A practical way to prepare isobutyronitrile amides through reactions between carboxylic acids and azobisisobutyronitrile

Article abstract of DOI:10.1002/adsc.201400919

A practical and efficient synthesis of N-isobutyronitrile amides has been achieved through the direct condensation of carboxylic acid and azobisisobutyronitrile (AIBN). Carboxylic acids bearing variously substituted phenyl rings and cinnamic or phenylpropiolic acids were employed to furnish both tertiary and secondary isobutyronitrile amides in moderate to high yields. A radical pathway was proposed. The methodology presented here requires no catalysts and additives, and represents the first practical approach to a variety of valuable amides containing the isobutyronitrile structural unit.

Full text of DOI:10.1002/adsc.201400919

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DOI: 10.1002/adsc.201400919
A Practical Way to Prepare Isobutyronitrile Amides through
Reactions between Carboxylic Acids and Azobisisobutyronitrile
Guangwei Rong,a Defu Liu,a Hong Yan,a Jie Chen,a Yang Zheng,a Guoqi Zhang,b,*
and Jincheng Maoa,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, Peopleꢀs Republic of China
Fax : (+86)-512-6588-0403; e-mail: jcmao@suda.edu.cn
Department of Sciences, John Jay College and The Graduate Center, The City University of New York, New York, NY
b
10019, USA
E-mail: guzhang@jjay.cuny.edu
Received: September 19, 2014; Revised: October 18, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400919.
Abstract: A practical and efficient synthesis of N-
isobutyronitrile amides has been achieved through
the direct condensation of carboxylic acid and azo-
bisisobutyronitrile (AIBN). Carboxylic acids bear-
ing variously substituted phenyl rings and cinnamic
or phenylpropiolic acids were employed to furnish
both tertiary and secondary isobutyronitrile amides
in moderate to high yields. A radical pathway was
proposed. The methodology presented here re-
quires no catalysts and additives, and represents the
first practical approach to a variety of valuable
amides containing the isobutyronitrile structural
unit.
Figure 1. Several useful aromatic amides that contain an N-
isobutyronitrile structure unit.
Keywords: azobisisobutyronitrile; carboxylic acids;
cinnamic acids; isobutyronitrile amides; phenylpro-
piolic acids
compounds C and D also show great potential for ap-
plications in the pesticide field.[4] Obviously, all these
compounds have the same structural unit of an N-iso-
butyronitrile aromatic amide. However, amongst the
known protocols to prepare aromatic amides, the syn-
thesis of N-isobutyronitrile amides is very limited.
Traditionally, ammonia is used as the nitrogen
Aromatic amides are one of the most important mo-
lecular building blocks that are widely found in natu- source for amide synthesis in the chemical industry.[5]
rally occurring compounds.[1] Over the past decades, However, the sequential introduction of an N-isobu-
considerable attention has been paid to exploration of tyronitrile moiety to the amide requires multiple-step
their synthesis as well as biological applications, be- reactions and tedious operating procedures, and
cause of the amphipathic arenes that are found in hel- hence it is quite energy-consuming. Thus, these meth-
ical oligomers.[2] Aromatic amides containing an iso- odologies are unpractical for large-scale industrial ap-
butyronitrile substituent on the amide nitrogen are es- plications. Although a synthesis of N-isobutyronitrile
sential structural motifs of a class of pharmaceutical benzamide from benzoyl 2-amino-2-methylpropaneni-
molecules that display significant biological activities. trile was revealed by Granger and co-workers in 1960,
For example, compound A (Figure 1), a simple N-iso- the high cost and poor availablility of the starting ma-
butyronitrile amide analogue, has been found to in- terial 2-amino-2-methylpropanenitrile has largely lim-
hibit the formation of thrombus in arterioles by 14 ited this protocol for any practical applications.[6]
percent;[3] the N-isobutyronitrile bis-amide B is a re- Therefore, it becomes urgent to develop a practical,
agent widely used in biological research. In addition, effective approach to useful N-isobutyronitrile amide
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Guangwei Rong et al.
acid and AIBN without a catalyst. Remarkably, it
turned out that the solvent plays a crucial role in de-
termining reactivity, and after screening of a variety
of solvents (Table 1), cyclohexane was found to be
most effective. Thus, when benzoic acid (0.3 mmol)
and AIBN (0.6 mmol) were employed in the reaction
using cyclohexane as solvent under an argon atmos-
phere for 12 h at 808C, a yield of 3a as high as 96%
Scheme 1. A plausible route to N-isobutyronitrile benz-
ACHTUNGTRENNUNGamide.
compounds from simple, inexpensive starting materi- (entry 11, Table 1) was achieved. Changing the
als. amount of 2a could influence the catalytic effect (en-
Azobisisobutyronitrile (AIBN), a molecule contain- tries 12 and 13, Table 1) and 2 equiv. is the best in
ing both an azo group and an isobutyronitrile unit, is view of the cost of the reaction. In addition, DMSO
a well-known radical initiator for polymer synthesis. (dimethyl sulfoxide), DMF (N,N-dimethylforma-
However, it has been scarcely exploited as a nitrogen mide), ethanol and PEG-400 were investigated in the
source in synthetic chemistry. We envisioned that the reaction as the solvents and the desired product 3a
N-isobutyronitrile motif could be introduced while could not be obtained.
using AIBN as a nitrogen source for the amide form-
With the optimized conditions in hand, we next ex-
ing reaction as proposed in Scheme 1. Herein, we plored the scope of substrates and the results are il-
report for the first time a catalyst-free, inexpensive lustrated in Table 2. It was found that various substi-
approach to a wide range of N-isobutyronitrile benza- tuted benzoic acids are tolerated and all furnished the
mides and other relevant analogues resulting from products in good to excellent yields. For most of the
direct condensations of carboxylic acids with AIBN.
mono-substituted substrates such as 4-methyl-, 4-tert-
In our initial attempt, benzoic acid and AIBN were butyl-, 4-fluoro- and 4-acetylbenzoic acids, high yields
chosen to react in toluene at 1208C for 12 h. To our of up to 99% were obtained. Under the same condi-
delight, the desired isobutyronitrile amide 3a was iso- tions, polysubstituted benzoic acids also performed
lated in 44% yield (entry 1, Table 1). In contrast, we well, affording the desired products in moderate to
also tested the same reaction in the presence of cata- excellent yields. It is worth noting that when ortho-ni-
lysts, but poorer conversions were obtained in all trobenzoic acid was applied, a secondary amide 3o
cases. Therefore, we focused on an optimization of was unexpectedly observed. However, in the case that
the conditions for the direct condensation of benzoic a nitro group is located in the meta or para position
of the benzene ring in benzoic acid, tertiary amides
3m and 3n were found to be the main products, re-
spectively. In view of the strong electron-withdrawing
ability of the nitro group, we speculated that tertiary
amides might be hydrolyzed into second amides when
using substrates bearing a strong EWG in the ben-
zene rings. In order to confirm our speculation, we
chose 2-chloro-4-nitrobenzoic acid as the substrate.
However, only product 3q was isolated. Although it is
insufficient to draw a conclusion on what would be
the exact driving forces for the two possible products
on the basis of these data, it is possible that both elec-
tronic and steric effects of substituted groups on the
phenyl ring play a key role in the reactivity. In addi-
tion, it was noticed that for some substrates, such as
2-iodo-, 2-phenyl- and 4-phenylbenzoic acids, the
yields of the desired products can be significantly im-
proved by raising the ratio of AIBN to benzoic acid
from 2:1 to 4:1. Aliphatic acids such as phenylacetic
acid and acetic acid were also investigated, and no
amide products could be detected after reaction. In
addition, para-substituted hydroxybenzoic acid was
investigated as the substrate and the desired product
3x could not be detected.
Table 1. Modification of the typical reaction conditions.[a]
Entry
Solvent
Temp. [oC]
Yield [%][b]
1
2
3
4
5
6
7
8
toluene
ethanol
DMSO
dioxane
CH2ClCH2Cl
1,4-xylene
CHCl2CH2Cl
acetonitrile
mesitylene
n-hexane
cyclohexane
cyclohexane
cyclohexane
110
80
100
100
80
100
100
80
100
80
44
37
NR
10
68
78
27
50
77
94
96
85
97
9
10
11
12[c]
13[d]
80
80
80
[a]
Reaction conditions: Benzoic acid 1a (0.3 mmol), AIBN
2a (0.6 mmol), solvent (2 mL), 12 h, 80–1108C, Ar.
Isolated yield. NR: no reaction.
Ratio of 1a/2a=1/1.5.
Ratio of 1a/2a=1/3.
[b]
[c]
[d]
Except for simple benzoic acids, two types of im-
portant conjugated carboxylic acids including cinnam-
ic acids and phenylpropiolic acids were also found to
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A Practical Way to Prepare Isobutyronitrile Amides
Table 2. Preparation of isobutyronitrile amides through the reaction between aromatic car-
boxylic acids and AIBN.[a]
[a]
Reaction conditions: benzoic acid (0.3 mmol), AIBN (0.6 mmol), cyclohexane (2 mL),
808C, 12 h, Ar, Isolated yield.
AIBN (1.2 mmol).
[b]
be suitable substrates for the preparation of the corre- amides might have been hydrolyzed into secondary
sponding isobutyronitrile amides. In these cases, the amides once formed, as proposed above.
best results were obtained when using trichloroethane
In order to gain further insights into the reaction
as a solvent under 1108C. Some cinnamic acids and mechanism, azo-tert-butane was used to replace
phenylpropiolic acids bearing different substituents AIBN for the reaction with benzoic acid under the
were investigated under the optimized conditions and same conditions. As expected, no reaction was ob-
the corresponding products were isolated in moderate served and only the starting materials were recovered
yields (Table 3). Notably, all of these products are sec- (Scheme 2), highlighting the essential role of AIBN
ondary amides, and no tertiary amides were detected for the desired transformation. Interestingly, one of
during the reaction, indicating that the tertiary the AIBN analogues, AMBN [2,2’-azodi(2-methylbu-
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Guangwei Rong et al.
Table 3. Preparation of isobutyronitrile amides through the reaction between cinnamic
or phenylpropiolic acids and AIBN.[a]
[a]
Reaction conditions: carboxylic acid (0.3 mmol), AIBN (0.6 mmol), trichloroethane
(2 mL), 1108C, 12 h; isolated yields are indicated.
Scheme 2. Some control experiments to elucidate the mechanism.
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A Practical Way to Prepare Isobutyronitrile Amides
These reactions were carried out smoothly under cat-
alyst-free conditions, and both tertiary and secondary
isobutyronitrile amide products are obtained in mod-
erate to high yields, depending on the given carboxyl-
ic acids. The methodology as disclosed here features
simple operating, environmentally friendly, highly ef-
ficient and excellent substrate tolerance, providing
a practical way to the synthesis of a class of isobutyro-
nitrile amide compounds that are remarkably valua-
ble in the development of novel chemical and biologi-
cal pharmaceuticals.
Experimental Section
General Experimental Methods
All reactions were carried out under air. Solvents were
dried and degassed by standard methods. All of the benzyl
halides and carboxylic acids are readily available. Flash
column chromatography was performed using silica gel
(300–400 mesh). Analytical thin-layer chromatography was
performed using glass plates pre-coated with 200–400 mesh
silica gel impregnated with a fluorescent indicator (254 nm).
NMR spectra were measured in CDCl3 on a Varian Inova-
400 NMR spectrometer (400 MHz or 300 MHz) with TMS
as an internal reference. Products were characterized by
Scheme 3. Proposed mechanism for the formation of N-iso-
butyronitrile amide.
tyronitrile)] also reacted smoothly with benzoic acid
to afford the product (3x) in 97% yield. Likewise, the
reactions between cinnamic or phenylpropiolic acids
and AMBN also gave the corresponding products (3y
and 3z) in 48% and 56% isolated yields. Finally, the
reaction was completely inhibited by TEMPO under
the standard conditions (Scheme 2), suggesting that
the reaction was likely to occur through a radical pro-
cess.
Based on the results described above as well as
those found in the literature,[7,8] we propose a plausible
mechanism as exhibited in Scheme 3. Firstly, an isobu-
tyronitrile radical is released from AIBN by heating,
which then reacts with another radical to generate
C.[7] Subsequently, benzoic acid undergoes addition to
the carbon-carbon double bond of C to form inter-
mediate D.[8] Then, intermediate D rearranges to give
the product by an oxygen-to-nitrogen migration of
the alkoxycarbonyl group.[8] In cases that the carbox-
ylic acids were alkynylcarboxylic acids or cinnamic
acids, secondary amine product 3 would be formed
via a hydrolysis process, and thus the isopropionyl
group could be removed. Indeed, the proposed hy-
drolysis process is supported by the fact that a similar
side product, N-(2-cyanopropan-2-yl)isobutyramide
1
comparison of their H NMR, 13C NMR and TOF-MS data
with those in the literature.
General Procedure for the Reaction between
Aromatic Carboxylic Acids and AIBN
To a Schlenk tube equipped with a magnetic stir bar was
added under argon, benzoic acid (0.3 mmol) and AIBN
(0.6 mmol). Under argon, cyclohexane (2.0 mL) was then
added. The resulting reaction mixture was kept stirring at
808C for 12 h. At the end of the reaction, the reaction mix-
ture was cooled to room temperature. After removal of the
solvent, the residue was subjected to column chromatogra-
phy on silica gel using ethyl acetate and petroleum ether
mixtures to afford the desired product in high purity.
General Procedure for the Reaction between
Cinnamic or Phenylpropiolic Acids and AIBN
To a Schlenk tube equipped with a magnetic stir bar was
added cinnamic acid or phenylpropiolic aicd (0.3 mmol),
AIBN (0.6 mmol) and trichloroethane (2.0 mL). The result-
ing reaction mixture was kept stirring at 1108C for 12 h. At
the end of the reaction, the reaction mixture was cooled to
room temperature. After removal of the solvent, the residue
was detected by LC-MS from the reaction mixture, as was subjected to column chromatography on silica gel using
ethyl acetate and petroleum ether mixtures to afford the de-
sired product in high purity.
was another species, cinnamic acid anhydride, which
is also a possible by-product resulting from the hy-
drolysis process. This is also in consistence with the
fact that only moderate yields of desired products 5
were isolated as listed in Table 3.
In conclusion, we reported an effective one-step
pathway to prepare isobutyronitrile amides through
Acknowledgements
We are grateful to the grants from the Scientific Research
the reaction between carboxylic acids and AIBN. Foundation for the Returned Overseas Chinese Scholars,
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Guangwei Rong et al.
State Education Ministry, the Priority Academic Program
Development of Jiangsu Higher Education Institutions, the
Project of Scientific and Technologic Infrastructure of
Suzhou (SZS201207) and the Key Laboratory of Organic
Synthesis of Jiangsu Province. GZ acknowledges a PSC-
CUNY award from the City University of New York (#67312-
0045).
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A Practical Way to Prepare Isobutyronitrile Amides
through Reactions between Carboxylic Acids and
Azobisisobutyronitrile
7
Adv. Synth. Catal. 2014, 356, 1 – 7
Guangwei Rong, Defu Liu, Hong Yan, Jie Chen,
Yang Zheng, Guoqi Zhang,* Jincheng Mao*
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