mL) was added dropwise over 3
h.
derivative 6g and acetal 6h were poor, despite increasing the
catalyst loading to 8−10 mol %. In these cases, the ruthenium
catalyst was deactivated by the nitrone during very sluggish
reactions.17 Therefore, a solution of nitrone 4d in DCE was
added to the reaction mixture over a period of 3 h via a syringe
pump, to prevent catalyst deactivation. As a result, 6g and 6h
were successfully obtained in 68% and 71% yields, respectively.
On the other hand, fluorene derivative 6i was obtained in 86%
yield without recourse to the slow addition technique. The
present method was found to be ineffective for intermolecular
reaction of phenyl(trimethylsilyl)acetylene. In addition to the
trimethylsilyl group, other silyl groups were examined as the
terminal groups on the diyne substrates. However, replacement
of the trimethylsilyl groups of 5a with bulkier triethylsilyl
groups (5j) dramatically decreased the yield of the correspond-
ing product 6j (39%).
Next, monosilyldiynes containing an ether tether were
investigated as substrates (Table 3). Diynes 7a and 7b,
possessing p-methoxyphenyl or p-fluorophenyl terminal groups,
underwent smooth reaction in the presence of 5 mol % 1a and
nitrone 4d (1.1 equiv) to afford 8a and 8b in 70% and 67%
yields, respectively. Notably, the reaction was faster with the
electron-donating terminal group. In contrast, the reaction was
sluggish for diyne 7c, which contained a bulky 1-naphthyl
group, and the expected product 8c was obtained in a moderate
yield via the slow addition technique with an increased catalyst
loading. Smaller thienyl groups gave favorable effects; diynes 7d
and 7e containing 2-thienyl or 3-thienyl terminal groups
afforded 8d and 8e in 75% and 78% yields, respectively, with
shorter reaction times. Diyne 7f, which contained a bulkier 2-
benzofuryl terminal group, required a prolonged reaction time
(20 h), affording 8f in 70% yield. On the other hand, the
reaction of diyne 7g, which possessed a ferrocenyl terminal
group, was completed within 40 min to afford 8g in an excellent
a
Standard conditions: 1a as the catalyst and nitrone 4d (1.1 equiv) in
b
DCE under reflux. Yields of isolated products were indicated.
solution of 4d (1.1 equiv) in DCE (1 mL) was added dropwise over 3
h. 7c was recovered (35%).
A
c
yield, although the ferrocenyl group is assumed to sterically
hinder the ruthenacycle intermediate.
In addition to aryl-substituted diynes, n-butyl- and t-butyl-
substituted diynes 7h and 7i were also converted into 8h and 8i
in 43% and 80% yields, respectively. The impact of the tether
moiety was also briefly investigated for malonate derivative 8j
and tosylamide derivative 8k, containing a phenyl terminal
group, and were obtained in 85% and 70% yields, respectively,
after reaction for 24 h with increased catalyst loadings of 8−10
mol %. Moreover, 4H-furo[3,4-c]chromene derivative 8l was
successfully synthesized in a good yield via six-membered-ring
formation of 1,7-diyne 7l.
In striking contrast to bissilyldiyne 5j, monosilyldiyne 7m,
which contains triethylsilyl and p-methoxyphenyl terminal
groups, was successfully converted into the corresponding
furan 8m in 83% yield. More sterically demanding diynes 7n
and 7o, bearing dimethylphenylsilyl or tert-butyldimethylsilyl
groups, also afforded 8n and 8o in high yields, albeit with
longer reaction times. In the same manner, bicyclic furans 8p
and 8q, bearing much more bulkier triisopropylsilyl and
triphenylsilyl groups, were also obtained in high yields. These
results corroborate the notion that oxygen atom transfer must
occur on the carbene carbon opposite to the one bearing the
silyl group.
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Notes
We further investigated the transformation of bicyclic
The authors declare no competing financial interest.
bissilylfuran 6b and monosilylfuran 8a (Scheme 3). Upon
ACKNOWLEDGMENTS
Scheme 3. Transformations of 2-Silylfuran Products 6b and
8a
■
a
This research is partially supported by the Platform Project for
Supporting in Drug Discovery and Life Science Research
(Platform for Drug Discovery, Informatics, and Structural Life
Science) from the Ministry of Education, Culture, Sports,
Science (MEXT) and Japan Agency for Medical Research and
development (AMED).
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.5b01855.
Experimental details, characterization data for all new
compounds, and NMR charts (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: yamamoto-yoshi@ps.nagoya-u.ac.jp.
■
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