Mn-Catalyzed Selective Double and Mono-N-Formylation and N-Methylation of Amines by using CO2

Article abstract of DOI:10.1002/cssc.201900152

Functionalization of amines by using CO₂ is of fundamental importance considering the abundance of amines and CO₂. In this context, the catalytic formylation and methylation of amines represent convenient and successful protocols for selective CO₂ utilization as a C₁ building block. This study represents the first example of selective catalytic double N-formylation of aryl amines by using a dinuclear Mn complex in the presence of phenylsilane. This robust system also allows for selective formylation and methylation of amines under a range of conditions.

Full text of DOI:10.1002/cssc.201900152

Accepted Article
Title: Mn-Catalyzed Selective Double and Mono N-Formylation and N-
Methylation of Amines Using CO2
Authors: Zijun Huang, Xiaolin Jiang, Shaofang Zhou, Peiju Yang,
Chen-Xia Du, and Yuehui Li
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10.1002/cssc.201900152
ChemSusChem
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Mn-Catalyzed Selective Double and Mono N-Formylation and N-
Methylation of Amines Using CO2
Zijun Huang,[a,d] Xiaolin Jiang,[a,b] Shaofang Zhou,[a] Peiju Yang,[a] Chen-Xia Du,[c] and Yuehui Li*[a]
Abstract: Functionalization of amines using CO2 is of fundamental
importance considering the abundance of amines and CO2. In this
context, the catalytic formylation or methylation of amines have been
developed and represent convenient and successful protocols for
selective CO2 utilization as C1 building block. Here, we present new
advances in this area and report the first example of selective catalytic
double N-formylation of aryl amines by using a di-nuclear Mn-complex
in the presence of phenylsilane. This robust system also allows for
selective formylation and methylation of amines under various
conditions.
complexes,[4] N-heterocyclic carbenes,[5] glycine betaine,[6] γ-
valerolactone[7] and metal–organic frameworks[8]. The selective
double N-formylation method to the best of our knowledge is yet
to be developed. Hence, the discovery of novel catalysts to
transform abundant CO2 for this purpose is highly desirable.
Herein, we report the first efficient example of selective double
N-formylation of primary arylamines using newly discovered
dinuclear Mn-complexes. The desired N,N-diformylanilines were
obtained in good to excellent yields. Furthermore, selective
formylation or methylation of amines could be achieved by tuning
the reaction parameters. These results demonstrate the important
application potential of this methodology for the versatile
reductive modification of amines using CO2 (Scheme 1).
Introduction
Catalytic utilization of CO2 as C1 building block in the
functionalization of N-H bond is of fundamental importance for
developing sustainable chemical transformations. Recent
progress in this area includes formylation, methylation as well as
urea/urethane formation are based on innovative discoveries of
organometallic and organo-catalysts.[1]
Complementary to known formylation reactions, double N-
formylation of primary amines provides bis-formylated amine
products (N,N-diformylamines), which constitutes useful
intermediates for drug discovery.[2] N,N-diformylamines
preparation is under developed with scarce reports limited to the
use of N,N-diformylacetamide or acetic-formic anhydride as the
source of formyl group (Scheme 1). However, these methods
have drawbacks of using harsh conditions and tedious synthetic
procedures.[3]
Alternatively, double N-formylation of primary amines to N,N-
diformylamines has been reported as side reactions when using
CO2 as carbon source for the reductive formylation of N-H bonds.
Specifically, mixtures of mono- and bis-formylated amines were
obtained in the presence of various catalysts, including Zn
Scheme 1. Formylation/methylation of amines.
Results and Discussion
[a]
Z. Huang, X. Jiang, Dr. S. Zhou, P. Yang, Prof. Dr. Y. Li *
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Suzhou Research Institute of LICP, Lanzhou Institute of Chemical
Physics (LICP), Chinese Academy of Sciences
Lanzhou 730000, (P. R. China)
E-mail: yhli@licp.cas.cn
X. Jiang,
Key Laboratory of Structure-Based Drug Design & Discovery of
Ministry of Education, Shenyang Pharmaceutical University,
Shenyang 110016, (P. R. China)
Double N-formylation
In continuation of our interest in catalytic utilization of CO2,[9] we
have undertaken a study to develop double N-formylation
methods for amine functionalization. For this purpose, double
formylation reactions were carried out via an in-situ catalyst
formation by using ligands and metal precursors combination
under various reaction conditions.
[b]
Initially, we used p-methoxy-aniline as model substrate and
screened various transition metal precursors. We observed that
the reactivity is clearly affected. We found that only Mn2(CO)10 has
higher catalytic activity with conversion of 23% (entry 5, Table 1),
while other metal precursors were mostly inactive. Then, we
proceeded by introducing different ligands (L1 - L8 and PPh3) to
Mn2(CO)10 and varied conversion results were observed (Table 1).
We found that Mn-catalyzed reactions with ligands L1, L4, L5, L6
and L8, gave improved conversions to doubly formylated product
[c] Prof. Dr. C.-X. Du
College of Chemistry and Molecular Engineering, Zhengzhou
University, Zhengzhou 450001, (P. R. China)
E-mail: dcx@zzu.edu.cn
[d]
Z. Huang
University of Chinese Academy of Sciences, Beijing 100049, (P. R.
China)
Supporting information for this article is given via a link at the end of
the document. CCDC 1890807 contains the supplementary
crystallographic data for this paper.
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(entries 7,10, 11, 13 and 15, Table 1). Mn-catalyzed reaction in
the presence of L1 afforded best conversion giving product 2a
(double formylation of amine) in 42% yield along with product 3a
(single formylation of amine) in 56% yield in 12 hours. To our
delight, enhanced catalytic reactivity and better yields were
achieved upon longer reaction time providing product 2a in 61%
(entry 16, Table 1). Furthermore, the reaction was improved
greatly in the presence of 4 equiv. of phenylsilane giving product
2a in 90% yield (entry 17, Table 1). Lastly, we found that
increasing CO2 pressure to 15 bar afforded product 2a in slightly
higher yield (93%; entry 18, Table 1).
In order to understand the coordination mode of L1 with Mn
metal center, single crystals of Mn2(CO)8(L1)2 were prepared from
mixture of Mn2(CO)10 and L1 in CH3CN at room temperature and
the structure elucidated by single X-ray diffraction method (Figure
1). On crystals bulk analysis, the simulated XRD pattern from
single crystal structure and the experimental XRD data of the
crystallized powder were in total agreement. Analysis of the
single-crystal X-ray diffraction structure revealed that
Mn2(CO)8(L1)2 crystallizes in P3121 space group. The
symmetrical unit of Mn2(CO)8(L1)2 consists of two Mn center and
two molecules of L1. Mn2(CO)8(L1)2 complex was deliberately
synthesized as pre-formed catalyst and tested in the formylation
reaction. The reaction of p-methoxy-aniline (1a) and CO2 with
phenylsilane in the presence of 0.5 mol% of Mn2(CO)8(L1)2
afforded formylation of amine to give 3a in 77% yield and bis-
formylated product 2a was not detected by GC indicating this
complex is related with the formation of active species.
Presumably, mononuclear Mn-complex might be responsible for
the high reactivity of double N-formylation. Moreover, the
presence of Lewis base pyridine moiety in L1 is important for the
crucial cleavage of Mn-Mn bond (Table S3 in the Supporting
Information).
Table 1. Catalytic double formylation of p-methoxy-aniline[a]
Yield [b] (%)
Ligand/
(mol%)
Conv.[b]
(%)
Entry
[M] (mol%)
2a
ND
ND
ND
ND
ND
ND
42
3a
1
-
-
-
<1
<1
Trace
Trace
Trace
Trace
22
2
3
Fe3(CO)12/0.5
Ni(cod)/1
-
<1
4
Co2(CO)8/0.5
Mn2(CO)10/0.5
-
-
<1
5
-
23
6
L1/2
L1/2
L2/2
L3/2
L4/2
L5/2
PPh3/2
L6/2
L7/2
L8/1
L1/2
L1/2
L1/2
70
58
Figure 1. ORTEP diagram of Mn2(CO)8(L1)2. All hydrogen atoms have been
omitted for clarity.
7
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
Mn2(CO)10/0.5
>99
56
56
8
ND
ND
37
55
Under the optimized reaction conditions, we firstly carried out
reactions of a variety of substituted arylamines 1 in the presence
of Mn2(CO)10 and L1 with phenylsilane and carbon dioxide
affording the bis-formylated product as shown in Table 2.
Electron-rich group substituted arylamines proceeded smoothly
furnishing the corresponding products 2a - 2f and 2k - 2n in
excellent yields. The reactions of arylamines bearing electron-
withdrawing groups such as Cl and Br could also be transformed
to bis-formylatied products in good yields. It is noteworthy that the
reaction of 4-fluoroaniline 1g and 4-iodoaniline 1j gave the
desired products 2g and 2j in slightly lower yields as 74% and
70%, respectively. The reaction of naphthalen-1-amine 1o also
afforded the corresponding bis-formylated product 2o in good
yield.
Subsequently, we further conducted the N-formylation of
amines by reducing CO2 pressure (Table 3; detailed reaction
conditions optimization described in Table S1 in the Supporting
Information). Various substituted primary arylamines (1a - 1m)
exhibited good activity and afforded the cooresponding products
in excellent yields. Meanwhile, reactions with secondary
arylamines bearing either electron-rich (1p - 1r; 1u - 1w) or
electron-withdrawing groups (1s, 1t) gave N-formylated products
in good yields.
9
42
40
10
11
12
13
14
15
16[c]
17[c, d]
18[c, d, e]
>99
>99
15
62
29
69
ND
25
14
>99
19
69
ND
26
16
>99
>99
>99
>99
72
61
35
90
8
93
4
[a] Reaction conditions: 1a (0.5 mmol), CO2 (10 bar), PhSiH3 (1.0 mmol). [b]
Conversion and yield determined by GC using n-dodecane as the internal
standard. [c] 24 h. [d] PhSiH3 (2.0 mmol). [e] 15 bar CO2. RT = room
temperature. ND = no detection. PPh3 = triphenylphosphine.
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The reactions of 1x, 1y and 1z with phenylsilane and carbon
dioxide were performed and the corresponding products 3x, 3y
and 3z were isolated in 85%, 89% and 93% yields respectively.
Noteworthy to mention that indoline (1aa) could also be utilized
as substrate to produce formamide 3aa in 78% yield. Furthermore,
in order to examine the generality of this procedure, we tested
aliphatic, heterocyclic and benzilc amines and they were all well
tolerated. Specifically, pyrrolidine (1ab), morpholine (1ac),
piperidine (1ad), 2-methylpropan-2-amine (1ae), hexylamime
(1af), piperazine (1ag), N-methylbenzylamine (1ah) and N-
ethylbenzylamine (1ai) were all N-fomylated with excellent yields
(82-96% yields; Table 3).
Table 2. Double formylation reactions of aryl amines.
[a]
Table 4. Substrate scope for N-methylation of amines using CO2
[a] Reaction conditions: Mn2(CO)10 (0.5 mol%), L1 (2 mol%),1 (0.5 mmol), CO2
(15 bar), PhSiH3 (2.0 mmol), CH3CN (2.0 mL), room temperature, 24 h. Isolated
yields. [b] Yield determined by GC using n-dodecane as the internal standard.
[a]
Table 3. Substrate scope for N-formylation of amines using CO2
[a] Reaction conditions: Mn2(CO)10 (0.5 mol%), L1 (2 mol%),1 (0.5 mmol), CO2
(1 bar), PhSiH3 (1.5 mmol), CH3CN (2.0 mL), 100 oC, 15 h. Isolated yields. [b]
Yield determined by GC using n-dodecane as the internal standard.
Finally, N-methylation of amines was also achieved when using
higher amounts of phenylsilane under low pressure (1 bar) at
elevated temperature under low pressure (1 bar). (Table 4;
conditions optimization depicted in Table S2 in the Supporting
Information). Bis-N-methylated products (4a - 4c and 4h, 4i, 4l)
were obtained in good to excellent yields (79% - 90%) with
substituted primary arylamines substrates. Secondary amines
having aryl substituents (1p - 1r,1u - 1w, 1y, 1z, 1aj, 1ak - 1ap)
were also well tolerated and afforded the corresponding N-
methylated products (4) in moderate to excellent yields (71% -
92%). Howerer, the reaction with sterically hindered amine (1an)
afforded N-methylated amines in lower yield (51%). Meanwhile,
aliphatic amine morpholine 1ac was successfully transformed to
the corresponding methylated product in good yield (89%).
Similarely, piperidine 1ad was also methylated to afforded N-
methylpiperidine in 89% yield. Secondary amines bearing
benzylic substitutent 1ah, 1ai, and 1ar were converted to
methylated products in comparable yields (86% - 89%). Moreover,
[a] Reaction conditions: Mn2(CO)10 (0.5 mol%), L1 (2 mol%),1 (0.5 mmol), CO2
(1 bar), PhSiH3 (1.0 mmol), CH3CN (2.0 mL), room temperature, 12 h. Isolated
yields are shown. [b] Yield determined by GC using n-dodecane as the internal
standard.
However, we observed significant decrease in the yield to 64%
due to the strong electron-withdrawing effect when N-methyl-4-
(trifluoromethyl) aniline (1t) was used. In order to evaluate the
effect of N-alkyl substituents on the reaction of arylamines, ethyl,
n-butyl, and allyl substituted arylamines substrates were used.
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N-methylcyclohexylamine (1aq) was also transformed to the
corresponding dimethylhexylamine in 90% yield.
p-methoxy-aniline (1a), giving bis-formylated product (2a) in 8%
yield and afforded N-(4-methoxyphenyl)formamide (3a) in higher
yield (87%), while comparable yield of 89% was obtained for the
reaction of N-methylaniline (Eq.2, Eq.3, Scheme 2). These control
experiments indicate that silyl formate is the active formylation
reagent in this transformation.
Furthermore, preliminary kinetic studies were performed to gain
mechanistic understanding for this bis-formylation reaction as
depicted in Figure 2. Firstly, primary amine 1a was converted
completely into N-formylated product 3a within four hours.
Interestingly, during this period bis-formylated product 2a was not
detected by GC. Subsequently, bis-formylated product 2a started
to be formed at a slightly lower reaction rate, with the consumption
Scheme 3. Proposed reaction pathways for Double N-Formylation
Recent studies[4,6,7,10,11] indicate that N-formylation of amines
might involve two main steps: 1) hydrosilylation of CO2 to form
silyl formates for the formation of formylated intermediates, and
2) reduction of formamides to produce the methylated product.
Consistently, N-formyl-N-methylaniline 3p could be formed
smoothly as indicated in the reaction profile of amine 1p. In
addition, 3p is rapidly consumed within six hours (Figure S6 in
Supporting Information). Specifically, when 3p reacts with PhSiH3
under heating conditions, 91% yield of 4p was obtained (Eq. 4,
Scheme 2).
On the basis of the above experimental results and recent
Figure 2. Reaction profiles for the bis-formylated of amines using CO2. Reaction
conditions: Mn2(CO)10 (0.5 mol%), L1 (2 mol%),1a (0.5 mmol), CO2 (15 bar),
PhSiH3 (2.0 mmol), CH3CN (2.0 mL), room temperature, yield determined by
GC using n-dodecane as the internal standard.
experimental evidence on CO2 reduction,[12,13]
a possible
mechanism for this Mn-catalyzed reductive functionalization of
CO2 in the presence of amine is proposed in Scheme 3. Our
findings imply that under the pressurized condition, diformylation
reaction is more favoured to obtain the desired N,N-diformylamine
product, although through mono-formylated intermediate with silyl
formate as the formylation reagent (pathway I). Meanwhile, the
reaction pathway II involves the formation of carbamate salt
intermediate first, followed by the Mn-catalyzed reduction to give
the mono-formylation product.
of 3a. This behaviour implies that primary amine substrates are
not favored for di-formylation reaction. Di-formylated product
would only start forming once the substrate is completely
consumed in the initial mono-formylation step. This imperative
tuning effect by substrate is suggested to be responsible for the
highly selective mono and di-formylation reactions using Mn-
catalysts.
Conclusions
In summary, we have demonstrated the first catalytic double N-
formylation of aryl amines using CO2 in the presence of
hydrosilanes. Specifically, under mild conditions, good to
excellent yields of the desired imide type N,N-diformylated
products were obtained. Furthermore, the same catalyst was
found to be efficient for both formylation and methylation of
aliphatic and aryl amines. Kenitic studies provided insights into
the reaction mechanism with the activity and selectivity is tuned
by reaction parameters.
Acknowledgements
We are grateful for the financial supports from NSFC (21633013,
21602228, 91745104), NSF of Jiangsu Province (BK20160394),
Scheme 2. Control experiments
National Program for Thousand Young Talents of China.
To gain further insight, we performed control experiments using
phenylsilane and CO2 at room temperature. The possible reaction
intermediate silyl formate was prepared through the reaction of
CO2 with phenylsilane in the presence of Mn-catalyst (Eq.1,
Scheme 2). Then, the in-situ formed silyl formate was exposed to
Keywords: double formylation, CO2 utilization, manganese,
amine, homogeneous catalysis
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Entry for the Table of Contents (Please choose one layout)
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Zijun Huang, Xiaolin Jiang, Shaofang
Zhou, Peiju Yang, Chen-Xia Du, and
Yuehui Li*
Page No. – PPage No. – Page No.
Mn-Catalyzed Selective Double and
Mono
N-Formylation
and
N-
Bis-formylated product! We have demonstrated the first example of selective
catalytic double N-formylation of aryl amines by using a di-nuclear Mn-complex in the
presence of phenylsilane. Furthermore, this robust system also allows for selective
formylation and methylation of amines under various conditions.
Methylation of Amines Using CO2
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