Synthesis of 1,2-bisalkylidenecyclopentanes from 1,6-allenynes via stereoselective addition of nucleophiles to ruthenacyclopentenes

Article abstract of DOI:10.1039/c2cc30640a

Ruthenium-catalyzed cyclization of 1,6-allenynes occurs via the addition of heteroatom nucleophiles to ruthenacyclopentenes, providing functionalized 1,2-bisalkylidenecyclopentanes in a highly regio- and stereoselective manner. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc30640a

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COMMUNICATION
Synthesis of 1,2-bisalkylidenecyclopentanes from 1,6-allenynes via
stereoselective addition of nucleophiles to ruthenacyclopentenesw
Nozomi Saito,* Yuh Kohyama, Yuki Tanaka and Yoshihiro Sato*
Received 30th January 2012, Accepted 20th February 2012
DOI: 10.1039/c2cc30640a
Ruthenium-catalyzed cyclization of 1,6-allenynes occurs via the
addition of heteroatom nucleophiles to ruthenacyclopentenes,
providing functionalized 1,2-bisalkylidenecyclopentanes in a highly
regio- and stereoselective manner.
A metallacycle intermediate formed via oxidative cycloaddition
of unsaturated bonds to a transition metal catalyst exerts high
reactivity toward various reactants.1 Addition of a heteroatom
nucleophile to the metallacycle intermediate is an attractive
transformation of metallacycles, since C–C bond formation
and addition of a polar functionality to non-polar multiple
bonds occur in one step, generally with high regio- and
stereoselectivity.2 In particular, ruthenium complexes have
been widely employed in these processes.3 Although various
functionalities could be appended by changing nucleophiles
(e.g. alcohols, carboxylic acids, and amines), only two types
of ruthenacycles, ruthenacyclopentane A (eqn (1))4 and
ruthenacyclopentatriene B (eqn (2)),5,6 have been applied in
this transformation. In both cases, protonation and addition
of a nucleophile occurred at each carbon proximal to the
ruthenium center. Here we report a new type of reaction of
ruthenacyclopentenes with nucleophiles, in which protonation
occurs at the carbon distal from the metal center, while an
attack of the nucleophile occurs at the proximal position of the
metal center in ruthenacyclopentene intermediate C (eqn (3))
in a highly regio- and stereoselective manner.
Scheme 1 Cyclization of 1,7- and 1,6-allenynes.
As we previously reported, when 1,7-allenyne 1 was reacted
with a catalytic amount of Cp*RuCl(cod) in MeOH, [2 + 2]
cyclization occurred to give bicyclic compound 2 through
reductive elimination from ruthenacyclopentene I (Scheme 1,
eqn (4)).7 During further studies on the [2 + 2] cyclization, we
found that the reaction of 1,6-allenyne 3a under the same
conditions did not afford the corresponding [2 + 2] cyclized
product, mainly due to the strain caused by a 5–4 bicyclic ring
system in the expected product, but gave an alternative cyclic
compound 4a, having a dienyl methyl ether structure, in 94%
yield as a single isomer (eqn (5)).8
Although the mechanism for the formation of 4a is not clear
at this stage, we investigated the generality of the methanolative
cyclization of various 1,6-allenynes (Table 1).9 The cyclized
product 4a having an alkyl-enol functionality was partly
decomposed during the purification process due to the acid-
and moisture-lability. Thus, in order to isolate the product as a
stable form, cyclization of 3a was carried out under the same
conditions and the reaction mixture was treated with 10%
HCl, producing ketone 5a in a quantitative yield (run 1). The
reaction of enynes having an ether or hydroxy group (3b and 3c)
on the linker part X also gave cyclized products 5b and 5c in
high yields after acidic work-up with 10% HCl (runs 2 and 3),
indicating that the corresponding dienyl methyl ethers 4b and 4c
were produced in these reactions. Alkyl substituents on the
alkyne (3d and 3e) were well tolerated in the reaction, giving 5d
and 5e, respectively (runs 4 and 5). In the case of substrates
bearing aromatic rings on the alkyne 3f–3h, the products 4f–4h
could be easily isolated as the original dienyl ether form in high
yields (runs 6–8). The reaction of allenyne having an ester group
on the alkyne 3i also provided dienyl ether 4i in 63% yield
(run 9). Allenynes 3j–3l, possessing an alkyl group on the
allene, were also applicable to the methanolative cyclization,
giving 5j–l in high yields (runs 10–12). On the other hand,
ð1Þ
ð2Þ
ð3Þ
Faculty of Pharmaceutical Sciences, Hokkaido University,
Sapporo 060-0812, Japan. E-mail: biyo@pharm.hokudai.ac.jp;
Fax: +81 11 706 4982; Tel: +81 11 706 4982
w Electronic supplementary information (ESI) available: Experimental
details and spectral data. See DOI: 10.1039/c2cc30640a
c
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Table 1 Ruthenium-catalyzed cyclization of various 1,6-allenynesa
intermediate D is directly formed from C by capture of a
proton from methanol at the g-position of the metal of
intermediate C (mono-carbene pathway). Nucleophilic attack
of methanol at the CQRu bond in intermediate D occurs from
the opposite side of the bulky Cp* ligand to give the common
ruthenacyclopentene E. Reductive elimination from E5b proceeds
to produce dienylether 4 in a stereoselective manner along with
regeneration of the Cp*Ru(OMe) complex. On the other hand,
similarity of the present reaction with the previously reported
ruthenium-catalyzed cyclization of diynes (eqn (2))5,6 reminds
us of another pathway via biscarbene ruthenium intermediate B
(bis-carbene pathway). Thus, the ruthenacyclopentatriene inter-
mediate B would be formed from C through a hydrogen
migration from the a-carbon to the g-one (i.e. 1,3-H-shift11).
Protonation of intermediate B would occur at the a-position
or a0-position to produce the corresponding intermediate D0
and/or D00. The structure of intermediate D0 is the same as that
of D derived by the above-mentioned mono-carbene pathway
except for the origin of a hydrogen with respect to the a-position
and g-position, which is distinguished by colors (red or blue).
Similar to the reaction course from the above-mentioned inter-
mediate D, the ruthenacyclopentene E0 or E00 was produced
through a nucleophilic attack of methanol at the CQRu bond in
intermediate D0 or D00. Reductive elimination from E0 or E00
occurs to give the corresponding 40 or 400 in a stereoselective
manner.
Time/
h
Run Substrate 3
Yield (%)
3a (X =
1
1
1
1
5a: quant
5b: 82%
5c: 87%
C(CO2Me)2)
3b (X =
2
C(CH2OBn)2)
3c (X =
C(CH2OH)2)
3
4
5
6
3d (R1 = Et)
3e (R1 = CH2OH)
3f (R1 = Ph)
3g (R1 =
2
2
16
5d: quant
5e: 84%
4f: quant
7
75
4g: 84%
4-MeO2CC6H4)
3h (R1 =
4-MeOC6H4)
8
9
5
4h: 84%
4i: 63%
3i (R1 = CO2Me) 72
10 3j (R2 = Me)
11 3k (R2 = Et)
24
24
4
5j: 81%
5k: 77%
5l: 84%
5m: 27% (3m: 19%)
In order to clarify which pathway operates in this reaction,
the reaction of 3f was carried out under the above-mentioned
conditions except for using methanol-d4 as a solvent. Thus, if
the reaction proceeded via the mono-carbene pathway in
Scheme 2, a deuterium atom should be incorporated at the
g-position in D (depicted as a red-H). On the other hand, a
deuterium atom should be incorporated at the a-position in D0
or at the a0-position in D00 (depicted as a blue-H), if the
bis-carbene pathway operated in this reaction. Indeed, when
the reaction of allenyne 3f in methanol-d4 was carried out,
only 4f–D was obtained in 83% yield with more than 95%
D-content (Scheme 3).
i
12 3l (R2 = Pr)
13 3m (R2 = CO2Me) 85
a
Reaction conditions: Cp*RuCl(cod) (5 mol%), MeOH, rt.
the reaction of 3m having an ester group on the allene
proceeded sluggishly to give 5m in low yield (run 13).
A plausible mechanism of this reaction is depicted in
Scheme 2. Initially, oxidative cycloaddition of 1,6-allenyne 3
to the ruthenium complex Cp*Ru(OMe), which is generated
from Cp*RuCl(cod) and methanol,10 stereoselectively occurs
so as to avoid steric repulsion between the substituent on the
allene and the Cp* ligand to give a ruthenacyclopentene C.
From the ruthenacyclopentene intermediate C, two pathways
can be considered. One is that a cationic ruthenium-carbene
Furthermore, if the present reaction proceeds via bis-
carbene intermediate B, nucleophiles would randomly attack
the two almost symmetrical CQRu bonds in B to produce
Scheme 2 Two possible pathways.
c
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In summary, we have succeeded in finding a new type of
reaction of ruthenacyclopentenes derived from 1,6-allenynes
toward nucleophiles, giving functionalized 1,2-bisalkylidene-
cyclopentanes with excellent regio- and stereoselectivity.
A mechanistic study disclosed that the reaction proceeded
via the mono-carbene pathway in Scheme 2, where a cationic
ruthenium-carbene intermediate D was directly formed from C
via capture of a proton from the nucleophile followed by
attack of the nucleophile at the CQRu bond of D. Further
studies including expansion of the scope of substrates and
nucleophiles are now in progress.
Scheme 3 Deuterium labeling experiment.
This work was supported by a Grant-in-Aid for Scientific
Research (B) (No. 23390001) from JSPS and by a Grant-in-Aid
for Scientific Research on Innovative Areas ‘‘Molecular Activation
Directed toward Straightforward Synthesis’’ (No. 23105501) from
MEXT, Japan. N.S. acknowledges NOVARTIS Foundation
(Japan) for the Promotion of Science and Takeda Science
Foundation for financial support.
Scheme 4 Synthetic feature of the reaction via the mono-carbene pathway.
Table 2 Cyclization of 3a with various nucleophiles
Notes and references
1 (a) J. P. Collman, L. S. Hegedus, J. R. Norton and R. G. Finke,
Principles and Applications of Organotransition Metal Chemistry,
University Science Books, Mill Valley, CA, 1987; (b) C. Elschenbroich,
Organometallics, Wiley-VCH, Weinheim, 2006.
2 For examples, see: (a) M. Murakami, T. Tsuruta and Y. Ito,
Angew. Chem., Int. Ed., 2000, 39, 2484; (b) K. Tanaka and
G. C. Fu, Angew. Chem., Int. Ed., 2002, 41, 1607; (c) A. Herath,
W. Li and J. Montgomery, J. Am. Chem. Soc., 2008, 130, 469;
(d) K. Tanaka, S. Saitoh, H. Hara and Y. Shibata, Org. Biomol.
Chem., 2009, 7, 4817.
3 For stoichiometric study on the addition of nucleophiles to
ruthenacyclopentadienes, see: R. Schmid and K. Kirchner, Eur. J.
Inorg. Chem., 2004, 2609 and references therein.
Run
NuH
Time/h
Yield (%)
1
2
3
4
5
6
MeOH
EtOH
iPrOH
tBuOH
AcOH
HC1
2
4
4
96
19
6
4a: 86%, 5a: 7%
4o: 74%, 5a: 16%
4p: 88%, 5a: 5%
3a: 70% recovery
4q: 95%
4r: 61%
4 (a) B. M. Trost and A. B. Pinkerton, J. Am. Chem. Soc., 1999,
121, 10842; (b) B. M. Trost, A. B. Pinkerton and D. Kremzow,
J. Am. Chem. Soc., 2000, 122, 12007; (c) B. M. Trost and
A. McClory, Org. Lett., 2006, 8, 3627.
both D0 and D00 depending on the steric and electronic nature
of substituents R1 and R2.6a However, as shown in Table 1, the
reaction of the allenyne 3k having an ethyl group on the allene
and a methyl group on the alkyne stereospecifically proceeded
to give 5k as a sole product. In contrast, the reaction of 3n
having two substituents as the inverse combination in 3k gave
the corresponding product 5n as a single isomer (eqn (6) and (7)).
These experiments strongly suggested that the present allenyne
cyclization proceeds via D according to the mono-carbene pathway
(Scheme 4).12
5 For intermolecular reactions, see: (a) J. L. Paih, S. De
P. H. Dixneuf, Chem. Commun., 1999, 1437; (b) J. L. Paih,
F. Monnier, S. Derien, P. H. Dixneuf, E. Clot and O. Eisenstein,
´
rien and
´
J. Am. Chem. Soc., 2003, 125, 11964; (c) M. Zhang, H.-F. Jiang,
H. Neumann, M. Beller and P. H. Dixneuf, Angew. Chem., Int. Ed.,
2009, 48, 1681.
6 For intramolecular reactions, see: (a) B. M. Trost and M. T. Rudd,
´ ´
J. Am. Chem. Soc., 2003, 125, 11516; (b) C. Gonzalez-Rodrıguez,
J. A. Varela, L. Castedo and C. Saa, J. Am. Chem. Soc., 2007,
´
129, 12916; (c) Y. Yamamoto, K. Yamashita and H. Nishiyama,
Chem. Commun., 2011, 47, 1556.
7 N. Saito, Y. Tanaka and Y. Sato, Org. Lett., 2009, 11, 4124.
8 The stereochemistry of 4a was determined by NOE measurements.
For details, see ESIw.
9 For details of the procedure for preparation of 1,6-allenynes,
see ESIw.
10 Although the real active species in this reaction system is not clear yet,
we thought that Cp*Ru(OMe) might be generated from Cp*RuCl(cod)
and MeOH. Similar dimeric complex, [Cp*Ru(OMe)]2, was synthesized
and its structural elucidation was conducted by X-ray crystallo-
graphic analysis. See: S. D. Loren, B. K. Campion, R. H. Heyn,
T. D. Tilley, B. E. Bursten and K. W. Luth, J. Am. Chem. Soc., 1989,
111, 4712.
11 For an example of intramolecular 1,3-H-shift, see: L. Gong, Z. Chen,
Y. Lin, X. He, T. B. Wen, X. Xu and H. Xia, Chem.–Eur. J., 2009,
15, 6258.
Next, we turned our attention to the reaction of 1,6-allenyne
3a using various nucleophiles. First of all, the reaction of 3a
was investigated using [Cp*Ru(MeCN)3]PF6 instead of
Cp*RuCl(cod) in THF in the presence of 10 equivalents of
methanol as a nucleophile (Table 2, run 1). As a result,
product 4a was obtained in high yield accompanied by the
formation of 5a in a manner similar to the reaction in
methanol using Cp*RuCl(cod) (cf. Scheme 1 and Table 1,
run 1). Thus, various nucleophiles were tested. The use of a
primary alcohol (EtOH) as well as a secondary alcohol
(iPrOH) gave the corresponding cyclized products 4o or 4p
in good yield (runs 2 and 3), whereas addition of more
t
hindered BuOH did not promote the cyclization and starting
material 3a was recovered in 70% yield (run 4). Interestingly,
dienylcarboxylate 4q was obtained in 75% yield when
acetic acid was employed as a nucleophile (run 5). Notably,
hydrogen chloride was also applicable to the cyclization, and
chlorodiene 4r was obtained in moderate yield (run 6).
12 Recently, Yamamoto reported Cp*RuCl(cod)-catalyzed reductive
cyclization of 1,6-diynes with methanol leading to bis-alkylidene-
cyclopentane via intermediate B. This also supports that our reaction
proceeds via the mono-carbene pathway. See: K. Yamashita,
Y. Nagashima, Y. Yamamoto and H. Nishiyama, Chem. Commun.,
2011, 47, 11552.
c
3756 Chem. Commun., 2012, 48, 3754–3756
This journal is The Royal Society of Chemistry 2012