Synthesis of Imidazoles and Oxazoles via a Palladium-Catalyzed Decarboxylative Addition/Cyclization Reaction Sequence of Aromatic Carboxylic Acids with Functionalized Aliphatic Nitriles

Article abstract of DOI:10.1021/acs.orglett.1c01762

We herein report an efficient approach for the assembly of multiply substituted imidazoles and oxazoles in a single-step manner. These transformations are based on a decarboxylation addition and annulation of readily accessible aromatic carboxylic acids a

Full text of DOI:10.1021/acs.orglett.1c01762

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Letter
Synthesis of Imidazoles and Oxazoles via a Palladium-Catalyzed
Decarboxylative Addition/Cyclization Reaction Sequence of
Aromatic Carboxylic Acids with Functionalized Aliphatic Nitriles
Ling Dai, Shuling Yu, Ningning Lv,* Xuanzeng Ye, Yinlin Shao, Zhongyan Chen, and Jiuxi Chen*
Cite This: Org. Lett. 2021, 23, 5664−5668
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ABSTRACT: We herein report an efficient approach for the assembly of multiply substituted imidazoles and oxazoles in a single-
step manner. These transformations are based on a decarboxylation addition and annulation of readily accessible aromatic carboxylic
acids and aliphatic nitriles and exhibit good functional group compatibility and a high step economy. The reaction is scalable, and as-
prepared products could be transformed into practical skeletons. Importantly, the late-stage derivatization of Momelotinib highlights
the potential utility of this methodology.
Scheme 1. Transformations of Aromatic Carboxylic Acids
midazoles and oxazoles represent important structural units
Ithat are ubiquitous in natural products, pharmaceuticals,
and biologically active molecules.1 In particular, 2,4,5-
trisubstituted oxazoles are the core structural scaffolds of the
antidiabetic agent AD-5061 and the peptide alkaloid
(−)-muscoride A,2a and the antiviral reagent BMS-790052
contains the key 2,5-disubstituted imidazole framework.2b In
addition, these skeletons have wide applications in optical
materials.3 To date, some existing methods to obtain these
compounds always require complex substrates and suffer from
tedious operations and harsh reaction conditions.4 Accord-
ingly, a facile and rapid access to accommodate multiply
substituted imidazoles and oxazoles in one pot from simple
starting materials is highly desirable.
Carboxylic acids are widely used chemical feedstocks due to
their low cost, no toxicity, and readily accessible nature. In the
past few decades, carboxylic acids had been employed as the
directing groups to achieve diverse functionalizations of inert
C−H bonds (Scheme 1a).5 In some cases, they could be
regarded as traceless auxiliary groups via a protodecarbox-
ylation course (Scheme 1a).6 Moreover, aromatic carboxylic
acids have also been extensively used as arylation reagent
surrogates in transition-metal-catalyzed cross-couplings
through the extrusion of CO2 (Scheme 1b)7 and have been
widely reported to react with aryl halides,8 organoboron
reagents,9 simple arenes,10 alkenes,11 and alkynes.12 In
contrast, transformations with a polar unsaturated cyano
group remain rare.13 In 2010, Larhed reported the first
example of palladium-catalyzed aromatic acids reacting with
simple nitriles to produce the aryl ketones.13a,b Shortly
thereafter, Larhed disclosed the nucleophilic addition of
aromatic acids with cyanamides.13c Recently, Swamy described
the synthesis of indolocarbolines and triindoles through Pd-
catalyzed decarboxylative nitrile insertion of indole-2-carbox-
ylic acids.13d Despite this progress, the reaction conditions of
the above examples were confined to microwave radiation or
Received: May 26, 2021
Published: July 12, 2021
https://doi.org/10.1021/acs.orglett.1c01762
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5664−5668
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a b
,
use of an excess amount of Ag oxidants, affording solely simple
products.
Scheme 2. Scope of Functionalized Nitriles
Nitrile as a versatile synthon can be turned into
miscellaneous skeletons via organic reactions. Among them,
transition-metal-catalyzed nitrile insertion has opened up a
sought-after pathway for the rapid assembly of varied nitrogen-
containing heterocycles.14 In this context, we have developed
several novel methods for the concise construction of value-
added heterocycles from aliphatic nitriles and arylboronic
acids.15 In light of our continuous interest in nitrile chemistry,
we herein present the first example of carboxylic acids as
arylation reagents reacting with cyanomethyl benzoates and N-
cyanomethylacetamides for the expeditious assembly of
multiply substituted oxazoles and imidazoles (Scheme 1c).
This transformation involves a decarboxylation addition and
cyclization process and features good functional group
tolerance, broad substrate scope, and concise handling.
Moreover, this transformation is easily scaled up, and the as-
prepared products can be transformed into value-added
scaffolds. The potential utility of this protocol is further
exemplified by the late-stage modifications of the pharmaceut-
ical Momelotinib.
We initiated our investigations with a model reaction of
cyano(phenyl)methyl benzoate (1a) and 2,6-dimethoxyben-
zoic acid (2a) to optimize the reaction parameters (see Table
S1 in the Supporting Information). To our delight, the target
oxazole product (3a) was obtained in 28% yield in the
presence of PdCl2, 6,6′-dimethyl-2,2′-bipyridine, trifluoroacetic
acid (TFA), and 1,4-dioxane as solvent at 100 °C for 24 h in
air (Table S1, entry 1). Then, we examined the effect of
solvents on the reaction, and it was found that trifluorome-
thylbenzene (PhCF3) gave the highest yield (Table S1, entries
1−3). Among the various palladium catalysts, Pd(OAc)2
showed the optimal efficiency to give the product 3a in 83%
yield (Table S1, entries 4−6). The screening of nitrogen-
containing ligands, containing 6,6′-dimethyl-2,2′-bipyridine
(L1), 2,2′-bipyridine (L2), 4,4′-dimethyl-2,2′-bipyridine
(L3), 2,9-dimethyl-1,10-phenanthroline (L4), 4,4′-di-tert-
butyl-2,2′-bipyridine (L5), and 5,5′-dimethyl-2,2′-bipyridine
(L6), revealed that 6,6′-dimethyl-2,2′-bipyridine (L1) was the
best candidate to yield the target product 3a (Table S1, entries
7−11). Further studies suggested that the acid additives had a
significant influence on this transformation, and heptafluor-
obutyric acid (HFBA) afforded the targeted oxazole in 96%
yield (Table S1, entries 12 and 13). Control experiments
confirmed that the palladium catalyst is vital to this conversion,
and a sluggish yield was detected in the absence of ligand or
acid additive (see Table S1, entries 14−16). Lowering the
amount of HFBA to 0.75 equiv did not affect the reaction
(Table S1, entry 17).
With the optimized reaction conditions established, we first
explored the substrate scope of the cyanomethyl benzoates
(Scheme 2). In general, substrates bearing electron-donating or
electron-withdrawing groups all proved to be amenable to this
conversion. For instance, diverse substituents, including
methoxyl, fluoro, chloro, and bromo, attached to the phenyl
ring on the α-position of the cyano group could participate in
this reaction favorably to furnish the target oxazoles in 75−
93% yields (3b−e). Analogous yields were obtained for
substrates 1f,g, suggesting that steric effects have little
influence on this transformation (3f,g). Additionally, substrates
with diverse R1 substituents, such as thienyl, furyl, propyl,
cyclohexyl ,and phenethyl groups, are viable in this reaction
a
The reaction conditions are the optimal conditions shown in Table
b
c
S1. Isolated yield. 5 mmol scale.
and exhibit excellent reactivity (3h−l). It should be mentioned
that strongly electron withdrawing groups, such as −NO2 and
−CF3, could also deliver the target products smoothly (3p,q).
Importantly, this protocol is also compatible with heterocyclic
and alkyl-substituted cyanomethyl carboxylates, efficiently
leading to a number of multisubstituted oxazole products
(3p−w). Importantly, the reaction could be carried out
efficiently on a 5 mmol scale with an 86% yield (3a). The
exact structure of product 3a was unambiguously confirmed by
a single-crystal X-ray diffraction (XRD) analysis.16
We next investigated the generality of aromatic carboxylic
acids for the construction of oxazoles by elevating the
temperature and the loading of the Pd catalyst (Scheme 3).
Generally, the electron-donating benzoic acid is facilitates this
conversion more to access the target oxazoles; aromatic acids
with electron-withdrawing groups are not viable in this
transformation, which might correlate with the difficulty of a
decarboxylation process occurring in the presence of a protic
acid.17a In addition, we have tried a Cu-Pd system, which could
promote the decarboxylative reaction through stabilizing the
intermediates formed upon release of carbon dioxide,17a,b but
there was no improvement in the reactivity of electron-
deficient acids, including pentafluorobenzoic acid, 4-nitro-
benzoic acid, 4-chlorobenzoic acid, and 4-(trifluoromethyl)-
benzoic acid. With respect to multiply substituted methyl,
isopropyl, and methoxyl groups at different positions on the
benzene ring of the aromatic acids, the desired products were
obtained in 36−73% yields (4a−h). The reaction tolerated 3-
bromo-2,6-dimethoxybenzoic acid (4i). Notably, diverse
motifs of heteroaromatic acids, covering pyridine, benzofuran,
thiophene, benzothiophene, and indole, are also compatible
and enable a decarboxylative coupling with cyanomethyl
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a b
,
a b
,
Scheme 3. Scope of Aromatic Carboxylic Acids
Scheme 4. Scope for the Synthesis of Imidazoles
a
a
Reaction conditions unless specified otherwises: Pd(OAc)2 (10 mol
%), 6,6′-dimethyl-2,2′-bipyridine (20 mol %), HFBA (0.75 equiv), T
The reaction conditions were the optimal conditions shown in Table
b
c
S2. Isolated yield. 7 mmol scale.
b
c
= 130 °C. Isolated yields. Pd(OAc)2 (10 mol %), 6,6′-dimethyl-
2,2′-bipyridine (20 mol %), Cu(OAc)2 (15 mol %), HFBA (0.75
equiv), T = 150 °C.
deliver the diphenol derivative (7a) (Scheme 5, eq a).
Moreover, the as-prepared oxazole 4i could be transformed
benzoates in good yields (4j−n) under the standard
conditions.
Scheme 5. Synthetic Applications
Inspiringly, when the cyanomethyl benzoates were replaced
with N-cyanomethylacetamides, the target 2,5-disubstituted
imidazoles were obtained smoothly by tailoring the reaction
conditions (see Table S2 in the Supporting Information).
Control experiments confirmed that the palladium catalyst, the
ligand, and the acid additive HFBA were essential in this
reaction.
Subsequently, the variation of different substitutions of N-
cyanomethylacetamides was investigated (Scheme 4). The
substrates containing electron-donating groups displayed
better efficiency in comparison to those with electron-
withdrawing groups (6e−l). The o-methyl-substituted N-
(cyanomethyl)benzamide afforded the target imidazole in a
lower yield in comparison with the p-methyl- and m-methyl-
substituted compounds (6a−c). Notably, aryl C−F, C−Cl, C−
Br, and C−I bonds could be incorporated with good yields
during the reaction course. Moreover, strongly electron
deficient groups, including −CN, −CF3 and −NO2, were
compatible in the reaction (6j−l). The reaction proceeded well
in the presence of furyl-, thienyl-, and naphthyl-substituted N-
(cyanomethyl)acetamides with 58−86% yields (6m−o). Addi-
tionally, diverse alkyl-substituted N-(cyanomethyl)amides were
also amenable to this reaction and gave the desired products in
excellent yields (6p−r). The reaction was proved to be feasible
for cycloalkyl amides, leading to the imidazoles in excellent
yields (6s−u). It should be mentioned that this reaction could
be scaled up to 7 mmol with good yield (6a). The exact
structure of 6a was further identified by a single-crystal X-ray
diffraction (XRD) analysis,16 which verified that the structure
of the target product was indeed a 2,5-disubstituted rather than
a 2,4-substituted imidazole.
into a more complex molecule (7b) via late-stage cross-
couplings (Scheme 5, eq b). It should be noted that the
versatility of this transformation is showcased by the
downstream modification of the pharmaceutical molecule
Momelotinib,18 which possesses efficacy in therapy for
myelofibrosis, providing the corresponding imidazole skeleton
(7c) in an acceptable yield (Scheme 5, eq c).
To better elucidate the possible reaction mechanism, a set of
experiments were conducted as outlined in the Supporting
Information. First, when the model reaction of N-
(cyanomethyl)benzamide (5a) and 2,6-dimethoxybenzoic
acid (2a) was conducted in the presence of 1 mL of H2O
under the standard conditions, the corresponding ketone was
isolated in 86% yield. Subsequently, when the ketone (7d) was
subjected to the reaction in the presence of 20 equiv of
CF3COONH4, the ultimate imidazole product 6a was isolated
in 71% yield in the absence of a palladium catalyst. These
Gratifyingly, the methoxyl group obtained on the resulting
oxazole product 3a could be conveniently hydrolyzed to
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results revealed that the ketimine was the key intermediate of
this conversion. Next, we performed a competitive experiment
of p-methyl and p-trifluoromethyl N-(cyanomethyl)benzamide,
and the results suggested that an electron-donating group was
much more favorable to this reaction, which was consistent
with the results in Scheme 4. It was found that the addition of
extra amounts of the radical scavengers BHT and DPE did not
influence the reaction, and a good yield was always obtained.
This result indicated that a single-electron transfer process
might not be involved in the decarboxylation course of the
aromatic carboxylic acids.
On the basis of the mechanistic investigations and the
previous reports,13,17 a plausible catalytic cycle was proposed,
as depicted in the Supporting Information. Initially, the PdII
catalyst coordinates with the nitrogen-containing ligand to give
the active palladium species A. With reference to relevant
reports,13a,b the ligand exchange of species A with carboxylic
acids affords the intermediate B, which undergoes the process
of decarboxylation to produce the arylpalladium complex C.
Subsequently, the coordination of species C with the cyano
group forms the intermediate D, followed by an insertion
process to produce the ketimine palladium species E. The
protonation of the intermediate E affords the free ketimine F
and regenerates the activated Pd(II) species A to complete the
catalytic cycle. The tautomerization of the ketimine followed
by an intramolecular nucleophilic addition and dehydration
delivers the ultimate imidazole and oxazole products
separately.
AUTHOR INFORMATION
Corresponding Authors
■
Ningning Lv − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, People’s Republic of
China; orcid.org/0000-0002-6111-0188;
Email: ningninglv@wzu.edu.cn
Jiuxi Chen − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, People’s Republic of
China; orcid.org/0000-0001-6666-9813;
Email: jiuxichen@wzu.edu.cn
Authors
Ling Dai − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, People’s Republic of
China
Shuling Yu − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, People’s Republic of
China
Xuanzeng Ye − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, People’s Republic of
China
Yinlin Shao − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, People’s Republic of
China; orcid.org/0000-0003-1935-0345
Zhongyan Chen − College of Chemistry & Materials
Engineering, Wenzhou University, Wenzhou 325035,
People’s Republic of China; orcid.org/0000-0003-3446-
0710
In conclusion, we have developed a palladium-catalyzed
decarboxylation addition and cyclization reaction sequence of
readily available carboxylic acids and aliphatic nitriles,
providing a novel method for the rapid assembly of multiply
substituted imidazoles and oxazoles in one pot. A wide range of
functionalized aliphatic nitriles and various benzoic acids and
heterocyclic carboxylic acids are effective inputs in the absence
of Ag oxidants, yielding manifold structural imidazole and
oxazole skeletons with good yields. Significantly, late-stage
modification of the drug molecule Momelotinib, gram-scale
production, and various derivatizations of the resulting
products highlight the synthetic utility and robustness of
these transformations. Control experiments provided insight
into the possible mechanism. Further investigations on
exploiting this expeditious protocol to afford privileged
nitrogen-containing heterocycles are underway in our labo-
ratory.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01762
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of
China (No. 21572162) and the Natural Science Foundation of
Zhejiang Province (No. LY20B020015 and Q21B050002) is
highly acknowledged.
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01762.
Characterization data and 1H and 13C NMR and HRMS
spectra for the target compounds (PDF)
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