Metal-Free Synthesis of 5-Trifluoromethyl-1,2,4-Triazoles from Iodine-Mediated Annulation of Trifluoroacetimidoyl Chlorides and Hydrazones

Article abstract of DOI:10.1002/adsc.201900983

A metal-free approach for the synthesis of 5-trifluoromethyl-1,2,4-triazoles from trifluoroacetimidoyl chlorides and hydrazones has been achieved under aerobic oxidative conditions. The reaction proceeds through a cascade base-promoted intermolecular C?N bond formation and iodine-mediated intramolecular C?N bond oxidative coupling sequence. The protocol features broad substrate scope and can be scaled up to gram scale. (Figure presented.).

Full text of DOI:10.1002/adsc.201900983

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DOI: 10.1002/adsc.201900983
Metal-Free Synthesis of 5-Trifluoromethyl-1,2,4-Triazoles from
Iodine-Mediated Annulation of Trifluoroacetimidoyl Chlorides
and Hydrazones
Sipei Hu,a Zuguang Yang,a Zhengkai Chen,a,* and Xiao-Feng Wua, b,*
a
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, People’s Republic of China
E-mail: zkchen@zstu.edu.cn; xiao-feng.wu@catalysis.de
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Straβe 29a, 18059 Rostock, Germany
b
Manuscript received: August 6, 2019; Revised manuscript received: September 6, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900983
ous trifluoromethyl-substituted N-heterocycles,[5] the
Abstract: A metal-free approach for the synthesis
using of trifluoroacetimidoyl halide as trifluoromethyl
of 5-trifluoromethyl-1,2,4-triazoles from trifluoro-
synthon is proven to be exceptional in many cases.[6–12]
acetimidoyl chlorides and hydrazones has been
Trifluoroacetimidoyl halides were usually applied
achieved under aerobic oxidative conditions. The
as useful building blocks for the assembly of
reaction proceeds through a cascade base-promoted
trifluoromethyl-substituted N-heterocycles in synthetic
intermolecular CÀ N bond formation and iodine-
organofluorine chemistry. In 2010, the research groups
mediated intramolecular CÀ N bond oxidative cou-
pling sequence. The protocol features broad sub-
strate scope and can be scaled up to gram scale.
of Wu[6a] and Zhang[6b] reported palladium- or copper-
catalyzed cyclization of trifluoroacetimidoyl chlorides
with sodium hydrosulfide hydrate to synthesize 2-
trifluoromethylbenzothiazoles, respectively (Sche-
me 1a). In 2012, Wu and coworkers described a PIDA
(phenyliodine (III) diacetate)-mediated oxidative intra-
molecular cyclization of the trifluoromethyl amidine
for the formation of 2-trifluoromethylbenzimidazoles
(Scheme 1b).[7] Two years later, Darehkordi’s group
Keywords: trifluoroacetimidoyl
chlorides;
5-
trifluoromethyl-1,2,4-triazoles; metal-free; CÀ N bond
formation; N-heterocyclic compounds
The trifluoromethyl-substituted nitrogen-containing
heterocycles have found wide applications in the fields
of pharmaceuticals, agrochemicals, and materials
science, due to the unique properties of fluorine atoms,
including improving the electronegativity, bioavailabil-
ity, metabolic stability and lipophilicity of the
compounds.[1] Considering the excellent properties of
the trifluoromethyl group, the exploration of efficient
methods for the incorporation of trifluoromethyl group
into the functionalized N-heterocyclic molecules has
emerged as an attractive research area over the past
decades.[2] In general, there are two mainstream path-
ways to access to versatile trifluoromethyl-substituted
N-heterocycles: 1st) trifluoromethylation of pre-synthe-
sized N-heterocycles by the employment of diverse
trifluoromethyl reagents;[3] 2ed) direct construction of
trifluoromethyl-substituted N-heterocycles through the
reaction of different trifluoromethyl-containing syn-
thons with suitable coupling substrates.[4] In this
context, in contrast to the frequent application of 2,2,2-
trifluorodiazoethane (CF3CHN2) as an appealing
trifluoromethyl-containing 1,3-dipole to build numer-
Scheme 1. The Reactions of Trifluoroacetimidoyl Halides for
the Synthesis of Trifluoromethyl-substituted N-Heterocycles.
Adv. Synth. Catal. 2019, 361, 1–7
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Table 1. Optimization of reaction conditions.[a]
explored a convenient approach for the preparation of
5-trifluoromethyl-tetrazoles via microwave-assisted [2
+3] cycloaddition reaction of trifluoroacetimidoyl
chloride and sodium azide. (Scheme 1c).[8] The Wu’s
group developed an novel Au-catalyzed protocol for
the synthesis of 2-fluoroalkyl imidazole derivatives
from trifluoroacetimidoyl chloride and propargyl
amines (Scheme 1d).[9] Additionally, transition-metal-
catalyzed transformations of trifluoroacetimidoyl hal-
ides with alkynes for the construction of 2-
trifluoromethyl quinolones have also been extensively
investigated (Scheme 1e).[10] The 2-trifluoromethyl
quinolone could also be obtained through palladium-
catalyzed tandem Suzuki/CÀ H arylation reaction of
trifluoroacetimidoyl chlorides with arylboronic
acids[11a–c] or norbornene-mediated intermolecular de-
hydrogenative annulation with aryl iodides[11d] (Sche-
me 1f). Recently, a Pd(0)-catalyzed C(sp3)À H function-
alization of trifluoroacetimidoyl chlorides to lead to 2-
(trifluoromethyl)indoles was reported by Cramer and
co-workers. (Scheme 1g).[12] Encouraged by the above
fruitful works and our continuous endeavors on the
synthesis of structurally diverse nitrogen-containing
heterocycles,[13] we present herein an efficient metal-
free multistep coupling reaction of trifluoroacetimidoyl
chlorides and hydrazones for the rapid preparation of
5-trifluoromethyl-1,2,4-triazoles (Scheme 1h). Note-
worthy was that the reports about the synthesis of
perfluoroalkyl-1,2,4-triazoles were quite rare, which
involved the hydrazinolysis reaction of 5-perfluoroalk-
yl-1,2,4-oxadiazoles or the conversion of the 2-chloro-
1,1,1-trifluoro-2-propyl azo compound.[14] Notably,
1,2,4-triazoles are highly privileged heterocyclic scaf-
folds and have been broadly applied in biological and
pharmaceutical fields as well as materials science.[15]
Initially, we chose 2,2,2-trifluoro-N-(p-tolyl)aceti-
Entry
Additive.
(equiv.)
Solvent
(mL)
Temperature
Yield[b]
(%)
°
( C)
1
2
3
4
5
6
7
8
–
DCE
DCE
DCE
DCE
DCE
DMSO
toluene
CH3CN
Dioxane
DMF
MeOH
DCE
80
80
80
80
80
80
80
80
80
80
80
rt
62
69
74
85
trace
48
ND
trace
59
trace
82
47
Cs2CO3
K2CO3
NaOAc
NEt3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
9
10
11
12
13
14
15
16
17
DCE
DCE
DCE
DCE
60
100
80
80
80
71
55
45[c]
86[d]
0–45[e]
DCE
[a] Reaction conditions: 1b (0.2 mmol), 2a (0.4 mmol), and
additive (2.0 equiv.) in solvent (2.0 mL) in seal tube under air
at specified temperature for 3 h, then adding I2 (0.2 mmol) for
another 1 h.
[b] Isolated yields.
[c] 0.5 equiv. of I2 was used.
[d] 1.5 equiv. of I2 was used.
[e] The iodine was replaced with Lewis acids FeCl3, CuI or Cu
(OTf)2. ND=No detection of the product.
midoyl chloride 1b and hydrazone 2a as the model the reaction temperature was implemented and the
°
substrates for our investigation. The corresponding reaction was carried out at room temperature, 60 C
°
trifluoroacetimidoyl chlorides could be readily pre- and 100 C, respectively. The inferior results were
°
pared by simply mixing the parent amine with obtained compared with that of 80 C (Table 1,
trifluoroacetic acid, CCl4, and PPh3.[16] It is enough entries 12–14). Decreasing the amount of I2 to 0.5
stable to be isolated by silica gel chromatography. The equivalent resulted in the decrease of reaction yield
°
reaction proceeded with 1b and 2a in DCE at 80 C and a slight increase of the reaction efficiency could be
for 3 h, and then 1.0 equiv. I2 was added to the achieved when 1.5 equivalents of I2 was used in the
reaction. Molecular iodine has been known as good second step (Table 1, entries 15–16). Given that the
catalyst or mediator in the CÀ N bond formation. To iodine could be served as Lewis acid to promote the
our delight, the 5-trifluoromethyl-1,2,4-triazole product reaction, we also investigated other Lewis acids
3b was formed in 62% yield (Table 1, entry 1). The (FeCl3, CuI and Cu(OTf)2) to replace iodine in the
exact structure of the obtained 5-trifluoromethyl 1,2,4- reaction. The results indicated that FeCl3 or Cu(OTf)2
triazole 3b was unambiguously confirmed by single could give the product in 37% or 45% yield and no
X-ray diffraction analysis (CCDC: 1940424).[17] Then, reaction occurred in the presence of CuI (Table 1,
different basic additives were added into the first step entry 17).
of the reaction, and NaOAc could give the best
Having established the optimal reaction conditions,
outcome (Table 1, entries 2–5). The solvent effect was the generality and limitation of the protocol were
examined by the employment of various solvents, and examined (Table 2). In general, a range of N-aryl-
the highest yield was observed with respect to DCE trifluoroacetimidoyl chlorides bearing electron-donat-
(Table 1, entries 6–11). Further optimization towards ing or -withdrawing groups were subjected into the
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Table 2. Scope of Fluorinated Imidoyl Chlorides.[a,b]
Table 3. Scope of Hydrazones Derived from Diverse Alde-
hydes.[a,b]
[a] Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), and
°
NaOAc (2.0 equiv.) in DCE (2.0 mL) under air at 80 C for
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), and
3 h, and then adding I2 (0.2 mmol) for another 1 h.
°
[b] Isolated yields.
NaOAc (2.0 equiv.) in DCE (2.0 mL) under air at 80 C for
[c] MeOH was used as solvent.
3 h, and then adding I2 (0.2 mmol) for another 1 h.
[b] Isolated yields.
[c] The reaction was performed on 3.5 mmol scale.
The scope of this transformation was further
standard conditions and good yields could be obtained examined by the employment of a variety of hydra-
in most cases (3a–p). Noteworthy was that steric zones derived from different aldehyde (Table 3).
hindrance (3b–d) and electronic factors (3a–p) of Hydrazones attaching electron-donating and -with-
trifluoroacetimidoyl chlorides seemingly had a little drawing groups on the phenyl ring reacted smoothly
influence on the transformation. The smooth tolerance with trifluoroacetimidoyl chloride 1a to afford the
of halogen atom (F, Cl, Br and I) at different relevant 5-trifluoromethyl-1,2,4-triazole products in
substituted positions on the aryl ring provides the moderate to good yields (4a–l). The orientation of
possibility for further derivatization through various substituents on the aromatic ring exerted a marginal
coupling reactions (3j–m, 3p–q). The transformation effect on the reaction, as illustrated by the slightly
could be readily reproducible on a gram scale in 81% decreased efficiency of ortho methyl substituted
yield for product 3l. More importantly, strong elec- hydrazone (4c). Diverse halogenated substituents
tron-withdrawing groups, such as À NO2 and CF3, were could be well tolerated, as well as several strong
compatible with the reaction system to deliver the electron-withdrawing groups (4f–j). Notably, better
corresponding products (3n–o) with decent efficiency. results could be afforded by using MeOH as the
Furthermore, the naphthalene group could be success- solvent as for product 4e and 4j. The naphthalene
fully incorporated into the 1,2,4-triazole product 3r in attached 1,2,4-triazole 4m could be furnished in 75%
excellent yield as well. It should be noted that other yield under the standard conditions.
fluoroalkyl-1,2,4-triazoles (3s–w) could also be pro-
Furthermore, hydrazone possessing heterocyclic
duced under the current reaction conditions by using skeletons, including pyridine, furan and thiophene,
the corresponding fluorinated imidoyl chlorides. Per- were also viable substrates to provide the target 1,2,4-
haps due to the unique properties of the CF2X groups, triazoles in moderate to excellent yields (4n–p). It is
the reaction failed to occur when the CF2X groups worth mentioning that the obtained 1,2,4-triazole
were replaced with other groups. Unfortunately, the products 4n–p have the great potential to be applied as
trifluoroacetimidoyl chlorides from heteroaryl amines bidentate ligands.[18] To our delight, 3-alkenyl sub-
could not be obtained and the trifluoroacetimidoyl stituted 1,2,4-triazole 4q and 4r could also be afforded
chlorides from aliphatic amines did not participate in in acceptable yield by the use of hydrazone from
the reaction.
cinnamaldehyde and 3-methylbut-2-enal as the reac-
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Scheme 2. One-pot Reaction.
tant. Unfortunately, the hydrazones from aliphatic
aldehydes failed to participate in the reaction, presum-
ably due to their instability and tendency to be
discomposed under the reaction conditions.
Scheme 4. Plausible Reaction Mechanism.
The protocol could be operated in a consecutive
one-pot manner (Scheme 2). Initially, the reaction of
On the basis of the results from the preliminary
benzaldehyde and hydrazine hydrate proceeded in mechanistic
investigations
and
in
previous
DCE at room temperature for 30 minutes. Then, literatures,[19] a plausible reaction mechanism was
trifluoroacetimidoyl chloride 1a was added to the proposed as depicted in Scheme 4. At first, the base-
mixture in the presence of anhydrous Na2SO4 and mediated CÀ N bond coupling of trifluoroacetimidoyl
2.0 equiv. of NaOAc. The reaction was conducted at chloride 1a and hydrazone 2a gave the trifluoroacet-
°
80 C for 3 hours whereas the isolation of the coupling amidine derivative 5. This step could also occur in the
product 5 was not necessary due to the operation as absence of base.[7] Then, the base-promoted oxidative
one-pot reaction. Finally, 1.0 equiv. of I2 was subjected iodination of 5 led to an iodo species A, which was
into the reaction for another 1 hour and the target successfully detected by LC-HRMS. The intramolecu-
product 3a could be attained in 82% overall yield.
lar nucleophilic attack of nitrogen to the iodo-
The intermediate 5 was successfully isolated as a substituted carbon could generate intermediate B.
mixture of cis- and trans-isomer and subjected into the Finally, the base-promoted deprotonation and rear-
reaction in the presence of 1.0 equiv. of I2 (Scheme 3a). omatization of B delivered the 5-trifluoromethyl-1,2,4-
Not surprisingly, the product 3a could be delivered in triazole product 3a.
92% yield. The intermediate 5 could not be trans-
In conclusion, we have developed an expeditious
formed into 3a in the absence of iodine even though and practical metal-free strategy for the assembly of 5-
the reaction was conducted at elevated temperature. trifluoromethyl-1,2,4-triazole through CÀ N bond for-
The result demonstrated the plausible intermediacy of mation from readily available trifluoroacetimidoyl
compound 5. In addition, a series of radical trapping chlorides and hydrazones. Compared with the conven-
experiments were conducted by the addition of radical tional multistep and tedious methods to access to
scavenger of 2.0 equiv. of TEMPO (2,2,6,6-tetrameth- perfluoroalkyl-1,2,4-triazoles, the current transforma-
ylpiperidine 1-oxyl), BHT (2,4-di-tert-butyl-4-meth- tion features mild reaction conditions, simple oper-
ylphenol) and BQ (1,4-benzoquinone) into the second ation, broad substrate scope and high efficiency, and
step of the standard conditions (Scheme 3b), but the can be easily scaled up to gram scale. The method-
reaction yield was not sharply decreased. Therefore, a ology provides a straightforward and environmentally
single electron transfer (SET) process might not be benign pathway for the synthesis of trifluoromethyl-
involved in the reaction.
substituted N-heterocycles. Further studies toward
extending the application of trifluoroacetimidoyl hal-
ides to construct more structurally diversified
trifluoromethyl-substituted N-heterocycles are under-
way.
Experimental Section
Typical Procedure for the Synthesis of
5-Trifluoromethyl-1,2,4-Triazoles
NaOAc (32.8 mg, 0.4 mmol) were added to a solution of
trifluoroacetimidoyl chloride 1 (0.2 mmol) and hydrazone 2
°
(0.4 mmol) in DCE (2 mL). The mixture was stirred at 80 C
Scheme 3. Mechanistic Investigations.
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under air for 3 h. Then, I2 (50.8 mg, 0.2 mmol) was added into
the reaction for another 1 h. After the completion of the reaction
(monitored by TLC), the reaction mixture was cooled to
ambient temperature, quenched by water and extracted with
ethyl acetate (3×15 mL). The extract was washed with 10%
Na2S2O3 solution (w/w) (2×15 mL), dried over anhydrous
Na2SO4 and the solvent was removed in vacuo to provide a
crude product, which was purified by column chromatography
on silica gel with petroleum ether/EtOAc as eluent to afford the
product 5-trifluoromethyl-1,2,4-triazoles.
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Acknowledgements
We acknowledge financial support from the Zhejiang Natural
Science Fund for Young Scholars (LQ18B020008), 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 (2019Q065).
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Adv. Synth. Catal. 2019, 361, 1–7
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COMMUNICATIONS
Metal-Free Synthesis of 5-Trifluoromethyl-1,2,4-Triazoles
from Iodine-Mediated Annulation of Trifluoroacetimidoyl
Chlorides and Hydrazones
Adv. Synth. Catal. 2019, 361, 1–7
S. Hu, Z. Yang, Z. Chen*, X.-F. Wu*