Direct Synthesis of Carbamoyl Fluorides by CO2 Deoxyfluorination

Article abstract of DOI:10.1002/anie.201907354

Herein, a new concept for the direct synthesis of carbamoyl fluoride derivatives is disclosed. The developed method makes use of CO₂ as an inexpensive and abundant C₁ source; a variety of amines were successfully converted in the presence of a deoxyfluorinating reagent. The corresponding products were often obtained in excellent yields under mild reaction conditions (1 atm and room temperature). The reaction was easily scaled up, demonstrating the efficiency of the developed process.

Full text of DOI:10.1002/anie.201907354

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Accepted Article
Title: Direct Synthesis of Carbamoyl Fluoride through Unprecedented
Deoxyfluorination of CO2
Authors: Killian Onida and Anis Tlili
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907354
Angew. Chem. 10.1002/ange.201907354
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10.1002/anie.201907354
Angewandte Chemie International Edition
COMMUNICATION
Direct Synthesis of Carbamoyl Fluoride through Unprecedented
Deoxyfluorination of CO2
Killian Onida,[a] and Anis Tlili*[a]
Abstract: Herein
a
new concept for the direct synthesis of
a starting material in the presence of reductants for the
synthesis of high valuable chemicals including formamides
derivatives, methyl amines etc [6] [7]
carbamoyl fluoride derivatives is disclosed. The developed
methodology makes use of the interesting CO2 as cheap and
abundant C1 source starting with a variety of amines in the presence
of deoxyfluorinating reagent. The performed products are often
obtained with excellent yields and the reactions are realized under
mild conditions of pressure (1atm) and temperature (room
temperature). The scalability of the reaction has been easily
implemented demonstrating the efficiency of the developed process.
We envisioned that the synthesis of new fluorinated
molecules making use of CO2 would constitute even a higher
added value in comparison to the state of the art. Herein we
report an unprecedented catalyst-free synthesis of carbamoyl
fluorides starting from amines and by using CO2 as a C1 source
in the presence of a deoxyfluorinating reagent (Scheme 1).
Worth noting, carbamoyl fluoride could be accessed by reacting
amines with high pressure of Carbonyl fluoride or by reacting
difluorocarbene with Hydroxylamines.[8]
Fluorinated compounds have found a plethora of novel
applications in all areas of life science technology.[1] The
particular interest in this class of compounds relies on their
unique physical-chemical properties as they affect for example
the lipophilicity of the molecule.[2] Also, C-F bonds can mimic C-
H bonds allowing a higher oxidation resistance more known as
NEW CONCEPT
O
O
C
O
R1
H
N
R1
C
F3S
Y
N
F
[3]
R2
the « block effect ». Hence, it is not surprising that nowadays
R2
deoxyfluorinating
reagent
more than 20% of pharmaceutical and 40% of agrochemical
active ingredients contain at least one fluorine atom. In this
context, the perpetual development of new concepts for the
introduction of fluorine or fluorine containing groups is highly
appealing.
Scheme 1. General scheme for the new concept
From a conceptual standpoint, the deoxyfluorination of CO2
will constitute the key of success to achieve our goal furnishing
the corresponding carbamoyl fluoride.
On the other hand, reducing the concentration of
atmospheric CO2 is considered one of the most challenging
tasks that scientists are facing nowadays. Furthermore, in recent
years, this challenge has been found to be enormously complex
since the impact of climate change is more obvious in daily life.
In recognition of the current CO2 phenomenon, political bodies in
most developing countries are implementing strategies to
discourage carbon growth. In parallel, the transformation of the
anthropogenic CO2 is an appealing field of research. From a
chemical viewpoint, CO2 is a cheap and abundant feedstock.
Nevertheless, its transformation as a C1 source constitutes a
major challenge to modern organic chemistry evoked by its
thermodynamic stability and kinetic inertness. To date, a handful
of industrial processes make use of CO2 as a C1 source.[4] In
this context, the developments of new transformations based on
the use of CO2 are highly covetable.[5] Thus, complementary to
bulk industry efforts the valorization of CO2 has recently become
more prominent in the fine chemical industry. For instance, the
capability of amines to uptake/bind CO2 is of fundamental
importance and is utilized industrially to remove CO2. In this
regard, the valorisation of amine/CO2 adduct have been used as
In order to confirm the feasibility of the concept we selected
piperidine as model amine substrate. The first reaction was
performed with DAST (1equiv.) in THF at room temperature
under 1 atm of CO2. This initial attempt enabled the formation of
the desired product in an encouraging yield of 39% (table 1,
entry 1). With this proof of concept in hand, we decided to
further investigate the reaction to improve the transformation
outcome. To do so, we chose to investigate the solvent effect. In
1,4-dioxane a lower reactivity was observed and only 24% of the
desired product was formed (Table 1, entry 2). Further
experiments demonstrated that also DMF as well as DMSO are
less effective solvents for this transformation leading to low
yields of 21% and 18%, respectively. Interestingly, the yield
increased to 48% when acetonitrile was used as solvent (table 1,
entry 5). Furthermore, we have demonstrated that the reaction
can be conducted under neat conditions although with inferior
reaction outcome (table 1, entry 6). To further improve the
reaction efficiency we tested the addition of additives. We
decided to investigate the presence of an external base on the
reaction outcome. The use of inorganic Cs2CO3 did not show
any positive impact on the reaction yield (table 1, entry 7). Next
we decided to investigate organic bases. While imidazole had a
detrimental effect on the yield (table 1, entry 8), the use of
DIPEA showed a positive impact (table 1, entry 9). NEt3 as well
[a]
K. Onida, Dr. A. Tlili
Institute of Chemistry and Biochemistry (ICBMS–UMR CNRS 5246)
Univ Lyon, Université Lyon 1, CNRS, CPE-Lyon, INSA
43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
E-mail: anis.tlili@univ-lyon1.fr
as 2,6-Lutidine proved to be enabling
a more efficient
transformation since respectively 72% and 74% yield were
obtained (Table 1, entries 10 & 11). Finally, an excellent yield of
90% was reached when DMAP was used as added base (table
1, entry 12). Performing the reaction with only 0.5 equivalents of
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10.1002/anie.201907354
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COMMUNICATION
DAST resulted in only 42% yield. A control experiment was
conducted in the absence of CO2 and did not lead to any product
formation.
starting from 4-(N-Boc-amino)piperidine 1e was isolated with a
synthetically useful yield of 51% (product 2e, Scheme 2).
Notably, the reaction proceed with high selectivity since only
transformation of the cyclic nitrogen was observed. The
corresponding structure has been confirmed by Hoesy NMR
and unambiguously by X-ray analysis. Piperazine substituted
with pyridine or 4-chlorobenzene was converted into their
corresponding carbamoyl derivatives 2g and 2h with excellent
reaction outcome. Tetrahydroisoquinoline 1i was transformed
into its corresponding product with 90% yield. Interestingly, the
presence of internal alkene is also tolerated and product 2j has
been obtained in almost quantitative yield. Moreover,
methylanilines were successfully transformed into their
carbamoyl analogues in moderate to very good yields
(products 2k, 2l, 2m). Benzylic amines are also compatible
with this methodology and were converted successfully even in
the presence of ester functionality (product 2o) although in low
yield. Interestingly, our protocol is applicable to bioactive
compounds. Nortriptyline and Desipramine was converted to
their corresponding carbamoyl compounds 2s and 2t in
excellent yields of up to 99%. It should be mentioned that the
respective starting materials were employed as hydrochloride
salts in conjunction with of 2 equivalents of DMAP.
Table 1. Reaction optimisation
O
C
Et
F
Et
O
C
O
H
N
S
F
Base
N
N
F
Solvent
2h, RT
F
DAST
(balloon) (1 equiv.)
Entry
Solvent
Base
Yield (%)b
1
2
THF
1,4-dioxane
DMF
-
39
24
21
18
48
24
45
33
51
72
74
90
42c
66d
-
-
3
4
DMSO
ACN
-
5
-
6
-
-
7
ACN
Cs2CO3
Imidazol
DIPEA
NEt3
8
ACN
9
ACN
Table 2. Evaluation of deoxyfluorinating agentsa
10
11
12
13
14
ACN
ACN
2,6-Lutidine
DMAP
DMAP
DMAP
DMAP
(1 equiv.)
O
C
ACN
O
C
O
H
DeoxF
reagent
N
N
F
ACN
ACN
2h, RT
ACN
(balloon) (1 equiv.)
[a] Reactions were performed with Piperidine (1 mmol, 1 equiv.), DAST (1
mmol, 1 equiv.), CO2 (1 atm), base (1 mmol) and solvent (2 mL). The
reaction mixture was stirred at rt for 2 hours. [b] Determined by 19F NMR
spectroscopy with PhOCF3 as an internal standard. [c] Reaction performed
with 0.5 equiv. of DAST. [d] Reaction performed with 0.5 equiv. of DMAP.
DAST=Diethylaminosulfur trifluoride. DIPEA= N,N-Diisopropylethylamine.
DMAP = 4-Dimethylaminopyridine.
F
S
O
F
F
Et
F
Et
Et
Et
N
N
S
DeoxF
reagent
BF4
BF4
N
S
S
F
F
tBu
F
F
F
F
DAST XtalFluor-E XtalFluor-M
Fluolead
Entry
DeoxF reagent
DAST
Yield (%)b
90
The testing of other common deoxyfluorinating agents such
as XtalFluor-E, XtalFluor-M[9] as well as Fluolead[10] led to only
moderate yield between 24% to 36% (table 2). It has been
demonstrated that an exogenous fluoride source is enhances
the performance of XtalFluor-E and XtalFluor-M. Indeed, in our
case adding 1 equivalent of 3HF.Et3N improved the reaction
outcome singificantly and yields up to 60% was obtained.
However, the latter results still fall short of those observed with
DAST.
1
2
3
4
XtalFluor-E
XtalFluor-M
Fluolead
24, 46c
30, 60c
36
[a] Reactions were performed with Piperidine (1 mmol, 1 equiv.), DeoxF
reagent (1 mmol, 1 equiv.), CO2 (1 atm), DMAP (1 mmol) and ACN (2 mL).
The reaction mixture was stirred at rt for 2 hours. [b] Determined by 19F NMR
spectroscopy with PhOCF3 as an internal standard. [c] Reaction performed in
the presence of 3HF.Et3N (1equiv., 0.33 mmol).
With the best conditions in hand, we investigated the
reaction scope under the optimized reaction conditions. Cyclic
piperidine, morpholine as well as N-methyl-piperazine
furnished the desired product with excellent yields (up to 99%,
products 2a, 2b and 2c, Scheme 2). Interestingly, BOC-
protected piperazine underwent fluorocarbonylation with
excellent reaction outcome (90%, product 2d). Noteworthy,
product 2d has been characterized by X-ray analysis. When
Runing the experiment with an hydroxylated amine 1u, 4-
Piperidine-methanol, furnishes the desired product 2u as well as
a deoxyfluorinated product 2u’ both in low yield.
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10.1002/anie.201907354
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COMMUNICATION
O
C
Et
F
Et
O
C
O
DMAP (1 equiv.)
N
S
F
R1
H
R1
N
N
F
ACN
2h, RT
F
R2
R2
DAST
1
(balloon)
(1 equiv.)
2
O
O
O
O
O
N
F
N
F
N
F
N
F
N
F
Boc
N
O
N
N
Boc
H
2a, 74% (90%)
2b, (99%)
2c, (99%)
2d, 74% (90%)
2e, 42% (51%)
O
O
O
N
F
N
F
N
F
N
F
N
N
Ph
N
O
N
Ph
Cl
2f, 84% (99%)
2g, 72% (96%)
2h, 83% (99%)
2i, 67% (90%)
O
F
O
F
O
F
N
O
N
Ph
N
Ph
F
Et
N
N
N
N
O
O
O
O
F
F
MeO
2l, 54% (69%)
Br
2j, 71% (99%)
2k, (60%)
2m, (60%)
2n, 84% (90%)
2o, 21 (24%)
O
O
F
O
N
N
O
N
F
N
N
N
F
F
O
F
2s, 42% (48%)b
2t, 64% (96%)b,c
2p, 90 (90%)
2q, 72 (78%)
2r, 83% (90%)
92% (99%)b,c
Scheme 2. [a] Reactions were performed with amine (1 mmol, 1 equiv.), DAST (1 mmol, 1 equiv.), CO2 (1 atm), DMAP (1 mmol) and ACN (2 mL) unless
otherwise noted. The reaction mixture was stirred at rt for 2 hours. Yields shown are those of isolated products; yields determined by 19F NMR spectroscopy with
PhOCF3 as internal standard are shown in parentheses. [b] HCl salt. [c] Reaction performed with 2 equiv. of DMAP.
HO
reagents as demonstrated for Notriptyline hydrochloride as well
N
N
O
O
as Desipramine hydrochloride. The respective 13C-labelled
carbamoyl analogues were obtained in very good to excellent
isolated yields (Scheme 5)
2u, (30%)
2u', (30%)
C
F
Et
F
Et
O
C
O
DMAP (1 equiv.)
N
S
F
HO
ACN
2h, RT
NH
F
F
DAST
C
F
O
1u (0.5 mmol) (balloon) (2 equiv.)
Et
F
Et
R2
H
O
13C
O
DMAP (2 equiv.)
N
S
F
R2 13C
N
Scheme 3. Reaction with hydroxylated amine: yields determined by 19F NMR
N
F
R1
Solvent
2h, RT
F
R1
spectroscopy with PhOCF3 as internal standard
H.Cl
DAST
Ph
1 atm
(1 equiv.)
Ph
Et
F
Et
O
C
O
DMAP (1 equiv.)
N
S
F
Ph
N
ACN
Ph
N
N
O
F
C
F
2h, RT
NH
DAST
O
O
N13
C
N13
C
20 mmol (balloon) (1 equiv.)
2f, 72% (99%)
N
4,3 g
F
F
Scheme 4. Scale-up experiment
[
13C]2s, 50% (58%)
[
13C]2r, 62% (70%)
In order to demonstrate the applicability of the reaction, we
performed scale-up experiment. Amine 1f (20 mmol)
underwent complete conversion and 4.3 g of the corresponding
Scheme 5. Direct formation of N-13COF by using 13CO2 : [a] Reactions were
performed with amine (1 mmol, 1 equiv.), DAST (1 mmol, 1 equiv.), CO2 (1
atm), DMAP (1 mmol) and ACN (2 mL).
a
product 2f could be isolated (72% yield, Scheme 4).
From a mechanistic standpoint, it is important to note that we
observed during the establishment of the reactions that upon
mixture of an amine with CO2 a subsequent formation of salt
In order to further explore the versatility of our methodology
we investigated the reaction in the presence of 13CO2. This
approach allows for the direct access of radiolabeled bioactive
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10.1002/anie.201907354
Angewandte Chemie International Edition
COMMUNICATION
(rotary evaporator). The residue was purified by column chromatography
to give the desired product in 74% as a colorless liquid.
takes place. Obviously, it is well documented that the formation
of carbamate could take place (Intermediate A, Scheme 7). In
order to confirm the hypothesis that DMAP is playing only a role
of base we decided to investigate the reaction with the
deprotonated amine. To do so, we performed the reaction with
n-BuLi (Scheme 6). Herein the desired product could be
obtained in 80% yield.
Acknowledgements
This work was supported by the CNRS, COLUMN, ICL (Institut
de Chimie de Lyon). We thank Dr. Guillaume Pilet (Université
Lyon 1) for collecting the crystallographic data. We are grateful
to Dr. E. Métay, Pr. J. Leclaire and Pr. A. Amgoune (ICBMS
Lyon) for fruitful discussion
Ph
Ph
1) n-BuLi (1 equiv.)
THF, 5 min, RT
Ph
N
Ph
N
N
O
2) CO2, DAST (1equiv.)
2 h, RT
NH
C
F
1 mmol
2f, (80%)
Keywords: Fluorination • Carbon dioxide • Amines •
Scheme 6. Synthesis of Carbamoyl fluoride 2f in the presence of strong base
Deoxyfluorination • Deoxyfluorinating agent
In light of the obtained preliminary mechanistic investigations,
we could propose the following mechanism (Scheme 7). Amine
reacts with CO2 to form the carbamate A. this later could react
with DAST to form intermediate B and the starting amine is
regenerated in the presence of a base. The desired product is
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a) in Fluorine in Life Sciences: Pharmaceuticals, Medicinal Diagnostics,
and Agrochemicals. (Eds.: G. Haufe, F. Leroux), Elsevier Science,
London, United Kingdom, 2018, pp. 459-518.e) P. Kirsch in Modern
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Chem. Soc. Rev. 2008, 37, 308-319.
[2]
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Alex, Angew. Chem. Int. Ed. 2016, 55, 674-678; Angew. Chem. 2016,
128, 684-688.
generated form intermediate
B
either via an inter/ or
intramolecular fluorine attack and diethylsulfuramidous fluoride
C that we identify in fluorine NMR.
[3]
[4]
[5]
W. K. Hagmann, J. Med. Chem. 2008, 51, 4359-4369.
Base
S. Dabral, T. Schaub, Adv. Synth. Catal. 2019, 361, 223-246.
a) J. Artz, T. E. Müller, K. Thenert, J. Kleinekorte, R. Meys, A.
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Ph
Ph
Ph
Ph
O
C
O
Ph
Ph
H
H
2
N
NH
+ CO2
N
N
N
N
A
F
[6]
[7]
F
S NEt2
F
Ph
Ph
O
N C
O
F
Ph
O
F
F
+
F
+
N
S
NEt2
N
N C
NEt2
S
O
Ph
C
F
a) C. Das Neves Gomes, O. Jacquet, C. Villiers, P. Thuéry, M.
Ephritikhine, T. Cantat, Angew. Chem. Int. Ed. 2012, 51, 187-190;
Angew. Chem. 2012, 124, 191-194. b) O. Jacquet, C. Das Neves
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Jacquet, X. Frogneux, C. Das Neves Gomes, T. Cantat, Chem. Sci.
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B
F
Scheme 7. Proposed mechanism
In conclusion, we demonstrated that carbamoyl fluorides
derivatives could be obtained for the first time starting with
amines and by using CO2 as a C1 source in conjunction with a
deoxyfluorinating reagent. The reactions are performed under
mild conditions of pressure (1atm) and temperature (room
temperature) and the scope encompasses a wide range of
starting amines derivatives. Moreover, the scalability of the
reaction was demonstrated without any loose in the reaction
outcome. Finally, the direct access to radiolabeled bioactive
reagents was also demonstrated by using 13CO2.
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Bolm, Adv. Synth. Catal. 2016, 358, 2293-2299; c) The formation of
carbamoyl fluroide has been observed also as a by product in a recent
insitu generation of fluorophosgene: D. Petzold, P. Nitschke, F. Brandl,
V. Scheidler, B. Dick, R. M. Gschwind, B. König, Chem. Eur. J. 2019,
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Experimental Section
Typical Procedure: Synthesis of Piperidine-1-carbonyl fluoride 2a:
to a flame-dried Schlenk flask were added DMAP (122 mg, 1.0 mmol, 1.0
equiv.). The flask was evacuated and back-filled with CO2 3 times, and
then dry ACN (2 mL) was added by syringe. Then, the amine (1.0 mmol,
1.0 equiv) and the DAST (dropwise) (1.0 mmol, 1.0 equiv.) were
successively added to the Schlenk flask equipped with a balloon of CO2.
The reaction mixture was stirred at 25°C for 2h (conversion is checked by
19F NMR with PhOCF3 as internal standard). The resulting mixture was
diluted with ether (10 mL) and water (2 mL). Following phase separation,
the aqueous layer was extracted with ether (3 x 5 mL). The resulting
organic layer was washed with brine (1 x 2 mL), The organic layer was
dried over anhydrous MgSO4 and evaporated under reduced pressure
[9]
a) F. Beaulieu, L.-P. Beauregard, G. Courchesne, M. Couturier, F.
LaFlamme, A. L’Heureux, Org. Lett. 2009, 11, 5050-5053; b) A.
L’Heureux, F. Beaulieu, C. Bennett, D. R. Bill, S. Clayton, F. LaFlamme,
M. Mirmehrabi, S. Tadayon, D. Tovell, M. Couturier, J. Org. Chem.
2010, 75, 3401-3411.
[10] T. Umemoto, R. P. Singh, Y. Xu, N. Saito, J. Am. Chem. Soc. 2010,
132, 18199-18205.
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COMMUNICATION
COMMUNICATION
K. Onida, and A. Tlili*
Page No. – Page No.
Direct Synthesis of Carbamoyl
Fluoride through Unprecedented
Deoxyfluorination of CO2
Deoxyfluorination of CO2: A new concept based on the reductive fluorination of
CO2 is disclosed herein. Carbamoyl fluoride are synthesised through
unprecedented deoxyfluorination of CO2. The reactions are easily scalable and the
concept is exploited for the syntheis13C-labelled carbamoyl analogues.
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