The cascade coupling/iodoaminocyclization reaction of trifluoroacetimidoyl chlorides and allylamines: metal-free access to 2-trifluoromethyl-imidazolines

Article abstract of DOI:10.1039/d1ob00986a

A metal-free cascade coupling/iodoaminocyclization reaction for the rapid assembly of 2-trifluoromethyl-imidazolines has been disclosed. The transformation applies readily accessible trifluoroacetimidoyl chlorides, allylamines andN-iodosuccinimides as the starting substrates, achieving an efficient and straightforward pathway to construct diverse imidazoline derivatives. Excellent efficiency of the reaction is observed (higher than 90% isolated yield for half of the examples), and the obtained imidazoline products bearing a pendent iodomethyl group could be easily transformed into other synthetically valuable compounds.

Full text of DOI:10.1039/d1ob00986a

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
The cascade coupling/iodoaminocyclization
reaction of trifluoroacetimidoyl chlorides and
allylamines: metal-free access to
Cite this: Org. Biomol. Chem., 2021,
19, 6115
2-trifluoromethyl-imidazolines†
Yufei Song,a Le-Cheng Wang,a Shiying Du,a Zhengkai Chen *a and
b,c
Xiao-Feng Wu
*
A metal-free cascade coupling/iodoaminocyclization reaction for the rapid assembly of 2-trifluoro-
methyl-imidazolines has been disclosed. The transformation applies readily accessible trifluoroacetimi-
doyl chlorides, allylamines and N-iodosuccinimides as the starting substrates, achieving an efficient and
straightforward pathway to construct diverse imidazoline derivatives. Excellent efficiency of the reaction is
observed (higher than 90% isolated yield for half of the examples), and the obtained imidazoline products
bearing a pendent iodomethyl group could be easily transformed into other synthetically valuable
compounds.
Received 21st May 2021,
Accepted 17th June 2021
DOI: 10.1039/d1ob00986a
rsc.li/obc
with aziridines was disclosed by the group of Tepe, which
stereospecifically yielded various tetrasubstituted 2-imidazo-
Introduction
Imidazolines exhibit a variety of biological and pharmaceutical lines.8 Although numerous elegant studies regarding 2-imida-
properties, including anticancer, antiinflammatory, antidia- zoline synthesis have been reported, the exploration of a more
betic, and antihypertensive activities (Fig. 1).1 Imidazoline general and efficient approach for the assembly of specifically
derivatives are also applied as versatile building blocks, functionalized 2-imidazolines, such as 2-trifluoromethyl-imi-
auxiliaries and chiral ligands for asymmetric synthesis.2 dazolines, is still highly desirable.
Consequently, tremendous synthetic methods have been devel-
The presence of trifluoromethyl or perfluoroalkyl groups
oped for the construction of this kind of valuable heterocyclic could drastically improve the physicochemical properties of
compound.3 The traditional route to 2-imidazolines is the the parent molecules, including electronegativity, bio-
Heine reaction, which involves NaI-mediated isomerization of availability, metabolic stability and lipophilicity.9 With regard
imidoyl aziridine.4 Several relevant transformations based on
the Heine-type reactions for producing imidazoline derivatives
have been hereby reported.5 Amide dehydration reactions from
β-amino alcohols through a multistep process could furnish
diverse 2-imidazolines.6 Tepe and co-workers reported a series
of trimethylsilyl chloride-mediated 1,3-dipolar cycloaddition
reactions of azlactones for the diastereoselective synthesis of
syn- or anti-imidazolines.7 In 2011, a convenient one-pot Heine
reaction via the ring expansion reaction of imidoyl chlorides
aDepartment of Chemistry, Key Laboratory of Surface & Interface Science of Polymer
Materials of Zhejiang Province, Zhejiang Sci-Tech University, Hangzhou 310018,
China. E-mail: zkchen@zstu.edu.cn
bDalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, 116023 Dalian, Liaoning, China
cLeibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Straβe
29a, 18059 Rostock, Germany. E-mail: xiao-feng.wu@catalysis.de
†Electronic supplementary information (ESI) available: General comments,
general procedures, analytical data, and NMR spectra. See DOI: 10.1039/
d1ob00986a
Fig. 1 Selected examples of bioactive molecules and ligands containing
the imidazoline scaffold.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6115–6119 | 6115

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 1 Optimization of the reaction conditionsa
Entry
I source
Solvent
Temp.
Yieldb (%)
1
2
3
4
5
6
7
8
NIS (4)
NIS (2)
NIS (1)
NIS (2)
NIS (2)
NIS (2)
NIS (2)
NIS (2)
NIS (2)
NIS (2)
NIS (2)
I2 (2)
THF
THF
THF
DMF
CH3CN
1,4-Dioxane
Toluene
EtOH
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
40
Rt
Rt
Rt
Rt
Rt
81
96
92
73
98
59
46
67
Scheme 1 Synthesis of 2-trifluoromethyl-imidazolines.
9
H2O
59
10
11
12
13
14
15
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
73
99 (99)c
95
to the synthesis of 2-(trifluoromethyl)-imidazolines, reports of
the synthetic routes have been scarce.10 The current synthetic
strategies include the reaction of trifluoroacetate with ethane-
1,2-diamine,11 intramolecular cyclization of phosphaxo com-
pounds from PPh3 and N-(2-azidoethyl)-trifluoroacetamide
(Scheme 1a),12 the reaction of 2,2,2-trifluoroethanethioamide
with ethylenediamine (Scheme 1b),13 and the condensation of
N-monosubstituted ethane-1,2-diamine with trifluoroacetic
acid in the presence of PPh3/CX4 (X = Cl/Br) (Scheme 1c).14
Nevertheless, some of the existing methods usually suffer from
not readily available reagents or narrow substrate scope.
Inspired by our continuous investigation on the synthesis of
trifluoromethyl-substituted N-heterocycles,15 we wish to
present our recent research findings on the cascade coupling/
iodoaminocyclization reaction of easily accessible trifluoroace-
timidoyl chlorides, allylamines and N-iodosuccinimides
(Scheme 1d). The simple cascade reaction offers an efficient
and straightforward pathway for the preparation of structurally
diverse 2-trifluoromethyl-imidazoline derivatives. In addition,
the pendent iodomethyl group of the imidazoline products
serves as a useful synthetic handle for further transformation.
TBAI (2)
ICl (2)
NIS (2)
28
98
99d
a Reaction conditions: 1b (0.3 mmol), 2a (0.75 mmol), an I source and
4 Å MS (60 mg) in solvent (2.0 mL) under air at specified temperature
for 4 h. b Yields are determined by GC analysis using dodecane as an
internal standard and the isolated yields are given in parentheses.
c The reaction was performed for 1 h. d The reaction was performed
under a N2 atmosphere. NIS = N-iodosuccinimide. TBAI = tetrabutyl-
ammonium iodide.
demonstrated that CH3CN was the optimal choice for deliver-
ing 3b in 98% yield (Table 1, entries 4–9). Noteworthy is that
the reaction could be performed in water for obtaining the
product 3b in 59% yield (Table 1, entry 9). Elevating the reac-
tion temperature to 40 °C had a negative impact on the trans-
formation (Table 1, entry 10). When the reaction time was
shortened to 1 hour, the reaction yield increased to 99% and
the product 3b could be furnished in up to 99% isolated yield
(Table 1, entry 11). Other iodine sources were also tested,
including I2, TBAI and ICl. The results revealed that I2 and ICl
could give a comparable yield, whereas only 28% yield was
observed with TBAI (Table 1, entries 12–14). Performing the
reaction under an inert atmosphere exerted no detrimental
effect upon the reaction efficiency (Table 1, entry 15).
Results and discussion
First, 2,2,2-trifluoro-N-(p-tolyl)acetimidoyl chloride 1b and
Having established the optimized reaction conditions, the
2-methylprop-2-en-1-amine 2a were selected as the scope and limitation of the cascade annulation reaction were
model substrates to optimize the reaction conditions. surveyed with regard to a library of fluorinated imidoyl chlor-
Trifluoroacetimidoyl chlorides have been identified as versatile ides (Scheme 2). Numerous N-aryl-trifluoroacetimidoyl chlor-
trifluoromethyl-containing building blocks and can be readily ides bearing electron-donating or -withdrawing groups reacted
prepared by simply mixing the parent amine with trifluoroace- smoothly with allylamine 2a to deliver the corresponding imi-
tic acid, CCl4, and PPh3.16 The reaction was performed in the dazoline products 3a–m. To our surprise, the protocol exhibi-
presence of 4.0 equiv. of iodosuccinimide (NIS) and 4 Å MS in ted very excellent reactivity, as almost quantitative yields of
THF at room temperature for 4 h. Gratifyingly, the target imi- many products were obtained. The electron effect had a little
dazoline product 3b could be produced in 81% GC yield influence on the reaction (3b–m), whereas the steric hindrance
(Table 1, entry 1). Decreasing the amount of NIS obviously of the aryl ring exerted an impact upon the reaction to some
improved the efficiency of the reaction and 2.0 equiv. of NIS extent due to the lower yield of the product 3d. A similar case
could promote the reaction in 96% yield (Table 1, entries 2 was observed in the reaction of trifluoroacetimidoyl chloride
and 3). A range of solvents were next examined, and the results bearing a bulky naphthalene ring and only moderate yield was
6116 | Org. Biomol. Chem., 2021, 19, 6115–6119
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 3 Scope of allylamines. Reaction conditions: 1b (0.3 mmol), 2
(0.75 mmol), NIS (0.6 mmol) and 4 Å MS (60 mg) in CH3CN (2.0 mL)
under air at room temperature for 1 h. Isolated yields. a Reaction con-
ditions: 1b (0.3 mmol), allylamine hydrochloride salt 2b (0.75 mmol), NIS
(0.6 mmol), Na2CO3 (0.6 mmol) and 4 Å MS (60 mg) in CH3CN (2.0 mL)
under air at room temperature for 1 h.
Scheme 2 Scope of fluorinated imidoyl chlorides. Reaction conditions:
1 (0.3 mmol), 2a (0.75 mmol), NIS (0.6 mmol) and 4 Å MS (60 mg) in
CH3CN (2.0 mL) under air at room temperature for 1 h. Isolated yields.
achieved (3n). Of note is that trifluoroacetimidoyl chloride
derived from an aliphatic amine, which was usually unstable
and unreactive in other transformations, could be applicable
to the current reaction system, albeit with moderate efficiency
(3o). More importantly, other fluorinated imidoyl chlorides
also served as viable reactants under the optimal conditions to
produce diverse fluoroalkyl-substituted imidazolines in excel-
lent yields (3p–s).
Scheme 4 Cascade reactions with different coupling partners or
halogen sources.
The generality of the reaction was further examined using
diverse allylamines (Scheme 3). First, an allylamine hydro- result of the previously reported studies.10b,17 Furthermore,
chloride salt was employed under the standard conditions other halogen sources, such as NCS and NBS, were also sur-
with the addition of a base to remove the hydrochloride, and veyed in the reaction and the corresponding chloromethyl and
the corresponding product 4a could be isolated in 45% yield. bromomethyl imidazoline products 6 and 7 were furnished in
Other 2-arylprop-2-en-1-amines served as suitable substrates in 50% and 99% yields, respectively (Scheme 4b).
the current reaction system to deliver the imidazoline products
Several control experiments were conducted to shed light
4b–d in 25–90% yields. The inferior efficiency of product 4e on the reaction mechanism. Radical trapping experiments
might result from the steric hindrance of the bulky naphtha- were performed by the addition of 2.0 equiv. of TEMPO
lene moiety. Unfortunately, allylamines with a pyridine ring (2,2,6,6-tetramethylpiperidine 1-oxyl) and BHT (2,4-di-tert-
did not participate in the reaction and only a trace amount of butyl-4-methylphenol) to the reaction (Scheme 5a). The reac-
product 4e was detected.
tion outcome was not significantly affected, which revealed
In order to further explore the applicability of the developed that a single electron transfer (SET) process was possibly not
protocol, another different coupling partners or halogen involved in the transformation. The coupling product amidine
sources were tested under the standard conditions (Scheme 4). 8 of 1b and allylamine 2a was synthesized and subjected to the
When prop-2-yn-1-amine 2g was subjected to the reaction, standard conditions (Scheme 5b). As expected, the desired imi-
2-trifluoromethyl imidazole-5-carbaldehyde
5
could be dazoline product 3b was isolated in 85% yield, suggesting the
obtained in 35% yield (Scheme 4a), which was similar to the intermediacy of amidine 8 in this transformation.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6115–6119 | 6117

View Article Online
Paper
Organic & Biomolecular Chemistry
reacting with NaN3 to afford the azide compound 9 with high
efficiency, which could undergo the CuAAC reaction with
phenylacetylene to generate the corresponding 1,2,3-triazole
product 10 in moderate yield. The above observation indicates
the application prospect of this protocol.
Conclusions
In conclusion, we have developed a metal-free approach for
the rapid assembly of 2-trifluoromethyl-imidazoline via a
cascade coupling/iodoaminocyclization reaction of trifluoroa-
cetimidoyl chlorides, allylamines and N-iodosuccinimides. A
high efficiency of this transformation is observed, demonstrat-
ing that more than half of the obtained imidazoline products
can be isolated in >90% yield. Other notable advantages of the
reaction include readily available reagents, mild reaction con-
ditions, a broad substrate scope and scalability. The protocol
represents a facile and efficient alternative to synthesize a
variety of biologically important imidazoline derivatives.
Scheme 5 Control experiments.
On the basis of the mechanistic investigations and previous
literature reports,18 a plausible reaction mechanism was pro-
posed as outlined in Scheme 6. Initially, the coupling of tri-
fluoroacetimidoyl chloride 1 with allylamine 2 could generate
amidine compound A. Then, the interaction of the alkene
moiety of A with NIS led to the iodonium species B and the
succinimide anion, followed by the intramolecular nucleophi-
lic cyclization of B to give rise to the intermediate C. Finally,
the deprotonation and isomerization process of C in the pres-
ence of the succinimide anion could deliver the desired imida-
zoline product 3 or 4 with the release of pyrrolidine-2,5-dione.
The reaction could be easily scaled up to a 5 mmol scale for
obtaining the imidazoline product 3b in 90% yield (Scheme 7).
Then, the synthetic transformation of 3b was conducted by
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We acknowledge the financial support from the Natural
Science Foundation of Zhejiang Province (LY19B020016).
Notes and references
1 (a) F. Rondu, G. Le Bihan, X. Wang, A. Lamouri,
E. Touboul, G. Dive, T. Bellahsene, B. Pfeiffer, P. Renard,
B. Guardiola-Lemaitre, D. Manechez, L. Penicaud,
A. Ktorza and J.-J. Godfroid, J. Med. Chem., 1997, 40, 3793–
3803; (b) L. T. Vassilev, B. T. Vu, B. Graves, D. Carvajal,
F. Podlaski, Z. Filipovic, N. Kong, U. Kammlott, C. Lukacs,
C. Klein, N. Fotouhi and E. A. Liu, Science, 2004, 303, 844–
848; (c) L. Crane, M. Anastassiadou, S. E. Hage,
J. L. Stigliani, G. Baziard-Mouysset, M. Payard, J. M. Leger,
J.-G. Bizot-Espiard, A. Ktorza, D.-H. Caignard and
P. Renard, Bioorg. Med. Chem., 2006, 14, 7419–7433;
(d) M. Zhao, Z. Li, L. Peng, Y.-R. Tang, C. Wang, Z. Zhang
and S. Peng, Eur. J. Med. Chem., 2008, 43, 1048–1058;
(e) D. K. Kahlon, T. A. Lansdell, J. S. Fisk, C. D. Hupp,
T. L. Friebe, S. Hovde, A. D. Jones, R. D. Dyer, R. W. Henry
and J. J. Tepe, J. Med. Chem., 2009, 52, 1302–1309;
(f) D. K. Kahlon, T. A. Lansdell, J. S. Fisk and J. J. Tepe,
Bioorg. Med. Chem., 2009, 17, 3093–3103; (g) N. Sato,
M. Ando, S. Ishikawa, M. Jitsuoka, K. Nagai, H. Takahashi,
A. Sakuraba, H. Tsuge, H. Kitazawa, H. Iwaasa, S. Mashiko,
A. Gomori, R. Moriya, N. Fujino, T. Ohe, A. Ishihara,
Scheme 6 Plausible reaction mechanism.
Scheme 7 Scalability and synthetic transformation.
6118 | Org. Biomol. Chem., 2021, 19, 6115–6119
This journal is © The Royal Society of Chemistry 2021

View Article Online
Organic & Biomolecular Chemistry
Paper
A. Kanatani and T. Fukami, J. Med. Chem., 2009, 52, 3385– 10 (a) V. M. Muzalevskiy, A. A. Iskandarov and
3396.
V. G. Nenajdenko, Mendeleev Commun., 2014, 24, 342–344;
(b) S. Li, J. Liang, X. Liu, L. Xian and M. Du, Chem. Pap.,
2021, 75, 1041–1053.
2 (a) Y. Hsiao and L. S. Hegedus, J. Org. Chem., 1997, 62,
3586–3591; (b) P. I. Dalko and Y. Langlois, J. Org. Chem.,
1998, 63, 8107–8117; (c) N. Li, W.-J. Zhu, J.-J. Huang, 11 H. Baganz and L. Domaschke, Angew. Chem., Int. Ed. Engl.,
X.-Q. Hao, J.-F. Gong and M.-P. Song, Organometallics, 1963, 2, 692–692.
2020, 39, 2222–2234; (d) S. Nakamura, K. Matsuzaka, 12 Y. G. Gololobov, N. I. Gusar and M. P. Chaus, Tetrahedron,
T. Hatanaka and Y. Funahashi, Org. Lett., 2020, 22, 2868–
2872.
1985, 41, 793–799.
13 A. V. Rudnichenko,
E.
I.
Kaminskaya
and
3 R. D. Crouch, Tetrahedron, 2009, 65, 2387–2397.
4 H. Heine and H. Bender, J. Org. Chem., 1960, 25, 461–463.
Y. G. Shermolovich, Zhurn. Org. Pharm. Khimii, 2006, 4, 38–
40.
5 (a) N. Murai, M. Komatsu, T. Yagii, H. Nishihara, 14 H. Jiang, L. Sun, S. Yuan, W. Lu, W. Wan, S. Zhu and
Y. Ohshiro and T. Agawa, J. Org. Chem., 1977, 42, 847–850; J. Hao, Tetrahedron, 2012, 68, 2858–2863.
(b) S. H. Jung and H. Kohn, J. Am. Chem. Soc., 1985, 107, 15 (a) S. Hu, Z. Yang, Z. Chen and X.-F. Wu, Adv. Synth. Catal.,
2931–2943; (c) Y. Han, Y.-X. Xie, L.-B. Zhao, M.-J. Fan and
Y.-M. Liang, Synthesis, 2008, 87–93.
6 (a) N. A. Boland, M. Casey, S. J. Hynes, J. W. Matthews and
M. P. Smyth, J. Org. Chem., 2002, 67, 3919–3922; (b) T. Isobe,
K. Fukuda, K. Yamaguchi, H. Seki, T. Tokunaga and
T. Ishikawa, J. Org. Chem., 2000, 65, 7779–7785.
7 (a) S. Peddibhotla, S. Jayakumar and J. J. Tepe, Org. Lett.,
2002, 4, 3533–3535; (b) S. Peddibhotla and J. J. Tepe,
Synthesis, 2003, 1433–1440; (c) V. Sharma and J. J. Tepe,
Org. Lett., 2005, 7, 5091–5094.
2019, 361, 4949–4954; (b) Z. Chen, W.-F. Wang, H. Yang
and X.-F. Wu, Org. Lett., 2020, 22, 1980–1984;
(c) L.-C. Wang, S. Du, Z. Chen and X.-F. Wu, Org. Lett.,
2020, 22, 5567–5571; (d) Z. Chen, L.-C. Wang, J. Zhang and
X.-F. Wu, Org. Chem. Front., 2020, 7, 2499–2504; (e) S. Du,
L.-C. Wang, Z. Yang, Z. Chen and X.-F. Wu, Adv. Synth.
Catal., 2020, 362, 5130–5134; (f) L.-C. Wang, Y. Zhang,
Z. Chen and X.-F. Wu, Adv. Synth. Catal., 2021, 363, 1417–
1426; (g) H. Yang, S.-N. Lu, Z. Chen and X.-F. Wu, J. Org.
Chem., 2021, 86, 4361–4370.
8 M. R. Kuszpit, W. D. Wulff and J. J. Tepe, J. Org. Chem., 16 (a) K. Tamura, H. Mizukami, K. Maeda, H. Watanabe and
2011, 76, 2913–2919.
9 (a) K. Müller, C. Faeh and F. Diederich, Science, 2007, 317,
K. Uneyama, J. Org. Chem., 1993, 58, 32–35; (b) Z. Chen,
S. Hu and X.-F. Wu, Org. Chem. Front., 2020, 7, 223–254.
1881–1886; (b) W. K. Hagmann, J. Med. Chem., 2008, 51, 17 S. Li, Z. Li, Y. Yuan, D. Peng, Y. Li, L. Zhang and Y. Wu,
4359–4369; (c) E. P. Gillis, K. J. Eastman, M. D. Hill, Org. Lett., 2012, 14, 1130–1133.
D. J. Donnelly and N. A. Meanwell, J. Med. Chem., 2015, 58, 18 (a) Y. Wang, K. H. Wang, Y. Su, Z. Yang, L. Wen, L. Liu,
8315–8359; (d) J. Wang, M. Sánchez-Roselló, J. L. Aceña,
C. del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok
and H. Liu, Chem. Rev., 2014, 114, 2432–2506; (e) Y. Zhou,
J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña,
V. A. Soloshonok, K. Izawa and H. Liu, Chem. Rev., 2016,
116, 422–518.
J. Wang, D. Huang and Y. Hu, J. Org. Chem., 2018, 83, 939–
950; (b) J. Santhi and B. Baire, Adv. Synth. Catal., 2016, 358,
3817–3823; (c) X.-Q. Hu, J.-R. Chen, Q. Wei, F.-L. Liu,
Q.-H. Deng, Y.-Q. Zou and W.-J. Xiao, Eur. J. Org. Chem.,
2014, 3082–3086; (d) T. Luo, J.-P. Wan and Y. Liu, Org.
Chem. Front., 2020, 7, 1107–1112.
This journal is © The Royal Society of Chemistry 2021
Org. Biomol. Chem., 2021, 19, 6115–6119 | 6119