Imidazolidinone-derived enamines: Nucleophiles with low reactivity

Article abstract of DOI:10.1002/anie.201201240

Extraordinarily weak nucleophiles: Enamines derived from imidazolidinones are 10³-10⁵ times less reactive than those derived from the Hayashi-Jorgensen catalyst. This finding explains the lower activity of MacMillan catalysts for enamine-activated reactions. Copyright

Full text of DOI:10.1002/anie.201201240

Angewandte
Chemie
DOI: 10.1002/anie.201201240
Organocatalysis
Imidazolidinone-Derived Enamines: Nucleophiles with Low
Reactivity**
Sami Lakhdar,* Biplab Maji, and Herbert Mayr*
Dedicated to Professor Wolfgang Beck on the occasion of his 80th birthday
Table 1: Amines 1a–e and the corresponding phenylacetaldehyde-
derived enamines 3a–e.
During the last decade the concept of enamine activation has
become a powerful tool in asymmetric synthesis. It uses chiral
secondary amines as catalysts to activate saturated carbonyl
compounds by conversion into enamines.[1] Among various
catalysts tested, diarylprolinol silyl ether 1b was found to be
particularly useful for the stereoselective introduction of
different functionalities to the a-position of aldehydes.[2,3]
Imidazolidinones 1c–e (Table 1), which have been used
extensively in iminium catalysis,[4] are less effective in
enamine-activated processes unless strong electrophiles are
employed. Typical examples are enantioselective a-halogen-
ations[5] and a-alkylations of aldehydes with stabilized
carbocations which were in situ generated by treatment of
alcohols with acids.[6] Mechanistic investigations, focusing on
the characterization and reactivities of the intermediate
enamines, are rare.[7–9]
While the synthesis and the X-ray structure of the
enamine 3b have previously been described by Seebach
et al.,[8] we are not aware of any X-ray structures of enamines
derived from imidazolidinones. Gellman et al. used 1H NMR
spectroscopy to characterize the enamine generated from
imidazolidinone 1c and 3-phenylpropanal in DMSO solution
and reported its reaction with methyl vinyl ketone catalyzed
by 4-ethoxycarbonylcatechol.[9]
Amine
Product
Yield [%]
86[a]
1a
1b
3a
3b
35[b]
1c
1d
3c
3d
44[c]
32[c]
1e
3e
87[d]
In order to elucidate the relationships between structure
and reactivities of enamines derived from 1a–e, we have now
synthesized the enamines 3a–e, performed X-ray analyses of
3d and 3e, and measured the kinetics of their reactions with
the stabilized benzhydrylium ions 4a–h (Table 2).
[a] After distillation. [b] 3b was prepared by heating 1b and 2 in benzene
at reflux following a procedure described by Seebach (Ref. [8]). After
solvent removal and crystallization from Et2O, 3b was obtained as a pure
material. [c] After column chromatography. [d] After crystallization.
Enamines 3c–e, which had not been isolated previously,
were obtained by refluxing phenylacetaldehyde (2) and the
amines 1c–e in the presence of 1 mol% of p-toluenesulfonic
acid in toluene under argon using a Dean–Stark apparatus
filled with molecular sieves (4 ꢀ) to remove the generated
water.[10] After evaporation of the solvent, 3e was immedi-
ately obtained as a crystalline material in 87% yield, while
column chromatography was employed to separate the
enamines 3c and 3d from the nonreacted imidazolidinones
1c and 1d, respectively.
Crystals of 3d and 3e suitable for X-ray analysis were
grown by the vapor diffusion crystallization method in diethyl
ether/n-pentane mixtures. As shown in Figure 1,[11] the C N
bond between the heterocyclic ring and the E-configurated
ꢀ
[*] Dr. S. Lakhdar, M. Sc. B. Maji, Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5–13 (Haus F), 81377 Mꢁnchen (Germany)
E-mail: sami.lakhdar@cup.uni-muenchen.de
=
C C bond has s-trans conformation in both enamines 3d and
3e. Whereas the benzylic phenyl group is located over the
imidazolidinone ring in 3d, possibly because of stabilizing
CH–p interactions (London dispersion interaction between
the phenyl ring and the cyclopentane ring),[12] the benzyl
herbert.mayr@cup.uni-muenchen.de
Homepage: http://www.cup.uni-muenchen.de/oc/mayr
[**] We thank the Alexander von Humboldt Foundation (research
fellowship for S.L.) and the Deutsche Forschungsgemeinschaft
(SFB 749) for financial support, Dr. P. Mayer for the determination
of the X-ray structures, and Dr. A. R. Ofial and Dr. M. Horn for
helpful discussions.
=
group is located over the C C bond in the enamine 3e and
[5]
=
thus directs electrophiles to the Si face of the C C bond.
NMR spectroscopy showed that the conformations of 3d and
3e, which were observed in the crystals, also dominate in
CDCl3 solution (see the Supporting Information).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201240.
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Vis absorbances of the diarylcarbenium ions 4 (Scheme 1),
using conventional and stopped-flow instruments. All kinetic
experiments were performed at 208C in acetonitrile with
a large excess of the enamines 3a–e in order to achieve
conditions for first-order kinetics.
Scheme 1. Reactions of the enamines 3 with the carbocations 4 in
acetonitrile at 208C.
Figure 1. Crystal structures of the enamines 3d (left) and 3e (right).
The first-order rate constants kobs were obtained by least-
squares fitting of the function At ¼ A0 expðꢀkobstÞ þ C to the
time-dependent absorbances of the electrophiles. Plots of kobs
versus the concentrations of the nucleophiles [3] were linear,
as exemplified in Figure 2. The slopes of these plots gave the
From the pyramidalization parameter D, defined by
Dunitz as the distance between the N atom and the plane
formed by the three attached carbon atoms,[13] one can derive
that the almost planar sp2-hybridized nitrogen in 3b (D =
0.037 ꢀ)[8] adopts more and more sp3 character as one
moves to 3d (D = 0.155 ꢀ) and eventually to 3e (D =
0.293 ꢀ).
In order to quantify the nucleophilic reactivities of 3a–
e we have studied the kinetics of their reactions with the
benzhydrylium ions 4a–h (Table 2), which have been used as
reference electrophiles for the construction of comprehensive
nucleophilicity scales on the basis of Equation (1). Herein,
nucleophiles are characterized by two parameters (nucleo-
philicity N and sensitivity parameter sN) and electrophiles by
one parameter (electrophilicity E).[14]
lg k2ð20 ꢁCÞ ¼ sNðN þ EÞ
ð1Þ
Figure 2. Exponential decay of the absorbance at 586 nm during the
reaction of 4c-BF4ꢀ (1.60ꢂ10ꢀ5 m) with 3c (3.90ꢂ10ꢀ4 m). Inset: Plot
of the rate constants kobs versus [3c] (208C in CH3CN).
As described previously,[14b] the rates of the reactions of
carbocations 4 with the enamines 3a–e were measured
photometrically by following the disappearance of the UV/
second-order rate constants k2 (in mꢀ1 sꢀ1), which are sum-
marized in Table 3.
Table 2: Reference electrophiles 4a–h.
Plots of lgk2 versus the empirical electrophilicity param-
eters E are linear for all reactions studied in this investigation
(Figure 3), indicating that Equation (1) can be used to
determine N and sN parameters for the enamines 3a–
e (Table 3).
E[a]
4a
ꢀ1.36
One can see that the enamine 3b, which is derived from
the Hayashi–Jørgensen catalyst 1b, is almost two orders of
magnitude less reactive than 3a, the parent compound of this
series. As one of the diastereotopic faces of 3b is completely
open for electrophilic attack, the reduction of reactivity must
predominantly be due to the electron-withdrawing inductive
effect of the trimethylsiloxybenzhydryl group in 3b.
The inductive electron-withdrawing effect of the extra
endocyclic amido group in the imidazolidinone derivatives 3c
and 3d, the pyramidalization of the enamine nitrogen, and the
X=N(Ph)CH2CF3
X=N(Me)CH2CF3
X=N(CH2CH2)2O
X=NMe2
4b
4c
4d
4e
ꢀ3.14
ꢀ3.85
ꢀ5.53
ꢀ7.02
4 f
ꢀ7.69
4g (n=2)
4h (n=1)
ꢀ8.22
ꢀ8.76
=
steric shielding of both faces of the C C bond by the two alkyl
[a] Electrophilicity parameters E from Ref. [14b].
groups at the 2-position of the imidazolidinone ring reduce
2
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Table 3: Second-order rate constants k2 for the reactions of the
carbocations 4a–h with the enamines 3a–e (acetonitrile, 208C).
Table 4: NMR chemical shifts (CDCl3) of the enamines 3a–e.
Enamine
R+
k2 [mꢀ1 sꢀ1
]
N, sN
3a
4e
4 f
4g
4h
1.38ꢂ105
3.48ꢂ104
9.94ꢂ103
2.64ꢂ103
12.25, 0.99
enamine
d(Cb–H) [ppm]
d(Cb) [ppm]
3a
3b
3c
3d
3e
5.18
5.02[a]
5.47
5.47
4.76
97.4
97.2[a]
101.9
102.1
102.9
3b
3c
4d
4e
4h
1.48ꢂ105
2.33ꢂ103
7.94ꢂ101
10.56, 1.01
7.20, 1.14
[a] From Ref. [8b].
4a
4b
4c
4d
4.73ꢂ106
7.80ꢂ104
2.24ꢂ103
1.15ꢂ102
The fact that 3b has significantly higher nucleophilicity
than 3c–e may explain why 1b is a more suitable catalyst than
1c–e for most enamine-activated reactions.
By using the N and sN values of 3b (Table 3) and the E
values of Michael acceptors,[14f] Equation (1) allows one to
predict whether a reaction may take place at room temper-
ature. Hayashiꢁs observation that 1b catalyzes Michael
additions of aldehydes to b-nitrostyrenes[16] is in line with
3d
3e
4b
4c
4d
2.77ꢂ105
7.26ꢂ103
4.93ꢂ102
7.92, 1.07
5.80, 0.87
4b
4c
4d
3.46ꢂ102
2.56ꢂ101
2.13
a
calculated second-order rate constant (kcalcd = 4.8 ꢂ
10ꢀ4 mꢀ1 sꢀ1) for the reaction of 3b with b-nitrostyrene (E =
ꢀ13.85).[17] It has been shown, however, that the initially
generated zwitterions from the enamines and nitrostyrene
collapse with formation of cyclobutanes, the ring opening of
which is the rate-determining step of the catalytic cycle.[7e,18]
For that reason, a sufficiently fast reaction of the enamine
with the Michael acceptor is only one of the criteria that have
to be fulfilled for a catalytic cycle to proceed.
The more than 100 times higher nucleophilicity of 3b
compared with 3c,d may also rationalize the fact that 1b and
not 1c–e are usually employed as catalysts for Mannich-type
reactions of imines with aldehydes.[19] In line with the low
nucleophilicity of 3c–e Gellman et al reported that 1c-
catalyzed conjugate additions of aldehydes to enones require
Brønsted acids as cocatalysts to activate the enones.[9]
In summary, we have described the first X-ray structures
of enamines derived from imidazolidinones. Nucleophilic
reactivities of these enamines have been determined from the
kinetics of their reactions with diarylcarbenium ions 4, which
showed that the enamine 3b, derived from the Hayashi–
Jørgensen catalyst, is 103 to 105 times more nucleophilic than
the enamines derived from the imidazolidinones 1c–e.
Figure 3. Plots of lgk2 for the reactions of 3a–c, and 3e with the
benzhydrylium ions 4 in CH3CN at 208C versus the corresponding
electrophilicity parameters E. (Correlation for 3d is omitted for the
sake of clarity; it is shown on page S19 of the Supporting Informa-
tion).
Received: February 14, 2012
Published online: && &&, &&&&
the nucleophilicities of these enamines by another two to
three orders of magnitude relative to 3b.
Keywords: enamines · kinetics · linear free energy relationships ·
nucleophilicity · pyramidalization
=
As the C C bond of 3e has one open face, its low
.
nucleophilicity (102 times less than that of 3c and 3d) must be
due to the enhanced pyramidalization of the enamine nitro-
gen in 3e (X-ray structure, Figure 1), which strongly reduces
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4
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Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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Communications
Organocatalysis
S. Lakhdar,* B. Maji,
H. Mayr*
&&&& — &&&&
Imidazolidinone-Derived Enamines:
Nucleophiles with Low Reactivity
Extraordinarily weak nucleophiles:
alyst. This finding explains the lower
Enamines derived from imidazolidinones
are 103–105 times less reactive than those
derived from the Hayashi–Jørgensen cat-
activity of MacMillan catalysts for enam-
ine-activated reactions.
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!