Supplementary material
Effects of tertiary amine catalysis on the regioselectivity of anisole chlorination with trichloroisocyanuric acid Nenad Maraš,a,b Marijan Kočevara Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia. E-mail:
[email protected] a
Current address: Lek Pharmaceuticals d.d., Sandoz Development Center Slovenia, API Development, Kolodvorska 27, SI-1234, Mengeš, Slovenia.E-mail:
[email protected] b
SUPPLEMENTARY MATERIAL
Experimental General NMR spectra were recorded at 29 °C on a Bruker Avance DPX 300-MHz spectrometer using tetramethylsilane (TMS) as the internal standard. Melting points are uncorrected and were determined on a Kofler micro hot stage. Mass spectra were recorded with a VG-Analytical AutoSpec Q instrument. All the reagents used were commercially available, except for the three ammonium salts, and 19, for which the synthesis is provided. The ammonium salts DABCO∙2CF3COOH, Et3N∙CF3COOH and Et3N∙HCl were prepared by adding a solution of the corresponding acid in diethyl ether to a cooled solution of the corresponding amine in diethyl ether. All the ammonium salts except one (Et3N∙CF3COOH) were obtained as crystalline solids. They were separated and dried under reduced pressure.
Study of the solvent and additive effects on the chlorination of anisole (1) with TCCA. To the solvent with the additive system described in Table 1 (6 mL) anisole (1; 1.10 mL, 10 mmol) was added and the mixture was stirred on an ice bath, after which TCCA (860 mg, 3.5 mmol) was added. The ice bath was removed after 30 min and the mixture was left stirring at about 25 °C for 24 h. The reaction was quenched with 1% aqueous Na2SO3 (25 mL), after which it was extracted with diethyl ether (20 mL), and the extract was washed with 5% NaOH(aq) (20 mL) and water (2 × 20 mL). In the reactions where a basic solvent or additive was used (pyridine, triethylamine and DABCO), the extract was additionally washed with 5% HCl(aq) immediately after the basic wash. After drying over anhydrous Na2SO4, the extract was evaporated at 75 mbar and 40 °C. The crude product was analyzed by 1H NMR spectroscopy to determine the ratio of chlorinated products (Figure 1). The conversion of anisole to chlorinated products was calculated on the basis of the crude product mass, composition, and the molar mass of the constituents.
1
Supplementary material Table 1 (extended): Influence of solvents and additives on the anisole chlorination selectivity using TCCA. Ratio of methoxy group singlets by 1H NMR* Solvent system / additive
Anisole conversion
4-chloroanisole (2)
2-chloroanisole (3)
2,4-dichloroanisole (4)
water
81%
81.3
17.1
1.6
water / acetic acid (1 : 1)
95%
69.4
24.3
6.3
acetic acid
96%
74.1
22.2
3.7
tert-butyl alcohol
94%
80.0
18.4
1.6
methanol
96%
78.1
20.3
1.6
acetone
95%
84.0
15.1
0.9
N,N-dimethylformamide (DMF)
94%
78.1
12.5
9.4
N,N,N',N'-tetramethylurea (TMU)
93%
92.6
6.5
0.9
acetonitrile
92%
62.5
30
7.5
CH2Cl2 / acetonitrile (6 : 1)
93%
84.1
15.0
0.9
CH2Cl2
89%
85.5
13.7
0.9
CHCl3
90%
84.0
15.1
0.8
water / acetic acid (1 : 1) / 24 mol% HCl
80%
55.9
18.4
25.7
CH2Cl2 / 11 mol% CF3SO3H
99%
62.1
29.8
8.1
pyridine
83%
92.6
6.5
0.9
CH2Cl2 / 125 mol% pyridine
88%
91.7
7.3
0.9
DMF / 125 mol% pyridine
98%
88.5
9.7
1.8
CH2Cl2 / 10 mol% pyridine
96%
83.3
12.5
4.2
CH2Cl2 / 10 mol% Et3N
61%
93.5
4.7
1.9
CH2Cl2 / 6 mol% Et3N∙HCl
72%
94.2
4.6
1.2
CH2Cl2 / 3 mol% Et3N∙CF3COOH
84%
89.9
8.3
1.8
CH2Cl2 / 3 mol% DABCO∙2CF3COOH
94%
88.1
9.6
2.3
methanol / 6 mol% Me3N∙HCl
96%
7.9
19.4
6.7
acetone / 6 mol% Me3N∙HCl
81%
93.7
5.4
