Construction of α,α-disubstituted α-Amino Acid Derivatives via aza-Morita-Baylis-Hillman Reactions of 2-Aminoacrylates with Activated Olefins

Article abstract of DOI:10.1002/cctc.201901987

A useful and convenient strategy for the synthesis of α,α-disubstituted α-amino acid (α-AA) derivatives via aza-Morita-Baylis-Hillman reaction of 2-aminoacrylates with activated olefins has been developed. A variety of α-AA derivatives containing an α-amino tertiary center were synthesized in good to excellent yields. The kinetic profiles and calculated methyl anion affinity (MAA) values were employed to rationalize the reactivities of different Michael acceptors used in the reaction.

Full text of DOI:10.1002/cctc.201901987

Full Papers
DOI: 10.1002/cctc.201901987
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Construction of α,α-disubstituted α-Amino Acid Derivatives
via aza-Morita-Baylis-Hillman Reactions of 2-
Aminoacrylates with Activated Olefins
Hou-Ze Gui,[a] Harish Jangra,[d] Ben Mao,[a] Tian-Yu Wang,[a] Heng Yi,[a] Qin Xu,[a] Yin Wei,*[b]
Hendrik Zipse,*[d] and Min Shi*[a, b, c]
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A useful and convenient strategy for the synthesis of α,α-
disubstituted α-amino acid (α-AA) derivatives via aza-Morita-
Baylis-Hillman reaction of 2-aminoacrylates with activated
olefins has been developed. A variety of α-AA derivatives
containing an α-amino tertiary center were synthesized in good
to excellent yields. The kinetic profiles and calculated methyl
anion affinity (MAA) values were employed to rationalize the
reactivities of different Michael acceptors used in the reaction.
Introduction
α,α-Disubstituted α-amino acids (α-AAs) are versatile building
blocks for biologically and pharmacologically important com-
pounds or natural products.[1] Numerous α-AAs such as selected
examples in Figure 1 have demonstrated great bioactivities.[2]
On the other hand, the introduction of α-AAs to the design of
novel non-natural peptides and proteins can extremely enhance
their pharmacological and biological capabilities.[3] Due to those
unique characteristics of α-AAs and their derivatives, it is
necessary to develop more synthetic strategies to construct
these architectures that contain the desired core scaffolds. In
the past few years, several methodologies have already been
developed to access α-AAs and their derivatives, and the main
synthetic methods have been summarized in Scheme 1 (pre-
vious work).[4] The first method is the further substitution of α-
substituted amino acids or their derivatives.[5] Another strategy
is the amination of secondary acids.[6] α-AAs and their
Figure 1. Representative bioactive molecules of α,α-disubstituted α-amino
acids and their derivatives.
derivatives can be easily obtained by the ring-opening of
disubstituted azlactones and similar heterocyclic substrates.[7]
The direct addition to ketoimines containing an ester group is
also considered to be an efficient approach to access α-AAs.[8]
Some special synthetic methods for the formation of α-AAs and
their derivatives by the rearrangement of unique substrates or
through a three-component reactions have been put forward as
well.[9,10]
The aza version of the Morita-Baylis-Hillman (MBH) reaction,
which is known as aza-MBH reaction, is a powerful and atom-
economic tool for constructing α-aminocarbonyl compounds.[11]
Extensive studies have probed the utility of aldimines to form
α-amino-substituted products through aza-MBH reactions. How-
ever, as far as we know, reports on the synthesis of α-amino-
disubstituted compounds through aza-MBH reaction of ketoi-
mines are quite limited, which is probably due to the instability
and the steric hindrance of the ketoimine moiety.[12] The
ketoimine substrates used in those successful cases are mainly
isatin-derived ketoimines or ketoimines containing electron-
deficient groups, which will lead to great substrate limitations.
To solve these problems, we now propose to employ a new
type of ketoimine species. Inspired by the recent reports on 2-
aminoacrylates together with the experimental phenomena
[a] H.-Z. Gui, B. Mao, T.-Y. Wang, H. Yi, Q. Xu, Prof. M. Shi
Key Laboratory for Advanced Materials and Institute of Fine Chemicals
School of Chemistry & Molecular Engineering
East China University of Science and Technology
Meilong Road No. 130, 200237 Shanghai (China)
[b] Dr. Y. Wei, Prof. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Linglin Lu, Shanghai 200032 (China)
E-mail: mshi@mail.sioc.ac.cn
[c] Prof. M. Shi
Shenzhen Grubbs Institute
Southern University of Science and Technology
Shenzhen, 518000 Guangdong (China)
[d] Dr. H. Jangra, Prof. H. Zipse
Department of Chemistry
LMU München
Butenandtstrasse 5–13, 81377 München (Germany)
E-mail: zipse@cup.uni-muenchen.de
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cctc.201901987
This publication is part of a Special Collection on “Phosphorus in Catalysis”.
Please check the ChemCatChem homepage for more articles in the collec-
tion.
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Table 1. Optimization of the reaction conditions.
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Entry[a]
1a [mmol]
2a [mmol]
Solvent
Yield [%][b]
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7
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9
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4
0.2
0.2
0.2
0.2
0.15
0.1
0.15
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
DCM
THF
91
21
18
78
91
85
83
N.D
MeCN
PhMe
DCM
DCM
DCM
DCM
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7[c]
8[d]
0.15
[a] Unless otherwise indicated, all reactions were carried out with 1a, 2a in
solvent (1.0 mL) at room temperature in a reaction tube for 12 h. [b]
Isolated yield. [c] 10 mol% PPh3 was used. [d] DABCO instead of PPh3.
reaction. However, when the proportion was changed to 1:1, a
decrease in yield occurred (Table 1, entries 5–6). Reducing the
catalyst loading to 10 mol% also decreased the yield from 91%
to 83% (Table 1, entry 7). No reaction occurred when DABCO
was used instead of PPh3 (Table 1, entry 8).
With the optimal conditions in hand, we next surveyed the
substrate scope of this aza-MBH reaction by using various 2-
aminoacrylates 2 to react with MVK. As shown in Table 2, we
first investigated the effect of substituents on the aryl group of
the benzenesulfonyl moiety for this aza-MBH reaction. Electron-
donating groups including alkyl groups (substrates 2a, 2g and
2j), alkoxy (substrate 2h) group as well as H atom (substrate 2f)
were well tolerated in the reaction, giving the desired products
Scheme 1. Previous work and this work.
about the tautomerization between 2-aminoacrylates and their
imine forms, we assume that such kind of in situ generated
ketoimine intermediate can be used as an active intermediate
to participate in the aza-MBH reaction to produce the target α-
AA derivatives as products.[13] Based on our previously success-
ful studies on aza-MBH reactions,[14] we made a series of
attempts of 2-aminoacrylates to react with methyl vinyl ketone
(MVK). Herein, we wish to report a tertiary phosphine catalyzed
aza-MBH reaction of 2-aminoacrylates with activated olefins,
affording a series of α-AA derivatives under mild conditions and
the studies on the reactivities of substrates.
Table 2. Reaction of 2-aminoacrylate 2 with electron-deficient olefin 1.[a,c]
Results and Discussion
To investigate the unprecedented aza-MBH reaction of 2-
aminoacrylates and MVK, we first surveyed the reaction of 2-
aminoacrylate 2a with MVK 1a in the presence of PPh3 in DCM.
The desired product 3aa was obtained in 91% yield (Table 1,
entry 1). To establish the optimal conditions for the reaction,
several solvents, different proportions of 1a and 2a, catalyst
loading and different catalysts have been examined as shown
in Table 1. The screening of the solvents revealed that the
reaction proceeded more smoothly in DCM, affording 3aa in
91% yield (Table 1, entries 1–4). Changing the proportion of 1a
and 2a from 2:1 to 1.5:1 had no obvious influence on the
[a] Unless otherwise indicated, all reactions were carried out with 1
(0.2 mmol), 2 (0.3 mmol) and PPh3 (0.04 mmol) in DCM (2.0 mL) at room
temperature in a reaction tube for 12 h. [b] Toluene instead of DCM. [c]
Isolated yield. [d] 0.2 mmol PPh3 was used.
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in yields ranging from 85% to 92%. However, the introduction
of electron-withdrawing groups to the aryl group of benzene-
sulfonyl group caused a large decrease in yield when the
reaction was carried out in DCM. In these cases, the yields could
be effectively improved by replacing the solvent with toluene
(substrates 2b, 2c, 2d, 2e and 2i). Subsequently, sulfonyl
groups containing a heteroaromatic ring such as thiophene
(substrate 2k) and 5-methylpyridine (substrate 2l) were tested;
the required products could also be obtained in the yields of
61% and 43%, respectively. The reaction proceeded smoothly
when the protecting group was a methylsulfonyl group
(substrate 2m); however, no reaction occurred when the
protecting group was replaced with an acyl protecting group.
To evaluate the effect of ester groups for this aza-MBH reaction,
the methyl ester was replaced by ethyl ester (substrate 2n),
phenyl ester (substrate 2o), 2-naphthyl ester (substrate 2p) and
benzyl ester (substrate 2q). The corresponding products 3an-
3aq were produced in good to excellent yields ranging from
48% to 92%. The relatively low yield of product 3ap containing
a naphthyl ester moiety was probably due to ambient moisture
leading to the hydrolysis of substrate.
Furthermore, different kinds of electron-deficient olefins 1
were subsequently examined. Ethyl vinyl ketone (substrate 1c,
EVK) exhibited good reactivity, giving the desired product 3ca
in 82% yield. When phenyl vinyl ketone (substrate 1b, PVK) was
tested, the yield of corresponding product was greatly reduced.
This was mainly owing to the self-polymerization of PVK.
Compared with PVK, phenyl acrylate (substrate 1d) showed
lower reactivity in this case, but the yield was greatly increased
when one equivalent of PPh3 was used. The reaction could not
take place when methyl acrylate (substrate 1e) was used.
Non-terminal olefin substrates 2r and 2s showed com-
pletely different reactivities. Instead of aza-MBH reactions, a
Michael addition type reaction took place, giving the Michael
type products 4ar and 4as in almost equivalent yield, and no
reactions occurred in the absence of phosphine catalyst
(Scheme 2).
energies of imine and enamine tautomers of substrates 2a, 2r
and 2s were thus calculated at the SMD(DCM)/B3LYP/6-311+
+G(3df,2pd)//B3LYP/6-31G(d) level of theory, and the results
are shown in Scheme 3. The free energy difference in DCM
between the enamine and the imine tautomer of 2a amounts
to À 8.9 kJ/mol, indicating that the enamine tautomer of 2a is
more stable at ambient temperature. However, this stability
difference is small enough for the imine tautomer to still form
sufficiently under our standard reaction conditions to undergo
the aza-MBH reaction. As for non-terminal olefin substrates 2r
and 2s, the free energy differences in DCM between the
enamine and imine tautomers are À 25.9 kJ/mol, À 17.2 kJ/mol
(E-isomer) and À 22.1 kJ/mol (Z-isomer), respectively. These
results indicate that the enamine tautomer forms of non-
terminal olefin substrates 2r and 2s are much more stable, thus
they are difficult to tautomerize to the imine form under our
standard reaction conditions, which may account for why they
could not undergo aza-MBH reactions.
Time-dependent NMR studies were carried out to explain
the reactivities of different Michael acceptors used in this
reaction, and the results were further correlated with the
calculated methyl anion affinity (MAA) values. In a recent
report[15] it was shown that calculated MAA values can serve as
indicators of the electrophilicities of Michael acceptors. The
reactions of 2-aminoacrylate 2a with Michael acceptors 1a, 1c
and 1d were investigated in the presence of 50 mol% PPh3 in
CDCl3, and the kinetic profiles are shown in Figure 2 (the kinetic
profiles were also investigated using 20 mol% PPh3, see SI). The
experimental results were basically consistent with the results
of quantum-chemical calculations, except for 1d (Figure 3). The
methyl acrylate (substrate 1e), having the lowest MAA value is
only weakly electrophilic; indeed, no aza-MBH reaction was
observed experimentally using 1e as substrate (see Table 2).
The kinetic curves of MVK (1a) and EVK (1c) also fit the
calculation results well. MVK (1a), having considerably higher
MAA and electrophilicity E than methyl acrylate (1e) now reacts
within minutes in the aza-MBH reaction. The slightly lower MAA
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The relative stabilities of imine and enamine tautomers of 2
may contribute to their reactivity differences. The relative
Scheme 3. Relative energies of imine and enamine tautomers of substrates
2a, 2r and 2s as calculated at the SMD(DCM)/B3LYP/6-311+ +G(3df,2pd)//
B3LYP/6-31G(d) level of theory.
Scheme 2. The reactions using non-terminal olefin substrates.
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of ethyl vinyl ketone (1c) than that of 1a is in accord with the
observed more sluggish reactions of 1c in the aza-MBH reaction
when compared to 1a (Figure 2). Several hours of reaction time
were needed at ambient temperature to achieve high yields
when starting from 1c. This observation also matches with
reported reactivity differences of methyl vinyl ketone (MVK, 1a)
and ethyl vinyl ketone (EVK, 1c) in Michael additions with
methoxide ions (in MeOH)[16] and glutathione (in water),[17]
which consistently show that MVK is about twice as electro-
philic as EVK in analogous reactions. However, phenyl acrylate
(substrate 1d), the most potent electrophile among the tested
Michael acceptors, gave relatively low yields. This may indicate
that for 1d the initial CÀ C σ-bond formation step is not rate-
determining for the overall process and the electrophilicity of
Michael acceptors ceases to serve as a useful indicator in this
situation.
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Conclusions
In summary, we have developed a novel tertiary phosphine-
catalyzed aza-MBH reaction of 2-aminoacrylates with MVK,
affording the corresponding α-AA derivatives under mild
conditions. A new type of in situ generated ketoimine is
introduced to the aza-MBH reaction for the first time and has
been powerfully proven to be the key intermediate of the
Figure 2. Time-dependent 1H-NMR spectroscopic monitoring of the aza-MBH
reaction.
reaction, which provides
a new way of thinking about
constructing biologically and pharmacologically important α-
AA derivatives. The kinetic profiles and the calculations of
methyl anion affinity (MAA) values reveal that the electro-
philicities of Michael acceptors effectively influence the overall
reaction rate. Further studies on the asymmetric catalytic
version of this reaction are currently underway in our
laboratory.
Experimental Section
General information: Melting points were determined on a digital
melting point apparatus and temperatures were uncorrected. 1H
NMR spectra were measured on a Bruker AC 400 (400 MHz)
spectrometer. Data were reported as follows: chemical shifts in
ppm referenced to the internal solvent signal (peak at 7.26 ppm in
the case of CDCl3), multiplicity (s=singlet, d=doublet, t=triplet,
q=quartet, dd=double-doublet, m=multiplet), coupling con-
stants (Hz), and assignment. 13C NMR spectra were measured on a
Bruker AC 400 (100 MHz) spectrometer with complete proton
decoupling. Chemical shifts were reported in ppm from the internal
solvent signal (peak at 77 ppm in the case of CDCl3). Infrared
spectra were recorded on a Perkin-Elmer PE-983 spectrometer with
absorption in cmÀ 1. Flash column chromatography was performed
using 300–400 mesh silica gel. For thin-layer chromatography (TLC),
silica gel plates (Huanghai GF254) were used. Mass spectra were
recorded by ESI, and HRMS was measured on a HP-5989 instrument.
The employed solvents were dried by standard methods when
necessary. Commercially obtained reagents were used without
further purification.
Figure 3. Methyl anion affinity (MAA) values for selected Michael acceptors
as calculated at the SMD(DCM)/B3LYP/6-311+ +G(3df,2pd)//B3LYP/6-31G(d)
level of theory.
General Procedure for the Preparation of 2: To a 100 ml round-
bottom flask equipped with a Dean-Stark trap was charged with p-
TsNH2 (1.71 g, 10 mmol), methyl pyruvate (9.19 g, 9 mmol), p-TsOH
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1.5 equiv), 2-aminoacrylates
2 (0.2 mmol, 1.0 equiv) and PPh3
(0.04 mmol, 0.2 equiv). Then, 2.0 mL DCM was added into the tube.
The reaction mixture was stirred at room temperature for 12 h. The
solvent was removed under reduced pressure and the residue was
purified by a flash column chromatography (SiO2) to give the
corresponding product 3.
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1.5 equiv), 2-aminoacrylates
2 (0.2 mmol, 1.0 equiv) and PPh3
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(0.04 mmol, 0.2 equiv). Then, 2.0 mL DCM was added into the tube.
The reaction mixture was stirred at room temperature for 12 h. The
solvent was removed under reduced pressure and the residue was
purified by a flash column chromatography (SiO2) to give the
corresponding product 4.
Acknowledgements
We are grateful for the financial support from the National Basic
Research Program of China [(973)-2015CB856603], the Strategic
Priority Research Program of the Chinese Academy of Sciences
(Grant No. XDB20000000) and sioczz201808, the National Natural
Science Foundation of China (21572052, 21421091, 21772226,
21772037 and 21861132014) and the Shenzhen Nobel Prize
Scientists Laboratory Project and the Fundamental Research Funds
for the Central Universities 222201717003.
Keywords: phosphine catalysis
· aza-MBH reaction · α,α-
disubstituted · α-amino acids · methyl anion affinity values
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Full Papers
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H.-Z. Gui, Dr. H. Jangra, B. Mao, T.-Y.
Wang, H. Yi, Q. Xu, Dr. Y. Wei*,
Prof. H. Zipse*, Prof. M. Shi*
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Construction of α,α-disubstituted
α-Amino Acid Derivatives via aza-
Morita-Baylis-Hillman Reactions of
2-Aminoacrylates with Activated
Olefins
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Alpha Amino Acids: A novel tertiary
phosphine catalyzed aza-MBH
reaction of 2-aminoacrylates with
MVK was disclosed, affording the cor-
responding α-AAs derivatives under
mild conditions.