Stereoselective Direct N‐Trifluoropropenylation of Heterocycles with a Hypervalent Iodonium Reagent

Abstract The availability and synthesis of fluorinated enamine derivatives such as N‐(3,3,3‐trifluoropropenyl)heterocycles are challenging, especially through direct functionalization of the heterocyclic scaffold. Herein, a stereoselective N‐trifluoropropenylation method based on the use of a bench‐stable trifluoropropenyl iodonium salt is described. This reagent enables the straightforward trifluoropropenylation of various N‐heterocycles under mild reaction conditions, providing trifluoromethyl enamine type moieties with high stereoselectivity and efficiency.

propen-1-yl group is relatively rare and methods which enable its incorporation into heterocycles through the formation of new CÀ N bond are hardly available and mostly limited to some specific substrates, such as cyclic amides. [11] The N-trifluoropropenylation of enamides such as pyrrolidin-2-one can be achieved through the palladium- [11a] or copper-catalyzed [11b] trifluoromethylation of N-vinylpyrrolidin-2-one with CF 3 I or under photocatalytic conditions (Figure 1a), [11c-e] while the same product can be obtained with trifluoropropionaldehyde (Figure 1b). [11f] The use of 3,3,3-trifluoropropyne gas as a C 2 -CF 3 surrogate requires the handling of gaseous reagent, but it was successfully applied as Michael acceptor in its reaction with 2'deoxyiodouridine used for iodinated DNA bases ( Figure 1c). [11g] The NH functionalities in uracil and thymine can be trifluoropropenylated with 2-bromo-3,3,3-trifluoropropene with moderate stereoselectivity (Figure 1c). [11h] However, the applicability of the previous methods was demonstrated with only a few trifluoromethylated examples.
Taking into consideration the importance of the compound class and the limitations of their versatile and selective synthesis, we aimed to develop a novel procedure which enables the direct introduction of trifluoropropenyl functional groups into heterocycles through the formation of new CÀ N bond in a selective and efficient manner under mild reaction conditions enabled by hypervalent iodonium species. [13] In our laboratory, we recently designed and synthesized a bench stable trifluoroisopropenyl iodonium salt (1) and studied its reactivity toward nitrogen nucleophiles. Primary amines provided trifluoromethylaziridines, [14] while the utilization of secondary amines ensured the synthesis of trifluoroalkyl amines and diamines through aziridinium intermediate. [15] To complete the spectrum of applicable nitrogen nucleophiles, we studied the reaction of nitrogen heterocycles with the trifluoropropenyl-iodonium salt to discover new synthetic possibilities and develop a stereoselective, versatile, and efficient methodology to the access of N-trifluoropropenyl heterocyclic species through a one-step direct functionalization ( Figure 2).
We choose benzotriazole (2) as model substrate for the reactivity and optimization studies, focusing on the effect of base and solvent. To our delight, in dichloromethane with Li 2 CO 3 base the desired trifluoropropenylation of benzotriazole with 1.2 equivalent of iodonium reagent 1 the trifluoropropenylation took place on N-1 resulting 3 in 83 % conversion in 2 h at 25°C (Table 1, Entry 1). However, formation of constitutional isomers was also observed as minor products [16] In further optimization, we aimed to improve both the selectivity and the efficiency of the trifluoropropenylation. In this regard, the use of other carbonates such as sodium and potassium resulted lower conversions (80 % and 60 % respectively, Table 1, Entry 2 and 3). In the presence of NaH, product 3 formed in 75 % conversion, while collidine could also be used effectively as simple organic base with complete reaction, providing the major product 3 in 85 % conversion. Next, we studied some solvent-base pairs including EtOAc, THF, and MeCN as solvents and Li 2 CO 3 , Na 2 CO 3 , and collidine as bases to find the best    -11). We found that the combination of MeCN and Li 2 CO 3 provided the best conditions for the reaction, which took place in full regio-and stereoselectivity and the E-trifluoropropenylated benzotriazole 3 was isolated in 95 % yield after workup.
After finding the optimal solvent-base pair for the transformation (we performed the same solvent-base optimization with indazole, and obtained the same result), [16] we were also able to lower the iodonium salt loading to 1.1 equivalents without any diminuation of isolated yield. Increasing the temperature had no effect on reaction time or yield. [16] With the optimized conditions in hand, we aimed to explore the scope of the reaction with the E-selective N-trifluoropropenylation of various heterocycles bearing NH functionality. In this regard, reactions of pyrazoles provided the desired products under the optimized reaction conditions. Although the parent compound 1H-pyrazole could be trifuoropropenylated with full Scheme 1. Substrate scope. NÀ H heterocycles (0.30-1.00 mmol, 1.0 equiv), Li 2 CO 3 (0.60-2.00 mmol, 2.0 equiv), trifluoroisopropenyl iodonium salt 1 (0.33-1.10 mmol, 1.1 equiv) and 3-10 mL of MeCN, room temperature, 2 h. [a] the major regioisomer is depicted on the scheme

Chemistry-A European Journal
Communication doi.org/10.1002/chem.202102840 conversion (not shown), [16] the isolation of this product was problematic due to its volatility. The presence of Br substituent on the pyrazole ring enabled the isolation of 4 in 80 % yield after the trifluoropropenylation.
Next, we examined a series of 3,5-symmetrically disubstituted pyrazoles such as 3,5 dimethyl-pyrazole and its 4iodinated derivative and we were able to isolate the corresponding products 5 and 6 in 63 and 80 % yield, respectively. Symmetric 3,5-diaryl pyrazoles were trifluoropropenylated without difficulties and the products 7-13 were isolated in 53-90 % yield range, similarly to the 4-iodo derivative 14 which was isolated in 50 % yield.
In case of non-symmetrically substituted pyrazoles, the 3phenyl and 3-trifluoromethyl-4-carbetoxy substituted pyrazoles gave exclusively one constitutional isomer 15 and 16 in 86 % and 63 % yield, indicating the steric and electronic influence on the functionalization. Other non-symmetrically substituted 3,5diaryl pyrazoles also reacted smoothly, however, only inseparable mixtures of constitutional isomers of 17, 18, and 19 could be isolated. In contrast, when 3-phenyl-5 trifluormethylpyrazole was transformed, isomers 20 and 21 were isolable in 31 and 36 % yield, respectively, similarly to products 22 and 23 which were separated and isolated with similar efficiency (48 and 39 % yield, respectively).
Next, we studied the reactivity of the benzene-fused nitrogen heterocycles having a ring NH functionality. Indazoles were also successfully trifluoropropenylated with iodonium reagent under the optimized conditions.
Presence of ethylcarboxylate group in the pyrazole ring caused the formation of two isomers 30 and 31 which were isolated after separation in 53 % and 24 %. Substituents such as Br, NO 2 , and TBDMSO on the benzene ring of indazole selectively form N-1-trifluoropropenylated products 32, 33, and 34 with similar high efficiency (83 %, 87 % and 88 % respectively). Beside the indazole derivatives, benzimidazoles were also successfully transformed and the desired products (35, 36) were formed selectively and isolated in 74 % and 40 % yield.
In this series, we aimed for the transformation of indole, but we observed the formation of complex reaction mixture without the detection of the desired product. [17] However, azaindoles were trifluoropropenylated successfully and enamine products 37 and 38 were isolated in 47 % and 37 % yields, respectively.
Although our model substrate benzotriazole used for the optimization studies, gave exclusively one product (3) under the optimized conditions in 95 % isolated yield, the reaction with its 4-nitro-substituted derivative gave three regioisomers 39, 40 and 41, which were isolated in 60 %, 18 %, and 15 % respectively after chromatographic purification.
To our delight, not just aromatic heterocycles, but also heterocyclic imides were transformed efficiently using the developed methodology. Phthalimide reacted smoothly and the corresponding trifluoropropenyl-phthalimide 45 was isolated in 80 % yield. Phenytoin was also a suitable substrate for the transformation, and we were able to isolate the Ntrifluoropropenylated product 46 in 60 % yield.
On the basis of our previous studies, we propose a mechanism for the trifluoropropenylation (Figure 3).
After the deprotonation step, the heterocyclic anion attacks to the terminal sp 2 carbon of the trifluoropropenyl moiety in a Michael addition type reaction, then the formed benzotriazolyl iodonium ylide (49) undergoes intramolecular proton transfer resulting anion 51. Alternatively, the stabilized carbanion (49) can be protonated by the HCO 3 À ion in an intermolecular fashion forming intermediate 50 which can be deprotonated by the base, with the resulting anion 51 undergoing E-selective elimination step to provide the final product 3.
To support the mechanistic hypothesis, especially the relevance of intramolecular and intermolecular proton transfers,

Chemistry-A European Journal
Communication doi.org/10.1002/chem.202102840 intermolecular base assisted proton transfer could also operate, beside some minor solvent effect on the proton transfer.
In summary, we developed a novel methodology for the direct N-trifluoropropenylation of heterocyclic molecules with the use of a trifluoropropenyl iodonium salt. The reaction enables the stereoselective synthesis of trifluoromethyl enamines having the potential in further transformations and adds to the synthetic applicability of trifluoropropenyl iodonium species toward versatile nitrogen nucleophiles.