Direct and Selective C-H Carbamoylation of (Hetero)aromatics with TMSOTf-Activated Carbamoyl Chloride

Article abstract of DOI:10.1002/ejoc.201801338

Exploiting trimethylsilyltrifluoromethanesulfonate as Lewis acid, (hetero)aromatics underwent regioselective and direct carbamoylation. The method is based on the in situ generation of a highly electrophilic carbamoyl triflate active species.

Full text of DOI:10.1002/ejoc.201801338

DOI: 10.1002/ejoc.201801338
Communication
Lewis Acid Activation | Very Important Paper |
Direct and Selective C-H Carbamoylation of (Hetero)aromatics
with TMSOTf-Activated Carbamoyl Chloride
Ayaka Uehara,[a] Sandra Olivero,[a] Bastien Michelet,[b] Agnès Martin-Mingot,[b]
Sébastien Thibaudeau,*[b] and Elisabet Duñach*[a]
Abstract: Exploiting trimethylsilyltrifluoromethanesulfonate as rect carbamoylation. The method is based on the in situ genera-
Lewis acid, (hetero)aromatics underwent regioselective and di- tion of a highly electrophilic carbamoyl triflate active species.
Introduction
and heteroaryl carbamates and amides are the directed-ortho-
metalation, as long as a well-adapted directing group is present
on the target.[5] Ruthenium-catalyzed ortho-carbamoylation of
arylpyridines[6] and the recently reported use of hydrazine-
carboxamides or formamide as agents for copper-catalyzed or
radical-based carbamoylation in ortho position of the nitrogen
Amide functionality is ubiquitously found, in particular in phar-
maceuticals, natural products, insecticides, polymers and pept-
ides (Figure 1).[1] Amide bond formation, which is identified as
one of the most used reactions for the preparation of drug
candidates,[2] is traditionally performed through the condensa-
tion of amines with acids or acylation of amines with acyl chlor-
ides or anhydrides. To generate aromatic amides, these meth-
ods are thus limited by the necessity to pre-install the amine
or the carboxylic functions into the (hetero)aromatic derivative.
Metal-catalyzed aminocarbonylation emerged as a particularly
versatile method to generate aromatic carboxamides.[3] The di-
rect Pd-catalyzed carbamoylation has also been reported, but
both synthetic routes need pre-activated aryl halide precur-
sors.[4]
of heteroarenes, respectively, are also specific methods.[7]
A
general route to aromatic carboxamides would reside in the
direct Friedel–Crafts type carbamoylation of aromatic rings.[8]
However, this strategy is rather limited to a few stoichiometric
examples, thus probably due to the low reactivity of the
carbamoyl chloride reagents. To overcome this difficulty, related
urea derivatives activated by trifluoromethanesulfonic an-
hydride led to the formation of the corresponding electron-rich
arenecarboxamides.[9] Trifluoromethanesulfonic acid was also
reported to activate carbamates and generate the required re-
active isocyanate cations, allowing the introduction of the
amide functionality into aromatic compounds,[10] a process that
can also be used from nitroaryl ureas.[11] In this context, our
attention was turned to the thirty-years-ago reported reaction
of carbonyl chloride with silver trifluoromethanesulfonate, de-
livering an active carboxylic trifluoromethanesulfonic anhydride
at –30 °C (Scheme 1).[12] In addition, the solvolysis of carbamoyl
chloride was recently shown to occur at the carbonyl carbon,
with replacement of the chloride ion.[13] It was also previously
shown that carbamoyl fluoride could be activated by the strong
antimony pentafluoride Lewis acid, enhancing the partial dou-
ble bond character between carbon and nitrogen.[14] Consider-
Figure 1. Examples of pharmaceutical and agrochemical commercialized aryl
amide containing products.
As a complement to these substitution-based strategies, the
direct C(sp2)-H carbamoylation can be considered as an inter-
esting alternative. Indirect methods to generate substituted aryl
[a] Université Côte d′Azur,
Institut de Chimie de Nice, CNRS, UMR7272,
Parc Valrose, 06108 NICE cedex 2, France
E-mail: Elisabet.Dunach-Clinet@unice.fr
http://unice.fr/recherche/laboratoires/icn
[b] IC2MP-UMR CNRS 7582, Université de Poitiers,
Superacid group-Organic Synthesis Team,
4 rue Michel Brunet TSA 51106, 86073 Poitiers cedex 9, France
E-mail: sebastien.thibaudeau@univ-poitiers.fr
http://superacidgroup.labo.univ-poitiers.fr/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201801338.
Scheme 1. Direct synthesis of aromatic amides by metal triflate activation of
carbamoyl chloride.
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Communication
ing these precedents, we hypothesize that carbamoyl chloride proposed to generate Brønsted acids,[15] the system thus acting
could be efficiently activated by metal triflate Lewis acids to as a hidden Brønsted acid.[16] In the presence of one equivalent
generate an active carbamoyl triflate intermediate in situ, with of triflic acid, only 32 % yield of amide 3a was obtained from
enhanced electrophilicity due to the presence of both the tri- 1a after 3 h in refluxing nitromethane (Table 1, entry 13). This
flate electron withdrawing effect and the metal cation. The result indicates the necessity to activate the carbamoyl chloride
carbamoyl triflate intermediate should thus favor the direct with a strong Lewis acid instead of a strong protic acid. Consid-
carbamoylation of aromatic derivatives (Scheme 1).
ering the generation of chloride ions after carbamoyl chloride
activation by a metal triflate (Scheme 1), these ions could be
detrimental to the desired process, the chloride ions being
competitive to triflate ones. The in situ trapping of chloride ions
could have a positive impact on the reaction. Silver triflate was
thus tested as the promoter, but it led only to 21 % yield of 3a
(Table 1, entry 14). In a different alternative, when trimethylsilyl
triflate was tested as the promoter, the amide 3a was obtained
in 80 % yield from 1a (Table 1, entry 15). The reactivity of
TMSOTf with isomer 1b afforded this time the amide 3b in 73 %
yield, indicating that these conditions could be applied to other
substrates. While triflic acid is known to cleave aromatic and
aliphatic amide bonds, thus limiting its use as catalyst in
carbamoylation reactions,[17] no cleavage of the generated aryl-
amide bond was observed under the TMSOTf conditions, con-
firming the potential of the methodology.
Results and Discussion
To test this hypothesis, resorcinol dimethyl ether 1a was se-
lected as the model substrate and submitted to reaction with
dimethylcarbamoyl chloride 2 in nitromethane (Table 1). The
reaction in the presence of bismuth(III) triflate as the Lewis acid
(25 mol-%) allowed to generate the corresponding amide 3a in
24 % yield at 84 °C (Table 1, entry 1). A series of metal triflate
Lewis acids was then scrutinized (Table 1, entries 2–7), but only
copper(II) and zinc(II) triflates allowed to convert 1a into amide
3a. We next evaluated the impact of carbamoyl chloride load-
ing on the reaction efficiency (Table 1, entries 8–12), revealing
that 2.5 equivalents of carbamoyl chloride after one-hour reac-
tion at refluxing nitromethane was the best conditions to ob-
tain amide 3a in 79 % yield. Moreover, any tentative carbamoyl-
ation performed without promoters was unsuccessful. Unfortu-
nately, when these conditions were further applied to the
carbamoylation of the isomer 1,4-dimethoxybenzene 1b, only
39 % of amide 3b were obtained.
To verify that a triflate-containing active species was gener-
ated in these conditions after chloride-triflate ion exchange, the
reaction of dimethylcarbamoyl chloride 2 with TMSOTf was fol-
lowed by in situ NMR spectroscopy (Figure 2A and Figure 2B).
1
The H NMR spectrum (Figure 2A) reveals the presence of two
Table 1. Optimization of the reaction conditions for the direct carbamoylation
of resorcinol dimethyl ether.
Entry
n
Catalyst
x
T [°C]
t [h]
Yield [%][a]
1
2
3
4
5
6
7
8
4
4
4
4
4
4
4
4
3.1
2.5
1.7
1.3
2.5
2.5
2.5
Bi(OTf)3
Yb(OTf)3
Y(OTf)3
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
1
84
84
84
84
84
84
84
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
1
1
1
1
1
1
1
1
1
1
1
1
3
3
3
24
–
–
–
–
[b]
Fe(OTf)2
Ba(OTf)2
Cu(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
HOTf
8[c]
46
39
60
79
44
18
32[d]
21[d]
80
9
10
11
12
13
14
15
AgOTf
TMSOTf
1
1
[a] Determined by GC analysis using 1,4-dichlorobenzene as internal stan-
dard. [b] Traces. [c] Along with other regioisomers. [d] Determined by 1H-
NMR analysis of the crude product using p-anisaldehyde as internal standard.
With the aim to find a more general method to perform
the direct carbamoylation of a large series of aryl derivatives,
trifluoromethanesulfonic acid was also tested to verify if a protic
acid could promote the reaction. The possibility of the presence
of traces of water in the metal triflates has previously been
Figure 2. Evaluation of the formation of an active carbamoyl triflate interme-
diate by in situ NMR monitoring A: 1H NMR spectra; B:13C NMR spectra.
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Communication
singlets at δ = 3.15 and 3.03 ppm attributed to the remaining chlorobenzene and dimethyl carbamoyl chloride 2, were unsuc-
dimethyl carbamoyl chloride. This was also confirmed by the cessful. The targeted amide from 2-methylthiophene 1j could
presence of two singlets at δ = 40.8 ppm and 38.9 ppm in be generated in 90 % yield, confirming the compatibility of this
addition to the carbonyl signal at δ = 150.5 ppm in the 13C
NMR spectrum corresponding to the signals observed from a
solution of carbamoyl chloride (Figure 2Ab and 2Bb). In addi-
transformation with heteroaromatic substrates. The conditions
could also be applied to the synthesis of 2- and 3-substituted
benzothiophene isomers 3k and 3k′, obtained in 72 % yield.
Analogously, the amides 3l and 3l′ derived from benzofurane
were obtained in 90 % yield. The conditions were also effective
to directly convert indole derivatives to their amide analogues,
as shown by the formation of both 3m and 3n in excellent
yields of 96–99 %. In some cases, it has been reported that the
synergistic combination of different Lewis acids could increase
the favorability of recalcitrant acid-catalyzed processes.[19] We
thus considered evaluating a similar strategy to favor the reac-
tion of substrates 1h and 1i, which had been converted into
their amide analogues in modest yields. When the same reac-
tion was performed by adding a catalytic amount of zinc(II)
triflate (5 mol-%) to TMSOTf, the yield of 3i enhanced from 38 %
to 83 % when similar yields were obtained from 1h.
1
tion, one singlet at δ = 0.52 ppm in the H NMR spectrum and
one signal at 0.2 ppm in the 13C NMR spectrum were attributed
to the remaining trimethylsilyltriflate reactant, as compared
with the data obtained from a solution of TMSOTf in deuterated
nitromethane (Figure 2Ac and 2Bc).
In the 1H NMR spectrum a singlet is also observed at δ =
0.44 ppm correlating with a carbon NMR signal at 3.1 ppm.
These signals were attributed to the in situ generation of a
trimethylsilyl chloride species, an hypothesis which was further
reinforced by comparing these data with the one obtained from
a solution of TMSCl in CD3NO2 (Figure 2Ad and Figure 2Bd). This
result confirmed our initial hypothesis, with the concomitant
formation of the trimethylsilyl chloride species. Interestingly, a
1
nice triplet was also observed at δ = 2.93 ppm in the H NMR
spectrum in a 2:3 ratio compared to the signal of TMSCl. This
signal could be correlated to a carbon signal at δ = 36.9 ppm
in the 13C NMR spectrum. At this stage we hypothesized that
this species must be formed from the “active” carbamoyl triflate
in solution. Considering that traces of water could be present
in these solutions, the formation of dimethylammonium triflate
after water nucleophilic attack on the highly electrophilic dim-
ethylcarbamoyl triflate active intermediate and further decarb-
oxylation was envisaged. To evaluate this aspect, a solution of
dimethyl ammonium chloride (0.5 mmol) and trimethylsilyltri-
flate (0.5 mmol) in [D3]MeNO2 was prepared and analyzed by
NMR spectroscopy (Figure 2Ae and Figure 2Be). The 1H NMR
and 13C NMR signals of this solution perfectly fit with the previ-
ously observed signals, confirming the formation of dimethyl-
ammonium triflate in solution. All these data further reinforced
our initial hypothesis, with the in situ generation of a highly
electrophilic carbamoyl triflate active species, prone to be
trapped by aromatic nucleophiles.[18]
Table 2. Direct carbamoylation of (hetero)aromatic derivatives in the presence
of trimethylsilyl triflate.
The use of TMSOTf in nitromethane was therefore selected
to further evaluate the potential of the direct carbamoylation
of several electron-rich aromatic and heteroaromatic substrates
(Table 2). As mentioned above, substrates 1a and 1b, bearing
two methoxy activating groups on the aryl moiety, could be
efficiently converted into their amide analogues in 80 % and
73 % yield, respectively. Anisole 1c, under the same conditions,
was also selectively transformed into 4-methoxy-N,N-dimethyl-
benzamide 3c in 73 % yield. When the aromatic ring was
strongly activated for electrophilic substitution with three
methoxy groups as in 1d, 90 % of the desired amide 3d could
be obtained by using only a slight excess of carbamoyl chloride.
Analogously, mesitylene 1e was carbamoylated in 67 % yield,
and its dimethylated analogue 3f could also be prepared. While
4-methylanisole 1g could be converted into its amide analogue
3g in 69 % yield, only 46 % of the amide 3h was formed from
3-methylanisole. Similarly, a modest yield was obtained when
[a] Only 1.2 equiv. of dimethylcarbamoyl chloride were necessary to fully
convert substrates 1 to the corresponding amides 3. [b] 5 mol-% of Zn(OTf)2
was added. [c] Traces of side products regioisomers could not be separated
from the desired major regioisomer.
These conditions were then briefly explored for the insertion
of other amide moieties to 1a, by modulating the alkyl substitu-
ents of carbamoyl chloride.[20] Using diethyl carbamoyl chloride
and pyrrolidinyl carbamoyl chloride, resorcinol dimethyl ether
1a could be efficiently converted into the corresponding
amides 3o and 3p, confirming the ability to use this methodol-
toluene 1i was submitted to carbamoylation. Any tentative re- ogy to directly generate a variety of amides from aromatic de-
action with strongly deactivated nucleophiles, such as 1,4-di- rivatives.
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Conclusions
The Lewis acid activation of carbamoyl chloride by trimethylsilyl
triflate generates in situ a highly electrophilic carbamoyl triflate
intermediate, which allows for the direct and selective forma-
tion of benzamide from (hetero)aromatic derivatives.
[4]
[5]
Experimental Section
[6]
[7]
[8]
General Procedure for the Direct Carbamoylation of (Hetero)-
aromatic Derivatives: Aromatic compounds (1 mmol) and 1,4-di-
chlorobenzene (74 mg, 0.5 mmol) were dissolved in dry nitrometh-
ane (15 mL) with stirring at room temperature under nitrogen at-
mosphere. N,N-dialkylcarbamoyl chloride (1.1 or 2.5 mmol), and
TMSOTf (181 μL, 1 mmol) were added to the solution. The reaction
mixture was heated at reflux and left for 3 h. The reaction mixture
was washed with a saturated NaHCO3 solution, extracted with di-
chloromethane, dried on MgSO4, filtered and concentrated under
reduced pressure. The crude product was submitted to column
chromatography on SiO2 with mixture of dichloromethane/meth-
anol or pentane/ethyl acetate as eluents to afford the expected
amide products (oils or powders).
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Acknowledgments
The authors acknowledge the University of Nice for financial
support of this work. The authors also thank the Université de
Poitiers and the Centre National de la Recherche Scientifique
(CNRS) for financial support. The French Fluorine Network is
also thanked for support. The authors acknowledge financial
support from the European Union (ERDF) and “Région Nouvelle
Aquitaine”.
Keywords: Carbamoyl chloride · Lewis acids · Amides ·
Electrophilic substitution · Aromatic substitution
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Received: August 31, 2018
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Lewis Acid Activation
A. Uehara, S. Olivero, B. Michelet,
A. Martin-Mingot, S. Thibaudeau,*
E. Duñach* ........................................... 1–5
Direct and Selective C-H Carbamoyl-
ation of (Hetero)aromatics with
TMSOTf-Activated Carbamoyl Chlor-
ide
TMSOTf acts as Lewis acid to activate in situ; these are active species for late-
carbamoyl chlorides and generates stage aromatic carbamoylation.
highly electrophilic carbamoyl triflates
DOI: 10.1002/ejoc.201801338
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