Copper(i)-catalyzed amidation reaction of organoboronic esters and isocyanates

Article abstract of DOI:10.1039/c5gc01374g

A simple and efficient methodology for the preparation of amides from easily available organoboronic esters and isocyanates has been accomplished using a ligand-free copper(i) catalyst. The reaction system demonstrated a broad substrate scope and provided convenient access to a wide variety of secondary amides.

Full text of DOI:10.1039/c5gc01374g

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DOI: 10.1039/C5GC01374G
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Copper(I)-Catalyzed Amidation Reaction of Organoboronic Esters
and Isocyanates
Received 00th January 20xx,
Accepted 00th January 20xx
Tedrick Thomas Salim Lew, Diane Shu Wen Lim and Yugen Zhang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A simple and efficient methodology for the preparation of amides applications. Furthermore, in Rh or Pd catalyst systems,
from easily available organoboronic esters and isocyanates has organoboron homo-coupling side reaction is unavoidable, leading
been accomplished using ligand-free copper(I) catalyst. The to the use of a large excess of organoboron reagents for the Rh
reaction system demonstrated broad substrate scope and system and low amide yield in Pd system.13 The preparation of
provided convenient access to a wide variety of secondary amides. sterically-hindered and electron-deficient amides in synthetically-
useful yields is also difficult to achieve with these precious metal
Amide bonds are one of the most important chemical building
blocks in nature. Not only do they constitute the backbone of
peptides and proteins, but they are also found extensively in
synthetic polymers, fine chemicals and pharmaceutically active
molecules.1 Despite their ubiquity, most amides are prepared
through the traditional approach of condensation reaction between
carboxylic acids and amine in the presence of stoichiometric
amounts of coupling reagents.2,3 It is therefore not surprising that a
catalytic and more atom-economical approach for amide formation
was recently highlighted as the top challenge in green chemistry
research.4 Aside from economic and environmental concerns, the
preparation of sterically-hindered and electron-deficient amides
from carboxylic acid-amine condensation is also widely recognized
to be a long-standing challenge.5
In recent years, there have been significant efforts to explore
new reaction pathways for amide synthesis from different starting
materials using transition metals as the catalysts.3,6-12 More
recently, the use of organoboron reagents in transition metal-
catalyzed addition reactions with isocyanates to form secondary
amides has been developed.13 These reactions are particularly
useful for the synthesis of various functionalized amides because of
the wide availability of organoboron reagents with different
functional groups.14 In addition, organoborons are non-toxic and
highly stable.15-16 However, the activation of organoboron reagents
in amidation reactions has thus far been the domain of precious
rhodium13a and palladium13b catalysts, thereby limiting its
catalyst systems. On the other hand, the use of cost-effective first
row transition metals such as copper as catalysts for amidation
reactions has attracted great attention.17 Herein we report an
efficient copper-catalyzed system for an amidation reaction
between arylboronates and isocyanates. Some of the notable
features of our approach include: 1) the use of cheap and earth-
abundant copper catalysts, 2) broad substrate scope of both
arylboronates and isocyanates, which includes sterically-
encumbered and electron-deficient substrates, and 3) suppression
of organoboron homo-coupling side reaction.
We began our investigation by using phenylboronic 1,3-
propanediol ester (1a) and 3,5-dimethylphenyl isocyanate (2a) as
the model substrates for the amidation reaction. It was encouraging
to find that in the presence of IPrCuCl (10 mol%), NaOt-Bu (1 equiv.)
o
and DMF (2 mL) at 120 C, the desired product (3a) was detected
after 16 hours, albeit in a low yield (Table 1, entry 1). Two of the
notable side products which were observed are amidine 4a and the
carbamate formed from the reaction between 2a and NaOt-Bu. As
the reaction time was extended to 48 h, the carbamate
intermediate was consumed and this was accompanied by a
substantial increase in the amide yield. When the reaction
temperature was increased to 140 oC, the yield of amide 3a
increased significantly (Table 1, entry 2) while there was only trace
amount of carbamate detected. This suggests that the carbamate
formation is reversible and that it decomposes at extended reaction
time or higher temperature to give 2a and the base. However, at
temperatures above 140 oC (Table 1, entry 3), isocyanate 2a
decomposes through reaction with DMF.18 No phenylboronic ester
homo-coupling side product (biphenyl) was observed in the
reaction mixture.
Various copper catalysts were then screened. To our delight,
ligand-free CuI catalyst was found to be the most efficient catalyst
for this reaction and the formation of amidine 4a was significantly
suppressed (Table 1, entries 4 - 6). Other Cu(I) catalysts were found
to be less effective than CuI, while the use of Cu(II) catalysts led to
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
Singapore 138669. E-mail: ygzhang@ibn.a-star.edu.sg
Electronic Supplementary Information (ESI) available: Details of experimental
procedures and product characterizations. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 2015
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significant formation of undesirable biphenyl side product, thereby OMe), as well as electron-withdrawing substituentsVi(eew.gA.rtichlealOidnleinse,
DOI: 10.1039/C5GC01374G
resulting in lower amide yields (Table 1, entries 5-10). Further CN, CF3), could provide the amide products in good yields (3d-3j).
optimization also revealed that LiOt-Bu gave the highest yield of 3a However, yields were decreased for arylboronate esters with very
among the different bases screened (Table 1, entries 6, 11-17). A strong withdrawing groups, such as nitro group (13% yield, SI). We
slight excess of 1a (1.5 equivalents) was found to further improve were particularly pleased to find that 3i could be efficiently
the yield of 3a to 82% by compensating for the loss of arylboronate prepared by this protocol as trifluoromethyl-substituted amides
ester to background protodeboronation. The use of other serve as important building blocks in the preparation of a wide
organoboron reagents in place of 1a gave the product in a lower variety of agrochemicals and pharmaceuticals.19 Importantly, the
yield under the same reaction conditions (Table S1 in the ESI). Both Cu(I)-catalyzed system was not restricted to aromatic substrates.
the Cu catalyst and the base were crucial for the formation of the Heteroaromatic substrates, such as pyridyl and thienyl derivatives,
amide as no product was formed in the absence of either reagent also furnished moderate yields of the desired amides (3k-3l).
(Table 1, entries 19 and 20).
Although a lower yield of 40% was initially obtained from the
alkenyl boronic ester (3m), extending the reaction time to 48 hours
Table 1 Optimization of reaction conditions for Cu-catalyzed amidation of resulted in a modest yield of 56%.
organoboronic ester and isocyanatea
Table 2 Substrate scope of arylboronate esters 1 for Cu-catalyzed ami-
dation reaction with isocyanatesa,b
Entry
Catalyst (mol%)
Base
T (oC)
Yield 3a (%)b
1
(IPr)CuCl (10)
(IPr)CuCl (10)
(IPr)CuCl (10)
CuCl (10)
CuCl (20)
CuI (20)
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
LiOt-Bu
KOt-Bu
LiOMe
CsF
120
140
160
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
16
34
23
40
53
60
52
34
35
15
64
-
2
3
4
5
6
7
CuCN (20)
CuOAc (20)
CuCl2 (20)
CuBr2 (20)
CuI (20)
8
9
10
11
12
13
14
15
16
17
18c
19
20
21
CuI (20)
CuI (20)
45
17
42
-
CuI (20)
CuI (20)
KF
a
Conditions: 1 (0.75 mmol), 2a (0.5 mmol), CuI (20 mol%), LiOt-Bu (0.5
CuI (20)
Cs2CO3
K3PO4
o
mmol), DMF (2 mL), 140 C, 16 h, Ar atmosphere, unless otherwise noted.
CuI (20)
-
b Isolated yields. c 48 h reaction time.
CuI (20)
LiOt-Bu
LiOMe
-
82
55
-
CuI (10)
CuI (20)
With good reactivity for organoboronate esters in hand, the
substrate scope of the isocyanate was then screened (Table 3).
Sterically-hindered substrates and aryl isocyanates bearing an
electron-donating group readily underwent amidation, resulting in
excellent product yields (3o-3p). In the condensation reaction
conventionally employed for amide synthesis, the preparation of
amides derived from electron-deficient amines is often difficult
because of the decreased nucleophilicity of the amines. On the
other hand, isocyanates bearing electron-withdrawing halide
groups were efficiently transformed into the desired amide
–
LiOt-Bu
-
a Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), base (0.5 mmol),
b
DMF (2 mL), 16 h, Ar atmosphere, unless otherwise noted. Yields were
determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as
c
internal standard. Reaction was carried out using 1.5 equivalents (0.75
mmol) of 1a.
With the optimized reaction conditions, the scope of products through this Cu(I)-catalyzed reaction system (3q-3r).
arylboronate esters was investigated (Table 2). The reaction Various functional groups such as cyano and nitro substituents were
proceeded well with sterically-hindered arylboronate esters, giving also well tolerated under the reaction conditions and the desired
the corresponding amides in moderate to excellent yields (3b-3c). A products were obtained in modest yields (3s-3t). Notably, the bulky
range of arylboronate esters bearing electron-donating groups (e.g.
adamantanyl isocyanate also proved to be an excellent substrate to
2 | Green Chem., 2015, 00, 1-3
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provide the corresponding sterically-hindered amide in high yield available organoboronate esters and isocyanates. The broad
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DOI: 10.1039/C5GC01374G
(3u), highlighting the versatility and efficacy of Cu(I)-catalytic substrate scope showcases the versatility and ability of copper
system for amide formation. In addition, gram scale synthesis of 3a catalysts to mediate this type of synthetic transformation which has
was also carried and 78% of yield was obtained (SI).
previously been achieved only by the use of precious metal
catalysts. Furthermore, this approach also provides an alternative
route to access amides which are difficult to synthesize through a
conventional condensation reaction. This new method would be of
significant use in the amide preparation for pharmaceuticals,
agrochemicals and materials synthesis.
Table 3 Substrate scope of isocyanates 2 for Cu-catalyzed amidation rea-
ction with phenylboronic 1,3-propanediol estera,b
Acknowledgements
This work was supported by the Institute of Bioengineering
and Nanotechnology (Biomedical Research Council, Agency
for Science, Technology and Research (A*STAR), Singapore).
Notes and references
1
(a) J. Zabicky, The Chemistry of Amides, Wiley-Interscience,
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a
Conditions: 1a (0.75 mmol), 2 (0.5 mmol), CuI (20 mol%), LiOt-Bu (0.5
mmol), DMF (2 mL), 140 oC, 16 h, Ar atmosphere, unless otherwise noted.
b Isolated yields.
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The amidation reaction may follow a similar mechanism to that
of the Cu-catalyzed carboxylation of organoboronic esters with CO2
reported by Hou and co-workers,20 with the major difference being
isocyanate as the carbon source instead of CO2. The arylboronate
ester will first undergo a transmetalation reaction with the alkoxide
complex 5 formed by the metathesis reaction between CuI and
LiOt-Bu (Scheme 1). The resulting organocopper complex would
then participate in an addition reaction with the electrophilic
isocyanate to form intermediate 6, which subsequently undergoes
metathesis reaction with LiOt-Bu to regenerate the complex 5.
Simultaneously, this metathesis reaction produces lithium salt 7
which, upon protonation, gives the desired amide product.
3
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Scheme 1 Proposed catalytic cycle for amidation reaction between
organo-boronic esters and isocyanates.
In summary, we have demonstrated an efficient copper-
catalyzed system for the amidation reaction between widely
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8
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DOI: 10.1039/C5GC01374G
A simple and efficient methodology for the preparation of amides from
easily available organoboronic esters and isocyanates with ligand-free
copper(I) catalyst.