Regioselectivity control in a ruthenium-catalyzed cycloisomerization of diyne-ols

Article abstract of DOI:10.1021/ol048351w

(Chemical Equation Presented) The ruthenium-catalyzed cycloisomerization of diynes containing one silyl alkyne and one propargyl alcohol yields 2-silyl-[6H]-pyrans instead of the expected unsaturated acylsilanes except when additional conjugation of a aro

Full text of DOI:10.1021/ol048351w

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4235-4238
Regioselectivity Control in a
Ruthenium-Catalyzed Cycloisomerization
of Diyne-ols
Barry M. Trost,* Michael T. Rudd, Moise´s Gul´ıas Costa, Philip I. Lee, and
Andrew E. Pomerantz
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
bmtrost@stanford.edu
Received August 18, 2004
ABSTRACT
The ruthenium-catalyzed cycloisomerization of diynes containing one silyl alkyne and one propargyl alcohol yields 2-silyl-[6H]-pyrans instead
of the expected unsaturated acylsilanes except when additional conjugation of a aromatic ring is present at the -position. Under certain
δ
conditions, a facile ruthenium-catalyzed isomerization of the product takes place as well. This regioselectivity of the cyclization can be controlled
by the choice of solvent system. DFT calculations confirm the expected greater stability of the silyl-pyrans relative to the acylsilanes.
Recently, we disclosed a variety of transformations1-5 of
propargyl alcohols and diynes catalyzed by the cationic
ruthenium complex [CpRu(CH3CN)3]PF6 (1).6 Cyclization
of 1,6- and 1,7-diynes containing a propargylic alcohol occurs
readily in the presence of water and a catalytic amount of 1
to produce R,â,γ,δ-unsaturated ketones and aldehydes in high
yields2 (Scheme 1). This methodology gives access to aldol
condensation-type products in a chemoselective and atom
economical7 fashion. It was envisioned that this method could
be extended to the construction of unsaturated acylsilanes,8-10
which are versatile synthetic intermediates, through incor-
poration of an alkynylsilane (Scheme 1: R ) SiR3). The
simplicity of synthesis of alkynylsilanes as compared to
acylsilanes motivates this endeavor, even though the ease
of protodesilylation of silyl-alkynes under protic conditions
raised concern regarding the feasibility of the process. In
the event, simple alkynylsilyl-diyne-ol 2 underwent complete
conversion when treated with 10 mol % 1 in aqueous acetone
at 60 °C. However, instead of the expected acylsilane 3, the
(1) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2001, 123, 8862.
(2) Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2002, 124, 4178.
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(6) Trost, B. M.; Older, C. M. Organometallics 2002, 21, 2544.
(7) Trost, B. M. Acc. Chem. Res. 2002, 35, 695.
Scheme 1. Ruthenium-Catalyzed Cyclization of Diyne-ols
(8) Stergiades, I. A.; Tius, M. A. J. Org. Chem. 1999, 64, 7547.
(9) Ricci, A.; Deglinnocenti, A. Synthesis 1989, 647.
(10) Page, P. C. B.; Klair, S. S.; Rosenthal, S. Chem. Soc. ReV. 1990,
19, 147.
10.1021/ol048351w CCC: $27.50
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Published on Web 10/22/2004

only product, isolated in 99% yield, was the doubly cyclized
isomeric dihydropyran 5 (Scheme 2).
and the similar stabilities of 4 and 5 justify the fact that either
can be isolated. A related acylsilane to 2-silyl-[6H]-pyran
isomerization is also known with allenyl-acylsilanes.13
The isomerization of 4 to 5 is rather facile, and even
standing neat at room temperature leads to some isomeriza-
tion. The process is accelerated somewhat by the presence
of protic acid and to a large extent by 1, possibly through a
π-allyl mechanism.14-16 We believe that the effect of water
on the reaction can be explained by proposing that water
acts as a ligand for ruthenium, thus slowing the isomerization
process without overly reducing the rate of the initial
cycloisomerization.17 This claim is supported by the fact that
other labile ligands can function similarly. For example,
DMF slows down the second isomerization as well, although,
in this case, the overall rate is also significantly reduced.
The structures of 4 and 5 were assigned on the basis of
1H NMR, 13C NMR, IR, and HRMS/EA and in analogy to
the HMBC and UV-vis of 30 and 31. The isolated
compounds were clearly not acylsilanes due to absence of
the characteristic 13C carbonyl peak at 230-240 ppm and
the presence of singlets accounting for 6 protons at 1.27 ppm
Scheme 2. Ruthenium-Catalyzed Cyclization of
Alkynyl-silyl-diyne-ols
It was discovered that the amount of water present in the
reaction mixture has a large effect on the product composi-
tion. Increasing the amount of water from 5 equiv to 10 vol
% in acetone led to isolation of a 1:1 mixture of 5 and
isomeric [6H]-pyran 4. Further increasing the percentage of
water led to increased amounts of 4. Addition of 40 vol %
water in acetone allowed isolation of 4 in 94% yield as a
17:1 mixture with 5 (Scheme 3). Higher percentages of water
1
for 4 and 1.08 ppm for 5 in the H NMR. These features
indicated that the two methyl groups in each were equivalent
and not allylic. The 13C NMR revealed four olefinic peaks
and one ether carbon resonance. The HRMS/EA data also
revealed that the mass had not changed from 2, while the
OH stretch disappeared in the IR. These data led us to
consider the isomeric compounds 4 and 5 on the basis of
the known valence isomerism of R,â,γ,δ-unsaturated ke-
tones.18 Utilization of HMBC data along with UV-vis
spectroscopy allowed us to distinguish between the two
isomers. The HMBC of related compound 31 indicated that
the single vinyl proton was 2-3 bonds away from the gem-
diester quaternary carbon and that one of the aliphatic
methylenes was 2-3 bonds away from the gem-dimethyl
quaternary carbon. The HMBC of 30 revealed the opposite
relationship.
Scheme 3. Ruthenium-Catalyzed Cyclization of
Alkynyl-silyl-diyne-ols
or use of only water led to lower yields of 4/5 because
turnovers of 1 were limited. Thus, the regioselectivity of the
cycloisomerization can be controlled by simple change of
solvent.
Additionally, the UV-vis spectra were taken to confirm
the identity of each based upon the well established differ-
ences for s-cis homoannular and s-trans heteroannular 1,3-
dienes.19-22 Dienes with an s-cis/homoannular structure are
known to have smaller extinction coefficients and λmax at
We reasoned that 5 was formed through three consecutive
isomerization reactions. The reaction involves initial cyclo-
isomerization to acylsilane 3 (Scheme 2), spontaneous 6π-
electrocyclization to 4, and ruthenium-catalyzed isomeriza-
tion to 5 (see below). Presumably, these subsequent
isomerizations proceed due to the thermodynamic equilib-
rium between the acylsilane and the 2-silyl-[6H]-pyran and
the strain of the latter relative to the isomerized dihydropyran
5. To support these claims we have calculated the relative
stabilities of the three isomers. Using the Gaussian 98 suite
of programs,11 the gas-phase free energies were computed
using the B3LYP/6-31G(d) level12 of density functional
theory (DFT). The most important term in the free energy
is the electronic energy, and more accurate calculations of
the electronic energies were performed using the improved
B3LYP/6-311G+(2d,p)//B3LYP/6-31G(d) method. Incor-
poration of this larger basis set did not significantly alter
the results, indicating that the present calculations are
sufficiently accurate. The calculations show that 5 is more
stable than 4 by 4 kcal/mol and more stable than 3 by 17
kcal/mol. The relative instability of 3 explains its absence,
(11) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.7; Gaussian,
Inc.: Pittsburgh, PA, 1998.
(12) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(13) Takanishi, K.; Urabe, H.; Kuwajima, I. Tetrahedron Lett. 1987, 28,
2281.
(14) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 9728.
(15) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2002, 124, 5025.
(16) Trost, B. M.; Toste, F. D. Angew. Chem., Int. Ed. 2001, 40, 1114.
(17) Rate of the initial cycloisomerization is not greatly affected by the
concentration of water.
(18) Kluge, A. F.; Lillya, C. P. J. Org. Chem. 1971, 36, 1977.
4236
Org. Lett., Vol. 6, No. 23, 2004

higher wavelengths than s-trans/heteroannular dienes. The
max of 307 nm (ꢀ 5000) for 30, compared to the λmax of 284
λ
Scheme 4. Elaboration of Silyl-pyrans
(ꢀ 8000) for 31, agrees with our structural assignment. The
two isomers can also be conveniently identified by the
location of the vinyl proton (∼4.8 ppm for 4 and ∼5.8 ppm
for 5 in C6D6). Further examples were assigned by analogy.
The resulting vinylsilanes have potential to be valuable
synthetic intermediates, and thus we wanted to examine the
range of silanes that could be used (Table 1).
further. On the other hand, oxidation of silanol 7 under
standard Tamao-Fleming27 oxidation conditions proceeded
very well to yield the unsaturated lactone 15 in quantitative
yield (Scheme 4). The scope of the reaction in terms of
varying the tether, the ring size, and the nature of the
propargyl alcohol was also explored (Table 2). Protected
Table 1. Variation of the Alkynylsilanea
Table 2. Variation of the Tethera
a Key: A: 10% 1, acetone, 5 equiv of water, 60 °C. A′: 10% 1, acetone,
5 equiv of water, 50 °C. E ) CO2Me; BDMS ) benzyldimethylsilyl-;
DMPS ) dimethylphenylsilyl-; TES ) triethylsilyl-.
A variety of silanes are tolerated in this cyclization,
including the easily functionalizable dimethylisopropoxy- and
benzyldimethylsilyl23 groups. The isopropoxy group in 6 is
removed under the aqueous Lewis-acidic conditions of the
reaction, and thus the product is isolated as the silanol (7).
The disiloxane dimer also forms readily but can be mini-
mized if desired by carrying out the reaction at lower
temperatures. To demonstrate some of the potential utility
of these unusual vinylsilanes, we attempted to carry out
various cross-coupling reactions with aryl-iodides and either
7 or 9. However, rapid protodesilylation occurs with TBAF
as the fluoride source to yield the dihydropyran 14 in nearly
quantitative yield (Scheme 4). Standing in CDCl3 for several
hours results in isomerization to the unsubstituted [2H]-pyran,
followed by ring opening to the corresponding R,â,γ,δ-
unsaturated aldehyde2 (40), likely due to the presence of
residual HCl.
a Key: A: 10% 1, acetone, 5 equiv of water, 60 °C. B′′: B at rt. B:
10% 1, 60 vol % acetone/40 vol % H2O, 60 °C. B′: B with 15% 1.
amines (16), ethers (20), and even unsubstituted carbon (18)
tethers are all permitted in this reaction. When the resulting
allylic protons are adjacent to a heteroatom (17, 21, 26), the
isomerization reaction is suppressed and the products are
generally isolated as the initially formed 2-silyl-[6H]-pyran
under any conditions. The â-silyl-R,â-unsaturated alkynone
22 also performs well in the cyclization to yield either
isomeric pyran (23 and 24) depending on the conditions of
the reaction. Six-membered rings can be formed (26);
however, the turnover number of the catalyst is limited. This
result is in contrast to the reactions without the alkynylsilyl
Utilization of the Denmark fluoride-free cross-coupling
conditions24-26 with 7 did lead to low (10-20%) yields of
coupling products; however, this method was not pursued
(19) Rao, C. N. R. Ultra-Violet and Visible spectroscopy: Chemical
Applications, 2nd ed.; Plenum Press: New York, 1967.
(20) Woodward, R. B. J. Am. Chem. Soc. 1941, 64, 72.
(21) Fieser, L. F.; Cambell, W. P. J. Am. Chem. Soc. 1938, 60, 159.
(22) Booker; Evans; Gillam J. Chem. Soc. 1940, 1453.
Org. Lett., Vol. 6, No. 23, 2004
4237

groups, in which six-membered rings are formed in only
slightly reduced yields.2 The main limitations in the makeup
of the tether are that internal propargylic alcohols and ethers
(e.g., 27) and carbonyl functionality in conjugation with the
leaving group (e.g., 28) are not well tolerated.
utilized to some degree, although the yields are diminished
(35). Additionally, unbranched secondary propargyl alcohols
do not participate in the reaction to a significant extent.
Benzylic secondary propargyl alcohols (36, 38) react well,
but instead of silylpyrans, the corresponding acylsilanes (37,
39) are isolated. These products are easily identified by the
presence of two olefinic proton signals along with the
expected 13C peak at 233 ppm (39) and 235 ppm (37). The
extra conjugation of the aromatic ring presumably stabilizes
the acylsilane to a sufficient extent that it is the stable
isomeric form of the product, as is known for related dienone/
pyran systems.18
In conclusion, we have shown that diyne-ols containing
an alkynylsilane undergo cycloisomerization in the presence
of cationic ruthenium complex 1 to form 2-silyl-[6H]-pyrans
or isomeric dihydropyrans. The regioselectivity of the
reaction can be controlled by substrate design (presence/
absence of a heteroatom in the tether) or by solvent selection.
Five- and six-membered rings can be formed, although
cyclization to a five-membered ring is much more facile.
Substrates bearing tertiary propargylic and secondary ben-
zylic alcohols participate more readily than do simple
secondary ones. If additional conjugation is present in the
molecule, the acylsilane itself is the stable isomeric form.
Last, the unusual ring structures formed through application
of this methodology may have important applications in
synthetic organic chemistry.
In addition to simple dimethylpropargyl alcohols, other
secondary and tertiary alcohols can be used (Table 3). In
Table 3. Variation of the Propargyl Alcohola
Acknowledgment. We thank Ian Sudyam for assistance
in obtaining UV-vis spectra. We thank the National
Institutes of Health, General Medical Science (GM 13598),
and the National Science Foundation for their generous
support of our programs. This material is partially based upon
work supported by the National Science Foundation under
Grant NSF CHE-0242103. M.G.C. thanks the Galician
Government for the predoctoral fellowship. M.T.R. thanks
Bristol-Myers Squibb for a graduate fellowship in synthetic
organic chemistry. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of California-
San Francisco supported by the NIH Division of Research
Resources.
a Key: E ) CO2Me. A: EE ) CO2Et; 10% 1, acetone, 5 equiv of water,
60 °C. B: 10% 1, 60 vol % acetone/40 vol % H2O, 60 °C.
Supporting Information Available: Experimental pro-
cedures for the preparation of new compounds and charac-
terization data. This material is available free of charge via
the Internet at http://pubs.acs.org.
general, tertiary propargyl alcohols function very well in this
reaction (29, 32). Secondary propargyl alcohols also can be
OL048351W
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