Difluorocarbene as a C–F source for the construction of fluorinated benzothiazoles

Abstract

Difluorocarbene has served as a versatile intermediate for the incorporation of fluorinated groups into organic molecules. Extensive studies have shown that difluorocarbene can act as a CF₂ source and a nonfluorinated C₁ source. However, the use of difluorocarbene as a C–F source remains a challenging task. Herein we disclose that difluorocarbene can function as a C–F source for the cyclization of 2-aminobenzenethiols, allowing for the construction of fluorinated benzothiazoles, which may provide new possibilities for drug developments due to the magic effects of the fluorine element and the pharmacological properties of benzothiazoles.

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Introduction

Owing to the unique properties of fluorine, including its strong electronegativity and a small atomic radius, the incorporation of a fluorinated group into organic molecules may lead to changes in their physicochemical properties, such as increasing the lipophilicity and membrane permeability of biologically active molecules.¹ The high demand for the presence of fluorinated groups in organic molecules has stimulated significant efforts for the development of efficient methods for fluorine incorporation.²

Difluorocarbene, a singlet carbene which is destabilized by the fluorine inductive effect and stabilized by the back-donating effect of fluorine lone pairs, has served as a versatile intermediate for the incorporation of various fluorine-containing groups, especially a –CF₂– unit.³ Typical transformations of difluorocarbene include [2 + 1] cycloaddition with alkenes or alkynes,⁴ X–H difluoromethylation (X = N, O, S, etc.),⁵ and coupling with other carbenes to give gem-difluoroalkenes⁶ (Scheme 1a, right side). In these typical transformations, difluorocarbene usually acts as an electrophilic species. Its electrophilicity also allows it to be a bipolar CF₂ source, i.e., difluorocarbene can be first attached to a nucleophile to generate a NuCF₂⁻ species, which would then readily attack an electrophile to form NuCF₂E (Scheme 1a, right side).^3b,7 The coordination of difluorocarbene to transition metals may lead to a reversal of the reactivity of the difluorocarbene carbon from electrophilicity to nucleophilicity.^3e,8 The coordination model offers new opportunities for difluorocarbene chemistry,⁹ and has found applications in the synthesis of unique R-CF₂-R′ molecules (Scheme 1a, left side).^8b,10 In all of the above reactions, difluorocarbene functions as a CF₂ source without the loss of any fluorine atom. Recent studies have shown that difluorocarbene can also act as a nonfluorinated C₁ precursor of various functional groups, such as carbonyl,^8b,11 cyanide¹² and isocyanide¹³ groups (Scheme 1b). The complete loss of the two fluorine atoms is mainly ascribed to the participation of neighboring groups. The outstanding accomplishments in difluorocarbene chemistry have revealed that difluorocarbene can act as both a CF₂ source and a nonfluorinated C₁ source. However, the use of difluorocarbene as a C–F source remains a challenging task, which was described only by very few reports (Scheme 1c, the first equation).¹⁴

Scheme 1 Transformations of difluorocarbene.

We recently developed an efficient difluorocarbene reagent, Ph₃P⁺CF₂CO₂⁻ (PDFA),¹⁵ the use of which led us to make new exciting discoveries in difluorocarbene chemistry^3d,12b,16 and which has been widely used by other research groups.^7d,17 We found that difluorocarbene can be captured by a suitable oxygen source, a sulfur source and a nitrogen source to in situ generate carbonyl fluoride (CF₂=O),^16d thiocarbonyl fluoride (CF₂=S),^16a–c and the cyanide anion (CN⁻),¹² respectively (Scheme 1a, left side). These transformations have been developed as synthetic tools for ¹⁸O-trifluoromethoxylation, ¹⁸F-trifluoromethylthiolation and cyanodifluoromethylation reactions. In these reactions, difluorocarbene acts as a CF₂ source (CF₂=O or CF₂=S) or a nonfluorinated C1 source (CN⁻). These interesting findings prompted us to further investigate new synthetic utilities of difluorocarbene, and allowed us to discover the use of difluorocarbene as a C–F source for cyclization of 2-aminobenzenethiols, allowing for the construction of a thiazole unit and the access to fluorinated benzothiazoles (Scheme 1c, the second equation).

Results and discussion

We have previously found that difluorocarbene generated from Ph₃P⁺CF₂CO₂⁻ can react with elemental sulfur (S₈) to produce thiocarbonyl fluoride (CF₂=S), an active intermediate which would readily be captured by 2-aminobenzenethiol (1a) to afford a HCF₂S-substituted benzothiazole via sequential transformations.^16b However, only a very low yield was obtained (31%). In order to find out the reason for the low yield, we decided to determine what the major byproduct was. To our surprise, a fluorinated benzothiazole (3a) was observed (Table 1, entry 1). Apparently, elemental sulfur did not convert difluorocarbene into CF₂=S in this process. Instead, elemental sulfur may only act as an oxidant. This rationale encouraged us to examine other reaction solvents (entries 2–4) and other oxidants (entries 5–9). NMP (1-methylpyrrolidin-2-one) was found to be a suitable reaction solvent (entry 4), and besides elemental sulfur (entry 4), both NFSI (N-fluorobenzenesulfonimide) (entry 6) and SeO₂ (entry 7) also seemed to be good oxidants. Elemental sulfur was not used for further screening because we were afraid that its side reaction with difluorocarbene to form CF₂=S may suppress the desired process. The conversion was not quite sensitive towards the reaction temperature (entries 10–12), and a reaction temperature of 90 °C gave the desired product in 40% yield (entry 11). Increasing the loading of the NFSI oxidant increased the yield significantly (entries 13 and 14). The conversion of 1a into 3a involves deprotonation, and thus various bases were screened (entries 15–18). The use of NaH as a base increased the yield slightly from 52% (entry 13) to 56% (entry 18). The yield was increased further by increasing the loading of NaH (entries 19 and 20). The loading of Ph₃P⁺CF₂CO₂⁻ was also examined (entries 21 and 22), and a good yield was obtained by using 2.5 equiv. of Ph₃P⁺CF₂CO₂⁻ (entry 22). Although BrCF₂CO₂K can easily generate difluorocarbene, the use of BrCF₂CO₂K instead of Ph₃P⁺CF₂CO₂⁻ cannot give a good yield (entry 23) (please see the ESI† for the optimization of reaction conditions). The good yield obtained with the use of Ph₃P⁺CF₂CO₂⁻ as a difluorocarbene reagent is partially because the equilibrium between difluorocarbene and the phosphonium ylide (:CF₂ + Ph₃P ↔ Ph₃P⁺-CF₂⁻)^3d may stabilize difluorocarbene.

Table 1 Optimization of reaction conditions

Entry	1a : 2 : [O] : base^a	[O]	Base	Temp. (°C)	Yield^b (%)
Reaction conditions: substrate 1a (0.2 mmol), Ph3P^+CF2CO2^− (2), oxidant [O], and a base in NMP (2 mL) under an N2 atmosphere at the indicated temperature for 60 min. ND = not detected.a Molar ratio of 1a : 2 : [O] : base.b The yields were determined by ^19F NMR analysis.c 1,2-Dimethoxyethane (DME) was used as the reaction solvent instead of NMP.d DMF was used as the reaction solvent instead of NMP.e THF was used as the reaction solvent instead of NMP.f BrCF2CO2K was used instead of Ph3P^+CF2CO2^−.
1^c	1 : 3 : 3 : 0	S	—	80	26
2^d	1 : 3 : 3 : 0	S	—	80	9
3^e	1 : 3 : 3 : 0	S	—	80	29
4	1 : 3 : 3 : 0	S	—	80	35
5	1 : 3 : 1 : 0	S	—	80	40
6	1 : 3 : 1 : 0	NFSI	—	80	39
7	1 : 3 : 1 : 0	SeO2	—	80	39
8	1 : 3 : 1 : 0	DDQ	—	80	12
9	1 : 3 : 1 : 0	Sb2O3	—	80	3
10	1 : 3 : 1 : 0	NFSI	—	70	39
11	1 : 3 : 1 : 0	NFSI	—	90	40
12	1 : 3 : 1 : 0	NFSI	—	100	38
13	1 : 3 : 2 : 0	NFSI	—	90	52
14	1 : 3 : 3 : 0	NFSI	—	90	52
15	1 : 3 : 2 : 1	NFSI	NaOH	90	45
16	1 : 3 : 2 : 1	NFSI	K2CO3	90	53
17	1 : 3 : 2 : 1	NFSI	DMAP	90	ND
18	1 : 3 : 2 : 1	NFSI	NaH	90	56
19	1 : 3 : 2 : 2	NFSI	NaH	90	61
20	1 : 3 : 2 : 3	NFSI	NaH	90	67
21	1 : 2 : 2 : 3	NFSI	NaH	90	58
22	1 : 2.5 : 2 : 3	NFSI	NaH	90	73
23^f	1 : 3 : 2 : 1	NFSI	NaH	110	39

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With the optimal reaction conditions in hand (Table 1, entry 22), we then investigated the substrate scope of the use of difluorocarbene as a C–F source for the cyclization of vicinal aminobenzenethiols. As shown in Scheme 2, the process could be extended to a wide range of 2-aminobenzenethiols. The substrates substituted by an electron-withdrawing group such as a halogen atom or a CF₃O unit can be converted smoothly into the desired products. However, the position of the electron-withdrawing group dramatically affects the reaction. No expected product was observed if the 4-position is substituted by a Cl or Br atom (3f and 3g), probably because the electron-withdrawing effect results in lower nucleophilicity of the ortho amino group. For the electron-donating groups, their substitution sites have no significant side effects. The structure of 3y was confirmed by X-ray analysis. The replacement of the SH group with an OH or a NH₂ group in the substrate failed to give the desired products.

Scheme 2 Substrate scope of the use of difluorocarbene as a C–F source for the cyclization of vicinal aminobenzenethiols. Isolated yields are shown. Reaction conditions: substrate 1 (0.5 mmol), Ph₃P⁺CF₂CO₂⁻ (2.5 equiv.), NFSI (2 equiv.), NaH (3 equiv.) in NMP (5 mL) under an N₂ atmosphere at 90 °C for 60 min. ND = not detected.

Benzothiazoles, occurring naturally, are an important group of heterocyclic compounds that exhibit a broad spectrum of pharmacological properties such as antitumor, antimicrobial, antidiabetic, anticonvulsant and anti-inflammatory properties.¹⁸ Considering the positive biological effects of the fluorine element, the incorporation of a fluorine atom into benzothiazoles may provide new possibilities for drug development of benzothiazoles. However, the efficient synthesis of 2-fluoro-benzothiazoles remains a significant challenge and only a handful of methods have been reported.¹⁹ Furthermore, in most reports, only one example was investigated, and the substrate scope is unknown.^19b–e Arisawa and co-workers described the use of ArSC₆F₅ as a fluorine source to allow for Rh-catalyzed transformations of benzothiazole ethers into 2-fluoro-benzothiazoles.^19a The reactions are highly efficient, but the fluorine source may be too expensive since only one fluorine atom in ArSC₆F₅ is useful. In contrast to these previous reports, our protocol is quite attractive as thiazoles can be easily constructed with the simultaneous incorporation of a fluorine atom.

Since NFSI can act as both an oxidant and an electrophilic fluorination reagent, it is necessary to figure out what role NFSI plays in this reaction and whether the fluorine atom in the product comes from NFSI. As mentioned above, NFSI should be just an oxidant. Indeed, the use of SeO₂ (Scheme 3, eqn (1)) or elemental sulfur (Scheme 3, eqn (2)), both of which are nonfluorinated oxidants, instead of NFSI can also give the desired product in moderate to good yields, reflecting that the fluorine atom in the product is not from NFSI. The path that benzothiazole is first formed and then undergoes fluorination with NFSI is excluded based on the evidence that no product 3a was detected for the fluorination of benzothiazole with NFSI irrespective of whether NaH is used or not (Scheme 3, eqn (3) and (4)), further suggesting that NFSI is not a fluorination reagent in this process.

Scheme 3 Exclusion of NFSI as a fluorine source and the exclusion of benzothiazole as a necessary intermediate. All yields are ¹⁹F NMR yields.

On the basis of the above results, we propose the reaction mechanism as shown in Scheme 4. Deprotonation of the thiol group (pK_a of the PhS-H group is 7.2)²⁰ produces the ArS⁻ anion, which attacks difluorocarbene generated from Ph₃P⁺CF₂CO₂⁻ to give SCF₂⁻ intermediate A (path I). SCF₂⁻ is an alkyl anion and thus may act as a strong base to deprotonate the neighboring NH₂ group to provide intermediate B.^5d,21 In this intermediate, the NH⁻ moiety is a strong electron-donating group and may favor the donation of the sulfur lone pair to the antibonding orbital of the C–F bond to deliver intermediate C. The subsequent attack of the nitrogen on the C=S unit furnishes intermediate D, which is oxidized to afford the final product. On the other hand, the amino group in the substrate may also attack difluorocarbene to generate intermediate E (path II). The donation of the nitrogen lone pair results in the formation of intermediate F,^3f and the following intramolecular nucleophilic attack also provides intermediate D.

Scheme 4 Plausible reaction mechanism.

More evidence was collected to support that D is a key intermediate. It is reasonable to speculate that D may be accumulated without the presence of any oxidant. However, this intermediate may be quite unstable since the donation of the N/S lone pair may easily lead to the elimination of a fluoride ion to produce benzothiazole (5a). Indeed, we couldn't isolate this intermediate at all, and benzothiazole (5a) was observed (Scheme 5, eqn (1)). Under these conditions, product 3a was not produced, further supporting the proposed mechanism. Besides, the S–H difluoromethylation product (4a) was also generated, supporting path I shown in Scheme 4. By the way, no N-CF₂H product was isolated. However, path II shown in Scheme 4 is still plausible. The unsuccessful isolation should be because the N-CF₂H group is highly unstable. Since it is hard to isolate intermediate D, we then performed a reaction under optimal conditions except that 20 min of reaction time instead of 60 min was used (Scheme 5, eqn (2)). Fortunately, intermediate D was detected by HRMS (EI).

Scheme 5 Evidence to support intermediate D. NMR yields are shown.

Conclusions

In summary, we have described the use of difluorocarbene as a C–F source for the cyclization of vicinal aminobenzenethiols to deliver fluorinated 2-fluoro-benzothiazoles. This work represents an exciting discovery of difluorocarbene chemistry. The protocol allows for the easy construction of a thiazole unit and the simultaneous incorporation of a fluorine atom. The facile access to 2-fluoro-benzothiazoles may provide more opportunities for drug development of benzothiazole derivatives.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors thank the National Key Research and Development Program of China (2021YFF0701700), the National Natural Science Foundation of China (21971252, 21991122, 22271181), and the Science and Technology Commission of Shanghai Municipality (22ZR1423600) for financial support.

References

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Footnote

† Electronic supplementary information (ESI) available: Materials and methods, experimental procedures, and ¹H NMR, ¹⁹F NMR, ¹³C NMR, IR, and MS data, and NMR spectra (PDF). CCDC 2283499 (compound 3y). For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3qo01422c

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