Quantification of the electrophilic reactivities of aldehydes, imines, and enones

Article abstract of DOI:10.1021/ja200820m

The rates of the epoxidation reactions of aldehydes, of the aziridination reactions of aldimines, and of the cyclopropanation reactions of α,β-unsaturated ketones with aryl-stabilized dimethylsulfonium ylides have been determined photometrically in dimethyl sulfoxide (DMSO). All of these sulfur ylide-mediated cyclization reactions as well as the addition reactions of stabilized carbanions to N-tosyl-activated aldimines have been shown to follow a second-order rate law, where the rate constants reflect the (initial) CC bond formation between nucleophile and electrophile. The derived second-order rate constants (log k₂) have been combined with the known nucleophilicity parameters (N, s_N) of the aryl-stabilized sulfur ylides 4a,b and of the acceptor-substituted carbanions 4c-h to calculate the electrophilicity parameters E of aromatic and aliphatic aldehydes (1a-i), N-acceptor-substituted aromatic aldimines (2a-e), and α,β-unsaturated ketones (3a-f) according to the linear free-energy relationship log k ₂ = s_N(N + E) as defined in J. Am. Chem. Soc.2001, 123, 9500-9512. The data reported in this work provide the first quantitative comparison of the electrophilic reactivities of aldehydes, imines, and simple Michael acceptors in DMSO with carbocations and cationic metal-π complexes within our comprehensive electrophilicity scale.

Full text of DOI:10.1021/ja200820m

ARTICLE
pubs.acs.org/JACS
Quantification of the Electrophilic Reactivities of Aldehydes, Imines,
and Enones
Roland Appel and Herbert Mayr*
Department Chemie, Ludwig-Maximilians-Universit€at M€unchen, Butenandtstrasse 5-13, 81377 M€unchen, Germany
S Supporting Information
b
ABSTRACT: The rates of the epoxidation reactions of alde-
hydes, of the aziridination reactions of aldimines, and of the
cyclopropanation reactions of R,β-unsaturated ketones with
aryl-stabilized dimethylsulfonium ylides have been determined
photometrically in dimethyl sulfoxide (DMSO). All of these
sulfur ylide-mediated cyclization reactions as well as the addi-
tion reactions of stabilized carbanions to N-tosyl-activated
aldimines have been shown to follow a second-order rate law,
where the rate constants reflect the (initial) CC bond formation
between nucleophile and electrophile. The derived second-
order rate constants (log k2) have been combined with the known nucleophilicity parameters (N, sN) of the aryl-stabilized sulfur
ylides 4a,b and of the acceptor-substituted carbanions 4cꢀh to calculate the electrophilicity parameters E of aromatic and aliphatic
aldehydes (1aꢀi), N-acceptor-substituted aromatic aldimines (2aꢀe), and R,β-unsaturated ketones (3aꢀf) according to the linear
free-energy relationship log k2 = sN(N þ E) as defined in J. Am. Chem. Soc. 2001, 123, 9500ꢀ9512. The data reported in this work
provide the first quantitative comparison of the electrophilic reactivities of aldehydes, imines, and simple Michael acceptors in
DMSO with carbocations and cationic metalꢀπ complexes within our comprehensive electrophilicity scale.
’ INTRODUCTION
nucleophilicity scale including aliphatic and aromatic π-systems,
hydride donors, and n-nucleophiles, such as alkoxides and amines.3
Whereas the use of solvent-independent electrophilicity para-
meters E also appears to work well for other types of carbocations
and a variety of Michael acceptors,1b,c solvation of the electro-
philes has to be considered explicitly in the treatment of SN2 re-
actions.5 From the fact that additions of nucleophiles to carbonyl
groups usually require hydrogen-bond-donating solvents or catalysts
or Lewis-acidic metal cations, e.g., Liþ or Mg2þ,6 which coordi-
nate to the developing alkoxide ions, one can conclude that the
electrophilicities of carbonyl compounds are also strongly af-
fected by the nature of the solvents.
While kinetics of the additions of nucleophiles to carbonyl groups
in aqueous and alcoholic solution have previously been reported,7 it
was the goal of this work to investigate the electrophilic reactivities of
nonactivated carbonyl groups in an aprotic polar solvent and to
compare them with the electrophilicities of imines and R,β-
unsaturated ketones. Inclusion of these synthetically important elec-
trophiles into our comprehensive reactivity scales will significantly
improve the value of these scales for designing organic syntheses.
Attempts to determine E parameters of aldehydes in DMSO
by their reactions with acceptor-stabilized carbanions (e.g., the
highly nucleophilic p-nitrophenylacetonitrile anion)3 failed, be-
cause no significant conversion of the carbanions was observed
when they were combined with an excess of ordinary aldehydes
The majority of reactions used in organic synthesis can be con-
sidered as combinations of electrophiles with nucleophiles. In recent
years, we have developed an ordering system, which uses eq 1 to
predict rates and selectivities for these reactions:1
log k20°C ¼ sNðN þ EÞ
ð1Þ
Equation 1 calculates the second-order rate constants k20°C
(L molꢀ1sꢀ1) from two solvent-dependent parameters for nucleo-
philes [sensitivity sN (previously termed s) and nucleophilicity N]
and one parameter E for electrophiles, which has usually been
treated as solvent independent. Using a series of benzhydrylium
ions and structurally related quinone methides as reference elec-
trophiles,2 we have been able to generate a comprehensive nucleo-
philicity scale covering more than 30 orders of magnitude.3 Vice
versa, the reactivity parameters E for electrophiles have been
derived from the rate constants of their reactions with carbon-
centered nucleophiles of known N and sN.3
The fact that linear log k20°C vs E plots were obtained with the
same set of E parameters for benzhydrylium ions and quinone
methides in solvents as different as dichloromethane, acetonitrile,
DMSO, and water does not mean that the degree of solvation is
the same for all electrophiles. It implies, however, that the solvation
of the reference electrophiles changes linearly with the electro-
philicities E. Variable solvation of these electrophiles is thus shifted
into the solvent-dependent nucleophile-specific parameters N
and sN.4 This procedure allowed us to construct an undivided
Received: January 27, 2011
Published: May 05, 2011
r
2011 American Chemical Society
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Scheme 1. Mechanism of Sulfur Ylide-Mediated Epoxidations,
Aziridinations, and Cyclopropanations (CoreyꢀChaykovsky
Reaction)9ꢀ11
Scheme 2. Aldehydes 1aꢀi, Imines 2aꢀe, and Enones 3aꢀf
Investigated in this Worka
Table 1. Sulfur Ylides 4a,b and Carbanions 4cꢀh and Their
Nucleophilicity Parameters N and sN in DMSO
a Ts = p-methylbenzenesulfonyl, and Boc = t-butoxycarbonyl.
a Nucleophilicity parameters N and sN for 4a,b were taken from ref 12b,
for 4c,d from ref 13, for 4e from ref 14, for 4f from ref 2b, and for 4g,h
from ref 15.
Scheme 3. Reactions of Sulfur Ylide 4a with the Aldehydes
1a,e,f,h
(e.g., PhCHO) in DMSO. Obviously, the low thermodynamic
stability of the developing alkoxides (pKa = 29.0 for MeOH in
DMSO)8b,c makes these reactions highly reversible in the aprotic
polar solvent DMSO, while they proceed readily in protic solvents,
where alkoxide ions are much better stabilized (pKa = 15.5 for
MeOH in H2O).8a
A possibility to achieve irreversible additions of carbon nucleo-
philes to carbonyl groups in DMSO is the rapid trapping of the
intermediate alkoxide anion by an internal electrophile, which is
encountered in the reactions of sulfur ylides with carbonyl com-
pounds (Scheme 1). Detailed investigations revealed a common
mechanistic course of these epoxidation reactions9 and of the
analogous aziridination10 and cyclopropanation reactions.9b,11 In
all cases, the sulfur ylide initially attacks at an electrophilic carbon
center to form a betaine intermediate, which then undergoes an
intramolecular nucleophilic displacement to yield an epoxide, an
aziridine, or a cyclopropane, respectively (Scheme 1).
As the formation of the betaine intermediate is often nonrever-
sible and rate determining (dependent on ylide stability and elec-
trophile),9e,h,n,10a,10c,10d,11b,11e,12 the kinetics of the reactions of the
sulfur ylides 4a,b(Table 1) with the aldehydes 1aꢀi, theN-activated
imines 2aꢀe, and the R,β-unsaturated ketones 3aꢀf (Scheme 2)
will now be employed to determine the electrophilicity parameters E
for these synthetically important compounds in DMSO.
a KOtBu, DMSO. b K2CO3 (aq), CHCl3.
5 with the benzaldehydes 1a and 1e as well as with p-nitrocinna-
maldehyde (1f) and butanal (1h) (Scheme 3).
The reactions of the sulfur ylides 4a,b with all imines 2 examined
yielded the aziridines 6 (Scheme 4). While the N-tosyl-substi-
tuted aziridines 6ab, 6ba, and 6bb were formed as mixtures of cis-
and trans-isomers, exclusively trans-isomers were isolated from
the N-tert-butoxycarbonyl-substituted imine 2d. NMR studies of
the crude products obtained from the N-diphenylphosphinoyl-
substituted imine 2e showed the formation of 6ea (cis/trans 1:3)
and 6eb (cis/trans 1:6) as mixtures of diastereomers, which were
separated by column chromatography. The corresponding trans
products were isolated and characterized, while the cis products
could not be obtained in pure form. Detailed descriptions of the
experimental procedures and the characterizations of the isolated
compounds are given in the Supporting Information.
’ RESULTS
Product Studies. In line with earlier investigations,9e,h,n the
semistabilized sulfur ylide 4a was found to give trans-epoxides
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Scheme 4. Reactions of the Sulfur Ylides 4a,b with the Imines
2a,b,d,e
a Cis/trans-ratio corresponds to the isolated products. b Yield isolated
refers to trans-isomer; cis/trans-ratio corresponds to the crude product.
Scheme 5. Reactions of the Sulfur Ylides 4a,b with the
Michael Acceptors 3aꢀf a
Figure 1. UVꢀvis spectroscopic monitoring at 318 nm of the reaction
of imine 2b (4.73 ꢁ 10ꢀ5 mol Lꢀ1) with the methylsulfinyl-stabilized
carbanion 4e (8.03 ꢁ 10ꢀ5 mol Lꢀ1) in DMSO at 20 °C.
the cyclopropanes 7ca and 7da were separated, and the major
isomers were isolated and characterized. The relative configura-
tions of the cyclopropanes 7 have been defined by the character-
istic coupling constants of the corresponding cyclopropane protons
in the 1H NMR spectra. Detailed descriptions of the experimental
procedures and the characterizations of the isolated compounds
are given in the Supporting Information.
In contrast to the N-Boc- and N-diphenylphoshinoyl-substi-
tuted imines 2d and 2e, which reacted only with the sulfur ylides
4a,b (see Scheme 4), the N-tosyl-substituted imines 2aꢀc also
reacted with the carbanions 4cꢀh in DMSO. As depicted in
Scheme 6, the addition products 8 were obtained from the re-
actions of the N-tosyl-activated imines 2aꢀc with the nitronates
4c,d and the diethyl malonate anion (4f).
a Diastereomeric ratios dr correspond to the isolated products. b Minor
diastereomer is a meso compound. c Yield isolated refers to major
diastereomer; dr corresponds to the crude product.
Scheme 6. Reactions of the Carbanions 4c,d,f with the Imi-
nes 2aꢀc
The methylsulfinyl-stabilized carbanion 4e and the phospho-
nate-stabilized carbanions 4g,h did not yield simple addition pro-
ducts with the imine 2b. Instead, Knoevenagel-type condensation
reactions took place with the formation of the olefins 9 (Figure 1
and Scheme 7), as previously described for the reactions of 4g
and 4h with N-tosyl-substituted imines.17 UVꢀvis spectroscopic
monitoring of these reactions showed that the fast additions of
the carbanions to the imine 2b are followed by slow eliminations of
the tosylamide group to give the Knoevenagel products 9 (Figure 1
and Supporting Information, Tables S18, S21, and S23).
In all investigated Knoevenagel-type condensation reactions,
only one stereoisomer was obtained. In the case of compound 9be
(Figure 1) the configuration of the double bond was not deter-
mined. However, the E-configurations of the olefins 9bg and 9bh
(Scheme 7) were derived from the characteristic coupling constant
a Only the major diastereomer was isolated and characterized (dr ∼ 1:3 for
the crude product). b Reaction conditions: KOtBu, THF, ꢀ80 to ꢀ40 °C.
In line with previous reports on the reactions of cinnamalde-
hyde with aryl-stabilized sulfur ylides,16 Scheme 3 shows that
p-nitrocinnamaldehyde (1f) reacts exclusively at the carbonyl group
with 4a. In contrast, the R,β-unsaturated ketones 3aꢀf reacted
selectively at the CdC double bond to yield the cyclopropanes 7
as mixtures of diastereomers (Scheme 5). The diastereomers of
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Scheme 7. Condensation Products from the Phosphoryl-
Stabilized Carbanions 4g,h and Imine 2b
component is not crucial for the determination of the pseudo-
first-order rate constants kobs (eqs 2a and 2b) when the rate of
decomposition is much slower than the reaction under consid-
eration, we have thus circumvented the problem that the absolute
concentrations of the semistabilized ylides 4a,b cannot precisely
be determined due to their low stability.
From the exponential decays of the UVꢀvis absorbances of
the imines 2aꢀc (Figure 2) or of the sulfur ylides 4a,b, the first-
order rate constants kobs were obtained. Plots of kobs (sꢀ1) against
the concentrations of the reaction partners used in excess were
linear with negligible intercepts, as required by the relation kobs
=
a KOtBu (18 mol %). b Et3N (18 mol %).
k2[Nu]0 (eq 2a and Figure 2) or kobs = k2[E]0 (eq 2b), respec-
tively. Only in the reactions of the carbanions 4fꢀh with 2b in-
complete consumption of the imine 2b as well as the positive in-
tercepts of plots of kobs vs [4] were observed due to the high
reversibility of the additions; because of slow subsequent reac-
tions a reliable determination of the equilibrium constants was
not possible. However, in all cases the second-order rate constants
could be derived from the slopes of the linear correlations of kobs
versus [Nu]0 or [E]0, respectively (Table 2):
ꢀ d½Eꢂ=dt ¼ k2½Nuꢂ½Eꢂ
ð2Þ
ð2aÞ
ð2bÞ
for ½Nuꢂ0 . ½Eꢂ0 w kobs ¼ k2½Nuꢂ0
for ½Eꢂ0 . ½Nuꢂ0 w kobs ¼ k2½Eꢂ0
’ DISCUSSION
Epoxidation Reactions. Elegant crossover experiments by
Aggarwal and co-workers9e have shown that the independently
generated anti-betaine 10 underwent fast cyclization with ex-
clusive formation of trans-stilbene oxide (Scheme 8). The
analogous generation of the syn-betaine 11 led to retro-addition,
however, and the regenerated sulfur ylide could be trapped by the
more electrophilic p-nitrobenzaldehyde.
Analogous crossover experiments showed that also in acetoni-
trile the anti-betaine does not cleave to sulfur ylide and aldehyde but
gives the trans-stilbene oxide selectively.9n
As a consequence, the selective formation of trans-epoxide
from benzaldehyde and semistabilized sulfur ylides (Scheme 8)
must either be due to selective formation of the anti-betaine
10 (kanti . ksyn) or to the parallel formation of both betaines
(kanti ≈ ksyn), followed by cyclization of the anti-betaine 10 and
retro-addition of the syn-betaine 11. The second mechanism is
only compatible with the observed second-order kinetics if the
retro-addition of the syn-betaine (kꢀsyn) is very fast. If significant
equilibrium concentrations of the syn-betaine would build up during
the reaction, then deviations from the second-order rate law
would be expected, as the UVꢀvis spectroscopically monitored
sulfur ylide 4a would continuously be regenerated from the re-
servoir of the syn-betaine. No matter whether the syn-betaine is
formed as a short-lived intermediate or not, the rate constants
listed in Table 2 reflect the rate-determining formation of the
anti-betaine (kanti) as exemplified in Scheme 8.19
Figure 2. UVꢀvis spectroscopic monitoring of the reaction of the
nitromethyl anion (4d, 4.44 ꢁ 10ꢀ4 mol Lꢀ1) with the imine 2b (3.77 ꢁ
10ꢀ5 mol Lꢀ1) at 330 nm in DMSO at 20 °C. Insert: Determination of
the second-order rate constant k2 = 4.31 ꢁ 104 L molꢀ1 sꢀ1 from the
dependence of the first-order rate constant kobs on the concentration of 4d.
of the olefinic proton with the phosphorus nucleus (JHP = 24 and
21 Hz, respectively).17,18 Detailed reaction conditions for the pre-
paration of the compounds 9be, 9bg; and 9bh are given in the Sup-
porting Information.
Kinetic Investigations. All kinetic investigations were per-
formed in DMSO solution at 20 °C. As reported earlier,12b the
aryl-stabilized sulfur ylides 4a,b decompose slowly at room tem-
perature and were, therefore, prepared by deprotonation of the
corresponding CH acids (4a,b-H)-BF4 with 1.00ꢀ1.05 equiv of
KOtBu in dry THF at eꢀ50 °C. Small amounts of these solutions
were dissolved in DMSO at room temperature directly before
each kinetic experiment. Stock solutions of the carbanions 4cꢀh
were prepared by deprotonation of the corresponding CH acids
(4cꢀh)-H with 1.00ꢀ1.05 equiv of KOtBu in DMSO. All kinetic
investigations were monitored photometrically, either by follow-
ing the disappearance of the colored imines 2aꢀc or of the colored
aryl-stabilized sulfur ylides 4a,b at or close to their absorption
maxima. The kinetic investigations of the reactions of the carbanions
4cꢀh with the imines 2aꢀc (also prepared as stock solutions in
DMSO) were performed with a high excess of the carbanions over
the imines to achieve first-order kinetics. Vice versa, first-order
kinetics for the reactions of the aryl-stabilized ylides 4a,b with the
electrophiles 1ꢀ3 were realized by using at least 10 equiv of the
electrophiles 1ꢀ3. As the absolute concentration of the minor
As shown in Table 2, the rates of the reactions of the sulfur
ylide 4a with the aldehydes 1aꢀe increase with the increasing
electron-withdrawing properties of the groups bound to the
meta- or para-positions of the benzaldehydes 1aꢀe. From the
fair correlation of log k2 versus Hammett’s substituent constants
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Table 2. Experimental and Calculated Second-Order Rate Constants (L molꢀ1sꢀ1) for the Reactions of the Sulfur Ylides 4a,b and
the Carbanions 4cꢀh with the Aldehydes 1, the Imines 2, and the Michael Acceptors 3 in DMSO at 20°C
exp
a Determined by least-squares minimization of Δ2 = ∑(log k2 ꢀ sN(N þ E))2 using the second-order rate constants k2exp given in this table and the N
and sN parameters of the nucleophiles 4aꢀh from Table 1. For details, see Tables S10, S27, S32, S38, S42 and Figures S1ꢀS3 of the Supporting
Information. b Calculated by eq 1 with the N and sN parameters for the nucleophiles 4 (Table 1) and the optimized electrophilicity parameters E for the
imines 2aꢀe and the enones 3a,b determined in this work. c Only one k2exp value was used for the determination of E. d Incomplete consumption of the
electrophile was observed indicating an equilibrium situation.
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Scheme 8. Mechanism Accounting for the High Trans
Selectivity in the Epoxidation Reaction of Benzaldehyde with
Semistabilized Sulfur Ylides9e,h
Figure 4. Comparison of the rate constants (log k2) for the reactions of
the aldehydes 1aꢀi with sulfur ylide 4a in DMSO at 20 °C.
In previous work we have determined rate constants for the
olefination reactions of aromatic aldehydes with phosphoryl-stabi-
lized carbanions and with phosphorus ylides.15 Table 3 compares
the experimental rate constants with those calculated by eq 1
from the E values of the aldehydes in Table 2 and the previously
reported N and sN parameters15 for phosphorus ylides and phos-
phoryl-substituted carbanions.
In view of the generally accepted model for salt-free Wittig
reactions, which involves concerted oxaphosphetane formation,22,23
exp
calcd
the similarity of k2 and k2
in Table 3 is unexpected and
remarkable: All rate constants calculated by using eq 1 for the
reactions of the phosphoryl-stabilized carbanions 4gꢀj and the
phosphorus ylide 4k listed in Table 3 with the benzaldehydes 1a,
d,e deviate by less than a factor of 66 from the corresponding
experimental values. As the confidence limit of eq 1, which uses
only three parameters to predict absolute rate constants in a
reactivity range of 40 orders of magnitude, is a factor of 10ꢀ100,
one cannot unambiguously assign the origin of these deviations.
In any case, the small k2exp/k2calcd ratios in Table 3 prove that the
oxaphosphetanes must be generated by highly asynchronous
processes from 4gꢀk and 1a,d,e via transition states which are
not significantly stabilized by the formation of the new PO bonds.
Though the similarity between k2exp and k2calcd in Table 3 suggests
that eq 1 may generally be applicable for defining scope and limi-
tations of the olefination reactions with Wittig and Hornerꢀ
WadsworthꢀEmmons reagents, it is presently not clear whether
this approximation also holds for reactions with other types of
phosphoryl-stabilized carbanions and phosphorus ylides.
While the electrophilicity parameters for aldehydes (Table 2)
reflect the intrinsic reactivities of aldehydes in DMSO, Scheme 9
demonstrates the striking increase of the electrophilic reactivity
of benzaldehyde (1e), when its carbonyl group is activated by a
Lewis acid or by O-methylation.24 Accordingly, the boron trichlor-
ide complex 1e-BCl3 is more than 20 orders and the carboxonium
ion 1e-Meþ is more than 22 orders of magnitude more reactive than
benzaldehyde (1e). The mild conditions for many Knoevenagel25
and Henry26 reactions indicate, however, that the electrophili-
cities of aldehydes increase significantly in aqueous or alcoholic
solvents.
Figure 3. Correlation of the second-order rate constants k2 for the
reactions of the sulfur ylide 4a with the benzaldehydes 1aꢀe in DMSO
at 20 °C versus Hammett’s σ (taken from ref 20).
σ shown in Figure 3, one can derive a reaction constant of F = 2.8
in line with a rate-determining nucleophilic addition of sulfur ylide
4a to the aldehydes 1aꢀe. A similar reaction constant of F = 2.5
was reported for the epoxidations of various benzaldehydes with
dimethylsulfonium benzylide in CD3CN.9n
As the second-order rate constants (Table 2) for the reactions
of sulfur ylide 4a with the aldehydes 1aꢀi reflect the rate of attack
of a carbon nucleophile at a carbonyl group with formation of an
alkoxide anion, they can be used for a quantitative comparison of
the electrophilic reactivities of the aldehydes 1aꢀi. Figure 4 shows
that the reactivities of the aldehydes 1aꢀi cover only 1.5 orders
of magnitude. The least reactive compound in this series is the
unsubstituted cinnamaldehyde (1g), which is approximately half
as reactive as benzaldehyde (1e). The aliphatic aldehydes 1h and
1i are three times more electrophilic than benzaldehyde. Equa-
tion 1 was used to calculate the electrophilicity parameters E of
1aꢀi (Table 2) from the rate constants listed in Table 2 and the
N and sN parameters of the sulfur ylide 4a (Table 1).
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Table 3. Comparison of the Experimental and Calculated Second-Order Rate Constants (L molꢀ1 sꢀ1) for the Olefination
Reactions of the Benzaldehydes 1a,d,e with Phosphoryl-Stabilized Carbanions 4gꢀj and Phosphorus Ylide 4k in DMSO at 20°C a,b
a N and sN parameters and rate constants k2exp (DMSO, 20 °C) taken from ref 15 if not indicated otherwise. b Rate constants k2calcd were calculated by
using eq 1, the N and sN parameters for the nucleophiles (column 1 of this table), and the electrophilicity parameters E for 1a,d,e (Table 2). c Taken from
ref 21.
the last column of Table 2. Though the nucleophile-specific param-
eters N and sN of the sulfur ylides 4a,b and of the carbanions 4cꢀh
have been derived from the rates of their reactions with benz-
hydrylium ions and Michael acceptors, the similarity between
k2calcd and k2exp in Table 2 shows that they can be combined with
the electrophilicity parameters of the N-tosyl-substituted benzaldi-
mines 2aꢀc to calculate the rate constants for the aziridination
reactions as well as for the addition reactions of the carbanions to the
CdN double bond. In 5 of 8 cases, the agreement between
calculated and experimental reactivities of 2b is better than factor
2.1 and in all other cases better than a factor of 6.
Scheme 9. Comparison of the Electrophilic Reactivity E of
Benzaldehyde 1e in DMSO with Those of the Boron
Trichloride Complex 1e-BCl3 and the Carboxonium Ion 1e-
Meþ in CH2Cl2
A graphical illustration for this agreement is presented in
Figure 5. The correlation lines drawn in this figure are derived
from the previously reported reactivities of the sulfur ylides 4a,b
and the nitromethyl anion (4d) toward reference electrophiles
(e.g., benzhydrylium ions, quinone methides, and diethyl ben-
zylidenemalonates)12b,13 without considering the rate constants
determined in this work. The good matching of the rate constants
for the reactions of the aryl-stabilized sulfur ylides 4a,b and the
carbanion 4d with the imines 2aꢀe to these correlation lines
illustrates the applicability of the previously reported N and sN
parameters of these nucleophiles to their reactions with imines.
Figure 5 furthermore emphasizes the mechanistic analogy be-
tween the rate-determining step of the aziridination reactions
and the nucleophilic attack of carbanions to imines.
Reactions with Imines. Previous mechanistic studies revealed
that the aziridination reactions of N-tosyl-substituted aldimines
(e.g., imines 2aꢀc) with aryl-stabilized sulfur ylides (e.g., 4a,b)
proceed in a stepwise manner via initial irreversible nucleophilic
attack.10a,c,d Thus, a single C—C bond is generated in the rate-
determining step of these aziridination reactions, like in the ad-
dition reactions of the carbanions 4cꢀh to the imines 2aꢀc. As a
consequence, eq 1 should be applicable to both types of reactions.
Therefore, we have calculated the electrophilicity parameters E
for 2aꢀc by least-squares minimization of Δ2 = ∑(log k2
ꢀ
exp
sN(N þ E))2 using the corresponding second-order rate con-
stants k2exp given in Table 2 and the N and sN parameters of 4aꢀh
from Table 1. The optimized E parameters for 2aꢀc listed in
Table 2 and the N and sN parameters of 4aꢀh listed in Table 1
have been substituted into eq 1 to give the k2calcd values listed in
Figure 5 illustrates the fact that the electrophilic reactivities
of the N-tosyl-activated imines 2aꢀc increase with decreasing
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electron-donating effects of the p-substituents. A correlation of
the rate constants for the reactions of 2aꢀc with 4d vs Ham-
mett’s σp is shown on page S42 of the Supporting Information.
The resulting Hammett reaction constant of F = 2.6 is similar to
that obtained for the reactions of the benzaldehydes 1aꢀe with
the sulfur ylide 4a (F = 2.8, see above). When the tosyl group of
the imine 2a is replaced by less electron-withdrawing substitu-
ents, i.e., the tert-butoxycarbonyl group in case of 2d or the di-
phenylphosphinoyl group in case of 2e, the electrophilic reactiv-
ity toward 4b decreases by a factor of 67 and 1290, respectively.
Cyclopropanation Reactions. As shown in previous work12b
and illustrated in Figure 6, we have observed that the rate con-
stants of the cyclopropanation reactions of Michael acceptors (e.g.,
diethyl benzylidenemalonates) with sulfur ylides fit the same
correlations of log k2 vs electrophilicity E as the corresponding
reactions of sulfur ylides with benzhydrylium ions. A stepwise
formation of the cyclopropanes with rate-determining formation
of the intermediate zwitterions was thus indicated. In analogy to
Figure 5, the depicted correlation lines in Figure 6 have been
derived from the previously reported reactivities of the sulfur
Figure 5. Matching of the rate constants for the reactions of the aryl-
stabilized sulfur ylides 4a,b and the carbanion 4d with the imines 2aꢀe
to the previously derived correlation lines for the reactions of 4a,b,d with
reference electrophiles (e.g., benzhydrylium ions, quinone methides,
and diethyl benzylidenemalonates) in DMSO at 20 °C.12b,13
Figure 7. Comparison of the rate constants (log k2) for the reactions of
the enones 3aꢀf and p-nitrocinnamaldehyde (1f) with the sulfur ylide
4a in DMSO at 20 °C.
Figure 6. Matching of the rate constants for the reactions of the semistabilized sulfur ylides 4a,b with the enones 3aꢀf to the previously derived
correlation lines for the reactions of 4a,b with reference electrophiles (e.g., benzhydrylium ions, quinone methides, and diethyl benzylidenemalonates) in
DMSO at 20 °C.12b Nonidentified points refer to reference electrophiles which are specified in Figure S4 of the Supporting Information.
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Figure 8. Comparison of the electrophilicity parameters E of aldehydes, imines, and enones with different Michael acceptors in DMSO.
ylides 4a,b toward reference electrophiles (e.g., benzhydrylium
ions, quinone methides, and diethyl benzylidenemalonates)12b
without considering the rate constants determined in this work.
The good match of the rate constants for the reactions of the aryl-
stabilized sulfur ylides 4a,b with the enones 3a,b to these correlation
lines shows that the relative reactivities of the sulfur ylides 4a and
4b toward 3a and 3b are identical to those previously observed
for their reactions with reference electrophiles.12b Analogous re-
action mechanisms are thus again indicated.
preferred over the cyclopropane formation when R,β-unsatu-
rated aldehydes are used as reactants. The attack at the carbonyl
group of 1f (i.e., epoxidation) is kinetically preferred over the attack
to the conjugate position (i.e., cyclopropanation). This selectivity
indicates that the CdC double bond of 1f is less reactive than
that of 3d and 3f, though the formyl group has a similar Hammett
σp value [σp(CHO) = 0.42]20 as the acetyl and benzoyl group.
’ CONCLUSION
From the Hammett correlation on page S48 of the Supporting
Information one derives a reaction constant of F = 1.3 for the
reactions of the enones 3aꢀc with the sulfur ylide 4a, indicating a
moderate increase of reactivity by electron-withdrawing substit-
uents. As illustrated in Figure 7, the reactivities of the R,β-
unsaturated ketones 3aꢀf differ by less than a factor of 25. While
variation of the alkyl group in the ketones 3dꢀf has almost no
effect on the reactivities of the CdC double bond, the corre-
sponding phenyl compound 3a is 24 times more reactive than 3f,
despite the opposite ordering of the Hammett substituent con-
stants [σp(COMe) = 0.50 and σp(COPh) = 0.43].20
Epoxidation, aziridination, and cyclopropanation reactions of
aldehydes, imines, and Michael acceptors with sulfur ylides, which
proceed by a stepwise mechanism with rate-determining forma-
tion of an intermediate zwitterion (Scheme 1), have been investi-
gated kinetically. As the first step of these reactions is mechanistically
related to the electrophileꢀnucleophile combinations which have
been employed to derive eq 1,1,2 the resulting second-order rate
constants (log k2) could be combined with the previously published
N and sN parameters of sulfur ylides12b to calculate the corre-
sponding reactivity parameters E of these electrophiles.
Figure 8 shows that N-tosyl-, N-tert-butoxycarbonyl-, and
N-phosphinoyl-substituted benzaldimines are significantly more
electrophilic in DMSO than the corresponding benzaldehydes.
While the reactions of most aldehydes and imines with stabilized
carbanions are highly reversible and cannot be investigated in
Product analysis of the reaction of p-nitrocinnamaldehyde (1f)
with the sulfur ylide 4a (Scheme 3) as well as several literature
reports on reactions of semistabilized sulfur ylides with R,β-un-
saturated aldehydes16 show that epoxide formation is generally
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aprotic solvents, the strong electron-withdrawing effect of the
N-tosyl group in the benzaldimines 2aꢀc allowed us also to
measure the rate constants of their reactions with ordinary
carbanions. In line with the stepwise mechanism for the azir-
idinations, the rates of the reactions of sulfur ylides and carba-
nions with imines were found to match with the correlation lines,
which were previously derived from the rate constants of the
reactions of these nucleophiles with benzhydrylium ions and
structurally related reference electrophiles (Figure 5).
Though rate constants for the reactions of phosphorus ylides
and phosphoryl-substituted carbanions with aldehydes have
already been published previously,15 we had been reluctant to use
these data for determining electrophilicity parameters of alde-
hydes, because of the evidence for the concerted formation of the
oxaphosphetanes.15,22,23 We were, therefore, surprised that the
rate constants for the Wittig and HornerꢀWadsworthꢀEmmons
reactions listed in Table 3 can properly be derived from the elec-
trophilicity parameters E of aldehydes in Table 2 and the N and
sN parameters of the phosphorus-stabilized nucleophiles 4gꢀk,
which have previously been derived from their one-bond-form-
ing reactions with benzhydrylium ions and quinone methides.15
From the agreement between calculated and experimental rate
constants of these olefination reactions, we can conclude that the
oxaphosphetane formation for the reactions in Table 3 proceeds
via a transition state which is only weakly stabilized by the for-
mation of the new PO bond. The concertedness of the oxapho-
sphetane formations as well as the rate-limiting steps of Wittig
and the related olefination reactions may significantly change,
however, when other types of phosphorus ylides and phosphoryl-
substituted carbanions are employed.
In previous work we had shown that the electrophilicity para-
meters E of our reference electrophiles (benzhydrylium ions and
quinone methides), which were derived from reactions in dichloro-
methane or DMSO, can also be employed for reactions in other
solvents, e. g., acetonitrile, methanol, and water.1ꢀ4 We, therefore,
concluded that these reference electrophiles do not experience
differential solvation, i.e., that the changes of their solvation energies
in different solvents are linearly correlated with E. By using solvent-
independent electrophilicity parameters E for the reference electro-
philes, solvent effects have been shifted into the solvent-dependent
nucleophile-specific parameters N and sN of eq 1, which allowed us
to develop a comprehensive nucleophilicity scale.4
Absence of differential solvation cannot generally be expected
for ordinary carbonyl compounds and imines, because strong
interactions of the polar CdO or CdN double bonds with protic
solvents may increase the corresponding electrophilicity para-
meters E in Figure 8,28 which restricts use of the E parameters for
these compounds to DMSO solution. Unlike the electrophilicity
parameters E of carbocations and Michael acceptors, which can
be employed for reactions with all types of nucleophiles (e.g., C-,
N-, O-, or P-centered), the E parameters for aldehydes and imines
may be restricted to their reactions with carbon nucleophiles. In
reactions with oxygen- or nitrogen-centered nucleophiles, the
well-known anomeric stabilization29 of the resulting products
may already affect the transition states. As anomeric effects are
not included in the reactivity parameters N, sN, and E, amines and
alkoxides can be expected to react faster with aldehydes and
imines than predicted by eq 1.
ethoxycarbonyl groups. Obviously, the electrophilicities of these
Michael acceptors are not closely correlated with the pKaH values
of the resulting carbanions, demonstrating the need for a sys-
tematic investigation of their electrophilicities.30
’ EXPERIMENTAL SECTION
Materials and Product Analysis. The sulfonium tetrafluorobo-
rates (4a,b-H)-BF4 were prepared as reported earlier.12b Ethyl
2-(methylsulfinyl)acetate (4e)-H,31 p-nitrocinnamaldehyde (1f),32 en-
one 3b,33 and imines 2aꢀe34 were prepared as reported in the literature.
The enones 3e,f were prepared in analogy to the procedure as for
p-nitrocinnamaldehyde (1f). The syntheses of the enones 3a,d were
achieved according to the same procedure as for 3b. All other chemicals
were purchased from commercial sources and (if necessary) purified by
recrystallization or distillation prior to use. A detailed description for the
preparation and characterization of the epoxides 5, the aziridines 6, the
cyclopropanes 7, the addition products 8, and the condensation pro-
ducts 9 is given in the Supporting Information.
Kinetics. The rates of all reactions were determined photometrically
in dry DMSO (H2O content <50 ppm). The temperature was kept
constant (20.0 ( 0.1 °C) by using a circulating bath thermostat. All
reactions were performed under first-order conditions by using conven-
tional diode array and stopped flow UVꢀvis spectrometers. A detailed
description of the procedure is given in the Supporting Information.
’ ASSOCIATED CONTENT
S
Supporting Information. Details of the kinetic experi-
b
ments, synthetic procedures, and NMR spectra of all character-
ized compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
herbert.mayr@cup.uni-muenchen.de
’ ACKNOWLEDGMENT
We gratefully acknowledge financial support by the Deutsche
Forschungsgemeinschaft (SFB 749) and the Fonds der Chemischen
Industrie (scholarship to R.A.). Furthermore, we thank Dr. Armin R.
Ofial and Dr. Sami Lakhdar for helpful discussions.
’ REFERENCES
(1) (a)Mayr, H.;Patz, M.Angew. Chem., Int. Ed. Engl. 1994,33, 938–957.
(b) Mayr, H.; Ofial, A. R. Pure Appl. Chem. 2005, 77, 1807–1821. (c) Mayr,
H.; Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584–595.
(2) (a) 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. (b) Lucius, R.; Loos, R.;
Mayr, H. Angew. Chem., Int. Ed. 2002, 41, 91–95.
(3) For a comprehensive database of nucleophilicity parameters N
and sN as well as electrophilicity parameters E, see http://www.cup.uni-
muenchen.de/oc/mayr/DBintro.html.
(4) Mayr, H. Angew. Chem., Int. Ed. 2011, 50, 3612–3618.
(5) (a) Alexander, R.; Ko, E. C. F.; Parker, A. J.; Broxton, T. J. J. Am.
Chem. Soc. 1968, 90, 5049–5069. (b) Parker, A. J.; Mayer, U.; Schmid,
R.; Gutmann, V. J. Org. Chem. 1978, 43, 1843–1854. (c) Phan, T. B.;
Breugst, M.; Mayr, H. Angew. Chem., Int. Ed. 2006, 45, 3869–3874.
(6) (a) Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289–296. (b) Doyle,
A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743. (c) Yamamoto,
H.; Nakashima, D. In Acid Catalysis in Modern Organic Synthesis;
The R,β-unsaturated ketones depicted in Figure 8 show
reactivities comparable to those of diethyl benzylidenemalonates,
indicating that a single benzoyl group has a similar activating
effect on the electrophilicity of a CdC double bond as two
8249
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Journal of the American Chemical Society
ARTICLE
Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH: Weinheim, Germany,
2008; Vol. 1, pp 35ꢀ108. (d) Imahori, T. In Acid Catalysis in Modern
Organic Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH:
Weinheim, Germany, 2008; Vol. 1, pp 109ꢀ134. (e) Hatano, M.; Ishihara,
K. In Acid Catalysis in Modern Organic Synthesis; Yamamoto, H., Ishihara, K.,
Eds.; Wiley-VCH: Weinheim, Germany, 2008; Vol. 1, pp 135ꢀ186.
(7) For selected references, see: (a) Svirbely, W. J.; Roth, J. F. J. Am.
Chem. Soc. 1953, 75, 3106–3111. (b) Svirbely, W. J.; Brock, F. H. J. Am.
Chem. Soc. 1955, 77, 5789–5792. (c) Noyce, D. S.; Reed, W. L. J. Am.
Chem. Soc. 1959, 81, 624–628. (d) Okano, V.; Do Amaral, L.; Cordes,
E. H. J. Am. Chem. Soc. 1976, 98, 4201–4203. (e) Guthrie, J. P. J. Am.
Chem. Soc. 1991, 113, 7249–7255 and references cited therein. (f)
Nagorski, R. W.; Mizerski, T.; Richard, J. P. J. Am. Chem. Soc. 1995, 117,
4718–4719. (g) Guthrie, J. P. J. Am. Chem. Soc. 2000, 122, 5529–5538
and references cited therein.
(17) Shen, Y.; Jiang, G.-F. J. Chem. Res. 2000, 140–141.
(18) Nickson, T. E. J. Org. Chem. 1988, 53, 3870–3872.
(19) The observed second-order kinetics would also be compatible
with the formation of an intermediate syn-betaine, if its retro-addition
would be much slower than the time window of our kinetic measure-
ments (vꢀsyn , vanti). The formation of a long-lived betaine intermedi-
ate 11 can be considered as rather unlikely, however, because it has been
shown that oxy-anion species, e.g., simple alkoxides, have very high pKaH
values in DMSO (see refs 8b and 8c) and are, therefore, thermodyna-
mically unstable species. The syn-betaine 11 must, therefore, be a short-
lived intermediate which rapidly reverts to sulfur ylide and aldehyde as
its cyclization has not been observed in DMSO.
(20) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165–195.
(21) R€uchardt, C.; Panse, P.; Eichler, S. Chem. Ber. 1967, 100,
1144–1164.
(8) (a) Ballinger, P.; Long, F. A. J. Am. Chem. Soc. 1960, 82, 795–798.
(b) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980,
45, 3295–3299. (c) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463.
(9) (a) Yoshimine, M.; Hatch, M. J. J. Am. Chem. Soc. 1967,
89, 5831–5838. (b) Johnson, C. R.; Schroeck, C. W. J. Am. Chem. Soc.
1971, 93, 5303–5305. (c) Volatron, F.; Eisenstein, O. J. Am. Chem. Soc.
1987, 109, 1–14. (d) For the special case of a CoreyꢀChaykovsky
reaction with oxathietane formation, see: Kawashima, T.; Ohno, F.; Okazaki,
R.; Ikeda, H.; Inagaki, S. J. Am. Chem. Soc. 1996, 118, 12455–12456.
(e) Aggarwal, V. K.; Calamai, S.; Ford, J. G. J. Chem. Soc., Perkin Trans.
1 1997, 593–599. (f) Lindvall, M. K.; Koskinen, A. M. P. J. Org. Chem.
1999, 64, 4596–4606. (g) Myllym€aki, V. T.; Lindvall, M. K.; Koskinen,
A. M. P. Tetrahedron 2001, 57, 4629–4635. (h) Aggarwal, V. K.; Harvey,
J. N.; Richardson, J. J. Am. Chem. Soc. 2002, 124, 5747–5756. (i) Silva,
M. A.; Bellenie, B. R.; Goodman, J. M. Org. Lett. 2004, 6, 2559–2562.
(j) Aggarwal, V. K.; Bi, J. Beilstein J. Org. Chem. 2005, 1, doi: 10.1186/
1860-5397-1-4. (k) Aggarwal, V. K.; Hebach, C. Org. Biomol. Chem.
2005, 3, 1419–1427. (l) Aggarwal, V. K.; Charmant, J. P. H.; Fuentes, D.;
Harvey, J. N.; Hynd, G.; Ohara, D.; Picoul, W.; Robiette, R.; Smith, C.;
Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2006, 128, 2105–2114.
(m) Edwards, D. R.; Du, J.; Crudden, C. M. Org. Lett. 2007, 9, 2397–2400.
(n) Edwards, D. R.; Montoya-Peleaz, P.; Crudden, C. M. Org. Lett. 2007,
9, 5481–5484.
(22) For selected references on the mechanism of the Wittig re-
action, see: (a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89,
863–927. (b) Yamataka, H.; Nagareda, K.; Ando, K.; Hanafusa, T. J. Org.
Chem. 1992, 57, 2865–2869. (c) Vedejs, E.; Peterson, M. J. Top.
Stereochem. 1994, 21, 1–157. (d) Vedejs, E.; Peterson, M. J. In Advances
in Carbanion Chemistry; Snieckus, V., Ed.; JAI Press: London, 1996; Vol.
2; p 1ꢀ85. (e) Yamataka, H.; Nagase, S. J. Am. Chem. Soc. 1998, 120,
7530–7536. (f) Robiette, R.; Richardson, J.; Aggarwal, V. K.; Harvey,
J. N. J. Am. Chem. Soc. 2005, 127, 13468–13469. (g) Robiette, R.;
Richardson, J.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc. 2006,
128, 2394–2409.
(23) The mechanism of the HornerꢀWadsworthꢀEmmons reaction
is closely related to that of the Wittig reaction, although it is still controversial
if the oxaphosphetane formation occurs concerted or stepwise. For selected
references, see: (a) Larsen, R. O.; Aksnes, G. Phosphorus, Sulfur Silicon Relat.
Elem. 1983, 15, 219–228. (b) Larsen, R. O.; Aksnes, G. Phosphorus, Sulfur
Silicon Relat. Elem. 1983, 15, 229–237. (c) Reference 22a. (d) Brandt, P.;
Norrby, P.-O.; Martin, I.; Rein, T. J. Org. Chem. 1998, 63, 1280–1289. (e)
Ando, K. J. Org. Chem. 1999, 64, 6815–6821. (f) Motoyoshiya, J.; Kusaura,
T.; Kokin, K.; Yokoya, S.-i.; Takaguchi, Y.; Narita, S.; Aoyama, H.
Tetrahedron 2001, 57, 1715–1721.
(24) The activation of carbonyl groups by Lewis acids has extensively
been reviewed. For selected examples, see: (a) Vaugeois, J.; Simard, M.;
Wuest, J. D. Coord. Chem. Rev. 1995, 145, 55–73. (b) Yamamoto, H.; Saito,
S. Pure Appl. Chem. 1999, 71, 239–245. (c) Sankararaman, S.; Nesakumar,
J. E. Eur. J. Org. Chem. 2000, 2003–2011. (d) Gawronski, J.; Wascinska, N.;
Gajewy, J. Chem. Rev. 2008, 108, 5227–5252. (e) Acid Catalysis in Modern
Organic Synthesis; Yamamoto, H., Ishihara, K., Eds.; Wiley-VCH: Weinheim,
Germany, 2008; Vol. 1 and 2. (f) Ali, A.; Singh, A. P.; Gupta, R. J. Chem. Sci.
2010, 122, 311–320.
(10) (a) Aggarwal, V. K.; Charmant, J. P. H.; Ciampi, C.; Hornby,
J. M.; O’Brien, C. J.; Hynd, G.; Parsons, R. J. Chem. Soc., Perkin Trans.
1 2001, 3159–3166. (b) Yang, X.-F.; Zhang, M.-J.; Hou, X.-L.; Dai, L.-X.
J. Org. Chem. 2002, 67, 8097–8103. (c) Robiette, R. J. Org. Chem. 2006,
71, 2726–2734. (d) Janardanan, D.; Sunoj, R. B. Chem.—Eur. J. 2007,
13, 4805–4815. (e) Janardanan, D.; Sunoj, R. B. J. Org. Chem. 2008,
73, 8163–8174.
(11) (a) Midura, W. H.; Krysiak, J. A.; Cypryk, M.; Mikolajczyk, M.;
Wieczorek, M. W.; Filipczak, A. D. Eur. J. Org. Chem. 2005, 653–662.
(b) Aggarwal, V. K.; Grange, E. Chem.—Eur. J. 2006, 12, 568–575.
(c) Deng, X.-M.; Cai, P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.;
Wu, Y.-D.; Dai, L.-X. J. Am. Chem. Soc. 2006, 128, 9730–9740.
(d) Janardanan, D.; Sunoj, R. B. J. Org. Chem. 2007, 72, 331–341. (e)
Riches, S. L.; Saha, C.; Filgueira, N. F.; Grange, E.; McGarrigle, E. M.;
Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 7626–7630.
(12) (a) Lakhdar, S.; Appel, R.; Mayr, H. Angew. Chem., Int. Ed. 2009,
48, 5034–5037. (b) Appel, R.; Hartmann, N.; Mayr, H. J. Am. Chem. Soc.
2010, 132, 17894–17900.
(13) Bug, T.; Lemek, T.; Mayr, H. J. Org. Chem. 2004, 69, 7565–7576.
(14) Appel, R.; Mayr, H. Chem.—Eur. J. 2010, 16, 8610–8614.
(15) Appel, R.; Loos, R.; Mayr, H. J. Am. Chem. Soc. 2009, 131,
704–714.
(16) (a) Aggarwal, V. K.; Ford, J. G.; Fonquerna, S.; Adams, H.;
Jones, R. V. H.; Fieldhouse, R. J. Am. Chem. Soc. 1998, 120, 8328–8339.
(b) Solladiꢀe-Cavallo, A.; Bouꢀerat, L.; Roje, M. Tetrahedron Lett. 2000,
41, 7309–7312. (c) Aggarwal, V. K.; Alonso, E.; Bae, I.; Hynd, G.; Lydon,
K. M.; Palmer, M. J.; Patel, M.; Porcelloni, M.; Richardson, J.; Stenson,
R. A.; Studley, J. R.; Vasse, J.-L.; Winn, C. L. J. Am. Chem. Soc. 2003,
125, 10926–10940. (d) Phillips, D. J.; Graham, A. E. Synlett 2010,
769–773.
(25) For selected reviews, see: (a) Jones, G. In Organic Reactions;
Wiley: New York, 1967; Vol. 15, pp 204ꢀ599. (b) Tietze, L. F.;
Beifuss, U. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Heathcock, C. H., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 2,
pp 341ꢀ394. (c) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry: Reactions, Mechanisms, and Structure; 6th ed.; Wiley: Hoboken,
NJ, 2007; pp 1358ꢀ1363.
(26) For selected reviews, see: (a) Rosini, G. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H., Eds.;
Pergamon Press: Oxford, U.K., 1991; Vol. 2, pp 321ꢀ340. (b) Ono, N.
The Nitro Group in Organic Syntheses; Wiley-VCH: New York, 2001; pp
30ꢀ69. (c) Luzzio, F. A. Tetrahedron 2001, 57, 915–945. (d) Palomo,
C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561–2574.
(27) (a) Mayr, H.; Gorath, G. J. Am. Chem. Soc. 1995, 117, 7862–7868.
(b) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–77.
(28) The observation that the noncatalyzed reaction of 2-methylin-
dole with p-nitrobenzaldehyde occurs at 90 °C in alcohols and water but
not in aprotic solvents, such as DMSO or DMF, illustrates the increase of
the electrophilicities of aldehydes in protic solvents: He, F.; Li, P.; Gu, Y.;
Li, G. Green Chem. 2009, 11, 1767–1773.
(29) For selected references, see: (a) Schleyer, P. v. R.; Jemmis, E. D.;
Spitznagel, G. W. J. Am. Chem. Soc. 1985, 107, 6393–6394. (b) Richard,
J. P.; Amyes, T. L.; Rice, D. J. J. Am. Chem. Soc. 1993, 115, 2523–2524.
8250
dx.doi.org/10.1021/ja200820m |J. Am. Chem. Soc. 2011, 133, 8240–8251

Journal of the American Chemical Society
ARTICLE
(c) Rakus, K.; Verevkin, S. P.; Peng, W.-H.; Beckhaus, H.-D.; R€uchardt,
C. Liebigs Ann. 1995, 2059–2067.
(30) For kinetics of the reactions of monoacceptor-substituted
ethylenes with pyridines in water, see: (a) Bunting, J. W.; Toth, A.;
Heo, C. K. M.; Moors, R. G. J. Am. Chem. Soc. 1990, 112, 8878–8885. (b)
Heo, C. K. M.; Bunting, J. W. J. Org. Chem. 1992, 57, 3570–3578.
(31) (a) Labuschagne, A. J. H.; Malherbe, J. S.; Meyer, C. J.; Schneider,
D. F. J. Chem. Soc., Perkin Trans. 1 1978, 955–961. (b) Coppola, G. M.;
Hardtmann, G. E. J. Heterocycl. Chem. 1979, 16, 1605–1610.
(32) Waley, S. G. J. Chem. Soc. 1948, 2008–2011.
(33) Reichardt, C.; Harbusch-G€ornert, E.; Sch€afer, G. Liebigs Ann.
Chem. 1988, 839–844.
(34) (a) Jennings, W. B.; Lovely, C. J. Tetrahedron Lett. 1988,
29, 3725–3728. (b) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991,
47, 5561–5568. (c) Kanazawa, A. M.; Denis, J.-N.; Greene, A. E. J. Org.
Chem. 1994, 59, 1238–1240.
8251
dx.doi.org/10.1021/ja200820m |J. Am. Chem. Soc. 2011, 133, 8240–8251