Fluorous 2,4-Dichloro-1,3,5-triazines (F-DCTs) as Nucleophile Scavengers

Short Communication

1H,1H,2H,2H,3H,3H-perfluoroundecanol- and 1H,1H,2H,2H-perfluorodecanethiol-displaced 2,4-dichloro-1,3,5-triazines 1 and 2 are synthesized and used as nucleophile scavengers to remove thiols and amines from solution-phase reactions. Two active sites on the triazine ring are able to remove two equivalents of nucleophiles. The purification of reaction mixtures is accomplished by plate-to-plate fluorous solid-phase extraction or automated solid-phase extraction on the RapidTrace system.

Introduction

2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride) and its derivatives have been widely used as chlorination and condensation agents in organic synthesis, as complexation agents in analytical chemistry, as multi-step redox agents in electrochemistry, as pesticides and herbicides in agricultural chemistry, as templates in crystal engineering, as scaffolds in combinatorial chemistry, and as building blocks for peptidomimetics [1]. 2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) is a well-known amide coupling agent [2]. The polymer-supported [3] and the fluorous [4,5] version of CDMTs have been developed for parallel and combinatorial syntheses. 2,4-Dichloro-6-methoxy-1,3,5-triazines (DCT) [6] and its solid-supported analogs [7] have also been employed as amide coupling agents as well as nucleophile scavengers. We recently synthesized fluorous alkoxy- and alkylthio-attached DCT compounds 1 and 2, and explored their utility in fluorous amide coupling reactions [8]. We report here the use of F-DCTs as nucleophile scavengers for fluorous solution-phase synthesis [9,10]. Since F-DCTs have two active electrophiles, we expected they can be used to remove two equivalents of nucleophiles from the reaction mixtures.

Results

The preparation of 1 was accomplished by reaction of 1.0 equiv of 1H,1H,2H,2H,3H,3H-perfluoroundecanol with 1.05 equiv of cyanuric chloride and 1.5 equiv of 2,4,6-collidine in benzotrifluoride (BTF) at room temperature for 10 h (Scheme 1, A). After removal of collidine salt by filtration, the concentrated crude product was passed through a plug of silica gel and eluted with 10% EtOAc-hexane. The crude product was further purified by recrystalization in hexane or by normal silica gel chromatography. F-DCT 2 was synthesized by reaction of cyanuric chloride with 1H,1H,2H,2H-perfluorodecanethiol. The reaction was performed using 1.5 equiv of cyanuric chloride at −30 °C to minimize the formation of dithiolation byproduct (Scheme 1, B). Both F-DCTs 1 and 2 are white solids, while compound 2 was found more stable for room temperature storage.

Scheme 1.

Synthesis of F-DCTs 1 and 2

With F-DCTs 1 and 2 in hand, we first studied their reactions with thiols (Scheme 2, A). A THF solution containing 0.2 mmol of DIPEA, 0.075 mmol of F-DCT 1 was reacted with 0.1 mmol of 4-methoxybenzyl thiol. After 1 h at room temperature, LCMS analysis with mass ion extraction and UV detection showed no thiol but monothio- and dithio-substituted triazines 3 and 4 in the reaction mixture. Similarly, monoamino- and diamino-substituted triazines 5 and 6 were detected from the reaction of 0.075 mmol of 1 with 0.1 mmol of tetrahydroisoquinoline (Scheme 2, B). The results suggest that both chlorines of the F-DCTs are reactive enough for thiol and amine scavenging reactions. The reactions of F-DCT 2 with 4-methoxybenzyl thiol or tetrahydroisoquinoline gave similar results; no noticeable differences were observed between F-DCTs 1 and 2.

Scheme 2.

Reactions of F-DCT 1 with thiol and amine

Encouraged by the initial results, we then used F-DCT 2 as a scavenger in an S-alkylation reaction to remove excess thiols (Scheme 3). Thus, a mixture of 0.1 mmol of a bromide, 0.15 mmol of 4-methoxybenzyl thiol, and 0.3 mmol DIPEA in 0.5 mL of CH₂Cl₂ was shaken at room temperature for 1 h before 0.05 mmol of F-DCT 2 in CH₂Cl₂ was added. The reaction mixture was shaken for another 1 h and then 0.6 mmol equiv of MP-CO₃ [11] was added to free the DIPEA salt. After filtration, the concentrated reaction mixture was dissolved in 0.6 mL of DMF and then loaded onto a 2 g FluoroFlash cartridge for fluorous solid-phase extraction (F-SPE) [12]. The cartridge was eluted with 6 mL of 8:2 MeOH/H₂O to elute the S-alkylation product, while the fluorous components remained on the cartridge. TheMeOH/H₂O fraction was concentrated to afford product 7 in 65% yield and 91% purity by LCMS analysis with UV254. From a control experiment without using F-DCT 2 as scavenger, a significant amount of 4-methoxybenzyl thiol was detected from the S-alkylation product. This result indicates that the thiol is not acidic enough to be trapped by MP-CO₃ and separated from the alkylated product.

Scheme 3.

S-Alkylation reaction with F-DCT 2 as thiol scavenger

To study the reaction scope and evaluate the feasibility of solution-phase parallel synthesis, eighteen reactions were conducted using three activated halides and six thiols including a thiolphenol and two heteroaromatic thiols. The reaction mixtures were purified by the newly developed plate-to-plate F-SPE [5]. Results summarized in Table 1 indicate that the yields of S-alkylation are in the range of 63–96%, fifteen out of eighteen products have purities greater than 90%.

Table 1.

S-Alkylation using F-DCT 2 as thiol scavenger

	91%(92%)*	88%(95%)	85%(94%)	92%(94%)	80%(92%)	63%(99%)
	70%(91%)	78%(81%)	67%(87%)	86%(93%)	71%(94%)	87%(99%)
	88%(97%)	96%(91%)	83%(87%)	86%(93%)	63%(96%)	76%(95%)

^*yield% (purity%), purities were determined by LCMS with UV254 detection

We also employed F-DCT 1 as amine scavenger in the reactions of isocyanates and amines (Scheme 4). A general procedure was developed as such: a mixture of 0.1 mmol of isocyanate and 0.15 mmol of amine in 0.5 mL of THF was shaken at room temperature for 1 h before 0.05 mmol of F-DCT 1 and 0.3 mmol of DIPEA was added. The reaction mixture was shaken for 1 h and then 0.6 mmol equiv MP-CO₃ was added to free the DIPEA salt. After filtration, the concentrated reaction mixture was dissolved in 0.6 mL of DMF and then loaded onto a 2 g FluoroFlash cartridge for F-SPE. The cartridge was eluted with 6 mL of 8:2 MeOH/H₂O to elute the urea product, while the fluorous components were remained on the cartridge. The MeOH/H₂O fraction was concentrated to afford product 8 in 62% yield and 96% purity by LCMS analysis with UV254. In separate experiments, we found that F-DCT did not react with ureas generated from isocyanates and primary amines. However, it reacted with thioureas generated from thioisocyanates and amines.

Scheme 4.

Urea formation reaction with F-DCT 1 as amine scavenger

Eighteen reactions were conducted in parallel using three isocyanates and six amines followed by amine scavenging with F-DCT 1. Instead of performing plate-to-plate SPE, we conducted automated SPE on a RapidTrace SPE station [13] equipped with 1.5 g FluoroFlash cartridges. Results summarized in Table 2 show that the yields of ureas are in the range of 48–96%, thirteen out of eighteen products have purities greater than 90%.

Table 2.

Urea formation reactions using F-DCT 1 as amine scavenger

	BuNH2
	47%(93%)*	63%(94%)	64%(94%)	89%(96%)	92%(90%)	96%(80%)
	67%(96%)	58%(96%)	52%(96%)	63%(95%)	57%(94%)	48%(97%)
	57%(77%)	77%(98%)	87%(90%)	96%(86%)	93%(80%)	79%(87%)

^*yield% (purity%), purities were determined by LCMS with UV254 detection

In summary, we have synthesized two fluorous DCT compounds and demonstrated their utilities as thiol and amine scavengers. Compared to their polymer- or silica gel-supported analogs, F-DCTs have good solution-phase reaction kinetics [14]. Reactions go faster and do not require large excess amount of scavengers to complete the reactions. Two active sites of F-DCTs are capable to remove up to two equiv of nucleophiles form the reaction mixtures.