Synthesis of Amides and Phthalimides via a Palladium Catalyzed Aminocarbonylation of Aryl Halides with Formic Acid and Carbodiimides

Article abstract of DOI:10.1002/asia.201601421

A novel method for the preparation of amides and phthalimides has been developed. The process involves a palladium catalyzed aminocarbonylation of an aryl halide, using a carbodiimide and formic acid as the carbonyl source. Experimental data suggest that the mechanistic pathway for this process involves in-situ generation of carbon monoxide from the reaction of formic acid with a carbodiimide in the presence of a palladium catalyst. The method can be used to produce a variety of amides and N-substituted phthalimides efficiently.

Full text of DOI:10.1002/asia.201601421

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Synthesis of Amides and Phthalimides by Palladium Catalyzed
Aminocarbonylation of Aryl Halides with Formic Acid and
Carbodiimides
Authors: Yong-Sik Seo, Dong-Su Kim, and Chul-Ho Jun
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To be cited as: Chem. Asian J. 10.1002/asia.201601421
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Synthesis of Amides and Phthalimides by Palladium Catalyzed
Aminocarbonylation of Aryl Halides with Formic Acid and
Carbodiimides
Yong-Sik Seo,† Dong-Su Kim† and Chul-Ho Jun*
Dedication ((optional)
Abstract: A novel method for the preparation of amides and
phthalimides was developed. The process involves palladium
catalyzed aminocarbonylation of an aryl halide, using a carbodiimide
and formic acid as the carbonyl source. Observations made in this
effort suggest that the mechanistic pathway for this process involves
in-situ generation of carbon monoxide by reaction of formic acid with
carbodiimide in the presence of the palladium catalyst. The method
can be utilized to produce a variety of amides and N-substituted
phthalimides efficiently.
Amides comprise one of the most important families of organic
compounds. Thus, a number of methods have been developed
to prepare these substances, which are employed in
pharmaceutical, biological and industrial arenas.1 Recently, atom
economic, transition-metal catalyzed, aminocarbonylation
reactions have been widely studied.2 Perhaps the most useful
method for promoting aminocarbonylation is the one developed
by Heck involving palladium catalyzed reactions of aryl halides
with amines.3 This process is typically carried out using high
Scheme 1. (a) Generation of CO2 from formic acid (b) Generation of CO from
the mixture of formic acid and disopropylcarbodiimide (c) New strategy for the
formation of amides and isocyanates through palladium catalyzed
aminocarbonylation
pressure of toxic CO as the carbonyl source. Because of this
drawback, carbon monoxide free palladium catalyzed
aminocarbonylation reactions using various CO surrogates have
become an attractive goal of investigations in this area.4-12
During the course of recent studies targeted at the design of
new CO surrogates,13 we observed that reaction of formic acid in
the presence of Pd(OAc)2 generates CO2 gas (Scheme 1a).14
Interestingly, addition of carbodiimide to formic acid under the
palladium catalysis conditions produces N,N’-diisopropylurea
(3a) in 78% yield along with CO (Scheme 1b; see ESI).15 We
proposed that urea 3a is formed in this process by reaction of
isocyanate 4a with amine 6a. Based on this hypothesis, we
In initial experiments designed to probe the feasibility of the
newly
proposed
strategy
for
palladium
catalyzed
aminocarbonylation, reaction of iodobenzene (8a) with formic
acid (1a) and N,N′-diisopropylcarbodiimide (9a) in the presence
of Pd(OAc)2 (2a, 5 mol %) was explored. This process was
found to form benzamide 11a in 79% yield (based on 8a) (Table
1, entry 1). Isocyanate 4a is also generated in this reaction in a
79% yield (based on 1a) as deduced from the isolation of N-
isopropyl-N’,N’-dimethyl urea formed following addition of
diethylamine to the reaction mixture. Note that two moles of 4a
are produced per mole of 11a because 2 equivalents of both
formic acid and the carbodiimide are used in the process.
Addition of metal ligands such as tricyclohexylphosphine (10a)
and imidazoles 10b and 10c leads to improved reaction
efficiencies. In this series, 10b was found to be the optimal
ligand while the related dialkyl-substituted imidazole 10d
displays low reactivity (entries 2-5). Other transition metal
catalysts such as PdCl2 (2b), NiCl2 (2c) and CoCl2 (2d) were
found to have lower catalytic activities than does 2a (entries 3,
6-8). Additionally, reaction does not take place in the absence of
Pd (entry 9). Finally, among various solvents tested, toluene was
found to be optimal (entries 3, 10-12).
designed
a
new
strategy for
palladium catalyzed
aminocarbonylation of aryl halides using formic acid and
carbodiimides (Scheme 1c). This effort resulted in the
development of
a new method to prepare amides and
phthalimides in a highly concise and efficient manner.
[a]
Y.-S. Seo,† Dr. D.-S. Kim,† Prof. Dr. C.-H. Jun*
Department of Chemistry
Yonsei University
50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea (Republic of)
E-mail: junch@yonsei.ac.kr
† These authors are equally contributed to this work
Supporting information for this article is given via a link at the end of
the document.
To gain insight into the carbonyl source in the
aminocarbonylation reaction, 13C-labelled formic acid (1a*) was
employed as a substrate (Figure 1). 13C NMR spectroscopic
analysis showed that the amide product 11a* generated in the
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reaction in 92% yield is 91% 13C-enriched at the carbonyl carbon. respective 43% and 13% yields (based on 8a) along with
This observation shows that the amide carbonyl group derives
from formic acid.
Table 1. Optimization of palladium catalyzed aminocarbonylation[a]
cyclohexyl (4b) and phenyl isocyanate (4c) in 57 and 29%
respective yields (based on 1a). This result shows that the
stoichiometric ratios of isocyanates 4b and 4c match those of
the corresponding amides 11b and 11c.
Use of silica balls simplifies the work-up/purification
procedures of getting coupling product (eq 2). We observed that
addition of silica balls to the mixture, produced by reaction of 8a
with 1a and 9c in the presence of 2a and 10b for 6 h, enabled
the amide product 11c to be isolated by simple filtration and
concentration of the filtrate. In this work-up procedure,
isocyanate 4b reacts with silica balls to produce 4b-grafted silica
at a 3.04 mmol/g loading rate, which was determined by using
elemental analysis.16, 17
[a] Unless otherwise noted, reactions were carried out with 8a (0.2 mmol), 1a
(0.4 mmol), 9a (0.7 mmol), 2 (5 mol %) and 10 (10 mol %) in 0.1 mL of solvent
at 150 oC. [b] Yield of 4a was determined by the amount of 1,1-diethyl-3-
isopropylurea formed in the following addition of diethylamine to the reaction
mixture. [C] Isolated yields.
Figure 1. (a) 13C NMR spectra of 11a* and (b) 11a
Scheme 2. Catalytic cycle for the palladium catalyzed aminocarbonylation
reaction
The non-symmetric carbodiimide 9b was also used as a
substrate in the amide forming process (eq 1). Reaction of this
substance leads to formation of two amides, 11b and 11c, in
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Based on the above results, we propose that the amide
forming reaction follows the mechanistic pathway depicted in
Scheme 2. In this route, initial reaction of 1a with 9a takes place
to form the mixed anhydride 12a, which then undergoes
palladium catalyzed formyl C-H bond cleavage and
decarbonylation to produce the Pd-complex 13a. -Elimination
reaction of 13a generates isocyanate 4a along with complex 5a,
which through reductive elimination forms amine 6a and the key
complex Pd(0)(CO) 7a. The ensuing steps in the catalytic cycle
involve oxidative addition of the aryl halide 8a to 7a followed by
migratory insertion to form acyl-Pd(II)-I intermediate 15a through
14a. Reaction of 15a with amine 6a produces complex 16a,
lower yield than aryl iodide 8g (entries 7, 9). 1-Iodonaphthalene
(8j) is also smoothly transformed to corresponding amide 11h
(entry 10) when subjected to the optimal reaction conditions.
Interestingly, reaction of 1,4-diiodobenzene (8k) with 9a
generates 4-iodo-N-isopropylbenzamide (11i) exclusively (entry
11). In addition, the diamide product is not produced when 11i is
subjected
to
the
optimal
conditions.18
Finally,
2-
bromovinylbenzene (8l) is a more reactive substrate than is
bromobenzene for this reaction (entries 2 and 11).
Table 3. Carbodiimide substrate scope of palladium catalyzed
aminocarbonylation[a]
which
then through reductive elimination generates
corresponding amide 11a along with Pd(0).
Table 2. Aryl halide substrate scope of palladium catalyzed
aminocarbonylation reaction[a]
[a] Unless otherwise noted, reactions were carried out with 8a (0.2 mmol), 1a
(0.4 mmol), 9 (0.7 mmol), 2a (5 mol %) and 10b (10 mol %) in 0.1 mL of
toluene at 150 oC. [b] Isolated yields.
A variety of carbodiimides (Table 3) serve as substrates for
the new aminocarbonylation reaction. For example, reaction of
iodobenzene (8a) with formic acid (1a) and N,N'-
dicyclohexylcarbodiimide (9c) in the presence of Pd(OAc)2 (2a, 5
mol %) and ligand 10b (10 mol %) occurs to form N-
cyclohexylbenzamide (11c) in 91% yield (entry 1). Aliphatic
carbodiimide 9d and aromatic carbodiimide 9e also participate in
reactions that generate the corresponding amides 11k and 11b
in 62 and 41% yield, respectively (entries 2-3). N,N'-
Dibenzylcarbodiimide (9f) also undergoes smooth reaction to
form N-benzylbenzamide (11l) in 64% yield. Steric
characteristics of carbodiimide substituents do not appear to
influence the reaction efficiency as shown by reaction of
carbodiimide 9g, which contains bulky tert-butyl groups, that
produces the corresponding amide 11m in 94% yield (entry 5).
Applications of the palladium catalyzed amide forming
reaction to the synthesis of N-substituted phthalimides were also
examined (Table 4). Reaction of 1,2-diiodobenzene (8m) with
formic acid (1a, 4 equiv) and N,N'-dicyclohexylcarbodiimide (9c,
[a] Unless otherwise noted, reactions were carried out with 8 (0.2 mmol), 1a
(0.4 mmol), 9a (0.7 mmol), 2a (5 mol %) and 10b (10 mol %) in 0.1 mL of
toluene at 150 oC. [b] Isolated yields.
The results of an exploration of the aryl halide substrate scope
of this process (Table 2) show that iodobenzene (8a) and
bromobenzene (8b) react to produce amide 11a in respective 93
and 29% yield, and that chlorobenzene (8c) and fluorobenzene
(8d) do not serve as effective substrates (entries 1-4).
Substituents in the aryl iodide do not affect the efficiency of the
process as shown by reactions of 8e-g which contain 4-methyl, -
chloro and -cyano groups, while aryl iodide containing ester
group 8h shows low reactivity (entries 5-8). Additionally, the
reaction employing 4-cyanobromobenzene (8i) displays much
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4 equiv) in the presence of Pd(OAc)2 (2a, 5 mol %) and ligand
10b (10 mol %) was found to form N-cyclohexylphthalimide
(17a) in 68% yield (entry 1). 1,2-Diiodobenzene (1l) also react
with various aliphatic and aromatic carbodiimides, including 9a,
9d, 9e and 9f, to generate the corresponding phthalimides 17b-e
in high to moderate yields (entries 2-5). Interestingly, reaction of
N-di-tert-butylcarbodiimide (9g) with diiodobenzene generates
N-tert-butylphthalimide (17f) along with phthalimide (17g) in 14
and 48% yields, respectively (entry 6).
Experimental Section
A
typical procedure for the preparation of N-
isopropylbenzamide (11a) (Table 1)
To a 1 mL pressure vial were added iodobenzene (8a, 22.4 μL,
0.2 mmol), formic acid (1a, 15.8 μL, 0.4 mmol), N,N ′ -
diisopropylcarbodiimide (9a, 108.4 μL, 0.7 mmol), Pd(OAc)2 (2a,
2.3 mg, 0.01 mmol), 1,3-Bis(2,4,6-trimethylphenyl)imidazolium
chloride (10b, 6.8 mg, 0.2 mmol) and toluene (100 μL). The
mixture was stirred at 150 °C for 6 h, cooled, diluted with
dichloromethane, dried over anhydrous MgSO4 and
concentrated in vacuo, giving a residue that was subjected to
column chromatography (n-hexane/ethyl acetate = 50:1) on
silica gel to give N-isopropylbenzamide (11a, 30.4 mg, 93%) as
a white solid.
Table 4. Synthesis of N-substituted phthalimides using various
carbodiimides[a]
Acknowledgements ((optional))
This study was financially supported by a grant from the
National Research Foundation of Korea (NRF) (Grant 2016-R-1-
A2b4009460).
Keywords: • Aminocarbonylation • Amides • Carbon monoxide •
Palladium catalyst • Phthalimides
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toluene at 150 oC. [b] Isolated yields.
[5]
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The investigation described above led to the development of a
palladium catalyzed aminocarbonylation process that serves as
a new method for facile, direct and efficient synthesis of amide
derivatives from aryl halides, carbodiimides and formic acid.
Observations made in this effort show that formic acid serves as
the carbon monoxide precursor in the Pd-catalyzed reaction.
[7]
[8]
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Furthermore, 1,2-diiodobenzene can be employed as
a
substrate in reactions that produce N-substituted phthalimides.
Further applications of the new methodology are being explored
in our continuing studies.
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5370.
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[18] Reaction of 4-iodo-N-isopropylbenzamide (11i) with formic acid (1a,
2equiv) and N,N'-diisopropylcarbodiimide (9a, 3.5 equiv) in the
presence of Pd(OAc)2 (2a, 5 mol%) and ligand 10b (10 mol%) does not
take place at all.
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Entry for the Table of Contents (Please choose one layout)
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Yong-Sik Seo, † Dong-Su Kim, † Chul-Ho
Jun*
Page No. – Page No.
Synthesis of Amides and
Phthalimides by Palladium Catalyzed
Aminocarbonylation of Aryl Halides
with Formic Acid and Carbodiimides
A novel method for the preparation of amides and phthalimides was developed.
The process involves palladium catalyzed aminocarbonylation of an aryl halide,
using a carbodiimide and formic acid as the carbonyl source. Observations made in
this effort suggest that the mechanistic pathway for this process involves in-situ
generation of carbon monoxide by reaction of formic acid with carbodiimide in the
presence of the palladium catalyst.
For internal use, please do not delete. Submitted_Manuscript
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