[W(CO)5]-catalyzed endo- or exo-cycloisomerization reactions of 1,1-disubstituted 4-pentyn-1-ols: Experimental and theoretical studies

Article abstract of DOI:10.1002/chem.200500537

The [W(CO)₅]-catalyzed cycloisomerization reaction of 1,1-disubstituted 4-pentyn-1-ol derivatives has been studied from both, an experimental and theoretical point of view. Three different catalytic systems have been evaluated {preformed [(thf)

Full text of DOI:10.1002/chem.200500537

FULL PAPER
DOI: 10.1002/chem.200500537
[
W(CO) ]-Catalyzed endo- or exo-Cycloisomerization Reactions of 1,1-
5
Disubstituted 4-Pentyn-1-ols: Experimental and Theoretical Studies
[
a]
[a]
[a]
[a]
JosØ Barluenga,* Alejandro DiØguez, FØlix Rodríguez, Francisco J. FaÇanµs,
[
b]
[b]
Tomµs Sordo, and Pablo Campomanes
Abstract: The [W(CO) ]-catalyzed cy-
2 mol% Et N]. We have found that the
ucts depending on the amount of Et N
5
3
3
cloisomerization reaction of 1,1-disub-
stituted 4-pentyn-1-ol derivatives has
been studied from both,an experimen-
tal and theoretical point of view. Three
different catalytic systems have been
reaction proceeds to give the formal
endo- or exo-cycloisomerization prod-
used and on the substitution along the
alkyl chain of the starting alkynol. The
theoretical study allowed us to find the
mechanisms of the reactions which ex-
plain the formation of the formal endo-
or exo-cycloisomerization products.
Keywords: alkynols · density func-
tional calculations · reaction mecha-
nisms · synthetic methods · tungsten
evaluated {preformed [(thf)W(CO) ],
5
[
W(CO) ]/excess Et N,and [W(CO) ]/
6 3 6
Introduction
Metal-catalyzed cycloisomerization reactions of w-alkynols
4-pentyn-1-ol derivatives) provide rapid and efficient access
to a variety of cyclic compounds for a great range of syn-
(
[
1]
thetic applications. In general,these reactions may proceed
through two different reaction pathways formally leading to
endo- or exo-cycloisomerization products (Scheme 1). The
formation of the endo-product proceeds through the forma-
tion of a vinylidene intermediate which further evolves to
Scheme 1. endo- or exo-cyclization products from the cycloisomerization
reaction of w-alkynols.
uct implies a simple 5-exo addition of the oxygen to the
[1b,2]
[6]
[7]
the formation of the final products.
process has been achieved by the use of ruthenium, rhodi-
um, and tungsten complexes. Formation of the exo-prod-
This catalytic endo-
alkyne. Several metal complexes (mercury, silver, palladi-
[3]
[8]
[9]
um, and alkyllithium compounds ) have been reported to
catalyze this transformation. Also,it has been observed that
those ruthenium and tungsten complexes which catalyzed
the endo-cycloisomerization reaction may,under some reac-
tion conditions,or depending on the structure of the starting
material,direct the reaction to the formation of the exo-pro-
[
4]
[5]
[
a] Prof. Dr. J. Barluenga,A. DiØguez,Dr. F. Rodríguez,
Dr. F. J. FaÇanµs
Instituto Universitario de Química Organometµlica
[3,5a,c,i]
duct.
“
Enrique Moles”,Unidad Asociada al CSIC
Recently,as part of a program directed to the synthesis of
Universidad de Oviedo
Juliµn Clavería 8,33006 Oviedo (Spain)
Fax : (+34)985-103-450
eight-membered carbocycles from Fischer carbene com-
[10]
plexes, we became interested in the [W(CO) ]-catalyzed
5
[11]
cycloisomerization reaction of 4-pentyn-1-ols. In order to
get some insight into the mechanism of this reaction,we
E-mail: barluenga@uniovi.es
[
b] Dr. T. Sordo,P. Campomanes
Departamento de Química Física y Analítica
Universidad de Oviedo,Juliµn Clavería,8
have also carried out a theoretical study about the
[W(CO) ]-promoted cycloisomerization reactions of 4-
5
3
3006 Oviedo (Spain)
[12]
pentyn-1-ol.
Thus,we have found new mechanisms for
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author: Full experimen-
tal details and spectroscopic data; optimized structures,absolute elec-
tronic energies,ZPVE corrections and relative Gibbs energies in the
gas-phase of all structures located in this work.
both the endo- and exo-pathways and we have shown that
although the endo-route is more favorable,the difference
between the rate-determining barriers for both mechanisms
À1
is only 1.1 kcalmol . In a wider investigation on this cata-
Chem. Eur. J. 2005, 11,5735 – 5741
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
5735

lytic reaction we have found new interesting results related
to the high dependence of the reaction on the catalytic
system used and the structure of the starting 4-pentyn-1-ol
derivative. These findings together with new theoretical
studies about the mechanisms of the reactions are reported
in deep within this paper.
cycle b). As shown,this mechanism implies that after an ini-
tial coordination of the pentacarbonyltungsten to the
alkyne,the hydroxy group adds to the internal position of
the triple bond to give a zwitterionic intermediate 5 which,
after migration of the hydrogen atom and elimination of the
metal fragment,produces the final furan derivative 6 regen-
erating the pentacarbonyltungsten species.
In our preliminary experiments we used the model com-
pound 1a and we evaluated different reaction conditions
Results and Discussion
(
Scheme 3). Thus,we observed that the treatment of this
Conceptual background and preliminary studies: Our ap-
proach to a catalytic synthesis of eight-membered carbocy-
cles was guided by the perception that tricyclic compounds
compound 1a with 25 mol% preformed [(thf)W(CO) ] in
5
THF at room temperature for 24 h led to the formation of
the tricyclic compound 4a in 74% yield. Although this
result was a significant achievement,a minor drawback of
the method is the fact that the catalyst [(thf)W(CO)5]
should be generated in a separated vessel,irradiating a THF
4
,which are known to be precursors of eight-membered car-
[10]
[11]
bocycles,
could be easily available from alkynols 1.
Thus,we argued that these alkynol derivatives 1,which con-
tain an allyl moiety in their structure,could react with pen-
tacarbonyltungsten complex species,through a cycloisomeri-
zation reaction,to give the vinylidene intermediate 2,which
further could evolve to the cyclic carbene complex 3. A sub-
sequent intramolecular cyclopropanation reaction of com-
plexes 3 should give the tricyclic compounds 4. This cyclo-
propanation reaction should regenerate the pentacarbonyl-
tungsten species and so,a catalytic process could be feasible
solution of [W(CO) ],and then added to the solution of the
6
alkynol 1a. Experimentally easier are those conditions de-
veloped by McDonald and co-workers which suppose the in
situ generation of the catalytic [W(CO) ] species by continu-
5
ous irradiation of a THF solution of the alkynol in the pres-
ence of a catalytic amount of [W(CO) ] (5 mol%) and an
6
[5i]
excess (200 mol%) of an amine (Et N or DABCO). Sur-
3
prisingly,when we carried out the reaction of 1a under
these catalytic conditions,we did not observe the formation
of the expected tricyclic compound 4a; instead,we observed
the exclusive formation of the furan derivative 6a (94%
yield). At this point it seemed clear that the presence of an
amine in the reaction media was playing an important role
directing the reaction to the formation of the tricyclic com-
(
Scheme 2,cycle a). However,we were aware about the pos-
sibility of a competitive 5-exo-dig mechanism (Scheme 2,
[13]
pound 4a or the furan derivative 6a. In fact,we observed
different 4a/6a ratios depending on the amount of triethyl-
amine used. Thus,as shown in Scheme 3,treatment of alky-
nol 1a with 5 mol% [W(CO) ] and 20 mol% triethylamine
6
under constant irradiation at 350 nm led to the formation of
1
a 43:57 mixture of 4a and 6a as determined by H NMR
analysis of the crude of the reaction. When the amount of
triethylamine was reduced to 5 mol%,the ratio 4a/6a in-
creased to 61:39. Finally,by the use of only 2 mol% triethyl-
amine,the ratio was increased to 86:14,allowing the isola-
tion of tricyclic compound 4a in a pleasant 80% yield.
Lower amounts of triethylamine led to the formation of ap-
preciable quantities of decomposition products.
Scheme 2. Proposed catalytic cycles for the cycloisomerization reaction of
w-alkynols.
These preliminary studies let us to identify three different
Abstract in Spanish: La reacción de cicloisomerización de
catalytic systems: i) first,the catalyst [(thf)W(CO) ] which
5
derivados 1,1-disustituidos del 4-pentin-1-ol catalizada por
leads to the formation of tricyclic compound 4a (method
A); ii) the second catalytic system consists in the use of
5 mol% [W(CO) ] and 2 mol% Et N under constant irradi-
[
W(CO) ] ha sido estudiada tanto desde el punto de vista ex-
5
perimental como desde el teórico. Se han evaluado tres siste-
mas catalíticos {[(thf)W(CO) ] preformado, [W(CO) ]/exceso
6
3
ation (method B). Also,under these conditions the reaction
5
6
de Et N, y [W(CO) ]/2 mol% Et N}. Se ha observado que la
mainly leads to the formation of tricyclic compound 4a; iii)
3
6
3
reacción da lugar al producto formal de cicloisomerizacion
endo o al exo dependiendo de la cantidad de amina usada y
de la sustitución en la cadena carbonada del alquinol inicial.
El estudio teórico que hemos realizado nos ha permitido en-
contrar los mecanismos que explican la formación de los pro-
ductos formales de cicloisomerización endo o exo.
finally,by the use of 5 mol% [W(CO) ] and an excess of
amine (200 mol%),the reaction leads to the exclusive for-
mation of furan derivative 6a (method C).
6
Scope of the reaction: In order to check the generality of
the catalytic reactions above referred we performed a set of
experiments starting from different 1,1-disubstituted alky-
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Chem. Eur. J. 2005, 11,5735 – 5741

Cycloisomerization Reactions
FULL PAPER
scribed to other 1,1-disubstituted 4-pentyn-1-ols, we at-
tempted the reactions with alkynols 1h–r. Note that these
alkynols are also substituted at C position (Table 2). In an
2
initial experiment we treated alkynol 1h with 10 mol%
[
W(CO) ],excess of Et N and constant irradiation (method
6
3
C),and as expected,the reaction led to the furan derivatives
6
f. Surprisingly,when we treated the same alkynol 1h with
1
0 mol% preformed [(thf)W(CO) ] under standard condi-
5
tions (method A) or by the using of 10 mol% [W(CO) ],
6
2
mol% Et N,and constant irradiation (method B),the re-
3
action also produced the furan derivative 6 f and the expect-
ed tricyclic compound analogous to 4,was not observed
(
Table 2,entry 1). The same behavior was observed for
other C -substituted alkynols such as 1i–r (Table 2). Thus,
2
Scheme 3. Different reaction conditions for the cycloisomerization reac-
the corresponding furan derivatives 6 were isolated in very
high yield independently on the catalytic system used. In
some cases,the final product was isolated as the correspond-
ing isomerized furan derivative 6’.
tion of the alkynol derivative 1a. a) 25 mol% [(thf)W(CO)
b) 5 mol% [W(CO) ],200 mol% Et N,THF,50 8C, hn; c) 5 mol%
W(CO) ], x mol% Et N,THF,50 8C, hn. d) Isolated yield of 4a when
x = 2.
5
],THF,RT;
6
3
[
6
3
nols 1b–g containing an allyl moiety (Table 1). In general,
Table 2. Cycloisomerization reactions of the C
atives 1h–r.
2
-substituted alkynol deriv-
by the use of 25 mol% preformed [(thf)W(CO) ] (method
5
A) or 10 mol% [W(CO) ] and 2 mol% Et N under constant
6
3
irradiation (method B),we were able to isolate the tricyclic
compounds 4b–g in very high yield (entries 1–12). On the
other hand,reaction of the allyl substituted alkynols 1c,e–g
with 10 mol% [W(CO) ] and excess of Et N under constant
1
2
3
4
[a]
Alkynol
R
R
R
R
Product
Yield [%]
6
3
irradiation (method C) led to the formation of furan deriva-
tives 6b–e (entries 13–16).
1h
allyl
allyl
allyl
Me
allyl
allyl
allyl
vinyl
vinyl
Me
allyl
allyl
allyl
Me
-(CH
-(CH ) -
-(CH
-(CH
-(CH
-(CH
-(CH
Me
Ph
-(CH
Me
Me
H
) -
2 5
6 f
97
94
98
93
95
96
93
96
96
95
93
1
1
1
1
i
6g
6’h
6i
6’j
6k
6’l
6’m
6n
6’o
6p
j
k
l
Me
H
H
H
H
H
H
H
Influence of the substitution in the aliphatic chain: In an at-
tempt to further extend the catalytic reactions above de-
2
)
5
-
1m
2
2
2
2
2
2
4
3
5
4
5
4
1
1
1
1
1
n
o
p
q
r
)
)
)
)
)
-
-
-
-
-
Table 1. Cycloisomerization reactions of the alkynol derivatives 1b–g.
Me
[
a] Isolated yield based on starting alkynol 1. The yield refers to reaction
performed following method C. However,similar yields (always >90%)
were obtained following methods A or B. Method A: 25 mol% pre-
[
a]
[b]
formed [(thf)W(CO) ],THF,RT; method B: 10 mol% [W(CO)
6],
Entry Alkynol
R
Method
Product
Yield [%]
5
2
2
mol% Et
00 mol% Et
3
N,THF,50 8C, hn (350 nm); method C: 10 mol% [W(CO)
N,THF,50 8C, hn (350 nm).
6
],
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1b
1b
1c
1c
1d
1d
1e
1e
1 f
1 f
1g
1g
1c
1e
1 f
1g
Me
Me
Bu
Bu
c-C
c-C
Ph
Ph
4-MeOC
4-MeOC
(E)-PhCH=CH
(E)-PhCH=CH
Bu
Ph
4-MeOC
A
B
A
B
A
B
A
B
A
B
A
B
C
C
C
C
4b
4b
4c
4c
4d
4d
4e
4e
4 f
4 f
4g
4g
69
70
85
87
60
61
82
83
84
84
80
82
3
3
3
H
H
5
5
In a similar way, o-ethynylbenzyl alcohols 1s, t were trans-
formed into the corresponding isobenzofuran derivatives 6q,
r independently on the catalytic conditions used (Scheme 4).
These products are easily hydrolyzed and they have been
characterized as the corresponding hemiacetal 7a, b.
Some interesting disparities were observed when we per-
formed the catalytic reactions starting from alkynols diast-
6
6
H
H
4
4
0
1
2
3
4
5
6
6b + 6’b 93
6c
6d
6e
97
94
96
1
m and diast-1n (Scheme 5). Thus,the reaction of diast-1m
6 4
H
with both catalytic systems {[(thf)W(CO) ] or [W(CO) ]/
5
6
(E)-PhCH=CH
Et N} led to the tricyclic compound 4h. The furan derivative
3
[
a] Method A: 25 mol% preformed [(thf)W(CO)
5
],THF,RT; method B:
N,THF,50 8C, hn (350 nm); method C:
],200 mol% Et N,THF,50 8C, hn (350 nm). [b] Isolat-
analogous to 6 which was expected by the use of [W(CO) ]/
6
1
1
0 mol% [W(CO)
0 mol% [W(CO)
6 3
],2 mol% Et
excess Et N was not observed. On the other hand,alkynol
3
6
3
ed yield based on starting alkynol 1.
diast-1n did not react in any of the catalytic reaction condi-
Chem. Eur. J. 2005, 11,5735 – 5741
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
5737

J. Barluenga et al.
THF-Assisted mechanism: To investigate this mechanism
[12]
we employed,as in our previous theoretical study,
a
mixed model in which one THF molecule is coordinated to
the hydroxyl hydrogen atom while bulk solvent effects are
evaluated by the PCM-UAHF method.
The critical structures located along the THF assisted exo-
cycloisomerization of 2-methyl-5-hexyn-2-ol are similar to
those previously obtained for 4-pentyn-1-ol. This is a two-
step process in which the rate-determining step is the
second one (see Figure 1). Initially the alkyne–[W(CO)5]
Scheme 4. Cycloisomerization reactions of the o-ethynylbenzyl alcohols
s, t. Method A: 25 mol% preformed [(thf)W(CO) ],THF,RT; method
B: 10 mol% [W(CO) ],2 mol% Et N,THF,50 8C, hn; method C:
0 mol% [W(CO) ],200 mol% Et N,THF,50 8C, hn.
1
5
[12]
6
3
1
6
3
Scheme 5. Cycloisomerization reactions of alkynols diast-1m and diast-
1
n. Method A: 25 mol% preformed [(thf)W(CO)
B: 10 mol% [W(CO) ],2 mol% Et N,THF,50
0 mol% [W(CO) ],200 mol% Et N,THF,50 8C, hn.
5
],THF,RT; method
8C, hn; method C:
6
3
1
6
3
tions attempted and starting material was recovered in all
attempts.
Mechanisms and theoretical studies: Experimental results
[1c,5c]
previously reported elsewhere
as well as some of the ex-
perimental findings presented above show clearly that the
endo/exo ratio for the cycloisomerization of w-alkynols is
very sensitive to the substituents on the carbon backbone. It
is also evident from the experimental observations reported
above that the amine plays an important role in the mecha-
Figure 1. Gibbs energy profile in solution for the THF assisted exo-cyclo-
isomerization of 2-methyl-5-hexyn-2-ol. For a more detailed drawing of
all structures,see Supporting Information.
[13]
nism of the process.
complex, M1,evolves into the cyclic intermediate M2exo
À1
Trying to get a deeper understanding of the mechanism of
these reactions that helped us rationalize the experimental
results we undertook a theoretical investigation of the mech-
(5.4 kcalmol ) after surmounting an energy barrier of
À1
13.9 kcalmol corresponding to the transition state (TS)
TS12exo. M2exo yields the corresponding enol ether P
exo
À1
À1
anisms of the [W(CO) ]-promoted endo- and exo-cycloiso-
(À33.4 kcalmol ) through the TS TS2P (18.7 kcalmol )
5
exo
merizations of 1,1-disubstituted 4-pentyn-1-ols in THF using
for the migration of the hydrogen atom from the oxygen to
2
-methyl-5-hexyn-2-ol as a model. We studied both a THF-
the C atom.
a
[12]
assisted mechanism,analogous to that recently proposed
The critical structures along the endo-cycloisomerization
for the cycloisomerization of the C -unsubstituted 4-pentyn-
of 2-methyl-5-hexyn-2-ol also resemble those previously re-
1
[12]
1
-ol,and a Me N-assisted mechanism trying to understand
ported for 4-pentyn-1-ol.
The process follows a three-
3
the role played by an amine molecule in this process. We
also investigated the influence on the process of a double
stage mechanism (see Figure 2) in which the first and the
third TSs display similar energy barriers. M1 transforms into
À1
substitution at C position.
the vinylidene complex M2endo (2.2 kcalmol ) after sur-
2
À1
Full geometry optimizations were performed with the
B3LYP density functional method,by using the relativistic
effective core pseudopotential LANL2DZ for tungsten and
the 6-31G* basis set for the remaining atoms. To take into
account condensed-phase effects we used a PCM-UAHF
model with a relative permittivity of 7.58 to simulate THF
as the solvent used in the experimental work (for details see
Experimental Section and Supporting Information).
We will discuss in the text the evolution of the relative
Gibbs energy in solution along the above mentioned mecha-
nisms.
mounting a barrier of 17.6 kcalmol
corresponding to
TS12endo,and in turn M2
evolves into the cyclic structure
endo
À1
M3
(1.4 kcalmol ) through the TS TS23
(5.4 kcal
endo
endo
À1
mol ). Finally M3
(À24.0 kcalmol ) through the TS TS3P
yields the carbene complex P
endo
endo
À1
À1
(17.5 kcalmol )
endo
for the H transfer from the oxygen atom to the C atom.
b
By comparing the above results with those previously re-
[12]
ported for 4-pentyn-1-ol
we see that the two methyl
groups at C1 position favor both processes kinetically by
À1
practically 1 kcalmol . Therefore,as in the case of 4-
pentyn-1-ol,the present theoretical results for 2-methyl-5-
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Chem. Eur. J. 2005, 11,5735 – 5741

Cycloisomerization Reactions
FULL PAPER
which presents a geometrical structure quite similar to that
of TS2Pexo. For the endo-cycloisomerization the rate-deter-
À1
mining energy barrier (16.2 kcalmol ) corresponds to
TS3P’endo for the migration of the H atom from the oxygen
atom to the C atom. The geometrical structure of this TS
b
shows clearly that the trajectory of the migrating H atom is
appreciably modified by one of the methyl substituents at
C position (see Supporting Information and compare the
2
geometrical structures of TS3Pendo and TS3P’endo) giving rise
to an endo route less favorable than the exo one by
À1
2
.2 kcalmol . Therefore,these theoretical results rationalize
the experimental findings as the products obtained in the cy-
cloisomerization of C -substituted alkynols are the exo ones
2
[15]
(
see Table 2).
Me N-Assisted mechanism: To take into account the effect
3
of an amine in the [W(CO) ]-catalyzed cycloisomerization
5
of tertiary 4-pentyn-1-ols we included a Me N molecule co-
ordinated to the hydroxyl hydrogen atom of 2-methyl-5-
hexyn-2-ol instead of a THF molecule.
3
Figure 2. Gibbs energy profile in solution for the THF assisted endo-cy-
cloisomerization of 2-methyl-5-hexyn-2-ol. For a more detailed drawing
of all structures,see Supporting Information.
Along the Me N-assisted exo-route (see Figure 3) the
3
alkyne–[W(CO) ] complex, M1’’,evolves through the TS
5
À1
hexyn-2-ol render the endo-route more favorable than the
TS12’’exo (16.0 kcalmol ) to form the cyclic intermediate
À1
exo one by only 1.2 kcalmol and,consequently,the cyclic
carbene complex Pendo as the major product in agreement
with experiment.
Effect of two methyl substituents at C position: To study
2
the effect of two methyl substituents at C position on the
2
nature of the product obtained in the THF-assisted cycloiso-
merization of tertiary 1-alkyn-5-ols we investigated the
structure and corresponding energy barrier of the rate-deter-
mining TSs for the endo- and exo-cycloisomerizations of
2,3,3-trimethyl-5-hexyn-2-ol (see Figure S3 of the Supporting
Information and Table 3).
Table 3. Relative electronic energies and relative Gibbs energies in THF
À1
solution [kcalmol ] corresponding to the rate-determining TSs for the
THF-assisted endo- and exo-cycloisomerization of 2,3,3-trimethyl-5-
hexyn-2-ol.
Structures
DEelec
DGsol
3
Figure 3. Gibbs energy profile in solution for the Me N assisted exo-cy-
cloisomerization of 2-methyl-5-hexyn-2-ol. For a more detailed drawing
of all structures,see Supporting Information.
endo-pathway
M1’
TS12’endo
TS3P’endo
exo-pathway
M1’
0.0
17.1
15.7
0.0
13.6
16.2
À1
M2’’exo (À4.5 kcalmol ). It is interesting to note that this
0.0
14.2
0.0
14.0
TS2P’exo
cyclization takes place simultaneously with the transfer of
the hydroxyl hydrogen atom to the amine in contrast with
the THF assisted mechanism. M2’’exo yields the final exo-
À1
The presence of two methyl substituents at C position
provokes a diminution of the C -C -C angle with respect to
the unsubstituted system all along the reaction coordinate.
This distortion due to steric repulsions is larger in the initial
complex M1’ thus explaining the decrease of all the energy
barriers theoretically obtained for the rate-determining TSs
for both mechanisms (see Table 3). For the exo-cycloisome-
product P’’exo through the TS TS2P’’exo (À2.2 kcalmol ).
2
Therefore,the rate-determining step is now the first one
which corresponds to the intramolecular cyclization of the
alkyne moiety.
1
2
3
[14]
The endo-cycloisomerization (see Figure 4) proceeds
À1
through TS12’’endo (17.3 kcalmol ) to yield the vinylidene
À1
intermediate M2’’endo (1.8 kcalmol ),which transforms into
À1
À1
rization the rate-determining TS is TS2P’exo (14.0 kcalmol )
the cyclic structure M3’’endo (À3.8 kcalmol ) through
Chem. Eur. J. 2005, 11,5735 – 5741
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5739

J. Barluenga et al.
Conclusion
We have studied in deep the [W(CO) ]-catalyzed cycloiso-
5
merization of 1,1-disubstituted 4-pentyn-1-ol derivatives
from both the experimental and theoretical point of view.
Experimentally,we observed that the reaction is highly de-
pendent on the amount of amine used in the catalytic
system. Thus,by the use of an excess of amine,the reaction
proceeds through an exo-cyclization reaction furnishing
furan derivatives. On the other hand,when only 2 mol%
amine is used,the reaction proceeds through a formal endo-
cyclization reaction. Following this later catalytic strategy
we were able to easily access to tricyclic derivatives which
are precursors of eight-membered carbocycles. Moreover,
the substitution along the alkyl chain of the alkynol may
also play a fundamental role on the reaction pathway. Spe-
cifically,we observed that exo-products are exclusively
formed when the starting alkynol is substituted at the C po-
2
sition.
Theoretically,we have found the endo- and exo-mecha-
nisms of the reactions in the absence and in the presence of
amine and also we have studied the effect of the substitution
3
Figure 4. Gibbs energy profile in solution for the Me N assisted endo-cy-
cloisomerization of 2-methyl-5-hexyn-2-ol. For a more detailed drawing
of all structures,see Supporting Information.
at C position. All the theoretical results are in agreement
2
with the experiments and clearly show that the rate deter-
mining barriers found for both the endo- and exo-mecha-
nisms are energetically close thus explaining that small
changes in the reaction conditions or the structure of the
starting alkynol may affect the distribution of the products.
Although the compounds obtained following the catalytic
reactions here described are of undoubted interest from a
synthetic point of view,probably the most interesting aspect
of the present study is that it provides an important advance
À1
TS23’’endo (8.4 kcalmol ). As in the exo-mechanism,this cyc-
lization takes place with the concerted transfer of the hy-
droxyl hydrogen atom to the amine. M3’’
evolves to the
endo
À1
intermediate M4’’endo (À6.4 kcalmol ) through the TS
À1
TS34’’endo (À2.4 kcalmol ) for the shift of the H-NMe
3
moiety close to the C atom. The final enol ether, P’’
a
endo
À1
(
À28.3 kcalmol ),is obtained from M4’’
by the transfer
in the understanding of the mechanisms of the [W(CO) ]-
endo
5
of the hydrogen atom of the H-NMe moiety to the C atom
catalyzed reactions. This will help to predict,in many cases,
the result of a proposed reaction and/or to choose the right
conditions to obtain the desired product.
3
a
À1
through the TS TS4P’’endo (1.2 kcalmol ). Thus the rate-de-
termining step is the first one corresponding to the alkyne–
vinylidene rearrangement.
It is interesting to note that in contrast with the THF as-
sisted mechanisms both in M2’’exo and M3’’endo the hydroxyl
hydrogen atom is completely transferred to the amine thus
facilitating its migration. Therefore,an important effect of
the assistance by the amine molecule consists in considera-
bly stabilizing the last part of the energy profiles thus reduc-
ing the implied energy barriers so that the rate-determining
step for both processes is the first one. Also the presence of
Experimental Section
1
General methods: H NMR spectra were recorded on a Bruker AMX-
400 (400 MHz) or Bruker DPX-300 (300 MHz). Chemical shifts are re-
ported in ppm from tetramethylsilane with the residual solvent resonance
3
as the internal standard (CHCl : d 7.26). Data are reported as follows:
chemical shift,multiplicity (s: singlet,d: doublet,dd: double doublet,td:
triplet of doublets,t: triplet,q: quartet,br: broad,m: multiplet),coupling
the Me N molecule modifies the endo-mechanism so that
3
the system does not evolves through the carbene complex
13
constants (J in Hz),integration and assignment. C NMR spectra were
anymore the final product being the enol ether P’’endo
According to the present theoretical results the Me N-as-
.
recorded on a Bruker AMX-400 (100 MHz) or Bruker DPX-300 (75
MHz) with complete proton decoupling. Chemical shifts are reported in
ppm from tetramethylsilane with the solvent resonance as internal stan-
3
sisted exo-mechanism is now favored over the endo one by
3
dard (CDCl : d 76.95). Two-dimensional NMR experiments (COSY,
À1
1
.3 kcalmol and,consequently,the major product predict-
HMQC,HMBC and NOESY) were recorded on a Bruker AMX-400
(400 MHz). High-resolution mass spectrometry was carried out on a Fin-
nigan-Mat 95 spectrometer. All reactions were conducted in flame-dried
glassware under an inert atmosphere of argon. Tetrahydrofuran was dis-
tilled from sodium/benzophenone and triethylamine was distilled from
calcium hydride and stored under nitrogen. Photochemical reactions
were performed with a medium-pressure mercury lamp (350 nm,400 W)
using a Pyrex reactor.
ed is the enol ether P’’exo in agreement with experiment.
5740
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Chem. Eur. J. 2005, 11,5735 – 5741

Cycloisomerization Reactions
FULL PAPER
General procedure for the domino tungsten-catalyzed cycloisomeriza-
tion–cyclopropanation of w-alkynols 1
[
1] For some reviews,see: a) F. Alonso,I. P. Beletskaya,M. Yus, Chem.
Rev. 2004, 104,3079–3160; b) B. Weyershausen,K. H. Dçtz, Eur. J.
Inorg. Chem. 1999,1057–1066; c) F. E. McDonald, Chem. Eur. J.
1999, 5,3103–3106.
2] a) M. I. Bruce, Chem. Rev. 1998, 98,2797–2858; b) A. Parlier,H.
Rudler, J. Chem. Soc. Chem. Commun. 1986,514–515.
3] B. M. Trost,Y. H. Rhee, J. Am. Chem. Soc. 2002, 124,2528–2533.
4] B. M. Trost,Y. H. Rhee, J. Am. Chem. Soc. 2003, 125,7482–7483.
5] a) E. Alcµzar,J. Pletcher,F. E. McDonald, Org. Lett. 2004, 6,3877–
Method A: The corresponding w-alkynol 1 (1 mmol) was added to a
5
THF solution of [W(CO) ]·THF complex (10 mL,0.025 m),previously
[
1]
prepared according to the literature procedure. The solution was con-
centrated under vacuum to approx. 2 mL volume and carefully degassed
following a standard freeze-pump-thaw method (three cycles). The result-
ing mixture was stirred at room temperature,in the absence of light,
during one or two days until complete conversion (monitored by TLC).
After removing of the solvent,the crude was purified by flash column
chromatography on silica gel or activated aluminum oxide neutral (com-
pound 2h). Hexane/ethyl acetate or pentane/diethyl ether were used as
eluents.
[
[
[
[
3
1
880; b) M. H. Davidson,F. E. McDonald, Org. Lett. 2004, 6,1601–
604; c) P. Wipf,T. H. Graham J. Org. Chem. 2003, 68,8798–8807;
d) K. A. Parker,W. Chang, Org. Lett. 2003, 5,3891–3893; e) F. E.
McDonald,M. Wu, Org. Lett. 2002, 4,3979–3981; f) W. W. Cutchins,
F. E. McDonald, Org. Lett. 2002, 4,749–752; g) F. E. McDonald,
K. S. Reddy, Angew. Chem. 2001, 113,3767–3769; Angew. Chem.
Int. Ed. 2001, 40,3653–3655; h) F. E. McDonald,K. S. Reddy, J. Or-
ganomet. Chem. 2001, 617–618,444–452; i) F. E. McDonald,K. S.
Reddy,Y. Díaz, J. Am. Chem. Soc. 2000, 122,4304–4309.
6
Method B: [W(CO) ] (36 mg,0.1 mmol), w-alkynol (1 mmol),dry tri-
ethylamine (2.8 mL,0.02 mmol),and freshly distilled THF (2 mL),were
placed in a sealed tube (Pyrex) under argon. The resulting slurry was
carefully degassed following a standard freeze-pump-thaw (three cycles).
The mixture was placed under an inert atmosphere of argon and irradiat-
ed with a medium-pressure mercury lamp (350 nm,400 W) during 12 h
without refrigeration. Solvent was removed and residue was worked up
as described in method A.
[
6] a) M. Suzuki,A. Yanagisawa,R. Noyori, Tetrahedron Lett. 1983, 24,
1
1
187–1188; b) M. Riediker,J. Schwartz, J. Am. Chem. Soc. 1982,
04,5842–5844.
General procedure for the tungsten-catalyzed 5-exo-cycloisomerization of
w-alkynols 1
[
7] a) P. Pale,J. Chuche, Eur. J. Org. Chem. 2000,1019–1025; b) P. Pale,
J. Chuche, Tetrahedron Lett. 1987, 28,6447–6448.
Method C: [W(CO)
6
] (36 mg,0.1 mmol), w-alkynol (1 mmol),dry tri-
[8] a) Y. Hu,Y. Z hang,Z. Yang,R. Fathi,
J. Org. Chem. 2002, 67,
Tetra-
ethylamine (0.18 mL,2 mmol),and freshly distilled THF (2 mL),were
placed in a sealed tube (Pyrex) under argon. The resulting slurry was
carefully degassed following a standard freeze-pump-thaw (three cycles).
The mixture was placed under an inert atmosphere of argon and irradiat-
ed with a medium-pressure mercury lamp (350 nm,400 W) during 12 h
without refrigeration. Solvents were removed and residue was filtered
over a short plug of dry Celite with hexane and the resulting solution was
concentrated in vacuo. The crude product was usually chromatographi-
cally pure. a-Methylene enol ethers thus obtained were very sensitive to
moisture and,in general,purification by flash-chromatography in silica
gel or alumina affords the corresponding hemiacetal or hydrolysis deriva-
tive.
2365–2368; b) K. Kato,M. Tanaka,Y. Yamamoto,H. Akita,
hedron Lett. 2002, 43,1511–1513; c) F.-T. Luo,I. Schreuder,R.-T.
Wang, J. Org. Chem. 1992, 57,2213–2215.
[9] J. S. Ravi Kumar,M. F. OꢁSullivan,S. E. Reissman,C. A. Hulford,
T. V. Ovaska, Tetrahedron Lett. 2002, 43,1939–1941,and references
therein.
[10] J. Barluenga,A. DiØguez,F. Rodríguez,J. Flórez,F. J. FaÇanµs,
Am. Chem. Soc. 2002, 124,9056–9057.
J.
[11] For a preliminary communication,see: J. Barluenga,A. DiØguez,F.
Rodríguez,F. J. FaÇanµs, Angew. Chem. 2005, 117,128–130; Angew.
Chem. Int. Ed. 2005, 44,126–128.
[12] T. Sordo,P. Campomanes,A. DiØguez,F. Rodríguez,F. J. FaÇanµs,
J.
Am. Chem. Soc. 2005, 127,944–952.
[
13] McDonald and co-workers have also observed that the nature of the
tertiary amine plays an important role on the endo/exo ratio,see
ref. [5a].
14] P. G. Sammes,D. J. Weller, Synthesis 1995,1205–1222.
Acknowledgements
[
[
2
15] A loss in endo-selectivity by introduction of a substitution at C po-
This research was supported by the DGICYT of Spain (BQU-2001-3853
and PB97-1271) and Principado de Asturias (PR-01-GE-9). A.D. ac-
knowledges predoctoral grants from FICYT of Principado de Asturias
and Universidad de Oviedo. F.R. is grateful to MEC of Spain (“Ramón y
sition was also observed by Wipf and co-workers,see ref. [5c].
Cajal” contract). Generous financial support from Merck Sharp
Dohme and computer facilities from CIEMAT are acknowledged.
&
Received: May 13,2005
Published online: July 20,2005
Chem. Eur. J. 2005, 11,5735 – 5741
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA,Weinheim
www.chemeurj.org
5741