Kinetic evidence for the formation of oxazolidinones in the stereogenic step of proline-catalyzed reactions

Article abstract of DOI:10.1002/anie.201004344

Neighboring-group participation: Anchimeric assistance of the carboxylate group accelerates the attack of the electrophiles at the double bond of the proline-derived enamine A by a factor of about 50. Copyright

Full text of DOI:10.1002/anie.201004344

Communications
DOI: 10.1002/anie.201004344
Organocatalysis
Kinetic Evidence for the Formation of Oxazolidinones in the
Stereogenic Step of Proline-Catalyzed Reactions**
Tanja Kanzian, Sami Lakhdar, and Herbert Mayr*
The stereoselectivity of proline-catalyzed reactions of alde-
hydes or ketones with electrophiles[1] is usually rationalized
by the activation of the electrophile through the proton of the
carboxy group as depicted in the List–Houk transition state
(TS-A) in Scheme 1.[2] Oxazolidinone formation was gener-
Scheme 2. The crucial role of oxazolidinones in proline-catalyzed
Scheme 1. Transition-state models for the proline-catalyzed reactions
of carbonyl compounds with electrophiles.
reactions according to Seebach, Eschenmoser et al.[3]
ally considered an unproductive dead end of the reaction
cascade[2g] until Seebach, Eschenmoser et al. suggested that
oxazolidinones, rather than being “parasitic species”, may
also play a decisive role in determining the stereochemical
course of proline-catalyzed reactions.[3] In this mechanism
(Scheme 2) proline and the carbonyl compound combine with
formation of the oxazolidinone I-1, which undergoes ring
opening to furnish the s-cis and/or s-trans conformer of the
enaminocarboxylate I-2. In order to account for the observed
stereoselectivities, it was assumed that TS-B (Scheme 1),
which yields the more stable oxazolidinone, is favored over
the stereoelectronically preferred TS-C.[3]
Support for the involvement of the enamine carboxylate
I-2 has recently been provided by Blackmond, Armstrong
et al., who reported that the enantioselectivity of proline-
catalyzed reactions of aliphatic aldehydes with azodicarbox-
ylates is reversed in the presence of tertiary amines.[4] This
reversal was explained by a change from TS-A to TS-C in the
presence of amines, where the attack of the electrophile
occurs at the s-trans isomer of the enamine carboxylate. The
role of the carboxylate group could not be clarified, however,
and it was suggested that CO2ꢀ either acts as a steric blocking
group, or in accordance with Seebach, Eschenmoser et al.,
participates in the addition step.[4]
Traditionally, anchimeric assistance (neighboring-group
participation) has been derived from stereochemical as well
as kinetic investigations in a variety of reactions, e.g.,
solvolytic displacement reactions, electrophilic additions,
and eliminations.[5] Owing to the conformational flexibility
of the intermediate enamines stereochemical investigations
did not provide unequivocal evidence for or against the
formation of oxazolidinones in the stereogenic step.[1e] There-
fore, we approached this problem with kinetic methods.
In order to separate steric and electronic effects, we
studied the kinetics of the reactions of the proline, pyrroli-
dine, and proline methyl ester derived enamines 1ꢀ, 2, and 3
with the benzhydrylium ions 4a–4 f and the quinone methides
4g–j (Table 1). As shown previously, their electrophilicities
[*] T. Kanzian, Dr. S. Lakhdar, Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13 (Haus F), 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77717
E-mail: Herbert.Mayr@cup.uni-muenchen.de
[**] We thank Johannes Ammer for help during the laser-flash-photolysis
experiments, Konstantin Troshin for help with the HPLC analysis,
Roland Appel and Dr. Armin Ofial for helpful discussions, and the
Deutsche Forschungsgemeinschaft (Ma 673/21-3) for financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004344.
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Table 1: Benzhydrylium ions 4a–f and quinone methides 4g–j employed
as reference electrophiles.
rate constants kobs were obtained from the observed mono-
exponential decays (Figure 1). From the linear plots of kobs
versus the concentrations [1ꢀ], [2], or [3] the second-order
rate constants k2 were obtained which are listed in Table 2.
Electrophile
E[a]
4a
4b
X=NMe2
X=N(CH2)4
ꢀ7.02
ꢀ7.69
4c
4d
n=2
n=1
ꢀ8.22
ꢀ8.76
4e
4 f
n=2
n=1
ꢀ9.45
ꢀ10.04
4g
4h
4i
Y=Ph; Z=OMe
ꢀ12.18
Y=Ph; Z=NMe2 ꢀ13.39
Y=tBu; Z=NO2
Y=tBu; Z=Me
ꢀ14.36
4j
ꢀ15.83
[a] Empirical electrophilicity parameter E for 4a–f from Ref. [6]; E for 4g–j
from Ref. [7].
Figure 1. Exponential decay of the absorbance A at 611 nm during the
reaction of 1ꢀ (5.27ꢂ10ꢀ4 m) with laser-flash-photolytically generated
4b at 208C in acetonitrile (kobs =4.25ꢂ104 sꢀ1). Inset: Determination
of the second-order rate constant (k2 =6.07ꢂ107 mꢀ1 sꢀ1) as the slope
of the correlation between the first-order rate constant kobs and the
concentration of the enamine 1ꢀ.
can be fine-tuned by variation of the para and meta
substituents, while the steric surroundings of the reaction
centers are kept constant.[6] The empirical
electrophilicity parameters listed in Table 1
show a continuous decrease of reactivity from
top to bottom by 8 orders of magnitude.
The prolinium trifluoroacetate catalyzed
reaction of cyclohexanone with 4,4’-bis(dime-
thylamino)benzhydrol (4a-OH) was recently
reported by Cheng et al. to yield (S)-5a with
16% ee.[8] Under the same conditions we
obtained (S)-5a with an enantioselectivity of
24% ee(Scheme 3). The corresponding reac-
tion of the benzhydrylium salt 4a-[BF4] with
the enaminocarboxylate 1ꢀ, which was
obtained by treatment of the oxazolidinone
1
with 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU), gave (R)-5a with 25% ee. The reac-
tion of the quinone methide 4j with 1ꢀ yielded
the a-substituted cyclohexanone 5j with
81% de. While the enantiomeric excess of
the major diastereomer could not be deter-
mined, an ee value of 53% was found for the
minor diastereoisomer. The reaction of 4a-
[BF4] with the proline ester 3 yielded 5a
almost in racemic form (0.7% ee).
The rates of the reactions of 1ꢀ, 2, and 3
with the electrophiles 4 were determined
photometrically in CH3CN at 208C by follow-
ing the decrease of the absorbances of
the colored electrophiles 4. Reactions with
k2 < 106 mꢀ1 sꢀ1 were studied with stopped-
flow techniques, while the laser-flash-
photolytic generation of benzhydrylium ions
was employed for determining rate constants
k2 > 106 mꢀ1 sꢀ1 as described previously.[9] By
using the enamines 1ꢀ, 2, and 3 in high excess
relative to the electrophiles 4, first-order
Scheme 3. Stereoselectivities of the reactions of cyclohexanone-derived enamines with
conditions were achieved, and the first-order the reference electrophiles 4a and 4j (TFA=trifluoroacetic acid).
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Table 2: Second-order rate constants for the reactions of 1ꢀ, 2, and 3 with reference electrophiles 4 in
acetonitrile at 208C.
2 and even 800 to 900 times more
reactive than 3 (Table 2, Figure 2).
In line with earlier observations
that the reactions of ordinary enam-
ines with the quinone methides 4g–i
in dichloromethane solution are
thermodynamically unfavorable, 2
was now found not to react with
4g–i.[14]
Nucleophile
Electrophile
k2 [mꢀ1 sꢀ1
]
Nucleophile
Electrophile
k2 [mꢀ1 sꢀ1
]
1ꢀ
4b
4c
4d
4g
4h
4i
6.07ꢂ107
3.03ꢂ107
1.31ꢂ107
4.41ꢂ104
1.35ꢂ104
8.58ꢂ102
6.43ꢂ105
2
4d
4e
4 f
4c
4d
4e
4 f
2.12ꢂ105
7.62ꢂ104
3.25ꢂ104
3.74ꢂ104
1.40ꢂ104
5.98ꢂ103
2.02ꢂ103
3
2
4c
Can one rule out that the
second-order rate constants listed
While the enamines 2 and 3 were used as pure samples,
solutions of 1ꢀ were freshly prepared by treatment of 1 with
one equivalent of DBU.[3] The quantitative conversion of 1 to
1ꢀ under these conditions was demonstrated by kinetic
investigations with solutions obtained from 1 with 0.95 or
1.3 equivalents of DBU.[10] Details are given in the Supporting
Information.
The second-order rate constants for the reactions of 2 with
4c–f in acetonitrile (Table 2) deviate from those previously
measured in dichloromethane solution[11] by less than a factor
of 3, in line with our previous observations that the rates of
the reactions of carbocations with neutral p systems are only
slightly affected by the nature of the solvent.[12] Plots of the
logarithms of the second-order rate constants against the
empirical electrophilicity parameters E of the reference
electrophiles 4 are linear, showing that Equation (1)[13] is
applicable (Figure 2). This allows us to calculate the nu-
cleophilicity parameter N and the nucleophile-specific slope
parameter s for the enamines 1ꢀ (N = 18.86; s = 0.70), 2
(N=16.42; s = 0.70), and 3 (N = 14.96; s = 0.68) in acetonitrile.
for 1ꢀ in Table 2 reflect the rates of addition of the
carboxylate group to the electrophiles 4 while the isolated
products 5 are the result of thermodynamic product control?
This possibility can be rigorously excluded for the reactions of
1ꢀ with the quinone methides 4g–i, as no decrease of
absorbance was observed when these electrophiles were
combined with carboxylate ions, for example tetrabutylam-
monium acetate in acetonitrile (thermodynamically unfavor-
able). The disappearance of the benzhydrylium ions 4b–d in
the reactions with 1ꢀ also cannot be explained by initial
reactions of the carbocations with the carboxylate group,
because previous studies on the kinetics of the reactions of the
amino-substituted benzhydrylium ions 4a–f with tetrabuty-
lammonium acetate[15] have shown that the reactions with
carboxylate anions are approximately 10 times slower than
the reactions with 1ꢀ, which are reported in Table 2.
Two reasons may account for the fact that 1ꢀ is by far the
most reactive enamine of this series (Figure 2). One is
anchimeric assistance of the electrophilic attack by the
carboxylate group as shown in TS-B/C of Scheme 1. The
second is electrostatic attraction between the cationic electro-
philes and the anionic nucleophile 1ꢀ, which may contribute
in the reactions with the benzhydrylium ions 4b–d. From the
comparison of the rate constants for the reactions
of 4a with aniline (k2 = 7.16 ꢀ 103 mꢀ1 sꢀ1)[16] and the
3-aminobenzenesulfonate anion (k2 = 7.68 ꢀ 104 mꢀ1 sꢀ1) in
acetonitrile, one can deduce that Coulombic attrac-
tions may be responsible for an acceleration of the
cation–anion combinations in acetonitrile by a factor
of approximately 10.[17] As a consequence, Coulomb
attraction can only partially account for the high
reactivity of 1ꢀ with 4b, 4c, and 4d, and anchimeric
assistance by the carboxylate group must play a
significant role.
lg k2ð20 ꢁCÞ ¼ sðN þ EÞ
ð1Þ
The enamine ester 3 is about 15 times less reactive than
the unsubstituted enamine 2, which reflects the electron-
withdrawing effect of the ester group. In contrast, the
enamino carboxylate 1ꢀ is 50 to 60 times more reactive than
This interpretation is corroborated by comparing
the reactivities of the enamines 1ꢀ and 2 toward the
neutral electrophiles b-nitrostyrene (6) and di-tert-
butyl azodicarboxylate (7), where Coulombic attrac-
tions cannot contribute (Scheme 4). The observation
that enaminocarboxylate 1ꢀ reacts 107 times faster
with b-nitrostyrene (6), but only 6 times faster with
azodicarboxylate 7 than enamine 2 (Table 3) indicates
that the magnitude of the anchimeric assistance is
strongly dependent on the nature of the electrophiles.
The kinetic data presented herein thus provide
Figure 2. Plots of lgk2 for the reactions of the enamines 1ꢀ, 2, and 3 with the
reference electrophiles 4b–i at 208C in acetonitrile versus their electrophilicity
parameter E.
clear evidence for anchimeric assistance by the
carboxylate group in electrophilic additions to the
enaminocarboxylate 1ꢀ. In combination with the
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and 7 in acetonitrile at 208C.
Electrophile
Nucleophile
k2 [mꢀ1 sꢀ1
]
6
1ꢀ
2
2.43ꢂ103
2.27ꢂ101
1.80ꢂ103
7
1ꢀ
2
2.99ꢂ102[a]
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results from the Blackmond and Armstrong groups[4] these
data support the proposal that oxazolidinone formation may
occur in the stereogenic step of proline-catalyzed reactions,[3]
particulary in the presence of strong bases. Our results do not
affect the rationalization of the stereoselectivities of a
manifold of proline-catalyzed reactions by TS-A when the
effective nucleophile is an enaminocarboxylic acid[1e,20] and
not an enaminocarboxylate anion.
Received: July 15, 2010
Published online: November 4, 2010
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Keywords: anchimeric assistance · enamine activation ·
kinetics · linear free energy relationships · nucleophilicity
.
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