Chromium-catalysed efficient: N -formylation of amines with a recyclable polyoxometalate-supported green catalyst

Article abstract of DOI:10.1039/d0dt03300f

A simple and efficient protocol for the formylation of amines with formic acid, catalyzed by a polyoxometalate-based chromium catalyst, is described. Notably, this method shows excellent activity and chemoselectivity for the formylation of primary amines; diamines have also been successfully employed. Importantly, the chromium catalyst is potentially non-toxic, environmentally benign and safer than the widely used high valence chromium catalysts such as CrO3 and K2Cr2O7. The catalyst can be recycled several times with a negligible impact on activity. Finally, a plausible mechanism is provided based on the observation of intermediate and control experiments.

Full text of DOI:10.1039/d0dt03300f

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PleasDeadltoonnoTtraandsjaucsttiomnsargins
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DOI: 10.1039/D0DT03300F
ARTICLE
Chromium-Catalysed Efficient N-formylation of Amines with a
Recyclable Polyoxometalate-supported Green Catalyst
Received 00th January 20xx,
Accepted 00th January 20xx
Demin Dan,†a Fubo Chen,†b Whenshu Zhao,†c Han Yu,*ad Sheng Han*a and Yongge Wei*de
DOI: 10.1039/x0xx00000x
A simple and efficient protocol for the formylation of amines with formic acid, catalyzed by a polyoxometalate-based
chromium catalyst, is described. Notably, this method shows excellent activity and chemoselectivity for the formylation of
primary amines; diamines have also been successfully employed. Importantly, the chromium catalyst is potentially non-
toxic, environmentally benign and safer than the widely used high valence chromium catalysts such as CrO3 and K2Cr2O7. The
catalyst can be recycled several times with a negligible impact on activity. Finally, a plausible mechanism is provided based
on the observation of intermediate and control experiments.
compounds, and allows for functional group tolerance too. Until
now, only a few examples of the N-formylation of primary and
secondary amines with formic acid and its derivatives to N-
Introduction
The formamide group is an important functional group in the
synthesis of pharmaceuticals and organic materials. 1-2 It is also a key
chemical raw material for the production of bioactive molecules
which possess high activity and reactivity in peptide synthesis. 3 The
most common preparations of formamide compounds utilize
formylating reagents, such as coupling reagents (e.g., DCC), 4 chloral,
5 carbon monoxide 6 and acetic anhydride, 7 to introduce the carbonyl
formamides, catalyzed by noble metal catalysts (e.g. Pd, 12 Pt, 13 Au,
14
15
Rh, etc.), have been reported. However, high costs and harsh
reactions
8
moiety to construct the formamide bond (Scheme 1). These
procedures often rely on materials that are not commercially
available and result in the generation of undesired waste products.
Therefore, the development of an efficient and atom-economic
method for the formation of formamide compounds is desirable.
Recently, tremendous progress has been made in the use of some
9-11
simple and readily available carbonyl-based starting materials,
9
10
11
such as ammonium formate, methanol, and carbon dioxide.
However, at present, these established methods all rely on utilizing
complicated/commercially unavailable organic ligands, and harsh
reaction conditions (such as high temperature and lengthy reaction
time) (Scheme 1a). A more attractive method involves the use of
formic acid as a coupling partner for formamide bond formation. This
has the advantage of being inexpensive, using readily available
a.School of Chemical and Environmental Engineering, Shanghai Institute of
Technology, Shanghai 201418, P.R. China.
b.Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University
School of Medicine, Shanghai 200072, China
c. Longhua Hospital Shanghai University of Traditional Chinese Medicine,
Shanghai200000, China
d.Key Lab of Organic Optoelectronics & Molecular Engineering of Ministry of Education,
Department of Chemistry, Tsinghua University, Beijing 100084, P.R. China
e. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing
100191, P.R. China
Scheme 1. Comparison between previous and present work for the
† Contributed equally to this work.
Electronic Supplementary Information (ESI) available: experimental conditions,
supplementary table and NMR spectra. See DOI: 10.1039/x0xx00000x
synthesis of formamides.
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Journal Name
conditions limit their industrial application, especially for the Cr(NO3)3·9H2O, or employing both together provided moderate
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DOI: 10.1039/D0DT03300F
synthesis of biologically active compounds due to the toxicity of the catalytic activity ( entry 2-4). Reducing the catalyst loading to 0.5
noble metal catalysts. In light of the prevalence of inefficient catalytic mol% resulted in a decrease in product yield. Increasing the catalyst
methods available for the synthesis of formamides, there is a loading to 1.5 mol% did not provide any substantial benefits to the
growing interest in the use of non-toxic and readily available reaction rate or efficiency (entry 5-6). (Full details are provided in the
catalysts.
Polyoxometalates (POMs), a large class of metal–oxide clusters
supplementary information and supplementary Table 1).
Finally, it was pleasing to see that the catalyst maintained its high
with oxidative redox and acidic properties, have received extensive activity over six reaction cycles. As confirmed by FT-IR spectroscopy,
attention in the field of organic synthesis. 16 As one of the types of the recovered catalyst still retains the structural characteristics of
POMs, the Anderson–Evans polyoxoanions exhibit good physical and Cat. 1 (Figures S1, S4-S5).
chemical properties and are highly versatile, but they depend
With the above optimized conditions in hand, we examined the
strongly on the heteroatom and few studies have been conducted direct formylation of various amine substrates with formic acid to
regarding the counter-cation. Furthermore, Anderson POMs can be determine the generality of the current procedure (Table 2).
easily grafted because they possess six hydroxyl groups which Benzylamine derivatives containing electron-rich aromatic amines
provide unique catalytic properties. 17
underwent formylation giving the desired products in good to
18
Spurred by our previous protocols employed in the Cr-POM- excellent isolated yields (3-7). Halogen-substituted aromatic amines,
catalyzed N-formylation of amines with methanol, herein, we report including F(8), Cl(9), Br(10), were also compatible with the catalyst,
that a Cr-catalyst [N(C4H9)4]3[CrMo6O18(OH)3C(OCH2)3CH3] (simplified indicating the catalyst system possesses good catalytic performance
as CrIIIMo6-CH3) can efficiently catalyze the direct coupling of various Table 2. N-formylation of amines using formic acidsa
primary and secondary amines with formic acid to afford the
corresponding formamides with high catalytic activity and selectivity;
the formylation of primary diamines has also been achieved (Scheme
1b). More importantly, the chromium catalyst is potentially non-
toxic, environmentally benign and safer compared with widely used
high valence chromium catalysts such as CrO3 and K2CrO7. The
catalyst can also be reused several times with the negligible loss of
activity.
Results and discussion
Our study was initiated by examining formamide formation
directly from benzylamine and formic acid in the presence of a
catalyst and additive. We surprisingly found that compound 1 and
Na2SO3 (0.05 equiv) were a suitable catalyst and additive for the
reaction, giving the desired product in the best yield at 80 °C after 4
h
reaction time (Table 1, entry 1). Interestingly, using
(NH4)6Mo7O24·4H2O,
Table 1: Optimization of reaction conditionsa
Entry
Cat.
Yield.(%)f
1
2
3
4
1
(NH4)6Mo7O24· 4H2O (1.0)
Cr(NO3)3·9H2O
(NH4)6Mo7O24· 4H2O+Cr(NO
3)3·9H2O
99
42
53
73
5b
6c
1 (0.5)
1 (1.5)
76
86
aReaction conditions: Cat. 1 (1.0 mol%), amine (1.0 mmol), formic
aReaction conditions: Cat. 1 (1.0 mol%), benzylamine (1.0 mmol),
acid (2.0 mmol), 1,4-dioxane (2.0 mL), Na2SO3 (0.05 eq.), stirring at
formic acid (2.0 mmol), Na2SO3 (0.05 eq.), 1,4-dioxane (2.0 mL),
b
80 oC for 4 h. Yields were determined by 1H-NMR, values in
o
b
c
stirring at 80 C for 4 h. Cat. 1 (0.5 mol%). Cat. 1 (1.5 mol%). d
Yields were determined by GC-MS analysis (internal standard is
toluene).
parentheses are the isolated yield.
and functional group tolerance. Additionally, primary amines
containing electron-rich heterocyclic and oxidizable functionalities
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such as thiophene, furan and pyridine groups gave their mL 1,4-dioxane. Analytically pure formamide was isVoielawteArdticilenO9n6lin%e
DOI: 10.1039/D0DT03300F
corresponding formamides in 96-99 % yields due to their ability to yield after 4 hours (Figure 1).
coordinate with the metal active sites (11-13). Other aromatic
amines incorporating sterically hindered groups (14-15) were also
amenable to the reaction conditions. In addition, aniline derivatives
(16) were also effective nucleophiles in the coupling reaction giving
the corresponding formamides in excellent yields. Similarly, the
scope of primary amines is not limited to benzylamines, with various
branched aliphatic amines also being tolerated; cyclohexylamine
(17), butylamine (18) and amylamine (19) afforded their
corresponding formamides in good yields (89 %-91 %), with slight
variation due to steric hindrance. We further examined the scope of
this reaction by employing various secondary amines. To our delight,
the corresponding formamide products, 1-formylpyrrolidine(20), N-
formylpiperidine(21), N-ethylformamide (22), were obtained.
Table 3. N-formylation of diamines with formic acid a,b
Figure 1: Gram-scale reaction.
To gain insight into the mechanism, some control experiments
involving the formylation of benzylamine with formic acid were
conducted. When only Na2SO3 was employed stoichiometrically,
none of the formamide product was detected after mixing with
formic acid, indicating that Na2SO3 is not an activating reagent
(Figure 1a(1)). On the contrary, the addition of CrIIIMo6-CH3 gave the
desired benzamide in 35 % yield (Figure 1a(2)), which indicates the
aReaction conditions: Cat.
1 (1.0 mol%), diamine (1.0 mmol),
formic acid (4.0 mmol), Na2SO3 (0.05 eq.) stirring at a
o
reaction tube at 80 C for 24 h. bYields were determined by
1H-NMR, values in parentheses are the isolated yield.
Finally, due to the high functional group tolerance and reactivity
of the present Cr-catalyzed N-formylation reaction of primary and
secondary amines, a series of primary diamine studies were also
carried out (Table 3). It is pleasing to note that the desired
dimethylene amide derivatives were obtained in good yields (23-24).
It is worth mentioning that commonly used chemical raw materials
and intermediates, TDI and MDI, generated their desired formamide
compounds 25 and 26 in 90 % and 92 % yields, respectively.
Surprisingly, sulfur-containing diamines were also transformed into
the corresponding diformamides in good yields (27-29). From the
above substrate study, it can be seen that our methodology is highly
chemoselective and that the catalytic system could play a pivotal role
in future formamide couplings of amines with formic acid. Finally, a
gram-scale reaction was conducted with 1.0 mol% of catalyst, 2.14
grams (20.0 mmol) benzylamine and formic acid (40.0 mmol) in 5.0
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complexation of catalyst 1 with formic acid. The Cr catalyst activates
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DOI: 10.1039/D0DT03300F
the carbonyl group of formic acid to form the covalent compound A.
The nucleophilic amines attack the carbonyl carbon of A to give the
active intermediate B. After N-H bond heterolysis, highly reactive
species C, which can be regard as active self-dehydrating agent.
Finally, the elimination of water from C gives the formamide product.
19
Conclusions
In conclusion, we have demonstrated a simple, efficient and
chemoselective one-pot strategy for the environmentally
friendly formylation of amines with formic acid using a
polyoxometalate-based Cr-catalyst (CrIIIMo6-CH3). A number of
primary and secondary amines can be successfully converted
into the corresponding formamide products. The catalyst can
also be recycled several times with the negligible loss of activity.
The generality of this methodology gives it the potential to be
used on an industrial scale.
Conflicts of interest
In There are no conflicts to declare.
Acknowledgements
This work is supported by the National Natural Science
Foundation of China (Nos. 21871183, 21631007, 21225103),
Doctoral Fund of Ministry of
Education of China
No.
20130002110042, Tsinghua University Initiative Foundation
Research Program No. 20131089204 and the State Key
Laboratory of Natural and Biomimetic Drugs K20160202. The
start-up fund of Shanghai Institute of Technology is also
gratefully acknowledged.
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