Access to α-Arylglycines by Umpolung Carboxylation of Aromatic Imines with Carbon Dioxide

Article abstract of DOI:10.1002/chem.201604623

A straightforward and transition-metal-free approach for the efficient synthesis of α-arylglycine derivatives from aromatic imines and carbon dioxide was enabled by an umpolung carboxylation reaction. Various substituted diphenylmethimines underwent the carboxylation smoothly with carbon dioxide in the presence of potassium tert-butoxide and 18-crown-6 to give the corresponding carboxylated products in good to high yields. Besides the enhancement of the solubility of potassium tert-butoxide in THF, 18-crown-6 also plays key roles in suppressing the reverse protonation or 1, 3-proton shift isomerization as well as by stabilizing the carboxylated intermediate.

Full text of DOI:10.1002/chem.201604623

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Title: Access to α-Arylglycines via Umpolung Carboxylation of Aromatic Imines with
Carbon Dioxide
Authors: Chun-Xiao Guo; Wen-Zhen Zhang; Hui Zhou; Ning Zhang; Xiao-Bing Lu
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To be cited as: Chem. Eur. J. 10.1002/chem.201604623
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Access to α-Arylglycines via Umpolung Carboxylation of
Aromatic Imines with Carbon Dioxide
Chun-Xiao Guo, Wen-Zhen Zhang*, Hui Zhou, Ning Zhang and Xiao-Bing Lu
Abstract: A straightforward and transition-metal-free approach for
the efficient synthesis of α-arylglycine derivatives from aromatic
imines and carbon dioxide was enabled by umpolung carboxylation
reaction. Various substituted diphenylmethimines underwent the
carboxylation smoothly with carbon dioxide in the presence of
potassium tert-butoxide and 18-crown-6 to give the corresponding
carboxylated products in good to high yields. Besides the
enhancement of solubility of potassium tert-butoxide in THF, 18-
crown-6 also plays key roles in suppressing reverse protonation or 1,
3-proton shift isomerization as well as stabilizing the carboxylated
intermediate.
c). Although the 2-azaallyl anion intermediate II has been used
as a nucleophile in various reactions,[9] to the best of our
knowledge, the direct umpolung carboxylation of imine has not
yet been described. The key to this conversion is to find a
suitable base and reaction system to accelerate the
carboxylation of the 2-azaallyl anion intermediate II, suppress
the reverse protonation, and simultaneously stabilize the formed
carboxylate III. Herein, we report
a transition-metal-free,
KOtBu/18-crown-6 mediated synthesis of α-arylglycine
derivatives from aromatic imines and carbon dioxide via
umpolung carboxylation reaction.[10]
As a class of non-proteinogenic α-amino acids, α-arylglycine is a
key structural unit presented in a vast array of important
biologically active compounds including many glycopeptide and
β-lactam antibiotics.[1] α-Arylglycines have also found various
applications in the synthesis of some fine chemicals as
privileged building blocks.[2] For the access to α-amino acids,
enzymatic transamination of α-keto acids catalyzed by vitamin
B6-dependent aminotransferase is one of the most important
ways in biological systems (Scheme 1, a).[3] Artificial method
including modification of substrates bearing pre-installed
carboxyl group has been mainly developed in the past
decades.[4] However, the synthetic strategy via introduction of
carboxyl group is less studied and relied heavily on the Strecker
reaction using imines and highly toxic cyanide compounds. The
development of an efficient and environmentally benign method
to prepare α-amino acids from easily available substrates is
highly desirable.
Synthesis of α-amino acids using carbon dioxide (CO2) as a
carboxyl source represents a highly attractive route since CO2 is
an abundant, non-toxic and renewable C1 feedstock.[5]
Organolithium mediated direct α-carboxylation of amines using
CO2 under harsh reaction conditions was previously
documented.[6] Recently, Sato and co-workers reported the
synthesis of α-arylglycine from CO2 under mild reaction
conditions via carboxylation of a series of α-amino stannanes or
silanes,[7] which were in-situ formed by the reaction of imines or
α-amino sulfone with metal reagents (Scheme 1, b). Inspired by
recent umpolung conversion of imines,[8] we envisioned that α-
Scheme 1. Biological and artificial synthesis of α-amino acids.
Initial investigations were conducted by subjecting N-
diphenylmethanimine (1a), which was readily prepared by
reaction of benzaldehyde with diphenylmethamine, to
amino
acid
might
be
directly
constructed
from
diphenylmethimine using CO2 as a carboxyl source (Scheme 1,
o
stoichiometric amounts of various bases in THF at 25 C under
CO2 atmosphere (Table 1). An organic base 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) only gave 13% yield of 1,
3-proton shift by-product ketimine 3a (entry 1). 14% yield of
desired carboxylative product 2a was obtained when NaHMDS
was used as a base (entry 2). Replacement of NaHMDS by
stronger base KHMDS provided an improved conversion and
selectivity of 2a (entry 3). KOtBu gave moderate conversion but
relatively low carboxylative selectivity (entry 5). To enhance the
solubility of base in THF, crown ethers were then introduced into
[a]
C.-X. Guo, Dr. W.-Z. Zhang, Dr. H. Zhou, N. Zhang and Prof. Dr. X.-
B. Lu
State Key Laboratory of Fine Chemicals
Dalian University of Technology
Dalian 116024 (China)
E-mail: zhangwz@dlut.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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the reaction system.[11] We delightedly found that the
combination of KOtBu and 18-crown-6 led to striking increases in
both conversion and selectivity, 2a was isolated in 93% yield
(entry 6). Among the tested solvents (see Supporting
Information), THF was revealed as an optimized solvent.
Furthermore, reaction temperature and CO2 pressure had a
profound effect on the product selectivity. An increase of
temperature to 80 °C caused the major formation of
isomerization product 3a (entry 9). When the reaction was
conducted at lower CO2 pressure, decreased yield and
selectivity of 2a were observed. This indicates that the
carboxylation is more predominant than 1, 3-proton shift under
high CO2 pressure (entries 10 and 11). Decreasing the loading
of 18-crown-6 from 1.2 to 0.4 equivalent resulted in an obvious
negative effect on yield and selectivity of 2a (entry 12). It’s
noteworthy that the carboxylative reaction using KOtBu/18-
crown-6 could be completed within 1 h, providing 93% isolated
yield of 2a (entry 13).
then investigated (Table 2). Aromatic aldimines bearing a wide
range of functional groups including electron-donating methyl,
methoxy, dimethylamino and electron-withdrawing fluoro, chloro,
bromo substituents all reacted smoothly to afford the
corresponding α-arylglycine derivatives (2b to 2l, 2s) in
moderate to good yields. Both α-, β-naphthyl substituted
substrates participated in the carboxylative reaction quite
efficiently to provide the corresponding products 2m and 2n in
good yields. Furan- and thiophene-containing aldimines (1o to
1r) are also suitable substrates for this reaction.
Table 2. Scope for the carboxylation of aldimines.
Table 1. Development of the reaction conditions.[a]
Yield [%][b]
Entry
Base
Additive
2a
<1
3a
13
3
1
DBU
-
2
NaHMDS
KHMDS
NaOtBu
KOtBu
KOtBu
LiOtBu
NaOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
-
14
3
-
44
3
4
-
<1
17
33
3
5
-
28
6
18-crown-6
12-crown-4
15-crown-5
18-crown-6
18-crown-6
18-crown-6
18-crown-6
18-crown-6
95(93)
<1
[a] Reaction condition: 1 (0.2 mmol), KOtBu (1.2 equiv.), 18-crown-6 (1.2
equiv.) 2.0 MPa of CO2, 2 mL THF, 25 oC, 1 h. Followed by treatment with 2.0
equivalent of TMSCHN2 in MeOH/Et2O. [b] Isolated yields.
7
<1
35
79
7
8
11
9[c]
10[d]
11[e]
12[f]
13[g]
6
90
71
16
23
4
51
93(93)
[a] Reaction condition: 1a (0.2 mmol), base (1.2 equiv.), additive (1.2 equiv.)
2.0 MPa of CO2, 2 mL THF, 25 oC, 18 h. Followed by treatment with 2.0
equivalent of TMSCHN2 in MeOH/Et2O. [b] Yields were determined by NMR
using 1,1,2,2-tetrachloroethane as an internal standard. Data given in
parentheses are isolated yields. [c] 80 oC. [d] 0.5 MPa of CO2. [e] 1 atm of
CO2. [f] 0.4 equivalent of 18-crown-6 was used. [g] carboxylation reaction
time: 1 h.
Scheme 2. KOtBu/18-crown-6 mediated carboxylation of ketimines with CO2.
Since the aldimine (2) and ketimine (3) precursors could
generate the same 2-azaallyl anion intermediate via
Under the optimized reaction conditions, the scope of the
umpolung carboxylation with respect to aldimine substrates was
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COMMUNICATION
deprotonation, ketimines (3) were then used as substrates under
the above optimized reaction condition. As shown in Scheme 2,
ketimines bearing electron-donating methoxy (3g), and electron-
withdrawing fluoro (3h) all conducted carboxylation smoothly to
afford the corresponding α-arylglycine derivatives in good yields.
Although the preparation of ketimines is more time-consuming
and their starting materials are relatively limited, direct
carboxylation of ketimines provided an efficient method to
intermediate A or B respectively (Figure 1).[12] In situ Fourier
transform infrared spectroscopy (see Figure S1 in Supporting
Information) showed that when KOtBu was added to THF
solution of 1a and 18-crown-6, absorbance peak at 1641 cm-1
disappeared and absorption at 1580 cm-1 which could be
assigned to intermediate B was observed immediately. When
CO2 was bubbled into the reaction system, the C=N absorption
of intermediate
D
(1655 cm-1) gradually increased with
synthesize α-arylglycines under mild conditions via
a
consecutive decrease of absorbance of intermediate B.
benzophenone-mediated α-carboxylation of benzyl amines
(Scheme 2).
1H NMR studies revealed that chemical shift of Ha in
intermediate A (10.83 ppm) is much higher than that in
intermediate B (5.18 ppm) (see Figure S3 in Supporting
Information), which suggested that intermediate A might be
more liable to conduct protonation intramolecularly back to form
aldimine or ketimine. This implied that the introduction of 18-
crown-6 to this reaction system could effectively inhibit the
reverse protonation of 2-azaallyl intermediate or 1, 3-proton shift
isomerization.
DFT studies showed that when carboxylated intermediate C
and D underwent the reverse decarboxylation, the intermediate
D with 18-crown-6 had a much higher energy barrier (15.5
kcal/mol) than intermediate C without 18-crown-6 (6.5 kcal/mol)
(see Supporting Information). This demonstrated another effect
of 18-crown-6 which stabilizes the carboxylated intermediate
and inhibits its decarboxylation.
Scheme 3. Gram-scale reaction and hydrolysis of carboxylative product.
In conclusion, we have developed an efficient, transition-
metal-free method for the synthesis of α-arylglycine derivatives
from aromatic imines and carbon dioxide via umpolung
carboxylation reaction. The key to the success of this
transformation is the use of 18-crown-6 as a pivotal additive.
Besides enhancing the solubility of KOtBu in THF, 18-crown-6
also plays key roles in suppressing the reverse protonation of 2-
azaallyl intermediate or 1, 3-proton shift isomerization and
stabilizing the carboxylated intermediate. Further investigations
into the detailed mechanism and enantioselective version of this
reaction are in progress in our laboratory.
Gram-scale carboxylation of 1a was carried out under 1.0
MPa CO2 pressure and 73% yield of product was isolated. More
convenient manipulation using Schlenk tube under 0.1 MPa CO2
pressure gave 53% isolated yield of 2a (Scheme 3, 1). This
indicated the utility and efficiency of this new reaction in
preparative-scale organic synthesis. Moreover, hydrolysis of
carboxylative product 2a readily afforded methyl phenylglycine
hydrochloride (4a) in 93% yield (Scheme 3, 2).[9c]
Acknowledgements
Financial support from the National Natural Science Foundation
of China (21172026), the Fundamental Research Funds for the
Central Universities (DUT15LAB21), and the Program for
Changjiang Scholars and Innovative Research Team in
University (IRT13008) is gratefully acknowledged.
Keywords: carbon dioxide fixation • umpolung •carboxylation •
transition-metal-free •α-amino acids
Figure 1. Possible intermediates in the absence (A, C) and presence (B, D) of
18-crown-6.
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Entry for the Table of Contents
COMMUNICATION
Chun-Xiao Guo, Wen-Zhen Zhang*, Hui
Zhou, Ning Zhang and Xiao-Bing Lu
Page No. – Page No.
Access to α-Arylglycines via
Umpolung Carboxylation of Aromatic
Imines with Carbon Dioxide
A transition-metal free synthesis of α-arylglycine derivatives from aromatic imines
and carbon dioxide via KOtBu/18-crown-6 promoted umpolung carboxylation
reaction is described
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