Visible-light promoted three-component tandem reaction to synthesize difluoromethylated oxazolidin-2-imine

Abstract

An effective synthetic method to achieve difluoromethylated oxazolidin-2-imine has been developed via visible-light promoted three-component tandem reaction of aryl allylamines, 2-BTSO2CF2H (BT = Benzothiazole) and isocyanates. This method features mild reaction conditions and good functional group tolerance, and the reaction mechanism was confirmed by experiments and interpreted by quantum chemical calculations.

Visible-light promoted three-component tandem reaction.

Difluoromethyl containing compounds have been widely used in the fields of pharmaceutics and agrochemistry because of their unique physical, chemical, and biological properties.¹ Generally, the –CF₂ moiety can act as a bioisostere of the –CH₂ or –CO group and the CF₂H is isopolar to the –OH and –SH group, which can be used as a lipophilic hydrogen bond donor.^2,3 In recent years, much attention has been focused on the synthesis of difluoromethylated molecules.⁴ FDA approved medicine Gemcitabine and Lubiprostone both contain difluoromethyl group (Fig. 1a).

Fig. 1. (a) Structure of Gemcitabine and Lubiprostone (b) selected bioactive oxazolidin-2-imine derivatives.

The oxazolidin-2-imine skeleton exists in many biologically active compounds. For example, compound I is a novel nitric oxide synthase inhibitor with an EC₅₀ value of 41 nM,⁵ and compound II acts as a very potent selective androgen receptor modulator (SARM) with a sub-nanomolar EC₅₀ value (Fig. 1b).⁶ In addition, substituted oxazolidin-2-imines are critical synthetic intermediates that can be transformed into a variety of other structures, and represent a useful chiral auxiliary for the asymmetric alkylations.⁷ The high value of oxazolidin-2-imine in medicinal chemistry and organic chemistry has driven successive efforts to develop effective synthetic methods. Shinichi Saito's group reported the cycloaddition of aziridines with isocyanates catalyzed by NiI₂ to furnish oxazolidin-2-imines in good yields (Scheme 1a).⁸ Beifuss's group revealed intermolecular 1,2-addition/intramolecular N-vinylation of 2-bromo-2-propen-1-ols and dicyclohexyl carbodiimide for the synthesis of oxazolidin-2-imines (Scheme 1b).⁹ Recently, Bu₂SnI₂–InCl₃ catalysed cycloaddition of propylene oxide with diphenyl carbodiimide was reported by Ikuya Shibata's group¹⁰ (Scheme 1c).

Scheme 1. Different protocols for the synthesis of oxazolidin-2-imine.

Radical-triggered cascade multi-component reactions serve as an ideal strategy in the synthesis of heterocyclic scaffolds, owing to forming multiple bonds under a single set of reaction conditions.¹¹ Particularly, the visible-light promoted radical addition–cyclization has demonstrated its synthetic utility in the construction of compounds with various scaffold,¹² including 2-oxazolidinones,¹³ coumarin,¹⁴ phenanthridines,¹⁵ and so on. We envisioned that the combination of difluoromethyl moiety with oxazolidin-2-imine scaffold may exert potential use in medicinal chemistry and other related fields. As part of our work on the visible-light mediated radical difluoromethylation,¹⁵ we try to explore a novel and convenient method to construct HCF₂-containing oxazolidin-2-imines via visible-light promoted three-component tandem reaction (Scheme 1d).

We began our investigation by using N-benzyl-2-phenylprop-2-en-1-amine 1a, 1-isocyanato-4-methylbenzene 3a as the model substrate and 2-BTSO₂CF₂H (Hu's reagent) 2 as the difluoromethylation reagent. Initially, DABCO was used as base and target compound 4aa can be produced in 29% yield using Ru(bpy)₃Cl₂·6H₂O as photocatalyst (Table 1, entry 1). Further screening of various bases, including Na₂CO₃, TMEDA, DBN, TEA and DIPEA, cannot get the 4aa, indicating the DABCO was the optimal base for this reaction (Table 1, entries 2–6). Then, a series of solvents, including DMF, acetonitrile, NMP, acetone and toluene were screened, and the results showed that DMF was more suitable for this reaction than others (Table 1, entries 7–11). In addition, the replacement of catalyst Ru(bpy)₃Cl₂·6H₂O with fac-Ir(ppy)₃ decreased the yield slightly (28%) (Table 1, entry 12). Interestingly, the decrease of temperature and increase the equivalence of 3a can improve the yields of 4aa obviously (entries 13 and 14). Therefore, the best result was obtained with a combination of 2 with 3a (2.5 equiv.), DABCO (1 mmol, 2.0 equiv.), Ru(bpy)₃Cl₂·6H₂O (5 mol%) in DMF (2.0 mL) were irradiated with a 6 W blue LED for 16 h at 8∼10 °C to furnish 4aa in 75% yield (entry 15).

Optimization of reaction conditions^a.

Entry	Base	Solvent	3a/equiv.	Yieldb (%)
1	DABCO	DMSO	1.2	29
2	Na2CO3	DMSO	1.2	0
3	TMEDA	DMSO	1.2	0
4	DBN	DMSO	1.2	Trace
5	TEA	DMSO	1.2	Trace
6	DIPEA	DMSO	1.2	Trace
7	DABCO	DMF	1.2	35
8	DABCO	CH3CN	1.2	26
9	DABCO	NMP	1.2	15
10	DABCO	Acetone	1.2	25
11	DABCO	Toluene	1.2	Trace
12c	DABCO	DMF	1.2	28
13d	DABCO	DMF	1.2	43
14d	DABCO	DMF	1.8	61
15d	DABCO	DMF	2.5	75
16d	DABCO	DMF	3.0	74

^aReaction condition: 1a (0.5 mmol, 1.0 equiv.), 2 (0.6 mmol, 1.2 equiv.), PC (0.025 mmol, 5 mol%), base (1 mmol, 2.0 equiv.), solvent (2.0 mL), irradiated with a 6 W blue LED for 10 h at room temperature under N₂ atmosphere.

^bIsolated yields.

^c fac-Ir(ppy)₃ instead of Ru(bpy)₃Cl₂·6H₂O.

^dIn the ice bath (8–10 °C) for 16 h.

With the optimized reaction conditions in hand, the substrate scope of aryl allylamines 1 was extensively investigated. As shown in Table 2, the reaction tolerates various substituents on the phenyl ring, including halogen and alkyl (4ba∼4ha). Substrates containing both electron-donating (–OCH₃) and electron-withdrawing (–CF₃, –CN) groups on phenyl can proceeded this reaction smoothly and give CF₂H-containing oxazolidin-2-imines in good yields (4ja, 4la). In addition, 2-naphthyl allylamine 1n and 2-thienyl allylamine 1o also can produce the corresponding CF₂H-containing compounds 4na and 4oa in moderate to good yields. The relative low yields of 4fa (48%) and 4ia (40%) indicated the obvious steric effect in this reaction. More interestedly, the success of approaching 4pa in moderate yield with 1p (N-allyl-2-phenylprop-2-en-1-amine) showed the good tolerance for various substituents on amine in this reaction.

Scope of aryl allylamines^a,b.

^aReaction conditions: 1 (0.5 mmol, 1.0 equiv.), 2 (0.6 mmol, 1.2 equiv.), 3a (1.25 mmol, 2.5 equiv.), [Ru(bpy)₃]Cl₂·6H₂O (0.025 mmol 5 mol%), and DABCO (1 mmol, 2.0 equiv.) in DMF (2.0 mL) were irradiated with a 6 W blue LED for 16 h at 8–10 °C under N₂ atmosphere.

^bYields isolated.

Subsequently, the substrate scope of isocyanates was also investigated (Table 3). The substituents on the phenyl ring were first evaluated, and the results showed that both electron-donating (Me, OMe) and electron-withdrawing groups (Cl, CF₃) on para or meta position were tolerated with good yields of corresponding products (50–72%). While similar to aryl allylamines 1, the steric hindrance of substituent affects the yields of products obviously, for example, the ortho-methyl phenyl isocyanate 3c and ortho-chloro phenyl isocyanate 3e only gave poor yields of 4ac (30%) and 4ae (25%), respectively. The 1-naphthyl isocyanate 3h also can produce the corresponding CF₂H-containing compound 4ah in 45% yield. However, the cyclohexyl-isocyanate 3j and isopropyl-isocyanate 3k cannot get target compounds in this reaction, which indicates the alkyl isocyanates are not suitable for this transformation.

Scope of isocyanates^a,b.

^aReaction conditions: 1a (0.5 mmol, 1 equiv.), 2 (0.6 mmol, 1.2 equiv.), 3 (1.25 mmol, 2.5 equiv.), [Ru(bpy)₃]Cl₂·6H₂O (0.025 mmol, 5 mol%), DABCO (1 mmol, 2.0 equiv.), in 2.0 mL DMF for 16 h at 8–10 °C under N₂ atmosphere.

^bIsolated yields.

To confirm the reaction mechanism, a radical inhibition experiment was conducted. In the presence of the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyl-oxy (TEMPO), the transformation was absolutely inhibited, and the TEMPO-CF₂H adduct product was detected by ¹⁹F NMR spectroscopy analysis in 48% yield (Scheme 2a), which indicating a free radical pathway might be involved in this reaction. Then, condition-control experiments showed that both irradiation and photocatalyst are indispensable for this transformation (Scheme 2b). Moreover, when 1a, 2, 3a and DABCO were mixed in DMF without photocatalyst and irradiation, the urea 5 was achieved in 83% yield, and further reaction of urea 5 with 2 in the standard conditions gave 50% yield of difluoromethylated oxazolidin-2-imine 4aa (Scheme 2c). This result further confirmed that urea 5 is the key intermediate for this type of transformation. Finally, Stern–Volmer luminescence studies demonstrated that the excited state *[Ru]²⁺ was quenched by DABCO (E^p_ox = +0.69 V vs. SCE, E[Ru(ii)*/Ru(i)] = +0.77 V) instead of allylamines 1a, or 2-BTSO₂CF₂H 2, or isocyanates 3a, and the quenching effect of DABCO increased with its concentration (see the ESI for details†).

Scheme 2. The reaction mechanism study.

According to above studies, a plausible reaction mechanism is proposed in Scheme 3. The excited state *[Ru]²⁺ is formed by visible light irradiation and reduced by DABCO to get [Ru]⁺, which triggers 2-BTSO₂CF₂H to generate HCF₂ radical. Then, the addition of HCF₂ radical to A (formed by the condensation of 1 and 3in situ) produces benzylic radical B, which is further oxidized by excited Ru(ii) species to form carbocation D accompanying with concurrent regeneration of [Ru]⁺ (Path a). It is also possible that B reacts with 2-BTSO₂CF₂H through a SET process to generate carbocation D (Path b). Subsequent cyclization of D to achieve difluoromethylated product 4.

Scheme 3. A possible reaction mechanism.

During the mechanism analysis, we found that the intermediate A and HCF₂ radical may experience two cyclization pathways to achieve difluoromethylated oxazolidin-2-imine (4) or difluoromethylated imidazolinone (4′), respectively (Scheme 3). The good selectivity of this transformation prompts us to carry out quantum chemical calculations to explain the inner mechanism.¹⁶4ai, with a single crystal structure (see the ESI for details†), was employed as the model substrate and state-of-the-art computational methods SMD-B3LYP-D3(BJ)/BS1//B3LYP/BS1 was used for calculation. As it shown in Fig. 2, the transition energies of B_ai and C_ai in different molecular orbitals, HOMO, LUMO, LUMO+1 and LUMO+2 were calculated. The values of intermediate B_ai were −4.556 eV, −0.477 eV, −0.447 eV and −0.359 eV, respectively. And which for intermediate C_ai were −4.737 eV, −0.502 eV, −0.458 eV and −0.322 eV, respectively (Fig. 2).

Fig. 2. Molecular Frontier orbital energy of intermediate B_ai and C_ai.

In photocatalytic process, it is well known that the lower energy level gap (HOMOs–LUMOs), the easier molecular will be excited.¹⁷ Therein, the energy level gaps between LOMO+2/LOMO+1/LOMO and HOMO of intermediate B_ai was 4.197 eV, 4.109 eV, 4.079 eV, respectively, which were lower than that of intermediate C_ai (4.415 eV, 4.279 eV, 4.235 eV, respectively). In addition, this can also be explained by a reaction between the hardest oxygen nucleophilic center with the hard carbocationic center.¹⁸ These results indicating that Path I is more favorable than Path II.

Conclusions

Overall, the one-pot synthesis of difluoromethylated oxazolidin-2-imine has been achieved by visible-light promoted three-component tandem reaction using aryl allylamines, 2-BTSO₂CF₂H, and isocyanates. With regard to the widely available materials, mild conditions, good tolerance of substituents on allylamines and isocyanates, this new method demonstrated potential application in medicinal chemistry, agricultural chemistry and other related fields. The quantum chemical calculations also explained the inner mechanism of this transformation.

Conflicts of interest

There are no conflicts to declare.