Copper-diphosphine complex catalysts for N-formylation of amines under 1 atm of carbon dioxide with polymethylhydrosiloxane

Article abstract of DOI:10.1039/c3cy00375b

N-formylation of a wide range of amines proceeded using copper-diphosphine complexes as homogeneous catalysts with polymethylhydrosiloxane (PMHS) under 1 atm of CO₂. In the reaction of piperidine, for example, the turnover number (TON) reached 11700 in 23 h with 90% yield of the formylated product. This TON value is much higher than those of the reported catalysts for the formylation of amines under 1 atm of CO₂ with hydrosilanes. The Cu complexes with phosphines having ortho-phenylene structures acted as good ligands for the formylation, as compared to a bidentate ligand connected with a propyl chain and a monodentate ligand. Among these diphosphines, ligands with alkyl functionalities, such as isopropyl and cyclohexyl groups, produced better results than the phenyl group. Not only cyclic secondary amines, but also linear secondary amines and aromatic and aliphatic primary amines were found to be reactive substrates. In the case of 2,2,6,6-tetramethylpiperidin-4-amine, the formylation proceeded regioselectively. A catalytic reaction pathway was proposed from a separate experiment using [Me₂NCO₂] [Me₂NH₂]. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cy00375b

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Copper-diphosphine complex catalysts for
N-formylation of amines under 1 atm of carbon
Cite this: DOI: 10.1039/c3cy00375b
dioxide with polymethylhydrosiloxane†
Ken Motokura, Naoki Takahashi, Daiki Kashiwame, Sho Yamaguchi, Akimitsu Miyaji
and Toshihide Baba*
N-formylation of a wide range of amines proceeded using copper-diphosphine complexes as homogeneous
catalysts with polymethylhydrosiloxane (PMHS) under 1 atm of CO2. In the reaction of piperidine, for
example, the turnover number (TON) reached 11 700 in 23 h with 90% yield of the formylated product.
This TON value is much higher than those of the reported catalysts for the formylation of amines under
1 atm of CO2 with hydrosilanes. The Cu complexes with phosphines having ortho-phenylene structures
acted as good ligands for the formylation, as compared to a bidentate ligand connected with a propyl
chain and a monodentate ligand. Among these diphosphines, ligands with alkyl functionalities, such as
isopropyl and cyclohexyl groups, produced better results than the phenyl group. Not only cyclic
secondary amines, but also linear secondary amines and aromatic and aliphatic primary amines were
found to be reactive substrates. In the case of 2,2,6,6-tetramethylpiperidin-4-amine, the formylation
proceeded regioselectively. A catalytic reaction pathway was proposed from a separate experiment
using [Me2NCO2][Me2NH2].
Received 31st May 2013,
Accepted 31st May 2013
DOI: 10.1039/c3cy00375b
www.rsc.org/catalysis
wide range of amines under 1 atm of CO2 using hydrosilanes as
reducing agents.
1. Introduction
The utilization of carbon dioxide (CO2) as a feedstock for fine
chemical synthesis is desirable, because CO2 is easy to use,
cheap, and highly abundant.1 Various efficient catalysts
have been reported for formylation of dimethylamine to
N,N-dimethylformamide (DMF) using CO2 and H2.2 In contrast,
formamide syntheses from CO2 and amines other than
dimethylamine have been investigated less often, although
the formylation of amines is an important reaction for syn-
thesis of various fine chemicals.3 In 2003, Baiker and co-workers
reported the Ru-catalyzed formylation of amines, such as
piperidine, pyrrolidine, and morpholine, under 180 atm total
pressure of CO2 and H2.4 From the standpoint of practical
utility on both laboratory and industrial scales, the use of 1 atm
of CO2 is highly desirable. Recently, Cantat and co-workers5
and Mizuno and co-workers6 demonstrated formylation of a
In 2012, our group reported Cu-diphosphine complexes
as efficient catalysts for hydrosilylation of CO2.7 The in situ
generated Cu–H species exhibited high nucleophilicity, thus
resulting in insertion of CO2 into the Cu–H bond. In the
formamide synthesis from amines and CO2, it is necessary to
promote the nucleophilic addition of the H atom to the CQO
bond of CO2 and/or a CO2–amine complex intermediate. These
facts encouraged us to investigate the applicability of the
Cu-diphosphine complex catalyst for the formylation of amines
with CO2. Among hydrosilanes as reduction agents, polymethyl-
hydrosiloxane (PMHS) is inexpensive, non-toxic, and stable to
air and moisture.8 Herein, we demonstrate Cu-diphosphine
complex catalysts for formylation of various amines under
1 atm of CO2 with PMHS [eqn (1)].
Department of Environmental Chemistry and Engineering,
Interdisciplinary Graduate School of Science and Engineering, Tokyo Institute of
Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8502, Japan.
E-mail: tbaba@chemenv.titech.ac.jp
(1)
† Electronic supplementary information (ESI) available: Experimental details,
Tables S1 and S2. See DOI: 10.1039/c3cy00375b
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Table 1 Formylation of piperidine using CO2 and PMHSa
2. Experimental
Methods and materials
Proton (1H) and carbon (13C) nuclear magnetic resonance (NMR)
spectra were recorded in CDCl3 using a Bruker AVANCE 400
spectrometer operating at 400 and 100.61 MHz, respectively.
A Shimadzu QP5000 instrument equipped with a DB-1 column
was used for GC-MS analysis.
Cu(OAc)2ÁH2O (purity >99.99%) was purchased from Aldrich
Inc. Polymethylhydrosiloxane (PMHS) was purchased from WAKO
Pure Chemicals (FW: ca. 1900). Unless otherwise noted, all
other materials were purchased from Wako Pure Chemicals,
Tokyo Kasei Co., Kanto Kagaku Co., or Aldrich Inc. p-Xylene or
mesitylene was used as an internal standard.
Conv. of Conv. of
Entry Cu source
Ligand Si–Hb (%) piperidineb (%) Yieldb (%)
1
2
3
4
5
6
Cu(OAc)2ÁH2O 1a
96
40
31
24
99
30
>99
25
24
98
o1
12
Cu(OAc)2ÁH2O None
None
None
1a
None
o1
o1
Cu(OAc)2ÁH2O 1b
92
85
None 1b
19
o1
a
Reaction conditions: piperidine (1.4 mmol), PMHS (Si–H: 3.2 mmol),
Cu(OAc)2ÁH2O (1.0 Â 10À3 mmol), ligand (P: 3.0 Â 10À3 mmol),
b
1,4-dioxane (5.0 mL), CO2 (1 atm, balloon), 5 h, 80 1C. Determined
by 1H NMR analysis using an internal standard. Yield (%) = [(formamide
Procedure for formylation of amines under CO2 with PMHS
product)/(amine used)] Â 100.
Into a glass reactor equipped with a CO2 balloon were placed
Cu(OAc)2ÁH2O (Cu: 1.0 Â 10À3 mmol), 1,2-bis(diisopropyl-
phosphino)benzene (1a, P: 3.0 Â 10À3 mmol), piperidine
(1.4 mmol), PMHS (0.211 g, Si–H: 3.2 mmol), and 1,4-dioxane
(5.0 mL). The resulting mixture was stirred vigorously at 80 1C
for 5 h. 1H NMR analysis of the reaction mixture showed a 98%
yield of N-formylpiperidine. Formamide products were identi-
fied by comparison with reported 1H NMR and GC-MS data.
Yield and conversion were determined using a CDCl3 solution
of the reaction mixture by the internal standard technique.
Mesitylene or 1,3,5-triisopropylbenzene was used as an internal
standard. The products were confirmed by the comparison of
their GC-MS spectra, and/or 1H and 13C NMR spectra with those
of authentic data.
was much lower than with the Cu salt. The yield of the form-
amide was 85% with 1,2-bis(diphenylphosphino)benzene (1b)
instead of 1a (entry 5). In the case of the ligand 1b, the formylation
scarcely proceeded without Cu(OAc)2ÁH2O (entry 6).
To optimize the reaction conditions, we also examined the
reaction at different reaction temperatures. At 100 1C, the
product yield decreased (72%) due to the rapid consumption
and polymerization of PMHS. Decreasing of the reaction tem-
perature to 60 1C also induced the lower product yield (69%)
due to the lower reaction rate.
To clarify the effect of ligand structure on the formylation,
N-formylation of piperidine using several bidentate and mono-
dentate phosphine ligands was investigated. The structures of
ligands are shown in Chart 1. The time course for the reaction
is shown in Fig. 1. Diphosphines with ortho-phenylene struc-
tures (1a–1c) acted as good ligands for the formylation, as
compared to a bidentate ligand connected with a propyl chain
(1d) and a monodentate ligand (1e). Among these diphosphines,
ligands with alkyl functionalities, such as isopropyl and cyclo-
hexyl groups, produced better results than the phenyl group.
A similar phenomenon was observed in the case of hydrosilyl-
ation of CO2 using Cu-phosphine complex catalysts.7 The
electron-donating effect of these alkyl chains on the ligands
may enhance the nucleophilicity of the Cu–H species, resulting
in high activity for the N-formylation.
Regioselective formylation
Into a glass reactor equipped with a CO2 balloon were placed
Cu(OAc)2ÁH2O (Cu: 1.0 Â 10À3 mmol), 1,2-bis(diisopropyl-
phosphino)benzene (1a, P: 1.0 Â 10À2 mmol), 2,2,6,6-tetra-
methylpiperidin-4-amine (1.4 mmol), PMHS (0.211 g, Si–H:
3.2 mmol), and 1,4-dioxane (5.0 mL). The resulting mixture
was stirred vigorously at 80 1C for 24 h. 1H NMR analysis using
a CDCl3 solution of the reaction mixture showed a 63% yield of
regioselective formylated product. Other formylated products
1
were not detected in either H NMR or GC-MS. The resulting
reaction mixture was purified over a column of silica gel (C200)
and eluted (ethyl acetate - acetone) to give the isolated product.
The product was identified by MS, 1H NMR, 13C NMR, and
1H–1H COSY NMR spectroscopy (Fig. S1, ESI†).
Table 2 shows the scope of amines in the formylation under
1 atm of CO2 using Cu(OAc)2ÁH2O and 1a. Various cyclic secondary
amines showed high reactivity to afford the corresponding amides
3. Results and discussion
The results for the formylation of piperidine using Cu(OAc)2ÁH2O
and phosphine ligands are summarized in Table 1. A 2.3 ratio of
the Si–H group in PMHS to piperidine was used. In the presence
of 1.5 equivalents of 1,2-bis(diisopropylphosphino)benzene (1a)
to Cu, a 98% yield of N-formylpiperidine was obtained after 5 h
under 1 atm of CO2 (entry 1). Without ligand 1a, no formylation
product was formed (entry 2). The reaction proceeded in the
absence of Cu(OAc)2ÁH2O (entry 3), however, the product yield
Chart 1
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Table 2 Formylation of various amines using CO2 and PMHSa
Entry Amine
1
Time (h) Product
5
Yieldb (%)
98
2
3
24
24
85
79
Fig. 1 Time course for formamide synthesis from CO2, PMHS, and piperidine
using various phosphine ligands. Yield of product with 1,2-bis(diisopropyl-
phosphino)benzene (1a: J), 1,2-bis(diphenylphosphino)-benzene (1b: n), 1,2-
bis(dicyclohexylphosphino)benzene (1c: &), 1,3-bis(diphenylphosphino)propane
(1d: B), and triphenylphosphine (1e: K) as ligand. Reaction conditions: amine
(1.4 mmol), PMHS (Si–H: 3.2 mmol), Cu(OAc)2ÁH2O (1.0 Â 10À3 mmol), ligand
(P: 3.0 Â 10À3 mmol), 1,4-dioxane (5.0 mL), CO2 (1 atm, balloon), 80 1C.
4
5
6
25
24
5
84
94
52c
75d
83
in 79–98% yields (entries 1–3). Secondary amines with ether
and tertiary amine functions also afforded amides with these
functional groups intact (entries 4 and 5). The reaction of
dimethylammonium dimethylcarbamate ([Me2NCO2][Me2NH2])
gave N,N-dimethylformamide in 75% yield (entry 7), indicating
that the reaction between amines and CO2 does not inhibit the
formylation. Secondary amines with linear alkyl chains showed
high reactivity (entries 8 and 9), whereas amines with branched
alkyl chains, such as diisopropyl amine, showed much lower
reactivity (entries 11–13). The reactivity of piperidine derivatives
decreased with an increasing number of methyl groups at the
2-position (entries 1, 12, and 13). These results indicate that
the steric bulkiness around the NH group strongly affects the
reactivity of the amines due to the copper catalyst center having
the bulky phosphine ligand. This phenomenon can be applic-
able to regioselective formylation: the reaction of 2,2,6,6-tetra-
methylpiperidin-4-amine using the Cu complex catalyst afforded
a single amide product with the secondary amine group intact
(entry 14). As the 2,2,6,6-tetramethylpiperidine skeleton is a
precursor structure for 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO),9 the Cu-catalyzed selective formylation has potential
for the synthesis of highly functionalized TEMPO derivatives.
The Cu-diphosphine catalyst system is also applicable to the
reaction of anilines: anilines having electron donating functions
showed good reactivity for the N-formylation (entries 16–21). This
substituent effect on the para-position of anilines indicates that the
product yield increases with increasing nucleophilicity of amines.
We also tried to reduce the amount of PMHS in the formyl-
ation. Table 3 shows the results of formylation with various
piperidine : PMHS ratios. Product yields decreased with decreasing
amounts of PMHS; however, a satisfactory yield (73%) of the
formamide product was obtained with only 1.6 equivalents of
the Si–H group of PMHS to piperidine. The reason for the
7
8
[Me2NCO2][Me2NH2]
5
24
9
24
24
87
96
10
11
12
30
30
4
47
13
14
90
24
3
63e
15
16
24
30
54
87
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Table 2 (continued )
Yieldb (%)
Scheme 2 Formylation of [Me2NCO2][Me2NH2] in the absence of CO2. Reaction
conditions: [Me2NCO2][Me2NH2] (N: 1.4 mmol), PMHS (Si–H: 3.2 mmol), Cu(OAc)2Á
H2O (1.0 Â 10À3 mmol), ligand 1a (P: 3.0 Â 10À3 mmol), 1,4-dioxane (5.0 mL), Ar
(1 atm, balloon), 80 1C. Yield was based on nitrogen in [Me2NCO2][Me2NH2].
Entry Amine
Time (h) Product
17
18
19
20
21
22
X = H
48
48
48
48
48
48
X = H
71
62
58
68
80
X = o-Me
X = m-Me
X = p-Me
X = p-OMe
X = p-NO2
X = o-Me
X = m-Me
X = p-Me
X = p-OMe
X = p-NO2
value reached 7640 and 11 700 after 3.5 and 23 h, respectively.
The average turnover frequency (TOF) values are calculated to
be 2180 and 510 hÀ1. The TON value reached up to 9000 in the
case of morpholine. These values are much higher than those of
the reported catalysts for the formylation of amines under 1 atm
o1
a
Reaction conditions: amine (1.4 mmol), PMHS (Si–H: 3.2 mmol),
Cu(OAc)2ÁH2O (1.0 Â 10À3 mmol), 1a (P: 3.0 Â 10À3 mmol), 1,4-dioxane
of CO2 with hydrosilanes [catalyst, TON, TOF: TBD,5a 20, 0.8 hÀ1
N-heterocyclic carbene,5b 20, 160 hÀ1; Rh2(OAc)4,6 172, 86 hÀ1
;
]
(5.0 mL), CO2 (1 atm, balloon), 80 1C. Determined by 1H NMR using
b
an internal standard. Yield (%) = [(formamide product)/(amine used)] Â
c
d
100. PMHS (Si–H: 3.6 mmol). Yield (%) = [(formamide product)/
(Table S1, ESI†). Additionally, the TON values for the Cu catalyst
were higher or only one-order lower than those of the CO2–H2
systems that used 90–200 atm of total pressure (Table S2, ESI†).4,10
The formation of Cu–H diphosphine complexes from a Cu
salt, ligand 1a or 1b, and PMHS was already reported by our
group.7b For the formamide synthesis from an amine, hydro-
silane, and CO2, two possible reaction pathways are proposed:
(1) formation of an amine–CO2 complex which is then reduced
to a formamide by the Cu–H species, and (2) a Cu–H-catalyzed
reaction between CO2 and the hydrosilane followed by the
addition of an amine. The former pathway (1) shows higher
possibility than the latter for the following three reasons:
(i) Formation of silylformate was not detected during the
formylation of piperidine and [Me2NCO2][Me2NH2].
(nitrogen in [Me2NCO2][Me2NH2])] Â 100. 1a (P: 1.0 Â 10À2 mmol).
e
Table 3 Cu-catalyzed formylation of piperidine using CO2 and PMHS with
various piperidine : Si–H ratiosa
Piperidine :
Si–H
Conv. of
Conv. of
Entry
Si–Hb (%)
piperidineb (%)
Yieldb (%)
1
2
3
4
1.0 : 2.3
1.0 : 2.1
1.0 : 1.6
1.0 : 1.1
96
>99
>99
>99
>99
98
89
98
89
73
41
75
a
Reaction conditions: piperidine (1.4 mmol), PMHS (Si–H: 3.2 mmol),
(ii) Anilines having electron-donating functions on the
para-position showed higher reactivity than those having electron-
withdrawing groups (Table 2, entries 17–22). The higher nucleo-
philicity of amine induced higher concentration of an amine–CO2
complex.
Cu(OAc)2ÁH2O (1.0 Â 10À3 mmol), ligand 1b (P: 3.0 Â 10À3 mmol), 1,4-
b
dioxane (5.0 mL), CO2 (1 atm, balloon), 5 h, 80 1C. Determined by
1H NMR analysis using an internal standard. Yield (%) = [(formamide
product)/(amine used)] Â 100.
excess consumption of the Si–H group may be the reaction
between Si–H and a silanol group, which is produced by the
reaction among an amine, CO2, and Si–H.
To increase the turnover number (TON) of the Cu-diphosphine
complex catalyst, the formylation of amines using 7.8 Â
10À5 equivalents of Cu to amine was examined. The results
are shown in Scheme 1. In the reaction of piperidine, the TON
(iii) [Me2NCO2][Me2NH2] can be converted to the corre-
sponding formamide (Table 2, entry 7). We also examined
the reaction of [Me2NCO2][Me2NH2] in the absence of CO2
(Ar atmosphere). The result is shown in Scheme 2. The form-
amide product was obtained in 23% yield for 5 h.
In the reaction of [Me2NCO2][Me2NH2], dimethylamine
should form along with the formamide product. In the above
reaction under an Ar atmosphere (Scheme 2), formation of
dimethyl amine was confirmed by 1H NMR analysis of the
reaction mixture. On the other hand, in the reaction under CO2
(Table 2, entry 7), dimethylamine was scarcely detected by
1H NMR during the reaction. These facts indicate the rapid
reaction between CO2 and amines with, especially, electron
donating functions such as alkyl groups.
4. Summary
In summary, Cu-diphosphine complexes were found to be
active homogeneous catalysts for formylation of various amines
under 1 atm of CO2 with PMHS. The reactivity of amines was
Scheme 1 Formylation of amines. Reaction conditions: amine (5.4 mmol), PMHS
(Si–H: 15.0 mmol), Cu(OAc)2ÁH2O (4.2 Â 10À4 mmol), ligand 1b (P: 4.4 Â 10À3 mmol),
1,4-dioxane (20 mL), CO2 (1 atm, balloon), 80 1C.
c
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selective formylation. In the copper-catalyzed reaction, the
highest TON and TOF values were observed, as compared with
previously reported catalyst systems using 1 atm of CO2.
A reaction pathway, formation of an amine–CO2 complex which
is then reduced to a formamide by the Cu–H species, was
proposed. The high catalytic activity of the copper-diphosphine
complexes may be applicable further to various reductive
transformations of CO2.
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Acknowledgements
This work was supported by Advanced Catalytic Transformation
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