Palladium-Catalyzed Four-Component Carbonylative Cyclization Reaction of Trifluoroacetimidoyl Chlorides, Propargyl Amines, and Diaryliodonium Salts: Access to Trifluoromethyl-Containing Trisubstituted Imidazoles

Article abstract of DOI:10.1021/acs.orglett.0c00328

A palladium-catalyzed four-component carbonylative cyclization reaction for the expeditious construction of trifluoromethyl-containing trisubstituted imidazoles has been achieved. With readily accessible trifluoroacetimidoyl chlorides, propargyl amines, a

Full text of DOI:10.1021/acs.orglett.0c00328

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed Four-Component Carbonylative Cyclization
Reaction of Trifluoroacetimidoyl Chlorides, Propargyl Amines, and
Diaryliodonium Salts: Access to Trifluoromethyl-Containing
Trisubstituted Imidazoles
Zhengkai Chen, Wei-Feng Wang, Hefei Yang, and Xiao-Feng Wu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00328
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A palladium-catalyzed four-component carbonyla-
tive cyclization reaction for the expeditious construction of
trifluoromethyl-containing trisubstituted imidazoles has been
achieved. With readily accessible trifluoroacetimidoyl chlorides,
propargyl amines, and diaryliodonium salts as the starting
materials, the carbonylative transformation proceeds smoothly
under mild conditions to enable the formation of multifunctionalized imidazole molecules in a one-pot, one-step manner.
Diaryliodonium salts serve as both oxidants and aryl sources in the reaction.
ulticomponent reactions (MCRs) have been recognized
as an appealing and powerful approach for the assembly
carbonylative synthesis of (hetero)aryl-substituted imidazoles
from aryl halides and imines, as well.9 The reaction proceeds
effectively under CO pressure (4 bar). As a continuation of our
ongoing pursuit of the construction of structurally diverse
nitrogen-containing heterocycles,10 we report a palladium-
catalyzed four-component carbonylative cyclization reaction for
preparing trifluoromethyl- and benzoyl-substituted imidazoles.
Here, the challenges for this novel MCRs are how to
circumvent troublesome issues such as the direct amino-
arylation without CO insertion, the direct carbonylative
reaction of trifluoroacetimidoyl chlorides and propargyl amines,
the quite unstable alkenyl−palladium complex formed in situ,
etc. It is noteworthy that the pendent trifluoromethyl group can
significantly influence the properties of the azaheterocycles,
such as the increased electronegativity, bioavailability, meta-
bolic stability, and lipophilicity.11 In addition, the manipulation
of toxic and flammable carbon monoxide gas is avoided here, as
demonstrated via application of formic acid as the CO source
via an in situ-generated formic acetic anhydride in an In-Ex
reaction tube.12
M
of a wide variety of valuable chemical scaffolds, especially
structurally complicated heterocycles, exhibiting a huge
advantage over traditional synthetic methods.1 The major
challenge of MCRs lies in the control of the subtle balance
between reactivity and selectivity with multiple reactive
components.2 The issue becomes more serious with an increase
in the number of reaction reagents and reactive sites.
Consequently, the development of new MCRs to access
multifunctionalized azaheterocycles is of great significance
and is still highly desirable.
On the other hand, palladium-catalyzed carbonylative
transformations have emerged as an expeditious route to the
synthesis of diverse carbonyl-containing molecules.3,4 In these
protocols, the highly reactive and nonstable acyl−palladium
complex is formed through the insertion of CO into the C−Pd
bond, which could be identified as the key intermediate. Then
the coupling of the acyl−palladium complex with different
nucleophiles gave rise to a series of desired carbonyl-containing
compounds.
Additionally, imidazoles are some of the highly privileged
heterocyclic scaffolds and have found wide applications in
pharmaceutical fields, ligand chemistry, and materials science.5
Numerous methods have been developed for the synthesis of
imidazoles over the past several decades.6 Among these,
isocyanide “CN” bond [3+2] cycloaddition reactions have
emerged as a mainstream synthetic route to imidazoles.7 In
2012, Wu and co-workers disclosed a gold(I)-catalyzed
synthesis of 2-fluoroalkyl imidazoles from a 5-exo-dig cyclization
of fluorinated propargyl amidines, and imidazole-5-carbalde-
hyde was produced in the presence of the electrophile NIS.8
Arndtsen and co-workers achieved a novel palladium-catalyzed
We initially chose N-[4-(tert-butyl)phenyl]-2,2,2-trifluoroa-
cetimidoyl chloride 1g, propargyl amine 2a, and diphenyliodo-
nium tetrafluoroborate as the model substrates for the
multicomponent carbonylative reaction (Table 1). The
trifluoroacetimidoyl chlorides could be easily prepared13 and
were frequently applied as versatile trifluoromethyl-containing
Received: January 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00328
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
was conducted in DMF or DMSO, the yields decreased to 38%
or 48%, respectively. 1,4-Dioxane and CH3CN could give a
reduced yield compared with that of THF (Table 1, entry 20).
With the optimal reaction conditions in hand, the scope and
limitation of the palladium-catalyzed multicomponent carbon-
ylative reaction were investigated (Scheme 1). A wide range of
Table 1. Optimization of Reaction Conditions
b
entry
X
[Pd]
ligand
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
P(p-OMePh)3
Sphos
Xantphos
dppm
dppf
base
yield (%)
b
Scheme 1. Scope of Fluorinated Imidoyl Chlorides
1
2
3
4
5
6
7
8
BF4
BF4
BF4
BF4
OTf
OTs
Cl
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
Pd(OAc)2
PdCl2
Pd(TFA)2
Pd(acac)2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
Pd(TFA)2
Pd(acac)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
Cs2CO3
63
77
59
55
64
trace
51
92 (89)
82
83
75
71
82
82
72
81
90
69
c
9
10
11
12
13
14
15
16
17
18
19
20
PPh3
PPh3
PPh3
PPh3
PdCl2
PdCl2
NEt3
NaHCO3
65
48−84
d
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), 3 (0.3 mmol),
[Pd] (5 mol %), ligand (10 mol % for monodentate ligands, 5 mol %
for bidentate ligands), [CO] (Ac2O + HCO2H, 2 mmol), and base
(2.0 equiv) in THF (2.0 mL) at 30 °C for 20 h. Abbreviations: OTf,
a
The reaction was run on a 1 mmol scale in the presence of 2.5 mol %
b
PdCl2 and 5 mol % PPh3. Reaction conditions: 1 (0.3 mmol), 2a
b
(0.2 mmol), 3a (0.3 mmol), PdCl2 (5 mol %), PPh3 (10 mol %),
[CO] (Ac2O + HCO2H, 2 mmol), and NaHCO3 (2.0 equiv) in THF
(2.0 mL) at 30 °C for 20 h, isolated yields.
-OSO2CF3; OTs, -OSO2-4-Me-Ph; TFA, -O2CCF3. Yields deter-
mined by GC analysis using n-dodecane as an internal standard.
c
d
Isolated yields. The solvent of the reaction was 1,4-dioxane (71%),
DMF (38%), DMSO (48%), or CH3CN (84%).
N-aryltrifluoroacetimidoyl chlorides bearing electron-donating
or -withdrawing groups were tested under the standard
conditions, and good to excellent efficiencies could be observed
in most cases (4a−r). In general, the electronic nature (4a−r)
and steric hindrance (4b−d, 4q, and 4r) of the aryl ring had a
marginal effect on the reaction, as verified by the comparable
yields of these substrates. The halogen substitutions could be
quite compatible with the current reaction conditions, affording
the synthetic handle for further derivatization (4k−n, 4r, and
4s). The transformation could be scaled up on a 1 mmol scale
with a reduced amount of catalyst and ligand, and product 4g
was obtained in 80% yield along with a 13% yield of coupling
product amidine isomers (7 and 7′) intact. Apart from halogen
groups, some trifluoroacetimidoyl chlorides with strongly
electron-withdrawing groups, including nitro and trifluoro-
methyl, were amenable substrates under the optimized
conditions (4o−q), which highlighted the good functional
group compatibility of the protocol. Furthermore, naphthalene
rings were smoothly incorporated into corresponding imidazole
products in 96−97% yields (4t and 4u). Notably, trifluor-
oacetimidoyl chloride derived from aliphatic amine was also
applied as a viable substrate, albeit a relatively low yield was
obtained for product 4v. Gratifyingly, a series of other
fluorinated imidoyl chlorides could successfully participate in
the transformation to lead to the diverse fluoroalkyl-substituted
imidazoles in moderate to good yields (4w−aa). The exact
structure of imidazole 4l was unambiguously confirmed by
single-crystal X-ray diffraction analysis (CCDC 1973692).15
synthons for the construction of trifluoromethyl-substituted N-
heterocycles.10b,14 To our delight, the desired carbonylative
reaction proceeded smoothly to give the target imidazole
product 4g in 63% yield using the combination of Pd(OAc)2 (5
mol %) and PPh3 (10 mol %) as the catalyst under a CO (2
mmol) atmosphere in THF at 30 °C for 20 h (Table 1, entry 1).
Then, different palladium catalysts were examined, and PdCl2
could enable the highest yield (Table 1, entries 2−4). The
nature of the diaryliodonium salt counterion has an obvious
influence on the reaction outcome. Diverse diaryliodonium
salts were tested, and the corresponding triflate and chloride
salts afforded the desired product in 51−64% yields without
reactivity of the tosylate salt (Table 1, entries 5−7). It is
noteworthy that the best result was obtained with respect to
trifluoroacetate salt, where imidazole 4g could be obtained in
89% isolated yield (Table 1, entry 8). By defining
trifluoroacetate as the diaryliodonium salt counterion, we
screened the palladium catalysts again, and PdCl2 was the best
choice (Table 1, entries 9−11). The effect of ligands was also
surveyed, and a series of phosphine ligands were examined for
the reaction. The results revealed that a comparable reactivity of
other phosphine ligands was observed, which was slightly
inferior to that of PPh3 (Table 1, entries 12−16). Further
investigation of different bases, including Na2CO3, Cs2CO3,
and NEt3, suggested that NaHCO3 proved to be the best choice
(Table 1, entries 17−19, respectively). Screening of the solvents
indicated that THF was the optimal solvent. When the reaction
B
https://dx.doi.org/10.1021/acs.orglett.0c00328
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
The generality of the protocol was next explored by
employing a variety of symmetrical diaryliodonium salts
(Scheme 2). The diaryliodonium trifluoroacetate salts bearing
more electron-deficient aryl moiety (5j). In the case of the
sterically differentiated diaryliodonium salts, the steric
hindrance exerted an obvious impact on the reaction (5k and
5l). The obtained 23% yield of 5l could presumably be
attributed to the comprehensive effect of the electronic nature
and steric hindrance. With respect to phenyl(naphthyl)-
iodonium salt 3m, the naphthalene moiety dominated the
reaction with 4.6:1 selectivity. In particular, the transformation
with unsymmetrical diaryliodonium salt 3n afforded the desired
products (5i and 5n) with a distinct electron-rich preference,
which agreed with the preliminary observations.
a
Scheme 2. Scope of Symmetrical Diaryliodonium Salts
The reactivity of substituted propargyl amines was also
investigated under the catalytic system described herein (for
details, see the Supporting Information). With regard to 3-
phenylprop-2-yn-1-amine 2b, the corresponding five-mem-
bered imidazole product 5o and six-membered 1,4-dihydropyr-
imidine 6a were generated in 30% isolated yields. Nevertheless,
only traces of cyclized products (5p and 6b) could be detected
by GC-MS analysis when but-2-yn-1-amine 2c was used as the
coupling reagent. Notably, no reaction occurred when 2-
methylbut-3-yn-2-amine 2d was employed. The observation
data also shed light on the mechanism of the reaction, implying
the extreme instability of alkenyl−palladium complex A derived
from substrate 2c or 2d in the proposed catalytic cycle.
To gain more insights into the mechanism, a series of control
experiments were performed (for details, see the Supporting
Information). From the results, we found that a typical Pd0/PdII
catalytic cycle might not be involved in the reaction and the
reaction did not proceed via a pathway involving a radical. We
also synthesized the coupling product amidine isomers 7 and 7′
between trifluoroacetimidoyl chloride 1g and propargyl amine
2a and applied them to react with diaryliodonium salt 3a under
the standard conditions. As expected, target imidazole product
4g was isolated in 90% yield, indicating the intermediacy of
compounds 7 and 7′.
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), 3 (0.3 mmol),
PdCl2 (5 mol %), PPh3 (10 mol %), [CO] (Ac2O + HCO2H, 2
mmol), and NaHCO3 (2.0 equiv) in THF (2.0 mL) at 30 °C for 20 h,
isolated yields.
diverse functional groups at different positions of the phenyl
ring reacted well to afford the desired imidazole products (5a−
g). With respect to the strongly electron-withdrawing
trifluoromethyl group, moderate reactivity was observed
under the current catalytic system (5d and 5e). In general,
the electron-rich diaryliodonium salts showed better reactivity.
To further demonstrate the compatibility and applicability of
the transformation, an array of unsymmetrical diaryliodonium
salts were examined (Scheme 3). The reaction of the
electronically differentiated diaryliodonium salts revealed a
slightly preferred transfer of the more electron-rich aryl moiety
(5h and 5i) over the phenyl group or the phenyl group over the
On the basis of the results from the preliminary mechanistic
study of the multicomponent carbonylative reaction and in
previous reports,5,16 a plausible mechanism was proposed as
depicted in Scheme 4. It was considered that a PdII/PdIV
catalytic cycle was involved in the reaction to a larger extent,
although a Pd0/PdII catalysis could not be entirely excluded.5,17
At first, the coupling of trifluoroacetimidoyl chloride 1g and
propargyl amine 2a in the presence of a base could deliver
a
Scheme 3. Scope of Unsymmetrical Diaryliodonium Salts
Scheme 4. Plausible Reaction Mechanism
a
Reaction conditions: 1g (0.3 mmol), 2a (0.2 mmol), 3 (0.3 mmol),
PdCl2 (5 mol %), PPh3 (10 mol %), [CO] (Ac2O + HCO2H, 2
mmol), and NaHCO3 (2.0 equiv) in THF (2.0 mL) at 30 °C for 20 h.
Yields determined by NMR analysis using 1,3,5-trimethoxybenzene as
an internal standard.
C
https://dx.doi.org/10.1021/acs.orglett.0c00328
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
fluorinated propargyl amidine 7, which underwent a 1,3-H shift
to form isomer 7′. Then, the nucleophilic amino-palladation of
compound 7′ occurred to give alkenyl−palladium intermediate
A, followed by another 1,3-H shift to isomerize it to the more
stable alkyl−palladium species B. Subsequently, coordination
and insertion of CO into alkyl−palladium B afforded acyl−
palladium intermediate C. The oxidation of C by diary-
liodonium salt 3a furnished PdIV complex D, which provided
the final imidazole product 4g after reductive elimination with
the release of the PdII catalyst to fulfill the catalytic cycle. In the
transformation, diaryliodonium salt 3a served as both the aryl
source and the oxidant.
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Xiao-Feng Wu − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China;
̈
r Katalyse e. V. an der Universitat Rostock,
Leibniz-Institut fu
18059 Rostock, Germany; orcid.org/0000-0001-6622-
̈
3328; Email: xiao-feng.wu@catalysis.de
To further illuminate the synthetic utility of the methodology
presented here, serval chemical transformations of the
imidazole products were conducted (Scheme 5). Imidazole
Authors
Zhengkai Chen − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China;
orcid.org/0000-0002-5556-6461
Wei-Feng Wang − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
Hefei Yang − Department of Chemistry, Zhejiang Sci-Tech
University, Hangzhou 310018, People’s Republic of China
Scheme 5. Synthetic Transformations of the Obtained
Imidazole Molecules
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00328
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge financial support from the National
Natural Science Foundation of China (21772177 and
21602202), the Natural Science Foundation of Zhejiang
Province (LY19B020016), and the Fundamental Research
Funds of Zhejiang Sci-Tech University (Grant 2019Q065).
molecule 4g could undergo [3+2] cycloaddition with an
organic azide in the presence of catalytic DBU to give
functionalized (1H-imidazol-5-yl)-1H-1,2,3-triazole framework
8 with high efficiency. In addition, (1H-imidazol-5-yl)-1,2-
dione derivative 9 was delivered in 77% yield under copper-
catalyzed aerobic oxidative conditions.
In conclusion, we have developed a new palladium-catalyzed
four-component carbonylative cyclization reaction for the rapid
assembly of multifunctionalized imidazoles. The reaction
proceeded smoothly at room temperature in the absence of
external oxidants and allowed general access to the formation of
multiple new bonds and CO insertion in one pot. A range of
imidazoles with trifluoromethyl and benzoyl groups were
directly constructed in good yields. This method featured
mild conditions, a broad substrate scope, and scalability, with
no manipulation of CO gas or additional oxidants, which made
it suitable for the late-stage functionalization of complex
molecules. A reaction mechanism has been proposed on the
basis of our control experiments and detected key inter-
mediates.
REFERENCES
■
̈
(1) (a) Domling, A. The Discovery of New Isocyanide-based Multi-
component Reactions. Curr. Opin. Chem. Biol. 2000, 4, 318−323.
(b) Muller, T. J. J. Multicomponent Reactions II. Beilstein J. Org. Chem.
̈
2014, 10, 115−116. (c) Muller, T. J. J. Multicomponent Reactions.
̈
Beilstein J. Org. Chem. 2011, 7, 960−961. (d) Tietze, L. F. Domino
Reactions in Organic Synthesis. Chem. Rev. 1996, 96, 115−136.
(e) D’Souza, D. M.; Muller, T. J. J. Multi-Component Syntheses of
̈
Heterocycles by Transition-metal Catalysis. Chem. Soc. Rev. 2007, 36,
1095−1108. (f) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.;
Sreekanth, A. R.; Mathen, J. S.; Balagopal, L. Strategies for
Heterocyclic Construction via Novel Multicomponent Reactions
Based on Isocyanides and Nucleophilic Carbenes. Acc. Chem. Res.
̈
2003, 36, 899−907. (g) Domling, A.; Wang, W.; Wang, K. Chem. Rev.
2012, 112, 3083−3135. (h) Willy, B.; Mu
̈
ller, T. J. J. Multi-component
Heterocycle Syntheses via Catalytic Generation of Alkynones. Curr.
Org. Chem. 2009, 13, 1777−1790.
ASSOCIATED CONTENT
* Supporting Information
■
(2) Mayr, H.; Ofial, A. R. The Reactivity-Selectivity Principle: An
Imperishable Myth in Organic Chemistry. Angew. Chem., Int. Ed. 2006,
45, 1844−1854.
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00328.
(3) (a) Kollar, L. Modern Carbonylation Methods; John Wiley & Sons,
2008. (b) Beller, M. Catalytic Carbonylation Reactions; Springer: Berlin,
2006. (c) Shen, C.; Wu, X.-F. Palladium-Catalyzed Carbonylative
Multicomponent Reactions. Chem. - Eur. J. 2017, 23, 2973−2987.
General comments, optimization details, procedures for
substrate preparation, analytic data for substrates and
products, and NMR spectra for substrates and products
(PDF)
(d) Karpov, A. S.; Merkul, E.; Rominger, F.; Muller, T. J. J. Concise
̈
Syntheses of Meridianins by Carbonylative Alkynylation and a Four-
Component Pyrimidine Synthesis. Angew. Chem., Int. Ed. 2005, 44,
6951−6956. (e) Yin, H.; de Almeida, A. M.; de Almeida, M. V.;
Lindhardt, A. T.; Skrydstrup, T. Synthesis of Acyl Carbamates via Four
Component Pd-Catalyzed Carbonylative Coupling of Aryl Halides,
Potassium Cyanate, and Alcohols. Org. Lett. 2015, 17, 1248−1251.
Accession Codes
CCDC 1973692 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
D
https://dx.doi.org/10.1021/acs.orglett.0c00328
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(f) Wang, Q.; Zheng, L.; He, Y.-T.; Liang, Y.-M. Regioselective
synthesis of difluoroalkyl/perfluoroalkyl enones via Pd-catalyzed four-
component carbonylative coupling reactions. Chem. Commun. 2017,
53, 2814−2817.
Looking Beyond Intuition. Science 2007, 317, 1881−1886. (c) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal
Chemistry. Chem. Soc. Rev. 2008, 37, 320−330. (d) Alvarez-Builla, J.;
Vaquero, J. J.; Barluenga, J. Modern Heterocyclic Chemistry, 1st ed.;
Wiley-VCH: Weinheim, Germany, 2011. (e) Gillis, E. P.; Eastman, K.
J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. Applications of
Fluorine in Medicinal Chemistry. J. Med. Chem. 2015, 58, 8315−8359.
(12) Yin, Z.; Wu, X.-F. The Design of an In-Ex Tube for Gas Related
Organic Reactions. Org. Process Res. Dev. 2017, 21, 1869−1871.
(13) Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.; Uneyama,
K. One-pot Synthesis of Trifluoroacetimidoyl Halides. J. Org. Chem.
1993, 58, 32−35.
(4) (a) Brennfuhrer, A.; Neumann, H.; Beller, M. Palladium
̈
Catalyzed Carbonylation Reactions of Aryl Halides and Related
Compounds. Angew. Chem., Int. Ed. 2009, 48, 4114−4133. (b) Peng,
J.-B.; Geng, H.-Q.; Wu, X.-F. The Chemistry of CO: Carbonylation.
Chem. 2019, 5, 526−552.
(5) (a) Zhang, L.; Peng, X.-M.; Damu, G. L. V.; Geng, R.-X.; Zhou,
C.-H. Comprehensive Review in Current Developments of Imidazole-
Based Medicinal Chemistry. Med. Res. Rev. 2014, 34, 340−437.
(14) (a) Zhu, J.; Chen, Z.; Xie, H.; Li, S.; Wu, Y. A General and
Straightforward Method for the Synthesis of 2-Trifluoromethylbenzo-
thiazoles. Org. Lett. 2010, 12, 2434−2436. (b) Zhu, J.; Chen, Z.; Xie,
H.; Li, S.; Wu, Y. An Efficient Method to Access 2-Fluoroalkylbenzi-
midazoles by PIDA Oxidation of Amidines. J. Fluorine Chem. 2012,
133, 134−138. (c) Li, S.; Li, Z.; Yuan, Y.; Peng, D.; Li, Y.; Zhang, L.;
Wu, Y. Au(I)-Catalyzed Intramolecular Hydroamination of the
Fluorinated N’-Aryl-N-Propargyl Amidines: Mild Conditions for the
Synthesis of 2-Fluoroalkyl Imidazole Derivatives. Org. Lett. 2012, 14,
1130−1133. (d) Li, S.; Yuan, Y.; Zhu, J.; Xie, H.; Chen, Z.; Wu, Y.
Efficient Synthesis of 2-Fluoromethylated Quinolines via Copper-
Catalyzed Alkynylation and Cyclization of Fluorinated Imidoyl
Iodides. Adv. Synth. Catal. 2010, 352, 1582−1586. (e) Dong, X.; Xu,
Y.; Liu, J.; Hu, Y.; Xiao, T.; Zhou, L. Visible-Light-Induced Radical
Cyclization of Trifluoroacetimidoyl Chlorides with Alkynes: Catalytic
Synthesis of 2-Trifluoromethyl Quinolines. Chem. - Eur. J. 2013, 19,
16928−16933. (f) Wang, Z.; Li, T.; Zhao, J.; Shi, X.; Jiao, D.; Zheng,
H.; Chen, C.; Zhu, B. Expeditious Synthesis of 6-Fluoroalkyl-
Phenanthridines via Palladium-Catalyzed Norbornene-Mediated De-
hydrogenative Annulation. Org. Lett. 2018, 20, 6640−6645. (g) Pe-
droni, J.; Cramer, N. 2-(Trifluoromethyl)indoles via Pd(0)-Catalyzed
C(sp3)-H Functionalization of Trifluoroacetimidoyl Chlorides. Org.
Lett. 2016, 18, 1932−1935. (h) Chen, J.; Yin, Z.; Huang, Y.
Phosphine-Catalyzed Divergent [4 + 3] Domino Annulations of
CF3-Containing Imines with MBH Carbonates: Construction of
Perfluoroalkylated Benzazepines. Org. Lett. 2019, 21, 7060−7064.
(i) Wang, W.-Y.; Feng, X.; Hu, B.-L.; Deng, C.-L.; Zhang, X.-G.
Synthesis of 6-(Trifluoromethyl)phenanthridines via Palladium-
Catalyzed Tandem Suzuki/C−H Arylation Reactions. J. Org. Chem.
2013, 78, 6025−6030. (j) Chen, Z.; Hu, S.; Wu, X.-F. Trifluor-
oacetimidoyl halides: a potent synthetic origin. Org. Chem. Front. 2020,
7, 223−254.
(b) Janssen-Muller, D.; Schlepphorst, C.; Glorius, F. Privileged chiral
̈
N-heterocyclic carbene ligands for asymmetric transition-metal
catalysis. Chem. Soc. Rev. 2017, 46, 4845−4854.
(6) (a) Kamijo, S.; Yamamoto, Y. Recent Progress in the Catalytic
Synthesis of Imidazoles. Chem. - Asian J. 2007, 2, 568−578.
(b) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V.
Transition Metal-Mediated Synthesis of Monocyclic Aromatic
Heterocycles. Chem. Rev. 2013, 113, 3084−3213. (c) Guo, X.-X.;
Gu, D.-W.; Wu, Z.; Zhang, W. Copper-Catalyzed C−H Functionaliza-
tion Reactions: Efficient Synthesis of Heterocycles. Chem. Rev. 2015,
115, 1622−1651.
(7) (a) Pooi, B.; Lee, J.; Choi, K.; Hirao, H.; Hong, S. H. Tandem
Insertion-Cyclization Reaction of Isocyanides in the Synthesis of 1,4-
Diaryl-1H-imidazoles: Presence of N-Arylformimidate Intermediate. J.
Org. Chem. 2014, 79, 9231−9245. (b) Wang, H.; Kumar, R. K.; Yu, Y.;
Zhang, L.; Liu, Z.; Liao, P.; Bi, X. Silver-Catalyzed Isocyanide-
Isocyanide [3 + 2] Cross-Cycloaddition Involving 1,2-Group
Migration: Efficient Synthesis of Trisubstituted lmidazoles. Chem. -
Asian J. 2016, 11, 2841−2845. (c) Yan, K.; Yang, D.; Wei, W.; Sun, P.;
Lu, Y.; Wang, H. A copper-catalyzed cascade reaction of o-
bromoarylisothiocyanates with isocyanides leading to benzo[d]-
imidazo[5,1-b]thiazoles under ligand-free conditions. Org. Chem.
Front. 2016, 3, 556−560. (d) Xu, P.; Zhu, Y.-M.; Li, X.-J.; Wang, F.;
Wang, S.-Y.; Ji, S.-J. Copper-Catalyzed Reaction of Aryl Isocyanides
with Active Methylene Isocyanides and Arylsulfonothioates: Synthesis
of Sulfur-Containing Trisubstituted Imidazoles. Adv. Synth. Catal.
2019, 361, 4909−4913. (e) Cai, J.; Bai, H.; Wang, Y.; Xu, X.; Xie, H.;
Liu, J. Base-mediated regioselective [3 + 2] annulation of ketenimines
and isocyanides: efficient synthesis of 1,4,5-trisubstituted imidazoles.
Chem. Commun. 2019, 55, 3821−3824.
(8) Li, S.; Li, Z.; Yuan, Y.; Peng, D.; Li, Y.; Zhang, L.; Wu, Y. Au(I)-
Catalyzed Intramolecular Hydroamination of the Fluorinated N’-Aryl-
N-Propargyl Amidines: Mild Conditions for the Synthesis of 2-
Fluoroalkyl Imidazole Derivatives. Org. Lett. 2012, 14, 1130−1133.
(9) (a) Tjutrins, J.; Arndtsen, B. A. A palladium-catalyzed synthesis of
(hetero)aryl-substituted imidazoles from aryl halides, imines and
carbon monoxide. Chem. Sci. 2017, 8, 1002−1007. (b) Aly, S.;
Romashko, M.; Arndtsen, B. A. Multicomponent Synthesis of
(15) Compound 4l was determined by X-ray crystallography. See the
Supporting Information for full details. CCDC 1973692 contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(16) (a) Yang, M.-N.; Yan, D.-M.; Zhao, Q.-Q.; Chen, J.-R.; Xiao, W.-
J. Synthesis of Dihydropyrazoles via Ligand-Free Pd-Catalyzed Alkene
Aminoarylation of Unsaturated Hydrazones with Diaryliodonium
Salts. Org. Lett. 2017, 19, 5208−5211. (b) Peng, J.; Chen, C.; Xi, C. β-
Arylation of oxime ethers using diaryliodonium salts through activation
of inert C(sp3)-H bonds using a palladium catalyst. Chem. Sci. 2016, 7,
1383−1387. (c) Wang, X.; Studer, A. Iodine(III) Reagents in Radical
Chemistry. Acc. Chem. Res. 2017, 50, 1712−1724. (d) Chen, J.; Yang,
M.-N.; Chen, J.-R.; Xiao, W.-J. Palladium-Catalyzed Ring-Forming
Alkene Aminoaroylation of Unsaturated Hydrazones and Sulfona-
mides. Org. Lett. 2018, 20, 3314−3318.
Substituted and Fused-Ring Imidazoles via Phospha-munchnone
̈
Cycloaddition. J. Org. Chem. 2015, 80, 2709−2714. (c) Siamaki, A.
R.; Arndtsen, B. A. A Direct, One Step Synthesis of Imidazoles from
Imines and Acid Chlorides: A Palladium Catalyzed Multicomponent
Coupling Approach. J. Am. Chem. Soc. 2006, 128, 6050−6051.
(10) (a) Hu, S.; Du, S.; Yang, Z.; Ni, L.; Chen, Z. Synthesis of Multi-
substituted Dihydropyrazoles by Copper-Mediated [4 + 1] Cyclo-
addition Reaction of N-Sulfonylhydrazones and Sulfoxonium Ylides.
Adv. Synth. Catal. 2019, 361, 3124−3136. (b) Hu, S.; Yang, Z.; Chen,
Z.; Wu, X.-F. Metal-Free Synthesis of 5-Trifluoromethyl-1,2,4-
Triazoles from Iodine-Mediated Annulation of Trifluoroacetimidoyl
Chlorides and Hydrazones. Adv. Synth. Catal. 2019, 361, 4949−4954.
(c) Peng, J.-B.; Wu, F.-P.; Li, D.; Geng, H.-Q.; Qi, X.; Ying, J.; Wu, X.-
F. Palladium-Catalyzed Regioselective Carbonylative Coupling/
Amination of Aryl Iodides with Unactivated Alkenes: Efficient
Synthesis of β-Aminoketones. ACS Catal. 2019, 9, 2977−2983.
(11) (a) Kirsch, P. Modern Fluoroorganic Chemistry, Synthesis,
Reactivity, Applications; Wiley-VCH: Weinheim, Germany, 2004.
(17) Alexanian, E. J.; Lee, C.; Sorensen, E. J. Palladium-Catalyzed
Ring-Forming Aminoacetoxylation of Alkenes. J. Am. Chem. Soc. 2005,
127, 7690−7691.
(b) Muller, K.; Faeh, C.; Diederich, F. Fluorine in Pharmaceuticals:
̈
E
https://dx.doi.org/10.1021/acs.orglett.0c00328
Org. Lett. XXXX, XXX, XXX−XXX