Reductive Coupling of CO2, Primary Amine, and Aldehyde at Room Temperature: A Versatile Approach to Unsymmetrically N,N-Disubstituted Formamides

Article abstract of DOI:10.1002/chem.201701420

We present a simple, metal-free, and versatile route to synthesize unsymmetrically N,N-disubstituted formamides (NNFAs) from CO₂, primary amine, and aldehyde promoted by an ionic liquid (1-butyl-3-methylimidazolium chloride) at room temperature. This approach features wide scopes of amines and aldehydes, and various unsymmetrical NNFAs could be obtained in good to excellent yields. The ionic liquid can be reused for at least five runs without obvious activity loss.

Full text of DOI:10.1002/chem.201701420

A Journal of
Accepted Article
Title: Reductive Coupling of CO2, Primary Amine and Aldehyde at
Room Temperature: A Versatile Approach to Unsymmetrically
N,N-Disubstituted Formamides
Authors: Zhimin Liu, Zhengang Ke, Leiduan Hao, Xiang Gao, Hongye
Zhang, Yanfei Zhao, Bo Yu, Zhenzhen Yang, and Yu Chen
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To be cited as: Chem. Eur. J. 10.1002/chem.201701420
Link to VoR: http://dx.doi.org/10.1002/chem.201701420
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10.1002/chem.201701420
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Reductive Coupling of CO2, Primary Amine and Aldehyde at
Room Temperature: A Versatile Approach to Unsymmetrically
N,N-Disubstituted Formamides
Zhengang Ke,[a,b] Leiduan Hao,[a] Xiang Gao,[a,b] Hongye Zhang, [a] Yanfei Zhao, [a] Bo Yu, [a] Zhenzhen
Yang, [a] Yu Chen, [a,b] and Zhimin Liu[a,b]*
Abstract: Herein we present a simple, metal-free and versatile route
to synthesize unsymmetrically N,N-disubstituted formamides
(NNFAs) from CO2, primary amine and aldehyde promoted by ionic
liquid (1-butyl-3-methylimidazolium chloride) at room temperature.
This approach features wide scopes of amines and aldehydes, and
various unsymmetrical NNFAs could be obtained in good to
excellent yields. The ionic liquid can be reused at least five runs
without obvious activity loss.
([BMIm]Cl), at ambient temperature (Scheme 1). This approach
was tolerable to wide scopes of alkyl/aryl amines and alkyl/aryl
aldehydes, and various unsymmetrical NNFAs could be
produced in good to excellent yields via changing amines and
aldehydes. More importantly, some unsymmetrical NNFAs with
reductive substitutes could be obtained without the
hydrogenation of the unsaturated bonds. The reaction
mechanism exploration indicated that the direct coupling of
amines and aldehydes formed imines in situ, which was further
reductively N-formylated with CO2 in the presence of PhSiH3
catalyzed by the IL. This protocol was scalable, and the IL could
be recycled five times without loss in activity. This solvent- and
metal-free protocol may have promising applications in the
commercial production of unsymmetrical NNFAs.
Unsymmetrically N,N-disubstituted formamides (NNFAs) are a
kind of N-formamides with wide applications in organic and
pharmaceutical synthesis, however, their synthesis is still
challenging. To date many methods have been developed for
synthesis of N-formamides, mainly based on the reactions of
halohydrocarbons with formamides,[1] or on the reactions of
imines/unsymmetrical secondary amines with formyl sources
including formic acid,[2] formaldehyde,[3] methanol[4] and
CO2/hydrogen[5]. Some of these methods could be applied in the
synthesis of limited unsymmetrical NNFAs. Therefore, exploring
simple, clean and versatile route to synthesis of unsymmetrical
NNFAs with various N-substituents is highly desirable.
Scheme 1. One-step synthesis of unsymmetrical NNFAs through three-
component coupling of primary amine, aldehyde and CO2.
The preliminary three-component coupling reaction was
performed using aniline, benzaldehyde and CO2 to explore the
suitable reaction conditions. Various imidazolium-based ILs
were first examined for catalysing this reaction because they
were proved to be effective for catalysing N-formylation of
amines with CO2 previously.[9] As listed in Table 1, most of the
tested ILs were effective for the reaction, among which [BMIm]Cl
exhibited the best performance, affording a product yield of 84%
within 12 h at room temperature (Table 1, entry 1). The ILs with
the same cation as [BMIm]Cl and different anions displayed the
activity in order: [BMIm]Cl>[BMIm]NO3>[BMIm]Br, while
[BMIm][BF4] and [BMIm][PF6] were ineffective for the reaction
(Table 1, entries 1-5). 1-hexyl-3-methy-limidazoliumchloride
([HMIm]Cl) showed similar activity to [BMIm]Cl, with a product
yield of 80% (Table 1, entries 1 and 6), suggesting that the alkyl
substitute in the imidazolium ring had a little influence on the
activity of the ILs with the Cl- anion, while the substitution with
acidic group (e.g., -BSO3H) significantly impacted the activity of
the IL (Table 1, entry 7). These results suggested that the
cooperative effect from the cation and anion of the ILs was
responsible for the activity of the ILs. The reaction could proceed
with [BMIm]Cl even at atmospheric pressure, affording a product
yield of 5%. Increasing the CO2 pressure to 10 atm significantly
improved the product yield to 84% (Table 1, entries 1,7,8). We
investigated the influence of the amount of the used IL on the
reaction. It was found that equimolar [BMIm]Cl was required for
getting a satisfied product yield (Table 1, entries 1 and 10-12). In
the case of small amount of IL (e.g., 0.2 equiv., entry 13) no
product was detectable, implying that enough amount of the IL
was indispensible. Examination of various silanes demonstrated
that only PhSiH3 was effective for this reaction under the
experimental conditions (Table 1, entries 14-19). In addition, the
amount of the used PhSiH3 also influenced the reaction activity.
Carbon dioxide (CO2) is an abundant, easily available,
nontoxic and renewable C1 building block, thus catalytic N-
formylation of amines with CO2 provides clean route to the
synthesis of N-formamides, which has been paid much attention
in recent years.[6] Due to the thermodynamic stability and kinetic
inertness of CO2, many efforts have been dedicated to the
transformation of CO2 under mild conditions.[7] Since the first
report of N-formylation of amine and CO2 with silanes as
reducing reagents[5f]
, many catalyst systems, such as N-
heterocyclic carbenes, carboxylates, metal complex, ionic liquids
and frustrated Lewis pairs, using silanes as reducing reagents
have been reported for the reductive N-formylation of amines
with CO2 under mild conditions.[6b,6c,8,9] However, the CO2-
involved direct synthesis of unsymmetrical NNFAs has not been
reported yet in a literature survey.
Herein, we present a simple, metal-free and versatile route to
synthesize unsymmetrical NNFAs via the direct three-
component reductive coupling of CO2, primary amine and
aldehyde using phenylsilane (PhSiH3) as a reducing reagent
promoted by the IL, 1-butyl-3-methylimidazolium chloride
[a]
Z. Ke, Dr. L. Hao, X. Gao, Dr. H. Zhang, Dr. Y. Zhao, Dr. B. Yu, Dr.
Z. Yang, Y. Chen, and Prof. Z. Liu
Beijing National Laboratory for Molecular Sciences, Key Laboratory
of Colloid, Interface and Thermodynamics, CAS
Research/Education Center for Excellence in Molecular Sciences,
Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China.
[b]
Z. Ke, X. Gao, Y. Chen, and Prof. Z. Liu
University of Chinese Academy of Sciences
Beijing 100049, China.
Supporting information for this article is given via a link at the end of
the document.
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The above results indicated that the protocol was highly efficient
for the synthesis of N-aryl-N-benzyl disubstituted formamides.
Table 1. Reaction conditions optimization [a]
.
Entr
y
PCO2
/atm
Solvent/mL
Yield[b]
%
/
Catalyst/mmol
silane/mmol
PhSiH3/2
Table 2. Synthesis of the unsymmetrical N-aryl-N-CH2-aryl-formamides.[a]
-
84
1
[BMIm]Cl/1
10
(80[c]
63
51
1
)
2
3
4
5
6
[BMIm]NO3/1
[BMIm]Br/1
[BMIm]BF4/1
[BMIm]PF6/1
[HMIm]Cl/1
[BSO3HMIm]Cl
/1
10
10
10
10
10
-
-
-
-
-
-
PhSiH3/2
PhSiH3/2
PhSiH3/2
PhSiH3/2
PhSiH3/2
0
80
7
10
PhSiH3/2
0
8
9
[BMIm]Cl/1
[BMIm]Cl/1
[BMIm]Cl/0.8
[BMIm]Cl/0.6
[BMIm]Cl/0.4
[BMIm]Cl/0.2
[BMIm]Cl/1
[BMIm]Cl/1
[BMIm]Cl/1
1
-
-
-
-
-
-
-
-
-
-
PhSiH3/2
PhSiH3/2
PhSiH3/2
PhSiH3/2
PhSiH3/2
PhSiH3/2
Ph2SiH2/3
Et2SiH2/3
Et3SiH/6
CH3(EtO)2SiH
/6
5
20
10
10
10
10
10
10
10
85
76
68
29
0
0
0
0
10
11
12
13
14
15
16
17
[BMIm]Cl/1
10
0
18
19
20
21
22
23
24
25
[BMIm]Cl/1
[BMIm]Cl/1
[BMIm]Cl/1
[BMIm]Cl/1
[BMIm]Cl/1
[BMIm]Cl/1
[BMIm]Cl/1
[BMIm]Cl/1
10
10
10
10
10
10
10
10
-
-
(CH3)2ClSiH/6
Et3SiH/6
PhSiH3/2
PhSiH3/2
PhSiH3/2
PhSiH3/2
PhSiH3/2
PhSiH3/2
0
0
6
0
38
29
30
17
n-hexane
acetone
DMSO
DMF
THF
1,4-dioxane
Reaction conditions: [a] aniline (1.0 mmol), benzaldehyde (1.0 mmol), CO2 (10
atm), [BMIm]Cl (1.0 mmol), room temperature, 12 h. [b] The yield was
determined by GC-FID, calibrated using n-dodecane as the internal standard.
[c] Isolated yield.
The effect of solvents was investigated, and the results are
listed in Table 1, entries 20-25. In sharp contrast, the solvents
significantly influenced the product yields. Especially, using
acetone as the solvent, the reductive formylation did not occur.
In this work, the reaction was performed under the solvent-free
conditions in most cases, thus the solvent effect was avoided.
Based on the above results, the optimized reaction conditions
were obtained as follows: 2 equiv. of PhSiH3, 1 equiv. of
[BMIm]Cl together with 10 atm of CO2 pressure, 30 oC.
Reaction conditions: [a] amine (1.0 mmol), aldehyde (1.0 mmol), PhSiH3 (2.0
mmol), CO2 (10 atm), [BMIm]Cl (1.0 mmol), room temperature, 12 h. Yields of
the isolated products. [b] The yield was determined by 1H NMR, calibrated
using 1,1,2,2,-tetrachloroethane as the internal standard.
Encouraged by the above results, we extended the scopes of
the amines and aldehydes to aliphatic ones. Interestingly, all the
three-component coupling reactions of CO2 with alkyl
amines/aryl aldehydes, or aryl amines/alkyl aldehyde, or alkyl
amine/alkyl aldehydes, took place successfully, affording the
corresponding products in the yields of 70%–92% (18c-29c). For
example, in the cases of n-hexylamine, n-pentylamine and
cyclohexanecarboxaldehyde, the yields of corresponding
products (28c and 29c) reached to 91% and 90%, respectively.
Notably, compared to the aryl amines or aryl aldehydes, the
aliphatic amines and aldehydes displayed relatively low
reactivity, probably because aliphatic imines are relatively
difficult to form and/or the electrophilic ability of aliphatic
aldehydes are relatively weak relative to the aromatic aldehydes.
Thus prolonged reaction time (e.g., 24h) was required for
reaching high isolated yields of the products. The amines and
aldehydes with reducible functional groups (e.g., -CN, -C=C-)
were also examined. It was indicated that the reaction system
was tolerable to the unsaturated chemical bonds, and the
unsymmetrical NNFAs with reducible groups could be obtained
in good yields (30c-36c). In addition, the reaction of 4-
nitrobenzaldehyde, aniline and CO2 was also performed, and no
target product was obtained. It was found that –NO2 was
Under the optimized conditions, the generality of the three-
component coupling of primary amine, aldehyde and CO2 was
investigated. To get N-aryl-N-benzylformamides, aryl amines
and aryl aldehydes were used as the substituent resources, and
the coupling reaction was investigated under the optimized
conditions (Table 2). To our delight, all the coupling reactions
proceeded well, yielding the corresponding unsymmetrical
NNFAs in good to excellent yields in most cases. For example,
the coupling of CO2 with aniline and benzaldehyde possessing
electron-withdrawing groups (e.g., Cl, F) afforded improved
product yields due to the substitution in the benzene rings of the
aldehydes (Table 2, 1c-3c). Similar results were observed in the
synthesis of 4c-6c and 7c-9c, and the isolated yields of 9c and
10c reached up to 92%. For the coupling of CO2 with
benzaldehyde and anilines, no matter what the substituents in
benzene ring of anilines were electron-donoring or –withdrawing
all the target products were obtained in enhanced yields (1c, 4c,
7c, 10c and 13c). Also, the coupling of CO2 with 4-
fluorobenzaldehyde and anilines possessing electron-donoring
groups gave rise to the products in very high yields. Notably,
considerable yields of the products (e.g., 14c and 15c) were
obtained when both anilines and benzaldehyde possessing
electron-withdrawing groups in benzene rings were adopted.
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Table 3. Synthesis of the unsymmetrical NNFAs with alkyl-substitution and/or
unsaturated chemical bonds.[a]
80
60
40
20
0
1
2
3
4
5
Catalyst recycle number
Figure 1. Recycling of [BMIm]Cl for the coupling of 4-methylaniline,
benzaldehyde and CO2. Reaction conditions: 4-methylaniline (1.0 mmol), 4-
fluorobenzaldehyde (1.0 mmol), PhSiH3 (2.0 mmol), CO2 (10 atm), [BMIm]Cl
(1.0 mmol), room temperature, 12 h.
As expected, the reaction of aniline and benzaldehyde
occurred
benzylideneaniline in
rapidly
at
a
room
temperature,
forming
yield of 99%. Thereafter, using
benzylideneaniline as the starting material, the experiments as
illustrated in Scheme 2 were carried out. The reaction of
benzylideneaniline with CO2 and PhSiH3 proceeded very well in
the presence of [BMIm]Cl, and the target product was obtained
in a similar yield to that of 1c in Table 2 (Scheme 2a). Moreover,
in this work it was demonstrated that benzylideneaniline could
not be hydrogenated by PhSiH3 to N-benzylaniline (Scheme 2b).
The above results suggest that the formation of the
unsymmetrical NNFA was realized via the formylation of the in-
situ generated imine with CO2/PhSiH3, rather than the N-
formylation of secondary amine that could not be obtained under
the experimental conditions. To explore the reaction mechanism
of reductive N-formylation of benzylideneaniline with CO2 and
PhSiH3, the reaction of PhSiH3 (2 mmol) and CO2 was carried
out at room temperature, and the reaction solution was detected
by 1H NMR to determine the amounts of the formed
formoxysilane and the residual PhSiH3. Subsequently, to the
reaction solution desired amount of benzylideneaniline was
added, and after 12h the reaction solution was examined again
by 1H NMR. As a result, N-benzyl-N-phenyl formamide was
detected in a high yield (Figures S3), meanwhile it was found
that PhSiH3 involved the formation of benzylideneaniline
(Scheme 2c). However, removing the IL through extraction with
diethyl ether before the addition of benzylideneaniline into the
solution, no N-benzyl-N-phenyl formamide was detected
(Scheme 2d). This suggests that the IL catalyzed the reductive
N-formylation of benzylideneaniline with formoxysilane and
PhSiH3.
Reaction conditions: [a] amine (1.0 mmol), aldehyde (1.0 mmol), PhSiH3 (2.0
mmol), CO2 (10 atm), [BMIm]Cl (1.0 mmol), room temperature, 24 h. Yields of
the isolated products. [b] The yield was determined by 1H NMR, calibrated
using 1,1,2,2,-tetrachloroethane as the internal standard.
reduced to –NH2 under the experimental conditions, resulting in
the complicated products including N-phenylformamide, (E)-4-
((phenylimino)methyl)aniline, N-(4-nitrobenzyl)aniline and N-(4-
aminobenzyl)-N-phenylformamide.
The reusability of the IL was investigated, and it was indicated
that the IL was reusable without obvious activity loss even
reused for five times (Figure 1). In addition, the scalability of the
protocol was examined by performing the reaction on the gram
scale. Using 1.07 g of 4-methylaniline and corresponding
amount of 4-fluorobenzaldehyde as starting materials, 2.14 g of
N-(4-fluorobenzyl)-N-(p-tolyl)-formamide was obtained after 24 h,
affording a satisfactory product yield of 88%. This indicated that
the above protocol was practical and scalable, which may have
promising application for the synthesis of the unsymmetrical
NNFAs.
From the above experiments, it was indicated that the IL,
[BMIm]Cl, play an important role in the reductive N-formylation
of imine with CO2/PhSiH3. As reported, the IL [BMIm]Cl has
strong ability to form hydrogen-bond, and a hydrogen-bond
network exists among the IL molecules.[11]
To reveal the mechanism of the N-formylation reaction, using
aniline and benzaldehyde as the model substrates control
experiments were performed. As known, amine could easily
react with aldehyde to form imine.[10]
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Scheme 2. Control experiments of benzylideneaniline with CO2 and/or PhSiH3
as well as the intermediate. Reaction conditions: [a] benzylideneaniline (1.0
mmol), PhSiH3 (2.0 mmol), CO2 (10 atm), [BMIm]Cl (1.0 mmol), 30 oC, 12 h. [b]
benzylideneaniline (1.0 mmol), PhSiH3 (2.0 mmol), [BMIm]Cl (1.0 mmol), 30
oC, 12 h.
Scheme 3. Plausible reaction mechanism of the unsymmetrical N-formylation
reaction.
formoxysilane, which further reacts with the IL-activated imine
accompanied with the reduction of the -C=N- bond, resulting in
the final product.
The mixing of PhSiH3 or benzylideneaniline with the IL may
destroy the original hydrogen-bond network of the IL and form a
new one, which thus activates the Si-H of PhSiH3 or the –N=CH-
of benzylideneaniline, facilitating them to convert further. To
verify the role of [BMIm]Cl in the reaction, the interaction
between the IL and PhSiH3 and that between the IL and
benzylideneaniline were examined by 1H NMR, 13C NMR, 1H-15N
HMBC, 35Cl NMR and 29Si NMR spectroscopy. It was indicated
that the 1H, 13C, 15N and 35Cl NMR spectra of [BMIm]Cl changed
as the IL mixed with phenylsilane or with benzylideneaniline,
respectively (Figures S4, S5, S12). Especially, these changes
became larger as the IL amount increased, suggesting that the
In summary, a new, simple, metal-free and versatile route was
presented for the synthesis of unsymmetrical NNFAs via a three-
component reductive coupling of primary amine, aldehyde and
CO2 using phenylsilane promoted by [BMIm]Cl at room
temperature. This approach allows wide substrate scope and
excellent functional-group tolerance, producing various
unsymmetrical NNFAs in good to excellent yields. It opens a
new way to synthesis of unsymmetrical NNFAs, may have
promising applications.
Experimental Section
interaction
between
the
IL
and
phenylsilane
or
benzylideneaniline enhanced with the increase in the amount of
the IL. This may explain the influence of the IL amount on the
All the formylation reactions were performed in a 16 mL high-pressure
reactor with a Teflon inner container in batch operation mode. Typically,
amine (1.0 mmol), aldehyde (1.0 mmol), [BMIm]Cl (1.0 mmol) and
PhSiH3 (2.0 mmol) were loaded into the reactor. After being sealed and
flushed with CO2 three times, the reactor was charged with CO2 up to 1.0
MPa at room temperature. Subsequently, the reactor was moved into a
water-bath of 30 oC and magnetically stirred for 12 h with a speed of 500
rpm. After reaction, excess CO2 was vented, and the reaction mixture
was extracted with 15 mL of diethyl ether for quantitative analysis by GC-
FID. Then, the crude reaction mixture was concentrated by a rotary
evaporator and purified by column chromatography using petroleum
ether/EtOAc (100:1~5:1) to get the pure product. The corresponding
formamide was identified by 1H and 13C NMR spectra.
1
reaction. In the H, and 29Si NMR spectra of the [BMIm]Cl and
1
PhSiH3 mixture, the H signal assigning to the Si-H shifted from
4.175 to 4.147 ppm as the IL amount increased to 1.0 equiv.
(Figure S6), and the 29Si signal assigning to the Si-H shifted
downfield from -67.572 to -66.761 ppm (Figure S7), suggesting
that the Si-H of PhSiH3 was activated by the IL to some extent.
The 1H-15N spectra of the mixture gave more information
(Figures S8,9). Obviously, the H atom of Si-H in PhSiH3 was
more electron-rich due to the interaction with the IL, which may
facilitate the insertion of the electron-deficient CO2 into the Si-H
to form formoxysilane intermediate. The NMR analysis on the
mixture of the IL and benzylideneaniline (Figures S10-14)
indicated that the electron cloud density of N atom in –N=CH-
increased, and that of H atom decreased owing to the interaction
with the IL, which may facilitate the C atom in –N=CH- to accept
H from the activated PhSiH3 in the reductive N-formylation of
imines.
.Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21533011, 21403252,
21503239, 21125314) and the Chinese Academy of Sciences
(QYZDY-SSW-SLH013).
Based on the above results, a plausible reaction pathway was
proposed as illustrated in Scheme 3. First, amine reacts with
aldehyde to form imine rapidly, meanwhile [BMIm]Cl activates
phenylsilane and the newly formed imine. Subsequently, CO2
inserts into the activated Si−H bond of PhSiH3 to form the
Conflict of interest
The authors declare no conflict of interest.
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Keywords: reductive coupling • primary amine • aldehyde •
Carbon dioxide • unsymmetrically N,N-disubstituted formamides
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10.1002/chem.201701420
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Zhengang Ke, Leiduan Hao, Xiang Gao,
Hongye Zhang, Yanfei Zhao, Bo Yu,
Zhenzhen Yang, Yu Chen, and Zhimin
Liu*
Page No. – Page No.
Reductive Coupling of CO2, Primary
Amine and Aldehyde: A Versatile
Approach to Unsymmetrically N,N-
Disubstituted Formamides
A simple and versatile route is presented for the synthesis of unsymmetrically N,N-
disubstituted formamides (NNFAs) via a three-component reductive coupling of
CO2, amine and aldehyde under mild conditions, which could afford various
unsymmetric NNFAs in good to excellent yields.
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