Ru-catalyzed cyclization of terminal alkynals to cycloalkenes

Article abstract of DOI:10.1021/ja0610434

Cycloalkenes can be efficiently prepared by a new Ru-catalyzed cyclization of terminal alkynals. Under appropriate conditions, cycloisomerizations to conjugated aldehydes may be observed. Both processes involve catalytic Ru vinylidenes. Copyright

Full text of DOI:10.1021/ja0610434

Published on Web 06/28/2006
Ru-Catalyzed Cyclization of Terminal Alkynals to Cycloalkenes
Jesu´s A. Varela, Carlos Gonza´lez-Rodr´ıguez, Silvia G. Rub´ın, Luis Castedo, and Carlos Saa´*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, Facultad de Qu´ımica,
UniVersidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Received February 13, 2006; E-mail: qocsaa@usc.es
Table 2. Ru-Catalyzed Cyclization of Alkynals 1a-e and 12a
Transition metal catalysts occupy a central role in improved or
newly developed cyclization reactions. For example, internal
alkynals undergo cycloisomerization to cycloalkenones through Rh-
catalyzed intramolecular hydroacylation,1 conversion to exo-and
endo-cycloalkenols through Ni-catalyzed reductive and Ni and Pd-
alkylative processes2 and through Rh-catalyzed arylative cycliza-
tions,3 and transformation into cyclic alkenyl ethers or conjugated
cyclic ketones by π-complexation to electrophilic Pd4 or Rh
complexes.5 However, some of these procedures fail to cyclize
terminal alkynals, which have accordingly received much less
attention. Here we describe a new, efficient Ru-catalyzed cyclization
of terminal alkynes 1 to cycloalkenes 2 (Scheme 1).6,7
Scheme 1. Ru-Catalyzed Cyclization of Terminal Alkynals 1
Heating the 5-alkynal 1a (n ) 1, X ) C(CO2Me)2) in a 5%
solution of the catalyst [CpRu(CH3CN)3]PF6 in AcOH afforded,
after 24 h at 90 °C, the cyclopentene 2a, with one carbon less than
1a, in excellent yield (Table 1, entry 1).8 Heating at higher
Table 1. Ru-Catalyzed Cyclization of Alkynal 1a [X ) C(CO2Me)2,
n ) 1] in Acetic Acid
entry
catalysta
T (
°C)
time
yield (%)b
2a:3a
1
2
3
4
5
6
[CpRuL3]PF6
90
130
150
90
150
90
24 h
95
95:5
60:40
50:50
80:20
50:50
100: 0
“
“
1.5 h
50 min
5.5 h
50 min
8 h
96c
93c
95c
92c
85
[Cp*RuL3]PF6
“
[Cp*RuL3]PF6 + 5% dppf
a L) CH3CN, dppf) diphenylphosphinoferrocene. b Isolated yields. c GC
yields.
a Typical conditions: alkynal 1 (0.1 M), 5% [CpRu(CH3CN)3]PF6,
AcOH, 90 °C, 24 h. b For 5-alkynals, up to 5% of the product was isomer
3. c Isolated yields. d [Cp*Ru(CH3CN)3]PF6 was used as catalyst. e Reaction
performed at 130 °C. f Ketone 8c (X ) COMe) was also obtained in 30%
temperatures led to faster reactions, but with increasing amounts
of the isomeric cyclopentene 3a (entries 2 and 3). Using the more
electron-rich, sterically more demanding catalyst [Cp*Ru(CH3CN)3]-
PF6 gave similar results (entries 4 and 5). Interestingly, addition of
5% dppf to the reaction mixture led exclusively to 2a in 85% yield
(entry 6).8b
Other terminal 5-alkynals with alternative 3,3-disubstitution (1b),
with 4-monosubstitution (1c), or with nitrogen at skeletal position
3 (1d) and the terminal 6-alkynal 1e behaved similarly affording
cyclopentenes 2b and 2c, 2,5-dihydropyrrole 2d, and cyclohexene
2e, respectively, in good to excellent yields (Table 2, entries 2-5).
To go into the reaction with more detail, a series of experiments
with several substrates were performed. When the alkynone 4 was
used, the corresponding cyclopentene 5 was obtained in moderate
yield (Table 2, entry 6),9 indicating that an oxidative addition of
the ruthenium to the aldehyde C-H bond is unlikely.
i
yield. g CpRu(dppm)Cl in PrOH/H2O was used as catalyst. h Deuteration
studies on 12, performed in AcOD at 90 °C, gave deuterated 13 with more
than 95% deuterium incorporation.
When the tether between the alkyne and the aldehyde was
enlarged, such as alkynal 1f, the noncyclized ketal 6 with loss of
one carbon was observed (Table 2, entry 7). Other alkynes with
terminal functional groups other than aldehyde behaved similarly
(Table 2, entry 8).10 The results from the last two entries seem to
indicate that the carbon lost during the reaction is most likely the
terminal alkyne carbon. This evidence was reinforced when the
reaction of internal alkynal 9 only gave the conjugated ketone 10,
in which all the carbons of the starting material are present (Table
2, entry 9). Interestingly, terminal alkynals 1a,e are able to
cycloisomerize to conjugated aldehydes 11a,e (all the carbons of
9
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J. AM. CHEM. SOC. 2006, 128, 9576-9577
10.1021/ja0610434 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Possible Mechanism of the Decarbonylative
Ru-Catalyzed Cyclization of Terminal Alkynals 1
supported by the Ministerio de Educacio´n y Ciencia (Spain) and
the European Regional Development Fund (Project CTQ2005-
08613), and by the Xunta de Galicia (Project PGIDT00PXI20908).
S.G.R. and C.G.-R. thank the M.E.C. and the Segundo Gil-Da´vila
Foundation, respectively, for predoctoral grants, and J.A.V. thanks
the M.E.C. for a Ramo´n y Cajal research contract.
Supporting Information Available: A typical procedure for the
Ru-catalyzed reaction and spectral data for all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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the starting material remained) by just using CpRu(dppm)Cl as
i
catalyst in PrOH/H2O as solvent (Table 2, entry 10).11
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To explain the above results on the basis of the findings of
Wakatsuki10a,b and in our own deuteration studies with alkynal 12
(Table 2, entry 11),8b we hypothesize the mechanism shown in
Scheme 2. When heated in AcOH, the cationic catalyst [CpRu-
(CH3CN)3]PF6 most likely generates an active Ru complex12,13 that
after coordination with 1 gives the Ru(II) vinylidene species I,6b,e,7
which upon nucleophilic addition of the acetic acid would afford
the vinyl Ru species II. Next, and only for the cases of aldehydes
1a-e, 12, and the ketone 4, an aldol-type condensation would then
give the acyl Ru hydride III.14 In the case of alkynal 1f, probably
the formation of a cycloheptene by an aldol-type reaction between
the vinyl Ru species and the aldehyde is not favored, while the
ester and nitrile groups of 8a and 8b are not enough electrophiles
for the aldol-type reaction. Then, the next step would be the
decarbonylation (being the terminal carbon of the alkyne the one
lost as CO) followed by reductive elimination to afford the observed
cycloalkenes 2 and 515 in the case of alkynals and alkynone,
respectively. Decarbonylation without cyclization occurred (not
shown in Scheme 2) for alkynal 1f and ester and nitrile 7a,b,
respectively, to give compounds 6 and 8a,b. The conjugated
aldehydes 11 observed when CpRu(dppm)Cl was used as catalyst
(Table 2 entry 10) can also be explained according to the proposed
mechanism if reductive elimination from III occurred (no decar-
bonylation takes place in this case due to the bidentate nature of
dppm ligand). Nevertheless, the conjugated ketone 10 obtained from
internal alkyne 9 would probably arise from a total different
mechanism (hydration of internal alkyne activated with a metal
acting as a Lewis acid) due to the impossibility of the formation of
vinylidene species.
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also: (b) Trost, B. M.; Fredericksen, M.; Rudd, M. T. Angew. Chem.,
Int. Ed. 2005, 44, 6630. For an Ru-catalyzed hydrative cyclization of
diynes, see: (c) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127,
4763. (d) Odedra, A.; Wu, C.-J.; Pratap, T. B.; Huang, C.-W.; Ran, Y.-
F.; Liu, R.-S. J. Am. Chem. Soc. 2005, 127, 3406. For an Ru-catalyzed
hydrative cyclization of 1,5-enynes, see: (e) Chen, Y.; Ho, D. M.; Lee,
C. J. Am. Chem. Soc. 2005, 127, 12184. For an Ru-catalyzed cyclocar-
bonylation of alkynals, see: (f) Chatani, N.; Morimoto, T.; Fukumoto,
Y.; Murai, S. J. Am. Chem. Soc. 1998, 120, 5335.
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197. For books, see: (c) Ruthenium in Organic Synthesis; Murahashi,
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Berlin, 2004; Vol. 11.
(8) (a) Minor amounts of the isomer 3a (<5%) have been observed. (b) See
Supporting Information for more details and for other catalytic conditions.
(9) Reaction performed at 130 °C being the decarbonylated ketone 8c (X )
COCH3) was also obtained in 30% yield.
(10) (a) Suzuki, T.; Tokunaga, M.; Wakatsuki, Y. Org. Lett. 2001, 3, 735. (b)
Tokunaga, M.; Suzuki, T.; Koga, N.; Fukushima, T.; Horiuchi, A.;
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Romerosa, A.; Zanobini, F. J. Am. Chem. Soc. 1996, 118, 4585.
(11) Conditions developed for anti-Markovnikov hydration of alkynes: (a) ref
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Am. Chem. Soc. 2004, 126, 12232.
(12) For formation of (η2-O2CCH3)Ru complexes, see: Werner, H.; Braun,
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127.
In conclusion, we have discovered a new Ru-catalyzed cycliza-
tion of terminal alkynals to give cycloalkenes. Under appropriate
catalytic conditions, cycloisomerization to conjugated aldehydes
may be observed. Both processes involve catalytic Ru vinylidenes.
On the basis of the findings described herein, we envisage new
possibilities of C-C bond formation catalyzed by transition metal
vinylidenes. Research in this direction is currently underway.
(13) It has been suggested that Cp*Ru(cod)Cl, when heated with AcOH at 65
°C, forms a hydrido-Ru(IV) complex that upon coordination with alkynes
gives a vinyl-Ru species. Le Paih, J.; Cuervo, D.; De´rien, S.; Dixneuf,
P. H. Synlett 2000, 1, 95. We observed no products suggestive of this
process.
(14) Reductive elimination products derived from intermediates II (vinyl acetate
IIa) or III (aldehyde 11a) did not afford the observed cycloalkene 2a
after heating their solutions in AcOH at 90 °C in the presence of the Ru
catalyst. See Supporting Information S5 for details.
(15) The isomeric cycloalkenes 3 probably arise through isomerization of the
Ru hydride IV.
Acknowledgment. This work is dedicated to Professor K. C.
Nicolaou on the occation of his 60th birthday. This work was
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