Structures and reactivities of 2-trityl- and 2-(triphenylsilyl)pyrrolidine-derived enamines: Evidence for negative hyperconjugation with the trityl group

Article abstract of DOI:10.1021/ja508065e

X-ray structures of enamines and iminium ions derived from 2-tritylpyrrolidine (Maruoka catalyst) and 2-(triphenylsilyl)pyrrolidine (Bolm-Christmann-Strohmann catalyst) have been determined. Kinetic investigations showed that enamines derived from phenyla

Full text of DOI:10.1021/ja508065e

Article
pubs.acs.org/JACS
Structures and Reactivities of 2‑Trityl- and
2‑(Triphenylsilyl)pyrrolidine-Derived Enamines: Evidence for
Negative Hyperconjugation with the Trityl Group
Hannes Erdmann,† Feng An,† Peter Mayer,† Armin R. Ofial,† Sami Lakhdar,*,†,‡ and Herbert Mayr*,†
†Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse 5-13, 81377 Munchen, Germany
̈
̈
̈
‡Laboratoire de Chimie Molec
́
ulaire et Thio-organique, UMR CNRS 6507, 6 Boulevard Marec
́
hal Juin, 14050 Caen, France
S
* Supporting Information
ABSTRACT: X-ray structures of enamines and iminium ions derived from
2-tritylpyrrolidine (Maruoka catalyst) and 2-(triphenylsilyl)pyrrolidine
(Bolm−Christmann−Strohmann catalyst) have been determined. Kinetic
investigations showed that enamines derived from phenylacetaldehyde and
pyrrolidine (R = H) or 2-(triphenylsilyl)pyrrolidine (R = SiPh3) have similar
reactivities toward benzhydryl cations Ar2CH+ (reference electrophiles),
while the corresponding enamine derived from 2-tritylpyrrolidine (R =
CPh3) is 26 times less reactive. The rationalization of this phenomenon by negative hyperconjugative interaction of the trityl
group with the lone pair of the enamine nitrogen is supported by the finding that the trityl group in the 2-position of the
pyrrolidine increases the electrophilic reactivity of iminium ions derived from cinnamaldehyde by a factor of 14. The
consequences of these observations for the rationalization of the reactivity of the Jørgensen−Hayashi catalyst (diphenylprolinol
trimethylsilyl ether) are discussed.
The corresponding transition state was proposed by List and
Houk to rationalize the enantioselectivity in proline-catalyzed
reactions.4 Inspired by this work, researchers have developed a
large number of bifunctional catalysts, which were expected to
operate by a mechanism similar to that for proline.5
INTRODUCTION
■
Enamine formation has emerged as a powerful mode of
activation in organocatalysis. This methodology is based on the
use of chiral secondary amines as catalysts to transform achiral
carbonyl derivatives into chiral enamines, which subsequently
react with electrophiles to yield enantioenriched α-function-
alized carbonyl compounds.1 The design of effective catalysts
for enamine activation has commonly been based on two
factors: hydrogen bonding and steric shielding.1,2
The first factor, i.e., hydrogen bonding, was probed by List,
Barbas, and Lerner for proline-catalyzed enantioselective
intermolecular aldol reactions.3 In this process, as well as in
many other proline-catalyzed reactions, the carboxylic proton
activates the electrophile through hydrogen bonding and directs
the electrophile to the Re face of the enamine (Scheme 1).
The second factor, which has been employed for the
development of other generations of organocatalysts, is the
steric effect, and various pyrrolidines bearing a bulky
substituent at the 2-position were used for enamine-activated
reactions. Diphenylprolinol trimethylsilyl ether, for instance,
also known as the Jørgensen−Hayashi catalyst, has been shown
to be a powerful catalyst in enamine-activated reactions as well
as in many other modes of activation (Scheme 1).1b,g−i,6
Substitution of the trimethylsiloxy group in the Jørgensen−
Hayashi catalyst by a phenyl ring yields Maruoka’s catalyst 1a,
which showed high efficiency in enamine-activated asymmetric
benzoyloxylations and hydroxyaminations of aldehydes7 but
gave only moderate yields and diastereoselectivities in Michael
additions of aldehydes to nitroolefins (Scheme 2).8a
Scheme 1. Hydrogen Bonding and Steric Control in
Enamine Activated Reactions
Better yields and diastereoselectivities have been reported
simultaneously by Bolm et al. as well as by Christmann,
Strohmann, et al., when 2-silyl-substituted pyrrolidines were
used.8 In particular, 2-(triphenylsilyl)pyrrolidine (1b) and 2-
(tert-butyldiphenylsilyl)pyrrolidine provided high diastereo-
and enantioselectivities.8a,c
Christmann et al. have attributed the higher efficiency of 1b
compared with 1a to the larger steric effect (C−Si longer than
Received: August 6, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja508065e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
reactivity scales for electrophiles and nucleophiles covering
more than 35 orders of magnitude.11 This methodology has
now been employed to characterize the nucleophilicities of the
enamines 3 derived from phenylacetaldehyde (2) and the
pyrrrolidines 1a,b and to compare them with that of the
corresponding enamine derived from the Jørgensen−Hayashi
catalyst.
Scheme 2. Michael Addition of Propionaldehyde to
Nitrostyrene Catalyzed by the Pyrrolidines 1a,b8a
RESULTS AND DISCUSSION
■
Synthesis of the Enamines 3a−c. The enamines 3a,b
were obtained as colorless crystals by condensation of the
racemic amines 1a,b and phenylacetaldehyde 2 in dry toluene
in the presence of molecular sieves (4 Å), as shown in Scheme
4.12
C−C) and higher polarization of the C−Si bond in comparison
to the C−C bond.8a MP2 calculations by Mersmann, Raabe,
and Bolm showed that β-trimethylsilyl-substituted iminium
ions, analogues to those formed from 1b and aldehydes
(Scheme 3), are stabilized by the interaction of the Si−C σ
bond with the π* orbital of the CN double bond.9
Scheme 4. Synthesis of the Enamines 3a,b
Scheme 3. Resonance Structures of β-Silyl-Substituted
Iminium Ion
Single crystals suitable for X-ray diffraction were grown by
vapor diffusion of n-pentane into dichloromethane solutions of
3a,b.13 Enamines 3a,b both have E-configured double bonds
and adopt the s-trans conformation, as shown in Figure 1.
We now report on structural and kinetic investigations of the
role of trityl and triphenylsilyl substituents on the catalytic
activities of the corresponding pyrrolidine derivatives.
In previous work, we have shown that the reactivities of
benzhydrylium ions (Table 1), quinone methides, Michael
Table 1. Benzhydrylium Ions 4a−g Employed in This Work
and Their Electrophilicity Parameters E
Figure 1. X-ray structures of the enamines 3a (left) and 3b (right).
The olefinic bonds (Cα=Cβ) of both enamines 3a,b have
comparable bond lengths, 1.347 and 1.339 Å, respectively,
showing that the substituents at the 2-position of the
pyrrolidine ring do not significantly affect the structures of
the enamines. Accordingly, the Dunitz parameters14 for the
enamine nitrogen, which is defined as the distance between the
nitrogen and the center of the plane defined by the three
nitrogen ligands, were measured to be 0.04 and 0.09 Å,
respectively, indicating that both enamines 3a,b are almost
planar.
a
Electrophilicities E were taken from ref 10b.
The NOESY spectra of 3a,b (in CDCl3) reveal strong
interactions between α-H and the 2-H as well as between β-H
and 5-H (see numbering in Table 2) and thus confirm that the
s-trans conformations observed in the crystals also dominate in
solution.
acceptors, and iminium ions with n, σ, and π nucleophiles can
be described by the linear free energy relationship (1), where sN
and N are solvent-dependent nucleophile-specific parameters
and E is an electrophilicity parameter.10
Though correlations between 13C NMR chemical shifts and
charge densities have to be interpreted with caution, the
distance between the substituents X in the 2-position and Cβ is
so large that the increased shielding of Cβ in the order 3a < 3c
< 3b might be assigned to the relative electron densities on Cβ.
log k2(20° C) = sN(E + N)
(1)
By studying the rates of various electrophile−nucleophile
combinations, we have been able to establish comprehensive
B
dx.doi.org/10.1021/ja508065e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
orbital is not observed, as the CN bond lengths are almost
the same in 5a (1.273 Å), 5b (1.278 and 1.272 Å), and 5c
(1.271 Å).
Table 2. NMR Chemical Shifts for the Enamines 3a−c (in
CDCl3) and the Corresponding Iminium Ions 5a−c (in
CD3CN)
Further evidence for the interaction of σC−Si with π*CN can
be derived from the 13C NMR chemical shifts of Cα of the
iminium ions 5 (Table 2). While δ(Cα) is exactly the same in
enamines 3a,b, Cα is shifted to high field by 4 ppm in the silyl-
substituted iminium ion 5b in comparison to the trityl-
substituted analogue 5a. As the nitrogen atoms are coordinated
in a trigonal-planar fashion in enamines 3 (Figure 1) and in the
iminium ions 5 (Figure 2), geometrical differences cannot
account for the differences in chemical shifts. The observation
that δ(Cα) is more shielded in 5b than in 5a,c can thus be
assigned to the electron-donating effect of the σC−Si bond.9
Kinetics. All kinetic investigations were carried out in
dichloromethane at 20 °C by following the disappearance of
the colored benzhydrylium ions 4a−g in the presence of more
than 10 equiv of the enamines 3a−c (first-order conditions).
The first-order rate constants kobs were obtained by least-
squares fitting of the single exponential At = A0 exp(−kobs t) to
the decays of the UV−vis absorbances of the electrophiles.
Plots of kobs (s−1) against the concentrations of the
nucleophiles 3a−c were linear, as exemplified for the reaction
of 3a with 4c in Figure 3. Negligible intercepts for these plots
were found for the reactions which proceeded quantitatively,
while positive intercepts were found for the reactions which led
to an equilibrium (for details see the Supporting Information).
In both cases, the second-order rate constants k2 were extracted
from the slopes of the plots of kobs against [3]0 (Table 3).
Figure 4 shows linear correlations between the logarithms of
the second-order rate constants (log k2) and the previously
published electrophilicity parameters E of the benzhydrylium
ions, as required by eq 1. The slopes of the correlation lines
yield the nucleophile-specific sensitivity parameters sN, and the
intercepts on the abscissa give the nucleophilicity parameters N,
which are given in Table 3.
compd
X
δ(Cα,3)
δ(Cβ,3)
δ(Cα,5)
3a or 5a
3b or 5b
3c or 5c
CPh3
SiPh3
H
136.9
136.9
98.0
97.1
178.0
174.0
176.6
a
a
135.8
97.4
a
From ref 12.
The differences are so small, however, that ground state effects
in enamines 3a−c cannot explain the different catalytic
activities of the corresponding pyrrolidines.
Products of the Reactions of the Enamines 3a,b with
Benzhydrylium Ions. Combination of the enamines 3a−c
with the dimethoxybenzhydrylium tetrafluoroborate 4h-BF4 in
dichloromethane at 20 °C resulted in quantitative formation of
iminium salts (5a−c)-BF4 (Scheme 5), which crystallized from
a mixture of dichloromethane and n-pentane or acetone,
yielding crystals suitable for X-ray diffraction analyses (Figure
2).15
Scheme 5. Reactions of the Enamines 3a−c with the
Electrophiles 4d,h,i
The similar values of the slopes (0.93 < sN < 1.06) of the
correlation lines imply that the relative nucleophilicities of the
enamines 3a−c are only slightly affected by the reactivities of
the electrophilic reaction partner.
Lewis Basicities of the Enamines 3a−c. As the reactions
of the enamines 3a−c with some benzhydrylium ions
proceeded incompletely, we have also studied the correspond-
ing equilibrium constants by UV−vis spectroscopy.
Assuming proportionality between the absorbances and the
concentrations of the benzhydrylium ions, the equilibrium
constants for the reactions (eq 2) can be determined from the
initial absorbances (A0) of the benzhydrylium ions and the
absorbances at equilibrium (A) according to eq 3 and are given
in Table 4.
The iminium ions formed analogously from 3a and the
benzhydryl chloride 4i-Cl and from the combination of 3b and
the benzhydrylium tetrafluoroborate 4d-BF4 were not isolated
but hydrolyzed with aqueous acetic acid to give the
corresponding aldehydes 6a,b (Scheme 5).
The X-ray structures depicted in Figure 2 show that the
major diastereoisomers of the iminium ions 5a,b have a syn
configuration and an E configuration about the CN bond.
While lengthening of the C−Si bond from 1.889 Å in enamine
3b to 1.924 Å in iminium 5b can be explained by the
interaction of the C−Si σ bond with π* of the CN bond in
5b (see above), the expected complementary lengthening of
the CN bond in 5b due to electron donation into the π*CN
K
Ar2CH+ + Nu HooooooI Ar2CH‐Nu+
CH2Cl2
(2)
[Ar2CH‐Nu+]
A0 − A
A[Nu]
K =
=
[Ar CH+][Nu]
(3)
2
Equilibrium constants for the reactions of 3b with the
benzhydrylium ions 4e−g could be determined in this way, and
the ratio of the equilibrium constants for the reactions of 3b
with 4e and 4g (K4e/K4g = 3.70; log(K4e/K4g) = 0.57) was in
good agreement with that derived from a statistical treatment of
the equilibrium constants for the reactions of these two
C
dx.doi.org/10.1021/ja508065e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
−
Figure 2. X-ray structures for the iminium ions 5a (left), 5b (center), and 5c (right). Hydrogens and the counterion BF4 are omitted for clarity.
Figure 3. Exponential decay of the absorbance A at 613 nm during the
reaction of 4c (1.12 × 10−5 M) with 3a (4.01 × 10−4 M). Inset: plot of
the rate constant kobs versus [3a] (20 °C in CH2Cl2).
Table 3. Second-Order Rate Constants k2 for the Reactions
of the Benzhydrylium Salts 4a−g with the Enamines 3a−c in
Figure 4. Plots of log k2 for the reactions of the enamines 3a−c with
CH2Cl2 at 20 °C
the benzhydrylium ions 4a−g versus their electrophilicity parameters E
in CH2Cl2 at 20 °C.
enamine
electrophile
k2/M−1 s−1
N, sN
3a (X = CPh3)
4a
4b
4c
4d
4d
4e
4f
7.66 × 105
6.40 × 104
3.56 × 104
2.56 × 103
4.71 × 104
8.97 × 103
3.25 × 103
8.77 × 102
10.19, 1.06
Table 4. Equilibrium Constants K (M−1) and Reaction Free
Energies ΔG° (kJ mol−1) for the Reactions of the Enamines
3a−c with the Benzhydrylium Ions 4 in CH2Cl2 at 20 °C
a
3b (X = SiPh3)
3c (X = H)
11.77, 0.98
12.26, 0.93
enamine
Ar2CH+
LA
K
ΔG°
3a (X = CPh3)
3b (X = SiPh3)
4d
4d
4e
4f
−9.30
−9.30
−10.46
−10.92
−11.16
−10.46
1.05 × 103
(8.02 × 104)
5.55 × 103
1.63 × 103
1.50 × 103
1.87 × 103
−17.0
(−27.5)
−21.0
−18.0
−17.8
−18.4
b
4g
4c
4d
4e
a
8.48 × 105
6.60 × 104
1.86 × 104
4g
4e
3c (X = H)
a
This value was determined under second-order conditions (small
excess of 3c).
a
LA = Lewis acidity derived from equilibrium constants for the
reactions of p- and m-substituted benzhydrylium ions with a variety of
Lewis bases (pyridines, phosphines, etc.). ΔLA values equal Δ(log K)
b
in dichloromethane at 20 °C.16 Calculated as described in the text.
benzhydrylium with a large number of Lewis bases (ΔLA =
0.70; see Table 4). For that reason, the difference of the Lewis
acidities of 4e and 4d (ΔLA = 1.16) could also be used to
calculate the equilibrium constant for the reaction of 3b with
4d (8.02 × 104 M−1), which is too large to be directly
measured.
From the ratio of the equilibrium constants for the reactions
of 3a,b with 4d, we can now derive that the triphenylsilyl-
substituted enamine 3b is a 76 times stronger Lewis base than
the trityl-substituted enamine 3a. The thermodynamic effect of
the triphenylsilyl stabilization is thus 4 times larger than the
kinetic effect derived from the relative rates of the reactions
with 4d (k3b/k3a = 18, Table 3).
While the reaction of 4e with the triphenylsilyl-substituted
enamine 3b is 2 times slower than the corresponding reaction
D
dx.doi.org/10.1021/ja508065e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
with the parent 3c (Table 3), the equilibrium constants for
these reactions showed that the triphenylsilyl-substituted
enamine 3b is an about 3 times stronger Lewis base than the
parent enamine 3c (Table 4), indicating that the hyper-
conjugative stabilization of the triphenylsilyl-substituted
iminium ion is not yet effective in the transition state of the
electrophilic additions to 3b.
Scheme 6. Reaction of the Trityl-Substituted Iminium Ion 7a
with the Silyl Ketene Acetal 8a in Dichloromethane at 20 °C
Origin of the Trityl Effect. Why is the trityl-substituted
enamine 3a approximately 26 times less reactive than the
parent enamine 3c? Since the planar arrangement of the
nitrogen substituents in 3a was shown by X-ray analysis (Figure
1), we can exclude perturbation of the enamine resonance as
the origin of the low reactivity of 3a. Shielding will block one
face of the enamine 3a and can account for a reduction of the
nucleophilic reactivity by a factor of 2.
In order to rationalize the remaining effect, we must
conclude that the trityl group acts as an electron acceptor in
3a. However, when standard reactions to determine Hammett
constants had been employed, i.e., reactions of substituted
benzoic acids with diphenyldiazomethane or alkylation of
phenolates with iodoethane, Hammett σ constants close to 0
were found (Table 5).17 Consequently, the trityl group was
considered to be an electronically neutral substituent,
comparable to H.
Kinetic investigations of the reactions of 7a with the ketene
acetals 8a,b, following the previously described procedure,19a
showed that 7a is indeed about 10 times more reactive than the
iminium ion 7c (Table 6).
Table 6. Comparison of the Electrophilic Reactivities of the
Iminium Ions 7a,c (k2/M−1 s−1, in CH2Cl2 at 20 °C)
Table 5. Determination of the Hammett σ Constant for the
a
Trityl Group
a
From ref 19a.
These observations prompted us to rationalize the low
nucleophilic reactivity of the trityl-substituted enamine 3a by a
negative hyperconjugative effect, as depicted in Scheme 7.20
X
k2/M−1 s−1
k1/s−1
m-CH3
H
1.54 × 10−2
1.83 × 10−2
1.85 × 10−2
2.01 × 10−2
3.12 × 10−2
3.21 × 10−2
7.70 × 10−4
6.48 × 10−4
7.65 × 10−4
7.43 × 10−4
Scheme 7. Negative Hyperconjugation in the Trityl-
Substituted Enamine 3a
m-Ph3C
p-Ph3C
p-Cl
p-Br
3.63 × 10−4
2.90 × 10−4
5.08 × 10−5
m-Cl
p-NO2
8.80 × 10−2
a
Data from ref 17.
This interaction, which reduces the nucleophilic reactivity of 3a,
is on the other hand a product-stabilizing factor in the
formation of the enamine 9 by nucleophilic attack at the
iminium ion 7a (Scheme 6) and thus explains the increase of
iminium reactivity by trityl substitution in the pyrrolidine.
Our postulate of a negative hyperconjugative effect of the
trityl group is not supported by geometrical parameters, as the
distance of the trityl group from the pyrrolidine ring (C3−C2
in Figures 1 and 2) is almost the same in the enamine 3a (1.574
Å) as in the iminium ion 5a (1.577 Å). Probably, the negative
hyperconjugative effect, which may explain the approximately 5
kJ mol−1 difference in activation energies, is too small to be
visible in geometrical changes.
If, on the other hand, the trityl group really acted as an
electron acceptor in enamine 3a, and thus would be the major
reason for the reduced nucleophilicity of 3a, the opposite effect
should be operating in iminium ions: i.e., iminium ions derived
from 2-tritylpyrrolidine would be expected to be more
electrophilic than the corresponding iminium ions derived
from the parent pyrrolidine.
Unfortunately, we have not been able to synthesize a
persistent iminium ion from 1b and phenylacetaldehyde. It was
possible, however, to prepare the cinnamaldehyde-derived
iminium ion 7a in analogy to a procedure described by
Gilmour and co-workers.18 The reaction of 7a-PF6 with the
cyclic ketene acetal 8a gave 71% of the conjugate addition
product 11 after aqueous workup (Scheme 6), in analogy to
our earlier studies with other cinnamaldehyde-derived iminium
ions.19
These observations have an important consequence for the
interpretation of the reactivities of iminium ions and enamines
derived from the Jørgensen−Hayashi catalyst.12,19 As shown in
Table 7, the CPh2(OSiMe3) substituent of the Jørgensen−
E
dx.doi.org/10.1021/ja508065e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
pyrrolidine, which we explain by negative hyperconjugation.
This effect rationalizes why the trityl-substituted enamine 3a is
26 times less nucleophilic than the parent analogue 3c and the
trityl substituted iminium ion 7a is 8−14 times more
electrophilic than the parent analogue 7c.
Table 7. Comparison of the Effects of the CPh2(OSiMe3)
Substituent (Jørgensen−Hayashi Catalyst) and CPh3
(Maruoka Catalyst) on the Nucleophilicities of Enamines
and Electrophilicities of Iminium Ions (krel in CH2Cl2 at 20
°C)
Comparison of the reactivities of the 2-tritylpyrrolidine-
derived enamine 3a and the 2-tritylpyrrolidine-derived iminium
ion 7a with the corresponding Jørgensen−Hayashi pyrrolidine-
derived analogues (Table 7) indicates that the CPh3 group and
the CPh2OSiMe3 group exert similar electronic effects on the
enamine and iminium intermediates of organocatalytic
reactions. This similarity rules out specific interactions between
the OSiMe3 group and the π system of the intermediate
enamines or iminium ions.
For that reason, the high stereoselectivity observed in
reactions catalyzed by the Jørgensen−Hayashi pyrrolidine can
be entirely assigned to a steric effect. Seebach and co-workers
have demonstrated that the enamines and iminium ions derived
from 2-(CPh2OSiR3)-substituted pyrrolidines preferred syncli-
nal-exo conformations, in which the silyloxy substituent shields
one face of the trigonal reaction center.21a,b Thus, steric effects
can also explain why even higher stereoselectivities have been
observed when the OSiMe3 substituent was replaced by the
OSiPh2Me group.21b,e,22 While 2-tritylpyrrolidine (1a) cata-
lyzed stereoselective additions of aldehydes to nitrostyrenes less
efficiently than the Jørgensen−Hayashi catalyst,8c high
enantioselectivities for 1a-catalyzed reactions have so far only
been reported for α-benzoyloxylations and hydroxyaminations
of aldehydes.7 It is not clear whether the small number of
reports using 1a as an organocatalyst7,8a,c,23 is due to its less
convenient accessibility7a,24 or its poorer performance in
comparison to the Jørgensen−Hayashi catalyst in other
enamine activated reactions.
a
Calculated from k = 2.33 × 103 M−1 s−1 for the reaction of the 2-
(CPh2(OSiMe3))-substituted enamine with 4d in MeCN.12 Calcu-
b
lated from k = 67.0 M−1 s−1 for the reaction of the 2-(CPh2(OSiMe3))-
substituted iminium ion with 8b.19a
Hayashi catalyst deactivates the enamine only slightly more
than the CPh3 substituent in the Maruoka catalyst. Vice versa,
the CPh2(OSiMe3) group has only a slightly larger activating
effect on the iminium ion than the trityl group.
For these reasons our earlier explanation of the
CPh2(OSiMe3) effect by the electronegativity of oxygen12 can
only account for a minor fraction of the effect and we now
suggest that negative hyperconjugation of the CPh2(OSiMe3)
group also accounts for the reactivities of the intermediates of
“Jørgensen−Hayashi catalyzed” reactions.
CONCLUSION
■
The X-ray structures of the enamines 3a,b derived from the
reactions of phenylacetaldehyde with 2-tritylpyrrolidine (1a)
and 2-(triphenylsilyl)pyrrolidine (1b), respectively, indicate
almost perfect planarity of the enamine nitrogen and closely
resemble that previously reported21 for the analogous enamine
derived from the Jørgensen−Hayashi catalyst.
ASSOCIATED CONTENT
* Supporting Information
■
S
Text, figures, tables, and CIF files giving experimental
procedures, product characterization, kinetic experiments, all
NMR spectra, and crystallographic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
Equilibrium measurements showed that the hyperconjugative
interaction of σC−Si with π*CN increases the Lewis basicity of
enamine 3b by a factor of 3 relative to that of the parent
compound 3c, corresponding to a factor of 6 if the reduced
symmetry (two faces accessible in 3c) is taken into account.
This interaction is not yet effective in the transition states of the
electrophilic additions, as the silylated enamine 3b reacts with
the same rate as one face of the enamine 3c (Figure 5).
Though the trityl group had previously been reported to be
an electronically neutral substituent with a Hammett
substituent constant of σ ≈ 0,17 the trityl group behaves as
an electron-withdrawing substituent at the 2-position of
AUTHOR INFORMATION
Corresponding Authors
*E-mail for S.L.: Sami.lakhdar@ensicaen.fr.
*E-mail for H.M.: Herbert.mayr@cup.uni-muenchen.de.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Deutsche Forschungsgemeinschaft (SFB 749,
project B1) and the CMST COST Action CM0905 for support
of this work. H.E. is grateful to the German National
Foundation (Studienstiftung des Deutschen Volkes e.V.) for a
fellowship. S.L. thanks the CNRS and Labex Synorg (ANR-11-
LABX-0029) for their support. The authors thank Prof. Dr. D.
Seebach and Dr. D. W. Lupton for stimulating comments. This
paper is dedicated to Professor Shinjiro Kobayashi on the
occasion of his 75th birthday.
REFERENCES
■
Figure 5. Reactivities of the enamines 3a−c toward 4d (data from
Table 3 and ref 12).
(1) (a) Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley:
Weinheim, Germany, 2006. (b) Mukherjee, S.; Yang, J. W.; Hoffmann,
F
dx.doi.org/10.1021/ja508065e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
S.; List, B. Chem. Rev. 2007, 107, 5471−5569. (c) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47,
6138−6171. (d) MacMillan, D. W. C. Nature 2008, 455, 304−308.
(e) Asymmetric Organocatalysis; List, B., Ed.; Springer: New York,
2009; Topics in Current Chemistry Vol. 291. (f) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178−2189. (g) Melchiorre,
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(16) Lewis acidities LA were evaluated from statistical analysis of a
large number of equilibrium constants for the reactions of
benzhydrylium ions with pyridines, phosphines, and related Lewis
bases (characterized by their Lewis basicities LB) using the correlation
log K = LA + LB with the definition LA = 0 for (4-MeOC6H4)2CH+ in
CH2Cl2; unpublished work.
(17) Benkeser, R. A.; Gosnell, R. B. J. Org. Chem. 1957, 22, 327−329.
(18) (a) Sparr, C.; Schweizer, W. B.; Senn, H. M.; Gilmour, R. Angew.
Chem., Int. Ed. 2009, 48, 3065−3068. (b) Tanzer, E.-M.; Zimmer, L.
E.; Schweizer, W. B.; Gilmour, R. Chem. Eur. J. 2012, 18, 11334−
11342.
P. Angew. Chem,. Int. Ed. 2009, 48, 1360−1363. (h) Cheong, P. H.-Y.;
̈
Legault, C. Y.; Um, J. M.; C
̧
elebi-Olcu
̧
m, N.; Houk, K. N. Chem. Rev.
̈
2011, 111, 5042−5137. (i) Science of Synthesis: Asymmetric
Organocatalysis; List, B., Maruoka, K., Eds.; Thieme: Stuttgart,
Germany, 2012.
(2) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen,
S.; Jørgensen, K. A. Chem. Commun. 2011, 47, 632−649.
(3) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000,
122, 2395−2396.
(4) (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123,
11273−11283. (b) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B.
J. Am. Chem. Soc. 2003, 125, 2475−2479. (c) Hoang, L.; Bahmanyar,
S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16−17. (d) List,
B.; Hoang, L.; Martin, H. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5839−5842. (e) Bock, D. A.; Lehmann, C. W.; List, B. Proc. Natl.
Acad. Sci. U.S.A. 2010, 107, 20636−20641.
(5) (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem.
Soc. 2001, 123, 5260−5267. (b) Martin, H. J.; List, B. Synlett 2003,
1901−1902. (c) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37,
570−579. (d) Dahlin, N.; Bøgevig, A.; Adolfsson, H. Adv. Synth. Catal.
2004, 346, 1101−1105. (e) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth.
Catal. 2004, 346, 1141−1146. (f) Momiyama, N.; Torii, H.; Saito, S.;
Yamamoto, H. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5374−5378.
(g) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558−560.
(19) (a) Lakhdar, S.; Tokuyasu, T.; Mayr, H. Angew. Chem., Int. Ed.
2008, 47, 8723−8726. (b) Lakhdar, S.; Ammer, J.; Mayr, H. Angew.
Chem., Int. Ed. 2011, 50, 9953−9956.
(20) (a) Kirby, A. J. Stereoelectronic Effects; Oxford University Press:
Oxford, U.K., 1996. (b) Kirby, A. J. The Anomeric Effect and Related
Stereoelectronic Effects at Oxygen; Hafner, K., Rees, C. W., Trost, B. M.,
Lehn, J.-M., Schleyer, P. v. R., Zahradnik, R.; Eds.; Springer Verlag:
Berlin, Germany, 1983; Reactivity and Structure Concepts in Organic
Chemistry Vol. 15. (c) Graczyk, P. P.; Mikołajczyk, M. In Anomeric
Effect: Origin and Consequences; Eliel, E. L., Wilen, S. H., Eds.; Wiley:
Hoboken, NJ, 1994; Topics in Stereochemistry Vol. 21, pp 159−350.
(21) (a) Seebach, D.; Grose
Beck, A. K. Helv. Chim. Acta 2008, 91, 1999−2034. (b) Grose
̌
lj, U.; Badine, D. M.; Schweizer, W. B.;
lj, U.;
̌
Seebach, D.; Badine, D. M.; Schweizer, W. B.; Beck, A. K.; Krossing, I.;
Klose, P.; Hayashi, Y.; Uchimaru, T. Helv. Chim. Acta 2009, 92, 1225−
1259. (c) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Angew. Chem.,
Int. Ed. 2010, 49, 4997−5003. (d) Schmid, M. B.; Zeitler, K.;
Gschwind, R. M. Chem. Sci. 2011, 2, 1793−1803. (e) Seebach, D.; Sun,
X.; Ebert, M.-O.; Schweizer, W. B.; Purkayastha, N.; Beck, A. K.;
́
(h) Duschmale, J.; Wiest, J.; Wiesner, M.; Wennemers, H. Chem. Sci.
2013, 4, 1312−1318.
(6) (a) Melgo, A.; Palomo, C. Chem. Asian J. 2008, 3, 922−948.
(b) Jensen, K. L.; Dickmeiss, G.; Jiang, H.; Albrecht, Ł.; Jørgensen, K.
A. Acc. Chem. Res. 2012, 45, 248−264.
Duschmale,
Hayashi, Y.; Reiher, M. Helv. Chim. Acta 2013, 96, 799−852.
(f) Carneros, M.; Sanchez, M.; Vilarrasa, J. Org. Lett. 2014, 16,
2900−2903.
́
J.; Wennemers, H.; Mukaiyama, T.; Benohoud, M.;
́
(7) (a) Kano, T.; Mii, H.; Maruoka, K. J. Am. Chem. Soc. 2009, 131,
3450−3451. (b) Kano, T.; Shirozu, F.; Maruoka, K. Org. Lett. 2014,
16, 1530−1532.
(22) (a) Kemppainen, E. K.; Sahoo, G.; Valkonen, A.; Pihko, P. M.
Org. Lett. 2012, 14, 1086−1089. (b) Hayashi, Y.; Okamura, D.;
Umemiya, S.; Uchimaru, T. ChemCatChem 2012, 4, 959−962.
(c) Silvi, M.; Cassani, C.; Moran, A.; Melchiorre, P. Helv. Chim.
Acta 2012, 95, 1985−2006. (d) Cassani, C.; Melchiorre, P. Org. Lett.
2012, 14, 5590−5593. (e) Mukaiyama, T.; Ishikawa, H.; Koshino, H.;
Hayashi, Y. Chem. Eur. J. 2013, 19, 17789−17800. (f) Kemppainen, E.
́ ́
(8) (a) Bauer, J. O.; Stiller, J.; Marques-Lopez, E.; Strohfeldt, K.;
Christmann, M.; Strohmann, C. Chem. Eur. J. 2010, 16, 12553−12558.
(b) Husmann, R.; Jorres, M.; Raabe, G.; Bolm, C. Chem. Eur. J. 2010,
̈
16, 12549−12552. See also: (c) Jentzsch, K. I.; Min, T.; Etcheson, J.
I.; Fettinger, J. C.; Franz, A. K. J. Org. Chem. 2011, 76, 7065−7075.
(9) Mersmann, S.; Raabe, G.; Bolm, C. Tetrahedron Lett. 2011, 52,
5425−5426.
K.; Sahoo, G.; Piisola, A.; Hamza, A.; Kot
Chem. Eur. J. 2014, 20, 5983−5993.
(23) (a) Kano, T.; Mii, H.; Maruoka, K. Angew. Chem., Int. Ed. 2010,
-Lopez, E.; Herrera, R. P.;
́ ́
ai, B.; Papai, I.; Pihko, P. M.
(10) (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33,
938−957. (b) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.;
Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.;
Schimmel, H. J. Am. Chem. Soc. 2001, 123, 9500−9512. (c) Lucius, R.;
Loos, R.; Mayr, H. Angew. Chem., Int. Ed. 2002, 41, 91−95. (d) Mayr,
H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66−77. (e) Mayr,
H.; Ofial, A. R. Pure Appl. Chem. 2005, 1807−1821. (f) Mayr, H.;
Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584−595. (g) Mayr, H.;
Lakhdar, S.; Maji, B.; Ofial, A. R. Beilstein J. Org. Chem. 2012, 8, 1458−
1478.
49, 6638−6641. (b) Stiller, J.; Marques
́
́
Frohlich, R.; Strohmann, C.; Christmann, M. Org. Lett. 2011, 13, 70−
̈
73. (c) Hermange, P.; Portalier, F.; Thomassigny, C.; Greck, C.
Tetrahedron Lett. 2013, 54, 1052−1055.
(24) Klumpp, D. A.; Aguirre, S. L.; Sanchez, G. V., Jr.; de Leon, S. J.
Org. Lett. 2001, 3, 2781−2784.
(11) For a comprehensive database of nucleophilicity parameters N
and sN as well as electrophilicity parameters E, see: http://www.cup.
lmu.de/oc/mayr/DBintro.html.
(12) Lakhdar, S.; Maji, B.; Mayr, H. Angew. Chem., Int. Ed. 2012, 51,
5739−5742.
(13) CCDC numbers: compound 3a, 1016097; compound 3b,
1016098. These supplementary crystallographic data can be obtained
free of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(14) Dunitz, J. D. X-Ray Analysis and the Structure of Organic
Molecules; Cornell University Press: London, 1979.
(15) CCDC numbers: for compound 5a, 1016100; for compound
5b, 1016099; for compound 5c, 1017314. These supplementary
crystallographic data can be obtained free of charge from The
G
dx.doi.org/10.1021/ja508065e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX