Solvent-promoted catalyst-free: N -formylation of amines using carbon dioxide under ambient conditions

Article abstract of DOI:10.1039/c6cc01234e

An unprecedented catalyst-free formylation of amines using CO₂ and hydrosilanes was developed. The solvent plays a vital role in promoting the interaction of amines with hydrosilanes and subsequent CO₂ insertion, thus facilitating the simultaneous activation of N-H and Si-H bonds. Based on relevant mechanistic studies, a plausible mechanism involving a silyl carbamate intermediate is proposed.

Full text of DOI:10.1039/c6cc01234e

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COMMUNICATION
Solvent-promoted Catalyst-free N-Formylation of Amines Using
Carbon Dioxide under Ambient Conditions
Received 00th January 20xx,
ab
b
b
a
b
Hui Lv, Qi Xing, Chengtao Yue, Ziqiang Lei* and Fuwei Li*
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An unprecedented catalyst-free formylation of amines with CO2 CO with amines to form the carbamate salts, followed by their
2
(
a) via formation of carbamate salts
and hydrosilanes was developed. Solvent plays a vital role in
promoting the interaction of amines with hydrosilanes and
subsequent CO2 insertion, thus facilitates the simultaneous
activation of N-H and Si-H bonds. Based on relevant mechanistic
O
R1
R2
O
R2
H
Cat
H
N
CO2
N
H2N
R2
R1
O
N
R2
N
R1
3
R SiH
R2
R1
R1
studies,
a
plausible mechanism involving silyl carbamates
(b) via formation of silyl formates
Cat.
O
O
intermediate is proposed.
1
2
R1
N
R2
R R NH
R3SiH
+
CO2
R3Si
H
O
H
The CO -involved chemical synthesis has been and continues
2
previous work
this work
to be a very active research area because CO is an abundant,
2
1
renewable, cheap and green C1 resource. Among the CO -
(
c) via formation of silyl carbamates
R2
2
O
O
involved chemical syntheses documented, the N-formylation
R2
CO2 R2
3
R SiH
R1
R3SiH
NH
N
N
SiR3
O
SiR3
N
H
reaction of amines with CO and hydrosilanes is a promising
2
R1
R1
R1
R2
pathway for the production of formamides, which have been
widely applied as solvents and key intermediates in organic
solvent controlled
Scheme 1. Formylation of amines with CO
no additional catalyst was needed
2
,3
2
and hydrosilanes.
9a,12
synthesis and industry.
However, due to the inherent
stability and kinetic inertness of CO , its conversion under mild
2
reduction with R
3
SiH (Scheme 1, a).
(2) activation of Si-H
conditions, especially at room temperature and atmospheric
pressure is a big challenge. Hence, chemists are committed to
developing more efficient catalytic methods for this reaction.
Among the methods developed, metal-based catalysts
bond accompanied by CO
2
insertion to form silyl formates,
which could act as a “formyl synthon” to react with amines
,7d,8,11b
4
(Scheme 1, b).
In these cases, an additional catalyst was
4
5
6
7
8
9
needed and generally only one component of the amine/silane
system was activated.
including Rh , Pd , Cu , Fe , Ni , Zn , have been widely
employed. Recently, metal-free catalytic systems such as N-
1
heterocyclic carbenes (NHCs) , ionic liquids (ILs) , organic
0
11
Mostly, the formylation of amines follows the catalytic
mode of Scheme 1b. Recently, Cantat and co-workers
1
2
bases ect. have also been developed as a green alternative.
Depending on the activation modes, these catalytic methods
are mainly classified into two types: (1) reaction of activated
developed NHCs-catalyzed N-formylation of amines using CO
2
1
0
and hydrosilanes. In this transformation, the nucleophilicity
and basicity of NHC played a crucial role. One possible
mechanism involves the activation of Si-H bond through Lewis
1
3
acid-base NHC-Si interaction. As we know, amines could also
act as a nucleophile and Lewis base by donating a pair of
electrons. Inspired by this property, it is speculated that
whether we can realize the activation mode of NHCs by using
the amine substrate. One potential problem is that the basicity
or nucleophilicity of amines is not strong enough to activate Si-
H bond. As is reported, the nucleophilicity and basicity of
a.
Key Laboratory of Eco-Environment-Related Polymer Materials of Ministry of
Education, College of Chemistry and Chemical Engineering, Northwest Normal
University, Lanzhou 730070, China. E-mail: Leizq@nwnu.edu.cn.
Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research
b.
Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of
Sciences, Lanzhou, 730000, China. E-mail: fuweili@licp.cas.cn;
Fax: +86-931-4968129
†Electronic Supplementary Informaꢀon (ESI) available: Experimental details and
characterization of products. See DOI: 10.1039/x0xx00000x
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amines could be tuned by solvation and polarization in
Journal Name
1
4
different solvents. In view of this, we envisioned it’s possible
that by utilizing appropriate solvent, the nucleophilicity and
basicity of amine could be tuned strong enough to activate
organosilanes via Lewis acid-base N-Si interaction, which is
similar to the Lewis acid-base NHC-Si interaction. Thus, amines
would probably be able to induce their formylation with CO
and hydrosilanes without using any additional catalysts
Scheme 1, c). In this reaction system, amines and hydrosilanes
were activated simultaneously, which makes subsequent
insertion of CO more favorable.
In our initial experiment, the formylation of morpholine(1a
with atmospheric pressure of CO and phenylsilane as a model
2
(
2
)
2
reaction was performed in various solvents and the results are
listed in Table 1. The reaction could hardly proceed in non-
polar solvents, such as n-hexane, benzene and toluene (Table
1
Figure 1. H NMR spectra for the mixture of morpholine and phenylsilane in different
1
, entries 1 to 3). Then we screened different polar solvents. solvents (A is corresponding to intermediate A in Scheme 2).
Weakly polar solvents such as THF, 1,4-dioxane and CHCl
were also not suitable for this reaction (entries 4 to 6). When
CH CN was used, 2a was obtained in 12% yield (entry 7). To investigated the mixture of morpholine and phenylsilane in
3
In order to clarify the special role of solvents, we
3
our delight, a quantitative yield of 2a was achieved in 24 h at different deuterated solvents. After stirring for four hours, the
room temperature when highly polar aprotic solvents, such as resulted mixtures were characterized by NMR. As shown in
6
DMSO or DMF was used (entries 8 and 9). This can probably be Figure 1, in non-to-weakly polar solvents such as d -benzene,
8
rationalized by the good solubility of CO
2
in DMSO or DMF and CDCl and d -THF, only signals for morpholine and phenylsilane
3
6
the appropriate basicity/nucleophilicity of amines in highly were observed. In contrast, for the mixture in highly polar d -
polar aprotic solvents. Meanwhile, some other factors such as DMSO, new signals appeared, which were assigned to a new
the solvents’ acidity/basicity are not negligible either. In a species
A resulted from the interaction of morpholine and
word, the solvent has comprehensive effect on the activity of phenylsilane (Scheme 2). These results indicated that one
the present formylation reaction. Furthermore, we reason for the outstanding efficiency of DMSO in this
investigated the effect of DMSO/THF mixed solvent. The formylation may be its ability in promoting the interaction of
results indicated that the product yield increases with amine and hydrosilane. This interaction facilitated the
increasing proportion of DMSO in the mixed solvent (Table S1 simultaneous activation of N-H and Si-H bonds, which might
in the ESI, entries 10 to 14). We were also pleased to find that make it more favorable for CO insertion. We speculated that
2
this reaction also proceeded successfully using Et
3
SiH or the interaction of amine with hydrosilane is mainly influenced
the polarity of solvent, which tuned the
(
EtO) SiH as the reductant, providing the desired product in by
3
almost quantitative yields (entries 10 and 11).
basicity/nucleophilicity of amine through solvation and
polarization. To confirm this, the solutions of morpholine in
a
Table 1 Optimization of reaction conditions.
6
different deuterated solvents (CDCl , d -benzene, CD CN and
3
3
6
d -DMSO) were examined by H NMR analysis (Figure S1 in the
1
1
supporting information). From the H NMR spectra, it’s found
1
that the H signals of N-H proton in morpholine appeared in a
b
6
range of 1.05 to 2.28 ppm, following the order: d -DMSO (2.28
Entry
Solvent
Hydrosilane
Yield (%)
6
ppm) ˃ CD CN (1.78 ppm) ˃ CDCl (1.71 ppm) ˃ d -benzene
3
3
1
2
3
4
5
6
7
8
n-Hexane
Benzene
Toluene
THF
PhSiH
PhSiH
PhSiH
PhSiH
PhSiH
PhSiH
PhSiH
PhSiH
PhSiH
3
3
3
3
3
3
3
3
3
n.r.
n.r.
(
1.05 ppm), which is in agreement with the polarity order of
these solvents. To some content, this result proved the
influence of solvents polarity on the properties of amine,
which was in accordance with the experimental results in
Table 1.
trace
trace
trace
n.r.
1,4-dioxane
CHCl
3
With the optimized conditions in hand, we further
investigated the scope of this formylation with various amines
3
CH CN
12
DMF
>99
>99
>99
>99
(Table 2). Primary or secondary aliphatic amines with different
9
DMSO
DMSO
DMSO
c
substituents were subjected to N-formylations and provide the
corresponding formamides 2b and 2c quantitatively. Steric
hindered amantadine could also undergo formylation
smoothly, giving 2d in nearly quantitative yield. Annular
secondary amine such as tetrahydroisoquinoline was also
acitve for this reaction, giving 2e in 89% yield. For
1
0
Et
3
SiH
SiH
d
1
1
(EtO)
3
a
Reaction conditions: morpholine (0.5 mmol), R
3
SiH (0.75 mmol), CO
2
(1 atm),
b
solvent (2 mL), room temperature, 24 h. The yield was determined by GC,
c
d
calibrated using n-hexadecane as the internal standard. Et
EtO) SiH (2.25 mmol).
3
SiH (2.25 mmol).
(
3
2
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a
phenylethylamine and different N-alkyl substituted
benzylamine, the formylation proceeded smoothly to provide
the desired products 2f to 2h in 80-82% yields. Delightfully,
weakly nucleophilic aromatic amines were also suitable for this
formylation. For example, the reaction of aniline provided 2i in
Reaction conditions: amine (0.5 mmol), PhSiH
3
(0.75 mmol), DMSO (2 mL), room
b
c
o
temperature, 24 h, isolated yield. The yield was determined by GC. 60 C.
97% yield. Both electron-donating (-OMe, -OH) and weakly
electron-withdrawing (-F, -Cl) substituents on the benzene ring
were well tolerated, providing 2j to 2m in 70-95% yields.
Unfortunately, strongly electron-withdrawing substituents (-
2
NO , -CN) on the benzene ring were not tolerated, with the
substrates recovered quantitatively. Notably, for the reaction
of bifunctionalized p-hydroxyaniline, N-formylation product 2k
was solely obtained, while no O-formylation product was
observed, which demonstrated the good chemoselectivity of
the present reaction system. Moreover, anilines substituted
with active halogen groups (-Br, -I) furnished the
corresponding halogen-substituted formamides in excellent
yields (2n and 2o), thus providing the potential for further
functionalization. Compared with the result of 4-iodoaniline
1
Figure 2. H NMR chemical shift of the reaction system at different time. We shaked
the reaction mixture in the first six hours to reduce the reaction rate and during the
period of 6-7 h in CO
2
the reaction mixture was stirred to accelerate the transformation
(
2o, 96% yield), yield of the reaction with 2-iodoaniline (2p
,
rate. (A and B are corresponding to the intermediates A , B in Scheme 2)
57% yield) was lower, which may be attributed to the steric
hindrance and the electron-withdrawing inductive effect of
iodine substituent. The steric hindered 2,4,6-trimethyl aniline
worked efficiently toward this formylation to afford 2q in 84%
yield. Naphthylamine was also conveniently converted into the
corresponding formamides 2r in 94% yield. In addition, the
current
formylation
reaction
was
regioselective
for phenylhydrazine where two N-H bonds could be
formylated, only one product generated from formylation of
the less sterically hindered N-H bond was obtained (2s). N-
methyl aniline was also compatible with the standard reaction
conditions, providing 2t in 95% yield. When o-
phenylenediamine was used, benzimidazole (2u) was obtained
in 51% yield as the final product, which may be generated
through intramolecular nucleophilic cyclization/dehydration of
the formylated intermediate. Notably, good chemoselectivity
13
was achieved for the formylation of primary amines, in which Figure 3. C NMR chemical shifts of the reaction system at different time. We shaked
only mono-formylated product was isolated and no double- the reaction mixture in the first six hours to reduce the reaction rate and during the
2
period of 6-7 h in CO the reaction mixture was stirred to accelerate the transformation
formylated product was observed. In contrast, the double-
formylated product was hard to be suppressed in some
rate. (A and B are corresponding to the intermediates A , B in Scheme 2)
7
a,10c,11b
catalytic systems.
Clarifying the mechanism of a novel reaction system is very
important from the viewpoint of its scientific interest and
application in designing other synthetic strategies. Initially, in
a
2
Table 2 Formylation of various amines with CO and phenylsilane.
1
13
6
situ NMR ( H and C) analyses in d -DMSO were conducted to
investigate the reaction of morpholine with phenylsilane in the
1
absence of CO . As shown in Figure 2a-2b, new H NMR signals
2
appeared after shaking the NMR tube for 7 hours. These new
signals were assigned to a new species
A resulted from the
cross coupling of amine with hydrosilane. Subsequently, CO2
was inflated and continued to shake the NMR tube. After 1
hour, a second batch of new peaks appeared (Figure 2c) and
became obviously stronger after
Meanwhile, the signals corresponding to
the same time, the formation of new intermediate
6
hours (Figure 2d).
decreased a lot. At
was
further approved by the appearance of a new C NMR signal
A
B
1
3
appeared at
δ
153.2 ppm (Figure 3c and 3d), which could be
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assigned to the carbonyl carbon of silyl carbamates
Journal Name
B
(Figure
and H. Yasuda, Chem. Rev. 2007, 107, 2365; (f) M. Aresta, A.
Dibenedetto and A. Angelini, Chem. Rev. 2014, 114, 1709.
A. Tlili, E. Blondiaux, X. Frogneux and T. Cantat, Green Chem.,
1
5
3
). These results strongly indicate that
insertion of CO into the Si-N species
faster than the formation of
the signals corresponding to substrate decreased and that of
B
was formed through
2
3
2
A
and this process is
2
015, 17, 157.
A
. With shaking time prolonged,
(a) K. C. Waterman, W. B. Arikpo, M. B. Fergione, T. W. Graul,
B. A. Johnson, B. C. Macdonald, M. C. Roy and R. J. Timpano,
J. Pharm. Sci., 2008, 97, 1499; (b) W.-P. Mai, H.-H. Wang, Z.-C.
Li, J.-W. Yuan, Y.-M. Xiao, L.-R. Yang, P. Mao and L.-B. Qu,
Chem. Commun., 2012, 48, 10117; (c) S. T. Ding and N. Jiao, J.
Am. Chem. Soc., 2011, 133, 12374.
B
increased gradually. Finally, the signals for amide product
appeared and that for amine substrate disappeared almostly
(
Figure 2e and Figure 3e). The formation of
A
and
B was also
2
9
confirmed by in situ Si NMR analysis (Figure S2 in the ESI).
4
For selected examples of Rh-catalyzed N-formylation with
2
CO , see: (a) T. V. Q. Nguyen, W.-J. Yoo and S. Kobayashi,
Angew. Chem. Int. Ed., 2015, 54, 9209; (b) S. Itagaki, K.
Yamaguchi and N. Mizuno, J. Mol. Catal. A-Chem., 2013, 366
47.
For select example of Pd-catalyzed N-formylation with CO
,
3
5
6
2
,
see: X. J. Cui, Y. Zhang, Y. Q. Deng and F. Shi, Chem. Commun.,
014, 50, 189.
For select examples of Cu-catalyzed N-formylation with CO
2
2
,
see: (a) K. Motokura, N. Takahashi, D. Kashiwame, S.
Yamaguchi, A. Miyaji and T. Baba, Catal. Sci. Technol., 2013,
3
, 2392; (b) K. Motokura, D. Kashiwame, N. Takahashi, A.
Miyaji and T. Baba, Chem. Eur. J., 2013, 19, 10030; (c) R.
Shintani and K. Nozaki, Organometallics, 2013, 32, 2459; (d)
K. Motokura, N. Takahashi, A. Miyaji, Y. Sakamoto, S.
Yamaguchi and T. Baba, Tetrahedron, 2014, 70, 6951; (e) M.
Nasrollahzadeh, S. M. Sajadi and A. Hatamifard, J. Colloid.
Interf. Sci., 2015, 460, 146.
Scheme 2. Proposed mechanism for N-formylation of amines with CO
2
and
hydrosilanes.
Based on the investigations above, a possible reaction
pathway was proposed in Scheme 2. Firstly, the nucleophilicity
and basicity of morpholine are tuned by solvation and
polarization in highly polar DMSO, which promotes the cross-
coupling of morpholine with phenylsilane to form intermediate
7
For select examples of Fe-catalyzed N-formylation with CO
see: (a) X. Frogneux, O. Jacquet and T. Cantat, Catal. Sci.
Technol., 2014, , 1529; (b) C. Federsel, A. Boddien, R.
Jackstell, R. Jennerjahn, P. J. Dyson, R. Scopelliti, G.
Laurenczy and M. Beller, Angew. Chem. Int. Ed. 2010, 49
2
,
4
,
A
. At the same time, hydrogen gas is released, which was
9
1
777; (c) M. Kooti, E. Nasiri, J. Mol. Catal. A-Chem., 2015, 406
68; (d) G. H. Jin, C. G. Werncke, Y. Escudié, S. Sabo-Etienne
,
observed as soon as the mixture of phenylsilane and
morpholine was added into anhydrous DMSO. Subsequently,
and S. Bontemps, J. Am. Chem. Soc. 2015, 137, 9563.
For select example of Ni-catalyzed N-formylation with CO2,
see: L. González-Sebastián, M. Flores-Alamo and J. J. García,
Organometallics, 2013, 32, 7186.
insertion of CO
2
into N-Si bond of
A
generates the silyl
8
9
carbamate B. Finally,
B
underwent hydrosilylation with a
second hydrosilane to provide the amide product.
2
For select examples of Zn-catalyzed N-formylation with CO ,
In conclusion, we have developed a catalyst-free system
for the formylation of amines with atmospheric pressure of
see: (a) Z.-Z. Yang, B. Yu, H. Y. Zhang, Y. F. Zhao, G. P. Ji and Z.
M. Liu, RSC Adv., 2015, , 19613; (b) O. Jacquet, X. Frogneux,
C. Das Neves Gomes and T. Cantat, Chem. Sci., 2013, , 2127.
0 For select examples of NHC-catalyzed N-formylation with
CO see: (a) O. Jacquet, C. Das Neves Gomes, M.
Ephritikhine, and T. Cantat, ChemCatChem, 2013, , 117; (b)
Q. H. Zhou and Y. X. Li, J. Am. Chem. Soc., 2015, 137, 10182;
(c) O. Jacquet, C. Das Neves Gomes, M. Ephritikhine and T.
Cantat, J. Am. Chem. Soc., 2012, 134, 2934.
5
4
2
CO at room temperature, affording the corresponding
1
formamides in excellent yield and selectivity. Solvent plays a
key role in this reaction by promoting the Lewis acid-base
interaction between amines and silanes and thus facilitates the
2
,
5
generation of
A with a new N-Si bond formation. A reaction
pathway, including formation of silyl carbamate which is then
reduced to formamide by hydrosilanes, was proposed based
on relevant mechanistic studies.
1
1
1 For select examples of ILs-catalyzed N-formylation with CO
see: (a) X. Gao, B. Yu, Z. Z. Yang, Y. F. Zhao, H. Y. Zhang, L. D.
Hao, B. X. Han and Z. M. Liu, ACS Catal., 2015, , 6648; (b) L.
D. Hao, Y. F. Zhao, B. Yu, Z. Z. Yang, H. Y. Zhang, B. X. Han, X.
Gao and Z. M. Liu, ACS Catal., 2015, , 4989.
2 For select examples of organic base-catalyzed N-formylation
with CO , see: C. Das Neves Gomes, O. Jacquet, C. Villiers, P.
Thuéry, M. Ephritikhine and T. Cantat, Angew. Chem. Int. Ed.,
012, 51, 187.
2
,
5
Acknowledgements
5
This work was supported by the Chinese Academy of Sciences
and the National Natural Science Foundation of China
2
2
(21133011, 21373246 and 21522309).
1
1
3 (a) M. J. Fuchter, Chem. Eur. J., 2010, 16, 12286; (b) S. N.
Riduan, Y. G. Zhang and J. Y. Ying, Angew. Chem. Int. Ed.
2
4 (a) D. H. Aue, H. M. Webb, M. T. Bowers, J. Am. Chem. Soc.,
009, 48, 3322.
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2
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