Nucleophilicity Parameters of Stabilized Iodonium Ylides for Characterizing Their Synthetic Potential

Article abstract of DOI:10.1021/jacs.6b05768

Kinetics and mechanisms of the reactions of the β-dicarbonyl-substituted iodonium ylides 1(a-d) with several π-conjugated carbenium and iminium ions have been investigated. All reactions proceed with rate-determining attack of the electrophile at the nucleophilic carbon center of the ylides to give iodonium ions, which rapidly expel iodobenzene and undergo different subsequent reactions. The second-order rate constants k₂ for the reactions of the iodonium ylides with benzhydrylium ions correlate linearly with the electrophilicity parameters E of the benzhydrylium ions and thus follow the linear free energy relationship log k(20 °C) = s_N(N + E) (eq 1), where electrophiles are characterized by one parameter (E), while nucleophiles are characterized by two parameters: the nucleophilicity N and the susceptibility s_N. The nucleophilicity parameters 4 < N < 8 for iodonium ylides 1(a-d) derived from these correlations show that substituting hydrogen for Ph-I⁺ at the carbanionic center of Meldrum's acid or dimedone, respectively, reduces the nucleophilicity by approximately 10 orders of magnitude. The iodonium ylides 1(a-d) thus have nucleophilicities similar to those of pyrroles, indoles, and silylated enol ethers and, therefore, should be suitable substrates in iminium-activated reactions. Good agreement of the measured rate constant for the cyclopropanation of the imidazolidinone-derived iminium ion 10a with the iodonium ylide 1a with the rate constant calculated by eq 1 suggests a stepwise mechanism in which the initial nucleophilic attack of the iodonium ylide at the iminium ion is rate-determining. The reaction of cinnamaldehyde with iodonium ylide 1a catalyzed by (5S)-5-benzyl-2,2,3-trimethyl-imidazolidin-4-one (11a, MacMillan's first-generation catalyst) gives the corresponding cyclopropane with an enantiomeric ratio of 70/30 and, thus, provides proof of principle that iodonium ylides are suitable substrates for iminium-activated cyclopropanations.

Full text of DOI:10.1021/jacs.6b05768

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Article
Nucleophilicity Parameters of Stabilized Iodonium
Ylides for Characterizing their Synthetic Potential
Saloua Chelli, Konstantin Troshin, Peter Mayer, Sami Lakhdar, Armin R. Ofial, and Herbert Mayr
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b05768 • Publication Date (Web): 18 Jul 2016
Downloaded from http://pubs.acs.org on July 24, 2016
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Nucleophilicity Parameters of Stabilized Iodonium Ylides for
Characterizing their Synthetic Potential
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Saloua Chelli,† Konstantin Troshin,*,‡ Peter Mayer, Sami Lakhdar,† Armin R. Ofial, and
Herbert Mayr*
Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13,
81377 München, Germany
* Corresponding Authors: kktroshin@gmail.com (K.T.), herbert.mayr@cup.uni-muenchen.de
(H.M.);
† Present address: ENSICAEN-Université de Caen Basse-Normandie, France
‡ Present address: University of California Berkeley, U. S. A.
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Abstract
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Kinetics and mechanisms of the reactions of the -dicarbonyl-substituted iodonium ylides
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1(a–d) with several -conjugated carbenium and iminium ions have been investigated. All
reactions proceed with rate-determining attack of the electrophile at the nucleophilic carbon
center of the ylides to give iodonium ions, which rapidly expel iodobenzene and undergo
different subsequent reactions. The second-order rate constants k2 for the reactions of the
iodonium ylides with benzhydrylium ions correlate linearly with the electrophilicity
parameters E of the benzhydrylium ions, and thus follow the linear free energy relationship
log k(20°C) = sN(N + E) (eq 1), where electrophiles are characterized by one parameter (E),
while nucleophiles are characterized by two parameters: the nucleophilicity N and the
susceptibility sN. The nucleophilicity parameters 4 < N < 8 for iodonium ylides 1(a–d) derived
from these correlations show that substituting hydrogen for Ph-I+ at the carbanionic center of
Meldrum’s acid or dimedone, respectively, reduces the nucleophilicity by approximately ten
orders of magnitude. The iodonium ylides 1(a-d) thus have similar nucleophilicities as
pyrroles, indoles, and silylated enol ethers, and therefore should be suitable substrates in
iminium-activated reactions. Good agreement of the measured rate constant for the
cyclopropanation of the imidazolidinone-derived iminium ion 10a with the iodonium ylide 1a
with the rate constant calculated by eq 1 suggests a stepwise mechanism, in which the initial
nucleophilic attack of the iodonium ylide at the iminium ion is rate-determining. The reaction
of cinnamaldehyde with iodonium ylide 1a catalyzed by (5S)-5-benzyl-2,2,3-trimethyl-
imidazolidin-4-one (11a, MacMillan's first generation catalyst) gives the corresponding
cyclopropane with an enantiomeric ratio of 70/30 and, thus, provides proof of principle that
iodonium ylides are suitable substrates for iminium-activated cyclopropanations.
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Introduction
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Polyvalent iodine compounds have attracted significant interest in the last decades due to their
great synthetic potential and easy accessibility.1,2 An important class of synthetically useful
polyvalent iodine derivatives are iodonium ylides, which have been applied as precursors for
carbenes or metal carbenoids3 as well as for transformations in which they act as electrophiles
or nucleophiles. Aryl iodonium ylides were found to undergo metal-catalyzed as well as
uncatalyzed reactions with alkenes,4,5 ketenes,6 alkynes,7 nitriles,8 isocyanates,9 thiols,10 and
carbodiimides.11 The uncatalyzed reactions with substituted ethylenes were postulated to be
initiated by attack of the electrophilic iodine center at the CC-double bond followed by
cyclization of the resulting betaine and extrusion of the iodoarene accompanied by ring
contraction or expansion.4,5,6a
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In the reactions with acyl halides, on the other hand, -dicarbonyl aryliodonium ylides
were reported to act as nucleophiles, which are attacked at the enolate oxygen of the carbonyl
groups to give the corresponding iodonium ions;6a,12 subsequent nucleophilic substitution of
iodobenzene by halide anions often results in the corresponding -carbonyl--haloenol
esters6a (Scheme 1). Analogous reactions have been observed with alkylating agents such as
trialkyloxonium salts or dialkyl sulfates.12
Scheme 1. Reactions of β-Dicarbonyl Aryliodonium Ylides with Acyl Halides
Iodonium ylides stabilized by only one acyl group, which can be generated in situ by
treatment of (-acetoxyvinyl)iodonium salts with alkoxide anions, were reported to react with
aldehydes and activated imines at the ylide carbon.13,14 Cyclization of the intermediate
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zwitterions with expulsion of iodoarene yields the corresponding epoxides13 or aziridines14
(Scheme 2).
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Scheme 2. Synthesis of Epoxides and Aziridines via Monoacyl Iodonium Ylides13,14
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Though the possibility of attack of carbon electrophiles at the nucleophilic carbon center of
isolable -dicarbonyl iodonium ylides has been considered in the literature,15 examples of
such reactions have, to our knowledge, not yet been reported. In fact, an electrophilic attack at
the ylide carbon was not even taken into consideration as a possible reaction pathway to
account for the regioselectivity of the reactions of -dicarbonyl iodonium ylides with
diphenylketene.6a
Benzhydrylium ions have previously been used as reference electrophiles16a in
investigations of the reactivities of various nucleophiles, including phosphonium,17
sulfonium,18 and pyridinium ylides.19 In order to explore the possibility of electrophilic attack
at the carbon center of iodonium ylides, we have now studied kinetics and mechanisms of the
reactions of four -dicarbonyliodonium ylides 1(a-d) with benzhydrylium ions of variable
electrophilicity (Table 1).
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Substitution of the measured rate constants into the linear free energy relationship (eq 1),
where E is an electrophilicity parameter, N is a nucleophilicity parameter, and sN is a
nucleophile-specific susceptibility parameter, yields N and sN for 1(a-d), the parameters
which are needed to predict potential electrophilic reaction partners.
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log k20°C = sN(N + E)
(1)
Table 1. Reference Electrophiles 2(a–k) and Their Electrophilicity Parameters E
Electrophile
R
Ea
2a
2b
0.00
–1.36
N(Ph)CH2CF3
N(Me)CH2CF3
NPh2
N-morpholino
N(Ph)Me
2c
2d
2e
2f
2g
2h
–3.14
–3.85
–4.72
–5.53
–5.89
–7.02
NMe2
2i
–8.76
n = 2
n = 1
2j
–9.45
2k
–10.04
a From ref 16a.
Results and Discussion
Synthesis of the iodonium ylides. The ylides 1(a–d) were prepared by condensation of the
corresponding CH acids with diacetoxyiodobenzene under basic conditions following
literature procedures.20,21
Product studies. To investigate the general course of the reactions of benzydrylium ions with
the iodonium ylides 1, the reaction of 1a with 2a was studied in detail. When the bis(p-
methoxy)benzhydryl cation (2a) was generated in situ in dichloromethane at −78 °C by
ionization of the benzhydryl chloride 2a-Cl with ZnCl2·OEt2 in the presence of the iodonium
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ylide 1a and tetra-n-butylammonium chloride (1 equiv with respect to ZnCl2), compound 3
was obtained in 62% yield22 (Scheme 3) and characterized by single crystal X-ray
crystallography.23 Combination of 2a-Cl and 1a in dichloromethane at ambient temperature
without Lewis acid additive yielded compound 3, accompanied by its isomer 4 (Scheme 3),
which was also characterized by single crystal X-ray diffraction analysis (Figure 1).
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Scheme 3. Reactions of the Benzhydryl Chloride 2a-Cl with the Iodonium Ylide 1a With or
Without Added Lewis Acid.
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Figure 1. ORTEP drawing (50% probability ellipsoids) of 2-(bis(4-methoxyphenyl)methyl)-
2-chloro-5,5-dimethylcyclohexane-1,3-dione (4).
Scheme 4. Hydrolysis of 3 in a Mixture of d6-Acetone and D2O
Hydrolysis of 3 in a d6-acetone/D2O mixture (2/1) led to the formation of p-anisaldehyde (5a)
and 2-(p-anisyl)dimedone (6a), which were characterized without separation by NMR and
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HRMS (Scheme 4). The H and C NMR spectra of compound 6a in d6-acetone/D2O (2/1)
showed only one signal for the two geminal methyl groups and one signal for C-1 and C-3
(for numbering see Scheme 4). From the chemical shifts at δ 186.0 (C-1, C-3) and δ 116.0 (C-
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2) one can derive that 6a exists as a rapidly equilibrating mixture of two enols, as previously
reported for unsubstituted dimedone in protic solvents.24
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A mechanism, which accounts for these experimental observations, is presented in
Scheme 5: In the first step, the adduct I1a is formed by attack of 2a at the nucleophilic carbon
of iodonium ylide 1a. If a strong nucleophile, such as Cl−, is present, it can substitute
iodobenzene in I1a to give 4. Concomitantly, iodobenzene is expelled from I1a (probably
anchimerically assisted by the anisyl group which migrates through a p-methoxy-stabilized
phenonium transition state) to give the benzyl cation I2a, which is trapped by Cl– to yield 3.
Adducts analogous to 4 do not form in the absence of a strong nucleophile, for example, when
the reaction of 1a with 2a-Cl is catalyzed by ZnCl2·OEt2 (i.e., conditions A in Scheme 3). In
this case, I1a exclusively decomposes with formation of the benzyl cation I2a, which is
intercepted by a chlorozincate anion to yield 3. In the presence of water, hydrolysis of I2a or
3 results in the formation of the intermediate I4a, which fragments into aldehyde 5a and the
2-arylated dimedone 6a.
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Scheme 5. Mechanism of the Reaction of the Iodonium Ylide 1a with Benzhydryl Cation 2a
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A different scenario was observed in the corresponding reactions of the ylides with
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benzhydrylium ions with weakly nucleophilic counterions (BF4 ) under anhydrous conditions.
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1
When 2a-BF4 was combined with 1 equiv. of the ylide 1a, the intensities of the H NMR
signals of the benzhydrylium ion 2a decreased to only 50% of the initial value. Complete
consumption of the cation 2a was observed, however, when 2a-BF4 was combined with 2
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equiv. of 1a. The H and C NMR spectra of the resulting mixture showed the formation of
iodobenzene as well as of a product with broad signals, which was assigned to structure I3a
by the following experiments: Mixing 2a-BF4 with 2 equiv of 1a in CD2Cl2 at 20 °C and
subsequent addition of tetrabutylammonium chloride (1 equiv) showed the formation of a
species, which was assigned to the structure I3a-Cl by its H, 13C, and 2D NMR spectra (see
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Supporting Information for details). When Bu4NBF4 (instead of Bu4NCl) was added to a
mixture of 2a-BF4 and 1a, the 1H NMR spectrum showed the same broad signals as they were
observed for the reaction without additives. This behavior can be rationalized on the basis of
previous literature reports: X-ray structures of vinyliodonium tetrafluoroborates show the
–
presence of dimers in the solid state, where two BF4 anions bridge the iodine atoms of two
iodonium ions to give an eight-membered ring.25 The broad NMR signals could be explained,
therefore, by an analogous dimerization of I3a-BF4 in solution. In line with previous reports
on iodonium chlorides,26 added chloride ions could effectively inhibit dimerization of I3a by
coordination to the iodonium center, in accord with the sharper NMR signals.
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As the iodonium salt I3a-Cl was the only species observed by H NMR immediately
after mixing 2a-BF4 with 2 equiv of 1a in CD2Cl2 and subsequent addition of Bu4NCl, it must
be formed in less than a few seconds. I3a-Cl could not be isolated and was converted into 3
when the reaction mixture was stored for two days under anhydrous conditions (as analyzed
by 1H NMR spectroscopy).
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Given that the benzyl cation I2a is more electrophilic than its benzhydrylium
precursor 2a, the ylide 1a will react faster with I2a than with 2a, in accord with the need for
two equivalents of ylide 1a to achieve full conversion of the benzhydrylium ion 2a.
Hydrolysis of the intermediate I3a during aqueous workup and chromatography on silica gel
eventually gave rise to the formation of the aldehyde 5a. As discussed below, two equivalents
of ylides 1a–d are also required for the quantitative conversion of other benzhydrylium
tetrafluoroborates.
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How can one explain the different regioselectivity in the reactions of the ylide 1a with
the carbocations 2a and I2a? Why is 1a attacked at carbon by 2a and at oxygen by I2a?
Probably, electrophilic attack at the enolate oxygen of ylide 1a is generally faster than attack
at carbon, as previously reported for the reactions of acyl stabilized iodonium ylides with acyl
chlorides,6a,12 trialkyloxonium ions,12 or dialkyl sulfates.12b Because of the high stabilization
of 2a, intermediates arising from O-attack at 2a are formed reversibly, and all isolated
products 3, 4, 5a, and 6a are derived from the thermodynamically favored intermediate I1a,
the result of C-attack. On the other hand, the steric bulk of the quaternary carbon adjacent to
the carbocationic center of I2a may give rise to a high barrier for its C-attack at 1a and favor
O-attack.
From the mono-exponential decays of the UV/Vis-absorbances of 2 (see below) in the
reactions of the benzhydrylium ions 2b-k (of E ≤ −1) with a large excess of the ylides 1(a–d)
(pseudo-first order conditions) one can derive that intermediates generated by attack of 2 at
the enolate oxygen of 1(a-d) do not accumulate at any time in the reaction mixtures.
The situation is different for the subsequent reaction of the intermediate I2a. Since the
benzyl cation I2a is less stabilized than the benzhydryl cation 2a, iodonium ion I3a, the
adduct arising from the kinetically preferred O-attack of I2a at 1a, persists as an NMR
detectable species (see above) and undergoes only slow retroaddition (conversion of I3a-Cl
into 3 takes two days).
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To examine the consistency of the reaction mechanism suggested in Scheme 5 we
have also examined the reaction of the iodonium ylide 1a with 1,3-bis(4-
(dimethylamino)phenyl)allylium tetrafluoroborate 7-BF4 (Scheme 6). When 7-BF4 was
combined with 4 equiv. of 1a (in synthetic grade CH2Cl2, 24 h, ambient temperature), two
products were isolated after aqueous workup and separation by column chromatography: the
tetrahydrochromenyl-substituted cyclohexane-1,3-dione 8 (51%, single crystal X-ray structure
shown in Figure 2, left) and the acrylaldehyde derivative 9 (25%, single crystal X-ray
structure shown in Figure 2, right).
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Scheme 6. Mechanism of the Reaction of the 1,3-Bis(4-dimethylaminophenyl)allylium
Tetrafluoroborate 7-BF4 (Ar = 4-Me2N-C6H4) with the Iodonium Ylide 1a.
In contrast, 9 was not observed in the 1H spectrum of the crude mixture when the reaction of
7-BF4 with 1a was carried out under rigorous anhydrous conditions (in the presence of
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molecular sieves) in dichloromethane at room temperature, while 8 was the major product.
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When the same reaction was carried out in CD2Cl2 (0.55 mL) containing one drop of D2O (9
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mg
)
, the enal 9 formed as the major product (1H NMR).
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Figure 2. ORTEP drawings (50% probability ellipsoids) of 2-(4-(dimethylamino)phenyl)-2-
(4a-(4-(dimethylamino)phenyl)-7,7-dimethyl-5-oxo-4a,5,6,7-tetrahydro-2H-chromen-2-yl)-
5,5-dimethylcyclohexane-1,3-dione (8, left) and (E)-3-(1-(4-(dimethylamino)phenyl)-4,4-
dimethyl-2,6-dioxocyclohexyl)acrylaldehyde (9, right, only one molecule of the asymmetric
unit shown).
These results are in full analogy to the mechanism suggested for the benzhydryl systems in
Scheme 5. According to Scheme 6, attack of the allyl cation 7 at the nucleophilic carbon of
the ylide 1a yields the intermediate I5. Expulsion of iodobenzene accompanied by aryl
migration generates the allyl cation I6. Since I6 is more electrophilic than 7, it immediately
reacts with a further molecule of ylide 1a to yield the iodonium ion I7. As in the step before,
expulsion of iodobenzene and aryl migration lead to the allyl cation I8, which undergoes
intramolecular cyclization followed by loss of a proton to yield the isolated product 8.
It should be noted that the cyclization leading to 8 requires one of the allylic CC bonds
in I8 to adopt (Z)-configuration. Though allyl cations with the dimedone group in (Z)-position
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may be formed during the aryl migration I5 → I6 or I7 → I8, it is likely that the (E,E)-
configuration of I8 is preferred. However, reversible addition of a nucleophile to (E,E)-I8
(→I10, Scheme 6) and subsequent elimination may give rise to a small equilibrium
concentration of (E,Z)-I8, which can undergo cyclization. Trapping of I8 by water gives the
intermediate I9, which fragments (analogous to I4a, Scheme 5) to give the 2-aryl substituted
dimedone 6h and the isolated propenal derivative 9. Generation of 9 by hydrolysis of 8 can be
excluded, as only trace amounts of 9 formed when D2O was added to a solution of crude 8
(Supporting Information, p S13).
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In line with these mechanistic schemes, the 4-(dimethylamino)benzaldehyde 5h was
obtained as the major product along with iodobenzene, when a drop of D2O (9 mg) was added
immediately after combining 1a (100 μmol) and 2h (30 μmol) in CD2Cl2 (0.55 mL, 1H NMR
analysis). In accord with the mechanism proposed in Scheme 5, all combinations of 3 equiv of
the iodonium ylides 1(a–d) with the benzhydrylium tetrafluoroborates or triflates 2(b–h)-X
(under anhydrous conditions) yielded the corresponding benzaldehydes 5(b–h) after aqueous
workup and column chromatography (Table 2). In contrast, a complex mixture of products
containing only traces of the aldehyde 5h formed, when equimolar amounts of 1a and 2h
were mixed in CD2Cl2 under anhydrous conditions (1H NMR spectrum recorded after 2 h).
Table 2. Reactions of Benzhydrylium Tetrafluoroborates 2(b–h)-BF4 with Iodonium Ylides
1(a–d) in Dichloromethanea
Nucleophile Electrophile
Product
Yieldb (%)
65
2bc
5b
5c
2c
68
2d
2e
2f
5d
5e
5f
88
68
64
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2g
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5g
5h
69
65
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2d
2d
2d
5d
5d
5d
88
65
53
Reaction conditions: Iodonium ylide 1 (3 equiv.) reacted with 2-X (1 equiv., X = TfO– for
a
2b, X = BF4 for 2c-h,) in CH2Cl2 at ambient temperature. b Yields refer to isolated products
after aq workup and purification by column chromatography (for details see Supporting
Information). c 2b-OTf was generated in situ from 2b-Cl and trimethylsilyl triflate.
–
Kinetic Investigations
All reactions of the nucleophiles 1(a-d) with the reference electrophiles 2(a-f) were
performed in dichloromethane at 20°C and monitored by UV−Vis spectroscopy at or close to
the absorption maxima of the electrophiles. In order to achieve pseudo-first-order conditions,
the ylides were used in excess (>10 equivalents) over the benzhydrylium ions. In each kinetic
run, a monoexponential decay of the absorbance of the benzhydrylium ion with complete
disappearance of the corresponding band was observed. First-order rate constants kobs (s–1)
were determined by fitting a function At = A0e–k + C to the experimental time-dependent
absorbances (Figure 3). These kobs were found to correlate linearly with the concentrations of
the ylides, which allowed us to derive the second-order rate constants k2 (M–1 s–1) listed in
Table 3 as the slopes of the kobs vs [1] plots (inset of Figure 3).
t
obs
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Figure 3. Exponential decay of the absorbance At (λ = 601 nm) in the reaction of 1a (2.00 ×
10−3 M) with the benzhydrylium ion 2c (1.98 × 10−5 M) in CH2Cl2 at 20 °C. Inset: Correlation
between the first-order rate constants kobs (s–1) and the concentration of 1a.
Figure 4 shows that the experimental second-order rate constants k2 correlate linearly with
electrophilicity parameters E of the corresponding benzhydryl cations, i.e., the gross rate
constants of the reactions of 1 with 2 follow eq 1.
Table 3. Second-Order Rate Constants (k2) for the Reactions of Iodonium Ylides 1(a–d) with
the Benzhydrylium Ions 2(a–f) in CH2Cl2 at 20 °C
a
Ylide
1a
1a
1a
1a
Electrophile
k2 (M–1 s–1)
1.07 × 104
2.12 × 102
N, sN
2b
2c
2d
2f
6.18, 0.81
6.69 × 101
4.29
1b
1b
1b
1b
2a
2b
2c
3.32 × 104
4.36, 1.06
2.21 × 103
1.40 × 101
3.95
2d
1c
1c
1c
2c
2d
2e
3.04 × 103
6.25 × 102
2.27 × 102
7.98, 0.71
4.67, 0.92
1d
1d
1d
1d
2c
2d
2e
2f
2.60 × 101
7.54
4.94 × 10–1
2.18 × 10–1
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a
The nucleophile-specific parameters sN and N were derived from the slopes and the
intercepts on the abscissa of the correlations between log k2 (this table) and the
electrophilicity parameters E of the benzhydryl cations (from Table 1). For details see text.
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Figure 4: Correlation of log k2 for the reactions of the iodonium ylides 1(a-d) with the
benzhydryl cations 2(a-f) versus the electrophilicity parameters E of the corresponding
carbenium ions.
Let us now analyze how the kinetic data can be interpreted in terms of the mechanism
presented in Scheme 5. In the following general analysis, which refers to different
benzhydrylium ions, specifying labels a,b,c etc. in the formula numbers in Scheme 5 are
omitted. As the expulsion of iodobenzene during the transformation of I1 into I2 must be
irreversible, the overall rate of disappearance of the electrophiles 2 (k2), which is
experimentally accessible by the kinetic experiments, will depend on the rates of the two first
steps of the reaction (kCC, k−CC, and kelim, Scheme 5; formation of 4 does not occur with the
–
BF4 salts).
The rate law for the consumption of 2 can be formulated as follows:
d[2]
 kCC[1][2] kCC[I1]
(2)
dt
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d[I1]
 kCC[1][2]  kCC[I1]  kelim[I1]
(3)
dt
5
6
7
8
9
As the experimental observations described above do not give evidence for an
observable concentration of I1, the steady-state approximation, d[I1]/dt = 0, applies and we
arrive at eq 4.
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kelim
d[2]
 k2 [1][2]  kCC
[1][2]
(4)
dt
kCC  kelim
The linear correlations depicted in Figure 4 either imply that k2 = kCC (for kelim >> kCC) or that
substituent variation in the benzhydrylium ions affects the second term of eq 4, i.e., the
quotient kelim/(k−CC + kelim) proportionally to kCC. As this coincidence is highly unlikely for
reactions of four different iodonium ylides with benzhydrylium ions of widely differing
electrophilic reactivities, we conclude kelim >> k−CC, equivalent to the conclusion that
iodobenzene is a better nucleofuge than the iodonium ylides 1(a-d). The second term of eq 4
thus becomes 1, leading to k2 = kCC. Monoexponential decays of the benzhydrylium
concentrations, would also be found if kelim << k−CC. In this case eq. 5 would hold with K =
kCC/k–CC
d[2]
 k2[1][2]  kelimK[1][2]
(4)
dt
Since kelimK cannot be expected to be linearly correlated with the electrophilic reactivities E of
the benzhydrylium ions (Figure 4), this possibility was also eliminated.
Additional support for rate-determining CC-bond formation (k2 = kCC) comes from the
observation that the reactivity parameters N and sN derived in this way correctly reproduce the
rate constants of the reactions of iodonium ylides with iminium ions, for which the subsequent
reaction steps are completely different (see next paragraph). One thus can conclude that the
nucleophilicity parameters sN and N given in Table 3 allow one to calculate the reactivities of
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the carbon centers of the iodonium ylides 1(a-d) towards any C(sp2)-centered electrophile
with a known value of E.
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Figure 5. Comparison of the nucleophilicity parameters N/sN (in CH2Cl2) of the iodonium
ylides 1a, 1b, and 1d with those of the corresponding carbanions (in DMSO). a From ref 27. b
This work, kinetics of the reactions of electrophiles 2i-k with 6-methyl-2,4-dioxotetrahydro-
2H-pyran-3-ide were used for the determination of N/sN in DMSO (see Supporting
Information).
Figure 5 illustrates that replacement of the hydrogen at the reaction center of carbanions (X =
+
H, Figure 5, left) by IPh reduces the nucleophilic reactivity by approximately ten orders of
magnitude.
Application in Organocatalysis: Reactions with α,β-Unsaturated Iminium Ions.28
In previous work we have discussed that iminium-activation of α,β-unsaturated carbonyl
compounds is restricted to reactions with nucleophiles of 2 < N < 14, because more reactive
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nucleophiles may undergo direct reactions with the carbonyl precursors, while less reactive
nucleophiles do not react readily with typical iminium ions.29 Given that the iodonium ylides
1(a–d) have now been found to have nucleophilicity parameters in this range (4 < N < 8,
Table 3) we selected iodonium ylide 1a to test whether iodonium ylides are suitable substrates
in iminium-activated reactions.
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As illustrated in Scheme 7, the reaction of 1a with the iminium ion 10a, derived from
cinnamaldehyde and MacMillan's first generation catalyst (5S)-2,2,3-trimethyl-5-benzyl-4-
imidazolidinone (11a),30 provided the cyclopropanation product 12 in 72% yield with an
enantiomeric ratio (e.r.) of 59/41 after purification by column chromatography. The
substituted spiro[2.5]octane 12 was crystallized from an ethyl acetate/n-pentane mixture (1:3)
and subsequently analyzed by single crystal X-ray diffraction.31,32
Scheme 7. Reaction of the Iminium Hexafluorophosphate 10a-PF6 with the Iodonium Ylide
1a in Acetonitrile at Room Temperature.
The experimental second-order rate constant of the reaction of 1a with 10a (kexp = 0.232 M–1
s–1 in CH2Cl2 at 20 °C, Supporting Information) deviates only by a factor of 2 from the rate
constant kcalc = 0.108 M–1 s–1 calculated by eq 1 using the N and sN parameters of 1a in Table
3 and the previously published33 electrophilicity parameter of 10a (E = −7.37). This good
agreement indicates a rate-determining step similar to that of the reactions of the iodonium
ylides 1 with benzhydrylium ions 2 (see above), i.e., rate-determining nucleophilic attack of
the ylide 1a at the iminium ion 10a, followed by intramolecular nucleophilic attack of the
resulting enamine moiety in 13 at the iodonium-substituted carbon (Scheme 8).
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Scheme 8. Reaction Mechanism for the Reaction of the Iminium Ion 10a with the Iodonium
Ylide 1a.
9
10
11
12
13
14
15
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O
O
N
N
Ph
Ph
N
N
–
–
PF6
PhI
PF6
Ph
O
O
I
Ph
Ph
10a
O
O
1a
13
– PhI
O
N
N
O
Ph
O
H2O
–
Ph
O
PF6
Ph
O
O
12
Table 4. Yields and Enantioselectivities of the Reactions of Iodonium Ylide 1a with Either
Iminium Ions 10a,b or a Combination of Cinnamaldehyde (14) and Catalysts 11a,b (in
MeCN).
entry Electrophile Catalyst
(0.2 equiv.)
AN/Wa T (°C) t (h) Yield e.r.b
(%)
72
10a-PF6
1
none
100/0
20
24
59/41
2
3
4
5
6
7
14
14
14
14
14
14
11a-TFA
11a-TFA
11a-TFA
11a-TFA
11a-TFA
11a-TFA
100/0
95/5
90/10
80/20
100/0
95/5
20
20
20
20
–30
0
12
12
12
12
12
12
66
61/39
69/31
71/29
72/28
69/31
70/30
46
c
c,d
43
c
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11a-TFA
11a-TFA
95/5
–30
20
12
68
48
50
69/31
70/30
95/5e
6
7
8
9
10
11
12
10
11
12
10b-PF6
10b-PF6
10b-PF6
none
none
none
100/0
100/0
100/0
20
20
–30
2
0.1
12
32
38/62f
38/62f
32/68f
c
c
47/53f
c
c
13
14
14
14
11b-PF6
11b-PF6
100/0
20
20
12
12
95/5
46/54f
a
b
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AN/W = acetonitrile-water mixture (v/v). Enantiomeric ratio (e.r.) from HPLC analysis
(Supporting Information). c Yield was not determined. d Significant amount of 1a insoluble in
diethyl ether was detected after dissolving of the crude mixture in this solvent, which
e
f
indicates a low degree of conversion. Acetone-water mixture (v/v). The major enantiomer
obtained with 10b or 11b has the opposite configuration to that formed by 11a.
Table 4 compares the yields and selectivities for the reactions of cinnamaldehyde (14) with
iodonium ylide 1a under organocatalytic conditions using MacMillan's catalysts of first34 and
second35 generation 11a and 11b, respectively. According to Scheme 7, the isolated iminium
hexafluorophosphate 10a-PF6 reacted with 1a in acetonitrile at 20 °C to give cyclopropane 12
in 72% yield (e.r. = 59/41) after aqueous workup (entry 1). When the reaction of
cinnamaldehyde (14) with iodonium ylide 1a was performed in the same solvent (MeCN, 20
°C) under organocatalytic conditions (20 mol-% of 11a-TFA), the yield dropped slightly but
the e.r. remained unchanged (entry 2). As in the 11a-Cl-catalyzed Diels-Alder reaction of
cinnamaldehyde with cyclopentadiene,34 addition of water was found to increase the
enantioselectivity of the catalyzed reactions (entries 2–5). While an increase of the e.r. from
61/39 to 69/31 was observed when the temperature was lowered from 20 to −30 °C for the
11a-TFA-catalyzed reaction in pure acetonitrile (entries 2 and 6), variation of temperature did
not affect the enantiomeric ratio in acetonitrile-water mixtures (entries 3, 7, 8). Almost the
same stereoselectivity as in aq. acetonitrile was observed when 95 % aq acetone was
employed (e.r. = 70/30, entry 9), but the reaction was much slower.
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MacMillan's second generation catalyst, 11b, was found to give slightly higher
(inverse) enantiomeric ratios but considerably lower yields than 11a when used under
stoichiometric conditions (isolated iminium salts, entries 1 and 10). A slight increase of the
e.r. was observed when the isolated iminium salt 10b-PF6 was combined with 1a in
acetonitrile at −30 °C (e.r. = 32/68, entry 12).
10
11
12
13
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In contrast to the situation with 11a, a change from stoichiometric to organocatalytic
conditions caused a significant drop in e.r. from 38/62 to 47/53 when 11b was employed
(entries 10 and 13). Addition of water was found to have only a marginal effect on the
selectivity of the organocatalytic reaction using 11b (entries 13, 14).
The lower performance of 11b in the reaction of 1a with 14 can be explained by the
different persistence of the different reaction products in the solutions obtained after aqueous
workup. Chiral HPLC indicated that the concentrations of both enantiomers of 12 decreased
significantly within several hours, when the crude mixtures were dissolved in
dichloromethane or acetonitrile.
As the enantiomer initially formed in excess decomposed faster in the presence of 11b
than the minor enantiomer, the e.r. decreased from initially 32/68 to ca 50/50 within 3 h. This
observation suggests that decomposition of 12 is induced by 11b or some chiral byproducts
that react with different rates with the two enantiomers, which explains the low performance
of 11b in terms of both yield and stereoselectivity. An attempt to increase the e.r. by
decreasing the reaction time from 2 h to 0.1 h did not increase the enantioselectivity36 (Table
4, entries 10–11).
Conclusions
While previous investigations of the reactions of stabilized -dicarbonyl substituted iodonium
ylides with acid chlorides and trialkyloxonium ions showed exclusive reactions at the enolate
oxygens of the ylides, we have now found the first examples for electrophilic attack at the
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ylide carbon of 1(a-d). These were the only observable reactions, when the iodonium ylides
1(a-d) were combined with stabilized carbenium or iminium ions, presumably because the
competing O-attack of these electrophiles is highly reversible. In all investigated cases, the
initial rate-determining CC-bond forming step was followed by fast expulsion of iodobenzene
and rearrangements.
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The reactions of 1(a-d) with the benzhydrylium ions 2 followed second-order kinetics,
and the resulting second-order rate constants correlated linearly with the electrophilicity
parameters E of the benzhydrylium ions, which allowed us to derive the N and sN parameters
of the iodonium ylides 1(a-d) according to eq (1). In this way, the nucleophilic reactivities of
the iodonium ylides can directly be compared with those of other C-nucleophiles, e.g.,
allylsilanes and -stannanes, pyrroles and indoles, silylated enol ethers and enamides, as well
as isonitriles and methyl hydrazones (Figure 6).16
Figure 6. Nucleophile-specific parameters N/sN of iodonium ylides 1(a-d) compared with
those of various C-nucleophiles in dichloromethane.16 a In acetonitrile.
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The fact that the rate constant for the cyclopropanation of the cinnamaldehyde-derived
iminium ion 10a by the iodonium ylide 1a closely resembles that calculated from E, N, and sN
by eq 1 indicates that this reaction proceeds through rate-determining nucleophilic attack of
the iodonium ylide at the electron-deficient CC-double bond. With nucleophilicity parameters
4 < N < 8 (Table 3) the iodonium ylides 1(a-d) are in the reactivity range suitable for
iminium-activated reactions. Accordingly, imidazolidinone 11a catalyzes the
cyclopropanation of cinnamaldehyde (14) to produce an enantiomeric ratio of ca. 70/30. In
spite of the moderate enantioselectivities observed so far, these results should trigger further
investigations of iminium-activated reactions. From the rule of thumb that electrophiles are
expected to react efficiently with nucleophiles if E + N > –5, one can predict that electrophiles
with E > –10 should be able to attack at the carbon center of the iodonium ylides 1(a-d). From
the formation of I3a (Scheme 5) one can expect, however, that highly reactive carbocations E
> (0 to 4) will attack the intrinsically preferred O-position of 1 as previously observed for the
reactions of 1(a-d) with acyl chlorides and oxonium ions.6a,12
10
11
12
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Acknowledgements.
We thank the Deutsche Forschungsgemeinschaft (SFB 749, project B1) for financial support
and Nathalie Hampel (LMU München) for preparing the reference electrophiles 2.
Supporting Information.
Detailed synthetic procedures and product characterization; details of kinetic measurements;
1
13
crystallographic data for 4, 8 and 9; copies of H and C{1H} NMR spectra for all isolated
products. (PDF)
Crystallographic data (CIF)
CCDC 1474094 (4, rv305), CCDC 1445166 (8, po046), and CCDC 1445164 (9, qo065)
contain the supplementary crystallographic data for this paper. These data can be obtained
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data_request/cif
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(30) For an x-ray structure determination of iminium hexafluorophosphate 10a, see:
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(32) The (1R,2S)-configuration of the major enantiomer of 12 (as shown in Schemes 7, 8
and Table 4) is based on the configuration of 10a (ref 30) and the assumption that nucleo-
philes attack 10a preferentially from the rear side with respect to the 5-benzyl group of 10a.
Crystals of 12 that were obtained from a 59/41 mixture of enantiomers (Supporting
Information, p S16) were investigated in the crystal structure analysis reported in ref 31.
Limitations of the X-ray analysis method used in ref 31 did not allow for an unequivocal
assignment of the absolute configuration of 12 whose structure was refined as perfect
inversion twin.
(33) Lakhdar, S.; Ammer, J.; Mayr, H. Angew. Chem., Int. Ed. 2011, 50, 9953-9956.
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(36) In this case, racemization caused by decomposition of the products could have been
accelerated during the column loading and column chromatography.
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