ACCEPTED MANUSCRIPT
based on
literature
this work
12.6
with recycle
11.8
total organic solvent
aqueous workup included
40
40
E Factors
54.8
11.8
3. Conclusion
A simple and highly efficient method was developed for the copper-catalyzed coupling reactions of 2-halobenzoic acids
derivatives with amidines and guanidines under green conditions. The reactions generated the corresponding quinazolinone
derivatives in good to excellent yields. The aqueous micellar media can be recycled six times, and the associated E factors imply
that this methodology increased overall level of greenness and provided an opportunity for the construction of diverse and useful
molecules in environment-friendly conditions.
4. Experimental section
4.1. General
All reactions were carried out under a nitrogen atmosphere. All commercially available reagents were used without further
purification unless otherwise stated. The aqueous solution of TPGS-750-M (2 wt %) is commercially available from Sigma-Aldrich.
Analytical thin layer chromatography (TLC) was performed using Silica Gel GF254 plates (Rushan Taiyang Desiccant co, .ltd, 0.2
mm thick). Compounds were purified using smart flash AI-580S (YAMAZEN co, .ltd). 1H and 13C spectra were recorded on Varian
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400 MHz and Bruker 600 MHz, respectively. Chemical shifts in H NMR spectra are reported in parts per million (ppm) on the δ
scale from an internal standard of DMSO-D6 (2.50 ppm). Data are reported as follows: chemical shift (δ ppm), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet, br = Broad), coupling constant in hertz (Hz), and integration. Chemical shifts of 13C
NMR spectra are reported in ppm from the central peak of DMSO-D6 (40.0 ppm) on the δ scale. MS data was recorded on Agilent
Technologies 6120 quadrupole mass spectrometer.
4.2. Surfactant screening
A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. 2-Bromobenzoic
acid (1a, 0.5 mmol, 101 mg) and acetamidine hydrochloride (2a, 0.75 mmol, 71 mg) in 2 wt % surfactant (3 mL) were added under
nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the flask. 15 min later, CuI (0.1 mmol, 19
mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the room temperature for 12 h. After
completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (1:1) as eluent to provide 3a.
4.3. Reaction conditions optimization
A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen (except for entry 10
in Table 2). 2-Bromobenzoic acid (1a, 0.5 mmol, 101 mg) and acetamidine hydrochloride (2a, 0.75 mmol, 71 mg) in 2 wt %
TPGS-750-M (3 mL) were added under nitrogen atmosphere. After a 10-min stirring, base (1 mmol) was added to the flask
(0.5mmol in entry 5 and 2.5mmol in entry 6, respectively). 15-min later, catalyst (0.1 mmol) was added to the flask (except for entry
7 in Table 2). The mixture was allowed to stir under nitrogen atmosphere at the room temperature for 12 h. After completion of the
reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel using petroleum ether/ethyl acetate (1:1) as eluent to provide 3a.
4.4. Representative procedure
A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. Substituted
2-halobenzoic acid (1, 0.5 mmol) and amidine hydrochloride (2, 0.75 mmol) or bis(guanidine) sulphate (2, 0.38 mmol) in 2 wt %
TPGS-750-M (3 mL) were added under nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the
flask. 15 min later, CuI (0.1 mmol, 19 mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the
shown temperature for 12 h. After completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated
under reduced pressure. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate (3:1
to 1:1) as eluent to provide the desired product.
4.5. Recycling study
A two-neck round bottom flask was charged with a magnetic stirrer, evacuated and backfilled with nitrogen. 2-Iodobenzoic acid
(1i, 0.5 mmol, 124 mg) and acetamidine hydrochloride (2a, 0.75 mmol, 71 mg) in 2 wt % TPGS-750-M (3 mL) were added under
nitrogen atmosphere. After a 10-min stirring, Cs2CO3 (1 mmol, 326 mg) was added to the flask. 15 min later, CuI (0.1 mmol, 19
mg) was added to the flask. The mixture was allowed to stir under nitrogen atmosphere at the room temperature for 12 h. After
completion of the reaction, the mixture was extracted with EtOAc (1 mL), and concentrated under reduced pressure. The residue
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