Organocatalytic Claisen rearrangement: Theory and experiment

Article abstract of DOI:10.1021/jo062455y

(Chemical Equation Presented) A combined computational and experimental study on the Claisen rearrangement of a 2-alkoxycarbonyl-substituted allyl vinyl ether in the presence of thioureas as potential noncovalent organocatalysts has been performed. DFT ca

Full text of DOI:10.1021/jo062455y

Organocatalytic Claisen Rearrangement: Theory and Experiment
Martin Kirsten,† Julia Rehbein,‡ Martin Hiersemann,*,‡ and Thomas Strassner*,†
Physical Organic Chemistry, Technical UniVersity Dresden, D-01069 Dresden, Germany, and Lehrbereich
Organische Chemie, Fachbereich Chemie, UniVersita¨t Dortmund, D-44227 Dortmund, Germany
martin.hiersemann@uni-dortmund.de; thomas.strassner@chemie.tu-dresden.de
ReceiVed NoVember 30, 2006
A combined computational and experimental study on the Claisen rearrangement of a 2-alkoxycarbonyl-
substituted allyl vinyl ether in the presence of thioureas as potential noncovalent organocatalysts
has been performed. DFT calculations employing different basis sets were utilized to predict a catalytic
cycle for the thiourea-catalyzed Claisen rearrangement. The nature of the transition state in the presence
and absence of thioureas was studied in detail. Critical geometrical data of the transition state that
are indicators for the relative barrier height of the Claisen rearrangement are discussed. Although we
did observe a significant transition state stabilization, due to endergonic conformational changes and
endergonic complexation the overall effect on the barrier is small, in accordance with experimental
results.
Introduction
Catalysis is a very important principle in chemistry and
biochemistry. Many processes in industry use catalysts which,
until recently, have frequently employed transition metals.
However, a steadily increasing number of transformations that
utilizes small “organic” molecules as organocatalysts are being
reported.1
FIGURE 1. Specific interaction of water molecules with allyl vinyl
ether and general catalyst design according to Jorgensen.
In noncovalent organocatalysis, the basic principle of activa-
tion is the selective stabilization of the transition state by
hydrogen bonding.2,3 Ureas and thioureas have been used
frequently for this purpose because of their well-known ability
of molecular recognition and complex formation.4
Before 1990, several research groups had noticed an ac-
celerating effect of protic solvents5 or Brønsted acids6 on the
rate of the thermal Claisen rearrangement. Jorgensen utilized
quantum mechanical calculations to explain the accelerating
effect of protic solvent systems (Figure 1).7 On the HF/6-31G(d)
level of theory Jorgensen found an enhanced polarization of
the transition state compared to that of the allyl vinyl ether
substrate. Proceeding from the substrate to the transition state,
the partial negative charge on the ether oxygen atom increases,
which promotes stronger hydrogen bonding. Furthermore, due
to the elongation of the C/O bond in the transition state, the
solvent accessibility of the ether oxygen atom is increased,
which supports the hydrogen bonding of two water molecules
instead of one water molecule in the substrate.8,9 On the basis
of these computational results, Jorgensen suggested a catalyst
design that incorporates two hydrogen bond-donating sites in
appropriate position to interact with the ether oxygen atom of
the transition state of the Claisen rearrangement.
The first attempt to realize the Jorgensen catalyst design
utilized the urea derivative 2a and the 6-methoxy-substituted
allyl vinyl ether 1 (Scheme 1).10,11 Using catalytic amounts of
2a, Curran et al. determined a small rate acceleration (kcat/kuncat
)
† Technical University Dresden.
‡ Universita¨t Dortmund.
2.7) at 80 °C by NMR experiments in benzene-d6. The rate
accelerating effect further increased in the presence of stoichio-
metric amounts of 2a (kcat/kuncat) 22.4). It is worth mentioning
that the thiourea derivative 2b was less efficient probably due
to its decomposition at the reaction temperature. In accordance
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10.1021/jo062455y CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/04/2007
J. Org. Chem. 2007, 72, 4001-4011
4001

Kirsten et al.
SCHEME 1. Urea-Catalyzed Claisen Rearrangement and
Bis(hydrogen) Bonded Transition State Model According to
Curran
The polarization of the transition state of the thermal aliphatic
Claisen rearrangement in general has been confirmed by many
computational studies at different levels of theory.12 However,
no detailed computational investigation to support the predicted
transition state stabilization in the presence of a bis(hydrogen)
bonded urea is currently available.13
It was shown before and particularly after the important work
of Curran that a variety of different reactions may be catalyzed
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White, W. N.; Wolfarth, E. F. J. Org. Chem. 1970, 35, 3585-3585. (e)
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4002 J. Org. Chem., Vol. 72, No. 11, 2007

Organocatalytic Claisen Rearrangement
FIGURE 2. Bis(hydrogen) bond binding modes of thiourea catalysts
according to Curran and Schreiner.
by ureas and thioureas.14 However, despite its undisputed
synthetic value, the Claisen rearrangement was apparently not
further investigated. Therefore, we have initiated a research
project aimed at the development of an organocatalytic asym-
metric Claisen rearrangement (OCAC).15 For the initial studies,
we opted for the achiral 1,3-bis-(3,5-bis(trifluoromethyl)phenyl)-
thiourea 5 as the potential noncovalent organocatalyst. This
particular thiourea has been developed and utilized by Schreiner
for the catalysis of a Diels-Alder reaction and, more recently,
acetalization as well as nucleophilic epoxide ring opening.16 On
the basis of computational studies, Schreiner proposed the bis-
(hydrogen) bond binding models B and C which complement
Curran’s initial binding model A for the Claisen rearrangement
(Figure 2).
FIGURE 3. Proposed transition state stabilization for the Claisen
rearrangement by bidentate thiourea coordination.
lization. A detailed computational study was performed to
predict the consequences of the two binding modes on the nature
of the transition state of the Claisen rearrangement. Here, we
report the results of this endeavor and provide preliminary
experimental data to support the conclusions from the compu-
tational study.
The substituent pattern of an allyl vinyl ether is pivotal for
its accessibility, its inherent reactivity in the thermal and the
catalyzed rearrangement, and most importantly, the synthetic
value of the rearrangement product. Acyclic 2-alkoxycarbonyl-
substituted allyl vinyl ethers are easily accessible on multigram
scale, storable, and provide useful R-keto ester building blocks
as products of the Claisen rearrangement.17 Therefore, we
selected the simple 2-isopropoxycarbonyl-1-methyl-substituted
allyl vinyl ether 718 as substrate for this study (Figure 3).19
Initially, we had to consider two general bis(hydrogen) bond
binding modes between the transition state of the Claisen
rearrangement and the thiourea catalyst (Figure 3). Complex 4
should be more favorable with respect to binding because of
the involvement of the more Brønsted basic carbonyl oxygen
atom. However, we expected that binding mode 6 would be
more favorable with respect to selective transition state stabi-
Computational Methods
All calculations were performed with Gaussian03.20 The density
functional hybrid model Becke3LYP21 was used together with the
valence double-ú basis set 6-31G(d) as well as the valence triple-ú
basis sets 6-311+G(d,p) and 6-311++G(d,p). It has been shown
that calculations with the Becke3LYP functional predict energies
and geometries of hydrocarbon pericyclic reactions in general, and
the aliphatic Claisen rearrangement in particular, with reasonable
accuracy.12e,22 No symmetry or internal coordinate constraints were
applied during optimizations. All reported intermediates were
verified as true minima by the absence of negative eigenvalues in
the vibrational frequency analysis. Transition-state structures were
located by using the Berny algorithm23 until the Hessian matrix
had only one imaginary eigenvalue. The identity of all transition
states was confirmed by the presence of only one negative
eigenvalue in the frequency analysis and animating this eigenvector
(20) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian03, Rev. C.02; Gaussian, Inc.: Wallingford, CT, 2004.
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C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789. (c) Stephens,
P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994,
98, 11623-11627. (d) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys.
1980, 58, 1200-1211.
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12652-12653. (e) Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 6366-6370. (f) De Rosa, M.; Citro, L.; Soriente, A.
Tetrahedron Lett. 2006, 47, 8507-8510. (g) Berkessel, A.; Roland, K.;
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on Lewis acid catalysis, see: (a) Abraham, L.; Ko¨rner, M.; Schwab, P.;
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(19) Experimentally determined activation parameters for thermal Claisen
rearrangement of (Z)-7: ∆G# ) 27.5 kcal mol-1 at 298.15 K, k ) 2.8 ×
10-5 s-1 in benzene-d6 at 80 °C.
J. Org. Chem, Vol. 72, No. 11, 2007 4003

Kirsten et al.
TABLE 1. Conformational Analysis of Thiourea 5 at Different
Levels of Theory
TABLE 2. Calculated (B3LYP/6-311++G**) Geometric Data and
Relative Free Energy of Relevant Conformers of the Allyl Vinyl
Ether 7
B3LYP free energy [kcal mol-1
]
entry
compd
6-31G*
6-311+G**
6-311++G**
1
2
3
5a
5b
5c
+1.76
+0.79
0
+0.87
+0.65
0
+0.84 (0.00)a
+0.78 (0.29)a
0 (1.79)a
a Single-point energies (HF) with use of the PCM solvent model for
dichloroethane (in parentheses).
bond distances [Å]
dihedral
Grel
entry
compd
O1-C1′ C3-C3′ angle ω [deg]
[kcal mol-1
]
1
2
3
4
s-trans-7a
s-trans-7b
s-cis-7a
1.45
1.45
1.44
1.45
5.53
4.57
5.49
4.34
-171
-169
+7
0 (0)a
coordinate with MOLDEN.24 Approximate free energies were
obtained through thermochemical analysis of the frequency calcula-
tion, using the thermal correction to the Gibbs free energy as
reported by Gaussian03. This takes into account zero-point effects,
thermal enthalpy corrections, and entropy. All energies reported in
+0.47 (+0.44)a
+0.55 (+0.08)a
+0.98 (+0.56)a
s-cis-7b
+10
a Single-point energies (HF) with use of the PCM solvent model
dichloroethane (in parentheses).
this paper, unless otherwise noted, are free energies (in kcal mol-1
)
at 298 K and 1 atm. Frequencies remain unscaled. All transition
states are maxima on the electronic potential energy surface. These
may not correspond to maxima on the free energy surface.
The charge separation between the positively charged allylic and
negatively charge oxallylic fragments of the allyl vinyl ether was
analyzed by Mullikan charges as well as the natural bond orbital
(NBO) approach of Weinhold et al.25a
TABLE 3. Calculated (B3LYP/6-311++G**) Geometric Data and
Relative Free Energy of Relevant Conformers of the r-Keto Ester 9
The free energy of solvation was calculated in terms of the
polarizable continuum model (PCM).25b The self-consistent reaction
field (SCRF) calculations with the PCM-UA0 solvation model25c
were carried out as single-point calculations at the B3LYP/6-
311++G** level of theory for the gas-phase optimized structures.
The dielectric constant in the PCM calculations was set to ꢀ )
10.36 to simulate dichloroethane as one solvent medium frequently
used in the experimental study.
bond distances [Å]
dihedral
Grel
[kcal mol-1
]
Computational Results and Discussion
entry
compd
O1-C1′ C3-C3′ angle ω [deg]
1
2
3
4
s-trans-9a
s-cis-9a
s-trans-9b
s-cis-9b
5.26
5.28
4.26
4.23
1.54
1.54
1.56
1.56
-144
+49
+160
-52
0 (0)a
To predict a complete catalytic cycle for the thiourea-
catalyzed Claisen rearrangement, a thorough conformational
analysis of the thiourea 5, the substrate 7, and the R-keto ester
9 was required. We embarked on this endeavor with a
+1.44 (+0.70)a
+1.43 (+0.99)a
+2.45 (+1.80)a
a Single-point energies (HF) with use of the PCM solvent model
dichloroethane (in parentheses)
26
conformational study of the thiourea derivative 5 (Table 1).
The conformer 5c was found to be most stable for all basis sets
in the gas phase, while solvent single-point calculations predict
5a to be the most stable conformer. The proposed bis(hydrogen)
bond binding mode requires the thiourea to adopt the conforma-
tion 5a. In agreement with previous DFT calculations of
Custelcean et al., the energetic difference between the conform-
ers decreases when the basis set increases.27 With the triple-ê
basis sets, the energetic difference between the thiourea
conformers 5a-c is very small and the conformers should be
in a rapid equilibrium. Entropy and enthalpy changes for the
conformational changes are given in the Supporting Information.
Because the accurate description of hydrogen bonding28 is
pivotal for the computational analysis of the proposed catalytic
cycle, we utilized the 6-311++G(d,p) basis set for further
calculations.
The conformational analysis of 2-alkoxycarbonyl-substituted
allyl vinyl ethers 7 has to consider the s-cis/s-trans equilibrium
of the R,â-unsaturated ester and the dihedral angle ω was
assigned to denote the conformation (Table 2). Qualitatively,
one would expect that a dihedral angle ω of 0° (synperiplanar)
(24) Schaftenaar, G.; Noordik, J. H. J. Comput.-Aided Mol. Des. 2000,
14, 123-124.
(25) (a) Reed, A. E.; Curtis, L. A.; Weinhold, F. Chem. ReV. 1988, 88,
899-926. (b) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55,
117-129. (c) Barone, V.; Cossi, M.; Tomasi, J. J. Chem. Phys. 1997, 107,
3210-3221.
(26) For recent computational studies on the conformation of substituted
ureas and thioureas, see: (a) Bryantsev, V. S.; Firman, T. K.; Hay, B. P. J.
Phys. Chem. A 2005, 109, 832-842. (b) Bryantsev, V. S.; Hay, B. P. J.
Phys. Chem. A 2006, 110, 4678-4688.
(27) Custelcean, R.; Gorbunova, M. G.; Bonnesen, P. V. Chem. Eur. J.
2005, 11, 1459-1466.
(28) (a) Zierkiewicz, W.; Jurecka, P.; Hobza, P. Chem. Phys. Chem. 2005,
6, 609-617. (b) Scheiner, S.; Grabowski, S. J.; Kar, T. J. Phys. Chem. A
2001, 105, 10607-10612. (c) Liu, Y.; Liu, W.-Q.; Li, H.-Y.; Yang, Y.;
Cheng, S. Chin. J. Chem. 2007, 25, 44-52. (d) Wojtulewski, S.; Grabowski,
S. J. Chem. Phys. 2005, 309, 183-188.
4004 J. Org. Chem., Vol. 72, No. 11, 2007

Organocatalytic Claisen Rearrangement
TABLE 4. Calculated (B3LYP/6-311++G**) Geometric Data and Free Energy (kcal mol-1) for the Proposed Catalytic Cycle
(Ar ) 3,5-CF3-C6H3) of s-trans-7b
bond distances [Å]
dihedral angle
G
rel [kcal mol-1
at 298.15 K
]
entry
compd
H-O1
H-OdC
O1-C1′
C3-C3′
ω [deg]
1
2
3
4
5
6
7
s-trans-7a + 5c
s-trans-7b + 5a
s-trans-7b‚5a
[s-trans-7b‚5a]#
s-cis-9b‚5a
s-cis-9b + 5a
s-trans-9a + 5c
0 (+1.35)c
+1.34 (0)c
2.08
1.95
2.04
1.97
1.97
2.02
1.46
2.05
4.03
4.18
2.46
1.57
-165
172
-7
+0.36 (-1.04)c
+23.76 (+20.81)c
-12.57 (-15.65)c
-10.93a (-14.12)c
-14.25b (-15.92)c
a Calculated according to the following: {G(s-cis-9b) + G(5a)} - {G(s-trans-7a) + G(5c)} [kcal mol-1]. Not explicitly stated in the depicted catalytic
cycle. b Calculated according to the following: {G(s-trans-9a) + G(5c)} - {G(s-trans-7a) + G(5c)} [kcal mol-1]. Not explicitly stated in the depicted
catalytic cycle. c Calculated single-point energies with use of the PCM solvent model in dichloroethane (in parentheses).
or 180° (antiperiplanar) should be favorable with respect to
conjugative stabilization. However, all relevant conformers that
have been studied computationally show a noticeable deviation
from planarity of 7-11° (Table 2, entries 1-4). It is tempting
to assume that the nonbonding interactions between the sub-
stituents on the highly substituted C2/C3 double bond are
responsible for the predicted deviation from planarity. The
s-trans conformers of 7a and 7b are more stable than their s-cis
counterparts by 0.5 kcal mol-1. As will be outlined later, the
nature of the transition state of the Claisen rearrangement can
be conveniently characterized by the length of the “breaking”
(O1-C1′) and the “forming” (C3-C3′) σ bond. As expected,
the length of the breaking bond is independent of the conforma-
tion of the allyl vinyl ether 7 (Table 2, entries 1-4). The
conformers 7b were calculated as reactive conformations in
which the allylic ether double bond is directed toward the vinyl
ether double bond. The reactive conformers 7b are less stable
by 0.5 kcal mol-1 compared to their stretched counterparts 7a
(Table 2, entries 1, 3 and 2, 4). Generally, as was the case for
the thiourea 5, the calculated energy differences between the
conformers of 7 are rather small and we expect a rapid
equilibrium between all possible conformers of the allyl vinyl
ether 7. This is also true for the solvent calculations given in
parentheses (Table 2).
Selected geometric data and the relative free energy of
relevant conformers of the R-keto ester 9 are summarized in
Table 3. Enthalpic and entropic contributions are given in the
Supporting Information. The dihedral angle ω was defined to
denote the conformational preferences of the R-keto ester moiety
(Table 3). A significant deviation from planarity is predicted
for all calculated conformers. As expected, the stretched
conformers s-cis- and s-trans-9a are more stable than the
J. Org. Chem, Vol. 72, No. 11, 2007 4005

Kirsten et al.
FIGURE 4. Optimized structures (B3LYP/6-311++G**) for stationary points of the catalytic cycle and conformers of the thiourea catalyst 5,
substrate 7, and product 9.
corresponding curved conformers s-cis- and s-trans-9b (Table
3, entries 1,3 and 2,4). s-cis-9b and s-trans-9b represent product
conformations that originate directly from the Claisen rear-
rangement. s-trans-9b is more stable than s-cis-9b by 1 kcal
mol-1 most likely due to the more favorable direction of the
local carbonyl dipoles in opposite directions (Table 3, entries 3
and 4). Furthermore, the repulsion of the two carbonyl groups
in s-cis-9b results in a dihedral angle of -52° thereby decreasing
4006 J. Org. Chem., Vol. 72, No. 11, 2007

Organocatalytic Claisen Rearrangement
TABLE 5. Comparison of Geometric and Energetic Data of the Transition State [s-trans-7b‚5a]# at Different Levels of Theory
bond distances [Å]
dihedral angle
charge
∆G#
total
b
entry
B3LYP
6-31G(d)
6-311+G(d,p)
6-311++G(d,p)
H-O1
H-OdC
O1-C1′
C3-C3′
ω [deg]
separation δa
[kcal mol-1
]
1
2
3
2.01
1.95
1.95
2.02
1.98
1.97
2.01
2.05
2.05
2.39
2.46
2.46
171
173
172
0.62 (0.50)
0.67 (0.47)
0.66 (0.43)
24.54c
23.77d
23.76d
a NBO and Mulliken (in parentheses) charge separation between the allylic and the oxallylic segment of the transition state. See Table 6 for a definition.
b At 298.15 K c Total activation barrier relative to the fully optimized lowest energy conformation of the 5a‚s-trans-7b complex. The barrier relative to the
.
uncomplexed 5c and s-trans-7a is 23.87 kcal mol-1 d Total activation barrier relative to the fully optimized lowest energy conformation of the uncomplexed
5c and s-trans-7a.
the stabilization by conjugation (Table 3, entry 4). Even for
the s-trans conformers, a significant deviation from planarity
was calculated most likely due to the unfavorable interaction
between the isopropoxy group and the keto carbonyl oxygen
atom (Table 3, entries 1 and 3). Generally, we expect a rapid
equilibrium between the relevant conformers in which s-trans-
9a should predominate. These conclusions are in agreement with
the results of a recently published conformational analysis of
R-keto esters by Baiker et al. based on FTIR spectroscopy and
computational studies at the B3PW91/6-31++G(d,p) level of
theory.29
atom O1 of s-trans-7b decreases. This could indicate an
increasing negative charge on the oxygen atom and/or a better
accessibility of O1 due to the elongated O1-C1 bond. Both
interpretations are in accordance with the original transition state
model of Jorgensen and Curran (vide supra).
The R-keto ester‚thiourea complex s-cis-9b‚5a is character-
ized by a very small dihedral angle (ω ) -7°) (Table 4, entry
5). The small deviation from a perfect synperiplanar conforma-
tion of the two carbonyl groups in s-cis-9b is a consequence of
the steric requirements of the two hydrogen bonds to the thiourea
5a catalyst. The calculation predicts an endergonic dissociation
process (∆Gdiss ) +1.64 kcal mol-1) of s-cis-9b‚5a to s-cis-9b
(ω ) -52°) and 5a. However, the exergonic formation (-2.45
kcal mol-1) of s-trans-9b from s-cis-9b renders the overall
dissociation process thermodynamically favorable and, therefore,
product inhibition of the catalyst is not predicted by calculation.
The initial conformational studies established that the inter-
conversion of the relevant substrate and catalyst conformers is
fast and reversible. The actual Claisen rearrangement was
investigated next. Starting points for our survey of the compu-
tationally predicted catalytic cycle are the lowest energy gas-
phase conformations of the thiourea (5c) and the allyl vinyl ether
(s-trans-7a) (Table 4, Figure 4). Formation of the “catalytically
active” conformation of the thiourea (5a) and the allyl vinyl
ether (s-trans-7b) is slightly endergonic in the gas phase, while
s-trans-7b‚5a is the lowest energy conformer according to the
solvent single-point calculations. A summary of the relevant
geometric properties of the complex s-trans-7b‚5a is given in
Table 4, entry 3. The hydrogen bond between the urea and the
carbonyl oxygen atom (1.97 Å) is slightly shorter compared to
the hydrogen bond to the ether oxygen atom (2.08 Å) as one
would qualitatively expect based on the relative Brønsted
basicity. The length of the O1-C1′ bond (1.46 Å) remains
unchanged upon complex formation (see Table 2, entry 2 for
comparison). The dihehydral angle ω decreases from -169° in
the uncomplexed s-trans-7b to -165° in the s-trans-7b‚5a
complex in order to match the steric requirements of the bis-
(hydrogen) bonding. Assuming that the barrier of the complex
formation is easily accessible at room temperature, the complex
s-trans-7b‚5a should be part of a rapid and reversible equilib-
rium between hydrogen bonded and nonbonded catalyst and
substrate conformers. The subsequent Claisen rearrangement of
s-trans-7b‚5a to s-cis-9b‚5a via the transition state [s-trans-
7b‚5a]# is the rate determining and irreversible step of the
calculated catalytic cycle. The rearrangement is exergonic by
-12.6 kcal mol-1 and has a total activation barrier (∆G#total) of
23.8 kcal mol-1. The free energy of activation of the Claisen
rearrangement step (∆G#[3,3] ) 23.4) is only slightly lower. The
solvent single-point calculations provide an identical picture,
with a little different (generally lower) numbers.
A comparative study on the total barrier of the thermal and
the thiourea-catalyzed Claisen rearrangement was performed
next. Many studies use B3LYP/6-31G* as the standard basis
set, sometimes in combination with high-level single-point
calculations. We were therefore interested in the influence of
the basis set on the geometry and the ∆G#
of the catalytic
total
cycle depicted in Figure 4. As can be seen from Table 5, the
relevant geometric data that characterize the [s-trans-7b‚5a]#
transition state are not significantly dependent on the size of
the utilized basis set. The total barrier is moderately higher for
the double-ê basis set due to an exergonic formation of 5a‚s-
trans-7b from 5c and s-trans-7a. The triple-ê basis sets predict
this transformation as endergonic. Although the double-ê basis
set 6-31G(d) can be considered a reasonable compromise
between cost and accuracy, we decided to use the triple- ê basis
set 6-311++G**.
The thermal Claisen rearrangement of the allyl vinyl ether 7
was studied first (Table 6). The two competing transition states
[s-trans-7b]# and [s-cis-7b]# are characterized by a concerted,
but asynchronous bond reorganization process (Table 6, entries
1 and 2). The bond breaking is more advanced (+39%) than
the bond making process (55% elongation of the C3-C3′ bond).
Therefore, the transition state is polarized and a significant
charge separation (δ) between the allylic and the oxallylic
fragment is predicted by the calculations.12 The barrier of the
rearrangement via [s-cis-7b]# is 0.75 kcal mol-1 lower than that
for the competing transition state [s-trans-7b]#. [s-cis-7b]#
should be intrinsically favored due to the less significant
deviation of the dihedral angle ω from planarity (+18° vs -147°
for [s-trans-7b]#). Furthermore, [s-cis-7b]# leads directly to the
thermodynamically more favorable rearrangement product
[s-trans-9b]#, which should contribute to the lower activation
barrier of the rearrangement via [s-cis-7b]# (see Table 3 for
comparison). At the B3LYP/6-311++G(d,p) level of theory,
the rearrangement via the bis(hydrogen) bonded transition state
Important geometric data of the transition state are sum-
marized in Table 4, entry 4. In proceeding from the complex
s-trans-7b‚5a to the transition state [s-trans-7b‚5a]#, the length
of the hydrogen bond between the thiourea 5a and the oxygen
(29) Ferri, D.; Bu¨rgi, T.; Baiker, A. J. Chem. Soc., Perkin Trans. 2 2000,
221-227.
J. Org. Chem, Vol. 72, No. 11, 2007 4007

Kirsten et al.
TABLE 6. Comparison of Calculated (B3LYP/6-311++G**) Geometric and Energetic Data for the Thermal and the Thiourea-Catalyzed
Claisen Rearrangement of 7
d
e
dihedral
∆H#/∆S#
∆G#
∆G#
∆G# f
[3,3]
bond distances [Å]
H-O1 H-OdC O1-C1′ a
total
]
total
total, solv
angle NBO charge
[kcal mol-1
[kcal mol-1
at 298.15 K at 298.15 K at 298.15 K
] ] ]
[kcal mol-1 [kcal mol-1
entry
compd
C3-C3′ b
ω [deg] separation δc
at 298.15 K
1
2
3
4
[s-trans-7b]#
2.00 (+39%) 2.39 (+55%) -147
1.98 (+38%) 2.39 (+55%) 18
2.05 (+42%) 2.46 (+60%) +172
2.05 (+42%) 2.50 (+62%) -1
0.54 (0.37) 24.80/-8.5 × 10-3
0.52 (0.30) 24.49/-8.08 × 10-3
0.66 (0.43) 10.53/-44.36 × 10-3
0.67 (0.52) 14.42/-42.29 × 10-3
27.34
26.90
23.76
27.03
24.78
24.52
20.81
24.45
26.87
25.45
23.76
19.96
[s-cis-7b]#
[s-trans-7b‚5a]# 1.95
1.97
[s-cis-7b‚5a]#
2.00, 2.01
a In parentheses: elongation of the breaking bond relative to 7a calculated according to [(d(O1-C1′)TS - d(O1-C1′)7a)/d(O1-C1′)7a] × 100. d(O1-
C1′)7a) 1.44 Å at B3LYP/6-311++G(d,p). bIn parentheses: Elongation of the forming bond relative to 9a calculated according to [(d(C3-C3′)TS - d(C3-
C3′)9a)/d(C3-C3′)9a] × 100. d(C3-C3′)9a) 1.54 Å at B3LYP/6-311++G(d,p). c NBO and Mulliken (in brackets) charge separation between the allylic
(blue) and the oxallylic (red) segment of the transition state. d Total activation barrier relative to the fully optimized lowest energy conformation of the
separated thiourea and allyl vinyl ether. e Calculated single-point energies with use of the PCM solvent model in dichloroethane. f Free energy of activation
for the [3,3]-rearrangement step.
FIGURE 5. Gas-phase free energy diagram for the thiourea (5)-catalyzed Claisen rearrangement (B3LYP/6-311++G**).
[s-trans-7b‚5a]# has a 3.3 kcal mol-1 lower ∆G#
compared
thiourea (5)-catalyzed Claisen rearrangement is the sum of three
free energies, namely the free energy of the formation of the
“catalytically active” conformation of the thiourea (5a) and the
allyl vinyl ether (s-trans-7b or s-cis-7b) (∆Gconform), the complex
formation between the thiourea and the catalyst (∆Gcomplex), and
finally, the actual free energy of activation of the [3,3]-
rearrangement step (∆G#[3,3]). It is apparent that ∆G#[3,3] for the
rearrangement via [s-cis-7b‚5a]# is significantly lower than the
total
to the thermal rearrangement via [s-cis-7b]#. The presence of
the coordinated thiourea significantly alters the relevant geo-
metric data of the transition state (Table 6, entry 3). The
asynchrony of the concerted bond reorganization is more
pronounced leading to a looser and more polarized transition
state compared to thermal rearrangement. Evidently, the dihedral
angle ω is closer to planarity in [s-trans-7b‚5a]# (+172°)
compared to [s-cis-7b]# (+18°) (Table 6, entries 2 and 3). To
evaluate the influence of the bis(hydrogen) bonding mode on
the height of ∆G#total, the rearrangement via the transition state
[s-cis-7b‚5a]# was investigated next (Table 6, entry 4). The
corresponding ∆G#total for the rearrangement is 3.3 kcal mol-1
higher than that for the rearrangement via [s-trans-7b‚5a]# and,
furthermore, provides no rate acceleration compared to the
thermal rearrangement via [s-cis-7b]# (Table 6, entries 2-4).
A comparative free energy diagram for the thiourea-catalyzed
Claisen rearrangement of s-trans-7a via either [s-trans-7b‚5a]#
rearrangement via [s-trans-7b‚5a]# (∆∆G#
) -3.8 kcal
[3,3]
mol-1) or the thermal rearrangement via [s-cis-7b]# (∆∆G#
[3,3]
) -5.5 kcal mol-1). However, the decreased ∆G#[3,3] is due to
“substrate destabilization”, namely an endergonic conformational
process (∆Gconform ) +2.7 kcal mol-1) and an endergonic
complex formation (∆Gcomplex ) +4.4 kcal mol-1). Therefore,
∆G#
remains almost unchanged compared to thermal rear-
total
rangement. With respect to the geometry of the transition state,
it should be noted that [s-cis-7b‚5a]# is even “looser” than
[s-trans-7b‚5a]# and, therefore, the charge separation between
the allylic and the oxallylic segment is more pronounced than
or [s-cis-7b‚5a]# is depicted in Figure 5. The ∆G#
4008 J. Org. Chem., Vol. 72, No. 11, 2007
for the
total

Organocatalytic Claisen Rearrangement
TABLE 7. Thiourea-Catalyzed Claisen Rearrangement
SCHEME 2. Synthesis of the Allyl Vinyl Ether 7
entry thiourea mol %
solvent a
T [°C]
t
conv.b [%]
1
2
3
4
5
6
7
8
9
CHCl3
25
25
45
25
25
25
45
45
25
5 d
5 d
6 h
5 d
5 d
5 d
6 h
6 h
5 d
10
41
41
7
17
44
15
44
14
CF3CH2OH
CF3CH2OH
DCE
CHCl3
CF3CH2OH
CHCl3
5
5
5
5
5
20
20
20
20
20
CF3CH2OH
DCE
a DCE) 1,2-dichloroethane. b For entries 5-8, 0.1 mmol of 7 was
dissolved in 2 mL of the indicated solvent. Conversion was determined by
NMR. For experimental details see the Experimental Section.
Table 8. Thiourea 5-Accelerated Claisen Rearrangement
the charge separation in [s-trans-7b‚5a]#. Furthermore, the
dihedral angle ω in [s-cis-7b‚5a]# shows only a small deviation
from planarity (-1°) compared to [s-trans-7b‚5a]# (+172°).
Experimental Results and Discussion
conversion [%]
Our aldol condensation approach was employed for the
synthesis of (Z)-7 (Scheme 2).30 Allylic alcohol 10 was first
converted into the allyloxy acetate 11 by etherification followed
by esterification with i-PrOH in the presence of N,N-dicyclo-
hexylcarbodiimide (DCC). Subsequent aldol addition with
acetaldehyde provided the â-hydroxy ester 12. Mesylation
followed by 1,8-diazabicyclo[5,4,0]undecene (DBU)-mediated
elimination provided 7 as a mixture of double bond isomers.
Subsequent separation by preparative HPLC led to isolation of
(Z)-7 on a multigram scale.
To qualitatively determine a rate accelerating effect of
thiourea 5 on the Claisen rearrangement, the allyl vinyl ether
(Z)-7 was treated with varying amounts of the corresponding
thiourea in different solvents and at different temperatures. Due
to the limited solubility of 5 in dichloroethane (DCE), chloro-
form was utilized as aprotic solvent. Trifluoroethanol was
employed as the polar protic solvent system for which a rate
accelerating solvent effect on the Claisen rearrangement may
be expected.5 The results are summarized in Table 7. Control
experiments in CHCl3 and trifluoroethanol were performed to
determine the intrinsic reactivity of the allyl vinyl ether (Z)-7
in the absence of the thiourea 5 (Table 7, entries 1-4). Stirring
(Z)-7 in CHCl3 or DCE for 5 days at room temperature led to
small but significant conversions (Table 7, entries 1 and 4). An
impressive solvent effect was observed when (Z)-7 was stirred
in trifluoroethanol. After 5 days at room temperature, a 41%
conversion was determined by 1H NMR (Table 7, entry 2). The
same conversion was obtained after 6 h at 45 °C (Table 7, entry
3). Next, we studied the influence of 20 mol % of the thiourea
5 on the conversion (Table 7, entries 5-9). As was predicted
by the calculation, the conversion in the presence of the thiourea
5 was almost unchanged compared to that of the control
experiments. Change of solvent or reaction temperature was not
suitable to improve the observed conversion.
entry
t [d]
100 mol % 5
no 5
1
2
3
4
5
1
2
3
5
7
41
63
72
84
87
23
41
52
57
74
In an attempt to elucidate a potential rate accelerating effect
of stoichiometric amounts of the thiourea 5, we determined the
conversion in chloroform at 45 °C over a period of several days
(Table 8). Comparison of the conversion in the presence and
absence of 100 mol % of 5 clearly indicates a small and
reproducible rate accelerating effect.31
Conclusions
A computational study concerning the nature of the transition
state of the Claisen rearrangement in the presence and absence
of the thioureas 1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea
(5) was performed. Although thiourea 5 is capable of lowering
the barrier for the actual Claisen rearrangement step based on
a bis(hydrogen) bond interaction with the ether oxygen atom
of (Z)-7, a detailed computational investigation of a conceivable
catalytic cycle for the thiourea-catalyzed Claisen rearrangement
at the B3LYP/6-311++G(d,p) level of theory indicates that the
transition state stabilization is not significant enough to over-
come the energetic costs of conformational changes and
complexation required for the formation of the reactive complex
s-cis-7b‚5a. The corresponding transition state [s-cis-7b‚5a]#
is characterized by a concerted but asynchronous bond reorga-
nization process that leads to its polarization. The calculated
reduction of the total barrier ∆G#total for the Claisen rearrange-
(31) Judging from a progressively yellowish colored reaction mixture,
the thiourea 5 is apparently unstable at the reaction temperature. A thermal
decomposition would diminish the effective concentration of 5.
(30) Hiersemann, M. Synthesis 2000, 1279-1290.
J. Org. Chem, Vol. 72, No. 11, 2007 4009

Kirsten et al.
syringe to a solution of LDA [prepared from diisopropylamine, (8.5
mL, 60.5 mmol, 1.3 equiv) and n-BuLi (2.3 M in n-hexane, 28
mL, 55.8 mmol, 1.2 equiv) in THF (3 mL/mmol) at -78 °C] in
THF (139 mL) at -78 °C. The bright yellow solution was stirred
for 15 min at -78 °C. Freshly distilled and cooled (-78 °C)
acetaldehyde was then added to the reaction mixture at -78 °C.
After the pale yellow solution was stirred for 15 min, saturated aq
NH4Cl solution (80 mL) was added at -78 °C. The mixture was
warmed to room temperature, the layers were separated, and the
aqueous phase was extracted with CH2Cl2 (3 × 50 mL). The
combined organic phases were then dried with MgSO4 and the
solvents were evaporated at reduced pressure. Purification by flash
chromatography (hexanes/ethyl acetate 10/1) provided the â-hy-
droxy ester 12 (6.5 g, 69%, dr ) 60/40 relative configuration not
assigned) as a yellowish oil (Rf 0.5 hexanes/ethyl acetate 1/1).
1H NMR (400 MHz, CDCl3) δ 1.19 (d, J ) 6.3 Hz, 6H) 1.26
(d, J ) 5.0 Hz, 3H), 2.30 (br smajor, 1H), 2.46 (br sminor, 1H), 3.67
(dminor, J ) 5.5 Hz, 1H) 3.85 (dmajor, J ) 4.3 Hz, 1H), 3.90-4.00
(m, 1H), 4.03-4.11 (m, 1H), 4.19 (m, 1H), 5.10 (sept, J ) 6.21
Hz, 1H), 5.20 (d, J ) 10.3 Hz), 5.27 (dd, J ) 17.31, 1.25 Hz),
5.82-5.96 (m, 1H); 13C NMR (100 MHz, CDCl3, mixture of
diastereomers) δ 18.2, 18.8, 21.9, 68.4, 68.8, 72.0, 81.8, 82.5, 118.5,
118.7, 133.8, 133.9, 170.4, 170.8; IR (in substance) ν 1729, 3469
cm-1. Anal. Calcd for C10H18O4: C, 59.39, H, 8.97. Found: C,
59.04, H, 9.11.
Allyl Vinyl Ether (E)- and (Z)-7. Et3N (5.52 mL, 39 mmol,
1.2 equiv) was added at 0 °C to a solution of 12 in CH2Cl2 (60
mL). MsCl (2.8 mL, 36 mmol, 1.2 equiv) was then added at 0 °C.
The ice bath was subsequently removed and the white suspension
was stirred at room temperature for 30 min. The reaction was
quenched by the addition of saturated aq NaHCO3. The layers were
separated and the aqueous phase was extracted with CH2Cl2 (3 ×
30 mL). The combined organic phases were dried with MgSO4 and
the solvents were evaporated under reduced pressure. The crude
product was then dissolved in THF (60 mL) and cooled to 0 °C.
DBU (13.6 mL, 90 mmol, 3 equiv) was added and the reaction
mixture was allowed to warm to room temperature overnight. The
progress of product formation may be followed by TLC (Rf mesylate
0.75, Rf allyl vinyl ether 0.9, hexanes/ethyl acetate 1/1). The reaction
mixture was then diluted with water and the two layers were
separated. The aqueous layer was extracted with CH2Cl2 (3 × 30
mL). The combined organic phases were dried with MgSO4 and
the solvents were removed under reduced pressure. Purification by
flash chromatography (hexanes/ethyl acetate 100/1) afforded the
allyl vinyl ether 7 (4.61 g, 84%, colorless liquid) as a mixture of
double bond isomers (Z/E ) 60/40). The two diastereomers were
separated by preparative HPLC: Nucleosil 50-7, 32 mm × 250
mm, n-heptane/ethyl acetate 99/1, flow 20 mL/min, pressure 31 ×
10-1 MPa, (Z)-4 ) 23.5 min, (E)-4 ) 27.3 min, baseline separation
with 100 mg (E/Z)-4/injection.
ment in the presence of 5 can be neglected. Solvent calculations
confirm this finding. They do predict lower activation energies
compared to the gas-phase values, but this is also true for the
uncatalyzed, thermal reaction. Our experimental efforts validate
that thioureas are ineffective as catalysts for the Claisen
rearrangement of 2-alkoxycarbonyl-substituted allyl vinyl ethers.
As initially suggested by Jorgensen, the design of a nonco-
valent organocatalyst for the Claisen rearrangement must clearly
focus on a significant polarization of the transition state by
strong hydrogen bonding to the ether oxygen atom. Increasing
polarization, indicated by the charge separation between the
allylic and the oxallylic segment of the transition state, is
reflected in increasing lengths of the breaking and the forming
bonds. An increasing polarization of the transition state appar-
ently indicates (not causes) a decreasing rearrangement barrier.
Last but not least, the choice of a suitable catalyst/substrate
combination should avoid energetic costs for conformational
changes and/or complex formation.
Experimental Section
Allyloxy Acetate 11. A solution of allylic alcohol (2.13 g, 36.6
mmol, 1.0 equiv) in THF (37 mL, 1 mL/mmol of allylic alcohol)
was cooled to -78 °C. n-BuLi (16.5 mL, 36.6 mmol, 1.0 equiv)
was added and the solution was stirred for 15 min at -78 °C. Solid
sodium iodoacetate (8 g, 38.5 mmol, 1.05 equiv) was subsequently
added at 0 °C. The resulting yellow suspension was allowed to
warm to room temperature overnight. Aqueous 1 N KOH (40 mL)
was added to the brownish suspension until the solid was completely
dissolved. The two phases were then separated and the organic layer
was extracted three times with aq 1 N KOH (10 mL). The combined
aqueous phases were cooled to 0 °C and aq conc HCl (ap-
proximately 5 mL) was added carefully until pH 2 was reached.
CHCl3 (30 mL) was added and the layers were separated. The
aqueous layer was extracted eight times with CHCl3 (10 mL). The
combined organic layers were dried over MgSO4 and the solvents
were removed under reduced pressure (40 °C, 300 mbar). The crude
product was purified by kugelrohr distillation (5 mbar, 85 °C) to
afford (allyloxy)acetic acid (2.13 g, 71%) as a colorless oil (Rf 0.1
hexanes/ethyl acetate 1/1).
1H NMR (400 MHz, CDCl3) δ 4.10 (d, J ) 6.02 Hz, 2H), 4.11
(s, 2H), 5.25 (d, J ) 10.3 Hz, 1H), 5.30 (dt, J ) 16.7, 0.8 Hz, 1H),
5.83-5.95 (m, 1H); 13C NMR (400 MHz, CDCl3) δ 66.6, 72.6,
118.9, 133.4, 175.6; IR (in substance) ν 1735, 3453 cm-1. Anal.
Calcd for C5H8O3: C, 51.72, H, 6.94. Found: C, 51.7, H, 6.3.
(Allyloxy)acetic acid (2.0 g, 17.2 mmol, 1.0 equiv) was dissolved
in CH2Cl2 (45 mL, 2.5 mL/mmol of (allyloxy)acetic acid) and
cooled to 0 °C. N,N-(dimethylamino)pyridine (DMAP, 105 mg, 0.86
mmol, 0.05 equiv) and a solution of N,N′-dicyclohexylcarbodiimide
(DCC, 3.90 g, 18.92 mmol, 1.1 equiv) in CH2Cl2 (7 mL, 0.4 mL/
mmol (allyloxy)acetic acid) was successively added. After the
reaction mixture was stirred for 5 min at 0 °C, i-PrOH (2.6 mL,
34.4 mmol, 2 equiv) was added to the brownish suspension. The
reaction mixture was allowed to warm to room temperature
overnight. The white precipitate was removed by filtration and
washed with CH2Cl2. The solvents were then evaporated under
reduced pressure (40 °C, 620 mbar) and the crude product was
purified by kugelrohr distillation (2 mbar, 80 °C) to provide the
ester 11 (2.18 g, 80%) as a colorless oil (Rf 0.8 hexanes/ethyl acetate
1/1).
(Z)-7: 1H NMR (300 MHz, CDCl3) δ 1.26 (d, J ) 6.3 Hz, 6H),
1.75 (d, J ) 7.0 Hz, 3H), 4.31 (d, J ) 6.0 Hz, 2H), 5.06 (sept, J
) 6.3 Hz, 1H), 5.19 (d, J ) 10.3 Hz, 1H), 5.30 (dd, J ) 17.1, 1.3
Hz, 1H), 5.92-6.04 (m, 1H), 6.31 (q, J ) 7.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 11.7, 22.2, 68.7, 73.3, 118.4, 124.4, 134.3,
145.9, 163.5; IR (in substance) ν 1743 cm-1. Anal. Calcd for
C10H16O3: C, 65.19, H, 8.75. Found: C, 65.29, H, 8.71.
(E)-7: 1H NMR (300 MHz, CDCl3) δ 1.30 (d, J ) 6.27 Hz,
6H), 1.92 (d, J ) 7.28 Hz, 3H), 4.23 (d, J ) 5.27 Hz, 2H), 5.11
(sept, J ) 6.27 Hz, 1H), 5.20 (dd, J ) 10.54, 1.51 Hz, 1H), 5.31
(dd, J ) 17.19, 1.63 Hz, 1H), 5.38 (q, J ) 7.45 Hz, 3H), 6.01-
5.89 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 12.6, 21.8, 68.5,
70.1, 112.7, 117.46, 133.3, 145.5, 163.5; IR (in substance) ν 1744
cm-1. Anal. Calcd for C10H16O3: C, 65.19, H, 8.75. Found: C,
65.11, H, 8.92.
General Procedure for the Thiourea-Catalyzed Claisen Rear-
rangement. The thiourea was dissolved in the minimum amount
of solvent required and the allyl vinyl ether (Z)-7 was added via
syringe under an atmosphere of argon. Reactions at elevated
1H NMR (CDCl3, 400 MHz) δ 1.24 (d, J ) 6.27 Hz, 6H), 4.02
(s, 2H), 4.07 (d, J ) 5.77 Hz, 2H), 5.08 (sept, J ) 6.40 Hz, 1H),
5.23 (dt, J ) 16.3, 10.3 Hz, 2H), 5.89 (m, 1H); 13C NMR (100.6
MHz, CDCl3) δ 21.8, 67.5, 68.7. 72.5, 118.3, 134.1, 169.9; IR (in
substance) ν 1750 cm-1. Anal. Calcd for C8H14O3: C, 60.74, H,
8.92. Found: C, 60.85, H, 9.06.
â-Hydroxy Ester 12. A cooled (-78 °C) solution of 11 (7.36
g, 46.5 mmol, 1 equiv) in THF (3 mL/mmol of 11) was added via
4010 J. Org. Chem., Vol. 72, No. 11, 2007

Organocatalytic Claisen Rearrangement
temperature were performed in a sealed tube (as specified in the
Methods and Materials section). The progress of the reaction was
monitored by NMR. For this purpose, samples were taken from
the reaction mixture at the indicated reaction times and the solvent
was removed from the sample at reduced pressure at room
temperature. The thiourea was then separated from the crude product
mixture by short column chromatography (3 cm × 0.5 cm, hexanes/
ethyl acetate 50/1). The conversion was determined by integration
of suitable 1H resonances (quartet at 6.31 ppm of (Z)-7 vs multiplet
at 2.39-2.51 ppm of 9).
Acknowledgment. This study was funded by the DFG-
Priority Program Organocatalysis (SPP 1179). We are grateful
for the computing time provided by the TU Dresden Center for
Information Services and High Performance Computing (ZIH)
and the Hochschulrechenzentrum of the Universita¨t Dortmund.
Financial support by the Fonds der Chemischen Industrie (FCI)
is gratefully acknowledged.
Supporting Information Available: Cartesian coordinates for
ground and transition states, number of imaginary frequencies, total
electronic energies, and zero-point vibrational energies of all
stationary points reported in the text; catalytic cycles for the three
different basis sets 6-31G(d), 6-311+G(d,p), and 6-311++G(d,p)
(Tables SI-1 to SI-4); experimental procedures for the synthesis of
thiourea 5; and copies of NMR spectra of all synthesized com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
R-Keto Ester 9. H NMR (300 MHz, CDCl3) δ 1.19 (d, J )
7.1 Hz, 3H), 1.34 (d, J ) 6.2 Hz, 6H), 2.09-2.22 (m, 1H), 2.39-
2.51 (m, 1H), 3.28 (tq, J ) 17.5, 7.3 Hz, 1 H), 5.00-5.09 (m, 2H),
5.14 (sept, J ) 6.3 Hz, 1H), 5.72 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 14.8, 21.6, 36.1, 41.9, 70.5, 117.4, 134.8, 161.5, 197.8;
IR (in substance) ν 1724 cm-1. Anal. Calcd for C10H16O3: C, 65.19,
H, 8.75. Found: C, 65.22, H, 8.84.
JO062455Y
J. Org. Chem, Vol. 72, No. 11, 2007 4011