Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous benzaldehyde-based Biginelli reaction and post-condensation modifications

Article abstract of DOI:10.3762/bjoc.7.150

Dihydropyrimidinones and dihydropyrimidinethiones generated from the Biginelli reactions of perfluorooctanesulfonyl-attached benzaldehydes are used as common intermediates for post-condensation modifications such as cycloaddition, Liebeskind-Srogl reactio

Full text of DOI:10.3762/bjoc.7.150

Supporting Information
for
Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous
benzaldehyde-based Biginelli reaction and post-condensation
modifications
Bruno Piqani and Wei Zhang*
Address: Department of Chemistry, University of Massachusetts Boston, 100 Morrissey
Boulevard, Boston, MA 02125, USA
Email: Bruno Piqani - piqani@gmail.com; Wei Zhang* - wei2.zhang@umb.edu
*Corresponding author
LC–MS, 1H NMR and 13C NMR data and spectra for compounds
4c, 5a, 6b, 7b, 8b, 9
General methods:
The 1H NMR and 13C NMR spectra were recorded on a 300 MHz Varian NMR spectrometer, in
CDCl3 solvent with tetramethylsilane as the internal standard. The temperature was 25 °C
(accuracy ±1 °C). Splitting patterns of 1H NMR spectra are designated as s, singlet; d, doublet; t,
triplet; q, quartet; and m, multiplet. LC–MS spectra were recorded on an Agilent 2100 system. A
C18 column (5.0 μm, 6.0 × 50 mm) was used for the separation. The mobile phases were
methanol and water, both containing 0.05% formic acid. A linear gradient was used to increase
the ratio from 25:75 v/v methanol/water to 100% methanol over 5.0 min at a flow rate of 0.7
mL/min. The UV measurements were made at 210 nm and 254.4 nm. Mass spectra were
recorded by atmospheric-pressure chemical ionization. All reactions were carried out in a self-
tuning single mode Biotage Initiator Microwave Synthesizer. Purification of intermediates took
place in a Thermo Scientific 16 SPE Vacuum Manifold.
S1

General
procedure
for
the
preparation
of
dihydropyrimidinones
and
dihydropyrimidinethiones derivatives and spectral data for selected compounds.
A general procedure for the synthesis of dihydropyrimidinone compound 4c. A solution of
p-perfluorooctanesulfonyl benzaldehyde 1 (1.2 g, 2.0 mmol), methylurea 2 (0.18 g, 2.4 mmol),
methyl acetoacetate 3 (0.35 g, 3.0 mmol) and Yb(OTf)3 (124 mg, 0.2 mmol) in acetonitrile (2
mL) in a microwave reaction tube was heated in Biotage microwave reactor at 120 °C for 20
min. The resulting mixture was purified by F-SPE eluted with 40 mL of 80:20 MeOH/H2O and
then 40 mL of acetone. The acetone (fluorous) fraction was concentrated to give 4c (1.3 g, 90%
yield).
5-Acetyl-4-(4-(perfluorooctylsulfonyloxy)phenyl)-1,6-dimethyl-3,4-dihydropyrimidin-
2(1H)-one (4c):
LC–MS (APCI+) m/z 743 [M + 1]+; 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J = 8.1 Hz, 2H), 7.23
(d, J = 7.7 Hz, 2H), 6.27 (d, J = 3.0 Hz, 1H), 5.45 (d, J = 3.0 Hz, 1H), 3.23 (s, 3H), 2.47 (s, 3H),
2.24 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 195.8, 153.8, 149.3, 148.8, 142.8, 133.6 128.2,
121.9, 121.0 120.3, 119.9, 118.6, 117.4 116.6, 114.8, 113.5, 53.2, 30.6, 29.7, 17.2; HRMS (ES+):
m/z [M + H]+ calcd for C22H15F17N2O5S: 743.0508; found: 743.0514.
A general procedure for Suzuki reactions. Synthesis of compounds 5a. A solution of 4a (75
mg, 0.1 mmol), 4-methoxyphenylboronic acid 10 (23 mg, 0.15 mmol), Cs2CO3 (81 mg, 0.25
mmol) and Pd(dppf)Cl2 (16 mg, 0.02 mmol) in 4:1:4 acetone:H2O:toluene (3 mL) was heated
under microwave irradiation at 140 °C for 30 min. The resulting mixture was purified by flash
chromatography with 0–50% gradient of EtOAc/hexanes to give 5a (24 mg, 67% yield).
S2

Methyl 4-(4'-methoxy-[1,1'-biphenyl]-3-yl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (5a)
1
LC–MS (APCI+) m/z 367 [M + 1]+; H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 11.7 Hz, 1H),
7.49–7.42 (m, 3H), 7.34 (t, J = 15.3 Hz, 1H), 7.19–6.95 (m, 2H), 6.76 (s, 1H), 6.03 (d, J = 3.0
Hz, 1H), 5.45 (d, J = 3.0 Hz, 1H), 3.85 (s, 3H), 3.67 (s, 3H), 3.24 (s, 3H), 2.53 (s, 3H); 13C NMR
(75.5 MHz, CDCl3) δ 166.5, 154.2, 149.7, 142.1, 140.6, 140.5 128.8, 128.7, 127.4, 127.3, 126.9,
126.5, 103.9, 54.9, 54.3, 53.2, 30.4, 16.6; HRMS (ES+): m/z [M + H]+ calcd for C21H22N2O4:
367.1658; found: 367.1659.
A general procedure for the synthesis of compounds 8b. A solution of 3,4-dihydropyrimidine-
thione 4f (0.76 g, 1 mmol), chloroacetone (185 mg, 1.5 mmol) in water (2 mL) was heated under
microwave at 120 °C for 30 min. The resulting mixture was purified by F-SPE eluted with 30
mL of 80:20 MeOH/H2O and then 30 mL of acetone. The Acetone (fluorous) fraction was
concentrated to give 8b (0.67 g, 85% yield).
Methyl 3,7-dimethyl-5-(3-(perfluorooctylsulfonyloxy)phenyl)-5H-thiazolo[3,2-
a]pyrimidine-6-carboxylate (8b)
LC–MS (APCI+) m/z 799 [M + 1]+; 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J = 7.5Hz, 2H) 7.74
(d, J = 2.7 Hz, 2H), 7.43–7.32 (m, 3H), 7.27–7.18 (m, 2H), 6.22 (s, 1H), 6.06 (s, 1H), 3.85 (s,
3H), 2.40 (s, 3H), 2.07(s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 169.7, 165.5, 153.8, 152.7, 149.6,
143.2 135.0, 131.2, 128.5, 126.3, 121.6, 120.5, 119.5, 118.9, 118.3, 117.7, 117.0 116.2, 114.4,
113.7, 57.2, 51.1, 23.1, 13.8.
S3

Methyl-5-(4'-methoxy-[1,1'-biphenyl]-3-yl)-3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidine-6-
carboxylate (6b).
LC–MS (APCI+) m/z 407 [M + 1]+; 1H NMR (300 MHz, CDCl3) δ 7.49–7.41 (m, 3H), 7.32–6.09
(m, 3H), 6.96 (d, J = 10.0 Hz, 2H), 6.68 (s, 1H), 6.16 (s, 1H), 3.84 (s, 3H), 2.40 (s, 6H), 2.12 (s,
13
3H); C NMR (75.474 MHz, CDCl3) δ 169.8, 166.5, 153.8, 152.7, 147.8, 141.1 136.4, 132.9,
129.2, 128.1, 126.4 124.6, 114.2, 57.2, 55.3, 51.3, 24.5, 13.9; HRMS (ES+): m/z [M + H]+ calcd
for C23H22N2O3S: 407.1426; found: 407.1429.
A general procedure for the synthesis of compound 9. A solution of 3,4-dihydropyrimidine-
thione 4f (152 mg, 0.20 mmol), phenylboronic acid 10 (82 mg, 0.3 mmol), CuTC (95 mg, 0.6
mmol), and Pd(PPh3)4 (3mol %) in THF (2 mL) was heated under microwave at 100 °C for 25
min. The mixture was purified by F-SPE eluted with 30 mL of 80:20 MeOH/H2O and then 30
mL of acetone. The acetone (fluorous) fraction was concentrated to give 9 (0.85 g, 76 % yield).
S4

Methyl 4-methyl-6-(3-(perfluorooctylsulfonyloxy)phenyl)-2-phenyl-1,6-dihydropyrimidine-
5-carboxylate (9).
LC–MS (APCI+) m/z 805 [M + 1]+; 1H NMR (300 MHz, CDCl3) δ 7.73–7.23 (m, 3H), 7.19–7.04
13
(m, 2H), 5.62 (s, 1H), 3.58 (s, 3H), 3.72 (s, 3H), 2.41 (s, 3H); C NMR (75.5 MHz, CDCl3) δ
170.1, 166.9, 160.2, 153.0, 149.9 146.0, 133.6, 132.3, 130.4, 128.9, 127.8, 127.3, 127.0, 120.5,
120.2, 119.7, 118.6, 117.6, 116.4, 114.9, 55.9, 51.4, 29.7, 23.8; HRMS (ES+): m/z [M + H]+
calcd for C27H17F17N2O5S: 805.0665; found: 805.0670.
Methyl-6-(4'-methoxy-[1,1'-biphenyl]-3-yl)-2-phenyl-1,6-dihydropyrimidine-5-carboxylate
(7b).
LC–MS (APCI+) m/z 413 [M + 1]+; 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 8.1 Hz, 2H), 7.68
(s, 1H), 7.56–7.48 (m, 3H), 7.40–7.26 (m, 3H), 6.74 (d, J = 8.1 Hz, 2H), 5.79 (s, 1H), 3.64 (s,
6H), 2.65 (s, 3H); 13C NMR (75.5 MHz, CDCl3) δ 170.2, 166.7, 153.8, 152.7, 149.6, 141.1
136.4, 133.0 132.3, 130.2, 129.4, 129.2, 128.4, 126.7, 124.6, 114.2, 57.2, 55.9, 51.7, 23.5;
HRMS (ES+): m/z [M + H]+ calcd for C21H24N4O5: 413.1865; found: 413.1864.
S5

4c
S6

S7

S8

S9

S10

S11

S12

S13

S14

6b
S15

S16

S17

S18

S19

S20

S21

S22

S23