A green synthesis of chemiluminescent N-sulfopropyl acridinium esters in ionic liquids without using the carcinogen 1,3-propane sultone

Figures & data

Figure 1.  Structures of chemiluminescent acridinium dimethylphenyl ester labels containing N-sulfopropyl groups in the acridinium ring that are used in automated immunoassays in Siemens Healthcare Diagnostics' ADVIA:Centaur® systems 1–3.

Figure 2.  N-Alkylation of acridine methyl ester 2a with 1,3-propane sultone 14. The reaction proceeds via a charged transition state and is facilitated by polar solvents such as the ILs [BMIM][PF₆] and [BMIM[BF₄].

Figure 3.  Synthetic scheme for the synthesis of acridan esters and their N-alkylation reactions with sodium 3-bromopropane sulfonate in [BMIM][BF₄]. The acridan N-alkylation reaction also has a charged transition state and is facilitated in the IL [BMIM][BF₄]. Reagents: (a) Thionyl chloride, ROH; (b) p-toluenesulfonyl chloride, pyridine; (c) picoline-borane, tetrahydrofuran, 10% HCl; (d) sodium 3-bromopropane sulfonate, potassium carbonate, [BMIM][BF₄]; (e) air or oxygen; (f) 1-2 M HCl; (g) TSTU, diisopropylethylamine, DMF.

Table 1. N-Alkylation of acridan dimethylphenyl esters with sodium 3-bromopropane sulfonate in [BMIM][BF₄].

Entry	Substrate	Reaction temperature (°C), time (h)	Base, equivalents	Sodium 3-Bromopropanesulfonate (equivalents)	Product, (% conversion^a)
1	3a	160–165, 3	–	10	5a (22)
2	3a	160–165, 3	2,6-di-t-butylpyridine, 2	10	5a (52)
3	3a	160–165, 3	2,6-di-t-butylpyridine, 4	20	5a (44)
4	3a	160–165, 3	Potassium carbonate, 2	10	5a (48)
5	3a	160–165, 3	Potassium carbonate, 2	10	5a (44) (reaction under argon)
6	3a	160–165, 3	Potassium carbonate, 2	20	5a (45)
7	3a	190, 2	Potassium carbonate, 2	10	5a (48)
8	3b	160–165, 3	Potassium carbonate, 2	10	5b (51)
^aMeasured by HPLC analysis and based on ratio of product (5a and 5b) to acridine ester (2a and 2b) (oxidized starting material); [acridan] = 0.065 M; N-alkylation reactions were conducted under a nitrogen atmosphere followed by air oxidation (Figure 3, steps d and e).

Table 2. N-Alkylation of acridine ester 2a with sodium 3-bromopropane sulfonate in ionic liquids.

Ionic liquid	Reaction temperature (°C), time (h)	Base, equivalents	Sodium 3-Bromopropanesulfonate (equivalents)	% Conversion to 5a^a
[BMIM][BF4]	160–165, 3	–	10	14
[BMIM][BF4]	160–165, 3	2,6-di-t-butylpyridine, 2	10	16
[BMIM][BF4]	160–165, 3	Potassium carbonate, 2	10	13
[BMIM][BF4]	160–165, 3	Potassium carbonate, 2	20	16
[BMIM][PF6]	160–165, 3	–	10	<10
^aMeasured by HPLC analysis; [acridine ester] = 0.065 M.

Figure 4.  HPLC traces. Upper panel: analysis of the reaction mixture from N-alkylation (Figure 3, steps d and e) on a gram scale of acridan isopropyl ester 3b with sodium 3-bromopropane sulfonate in [BMIM][BF₄] followed by oxidation. Compound eluting at 6.4 minutes is product 5b and compound eluting at 10.2 minutes is acridine isopropyl ester 2b. Small peaks eluting at 4.4 minutes and 7.3 minutes are the corresponding carboxylic acids of 5b and 2b, respectively; middle panel: analysis of the product 5b following purification by column chromatography; lower panel: analysis of the N-sulfopropyl acridinium carboxylic acid 6 obtained by hydrolysis of the isopropyl ester 5b.

Natrajan A , Wen D. Facile N-Alkylation of Acridine Esters with 1,3-Propane Sultone in Ionic Liquids . Green Chem . 2011 ; 13 : 913 – 921 . doi: 10.1039/c0gc00758g

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