Ritter-type amidation of alkylboron derivatives with nitriles

Article abstract of DOI:10.1016/j.tetlet.2009.09.132

A mild and facile synthesis of amides from alkylboron compounds and nitriles promoted by copper acetate and BF₃·OEt₂ at room temperature is disclosed.

Full text of DOI:10.1016/j.tetlet.2009.09.132

Tetrahedron Letters 50 (2009) 6855–6857
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Tetrahedron Letters
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Ritter-type amidation of alkylboron derivatives with nitriles
*
Clément Cazorla, Estelle Métay, Bruno Andrioletti, Marc Lemaire
Université de Lyon, UCBL, ICBMS, UMR-CNRS 5246, Campus de la Doua, Bâtiment Curien-CPE, 3° étage, 43Boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and facile synthesis of amides from alkylboron compounds and nitriles promoted by copper ace-
tate and BF3ÁOEt2 at room temperature is disclosed.
Received 7 September 2009
Revised 18 September 2009
Accepted 22 September 2009
Available online 25 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Alkylboronic
Ritter amidation
Copper
Oxidative nucleophilic substitution
The search for new, simple and selective methods for the C–N
bond formation remains a challenge for chemists. Among the
classical approaches towards the amide functionality, the Ritter
reaction appears as a general method for the amidation of alcohols
or alkenes.1 However, Ritter amidifications are usually performed
using Lewis2 (SnCl4, BF3ÁOEt2, AlCl3, etc.) or Brønsted acids3 (con-
centrated H2SO4 or AcOH) and high temperature. During the past
decade, alternative milder methods were developed. Thus, Barret
proposed a bismuth triflate-catalyzed amidation4 and more re-
cently, an iron-catalyzed Ritter reaction provided amides from
benzylic alcohols in moderate to high yields.5 However, these
methods require high temperatures (100 °C and 150 °C, respec-
tively), hence limiting the scope of the reaction. In addition,
Ritter-type reactions were used for epoxide ring openings with
nitriles to afford amides.6
Boronic acids and trifluoroborate salts are generally used as effi-
cient cross-coupling partners in Suzuki reactions7 or for 1,4-rho-
dium-catalyzed addition reactions.8 Genet and Darses reported
that the trifluoroborate functionality constitutes an excellent
moiety for Suzuki–Miyaura type cross-couplings giving access to
a large range of elaborated molecules.9 Recently, different groups
have shown that organotrifluoroborate salts could be used for
the elaboration of highly functionalized molecules.9,10 Thus,
Molander and Ham reported that the relative stability of trifluorob-
orate salts tolerates significant chemical transformations such as
the reductive amination11 or SN2 halide substitution of potassium
bromoethyltrifluoroborate.12 Recently, we have used boron com-
pounds as nucleophilic partners in electrophilic fluorination
reactions.13
During the course of our studies dealing with the peculiar reac-
tivity of organotrifluoroborates, we became interested in studying
the reactivity of the organoboron moiety towards nitriles under
mild conditions. To the best of our knowledge, such specific reac-
tivity for boronic derivatives has never been described to date.
We discovered that the C–N bond formation could be promoted
by a stoichiometric amount of copper acetate in the presence of
two equivalents of boron trifluoride diethyl etherate at room tem-
perature (Scheme 1).
In order to determine the role of each reagent, different exper-
iments were carried out. Using the same experimental conditions
but in the absence of copper acetate, the expected compound
was not detected. Similarly, no reaction occurred in the absence
of BF3ÁOEt2. In consequence, each of these reagents is necessary
for the amide bond formation.
The optimized conditions for the coupling involved the treat-
ment of an organotrifluoroborate potassium salt (0.5 M in MeCN)
with a stoichiometric amount of anhydrous Cu(OAc)2 and two
equivalents of BF3ÁOEt2 at room temperature. Using these condi-
tions, 1-phenyltrifluoroborate potassium salt afforded the corre-
sponding acetamide in 75% isolated yield in 10 min (Table 1,
entry 1). Similarly, diversely substituted benzyltrifluoraborates
O
Cu(OAc)2 1 equiv,
BF3.OEt2 2 equiv
N
BF3K
H
Acetonitrile, RT
* Corresponding author. Tel.: +33 4 72 43 14 07; fax: +33 4 72 43 14 08.
E-mail address: marc.lemaire@univ-lyon1.fr (M. Lemaire).
Scheme 1. Copper-promoted addition of acetonitrile on alkytrifluoroborates.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.132

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C. Cazorla et al. / Tetrahedron Letters 50 (2009) 6855–6857
Table 1
Amidification of various boron compounds and acetonitrile
Entry
1
Substrates
Products
Yielda (%)
75
O
BF3K
BF3K
N
H
O
2
3
61
66
N
H
O
BF3K
N
F3C
O
H
F3C
O
O
BF3K
4
5
80
N
H
H
N
BF3K
70
0
O
O
6
BF3K
N
H
a
Isolated yield.
Table 2
Amidification of various nitriles with potassium 1-phenylethylboronate
afforded the expected amides in 61–66% yield (Table 1, entries 2
and 3). However, it is worth noting that for primary benzyltrifluo-
raborates, the reaction generally requires longer reaction times (up
to 48 h) in order to obtain a good conversion. Interestingly, trans-
2-phenylvinylboronic acid (Table 1, entry 4) afforded the unex-
pected N-(1-phenylethyl)acetamide in 80% yield. Formation of
the latter can be explained by considering that the attack of the
nucleophile (acetonitrile) is favoured on the most reactive benzylic
position. Secondary alkylboronic acids give also the expected prod-
uct. Nevertheless their lower reactivity involves also a longer reac-
tion time (up to 96 h), and hence oxidative degradation. Thus,
cyclohexanol was identified as a major by-product when cyclo-
hexylboronic acid was used as a substrate (Table 1, entry 5). The
limitation of this reaction appeared for primary potassium alkyltri-
fluoroborate salts, as no conversion was observed. In this case, the
reduced alkane (here octane) was the only newly formed com-
pound (Table 1, entry 6).
Entry
Substrates
Products
Yielda (%)
85
O
O
O
O
1
CN
N
H
CN
2
3
4
70
93
70
N
H
*
CN
*
N
H
9
9
CN
N
H
The scope and limitations of this protocol were examined using
a series of nitriles. However, as some nitrile parts of this study
were solid, we had to check if the presence of a solvent would have
an impact on the outcomes of the reaction. Accordingly we re-
peated the reaction between 1-phenyltrifluoroborate potassium
salt and acetonitrile in toluene at a concentration of 0.5 M. The ni-
trile was introduced in 10-fold excess, copper acetate and BF3ÁOEt2
in onefold and twofold excesses, respectively (Scheme 2). Using
these conditions, the expected acetamide was isolated in 75%. This
result demonstrated that the presence of a solvent was not delete-
rious. According to the same experimental procedure, we tested a
series of primary alkylnitriles, (Table 2, entries 1, 3 and 4). Each of
O
CN
5
51b
N
H
O2N
NO2
a
Isolated yield.
b
Determined by GC analysis.
these reactions afforded the corresponding amide in good isolated
yield in 1 h at room temperature. Similarly, the amide obtained
from benzonitrile was isolated in 70% yield (Table 2, entry 2). As
expected, the presence of electron-withdrawing groups on the aro-
matic ring decreases the nucleophilicity of the nitrile and favours
the dimerization of the boron compound. Thus, in the case of
4-nitrobenzonitrile (Table 2, entry 5) a GC analysis revealed the
formation of amide and 2,3-diphenylbutane (dimer) in a 1:1 ratio.
In the case of 4-bromoacetonitrile, the expected compound was
not observed. On the other hand, the reduced bromide was de-
tected as the major by-product.
O
Cu(OAc)2, 1 equiv
BF3.OEt2 2 equiv
N
R
BF3K
H
R
CN
Toluene, RT
Scheme 2. Amidification with potassium 1-phenylethylboronate and different
nitriles.

C. Cazorla et al. / Tetrahedron Letters 50 (2009) 6855–6857
6857
trifluoride. This transformation was realized at room temperature
without the need of ligand for the copper. We propose that the
coupling involves an oxidative nucleophilic substitution mecha-
nism followed by the subsequent attack of the nitrile as nucleo-
phile. More detailed mechanistic investigations are currently
under way in our laboratory, in order to understand the exact role
of copper acetate and boron trifluoride diethyl etherate.
Cu(OAc)2,
BF3.OEt2
R 2
R1
R2
R1
BF3K
CuII Cu0
Me C N
O
R 2
R1
R 2
R1
H2O
NH
N
Me
Acknowledgement
Scheme 3. Proposed mechanism for the Ritter-type amidification.
C.C. thanks the French Ministry for teaching and research
(MESR) for financial support.
Based on the afore-mentioned results and on the basis of the
mechanism proposed for the Ritter amidification,14 we believe that
the combination of copper acetate and boron trifluoride generates
an oxidative complex able to reverse the polarity of the C–B bond,
hence creating a carbocation that is able to react subsequently
with the nucleophilic nitrogen atom of the nitrile (Scheme 3).
Upon quenching, the latter intermediate is hydrolyzed affording
the corresponding amide. Two major observations support this
mechanism. Firstly, a precipitate of metallic copper was observed
every time the coupling occurred. Secondly, we excluded the
mechanism that involved direct oxidation of the boronate with
the corresponding alcohol as no alcohol was detected by GC anal-
yses for any of these tests with the exception of the reaction with
octyltrifluoroborate (Table 1, entry 6). However, in this case, no
amide was detected. This result demonstrates that in our condi-
tions the ‘classical’ Ritter-type mechanism does not occur. Never-
theless, in some case, Table 1 entry 4 and Table 2 entry 5, the
mechanism could be different. The product obtained (Table 1 entry
4) or the formation of 2,3-diphenylbutane (Table 2, entry 5)
suggests a free radical intermediate. In these two cases, the active
species could result from the reaction of BF3ÁOEt2 with alkyltriflu-
oroborate affording the very reactive RBF2 entity.15
References and notes
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In conclusion, we have developed a mild and efficient method
for the preparation of amides from nitriles and trifluoroborate
potassium salt derivatives promoted by copper acetate and boron