Thiazolium carbene catalysts for the fixation of CO2 onto amines

Article abstract of DOI:10.1039/c5cc08741d

The catalytic N-formylation and N-methylation of amines using CO₂ as the carbon source represents a facile and sustainable approach for the synthesis of pharmaceuticals and natural products. Herein, we describe highly effective and inexpensive thiazolium carbene-based catalysts derived from vitamin B1 for the N-formylation and N-methylation of amines, using polymethylhydrosiloxane (PMHS) as a reducing agent, which operate under ambient conditions.

Full text of DOI:10.1039/c5cc08741d

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Thiazolium Carbene Catalysts for the Fixation of CO onto Amines
2
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
a,b
a
a
a
a
Shoubhik Das *, Felix D. Bobbink , Safak Bulut , Mylène Soudani , and Paul J. Dyson *
www.rsc.org/
The catalytic N-formylation and N-methylation of amines using procedures require high pressures and harsh reaction conditions,
CO as the carbon source represents a facile and sustainable which limit practical applications of these methods in industry.
2
approach for the synthesis of pharmaceuticals and natural Therefore, mild reaction conditions are desirable, preferably taking
products. Herein, we describe highly effective and inexpensive place at atmospheric pressure and at ambient temperatures.
thiazolium carbene-based catalysts derived from vitamin B1 for
the N-formylation and N-methylation of amines, using Recently, N-heterocyclic carbenes (NHCs) were shown to activate
6
polymethylhydrosiloxane (PMHS) as a reducing agent, which CO
2
under mild reaction conditions. Based on this discovery we
operate under ambient conditions.
investigated their applications for the synthesis of various N-
methylated amines using Ph SiH
as a hydrogen source.7
2
2
Continued emissions of carbon dioxide has led to increased CO
2
1
In addition to the N-methylation of amines, N-formylation via CO
2
levels in the atmosphere that is impacting on climate. Various
approaches to reduce CO levels in the atmosphere, such as capture
of CO and injection deep into the earth, a practice known as carbon
capture and storage (CCS), are under intensive investigation. To
increase the viability of such processes, CO , often regarded as a
fixation is also an attractive reaction as N-formylated compounds are
key chemical intermediates and for the synthesis of drugs,
2
2
8
2
agrochemicals, dyes and fragrances. Formyl groups may also be
transformed into other functional groups, as in the Vilsmeier
2
9
10
reaction, allylation reactions, etc. Their typical synthesis includes
the use of chloral, formic acid, formaldehyde or formate,11 and
generating them from carbon dioxide would be advantageous.
waste, can be considered as an increasingly abundant chemical
3
feedstock, and can be employed to generate value-added products.
This approach is referred to as CCUS (carbon capture, use and
storage).
Scheme 1: Thiazolium carbene catalysts employed in the selective N-
2
formylation or N-methylation of amines using CO .
The activation of CO
2
is highly challenging due to its high
4
thermodynamic stability and kinetic inertness. One approach is to
use energy-rich substrates such as epoxides and aziridines to
overcome this high activation barrier to generate heterocycles.5
Strong (energy rich) nucleophiles such as Grignard reagents,
organolithium agents, organoboranes and organozinc compounds
Cheap and commercially available
Biomimetic in nature
R
2
R
3
R1
Thiazolium carbene
This work:
N
S
Corresponding salt is air stable
Non toxic
NH
2
have also been used to form new C-C bonds with CO . Often these
2
R
1
O
H
H
50°C
N
OH
R1
CO
1 atm.)
2
(
Ph
N
S
PMHS
DMA
NH2
CH
3
Thiazolium carbene
R
1
N
100°C
R
1
CH
3
In a seminal paper ruthenium-based catalysts were used to prepare
N-formylated amines using carbon dioxide and hydrogen the
reducing agent.12 Subsequent papers describe the use of palladium-
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and copper-based heterogeneous catalysts for this reaction.13,14 Due in toluene, THF and acetonitrile, possibly due to the instability of the
to the relatively harsh reaction conditions of these reactions catalyst in these solvents.
employing H
broad appeal,15 especially as they are stable, easy to handle and
commercially available.16 Inspired by the role of vitamin B1 in CO
fixation in animal tissues to synthesize oxaloacetate from pyruvate,
we decided to evaluate thiazolium carbenes (Scheme 1) as
alternatives to NHC catalysts.17 Compared to typical NHC catalysts,
2
, other reducing agents such as hydrosilanes have
Based on the optimized reaction conditions the scope of the
thiazolium carbene catalyzed N-formylation reaction was explored
using catalyst B (Table 2). Aromatic, alicyclic and aliphatic amines
afforded yields of up to 90%. Different amino acids such as
methionine and tryptophan ethyl ester (substrates 1a-3a) reacted
smoothly under the optimized reaction conditions. Moreover, para-
bromo-substituted amines gave the corresponding products in 80%
yield (e.g. substrate 9a) and reductive dehalogenation was not
observed. Notably, the reaction may also be performed on a
multigram scale without the formation of N-methylated products.
2
thiazolium carbenes are inexpensive and non-toxic. Additionally, the
corresponding salt is air stable and can be stored without the need to
18
exclude moisture and oxygen. Carbene catalysts employ silanes as
reductants which can also help to control chemoselectivity.19
Polymethylhydrosiloxane (PMHS) is stable, inexpensive and easily
removed after reaction and, therefore, was selected for this study.
The formyl group is used as an amino-protecting reagent in peptide
synthesis,20 subsequently being converted into isocyano acids.
Table 1: Optimization of reaction conditions for the N-formylation of
ethylphenylalaninate employed as model substrate.[a]
Formylation of peptides is achieved using formic anhydride,
ammonium formate or related reagents.21 These methods have
several limitations such as the thermal instability of peptides at
elevated temperatures resulting in decomposition and the formation
of by-products. We evaluated the N-formylation of dipeptides using
catalyst B (10 mol%) and full conversion of the starting material was
obtained (see supporting information). N-methylation of the amide
bonds or other by-products were not observed. We also conducted a
competition reaction in which N-methylbenzyl amine and benzyl
amine were reacted in the same pot under the optimized conditions.
The secondary amine was found to react faster (ca. 2-3 times) than
the primary amine and, hence, selectivity for a substrate containing
both primary and secondary amines is expected to be low.
O
O
2
CO (1 atm.)
Catalyst (7.5 mol%)
OEt
H
OEt
HN
PMHS (200 µL)
Solvent (3.5 mL)
NH
2
O
50°C
OH
OH
OH
N
N
N
S
N
N
S
2
H N
Vitamin B1 carbene
OH
A
C
N
S
S
B
Table 2: Catalytic N-formylation of amines using CO as carbon
2
Entry
Catalyst
Silane
Solvent
Yield
b
source.[a]
(
%)
58
63
95
43
77
0
1
2
3
4
5
6
7
8
Vit. B1
PMHSc
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
DMAd
DMA
DMA
DMA
2
CO (1 atm.)
Catalyst B (7.5 mol%)
A
B
C
B
B
B
B
O
H
R
1
NH
2
PMHS (200 µL)
DMA (3.5 mL)
R
1
NH
e
DMF
50°C
Acetonitrile
Toluene
THF
0
0
Entry
1
Substrate (a)
Product (b)
Yieldb
(%)
O
[
a] Reaction conditions: substrate (0.5 mmol), catalyst (7.5 mol%), silane (200 μL), solvent (3.5
O
OEt
H
mL), CO (1 atm.), 50°C, 15 h. [b] Yield determined by GC using n-decane as an internal
2
90
HN
OEt
standard. [c] PMHS = polymethylhydrosiloxane. [d] DMA = N,N-dimethylacetamide. [e] DMF =
N,N-dimethylformamide
NH
2
O
O
Several thiazolium carbenes were investigated for the N-formylation
of ethylphenylalaninate, used as a model substrate to identify and
optimize the reaction and key reaction parameters (Table 1). In the
presence of 7.5 mol % of B (Table 1) the corresponding ethyl
formylphenylalaninate was obtained in 95% yield. The other
catalysts evaluated are active, but gave lower yields of the product.
The solvent used is critical, high yields were obtained in DMA and
O
2
3
S
87
75
OEt
H
S
OEt
HN
NH
2
O
O
O
O
H
O
O
H
NH
2
N
NH
N
H
DMF in which the solubility of CO is high. No activity was observed
2
2
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O
The thiazolium carbene catalyst may also be used for N-methylation
reaction using CO combined with PMHS under slightly more forcing
conditions. Numerous reports describe methylation using CO and
hydrogen or silanes as the reducing agent.22,23 In the presence of
catalyst B, 4-methoxyaniline was converted to the corresponding
N,N-dimethylated aniline at 100°C in 81% yield (Scheme 2).
NH
2
2
HN
H
4
53c
83
2
O
HN
H
NH
2
5
6
N-methylation of amines has been shown to enhance the biological
activity of certain drug molecules.24 For example, inserting one or
more methyl groups into a bioactive molecule can enhance
lipophilicity and thereby facilitate transport through cell membranes.
We successfully applied catalyst B to the N-methylation of cinacalcet
OMe
O
OMe
NH2
HN
H
78
(Scheme 3). The N-methylated products were purified in a facile
fashion.
O
NH
2
Scheme 3: Catalytic N-methylation of cinacalcet using CO
carbon source.
2
as a
HN
H
7
8
75
81
2
CO (1 atm.)
Catalyst B (7.5 mol%)
H
PMHS (300 µL)
DMA (3.5 mL)
100°C
NH
2
NH
Cinacalcet
N
N
O
F3C
F3C
CH3
H
83%
O
NH
2
HN
H
Conclusions
9
80
86
In summary, we have demonstrated that a bioinspired thiazolium
carbene compound is an efficient catalyst for fixing CO onto
Br
Br
2
H
O
different amines in the presence of PMHS. The lead catalyst is
cheap and non-toxic. The reaction product, i.e. N-formylation versus
N-methylation, may be tuned by simply changing the reaction
temperature. The catalyst shows a broad substrate scope and
NH
2
NH
10
O
O
1
1
2
(CH2)4 NH2
(CH2)6 NH2
73
75
thereby providing high application in CO fixation reactions.
H
2
(
CH2)4
N
H
Experimental Section
1
2 6
(CH )
N
H
H
Full details are provided in the SI. General procedure for the N-formylation
reaction: The thiazolium salt (0.15 mmol) and sodium hydride (0.15 mmol)
were dissolved in DMA (2 mL) in a 10 mL Schlenk flask and stirred for 30
min to generate the carbene (0.075 mmol/mL solution). The solution was
then stored under nitrogen without stirring, until the inorganic salts settled at
the bottom of the flask. 1 mL of the carbene solution was transferred into a
[
a] Reaction conditions: substrate (0.5 mmol), catalyst
B
(7.5 mol%), PMHS (200
μ
L), solvent (3.5
2
mL), CO (1 atm.), 50°C, 15-24 h. [b] Isolated yield. [c] Yield determined by GC using n-decane as
an internal standard for substrate 4a.
Scheme 2: Catalytic N-methylation of amines using CO as a carbon
2
dry three neck flask (after three vacuum and CO
2
–purge cycles), already
source.
O
H
charged with the amine (0.5 mmol) and connected to a CO
2
balloon. Next,
NH
2
NH
DMA (2.5 mL) and PMHS (200-300 µL) were introduced and the reaction
was monitored by TLC and GC-MS. Upon completion, the reaction mixture
was filtered through celite and washed with ethyl acetate and an aqueous
work up was performed, the solution dried with anhydrous sodium sulfate,
and the product purified using column chromatography using ethyl
acetate/pentane and 1% triethyl amine. All yields are isolated yields unless
otherwise stated.
MeO
PMHS (200 µL), DMA
MeO
MeO
8
3%
OH
CO
1 atm.)
2
50°C
(
CH
3
Ph
NH
2
N
S
N
CH
3
Thiazolium carbene
MeO
PMHS (300 µL), DMA
8
1%
100°C
Acknowledgements
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We thank The CTI Swiss Competence Center of Energy Research
SCCER) on Heat and Electricity Storage for financial support. We are
also thankful to Bastien Lucas Roulier for assistance with some of the
reactions.
(
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