Ruthenium-catalyzed transfer-hydrogenative cyclization of 1,6-diynes with hantzsch 1,4-dihydropyridine as a H2 surrogate

Article abstract of DOI:10.1002/chem.201301846

The transfer-hydrogenative cyclization of 1,6-diynes with Hantzsch 1,4-dihydropyridine as a H₂ surrogate was performed in the presence of a cationic ruthenium catalyst of the type [CpRu(MeCN)₃PF ₆]. Exocyclic 1,3-dienes or their 1,4-hydrogenation products, cycloalkenes, were selectively obtained, depending on the substrate structure and the reaction conditions. Copyright

Full text of DOI:10.1002/chem.201301846

DOI: 10.1002/chem.201301846
Ruthenium-Catalyzed Transfer-Hydrogenative Cyclization of 1,6-Diynes with
Hantzsch 1,4-Dihydropyridine as a H2 Surrogate
Yoshihiko Yamamoto,* Shota Mori, and Masatoshi Shibuya[a]
Abstract: The transfer-hydrogenative cyclization of 1,6-diynes with Hantzsch 1,4-
dihydropyridine as a H2 surrogate was performed in the presence of a cationic
ruthenium catalyst of the type [Cp’Ru(MeCN)3PF6]. Exocyclic 1,3-dienes or their
1,4-hydrogenation products, cycloalkenes, were selectively obtained, depending on
the substrate structure and the reaction conditions.
Keywords: alkenes · alkynes · cycli-
zation · ruthenium · transfer hydro-
genation
AHCTUNGTRENNUNG
Introduction
by directly using H2 or by carrying out a hydrogen transfer
from formic acid.[5] In addition, trans-selective semihydroge-
nation reactions have also been performed, although they
remain uncommon.[6] Along these lines, ruthenium-catalyzed
semihydrogenation systems have been developed; for exam-
ple, transfer hydrogenations,[8a,c,e,f] hydrogenation reactions
under biphasic conditions,[8d] and highly trans-selective semi-
hydrogenations.[8b,g,h]
The controlled hydrogenation of alkynes is a highly impor-
tant process for the industrial, large-scale production of light
olefins, as well as for the laboratory-scale implementation of
elaborate syntheses of fine chemicals.[1] In particular, the
stereoselective semihydrogenation of internal alkynes is a
powerful approach for synthesizing thermodynamically un-
favorable cis-alkenes (Scheme 1). Although heterogeneous
The hydrogenation of alkynes that possess a pendant un-
saturated component provides a viable approach for carbo-
cyclization reactions, in which a hydrometalation intermedi-
ate, vinyl-metal species I,[9] can be effectively intercepted by
the pendant group (II!III, Scheme 1). Indeed, Trost and
co-workers extended their Pd-catalyzed alkyne semhydroge-
nation reaction[4a] to accomplish the first hydrogenative cyc-
lizations of 1,6-enynes and diynes by using acetic acid and
hydrosilanes as proton and hydride sources, respectively.[10a,b]
Later, the Pd-catalyzed hydrogenative cyclization of enynes
was also achieved by using formic acid as a single H2 surro-
gate.[10c] Since these pioneering achievements, the direct use
of inexpensive H2 gas for hydrogenative carbocyclization re-
actions of diynes and enynes has been studied. For example,
Krische and co-workers developed the cationic Rh-catalyzed
hydrogenative cyclization of 1,6-diynes and the asymmetric
cyclization of enynes.[11] Chung and co-workers also devel-
oped a Pt-catalyzed hydrogenative cyclization of diynes, al-
though cycloalkenes rather than exocyclic 1,3-dienes were
exclusively obtained.[12] Furthermore, Sylvester and Chirik
found that an iron pincer complex catalyzed the hydrogena-
tive cyclization of diynes and enynes.[13] In striking contrast,
the related transfer-hydrogenative carbocyclization reaction
by using alcohols as H2 surrogates remained elusive until
Chung and co-workers and ourselves independently report-
ed the rhodium- and ruthenium-catalyzed transfer-hydroge-
native cyclization of a,w-enynes and diynes, respective-
ly.[14–16] In addition to the practical advantage of utilizing an
inexpensive and safe H2 source, our reaction has a fascinat-
ing mechanism, which proceeds through a ruthenacyclo-
pentatriene intermediate (Scheme 2), rather than through a
common hydrometalation pathway (Scheme 1). To extend
Scheme 1. Semihydrogenation of internal alkynes.
palladium catalysts, such as the Lindlar catalysts, have con-
ventionally been employed for this purpose, their poor
chemo- and stereoselectivity, as well as their propensity for
over-hydrogenation to afford alkanes, are unresolved prob-
lems.[1,2] To address these issues, well-defined homogenous
catalysts are required.[3] Nevertheless, complete stereoselec-
tivity, together with a wide substrate scope, including func-
tional-group compatibility, has remained very difficult to
achieve.[4–8] Among the homogeneous catalytic reactions, the
most-extensively investigated are the palladium-catalyzed
methods.[4,5] For example, Elsevier’s group has successfully
performed highly cis-selective semihydrogenation reactions
[a] Prof. Dr. Y. Yamamoto, S. Mori, Dr. M. Shibuya
Department of Basic Medicinal Sciences
Graduate School of Pharmaceutical Sciences
Nagoya University, Chikusa, Nagoya 464-8601 (Japan)
Fax : (+81) 52 747 6800
E-mail: yamamoto-yoshi@ps.nagoya-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301846.
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FULL PAPER
Table 1. Transfer-hydrogenative cyclization reactions of diynes 3 by using
Hantzsch ester 2.
Scheme 2. Ruthenium-catalyzed transfer-hydrogenative cyclization of 1,6-
diynes with MeOH as a H2 surrogate.
Run
3
X
1 (mol%) Solvent
t
4 [%][a]
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3b
3c
3d
3d
3d
O
O
O
O
O
1a (3)
1a (2)
1a (5)
1a (5)
1a (5)
1a (3)
1a (8)
DMF
DMF
THF
CHCl3
MeCN
DMF
DMF
DMF
DMF
THF
20 min
8 h
12 h
12 h
12 h
10 min
1.5 h
8 h
0.5 h
1.5 h
81
our study, we have further investigated the transfer-hydroge-
native cyclization of 1,6-diynes by using an alternative H2
surrogate, that is, the Hantzsch 1,4-dihydropyridine.
78 (trace)[b]
trace (76)[b]
27 (42)
0 (89)[b]
88
NTs
S
79
Results and Discussion
C
C
C
N
48[c] (14)
67[c]
In our study on new reactivities of ruthenacyclopentatriene
intermediates,[17] we found that the ruthenium-catalyzed
transfer-hydrogenative cyclization of 1,6-diynes could pro-
ceed with MeOH as a H2 surrogate at reflux in THF.[15] Al-
though this procedure effectively converted 1,6-diynes with
terminal aryl groups into exocyclic 1,3-dienes in good yields,
substrates with terminal alkyl groups failed to cleanly pro-
duce their corresponding products because of a dimerization
side reaction that proceeded through [2+2+2] cycloaddition
between two diyne molecules. Thus, we presumed that such
a side reaction could be suppressed by using a cationic com-
10
91
11
12
13
14
3e
3 f
3g
3h
1b (15)
THF
THF
THF
DMF
12 h
0.5 h
4 h
82 (13)
97
CACHTUNGTRENNUNG
93
C(CN)2
1a (4)
10 min
88
[a] Yield of the isolated product; the yield of recovered compound 3 is in
parentheses. [b] Yield determined by 1H NMR analysis of the crude prod-
ucts. [c] Yield of compound 4d was determined by 1H NMR analysis of
the isolated products that contained compound 5d (about 15%). Ts=
tosyl.
plex, [CpRu
ACHTUNGTRENNUNG
catalyst instead of [Cp*RuClAHCNUTGTRENNUNG
clopentadienyl, cod=1,5-cyclooctadiene), which was used in
the previous study (Figure 1).[15] In addition, cationic ruthe-
At the outset, the reaction conditions were optimized for
the transfer-hydrogenative cyclization of diyne 3a (X=O),
which contained terminal phenyl groups, by using complex
1a as a catalyst (Table 1). According to a previous study on
the transfer-oxygenative cyclization of diynes,[17b] 3a was
heated with Hantzsch ester 2 (2 equiv) in the presence of
3 mol% catalyst 1a in DMF at 708C. After 20 min, 3a was
Figure 1. Ruthenium complexes and Hantzsch ester 2.
1
completely consumed and H NMR analysis of the crude re-
nacyclopentatriene intermediates are expected to efficiently
abstract hydride from MeOH because of their high electro-
philicity. However, Trost and Rudd demonstrated that, with
a cationic ruthenium catalyst, a 1,6-diyne with terminal
methyl groups underwent methoxylative cyclization in the
presence of MeOH.[18] Therefore, we sought an alternative
H2 surrogate that was inactive toward addition to diynes. To
achieve this goal, a biomimetic H2 donor, that is, Hantzsch
1,4-dihydropyridine (2),[19] was found to be appropriate. Re-
cently, Hantzsch esters have gathered renewed interest as an
effective H2 donor for asymmetric transfer hydrogenations
by using organocatalysts.[20] Moreover, they have been em-
ployed in Pd/C-catalyzed heterogeneous hydrogenation re-
actions of alkenes, alkynes, nitro aromatic compounds,
etc.,[21] as well as the gold-catalyzed reductive amination of
aromatic aldehydes and the amination of alkynes.[22] Howev-
er, to the best of our knowledge, Hantzsch esters have not
been reported to be involved in transition-metal-catalyzed
carbocyclization reactions.
action mixture showed that the desired exocyclic 1,3-diene
4a had selectively been formed. Purification by column
chromatography on silica gel exclusively afforded 4a in
81% yield (Table 1, run 1). The use of smaller amounts of 2
(1.5 equiv) resulted in an incomplete reaction; thus, two
equivalents of 2 were necessary. A lower loading of catalyst
1a (2 mol%) led to a longer reaction time (8 h) and diene
4a was formed in 78% yield (by NMR spectroscopy), to-
gether with trace amounts of intact diyne 3a (Table 1,
run 2). THF, CHCl3, and MeCN as the solvent were found
to lead to much-lower conversions, even with higher catalyst
loadings (Table 1, runs 3–5). Therefore, amide 3b and sul-
fide 3c were subjected to the optimal conditions by using
DMF as the solvent. As a result, diene 4b was readily ob-
tained in 88% yield (Table 1, run 6), although an increased
catalyst loading of 8 mol% and a prolonged reaction time of
1.5 h were required for the formation of diene 4c in 79%
yield (Table 1, run 7).
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Y. Yamamoto et al.
In contrast to these diynes, which contained heteroatoms
in their tethers, malonate derivative 3d was found to be a
problematic substrate. The reaction of 3d did not proceed
to completion under similar conditions by using 5 mol% cat-
alyst 1a after 8 h (Table 1, run 8). In addition, exocyclic 1,3-
diene 4d was inseparable from the minor product. This side
product was presumed to be cyclopentene 5d, which was
formed by the 1,4-hydrogenation of 4d. At a higher catalyst
loading (8 mol%), diyne 3d was completely consumed
within 0.5 h to afford an inseparable mixture of products 4d
and 5d in 67% and 15% yields, respectively (Table 1,
run 9). The tendency of 3d to produce a notable amount of
cyclopentene 5d is presumably attributed to a resting state
6, which is stabilized by the coordination of one of the
two carbonyl groups and undergoes hydrogenation with
Hantzsch ester 2 (Scheme 3).[23] Accordingly, we employed
Figure 2. Impact of aryl terminal groups on the reaction efficiency.
and 4l were obtained in high yields. These results imply that
electron-donating terminal groups lower the electrophilicity
of the corresponding ruthenacycle intermediates, thereby re-
sulting in slower hydride abstraction from Hantzsch ester 2.
Diyne 3m, which was substituted with 2-thienyl groups, was
also successfully converted into the corresponding exocyclic
1,3-diene 4m in 89% yield.
The transfer-hydrogenative cyclization reaction of diynes
with terminal alkyl groups was then investigated
(Scheme 4). First, the optimal conditions, that is, catalyst 1a
(5 mol%) and 2 (2 equiv) in DMF at 708C, were applied to
Scheme 3. Proposed 1,4-hydrogenation pathway to compound 5d from
compound 6.
complex 1b to improve the selectivity for diene 4d, because
the bulkier and more-electron-donating Cp* ligand was ex-
pected to promote the dissociation of 4d from the rutheni-
um center and thereby suppress its over-hydrogenation. In
fact, the same reaction was carried out by using 10 mol%
catalyst 1b and two equivalents of 2 in THF at 708C for
1.5 h to exclusively furnish 4d in 91% yield (Table 1,
run 10). Similarly, diene 4e was solely obtained in 82%
yield from Meldrum’s acid derivative 3e, although 15 mol%
loading of catalyst 1b and a prolonged reaction time of 12 h
were required because of the sluggish reaction (Table 1,
run 11). By using 1b as a catalyst, 1,3-diketone analogues 3 f
and 3g were also converted into dienes 4 f and 4g in 97%
and 93% yields, respectively, although a longer reaction
time was required for the latter reactions (Table 1, runs 12
and 13). In contrast, the formation of a similar resting state
to 6 is unlikely for malononitrile analogue 3h, because of
the inability of the linear cyano groups to coordinate to the
ruthenium center. Therefore, 4 mol% catalyst 1a selectively
catalyzed the transfer-hydrogenative cyclization of diyne 3h
to exclusively afford diene 4h in 88% yield (Table 1,
run 14).
Then, we examined the impact of terminal aryl groups on
the efficiency of the hydrogenative cyclization reaction
(Figure 2). Diynes 3i and 3j, which contained p-fluorophen-
yl and p-bromophenyl terminal groups, respectively, were
successfully converted into their corresponding exocyclic
1,3-dienes 4i and 4j in high yields (over 80%). In contrast,
diynes with more-electron-rich aryl terminal groups 3k and
3l required prolonged reaction times (20 h and 24 h, respec-
tively), although the corresponding exocyclic 1,3-dienes 4k
Scheme 4. Transfer-hydrogenative cyclization of diyne 7.
tosylamide derivative 7a; however, the expected reaction
did not occur and about 70% of 7a was recovered. Thus, we
used alternative conditions by using catalyst 1b, which were
effective for the transfer-oxygenative cyclization of diynes
with terminal alkyl groups.[17b] In the presence of 2 mol%
catalyst 1b and two equivalents of 2, diyne 7a was heated in
THF. To our surprise, 7a was consumed within 10 min and
3-pyrroline derivative 8a, which was possibly formed
through 1,4-hydrogenation of the expected exocyclic 1,3-
diene 9a, was exclusively obtained in 64% yield. Similarly,
the reaction of malonate derivative 7b was carried out at a
decreased catalyst loading of 0.5 mol% for 30 min to obtain
cyclopentene 8b in a higher yield (94%). In this case, turn-
over numbers and frequencies reached 188 and 376 hꢀ1, re-
spectively. However, further decrease in the catalyst loading
resulted in an incomplete reaction. To examine the solvent
effect, the reaction of diyne 7b was also carried out in
CHCl3 and MeCN under the same conditions. As a result,
the reaction rates were significantly lowered, thereby lead-
ing to incomplete conversions, even after 3 h (86% and
44%, respectively). Furthermore, the product yields were
low to moderate: 48% of 8b and 5% of exocyclic 1,3-diene
9b were obtained by using CHCl3 and MeCN, respectively.
The reaction of acetylacetone analogue 7c resulted in the
formation of an inseparable mixture of the expected product
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Ru-Catalyzed Transfer-Hydrogenative Cyclization of 1,6-Diynes
FULL PAPER
8c and its precursor 9c, even though 10 mol% catalyst 1b
was used. Analysis of the crude reaction mixture by
1H NMR spectroscopy revealed that Hantzsch ester 2 was
fully consumed. Therefore, the reaction was repeated at an
increased loading of 2. In the presence of 5 mol% catalyst
1b and three equivalents of 2, compound 7c was heated for
1 h to exclusively afford cyclopentene 8c in 98% yield. In
contrast to these substrates, the malononitrile derivative
(X=C(CN)2) gave a complex product mixture under similar
reaction conditions, presumably because of a [2+2+2] cyclo-
addition reaction between the diyne and malononitrile moi-
eties, thus leading to pyridine-containing oligomers.
As summarized in Scheme 5, the reactions of ether-teth-
ered diynes with terminal alkyl and alkenyl groups were car-
ried out to investigate the impact of these groups. n-Propyl-
substituted diyne 7d underwent smooth cyclization under
the conditions with catalyst 1b to produce 2,5-dihydrofuran
8d in 75% yield. On the other hand, the reaction of cyclo-
responded to four sp2 carbon atoms and five sp3 carbon
atoms were observed, thus showing its symmetrical struc-
ture. Based on these facts, we reasonably assigned this prod-
uct as 3,4-dialkenylfuran 10.
As shown in Figure 2 and Scheme 5, the terminal alkyne
substituents play a critical role in determining the reaction
efficiency. For instance, the presence of electron-donating
substituents on the terminal phenyl groups significantly
retard the reaction (Figure 2). Similarly, diyne 7e, which
contained terminal cyclopropyl substituents, was found to be
a much-less-efficient substrate compared with diyne 7d,
which contained n-propyl terminal substituents (Scheme 5).
This result is probably because the cyclopropyl group is
more electron-donating than the n-propyl group. An in-
creased loading of catalyst 1b was required for cyclohexenyl
derivative 7 f compared with that for 7d. These facts suggest
that the electrophilicity of the ruthenacycle intermediates,
which can be predicted from their LUMO levels, can be cor-
related with the reaction efficiency. Therefore, we calculated
the LUMO levels of the model ruthenacycle complexes by
using the density functional method (Figure 3). For calculat-
Scheme 5. Impact of alkyl and alkenyl terminal groups.
propyl analogue 7e was sluggish, even at an increased cata-
lyst loading of 15 mol%. After prolonged reaction time
(24 h), 39% of 7e was recovered and small amounts of the
corresponding exocyclic 1,3-diene and dihydrofuran were
observed in the crude reaction mixture. The diminished re-
activity of 7e can be attributed to the electron-donating
ability of the cyclopropyl groups, which lowers the electro-
philicity of the corresponding ruthenacyclopentatriene inter-
mediate. Thus, the reaction of diyne 7e was repeated by
using more-electron-deficient catalyst 1a (8 mol%) in DMF
at 708C for 1.5 h. This reaction resulted in the isolation of
dihydrofuran 8e in 69% yield. In contrast, the use of cata-
lyst 1a in DMF again failed to catalyze the transfer-hydroge-
native cyclization of n-propyl analogue 7d.
Figure 3. LUMO levels of model ruthenacycles A–H.
ing the efficiency, bicyclic complexes A–H with Cp and H2O
ligands were fully optimized to obtain MOs. As shown in
Figure S1 in the Supporting Information, the LUMOs, which
mainly comprise the p orbitals of the cyclic biscarbene li-
gands and the ruthenium dxz orbital, extend onto the Cp
ligand, as well as the terminal cyclopropyl (C), alkenyl (D),
or aryl substituents (E).
Among ruthenacycles with non-aromatic terminal groups,
C and D, which possess cyclopropyl or terminal cyclohexen-
yl substituents, have higher LUMO levels than those of A
and B, which have terminal methyl and isopropyl substitu-
ents. This result is in good agreement with the fact that
diynes 7e and 7 f are less-efficient substrates than diyne 7d
(Scheme 5). A similar trend was also revealed for diynes
with terminal aromatic groups. Models E, F, and H, which
possess phenyl, p-fluorophenyl, and 2-thiophenyl substitu-
We then examined the influence of terminal alkenyl
groups on this reaction. Thus, cyclohexenyl-substituted
diyne 7 f was used in transfer-hydrogenative cyclization reac-
tions with catalyst 1b (Scheme 5). However, the as-obtained
product was neither an exocyclic 1,3-diene nor a 2,5-dihy-
1
drofuran derivative. Careful inspection of its H NMR spec-
trum revealed the presence of furan and olefinic moieties as
aromatic and olefinic protons, whose peaks appeared as sin-
glets at d=7.29 and 5.77 ppm, respectively, along with ali-
phatic multiplets. In its 13C NMR spectrum, peaks that cor-
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Y. Yamamoto et al.
ents, respectively, have comparable LUMO levels at approx-
imately ꢀ0.23 eV; in fact, the corresponding diynes 3i, 3d,
and 3m exhibit similar reaction efficiencies (10 mol% 1b,
1–2 h). On the other hand, complex G, which contained the
electron-donating p-methoxyphenyl terminal group, has the
highest LUMO level and the corresponding diyne 3l re-
quired an exceptionally longer reaction time of 24 h under
the same conditions. Therefore, it is reasonable to consider
that electron-donating terminal groups diminish the electro-
philicity of biscarbenoid moieties, thereby leading to lower
hydride-abstracting ability.
Scheme 7. Catalytic transfer semihydrogenation of isolated exocyclic 1,3-
dienes 4d and 9b.
To shed light on the reaction mechanism, we conducted
several control experiments. First, we investigated the reac-
tivity of isolable ruthenacyclopentatriene 11[24] toward
Hantzsch ester 2. In the absence of any additive, no reaction
occurred, at least within one hour. However, in the presence
of AgPF6 (2 equiv), 11 reacted with 2 in THF at room tem-
perature for 30 min to afford exocyclic 1,3-diene 4a in 37%
yield (by NMR spectroscopy, Scheme 6). This result implies
cyclization conditions by using catalyst 1a (5 mol%) at
708C for 5 h. This result is in good agreement with the selec-
tive formation of exocyclic 1,3-dienes 4 from diynes 3 with
terminal phenyl groups (Table 1). In striking contrast, com-
pound 9b, which contained terminal methyl groups and was
independently prepared from diyne 7b according to a
method reported by Jang and Krische,[11a] was completely
consumed within 1 h under the conditions by using catalyst
1b (5 mol%) in THF at 708C. As a result, cyclopentene de-
rivative 8b was isolated in 81% yield. Therefore, we can
conclude that 1,4-hydrogenation only occurs with exocyclic
1,3-dienes that contain terminal alkyl substituents.[23] Thus,
these results clearly explain why exocyclic 1,3-dienes or
their 1,4-hydrogenation products are selectively produced,
depending on the terminal substituents on the diyne in the
ruthenium-catalyzed transfer-hydrogenative cyclization reac-
tion.
On the basis of the control experiments, a possible cata-
lytic cycle is proposed in Scheme 8. Cationic diyne complex
IV undergoes oxidative cyclization to produce cationic ruth-
enacyclopentatriene V. Although the exact details are un-
Scheme 6. Reaction of ruthenacyclopentatriene 11 and h4-diene complex
12 with Hantzsch ester 2.
that a cationic ruthenacyclopentatriene that is produced
from 11 with the silver salt is able to react with 2 to afford
the corresponding h4-diene complex, which is nevertheless
unstable under the reaction conditions and undergoes de-
composition into exocyclic 1,3-diene 4a (see below).
We then examined the reactivity of the known h4-diene
complex 12, which was previously obtained from the reac-
tion of ruthenacycle 11 with MeOH.[15] In the presence of
AgPF6 (2 equiv), 12 was treated with Hantzsch ester 2
(1.2 equiv) in THF at room temperature for 30 min
(Scheme 6). Although a complex product mixture was ob-
tained, probably because of extensive decomposition of the
cationic h4-diene intermediate, careful analysis of the crude
1
reaction mixture by H NMR spectroscopy and DART mass
spectrometry revealed the formation of dihydrofuran deriva-
tive 5a, which was previously reported by Chung and co-
workers,[12] albeit in a low yield. This result shows that trans-
fer hydrogenation of the cationic h4-diene intermediates
possibly occurs to furnish 1,4-hydrogenation products.
Scheme 8. Proposed catalytic cycle for the ruthenium-catalyzed transfer-
hydrogenative cyclization of diynes by using Hantzsch ester.
To obtain further insight into the 1,4-hydrogenation of the
exocyclic 1,3-diene products, we examined the reactivity of
representative exocyclic 1,3-dienes 4d and 9b under catalyt-
ic transfer-hydrogenation conditions (Scheme 7). No reac-
tion took place when isolated diene 4d was subjected to the
clear at this stage, transfer hydrogenation of
V with
Hantzsch ester 2 affords cationic h4-1,3-diene complex VI.
When the R groups are aryl groups, ligand exchange occurs
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Ru-Catalyzed Transfer-Hydrogenative Cyclization of 1,6-Diynes
FULL PAPER
between VI and the diyne substrate, thereby resulting in the
formation of exocyclic 1,3-diene products with the concomi-
tant restoration of diyne complex IV. On the other hand, a
subsequent transfer hydrogenation proceeds from cationic
h4-1,3-diene complex VI when the R groups are alkyl
groups. As a result, cycloalkene complex VII is produced.
Ligand exchange between VII and the diyne substrate
closes the catalytic cycle.
Finally, we examined the synthetic utility of these exocy-
clic 1,3-diene products by investigating their Diels–Alder cy-
cloaddition reactions with various dienophiles. Malonate-de-
rived product 4d was subjected to reaction with N-phenyl
maleimide (1.2 equiv) in toluene at 808C for 5 h (Scheme 9).
Scheme 10. One-pot Diels–Alder cycloaddition/aromatization of exocy-
clic 1,3-diene 4d.
diynes, such as 3d, with DMAD is problematic.[24,25] There-
fore, the combination of transfer-hydrogenative cyclization
and one-pot Diels–Alder cycloaddition/aromatization proce-
dures provides an alternative practical approach to the prep-
aration of fully substituted benzenes, which are otherwise
difficult to synthesize.
Conclusion
We have developed the transfer-hydrogenative cyclization of
1,6-diynes by using cationic ruthenium catalysts and
Hantzsch 1,4-dihydropyridine as a H2 surrogate. A cationic
complex with a Cp ligand, [CpRuACTHNUTRGNEUNG(MeCN)3PF6], was found
Scheme 9. Diels–Alder cycloaddition of exocyclic 1,3-dienes 4.
to be the optimal catalyst for the cyclization of diyne sub-
strates that contained terminal aryl groups, which produced
exocyclic 1,3-dienes as the predominant products. On the
other hand, the corresponding Cp* complex, [Cp*Ru-
As a result, the expected cycloadduct 13a was obtained in
95% yield. The cycloadduct of tosylamide derivative 4b
with the same dienophile required higher reaction tempera-
tures; thus, a reaction at reflux in toluene for 8 h afforded
cycloadduct 13b in 69% yield. The reaction of 4d with 4-
phenyl-3H-1,2,4-triazole-3,5(4H)-dione proceeded within
5 min, even at room temperature, to quantitatively afford
cycloadduct 14a. Similarly, ether derivative 4a reacted with
this efficient dienophile to furnish cycloadduct 14c in 91%
yield, although tosylamide analogue 14b was obtained in a
diminished yield under the same reaction conditions.
We further investigated the Diels–Alder cycloaddition of
diene 4d with an electron-deficient alkyne, dimethyl acetyle-
nedicarboxylate (DMAD), to obtain a cyclohexadiene deriv-
ative that could be readily aromatized (Scheme 10). Thus,
4d and DMAD were heated at reflux in toluene for 8 h to
afford cycloadduct 15 in 85% yield. After obtaining the de-
sired cyclohexadiene, we examined a one-pot Diels–Alder
cycloaddition/aromatization procedure to directly obtain a
fully substituted benzene derivative from 4d and DMAD.
As expected, p-terphenyl derivative 16 was successfully ob-
tained in 82% yield when the crude cycloadduct was subse-
quently treated with 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ, 1.2 equiv) at reflux in toluene for 1 h. Because
DMAD efficiently undergoes transition-metal-catalyzed cy-
clotrimerization reactions under mild conditions, the cross-
[2+2+2] cycloaddition of sterically demanding, inactivated
AHCTUNGRTENGUN(N MeCN)3PF6], was found to be suitable for diyne substrates
that contained terminal alkyl groups, which produced cyclo-
alkenes through 1,4-hydrogenation of the expected exocyclic
1,3-dienes. As a general trend, electron-donating terminal
groups lower the reaction efficiency by decreasing the elec-
trophilicity of the ruthenacyclopentatriene intermediates.
This result was reasonably corroborated by the correlation
of the LUMO levels of model ruthenacycles with the results
of the corresponding cyclization reactions.
A stoichiometric reaction of the isolated ruthenacyclopen-
tatriene that possessed a [Cp*RuCl] fragment with Hantzsch
ester in the presence of AgPF6 afforded the corresponding
exocyclic 1,3-diene in moderate yield (by NMR spectrosco-
py), thus suggesting that ruthenacycles are key intermedi-
ates. Furthermore, the stoichiometric reaction of the isolated
h4-exocyclic 1,3-diene complex with Hantzsch ester in the
presence of AgPF6 furnished a 1,4-hydrogenation product,
albeit in a low yield (by NMR spectroscopy). This result im-
plies that the 1,4-hydrogenation reaction possibly proceeds
through a cationic h4-exocyclic 1,3-diene complex. We also
performed catalytic transfer-hydrogenation reactions of the
independently prepared exocyclic 1,3-dienes. As a result, the
diene with methyl terminal groups underwent transfer hy-
drogenation in significant yield, although the diene with
phenyl terminal groups failed to produce the 1,4-hydrogena-
tion product. These observations explain the dependence of
Chem. Eur. J. 2013, 19, 12034 – 12041
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12039

Y. Yamamoto et al.
Vol. 1 (Eds.: J. G. de Vries, C. J. Elsevier), Wiley-VCH, Weinheim,
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Experimental Section
General catalytic procedure A: Cyclization of diyne 3a: A solution of
diyne 3a (73.8 mg, 0.30 mmol), Hantzsch ester 2 (152.2 mg, 0.60 mmol),
and [CpRuACHTUNGTRENNUNG(MeCN)3PF6] (1a, 3.98 mg, 0.009 mmol) in dry, degassed
DMF (1.5 mL) was stirred under an argon atmosphere at 708C for
20 min. The reaction progress was monitored by TLC analysis. After
cooling to RT, the reaction mixture was diluted with a mixed n-hexane/
EtOAc solvent (1:9, 10 mL) and washed with water (10 mL). The aque-
ous layer was extracted with n-hexane/EtOAc (1:9, 3ꢁ15 mL). The com-
bined organic layer was washed with water (15 mL) and brine (15 mL)
and dried over MgSO4. The organic layer was concentrated in vacuo and
the crude material was purified by column chromatography on silica gel
(n-hexane/toluene, 1:1) to give exocyclic 1,3-diene 4a[15] (60.5 mg, 81%)
as a colorless solid. M.p. 161.0–164.58C (lit.[15] 157.5–158.58C); 1H NMR
(300 MHz, CDCl3, 258C): d=4.86 (d, J=2.4 Hz, 4H), 6.98 (t, J=2.4 Hz,
2H), 7.24–7.29 (m, 6H), 7.36–7.42 ppm (m, 4H); 13C NMR (75 MHz,
CDCl3, 258C): d=71.1, 118.5, 127.0, 128.4, 128.5, 136.7, 138.8 ppm.
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General catalytic procedure B: Cyclization of diyne 3d: A solution of
diyne 3d (108.2 mg, 0.30 mmol), Hantzsch ester 2 (152.4 mg, 0.60 mmol),
and [Cp*RuACHTUNGTRENNUNG(MeCN)3PF6] (1b, 15.19 mg, 0.030 mmol) in dry, degassed
THF (1.5 mL) was stirred under an argon atmosphere at 708C for 1.5 h.
The reaction progress was monitored by TLC analysis. After cooling to
RT, the reaction mixture was concentrated in vacuo and the crude mate-
rial was purified by column chromatography on silica gel (n-hexane/tol-
uene, 1.5:1) to give exocyclic 1,3-diene 4d[15] (98.6 mg, 91%) as a color-
1
less solid. M.p. 134.0–136.08C (lit.[15] 146.5–148.08C); H NMR (300 MHz,
CDCl3, 258C): d=6.81 (d, J=2.0 Hz, 4H), 3.72 (s, 6H), 7.00 (t, J=
2.0 Hz, 2H), 7.22–7.27 (m, 2H), 7.34–7.44 ppm (m, 8H); 13C NMR
(75 MHz, CDCl3, 258C): d=39.1, 53.0, 58.9, 120.4, 126.6, 128.2, 128.7,
137.1, 139.2, 171.3 ppm.
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Acknowledgements
This research was supported by the Naito Foundation. We thank Dr. K.
Yamashita for performing the preliminary experiments.
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Received: May 14, 2013
Published online: July 25, 2013
Chem. Eur. J. 2013, 19, 12034 – 12041
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12041