Comparative investigation of kinetic consequences associated with long-range electronic effects on catalytic ruthenium-promoted ring-closing metathesis

Article abstract of DOI:10.1016/S0040-4039(02)01064-X

When exposed to the Grubbs ruthenium catalyst, trienyl substrates of type 4 undergo highly regioselective ring closure to give the common product 5. These reactions proceed invariably under pseudo-first-order kinetics, considerably faster when X=H (t

Full text of DOI:10.1016/S0040-4039(02)01064-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5453–5456
Comparative investigation of kinetic consequences associated
with long-range electronic effects on catalytic
ruthenium-promoted ring-closing metathesis
Kallol Basu, Jose A. Cabral and Leo A. Paquette*
Evans Chemical Laboratories, The Ohio State University, Columbus, OH 43210, USA
Received 14 March 2002; accepted 4 June 2002
Abstract—When exposed to the Grubbs ruthenium catalyst, trienyl substrates of type 4 undergo highly regioselective ring closure
to give the common product 5. These reactions proceed invariably under pseudo-first-order kinetics, considerably faster when
X=H (t1/2=9.1), followed by X=CO Et (t1/2=26.5). © 2002 Elsevier Science Ltd. All rights reserved.
2
The ready availability of stable, user-friendly ruthe-
phine dissociation in 1 is a critical step along the
reaction coordinate, that phosphine exchange operates
by way of a dissociative scheme, and that metallocy-
clobutanes are likely not intermediates but transition
states along the reaction pathway.
1
nium-based catalysts and the excellent tolerance o2f
these agents toward many polar functional groups
represent two factors responsible for the recent wide-
spread adoption of ring-closing metathesis in organic
3
synthesis. High reaction efficiency and the straightfor-
ward manner in which a,v-dienes can be transformed
4
into 5- to 12-membered cyclic dienes and beyond have
also served as important considerations. A given trans-
formation is notably favored if nonbonded steric con-
gestion is absent and the associated enthalpic term is
5
small. The potential reversibility of the process is
thereby turned to advantage.
In contrast to the above, relatively little systematic
effort has been directed toward an appreciation of
catalyst reactivity vis- a` -vis alkenes characterized by
The general mechanistic paradigm advanced by Chau-
6
9
vin in 1970 involves the production of a metal car-
widely divergent p characteristics. In a singular study,
benoid, which is subject in turn to intramolecular [2+2]
cycloaddition. Subsequent electronic reorganization
resulting in [2+2] cycloreversion liberates the cyclic
olefin and regenerates the parent metal alkylidene. The
latter engages the starting diene in a second (now
intermolecular) cycloaddition, liberation of ethylene
from which eventuates in catalyst turnover and the
conversion to more of the initial reactant. Recent mech-
anistic investigation has provided additional important
Kirkland and Grubbs examined the response of 2 to the
10
action of 1 as a function of the substituent R. When
2
(R=C H ) was exposed to 1 in CH Cl at room
2
5
2
2
temperature, conversion to 3 (R=C H ) proceeded in
2
5
9
3% yield over 24 h. Under comparable conditions,
enol ethers (e.g. R=OCH ) proved unreactive as fore-
shadowed.
3
11
Substitution with electron-withdrawing
groups such as phenyl and carbomethoxy resulted in
cyclization levels of 25 and 5%, respectively. For the
derivatives having R=CH OH and CH OAc, behavior
7,8
insight into this catalytic cycle. For example, the new
experimental observations have established that phos-
2
2
comparable to ethyl was noted.
Keywords: cyclization; metathesis; kinetics; ruthenium; electronic
effects.
*
Corresponding author. Tel.: 614-292-2520; e-mail: paquette.1@
osu.edu
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01064-X

5
454
K. Basu et al. / Tetrahedron Letters 43 (2002) 5453–5456
In the present study, we have chosen to probe the
reactivity limits of ruthenium alkylidenes in a different
manner, and in doing so to answer several mechanistic
questions and offer useful new preparative insight. Our
guidelines provided for attachment of the group X
directly to the double bond as in 4 in order to achieve
maximum electronic impact, while simultaneously
arranging for a neighboring conjugated double bond to
serve as the reaction center in order to normalize
possible steric contributions (Scheme 1). The process is
illustrated by the conversion of 4 to 5. The substrates
were designed to generate 4-benzyloxycyclohexene in
every case as a consequence of the more favored rate of
Scheme 1.
15
encountered. The least reactive nature of enol ether 4a
and the overall kinetic profile reflected in Table 1 reveal
that electronic modulation is an important contributing
factor in ring-closing metathesis even when the sub-
stituent is not directly connected to the double bond
that is undergoing cleavage. These phenomena are con-
sistent with the concept that polarization within the
12
6
-membered ring formation. The object was to deter-
mine how the electronic character in the C3ꢀC4 double
bond would affect the rate at which 5 was generated.
The catalyzed transformations of 4 were followed by
monitoring the disappearance of the methine proton in
16
ruthenium alkylidene is central to its reactivity,
although alternative explanations cannot be entirely
4
and the appearance of the methine proton in 5. The
1
concentrations of 4 were derived from integration of H
NMR resonances as a function of time (Fig. 1). The
fraction of 4 was established as CH /(CH +CH ),
S
S
P
where CH is the integration of the methine proton in
P
5
. This method assumes that all CH is converted to
S
CH , in line with the spectral observations and isolated
P
yields. In the case of the methoxy derivative 4a, the
integration of CH was not possible due to the coinci-
P
dence of the chemical shift resonances for CHP and
OCH . In this instance, the fraction of starting material
3
was established by referencing the integration of CHS
to the integration of the C H signal, or CHS=CHS/
6
5
[
C H /5]. Each fraction of CH was then multiplied by
6 5 S
the starting concentration 0.030 M to yield the concen-
tration of CH as a function of time for each run.
S
The resulting concentration of CH at time t for each
S
run was then plotted as a function of t in min according
to first-order (Eq. (1)) and second-order rate equations
(
Eq. (2)), where [CH ] is the concentration of the
S t
methine proton at time t and [CH ] at the initial time.
S 0
ln[CH ] =−k×t+ln[CH ] where t1/2=ln 2/k
(1)
(2)
S t
S 0
1
/[CH ] =+k×t+1/[CH ] where t1/2=1/k×[CHS]0
S t S 0
A linear correlation obtained from these plots indicates
the order of the reaction and provides the apparent rate
constant, k, for the reaction. Second-order rate analysis
yielded linear regression correlation values of less than
0
.94. Instead, all of the kinetic data recorded were
found to obey the first-order linear regression analysis
Eq. (1)). The relevant data are compiled in Table 1 and
(
a sample plot is given in Fig. 2.
Of the four examples bearing electron-withdrawing sub-
stituents, ethyl ester 4e was the most reactive, followed
1
3
in turn by phenyl sulfone 4c and methyl ketone 4b.
Nitrile 4h did not enter productively into the cyclization
process, mirroring instead the well-known unreactivity
of acrylonitrile toward olefin metathesis. Treatment of
substrate 4d with 1 led smoothly to 5, but at a some-
what faster rate than those exhibited by 4b and 4c. In
the case of sulfide 4g, rapid catalyst deactivation was
14
1
Figure 1. A stacked H NMR plot for the ring-closing
metathesis of 4e.

K. Basu et al. / Tetrahedron Letters 43 (2002) 5453–5456
5455
a
Table 1. Summary of kinetic data and isolated yield of 5
Compd
X
k (1/min) (first order)
t1/2 (min)
Regression analysis, r
Isolated yield of 5 (%)
4
4
4
4
4
4
4
4
a
b
c
d
e
f
CH O-
0.0062
0.0154
0.0178
0.0215
0.0261
112.994.6
45.090.9
38.890.3
32.291.1
26.590.4
9.190.4
0.9933
0.9612
0.9866
0.9712
0.9948
0.9695
85
83
86
77
65
80
–
3
CH CO-
3
PhSO2-
HOCH2-
EtOOC-
H-
PhS-
NC-
0.0762
b
g
h
b
–
a
The ring closures were performed in duplicate at 300 K in the probe of a Bruker 300 MHz spectrometer under N2 in the presence of 5 mol%
of 1 at a substrate concentration of 0.030 M.
Rapid poisoning of the catalyst was observed.
b
nium atom in these metal carbenoids. If operational
here, approach of the two ends of the reactant would be
facilitated somewhat
consequences.
with
associated
kinetic
In conclusion, we have demonstrated that the conver-
sion of 4a–g to the common product 5 proceeds
efficiently, albeit at rates that reflect their electronic
makeup. The observation that electron-donating sub-
stituents on the double bond adjoining the seat of
reaction decelerate the metathesis does not impact on
reaction efficiency, which remains high throughout the
series.
Acknowledgements
Figure 2. First-order kinetic plot for 4a.
K.B. was the recipient of a fellowship funded by Aven-
tis Pharmaceuticals.
dismissed. In actuality, the present investigation raises
many interesting mechanistic issues. For example, is the
terminal alkene invariably the site of initiation in elec-
tronically strongly biased substrates of the type 4a–f? If
so, is the presence of a remote electron-withdrawing
substituent capable of negative charge stabilization con-
ducive to a Michael-type intramolecular addition
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