diversity-oriented synthesis of substituted furo[2,3-b
TRANSCRIPT
1
SUPPORTING INFORMATION
Diversity-Oriented Synthesis of Substituted Furo[2,3-b]pyrazines
Vaibhav P. Mehta,a Sachin G. Modha,
a Denis S. Ermolat’ev,
a Kristof Van Hecke,
b Luc Van
Meervelt,b and Erik V. Van der Eycken
a*
aLaboratory for Organic & Microwave-Assisted Chemistry (LOMAC); bBiomolecular
Architecture, Department of Chemistry , Katholieke Universiteit Leuven, Celestijnenlaan
200F, B-3001 Leuven, Belgium
* To whom correspondence should be addressed.
E-mail: [email protected]
Table of Contents
This page·······································································································································1 General experimental methods······································································································2 Spectroscopic and analytical data for compounds 1a-d·························································· 2-3
Acetylenes and Boronic acids used in reactions ···········································································4
Spectroscopic and analytical data for compounds 3a-k······················································· 5 – 10
Spectroscopic and analytical data for compounds 4a-e······················································10 – 12
Spectroscopic and analytical data for compounds 5a-g······················································12 – 14
Spectroscopic and analytical data for compounds 7a-j······················································ 14 – 17
Spectroscopic and analytical data for compounds 8a-d······················································17 – 20
Spectroscopic and analytical data for compounds 9a-c······················································ 21 – 23
Spectroscopic and analytical data for compounds 10a-c·····················································23 – 25
Spectroscopic and analytical data for compounds 11a-d····························································25
Spectroscopic and analytical data for compounds 12a····························································· 26
Crystallographic details for compound 8d··········································································27 - 28
Appendix·····························································································································28 - 73
2
General experimental methods.
1H NMR spectra were recorded on a Bruker Avance 300 MHz instrument using CDCl3 as
solvent unless otherwise stated. The 1H and 13C chemical shifts are reported in parts per million
relative to tetramethylsilane using the residual solvent signal as an internal reference. Mass
spectra were recorded by using a Kratos MS50TC and a Kratos Mach III system. The ion
source temperature was 150-250°C, as required. High-resolution EI-mass spectra were
performed with a resolution of 10 000. The low-resolution spectra were obtained with a
HP5989A MS instrument. For thin-layer chromatography, analytical TLC plates (Alugram SIL
G/UV254 and 70-230 mesh silica gel (E. M. Merck) were used.
Microwave Irradiation Experiments. A multimode Milestone MicroSYNTH microwave
reactor (Laboratory Microwave Systems) was used in the standard configuration as delivered,
including proprietary software. All experiments were carried out in sealed microwave process
vials (15, 50 mL). A temperature control was performed using both external infrared and
internal fiber optic sensors. After completion of the reaction, the vial was cooled to 25 °C via
air jet cooling before opening.
A typical procedure for preparation of 1-(4-methoxybenzyl)-3,5-dichloropyrazin-2(1H)-
ones 1a-d.
In a 1 L round-bottomed flask NaHSO3 (26.1 g, 0.25 mol) was dissolved in 400 mL water and
aldehyde was added dropwise under an argon atmosphere. After stirring for 45 min, a solution
of 4-methoxybenzylamine (32 mL, 0.25 mol) in methanol (100 mL) was added dropwise to the
reaction mixture and stirring was continued for 2 h at 60 °C. Then NaCN (14.7 g, 0.25 mol)
was added and the reaction mixture was left stirring overnight at 60 °C (under hood!). The
reaction mixture was cooled to the room temperature and extracted with dichloromethane
(3×300 mL). The organic phases were combined, washed with brine (1×200 mL), then dried
for 2 h over Na2SO4 and concentrated. The residue was dissolved in dry ether (500 mL) and the
resulting solution was cooled to 0 °C. Dry HCl gas was bubbled through the solution upon
vigorous stirring for 20 min and the precipitate was filtered off and dried. Then the precipitate
was suspended in 1 L flask in dry toluene (400 mL) and oxalyl chloride (86 mL, 1 mol, 4.0
3
equiv) was added dropwise under an argon atmosphere. After stirring for 45 min, triethylamine
hydrochloride (52 g, 0.38 mol, 1.5 equiv) was added by small portions, DMF (2 mL, 25 mmol,
0.1 equiv) and the reaction mixture was kept stirring for 2 days. The reaction mixture was
concentrated and the residue was purified by silica gel column chromatography (from 10% to
30% EtOAc in petroleum ether) to afford 3,5-dichloropyrazin-2(1H)-one 1 as a white solid.
3,5-Dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (1a): 53% yield. 1H NMR (300 MHz,
CDCl3): δ 7.29 (d, J = 7.2 Hz, 2H), 7.18 (s, 1H), 6.91 (d, J = 7.2 Hz, 2H), 5.04 (s, 2H), 3.81 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 160. 4, 152.0, 147.4, 130.6, 126.1, 125.5, 124.2, 114.9,
55.5, 53.4. HR-MS (EI): C12H10Cl2N2O2 calcd. 285.0119, found 285.0119.
3,5-Dichloro-1-(4-methoxybenzyl)-6-methyl-pyrazin-2(1H)-one (1b): 51% yield. 1H NMR
(400 MHz, CDCl3): δ 7.16 (d, J = 7.1 Hz, 2H), 6.86 (d, J = 7.3Hz, 2H), 5.29 (s, 2H), 3.79 (s,
3H), 2.44 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.6, 153.2, 143.7, 136.2, 128.7, 125.9,
123.9, 114.5, 55.4, 49.6, 16.8. DEPT (100 MHz, CDCl3): δ 128.6, 114.5, 113.8, 55.3, - 49.8,
16.9. HR-MS (EI): C13H12Cl2N2O2 calcd. 298.0276, found 298.0279.
6-Benzyl-3,5-Dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-one (1c): 32% yield. 1HNMR
(300 MHz, CDCl3): δ 7.40 - 7.32 (m, 3H), 7.12 - 7.07 (m, 4H), 6.88 (d, J = 9.6 Hz, 2H), 5.10
(s, 2H), 4.15 (s, 2H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 159.7, 153.4, 145.3, 137.4,
133.9, 129.6, 128.2, 127.9, 127.5, 126.3, 125.4, 114.7, 55.5, 49.3, 32.3. DEPT (75 MHz,
CDCl3): δ 129.9, 128.5, 128.2, 127.8, 115.0, 55.7, - 49.6, - 35.6. HR-MS (EI): C13H15ClN2O
calcd. 250.0873, found 250.0879.HR-MS (EI): C19H16Cl2N2O2 calcd. 374.0589, found
374.0596.
3,5-Dichloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)pyrazin-2(1H)-one (1d): 76%
yield. 1H NMR (400 MHz, CDCl3): δ 7.04 (d, J = 7.2Hz, 2H), 6.97 (d, J = 7.3 Hz, 2H), 6.81 (d,
J = 7.2 Hz, 2H), 6.72 (d, J = 7.1Hz, 2H), 5.05 (s, 2H), 3.88 (s, 3H), 3.76 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 161.1, 159.5, 152.9, 145.8 138.6, 130.9, 129.4, 126.9, 124.7, 122.3,
114.5, 113.9, 55.5, 55.3, 50.8. DEPT (100 MHz, CDCl3): δ 130.9, 129.4, 114.4, 113.8, 55.4,
55.3, - 50.7. HR-MS (EI): C19H16Cl2N2O3 calcd. 390.0538, found 390.0549.
4
No. R No. R No. R
2a 4-MeO-Ph 2f Cyclopentyl 2k Cyclopropyl
2b 4-Et-Ph 2g 2-Me-Ph 2l Cyclohexyl
2c 4-BiPh 2h 3-F-Ph 2m Phenyl
2d 4-pyridyl 2i 3-thiophene 2n Hexyl
2e 4-Me-Ph 2j 4-tBu-Ph
No. R No. R No. R
6a 4-MeO-Ph 6f 4-tBu-Ph 6k 2-benzyloxy-Ph
6b 4-Me-Ph 6g 4-EtO-Ph 6l 4-CN-Ph
6c 3,5-diMe-Ph 6h 4-COCH3-Ph 6m 3-EtO-Ph
6d 3-CF3-Ph 6i 4-COOEt-Ph 6n 2-F-Ph
6e 1-Naphthyl 6j 3-Br-Ph 6o 4-F-Ph
5
Sonogashira coupling reaction on 1-(4-methoxybenzyl)-3,5-dichloropyrazin-2(1H)-ones 1a-d.
A typical procedure. In a 50 mL microwave vial were successively dissolved in DMF/Et3N (1:1,
20 mL) pyrazinone 1 (5 mmol), acetylene 2 (6.25-7.5 mmol), Pd(PPh3)Cl2 (35 mg, 1 mol %) and
CuI (28 mg, 3 mol %). The reaction tube was sealed, and irradiated in microwave reactor at a
ceiling temperature of 80 °C at 80 W maximum power for 10 min. After the reaction mixture was
cooled with an air flow for 15 min, extracted with dichloromethane (2×150 mL) and dried over
MgSO4. The solvent was removed under reduced pressure and the residue was subjected to silica
gel column chromatography (from 10% to 30% EtOAc in petroleum ether) to afford compounds
3a-k.
N
N
Cl
O
O
O
O 1-(4-methoxybenzyl)-5-chloro-6-(4-methoxyphenyl)-3-
(2-(4-methoxyphenyl)ethynyl)pyrazin-2(1H)-one (3a): 99 % yield. 1H NMR (300 MHz,
CDCl3): δ 7.63 (d, J = 8.91 Hz, 2H), 7.06 (d, J = 8.79 Hz, 2H), 6.96 (d, J = 8.43 Hz, 2H), 6.90
(d, J = 8.85 Hz, 2H), 6.84 (d, J = 8.49 Hz, 2H), 6.73 (d, J = 8.55 Hz, 2H), 5.05 (s, 2H), 3.87 (s,
3H), 3.84 (s, 3H), 3.76 (s, 3H). 13C NMR (75 MHz, CDCl3): 160.9, 159.3, 139.6, 138.1, 134.5,
131.0, 129.3, 127.6, 123.0, 114.3, 113.9, 98.9, 85.3, 55.5, 55.4, 55.3, 49.9. HRMS (EI): calcd
for C28H23O4N2Cl: 486.1346, found: 486.1353.
N
N
Cl
O
O
O
1-(4-methoxybenzyl)-5-chloro-3-(2-(4-ethylphenyl)-
ethynyl)-6-(4-methoxyphenyl)pyrazin-2(1H)-one (3b): 92% yield. 1H NMR (300 MHz,
CDCl3): δ 7.60 (d, J = 8.1 Hz, 2H), 7.22 (m, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.4 Hz,
6
2H), 6.83 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 5.06 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H),
2.66 (m, 2H), 1.25 (t, J = 15.3, 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 161.3, 159.7,
156.2, 146.9, 139.8, 138.8, 133.2, 131.3, 129.6, 128.4, 127.9, 127.7, 123.3, 119.1, 114.7, 114.3,
99.0, 85.9, 55.8, 55.7, 50.3, 29.4, 15.6. HR-MS (EI): calcd for C29H25O3N2Cl: 484.1554, found:
484.1577.
N
N
Cl
O
O
O
3-(1,1'-Biphenyl-4-ylethynyl)-5-chloro-1-(4-methoxy-
benzyl)-6-(4-methoxyphenyl)pyrazin-2(1H)-one (3c): 83% yield. 1H NMR (300 MHz,
CDCl3): δ 7.75 (d, J = 8.2 Hz, 2H), 7.61 (m, 5H), 7.43 (m, 3H), 7.07 (d, J = 8.7 Hz, 2H), 6.97
(d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 5.07 (s, 2H), 3.88 (s,
3H), 3.77 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 160.9, 159.3, 155.8, 142.5, 140.0, 139.1,
138.6, 133.1, 132.9, 130.9, 129.2, 128.9, 127.9, 127.6, 127.2, 127.1, 122.8, 120.4, 114.3, 113.9,
98.1, 86.5, 55.4, 55.2, 49.9. HR-MS (EI): calcd for C33H25O3N2Cl: 532.1554, found: 532.1549.
N
N O
Cl
N
O
O
1-(4-methoxybenzyl)-5-chloro-6-(4-methoxyphenyl)-3-(2-
(pyridin-4-yl)ethynyl)pyrazin-2(1H)-one (3d): 85 % yield. 1H NMR (300 MHz, CDCl3): δ
8.65 (d, J = 5.2 Hz, 2H), 7.50 (d, J = 6.0 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.7 Hz,
2H), 6.83 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 8.4 Hz, 2H), 5.08 (s, 2H), 3.89 (s, 3H), 3.77 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 161.1, 159.4, 155.7, 149.9, 140.2, 130.7, 129.7, 129.3, 128.6,
128.4, 127.8, 126.9, 126.0, 114.4, 113.9, 93.7, 89.0, 55.5, 55.3, 50.1. HR-MS (EI): calcd for
C26H20ClN3O3: 457.1193, found: 457.1208.
7
N
N O
Cl
O
1-(4-methoxybenzyl)-6-benzyl-5-chloro-3-(2-p-tolylethynyl)
pyrazin-2(1H)-one (3e): in 99 % yield. 1H NMR (300 MHz, CDCl3): δ 7.56 (d, J = 8.07 Hz,
2H), 7.38 – 7.33 (m, 3H), 7.19 – 7.10 (m, 6H), 6.88 (d, J = 8.79 Hz, 2H), 5.11 (s, 2H), 4.17 (s,
2H), 3.79 (s, 3H), 2.38 (s, 3H). 13C NMR (75 MHz, CDCl3): 159.5, 156.2, 140.4, 138.9, 137.3,
134.3, 132.6, 129.5, 128.3, 127.7, 126.6, 118.5, 114.6, 98.8, 85.3, 55.4, 48.4, 35.6, 21.8.
HRMS (EI): calcd for C28H23O2N2Cl: 454.1448, found: 454.1464.
N
N O
Cl
O
1-(4-methoxybenzyl)-5-chloro-3-(2-cyclopentylethynyl)pyrazin-
2(1H)-one (3f): Yellow solid in 82 % yield. 1H NMR (300 MHz, CDCl3): δ 7.28 (d, J = 9.12
Hz, 2H), 7.10 (s, 1H), 6.90 (d, J = 9.12 Hz, 2H), 4.99 (s, 2H), 3.81 (s, 3H), 2.96 – 2.91 (m,
1H), 2.24 – 1.99 (m, 2H), 1.78 (s, 4H), 1.60 (s, 2H). 13C NMR (75 MHz, CDCl3): 160.1, 155.0,
141.4, 130.5, 126.4, 125.9, 125.4, 114.7, 106.0, 55.4, 52.5, 33.5, 31.0, 25.4. HRMS (EI): calcd
for C19H19O2N2Cl: 342.1135, found: 342.1141.
.
N
N O
Cl
O
1-(4-methoxybenzyl)-5-chloro-6-methyl-3-(2-o-tolylethynyl) pyrazin-
2(1H)-one (3g): Orange solid m.p. 144 - 147 °C in 94 % yield. 1H NMR (300 MHz, CDCl3): δ
7.61 (d, J = 7.32 Hz, 1H), 7.29 – 7.16 (m, 5H), 6.87 (d, J = 8.22 Hz, 2H), 5.32 (s, 2H), 3.79 (s,
8
3H), 2.60 (s, 3H), 2.48 (s, 3H). 13C NMR (75 MHz, CDCl3): 159.5, 156.1, 141.7, 137.5, 136.3,
132.9, 129.8, 128.5, 126.8, 126.3, 125.7, 121.5, 114.5, 96.8, 89.4, 55.4, 48.9, 20.8, 17.3.
HRMS (EI): calcd for C22H19O2N2Cl: 378.1135, found: 378.1141.
N
N O
O
O
ClF
1-(4-methoxybenzyl)-5-chloro-3-(2-(3-fluorophenyl)
ethyn- yl)-6-(4-methoxyphenyl)pyrazin-2(1H)-one (3h): Yellow solid m.p. 142 - 145 °C in
99 % yield. 1H NMR (300 MHz, CDCl3): δ 7.46 (d, J = 7.32 Hz, 1H), 7.38-7.32 (q, J = 5.49,
2.73, 2H), 7.11-7.05 (m, 3H), 6.97 (d, J = 8.22 Hz, 2H), 6.83 (d, J = 9.03 Hz, 2H), 6.72 (d, J =
9.12 Hz, 2H), 5.06 (s, 2H), 3.88 (s, 3H), 3.76 (s, 3H). 13C NMR (75 MHz, CDCl3): 163.9,
161.0, 159.4, 155.84, 139.3, 138.7, 130.9, 130.2, 129.3, 128.6, 127.6, 127.2, 123.5, 122.7,
119.5, 117.3, 114.4, 113.9, 96.1, 86.3, 55.5, 50.0. HRMS (EI): calcd for C27H20O3N2ClF:
474.1146, found: 474.1154.
.
N
N O
Cl
O
S
1-(4-methoxybenzyl)-6-benzyl-5-chloro-3-(2-(thiophen-3-yl)
ethynyl)pyrazin-2(1H)-one (3i): 88% yield. 1H NMR (300 MHz, CDCl3): δ 7.76 (s, 1H), 7.38
– 7.30 (m, 5H), 7.14 – 7.09 (m, 4H), 6.88 (d, J = 8.94, 2H), 5.11 (s, 2H), 4.17 (s, 2H), 3.79 (s,
3H). 13C NMR (75 MHz, CDCl3): 159.5, 156.2, 138.7, 137.5, 134.3, 132.2, 130.3, 129.5,
128.3, 127.6, 126.5, 125.7, 120.8, 114.6, 93.5, 85.5, 55.4, 48.4, 35.6. HRMS (EI): calcd for
C25H19O2N2SCl: 446.0856, found: 446.0858.
9
N
N O
Cl
O
O
1-(4-methoxybenzyl)-3-(2-(4-tert-butylphenyl)ethynyl)-
5-chloro-6-(4-methoxyphenyl)pyrazin-2(1H)-one (3j): Yellow solid m.p. 178 - 180 in 96 %
yield. 1H NMR (300 MHz, CDCl3): δ 7.62 (d, J = 9.4 Hz, 2H), 7.39 (d, J = 9.1 Hz, 2H), 7.05
(d, J = 9.6 Hz, 2H), 6.96 (d, J = 9.2 Hz, 2H), 6.84 (d, J = 9.3 Hz, 2H), 6.73 (d, J = 9.4 Hz, 2H),
5.06 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 1.33 (s, 9H). 13C NMR (75 MHz, CDCl3): δ 160.9,
159.3, 155.9, 153.4, 139.5, 138.4, 132.6, 131.0, 129.5, 129.3, 127.6, 127.4, 125.6, 123.0, 122.3,
118.6, 114.4, 113.9, 98.7, 85.6, 55.5, 55.3, 50.0, 35.1, 31.2. HRMS (EI): calcd for
C31H29O3N2Cl: 512.1867, found: 512.1867.
N
N O
Cl
O
1-(4-methoxybenzyl)-5-chloro-3-(2-cyclopropylethynyl)-6-methyl
pyrazin-2(1H)-one (3k): 84 % yield. 1H NMR (300 MHz, CDCl3): δ 7.17 (d, J = 8.22 Hz,
2H), 6.85 (d, J = 9.12 Hz, 2H), 5.25 (s, 2H), 3.78 (s, 3H), 2.44 (s, 3H), 1.61 – 1.57 (s, 1H), 0.97
– 0.93 (m, 4H). 13C NMR (75 MHz, CDCl3): 159.4, 156.2, 137.6, 135.5, 128.6, 126.4, 114.4,
103.7, 55.3, 48.8, 17.1, 9.5. HRMS (EI): calcd for C18H17O2N2Cl: 328.0979, found: 328.0982.
A typical procedure for the preparation of furopyrazines 4a-e.
In a 25 mL flask pyrazinone 3 (2 mmol) was dissolved in dry dichloromethane (12 mL). Then
AgOTf (11 mg, 2 mol %) and trifluoroacetic acid (0.8 mL, 10 mmol, 5 equiv) were added and
the reaction mixture was stirred at room temperature for 5-20 min. After reaction completion
10
the solvent was evaporated and the residue was subjected to silica gel column chromatography
(from 20% to 50% CH2Cl2 in petroleum ether) to afford compounds 4a-e.
N
N O
Cl
O
O
2-chloro-3,6-bis(4-methoxyphenyl)furo[2,3-b]
pyrazine (4a): Yellow Colour m.p.118 – 119 °C in 96 % yield. 1H NMR (300 MHz, CDCl3): δ
7.88 (d, J = 9.1 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 7.04 – 6.99 (m, 5H), 3.89 (s, 6H). 13C NMR
(75 MHz, CDCl3): 161.9, 161.7, 160.5, 154.1, 144.5, 143.1, 140.1, 131.4, 129.2, 129.1, 128.9,
127.5, 121.3, 114.7, 114.6, 113.7, 88.9, 55.6, 55.5. HRMS (EI): calcd for C20H15O3N2Cl:
366.0771, found: 366.0793.
N
N O
Cl
O
2-chloro-6-(4-ethylphenyl)-3-(4-methoxyphenyl) furo
[2,3-b]pyrazine (4b): 92 % yield. 1H NMR (300 MHz, CDCl3): δ 7.85 (m, 4H), 7.34 (d, J =
8.1 Hz, 2H), 7.12 (s, 1H), 7.03 (d, J = 8.3 Hz, 2H), 3.89 (s, 3H), 2.72 (m, 2H), 1.28 (t, J = 7.4
Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 162.3, 160.8, 154.4, 147.9, 145.2, 143.5, 140.1, 131.7,
129.4, 129.1, 126.5, 126.1, 114.0, 100.3, 55.8, 29.3, 15.7. HRMS (EI): calcd for
C21H17O2N2Cl: 364.0979, found: 364.0975.
N
N O
Cl
O
6-(1,1'-Biphenyl-4-yl)-2-chloro-3-(4-methoxy-
phenyl)furo[2,3-b]pyrazine (4c): 91 % yield. 1H NMR (300 MHz, CDCl3): δ 8.03 (d, J = 9.00
Hz, 2H), 7.86 (d, J = 9.00 Hz, 2H), 7.77 – 7.65 (m, 4H), 7.52 – 7.47 (m, 3H), 7.21 (s, 1H), 7.05
(d, J= 9.00 Hz, 2H), 3.90 (s, 3H). 13C NMR (75 MHz, CDCl3): 161.3, 160.5, 145.2, 143.5,
139.9, 131.3, 129.0, 128.1, 127.8, 127.1, 126.2, 113.7, 100.6, 55.4. HRMS (EI): calcd for
C25H17O2N2Cl: 412.0979, found: 412.0983.
11
N
N O
Cl
N
O
2-Chloro-3-(4-methoxyphenyl)-6-pyridin-4-ylfuro[2,3-b]
pyrazine (4d): 79 % yield. 1H NMR (300 MHz, CDCl3): δ 8.84 (br, 2H), 7.89 (m, 4H), 7.48 (s,
1H), 7.05 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 160.9, 157.3, 154.4,
149.4, 147.6, 144.4, 138.0, 136.9, 132.1, 131.5, 128.5, 128.4, 119.5, 113.8, 104.9, 55.4. HR-
MS (EI): calcd for C18H12O2N3Cl: 337.0618, found: 337.0621.
N
N O
Cl 3-benzyl-2-chloro-6-p-tolylfuro[2,3-b]pyrazine (4e):
White solid m.p. 214 – 216 °C in 91 % yield. 1H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 9.0
Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 7.33 – 7.22 (m, 5H), 7.05 (s, 1H), 4.37 (s, 2H), 2.42 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 161.6, 154.0, 146.5, 144.7, 141.3, 140.2, 137.6, 131.4, 129.9,
128.7, 126.9, 125.9, 125.7, 99.8, 42.3, 21.7 HRMS (EI): calcd for C20H15ON2Cl: 334.0873,
found: 334.0858.
A typical procedure for the preparation of furopyrazines 5a-g.
In a 25 mL flask pyrazinone 3 (2 mmol) was dissolved in dry dichloromethane (12 mL). Then
I2 (2.0 equiv) was added and the reaction mixture was stirred at room temperature for 5-15
min. After reaction completion the solvent was evaporated and the residue was subjected to
silica gel column chromatography (from 5% to 10% CH2Cl2 in petroleum ether) to afford
compounds 5a-g.
N
N O
Cl
I 2-chloro-6-cyclopentyl-7-iodofuro[2,3-b]pyrazine (5a): White solid
m.p. 128 – 131 °C in 76 % yield. 1H NMR (300 MHz, CDCl3): δ 8.17 (s, 1H), 3.56 – 3.45 (m,
1H), 2.13 – 2.07 (m, 2H), 1.93 (s, 4H), 1.76 (s, 2H). 13C NMR (75 MHz, CDCl3): 169.2, 153.4,
142.2, 136.8, 62.2, 39.5, 31.7, 26.2. HRMS (EI): calcd for C11H10ON2ICl: 347.9526, found:
347.9547.
12
N
N O
Cl
I 2-chloro-7-iodo-3-methyl-6-o-tolylfuro[2,3-b]pyrazine (5b): yellow
solid m.p. 158– 161 °C in 86 % yield. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J = 7.32 Hz,
1H), 7.45 (m, 1H), 7.34 (m, 2H), 2.77 (s, 3H), 2.41 (s, 3H). 13C NMR (75 MHz, CDCl3):160.9,
153.3, 147.3, 145.7, 139.8, 138.4, 131.1, 128.2, 125.8, 64.6, 22.6, 20.6. HRMS (EI): calcd for
C14H10ON2ICl: 383.9526, found: 383.9522.
N
N O
ClI
FO
2-chloro-6-(3-fluorophenyl)-7-iodo-3-(4-methoxyphenyl)
furo[2,3-b]pyrazine (5c): light yellow solid m.p. 210 – 214 °C in 88 % yield. 1H NMR (300
MHz, CDCl3): δ 8.13 (d, J = 8.22 Hz, 1H), 8.03 (d, J = 10.05 Hz, 1H), 7.85 (d, J = 8.22 Hz,
2H), 7.53 (m, 1H), 7.24 (d, J = 2.73 Hz, 1H), 7.03 (d, J = 8.22 Hz, 2H), 3.89 (s, 3H). 13C NMR
(75 MHz, CDCl3): 160.9, 156.4, 144.5, 131.6, 130.7, 128.4, 123.6, 118.2, 117.1, 114.9, 114.6,
113.8, 55.5. HRMS (EI): calcd for C19H11O2N2IClF: 479.9538, found: 479.9565.
N
N O
Cl
I 3-benzyl-2-chloro-7-iodo-6-p-tolylfuro[2,3-b]pyrazine (5d):
yellow solid m.p. 157– 159 °C in 91 % yield. 1H NMR (300 MHz, CDCl3): δ 8.16 (d, J = 9.15
Hz, 2H), 7.37 – 7.26 (m, 7H), 4.40 (s, 2H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3):158.0,
152.8, 148.5, 145.5, 141.6, 141.2, 137.3, 129.6, 129.4, 128.7, 127.9, 126.9, 125.8, 59.7, 41.2,
21.7. HRMS (EI): calcd for C20H14ON2ICl: 459.9839, found: 459.9829.
N
N O
Cl
I
S
3-benzyl-2-chloro-7-iodo-6-(thiophen-3-yl)furo[2,3-b]pyrazine
(5e): yellow solid m.p. 168– 171 °C in 96 % yield. 1H NMR (300 MHz, CDCl3): δ 8.40 (d, J =
1.83 Hz, 1H), 7.98 (d, J = 5.49 Hz, 7H), 7.50 – 7.48 (m, 1H), 7.37 - 7.23 (m, 5H), 4.40 (s, 2H). 13C NMR (75 MHz, CDCl3): 155.3, 152.5, 148.5, 145.6, 141.0, 137.2, 130.1, 129.1, 128.7,
13
127.8, 126.9, 126.2, 59.6, 41.2. HRMS (EI): calcd for C17H10ON2SICl: 451.9247, found:
451.9242.
.N
N O
Cl
I
O
6-(4-tert-butylphenyl)-2-chloro-7-iodo-3-(4-methoxy
phenyl)furo[2,3-b]pyrazine (5f): yellow solid m.p. 146 – 150 °C in 96 % yield. 1H NMR (300
MHz, CDCl3): δ 8.26 (d, J = 9.12 Hz, 2H), 7.85 (d, J = 9.12 Hz, 2H), 7.58 (d, J = 8.22 Hz, 1H),
7.03 (d, J = 9.15 Hz, 5H), 3.89 (s, 3H), 1.38 (s, 9H). 13C NMR (75 MHz, CDCl3):160.7, 158.4,
154.8, 152.9, 146.9, 144.1, 141.0, 131.5, 128.7, 127.8, 125.9, 113.8, 59.8, 55.5, 35.2, 31.2.
HRMS (EI): calcd for C23H20O2N2ICl: 518.0258, found: 518.0268.
N
N O
Cl
I 2-chloro-6-cyclopropyl-7-iodo-3-methylfuro[2,3-b]pyrazine (5g):
yellow solid m.p. 82 – 85 °C in 68 % yield. 1H NMR (300 MHz, CDCl3): δ 2.69 (s, 3H), 2.34 –
2.25 (m, 1H), 1.31 – 1.19 (m, 4H). 13C NMR (75 MHz, CDCl3):164.9, 152.2, 145.1, 140.2,
130.1, 114.3, 60.7, 22.3, 11.0, 9.4. HRMS (EI): calcd for C10H8ON2ICl: 333.9370, found:
333.9363.
A typical procedure for selective Suzuki-Miyaura reaction on compounds 5a-g.
In a 15 mL microwave vial were successively dissolved in DMF (4 mL) furopyrazine 5a-g (0.3
mmol), boronic acid 6a,b,f-l (0.375 mmol, 1.25 equiv), Pd(PPh3)4 (3 mg, 1 mol %) and K2CO3
(82 mg, 2 equiv). The reaction tube was sealed and irradiated at a ceiling temperature of 120
°C at 100 W maximum power for 10-30 min. After the reaction mixture was cooled with an air
flow for 15 min, extracted with dichloromethane (2×50 mL) and dried over MgSO4. The
solvent was removed under reduced pressure and the residue was subjected to silica gel
chromatography (from 5% to 20% EtOAC in Heptane) to afford compounds 7a-j.
14
N
N O
Cl
O 2-chloro-6-cyclopentyl-7-(4-methoxyphenyl)furo[2,3-b]pyrazine
(7a): Yellow oil in 91 % yield. 1H NMR (300 MHz, CDCl3): δ 8.16 (s, 1H), 7.54 (d, J = 9.15
Hz, 2H), 7.04 (d, J = 9.15, 2H), 3.86 (s, 3H), 3.55 – 3.50 (m, 1H), 2.05 - 1.94 (m, 6H), 1.74 –
1.68 (m, 2H). 13C NMR (75 MHz, CDCl3):164.8, 159.4, 153.4, 145.1, 140.9, 135.4, 130.4,
121.6, 115.7, 114.5, 55.4, 37.7, 32.4, 26.4. HRMS (EI): calcd for C18H17O2N2Cl: 328.0979,
found: 328.0987.
N
N O
Cl
7-(4-tert-butylphenyl)-2-chloro-6-cyclopentylfuro[2,3-b]pyrazine
(7b): White solid m.p. 97 – 99 °C in 78 % yield. 1H NMR (300 MHz, CDCl3): δ 8.17 (s, 1H),
7.57 – 7.50 (m, 4H), 3.59 – 3.53 (m, 1H), 2.06 - 1.94 (m, 6H), 1.75 – 1.71 (m, 2H), 1.36 (s,
9H). 13C NMR (75 MHz, CDCl3):165.2, 153.5, 151.1, 145.2, 140.9, 135.5, 128.9, 126.4, 126.0,
116.0, 37.8, 34.8, 32.5, 31.4, 26.4. HRMS (EI): calcd for C21H23ON2Cl: 354.1499, found:
354.1506.
N
N O
Cl
O 2-chloro-6-cyclopropyl-7-(4-ethoxyphenyl)-3-methylfuro[2,3-b]
pyrazine (7c): White solid m.p. 82 – 85 °C in 86 % yield. 1H NMR (300 MHz, CDCl3): δ 7.71
(d, J = 8.22 Hz, 2H), 7.03 (d, J = 9.12 Hz, 2H), 4.12 – 4.05 (q, 2H), 2.68 (s, 3H), 2.35 – 2.33
(m, 1H), 1.45 (t, J = 13.71, 6.39 Hz, 3H), 1.29 – 1.26 (m, 4H). 13C NMR (75 MHz,
CDCl3):160.3, 158.6, 152.5, 144.3, 143.6, 138.9, 130.1, 121.9, 115.0, 63.6, 22.4, 14.9, 9.5, 8.9.
HRMS (EI): calcd for C18H17O2N2Cl: 328.0979, found: 328.0987.
15
N
N O
Cl
S
O 1-(4-(3-benzyl-2-chloro-6-(thiophen-3-yl)furo[2,3-b]pyrazin-
7-yl)phenyl)ethanone (7d) White solid m.p. 209 – 214 °C in 87 % yield. 1H NMR (300 MHz,
CDCl3): δ 8.08 (d, J = 8.22 Hz, 2H), 7.84 (d, J = 2.76 Hz, 1H), 7.75 (d, J = 8.22 Hz, 2H), 7.40
– 7.23 (m, 7H), 4.40 (s, 2H), 2.66 (s, 3H). 13C NMR (75 MHz, CDCl3): 197.7, 153.2, 152.9,
147.7, 145.2, 139.0, 137.4, 137.0, 134.4, 130.1, 129.2, 128.7, 127.0, 126.9 126.0, 114.5, 41.4,
29.8, 26.8. HRMS (EI): calcd for C25H17O2N2SCl: 444.0699, found: 444.0691.
N
N O
Cl
O2-chloro-7-(4-methoxyphenyl)-3-methyl-6-o-tolylfuro[2,3-b]-
pyrazine (7e): White solid m.p. 136 – 140 °C in 89 % yield. 1H NMR (300 MHz, CDCl3): δ
7.53 (d, J = 8.22 Hz, 2H), 7.44 (d, J = 8.19 Hz, 1H), 7.38 (d, J = 7.32 Hz, 1H), 7.32 – 7.23 (m,
2H), 6.88 (d, J = 9.15 Hz, 2H), 3.80 (s, 3H), 2.76 (s, 3H), 2.22 (s, 3H). 13C NMR (75 MHz,
CDCl3): 159.4, 155.8, 153.7, 145.6, 144.7, 138.1, 131.1, 130.9, 130.4, 129.8, 129.4, 126.1,
122.1, 117.0, 114.3, 55.3, 22.7, 20.3. HRMS (EI): calcd for C21H17O2N2Cl: 364.0979, found:
364.0984.
N
N O
Cl
F
O
OO
ethyl4-(2-chloro-6-(3-fluorophenyl)-3-(4-methoxyphenyl)
furo[2,3-b]pyrazin-7-yl)benzoate (7f): White solid m.p. 163 – 167 °C in 78 % yield. 1H NMR
16
(300 MHz, CDCl3): δ 8.18 (d, J = 7.29 Hz, 2H), 7.87 (d, J = 9.12 Hz, 2H), 7.73 (d, J = 8.22
Hz, 2H), 7.52 – 7.45 (m, 2H), 7.39 – 7.32 (q, 1H), 7.16 – 7.10 (m, 1H), 7.04 (d, J = 9.12 Hz,
2H), 4.46 – 4.39 (q, 2H), 3.89 (s, 3H), 1.45 – 1.40 (t, J = 14.61, 7.29 Hz, 3H). 13C NMR (75
MHz, CDCl3): 166.3, 164.5, 161.2, 160.8, 154.8, 153.5, 146.8, 144.0, 138.3, 133.8, 131.5,
130.9, 130.6, 129.7, 128.8, 123.6, 117.8, 116.7, 114.9, 113.3, 61.3, 55.5, 14.5. HRMS (EI):
calcd for C28H20O4N2ClF: 502.1096, found: 502.1089.
N
N O
Cl
2-chloro-3-methyl-6-o-tolyl-7-p-tolylfuro[2,3-b]pyrazine (7g):
White solid m.p. 97 – 99 °C in 90 % yield. 1H NMR (300 MHz, CDCl3): δ 7.48 – 7.39 (m, 4H),
7.36 - 7.22 (m, 2H), 7.15 (d, J = 7.32 Hz, 2H), 2.76 (s, 3H), 2.34 (s, 3H), 2.22 (s, 3H). 13C
NMR (75 MHz, CDCl3):156.2, 153.7, 145.7, 144.8, 138.1, 137.9, 131.1, 130.4, 129.5, 128.5,
126.8, 126.1, 117.4, 22.7, 21.4, 20.3. HRMS (EI): calcd for C21H17ON2Cl: 348.1029, found:
348.1013.
N
N O
Cl
Br3-benzyl-7-(3-bromophenyl)-2-chloro-6-p-tolylfuro[2,3-b]
pyrazine (7h): 79 % yield. 1H NMR (300 MHz, CDCl3): δ 7.73 (s, 1H), 7.62 - 7.49 (m, 4H),
7.39 – 7.28 (m, 5H), 7.26 – 7.18 (m, 3H), 4.40 (s, 2H), 2.39 (s, 3H). HRMS (EI): calcd for
C26H18ON2BrCl: 488.0291, found: 488.0303.
N
N O
Cl
O
O
7-(2-(benzyloxy)phenyl)-6-(4-tert-butylphenyl)-2-
chloro-3-(4-methoxyphenyl)furo[2,3-b]pyrazine (7i): White solid m.p. 61 – 65 °C in 89 %
17
yield. 1H NMR (300 MHz, CDCl3): δ 7.83 (d, J = 9.12 Hz, 2H), 7.67 (d, J = 8.22 Hz, 2H), 7.50
– 7.35 (m, 4H), 7.17 – 7.13 (m, 3H), 7.11 – 7.00 (m, 6H), 4.96 (s, 2H), 3.87 (s, 3H), 1.31 (s,
9H). 13C NMR (75 MHz, CDCl3): 207.0, 160.4, 156.9, 156.6, 153.5, 153.3, 145.0, 143.1,
140.1, 136.6, 132.1, 131.3, 130.2, 129.3, 128.2, 127.6, 127.3, 127.0, 126.8, 125.6, 121.4,
119.1, 113.6, 113.0, 55.4, 34.9, 31.1. HRMS (EI): calcd for C36H31O3N2Cl: 574.2023, found:
574.2027.
N
N O
Cl
CN 4-(3-benzyl-2-chloro-6-p-tolylfuro[2,3-b]pyrazin-7-yl)-
benzonitrile (7j): White solid m.p. 158 – 162 °C in 91 % yield. 1H NMR (300 MHz, CDCl3): δ
7.74 (m, 4H), 7.58 (d, J = 8.22 Hz, 2H), 7.38 (d, J = 7.32 Hz, 2H), 7.33 – 7.21 (m, 5H), 4.46 (s,
2H), 2.41 (s, 3H). 13C NMR (75 MHz, CDCl3): 157.2, 153.4, 148.0, 145.1, 141.6, 138.6, 137.3,
134.8, 132.7, 130.2, 129.8, 129.1, 128.7, 128.0, 126.9, 125.6, 118.7, 114.0, 111.9, 41.3, 21.6.
HRMS (EI): calcd for C27H18ON3Cl: 435.1138, found: 435.1132.
A typical procedure for the preparation of furopyrazines 8a-d.
In a 15 mL microwave vial were successively dissolved in DMF/H2O (1:1, 4 mL) furopyrazine 4a-
c,e (0.3 mmol), boronic acid 6b-e (0.45 mmol, 1.50 equiv), Pd(PPh3)4 (3 mg, 1 mol %) and
Na2CO3 (64 mg, 2 equiv). The reaction tube was sealed and irradiated at a ceiling temperature of
100 °C at 100 W maximum power for 10 min. After the reaction mixture was cooled with an air
flow for 15 min, extracted with dichloromethane (2×50 mL) and dried over MgSO4. The solvent
was removed under reduced pressure and the residue was subjected to silica gel flash
chromatography (from 10% to 50% CH2Cl2 in petroleum ether) to afford compounds 8a-d.
18
N
N O
O
O
2-(3,5-dimethylphenyl)-3,6-bis(4-methoxyphenyl) furo-
[2,3-b]pyrazine (8a): Yellow solid m.p. 72 - 75 °C in 90 % yield. 1H NMR (300 MHz,
2CDCl3): δ 7.92 (d, J = 9.15, 2H), 7.43 (d, J = 9.12, 2H), 7.11 (s, 1H), 7.05 – 6.96 (m, 5H),
6.82 (d, J = 9.12, 2H), 3.89 (s, 3H), 3.81 (s, 3H), 2.26 (s, 6H). 13C NMR (75 MHz, CDCl3):
161.4, 160.6, 159.7, 154.4, 150.4, 145.6, 140.0, 137.9, 131.5, 129.8, 129.4, 128.8, 128.0, 127.7,
127.3, 121.9, 114.6, 113.5, 99.6, 55.5, 21.4. HRMS (EI): calcd for C28H24O3N2 : 436.1787,
found: 436.1793.
N
N O
O
6-(4-ethylphenyl)-3-(4-methoxyphenyl)-2-p-tolylfuro-
[2,3-b]pyrazine (8b): Light yellow solid m.p. 172 – 175 °C in 85 % yield. 1H NMR (300 MHz,
CDCl3): δ 7.89 (d, J = 8.22, 2H), 7.43 (d, J = 9.12, 2H), 7.36 – 7.33 (m, 4H), 7.20 (s, 1H), 7.14
(d, J = 8.22, 2H), 6.83 (d, J = 8.22, 2H), 3.81 (s, 3H), 2.76 - 2.68 (m, 2H), 2.36 (s, 3H), 1.31 –
1.26 (t, J = 14.61, 7.29, 3H). 13C NMR (75 MHz, CDCl3): 160.7, 159.8, 154.4, 150.3, 147.1,
146.0, 139.9, 138.0, 137.0, 131.5, 129.8, 128.7, 126.7, 125.7, 113.7, 100.6, 55.3, 29.0, 21.4,
15.5. HRMS (EI): calcd for C28H24O2N2Cl: 420.1838, found: 420.1821.
N
N O
O
CF3 6-(biphenyl-4-yl)-3-(4-methoxyphenyl)-2-(3-
(trifluoromethyl)phenyl)furo[2,3-b]pyrazine (8c): Yellow solid m.p. 150 – 153 °C in 87 %
yield. 1H NMR (300 MHz, CDCl3): δ 8.06 (d, J = 8.22 Hz, 2H), 7.84 (s, 1H), 7.76 (d, J = 8.22
Hz, 2H), 7.67 (d, J = 7.32 Hz, 2H), 7.60 (d, J = 7.29 Hz, 2H), 7.51 – 7.37 (m, 7H), 7.31 (s,
1H), 6.85 (d, J = 8.22 Hz, 2H), 3.82 (s, 3H). 13C NMR (75 MHz, CDCl3): 160.7, 160.1, 148.7,
19
146.5, 143.3, 140.6, 140.0, 133.4, 131.6, 130.8, 130.5, 129.1, 128.7, 128.1, 127.2, 126.9, 126.2,
124.9, 113.9, 101.2, 55.4. HRMS (EI): calcd for C32H21O2N2F3: 522.1555, found: 522.1566.
N
N O
3-benzyl-2-(naphthalen-1-yl)-6-p-tolylfuro[2,3-b]pyrazine
(8d): 100 % yield. 1H NMR (300 MHz, CDCl3): δ 7.89 (m, 4H), 7.52 (m, 2H), 7.35 (m, 5H),
7.16 (s, 1H), 7.10 (m, 3H), 6.90 (m, 2H), 3.95 (m, 2H), 2.44 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 160.6, 154.6, 150.5, 148.4, 140.0, 136.2, 133.7, 131.9, 129.8, 128.9, 128.4, 128.2,
127.7, 126.6, 126.2, 126.1, 125.3, 100.5, 41.3, 21.6 HRMS (EI): calcd for C30H22ON2:
426.1732, found: 426.1735.
Sonogashira coupling reaction on substituted 2-chloro furo[2,3-b]pyrazine 4a-c. A typical
procedure. In a 15 mL microwave vial were successively dissolved in DMF/Et3N (1:1, 4 mL)
pyrazine 4a-c (0.3 mmol), acetylene 2e,l,m (0.375 mmol, 1.25 equiv), Pd(PPh3)Cl2 (17 mg, 5 mol
%) and CuI (5.7 mg, 10 mol %). The reaction tube was sealed, and irradiated in microwave reactor
at a ceiling temperature of 100 °C at 80 W maximum power for 15 min. After the reaction mixture
was cooled with an air flow for 15 min, extracted with dichloromethane (2×150 mL) and dried
over MgSO4. The solvent was removed under reduced pressure and the residue was subjected to
silica gel column chromatography (from 10% to 30% EtOAc in Heptane) to afford compounds 9a-
c.
N
N O
O
O
2-(2-cyclohexylethynyl)-3,6-bis(4-methoxyphenyl)furo-
[2,3-b]pyrazine (9a): Yellow solid m.p. 140 – 143 °C in 85 % yield. 1H NMR (300 MHz,
CDCl3): δ 8.09 (d, J = 9.15 Hz, 2H), 7.89 (d, J = 8.22 Hz, 2H), 7.03 - 6.98 (m, 5H), 3.89 (s,
20
6H), 2.66 -2.62 (m, 1H), 1.88 – 1.86 (m, 2H), 1.73 – 1.70 (m, 2H), 1.56 – 1.52 (m, 6H). 13C
NMR (75 MHz, CDCl3): 161.4, 160.4, 153.6, 148.3, 139.9, 133.9, 131.1, 129.9, 129.1, 128.7,
127.3, 121.5, 114.5, 114.0, 113.3, 99.1, 79.7, 55.4, 31.9, 29.9, 25.8, 24.9. HRMS (EI): calcd for
C28H26O3N2: 438.1943, found: 438.1964.
N
N O
O
6-(4-ethylphenyl)-3-(4-methoxyphenyl)-2-(2-p-tolyl-
ethynyl)furo[2,3-b]pyrazine (9b): Yellow solid m.p. 156 – 159 °C in 92 % yield. 1H NMR
(300 MHz, CDCl3): δ 8.17 (d, J = 8.22 Hz, 2H), 7.89 (d, J = 8.22 Hz, 2H), 7.43 (d, J = 8.22
Hz, 2H), 7.35 (d, J = 8.22 Hz, 2H), 7.16 (d, J = 8.22 Hz, 2H), 7.05 (d, J = 8.22 Hz, 2H), 3.91
(s, 3H), 2.77 – 2.69 (m, 2H), 2.37 (s, 3H), 1.31 – 1.26 (t, J = 15.54, 7.32 Hz, 3H). 13C NMR
(75 MHz, CDCl3): 161.4, 160.6, 149.0, 147.3, 139.9, 133.6, 131.7, 131.1, 129.2, 128.6, 126.2,
125.7, 119.2, 113.4, 100.1, 93.1, 55.4, 28.9, 21.6, 15.3. HRMS (EI): calcd for C30H24O2N2:
444.1838, found: 444.1841.
N
N O
O
6-(biphenyl-4-yl)-3-(4-methoxyphenyl)-2-(phenyle-
thynyl)furo[2,3-b]pyrazine (9c): Yellow solid m.p. 191 – 194 °C in 96 % yield. 1H NMR (300
MHz, CDCl3): δ 8.16 (d, J = 9.15 Hz, 2H), 8.04 (d, J = 8.22 Hz, 2H), 7.75 (d, J = 9.15 Hz, 2H),
7.66 (d, J = 7.32 Hz, 2H), 7.55 – 7.46 (m, 4H), 7.42 – 7.36 (m, 4H), 7.24 (s, 1H), 7.07 (d, J =
8.22 Hz, 2H), 3.91 (s, 3H). 13C NMR (75 MHz, CDCl3): 160.9, 154.1, 149.5, 143.3, 140.0,
133.7, 131.9, 131.3, 129.7, 129.2, 128.5, 128.1, 127.8, 127.6, 127.1, 126.2, 122.4, 113.6, 101.0,
93.0, 88.4, 55.5. HRMS (EI): calcd for C33H22O2N2: 478.1681, found: 478.1671.
A typical procedure for selective Sonogashira coupling reaction on dihalo-substituted
furo[2,3-b]pyrazine 5c,e. In a 15 mL microwave vial were successively dissolved in DMF/Et3N
21
(1:1, 4 mL) pyrazine 5c,e (0.3 mmol), acetylene 2i,e,n (0.315 mmol, 1.05 equiv), Pd(PPh3)Cl2 (3.4
mg, 1 mol %) and CuI (2.0 mg, 3 mol %). The reaction tube was sealed, and irradiated in
microwave reactor at a ceiling temperature of 95 °C at 80 W maximum power for 7-10 min. After
the reaction mixture was cooled with an air flow for 15 min, extracted with dichloromethane
(2×150 mL) and dried over MgSO4. The solvent was removed under reduced pressure and the
residue was subjected to silica gel column chromatography (from 5% to 10% EtOAc in Heptane)
to afford compounds 10a-c.
N
N O
Cl
S
S 3-benzyl-2- chloro-6-(thiophen-3-yl)-7-(2-(thiophen-3-yl)
ethynyl)furo[2,3-b]pyrazine (10a): Yellow solid m.p. 140 – 144 °C in 89 % yield. 1H NMR
(300 MHz, CDCl3): δ 8.32 (d, J = 1.83 Hz, 1H), 7.97 (d, J = 5.49 Hz, 1H), 7.66 (d, J = 4.0 Hz,
1H), 7.48 – 7.45 (m, 2H), 7.35 - 7.28 (m, 6H), 4.39 (s, 2H). 13C NMR (75 MHz, CDCl3):
155.4, 152.6, 148.8, 145.2, 141.3, 137.4, 130.6, 129.2, 128.7, 128.2, 127.8, 126.9, 126.2, 125.8,
125.9, 116.0, 89.0, 77.8, 41.2. HRMS (EI): calcd for C23H13ON2S2Cl: 432.0158, found:
432.0145.
N
N O
Cl
S
3-benzyl-2-chloro-6-(thiophen-3-yl)-7-(2-p-tolylethynyl)
furo[2,3-b]pyrazine (10b): Yellow solid m.p. 121 – 125 °C in 86 % yield. 1H NMR (300
MHz, CDCl3): δ 8.33 (s, 1H), 7.98 (d, J = 5.49 Hz, 1H), 7.53 (d, J = 8.22 Hz, 2H), 7.47 – 7.43
(m, 1H), 7.37 – 7.19 (m, 7H), 4.39 (s, 2H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3): 157.8,
153.0, 147.9, 145.3, 139.4, 138.4, 137.3, 132.0, 130.5, 129.4, 128.7, 126.9, 125.7, 119.5, 98.8,
98.3, 41.3, 21.7. HRMS (EI): calcd for C26H17ON2SCl: 440.0750, found: 440.0746.
22
N
N O
Cl
O
F
2-chloro-6-(3-fluorophenyl)-3-(4-methoxyphenyl)-7-
(oct-1-ynyl)furo[2,3-b]pyrazine (10c): Yellow solid m.p. 97 – 100 °C in 74 % yield. 1H NMR
(300 MHz, CDCl3): δ 8.14 (m, 2H), 7.85 (d, J = 8.19 Hz, 2H), 7.52 – 7.47 (m, 1H), 7.21 – 7.15
(m, 1H), 7.03 (d, J = 9.15 Hz, 2H), 3.89 (s, 3H), 2.66 – 2.61 (t, J = 13.71, 7.32 Hz, 2H), 1.79 –
1.69 (m, 2H), 1.57 – 1.54 (m, 2H), 1.37 – 1.35 (m, 4H), 0.94 – 0.89 (t, J = 13.71, 6.39 Hz, 3H). 13C NMR (75 MHz, CDCl3): 164.5, 161.2, 160.8, 158.9, 152.9, 147.0, 144.1, 139.0, 131.5,
130.5, 128.7, 122.2, 117.6, 113.8, 113.2, 102.3, 69.1, 55.5, 31.4, 28.9, 28.4, 22.6, 20.3, 14.1.
HRMS (EI): calcd for C27H24O2N2ClF: 462.1510, found: 462.1516.
A typical procedure for the preparation of furopyrazines 11a-c.
In a 15 mL microwave vial were successively dissolved in DMF/H2O (1:1, 4 mL) furopyrazine
7b,d,e (0.3 mmol), boronic acid 6f,m,n (0.45 mmol, 1.50 equiv), Pd(PPh3)4 (3 mg, 1 mol %)
and Na2CO3 (64 mg, 2 equiv). The reaction tube was sealed and irradiated at a ceiling
temperature of 100 °C at 100 W maximum power for 10 min. After the reaction mixture was
cooled with an air flow for 15 min, extracted with dichloromethane (2×50 mL) and dried over
MgSO4. The solvent was removed under reduced pressure and the residue was subjected to
silica gel flash chromatography (from 10% to 30% CH2Cl2 in petroleum ether) to afford
compounds 11a-c.
N
N O
O
7-(4-tert-butylphenyl)-6-cyclopentyl-2-(3-ethoxyphenyl)furo[2,3-
b]pyrazine (11a): White solid m.p. 102 – 104 °C in 92 % yield. 1H NMR (300 MHz, CDCl3):
δ 8.60 (s, 1H), 7.70 (d, J = 8.22 Hz, 2H), 7.61 – 7.53 (m, 4H), 7.41 – 7.36 (t, J = 16.44, 8.22
23
Hz, 1H), 6.98 (d, J = 9.12 Hz, 1H), 4.15 – 4.08 (m, 2H), 3.67 – 3.56 (m, 1H), 2.11 – 1.96 (m,
6H), 1.74 – 1.72 (m, 2H), 1.47 – 1.39 (m, 12H). 13C NMR (75 MHz, CDCl3): 161.4, 160.6,
149.0, 147.3, 139.9, 133.6, 131.7, 131.1, 129.2, 128.6, 126.2, 125.7, 119.2, 113.4, 100.1, 93.1,
55.4, 28.9, 21.6, 15.3. HRMS (EI): calcd for C29H32O2N2: 440.2464, found: 440.2461.
N
N OS
O 1-(4-(3-benzyl-2-(4-tert-butylphenyl)-6-(thiophen-3-yl)furo
[2,3-b]pyrazin-7-yl)phenyl)ethanone (11b): White solid m.p. 149 – 152 °C in 87 % yield. 1H
NMR (300 MHz, CDCl3): δ 8.04 (d, J = 8.22 Hz, 2H), 7.84 – 7.80 (m, 3H), 7.44 – 7.43 (m,
4H), 7.31 (s, 2H), 7.24 – 7.10 (m, 5H), 4.33 (s, 2H), 2.63 (s, 3H), 1.36 (s, 9H). 13C NMR (75
MHz, CDCl3): 197.8, 153.5, 152.2, 151.6, 148.0, 139.4, 136.6, 135.3, 130.5, 129.3, 128.9,
126.7, 126.4, 125.4, 115.0, 41.2, 34.8, 31.5, 26.8. HRMS (EI): calcd for C35H30O2N2S:
542.2028, found: 542.2029.
N
N O
F
O 2-(2-fluorophenyl)-7-(4-methoxyphenyl)-3-methyl-6-o-tolylfuro
[2,3-b]pyrazine (11c): 95 % yield. 1H NMR (300 MHz, CDCl3): δ 7.61 (m, 10H), 6.84 (d, J =
8.22 Hz, 2H), 3.77 (s, 3H), 2.60 (s, 3H), 2.26 (s, 3H). 13C NMR (75 MHz, CDCl3): 161.7,
159.1, 158.4, 154.9, 154.4, 146.9, 146.1, 138.1, 132.0, 131.0, 130.5, 129.9, 127.6, 126.1, 124.4,
122.7, 117.3, 115.9, 114.2, 55.2, 22.2, 20.3. HRMS (EI): calcd for C27H21O2N2F: 542.2028,
found: 542.2035.
24
A typical sonogashira coupling for 11d. In a 15 mL microwave vial were successively dissolved
in DMF/Et3N (1:1, 4 mL) pyrazine 7d (0.3 mmol), acetylene 2e (0.39 mmol, 1.3 equiv),
Pd(PPh3)Cl2 (17 mg, 5 mol %) and CuI (5.7 mg, 10 mol %). The reaction tube was sealed, and
irradiated in microwave reactor at a ceiling temperature of 100 °C at 80 W maximum power for 15
min. After the reaction mixture was cooled with an air flow for 15 min, extracted with
dichloromethane (2×150 mL) and dried over MgSO4. The solvent was removed under reduced
pressure and the residue was subjected to silica gel column chromatography (from 10% to 30%
EtOAc in Heptane) to afford compounds 11d.
N
N OS
O 1-(4-(3-benzyl-6-(thiophen-3-yl)-2-(2-p-tolylethynyl)furo
[2,3-b]pyrazin-7-yl)phenyl)ethanone (11d): Light yellow solid m.p. 210 – 215 °C in 86 %
yield. 1H NMR (300 MHz, CDCl3): δ 8.08 (d, J = 8.22 Hz, 2H), 7.79 – 7.76 (m, 3H), 7.50 –
7.44 (m, 4H), 7.33 – 7.12 (m, 8H), 4.54 (s, 2H), 2.66 (s, 3H), 2.39 (s, 3H). 13C NMR (75 MHz,
CDCl3): 197.8, 152.9, 152.4 139.7, 139.3, 138.5, 136.9, 136.1, 134.8, 131.9, 130.3, 129.4,
128.7, 126.9, 126.0, 119.1, 114.7, 94.8, 86.5, 41.9, 26.8, 21.7. HRMS (EI): calcd for
C34H24O2N2S: 524.1558, found: 524.1551.
Disubstituted Suzuki Cross coupling. A typical procedure for the preparation of
furopyrazine 12a.
In a 15 mL microwave vial were successively dissolved in DMF (4mL) furopyrazine 5g (0.3
mmol), boronic acid 6o (0.9 mmol, 3.0 equiv), Pd(PPh3)4 (16 mg, 5 mol %) and K2CO3 (166
mg, 5 equiv). The reaction tube was sealed and irradiated at a ceiling temperature of 140 °C at
300 W maximum power for 25 min. After the reaction mixture was cooled with an air flow for
25
15 min, extracted with dichloromethane (2×50 mL) and dried over MgSO4. The solvent was
removed under reduced pressure and the residue was subjected to silica gel flash
chromatography (from 0% to 5%EtOAc in Heptane) to afford compound 12a in 93% of yield
N
N O
F
F
6-cyclopropyl-2,7-bis(4-fluorophenyl)-3-methylfuro[2,3-b]-
pyrazine (12a): White solid m.p. 81 – 84 °C in 93 % yield. 1H NMR (300 MHz, CDCl3): δ
7.86 – 7.81 (m, 2H), 7.58 – 7.54 (m, 2H), 7.20 – 7.13 (m, 4H), 2.64 (s, 3H), 2.37 – 2.32 (m,
1H), 1.35 – 1.13 (m, 4H). 13C NMR (75 MHz, CDCl3): 164.5, 163.9, 161.2, 160.6, 159.8,
152.8, 149.5, 143.9, 138.6, 135.6, 131.4, 130.7, 126.3, 116.0, 115.5, 115.1, 23.3, 9.5, 8.8.
HRMS (EI): calcd for C22H16ON2F2: 362.1231, found: 362.1225.
26
Description of X-ray structure of compound 8d
The asymmetric unit of the X-ray structure consists of two molecules of compound 8d. The
benzyl and naphthyl aromatic rings are torsioned with respect to the furopyrazine moiety with
angles of 63.5(3)° and 79.9(2)°, respectively, for the first molecule and 78.5(3)° and 73.3(2)°,
respectively, for the second molecule (angles between planes through the component aromatic
rings). This furopyrazine moiety is almost planar with the methylphenyl ring (angles of 6.9(3)°
and 9.9(3)°between planes through the aromatic rings for the first and second molecule,
respectively).
Clear π-π stacking is observed in the packing between the furan ring of the furopyrazine part of
one of the molecules and the phenyl ring of the methylphenyl part of the other molecule in the
asymmetric (distance of 3.547(4) Å between the ring centroids) and between the phenyl ring of
the former molecule and the furan ring of a symmetry equivalent molecule (centroids distance
of 3.539(4) Å).
Experimental: Crystallography
Compound 8d: needle-shaped, transparent crystals grown, by vapor diffusion, from a 1:1
dichloromethane/heptane mixture at room temperature, C30H22N2O, M = 426.50, monoclinic,
P21/n (No. 14), a = 10.2598(8), b = 12.2746(9), c = 35.342(2) Å, β = 97.671(4), V = 4411.0(5)
Å3, T = 100(2) K, Z = 8, Dc = 1.285 g cm-3, µ(Cu-Kα) = 0.610 mm-1, F(000) = 1792, crystal
size 0.6 × 0.05 × 0.05 mm, 4607 independent reflections. Final R = 0.0736 for 1879 reflections
with I > 2σ(I) and ωR2 = 0.1936 for all data and GooF = 0.920.
Intensity data were collected on a SMART 6000 diffractometer equipped with CCD detector
using Cu-Kα radiation (λ = 1.54178 Å). The images were interpreted and integrated with the
program SAINT from Bruker[1] The structure was solved by direct methods and refined by full-
matrix least-squares on F2 using the SHELXTL program package.[2] Non-hydrogen atoms were
anisotropically refined and the hydrogen atoms in the riding mode with isotropic temperature
factors fixed at 1.2 times U(eq) of the parent atoms (1.5 times for methyl groups). CCDC-
698969 contains the supplementary crystallographic data for this paper and can be obtained
free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
27
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-
336033; or [email protected]).
[1] SAINT, Manual Version 5/6.0, Bruker Analytical X-ray Systems Inc.: Madison,
Wisconsin, 1997.
[2] SHELXTL-NT, Manual Version 5.1, Bruker Analytical X-ray Systems Inc.: Madison,
Wisconsin, 1997.
Figure. X-Ray crystal structure of 8d. Thermal ellipsoids at the 50% probability level.
28
1H and
13C Spectra of compound 3b (300 MHz, CDCl3).
6.354.264.11 3.302.20 2.182.022.00
0.0
0
1.2
3
1.2
5
1.2
8
1.5
8
2.6
4
2.6
7
2.6
9
2.7
2
3.7
7
3.8
8
5.0
6
5.3
0
6.7
2
6.7
5
6.8
3
6.8
5
6.9
5
6.9
8
7.0
5
7.0
8
7.2
0
7.2
3
7.2
6
7.5
9
7.6
2
N
N
O
CH3
O
Cl
O
CH3
CH3
3m
15.6
3
29.4
0
50.2
9
55.6
8
55.8
7
77.1
0
77.5
3
77.9
2
99.0
6
114.2
9
114.7
2
119.1
7
123.2
8
127.7
3
127.9
4
128.4
6
129.6
5
131.3
2
133.1
8
138.8
2
139.7
9
146.9
8
156.2
4
159.6
8
161.3
0
N
N
O
CH3
O
Cl
O
CH3
CH3
3m
29
1H and
13C Spectra of compound 3c (300 MHz, CDCl3).
6.074.72 4.00 4.003.48 1.94
N
N
O
CH3
O
Cl
O
CH3
3o
49.9
2
55.2
5
55.4
4
76.6
4
77.0
6
77.4
9
86.5
4
98.0
8
113.8
6
114.3
2
120.4
4
122.8
5
127.1
1
127.2
7
127.6
0
127.9
4
128.9
1
129.2
5
130.8
9
133.1
8
138.6
6
139.1
8
140.0
6
142.5
0
155.8
1
159.2
8
160.9
0
N
N
O
CH3
O
Cl
O
CH3
3o
30
1H and
13C Spectra of compound 3d (300 MHz, CDCl3).
6.294.27 4.002.17 2.12 1.99
0.0
0
3.7
7
3.8
9
5.0
8
5.3
0
6.7
3
6.7
5
6.8
3
6.8
6
6.9
7
7.0
0
7.0
6
7.0
9
7.2
7
7.5
0
7.5
2
8.6
5
8.6
7
N
N
O
CH3
O
Cl
N
O
CH3
3n
0.0
3
50.1
4
55.2
9
55.5
0
76.6
4
77.0
7
77.2
8
77.4
9
89.0
7
93.7
3
113.9
6
114.4
4
122.5
5
126.0
2
127.8
2
128.4
6
128.6
1
129.3
1
129.7
7
130.7
7
131.9
9
137.9
6
140.2
1
149.9
0
155.7
2
159.4
1
161.0
8
N
N
O
CH3
O
Cl
N
O
CH3
3n
31
1H and
13C Spectra of compound 3e (300 MHz, CDCl3).
6.12 3.273.12 3.072.00 1.951.941.94
0.0
0
1.6
0
2.3
8
3.8
0
4.1
8
5.1
2
5.3
0
6.8
6
6.8
9
7.1
0
7.1
2
7.1
3
7.1
7
7.2
0
7.2
6
7.3
4
7.3
6
7.3
8
7.4
1
7.5
5
7.5
8
N
N
O
CH3
O
Cl
CH3
3k
21
.72
35
.58
48
.34
53
.46
55
.35
76
.64
77
.07
77
.49
85
.23
98
.73
11
4.5
7
11
8.4
6
12
6.6
0
12
7.5
1
12
7.6
9
12
8.1
2
12
9.2
5
12
9.4
9
13
2.6
0
13
4.3
1
13
7.2
3
13
8.8
1
14
0.3
7
15
9.4
7
N
N
O
CH3
O
Cl
CH3
3k
32
1H and
13C Spectra of compound 3f (300 MHz, CDCl3).
N
N O
Cl
O
2.4
37
4
0.9
24
0
1.9
20
9
1.9
79
8
3.0
00
0
0.9
04
1
1.8
62
8
3.7
29
7
2.6
90
5
Inte
gra
l
7.2
97
37
.26
69
7.1
05
56
.91
98
6.8
89
4
4.9
92
8
3.8
14
6
2.9
62
22
.94
09
2.9
13
5
2.0
45
82
.01
84
2.0
00
21
.99
10
1.7
87
11
.60
44
0.0
00
0
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5
N
N O
Cl
O
16
0.1
98
6
15
5.0
50
6
14
1.4
64
7
13
0.5
59
41
26
.41
66
12
5.9
59
61
25
.44
18
11
4.7
19
3
10
6.0
98
6
77
.58
65
77
.16
00
76
.85
54
76
.73
35
55
.44
08
52
.54
69
33
.56
93
31
.07
14
25
.40
56
(ppm)
102030405060708090100110120130140150160170180
33
1H and
13C Spectra of compound 3g (300 MHz, CDCl3).
N
N OMe
Cl
O
Me
0.9
47
3
5.4
37
8
1.9
57
7
1.9
97
7
3.0
00
0
2.8
79
0
2.9
98
3
Inte
gra
l
7.6
20
07
.59
56
7.2
94
37
.26
38
7.2
54
77
.23
03
7.1
90
77
.16
03
6.8
86
36
.85
89
5.3
21
5
3.7
90
2
2.6
02
92
.48
11
0.0
00
0
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
N
N OMe
Cl
O
Me
15
9.5
58
9
15
6.1
47
2
14
1.7
99
71
37
.50
46
13
6.3
47
11
32
.93
54
12
9.8
28
31
29
.67
60
12
8.5
79
41
26
.87
35
12
6.3
25
21
25
.71
60
12
1.5
73
2
11
4.5
67
0
96
.80
78
89
.40
56
77
.58
65
77
.16
00
76
.73
35
55
.41
03
48
.92
20
20
.89
72
17
.30
28
(ppm)
102030405060708090100110120130140150160170180190
34
1H and
13C Spectra of compound 3h (300 MHz, CDCl3).
0.9
595
1.9
855
2.9
654
2.0
265
1.9
505
1.9
869
1.9
557
3.0
000
2.9
924
Inte
gra
l
7.4
739
7.4
495
7.3
795
7.3
612
7.3
521
7.3
338
7.2
638
7.1
177
7.0
842
7.0
538
6.9
868
6.9
594
6.8
528
6.8
224
6.7
493
6.7
189
5.0
658
3.8
846
3.7
659
0.0
000
(ppm)
0.01.02.03.04.05.06.07.08.09.010.011.0
N
N O
O
O
ClF
N
N O
O
O
ClF
16
3.9
75
91
61
.05
15
15
9.4
06
6
15
5.8
42
6
13
9.3
62
81
38
.72
31
13
0.9
24
91
30
.22
43
13
0.1
32
91
29
.34
09
12
8.6
09
81
27
.69
60
12
7.2
08
61
23
.55
32
12
3.4
31
31
22
.79
16
11
9.5
01
81
19
.19
71
11
7.3
99
91
17
.12
58
11
4.4
45
11
13
.98
82
96
.13
76
86
.35
94
77
.58
65
77
.16
00
76
.76
40
55
.53
22
55
.34
94
50
.07
95
(ppm)
0102030405060708090100110120130140150160170180190
35
1H and
13C Spectra of compound 3i (300 MHz, CDCl3).
N
N O
Cl
O
S
0.8
08
2
5.2
81
4
4.0
31
5
2.0
58
1
1.9
16
0
1.9
96
4
3.0
00
0
Inte
gra
l
7.7
66
17
.76
00
7.3
85
67
.36
12
7.3
43
07
.31
56
7.3
06
47
.26
08
7.1
42
07
.12
99
7.1
20
77
.09
94
6.8
92
46
.86
20
5.1
11
5
4.1
79
9
3.7
99
3
-0.0
00
0
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
N
N O
Cl
O
S
15
9.5
89
4
15
6.2
08
1
13
8.7
23
11
37
.50
46
13
4.3
36
61
32
.23
48
13
0.3
15
71
29
.58
46
12
8.3
66
11
28
.21
38
12
7.8
17
81
27
.60
46
12
6.5
99
31
25
.77
69
12
0.8
72
5
11
4.6
58
4
93
.51
79
85
.50
65
77
.58
65
77
.16
00
76
.73
35
55
.47
13
48
.46
51
35
.67
12
(ppm)
102030405060708090100110120130140150160170180
36
1H and
13C Spectra of compound 3k (300 MHz, CDCl3).
N
N O
Cl
Me
O
2.0
096
2.0
218
2.0
138
3.0
990
3.0
000
Inte
gra
l
7.2
670
7.1
727
7.1
453
6.8
682
6.8
378
5.2
578
3.7
873
2.4
417
1.6
167
1.5
711
0.9
774
0.9
683
0.9
409
0.9
317
0.0
002
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
N
N O
Cl
Me
O
15
9.4
98
0
15
6.2
99
5
13
7.6
26
51
35
.52
46
12
8.6
70
71
26
.41
66
11
4.4
75
6
10
3.7
83
5
77
.58
65
77
.16
00
76
.73
35
72
.65
17
55
.37
99
48
.83
06
17
.15
05
9.5
35
0
0.8
53
4
(ppm)
0102030405060708090100110120130140150160170
37
1H and
13C Spectra of compound 4a (300 MHz, CDCl3).
N
N O
Cl
O
O
3.9
696
4.9
852
6.0
000
Inte
gra
l
7.8
972
7.8
667
7.8
485
7.8
211
7.2
609
7.0
417
7.0
356
7.0
204
7.0
113
6.9
960
3.8
878
(ppm)
2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
N
N O
Cl
O
O
16
1.9
34
91
61
.78
26
16
0.5
03
2
15
4.1
06
3
14
4.4
49
91
43
.14
00
14
0.1
24
3
13
1.3
81
81
29
.21
90
12
9.1
58
11
28
.91
44
12
7.4
82
7
12
1.3
29
5
11
4.7
19
31
14
.59
74
11
3.7
14
0
98
.90
97
77
.55
60
77
.16
00
76
.73
35
55
.59
31
55
.47
13
(ppm)
0102030405060708090100110120130140150160170180
38
1H and
13C Spectra of compound 4b (300 MHz, CDCl3).
4.00 3.073.002.972.04 1.98
0.0
0
1.2
6
1.2
9
1.3
1
1.5
7
2.6
9
2.7
2
2.7
4
2.7
7
3.9
0
5.3
0
7.0
2
7.0
5
7.1
2
7.2
6
7.3
4
7.3
6
7.8
3
7.8
6
7.8
8
N
N
O
Cl
O
CH3
CH3
4m
N
NO
Cl
O
16
2.0
56
81
60
.56
41
15
4.1
97
7
14
7.6
78
81
44
.96
78
14
3.2
92
4
13
9.8
80
7
13
1.4
42
81
29
.12
77
12
8.8
23
1
12
6.2
03
31
25
.89
87
11
3.7
44
5
99
.97
58
77
.58
65
77
.16
00
76
.73
35
55
.50
17
29
.03
05
15
.44
46
(ppm)
102030405060708090100110120130140150160170180
39
1H and
13C Spectra of compound 4c (300 MHz, CDCl3).
4.84 3.27 3.152.15 2.00
0.0
0
1.5
6
2.1
7
3.9
0
5.3
0
7.0
3
7.0
6
7.2
1
7.2
6
7.4
7
7.4
9
7.5
2
7.6
5
7.6
7
7.7
4
7.7
7
7.8
4
7.8
7
8.0
1
8.0
4
N
N
O
Cl
O
CH3
4o
5
5.4
4
76
.64
77
.06
77
.25
77
.46
10
0.6
1
11
3.7
1
12
6.2
0
12
7.1
1
12
7.4
8
12
7.8
1
12
8.1
2
12
9.0
3
13
1.3
8
13
9.6
3
13
9.9
1
14
3.5
0
14
5.2
7
16
0.5
6
16
1.3
8
N
N
O
Cl
O
CH3
4o
40
1H and
13C Spectra of compound 4e (300 MHz, CDCl3).
7.36 3.012.00 2.001.01
0.0
0
2.4
2
4.3
8
7.0
5
7.2
3
7.2
6
7.2
9
7.3
1
7.3
3
7.3
8
7.4
0
7.7
9
7.8
2
N
N
O
Cl
CH3
4k
21.6
0
41.2
4
76.6
4
77.0
7
77.4
9
99.7
6
125.6
2
125.8
4
126.7
8
128.5
8
129.1
3
129.8
6
137.5
3
140.0
6
141.2
2
144.6
0
146.4
3
153.9
2
161.5
1
N
N
O
Cl
CH3
4k
41
1H and
13C Spectra of compound 5a (300 MHz, CDCl3).
N
N O
Cl
I
0.9
23
6
1.0
00
0
2.1
01
5
4.2
26
8
2.1
50
0
Inte
gra
l
8.1
71
0
7.2
76
0
3.5
61
93
.53
45
3.5
10
13
.48
27
3.4
55
3
2.1
31
02
.12
19
2.1
03
62
.07
93
1.9
36
21
.76
57
-0.0
00
0
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
N
N O
Cl
I
169.2
153
153.4
056
142.2
567
136.8
040
77.5
865
77.1
600
76.7
335
62.2
338
39.5
703
31.7
111
26.2
585
(ppm)
102030405060708090100110120130140150160170180
42
1H and
13C Spectra of compound 5b (300 MHz, CDCl3).
N
NO
Cl
I
Me
Me
0.9
93
3
1.0
30
4
1.9
86
8
3.0
00
0
3.0
26
6
Inte
gra
l
7.6
32
27
.60
78
7.4
80
07
.45
56
7.4
31
37
.37
65
7.3
49
17
.32
17
7.2
63
8
2.7
76
4
2.4
17
2
1.5
67
8
0.0
00
0
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
N
NO
Cl
I
Me
Me
16
0.9
90
6
15
3.3
44
7
14
7.3
74
21
45
.75
98
13
9.8
19
71
38
.41
85
13
1.3
20
91
31
.16
86
13
1.0
77
2
12
8.2
13
81
25
.89
87
77
.58
65
77
.16
00
76
.73
35
64
.67
07
22
.66
40
20
.68
40
(ppm)
0102030405060708090100110120130140150160170
43
1H and
13C Spectra of compound 5c (300 MHz, CDCl3).
0.9
536
0.9
191
1.9
075
1.0
049
1.9
922
1.9
746
3.0
000
Inte
gra
l
8.1
436
8.1
162
8.0
493
8.0
158
7.8
727
7.8
453
7.5
469
7.5
256
7.2
638
7.2
455
7.2
364
7.0
538
7.0
264
3.8
998
1.5
739
0.0
000
(ppm)
0.01.02.03.04.05.06.07.08.09.0
N
N O
Cl
I
F
O
160.9
602
156.4
518
144.5
413
131.6
255
130.7
726
130.6
812
128.4
575
123.6
750
118.2
224
117.9
482
117.1
867
114.9
934
114.6
888
113.8
664
77.5
865
77.1
600
76.7
335
55.5
627
(ppm)
0102030405060708090100110120130140150160170180
N
N O
Cl
I
F
O
44
1H and
13C Spectra of compound 5d (300 MHz, CDCl3).
1.8
16
9
7.7
17
5
1.8
79
7
3.0
00
0
Inte
gra
l
8.1
80
28
.14
97
7.3
73
47
.35
51
7.3
27
77
.30
34
7.2
60
8
4.4
05
2
2.4
41
6
-0.0
00
0
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
N
N O
Cl
I
Me
N
N O
Cl
I
Me
158.0
967
152.8
269
148.5
927
145.5
465
141.6
474
141.2
514
137.3
219
129.6
455
129.1
886
128.7
012
127.9
092
126.9
649
125.8
987
77.5
865
77.1
600
76.7
335
59.7
664
41.2
457
21.7
502
(ppm)
0102030405060708090100110120130140150160170180190
45
1H and
13C Spectra of compound 5e (300 MHz, CDCl3).
N
N O
Cl
I
S
0.8
618
0.9
376
1.0
667
6.2
388
2.0
000
Inte
gra
l
8.4
085
8.4
024
7.9
914
7.9
731
7.5
074
7.4
952
7.4
891
7.4
800
7.3
704
7.3
460
7.3
277
7.3
034
7.2
790
7.2
608
7.2
303
4.4
021
-0.0
000
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0
N
N O
Cl
I
S
155.3
552
152.5
223
148.5
927
145.6
074
141.0
382
137.2
609
130.1
024
129.1
886
128.7
317
127.8
178
126.9
953
126.8
430
126.2
947
77.5
865
77.1
600
76.7
335
59.6
445
41.2
152
(ppm)
0102030405060708090100110120130140150160170
46
1H and
13C Spectra of compound 5f (300 MHz, CDCl3).
1.8
757
1.9
857
1.9
982
2.0
287
3.0
000
8.9
842
Inte
gra
l
8.2
806
8.2
502
7.8
605
7.8
301
7.5
926
7.5
652
7.2
608
7.0
477
7.0
172
3.8
937
1.3
852
-0.0
000
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
N
NO
Cl
I
O
N
NO
Cl
I
O
16
0.7
77
41
58
.40
14
15
4.8
06
91
52
.97
92
14
6.9
17
3
14
4.1
45
3
14
1.0
07
7
13
1.5
64
61
28
.70
12
12
7.8
17
81
25
.99
01
11
3.8
35
9
77
.58
65
77
.16
00
76
.73
35
59
.82
73
55
.53
22
35
.24
47
31
.25
42
(ppm)
0102030405060708090100110120130140150160170
47
1H and
13C Spectra of compound 5g (300 MHz, CDCl3).
3.0
000
0.9
582
4.2
922
Inte
gra
l
7.2
669
2.6
912
2.3
441
2.3
259
2.3
167
2.2
985
2.2
833
2.2
711
2.2
559
1.5
800
1.3
152
1.3
060
1.2
969
1.2
908
1.2
299
1.2
208
1.2
025
1.1
934
0.0
000
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0
N
N O
Cl
I
Me
N
N O
Cl
I
Me
164.9
811
152.2
786
145.1
810
140.2
157
130.1
329
114.3
537
77.5
865
77.1
600
76.7
335
60.7
716
22.3
594
11.0
581
9.4
741
(ppm)
0102030405060708090100110120130140150160170180
48
1H and
13C Spectra of compound 7a (300 MHz, CDCl3).
N
N O
Cl
O
0.8
820
1.9
375
1.9
423
3.0
000
1.0
191
6.1
911
2.2
326
Inte
gra
l
8.1
649
7.5
622
7.5
317
7.2
669
7.0
538
7.0
233
3.8
633
3.5
558
3.5
284
3.5
010
2.0
519
2.0
458
2.0
367
2.0
245
2.0
062
1.9
666
1.9
514
1.9
423
1.7
475
1.7
353
1.7
261
1.7
109
1.6
987
1.6
896
0.0
000
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
N
N O
Cl
O
164.8
897
159.4
980
153.4
361
145.1
505
140.9
163
135.4
942
130.4
680
121.6
645
115.7
550
114.5
060
77.5
865
77.1
600
76.7
335
55.4
713
37.7
730
32.4
422
26.4
108
(ppm)
0102030405060708090100110120130140150160170180190
49
1H and
13C Spectra of compound 7b (300 MHz, CDCl3).
0.8
84
4
3.9
63
6
1.0
03
7
6.2
51
2
2.0
58
7
9.0
00
0
Inte
gra
l
8.1
74
1
7.5
74
37
.54
39
7.5
37
87
.51
65
7.5
07
4
7.2
60
8
3.5
92
33
.56
49
3.5
37
5
2.0
61
02
.04
28
2.0
33
62
.00
93
1.9
72
71
.95
75
1.9
48
41
.75
05
1.7
38
31
.72
92
1.7
14
01
.56
78
1.3
66
9
-0.0
00
0
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
N
N O
Cl
N
N O
Cl
16
5.2
85
7
15
3.5
27
51
51
.12
10
14
5.2
11
5
14
0.9
16
4
13
5.5
55
1
12
8.9
44
91
26
.44
70
12
6.0
20
6
11
6.0
29
1
77
.55
60
77
.16
00
76
.73
35
37
.80
35
34
.81
82
32
.53
36
31
.43
70
26
.47
17
(ppm)
102030405060708090100110120130140150160170
50
1H and
13C Spectra of compound 7c (300 MHz, CDCl3).
2.0
47
9
2.0
33
9
3.0
00
0
1.0
11
2
3.6
87
3
5.6
05
2
Inte
gra
l
7.7
20
57
.69
31
7.2
63
8
7.0
44
67
.01
42
4.1
28
14
.10
38
4.0
82
54
.05
81
2.6
88
2
2.3
53
32
.33
50
1.6
01
31
.47
35
1.4
52
21
.42
78
1.2
96
91
.26
04
(ppm)
1.52.02.53.03.54.04.55.05.56.06.57.07.58.0
N
N O
Cl
Me
O
N
N O
Cl
Me
O
160.3
509
158.6
755
152.5
223
144.3
585
143.6
884
138.9
059
130.1
634
121.9
387
115.0
239
77.5
865
77.1
600
76.7
335
63.6
655
22.4
508
14.9
877
9.5
655
8.9
562
(ppm)
0102030405060708090100110120130140150160170180190
51
1H and
13C Spectra of compound 7d (300 MHz, CDCl3).
N
N O
Cl
S
Me
O
1.9
695
0.8
715
2.0
030
6.0
454
0.9
298
1.9
824
3.0
000
Inte
gra
l
8.0
949
8.0
675
7.8
453
7.8
361
7.7
600
7.7
326
7.4
008
7.3
765
7.3
582
7.3
491
7.3
399
7.3
308
7.3
125
7.2
912
7.2
729
7.2
608
7.2
364
4.4
052
2.6
638
-0.0
000
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
N
N O
Cl
S
Me
O
197.7
579
153.2
533
152.9
487
147.7
702
145.2
115
139.0
582
137.4
742
137.0
477
134.4
585
130.1
329
129.2
191
129.0
972
128.7
317
127.0
258
126.9
649
126.0
815
114.5
365
77.5
865
77.1
600
76.7
335
41.4
284
29.8
225
26.8
373
(ppm)
0102030405060708090100110120130140150160170180190200
52
1H and
13C Spectra of compound 7e (300 MHz, CDCl3).
1.9
67
0
2.0
31
7
2.5
43
0
2.0
14
5
3.0
62
3
3.0
24
4
3.0
00
0
Inte
gra
l
7.5
43
97
.51
65
7.4
58
67
.43
13
7.3
97
87
.37
34
7.3
24
77
.30
03
7.2
82
17
.26
08
7.2
33
46
.89
85
6.8
68
0
3.8
08
5
2.7
64
3
2.2
22
4
-0.0
00
0
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5
N
N O
Cl
Me
Me
O
N
N O
Cl
Me
Me
O
159.4
066
155.8
426
153.7
103
145.6
988
144.7
545
138.1
443
131.1
077
130.9
249
130.4
071
129.8
588
129.4
932
126.1
729
122.1
824
117.0
953
114.3
233
77.5
865
77.1
600
76.7
335
55.3
799
22.7
249
20.3
489
(ppm)
102030405060708090100110120130140150160170180
53
1H and
13C Spectra of compound 7f (300 MHz, CDCl3).
N
N O
Cl
F
O
O
O
1.9
987
1.9
873
1.9
855
1.9
398
1.0
251
0.9
927
1.9
826
8.1
923
8.1
680
7.8
818
7.8
514
7.7
479
7.7
205
7.5
256
7.4
982
7.4
587
7.3
947
7.3
704
7.3
491
7.3
247
7.2
638
7.1
633
7.1
573
7.1
360
7.1
086
7.0
568
7.0
264
(ppm)
7.27.68.0
1.9
987
1.9
873
1.9
855
1.9
398
1.0
251
0.9
927
1.9
826
2.0
062
3.0
000
3.3
604
Inte
gra
l
8.1
923
8.1
680
7.8
818
7.8
514
7.7
479
7.7
205
7.5
256
7.4
982
7.4
587
7.3
947
7.3
704
7.3
491
7.3
247
7.2
638
7.1
633
7.1
573
7.1
360
7.1
086
7.0
568
7.0
264
4.4
691
4.4
447
4.4
204
4.3
991
3.8
998
1.4
582
1.4
339
1.4
095
0.0
000
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0
166.3
214
164.5
242
161.2
343
160.8
383
154.8
983
153.5
275
146.8
564
144.0
539
138.3
576
133.8
492
131.5
341
130.9
858
130.8
640
130.8
031
130.6
812
130.4
680
129.7
978
128.8
231
123.6
141
117.8
264
117.5
218
116.7
907
114.9
021
114.5
670
77.5
865
77.1
600
76.7
335
61.3
504
55.5
322
14.5
003
(ppm)
0102030405060708090100110120130140150160170180
N
N O
Cl
F
O
O
O
54
1H and
13C Spectra of compound 7g (300 MHz, CDCl3).
3.9
86
7
2.3
40
2
1.9
74
5
3.1
44
1
3.0
00
0
2.9
77
2
Inte
gra
l
7.4
86
07
.45
87
7.4
22
17
.39
47
7.3
67
37
.31
86
7.2
94
37
.26
99
7.2
57
77
.24
55
7.2
21
27
.16
03
7.1
35
9
2.7
64
3
2.3
41
1
2.2
25
4
(ppm)
2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
N
NO
Me
Me
Me
Cl
N
N O
Me
Me
Me
Cl
156.2
690
153.7
103
145.7
293
144.8
154
138.1
443
137.9
311
131.1
077
130.9
249
130.4
071
129.5
541
129.4
323
128.5
184
126.8
126
126.1
729
117.4
608
77.5
865
77.1
600
76.7
335
22.7
249
21.4
455
20.3
794
(ppm)
0102030405060708090100110120130140150160170180190
55
1H Spectra of compound 7h (300 MHz, CDCl3).
0.9
177
4.0
122
4.9
775
2.8
766
1.9
850
3.0
000
Inte
gra
l
7.7
357
7.7
296
7.6
200
7.5
926
7.5
256
7.4
982
7.3
978
7.3
734
7.3
491
7.3
308
7.3
247
7.3
095
7.2
851
7.2
608
7.2
303
7.2
151
7.1
877
5.3
002
4.4
052
2.3
929
(ppm)
2.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0
0.9
177
4.0
122
4.9
775
2.8
766
Inte
gra
l
7.7
357
7.7
296
7.6
200
7.5
926
7.5
256
7.4
982
7.3
978
7.3
734
7.3
491
7.3
308
7.3
247
7.3
095
7.2
851
7.2
608
7.2
303
7.2
151
7.1
877
(ppm)
7.07.27.47.67.8
N
N O
Cl
Me
Br
56
1H and
13C Spectra of compound 7i (300 MHz, CDCl3).
1.9
59
2
1.9
86
6
0.9
62
9
3.0
46
9
3.1
73
3
1.7
95
9
4.0
24
6
1.9
87
5
3.0
00
0
9.0
37
2
Inte
gra
l7
.50
43
7.4
98
27
.48
00
7.4
73
97
.44
65
7.4
40
47
.41
91
7.3
85
67
.35
82
7.2
42
57
.17
86
7.1
69
47
.15
73
7.1
36
07
.11
16
7.0
93
37
.06
59
7.0
35
57
.02
64
7.0
05
0
4.9
62
3
3.8
72
4
1.3
15
2
0.0
00
0
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0
1.9
59
2
1.9
86
6
0.9
62
9
3.0
46
9
3.1
73
3
1.7
95
9
4.0
24
6
Inte
gra
l
7.8
48
37
.81
79
7.6
87
07
.65
96
7.5
04
37
.49
82
7.4
80
07
.47
39
7.4
46
57
.44
04
7.4
19
17
.38
56
7.3
58
27
.24
25
7.1
78
67
.16
94
7.1
57
37
.13
60
7.1
11
67
.09
33
7.0
65
97
.03
55
7.0
26
47
.00
50
(ppm)
7.07.27.47.67.8
N
N O
Cl
O
O
207.0
487
160.4
118
156.9
087
156.6
651
153.5
275
153.3
447
145.0
287
143.1
705
140.1
548
136.6
822
132.1
434
131.3
818
130.2
852
129.3
104
128.2
747
127.6
655
127.3
609
127.0
867
126.8
430
125.6
246
121.4
818
119.1
058
113.6
531
113.0
439
112.7
697
77.5
865
77.1
600
76.7
335
70.3
366
55.4
408
34.9
706
31.1
933
30.9
801
(ppm)
020406080100120140160180200220
N
N O
Cl
O
O
57
1H and
13C Spectra of compound 7j (300 MHz, CDCl3).
N
N O
Cl
CN
Me3
.94
27
1.9
98
7
1.8
34
2
1.9
60
1
3.1
62
5
2.0
09
6
3.0
00
0
Inte
gra
l
7.7
50
97
.73
87
7.5
95
67
.56
82
7.3
97
87
.37
34
7.3
33
87
.30
95
7.2
85
17
.26
08
7.2
39
57
.21
21
4.4
11
3
2.4
11
1
(ppm)
2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
N
N O
Cl
CN
Me
157.2
134
153.4
056
148.0
139
145.1
505
141.6
474
138.6
013
137.3
828
134.8
545
132.7
831
130.2
852
129.8
892
129.1
886
128.7
317
128.0
006
126.9
649
125.6
855
118.7
707
114.0
491
111.9
777
77.5
865
77.1
600
76.7
335
41.3
980
21.6
892
(ppm)
0102030405060708090100110120130140150160
58
1H and
13C Spectra of compound 8a (300 MHz, CDCl3).
N
N O
O
O
Me
Me1.7
523
1.9
941
0.9
154
5.0
397
2.2
703
2.5
598
3.0
000
6.1
369
Inte
gra
l
7.9
307
7.9
002
7.4
466
7.4
162
7.2
609
7.1
148
7.0
539
7.0
448
7.0
174
6.9
626
6.8
347
6.8
043
3.8
908
3.8
178
2.2
621
(ppm)
2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0
N
N O
O
O
Me
Me
161.4
475
160.6
251
159.7
721
154.4
718
150.4
813
145.6
075
140.0
025
139.8
197
137.9
006
137.6
874
131.5
341
131.4
123
129.8
283
129.4
628
128.8
231
128.0
311
127.7
264
127.3
304
121.9
692
114.6
888
113.5
922
99.6
712
77.5
865
77.1
600
76.7
335
55.5
931
55.4
103
21.4
455
(ppm)
0102030405060708090100110120130140150160170
59
1H and
13C Spectra of compound 8b (300 MHz, CDCl3).
2.0
01
2
2.0
39
1
4.0
45
0
0.9
80
7
2.0
67
5
2.0
17
3
3.0
00
0
2.0
17
5
3.0
21
1
3.4
12
6
Inte
gra
l
7.9
06
27
.87
88
7.4
43
47
.41
30
7.3
64
37
.35
82
7.3
36
97
.33
08
7.2
60
87
.20
29
7.1
51
27
.12
38
6.8
40
66
.81
32
3.8
17
6
2.7
64
32
.73
99
2.7
15
62
.68
82
2.3
65
5
1.3
12
11
.28
78
1.2
63
4
-0.0
00
0
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
2.0
01
2
2.0
39
1
4.0
45
0
0.9
80
7
2.0
67
5
2.0
17
3
Inte
gra
l
7.9
06
27
.87
88
7.4
43
47
.41
30
7.3
64
37
.35
82
7.3
36
97
.33
08
7.2
60
87
.20
29
7.1
51
27
.12
38
6.8
40
6
6.8
13
2
(ppm)
6.87.07.27.47.67.88.0
N
N O
O
Me
N
NO
O
Me
16
0.7
16
51
59
.80
26
15
4.4
71
8
15
0.3
89
91
47
.10
01
14
6.0
03
5
13
9.9
11
11
38
.05
30
13
7.0
17
31
31
.56
46
13
1.4
42
81
29
.85
88
12
9.1
58
11
28
.73
17
12
6.7
82
11
25
.74
64
11
3.7
14
0
10
0.6
76
4
77
.55
60
77
.16
00
76
.73
35
55
.37
99
29
.03
05
21
.41
51
15
.50
55
(ppm)
102030405060708090100110120130140150160170180
60
1H and
13C Spectra of compound 8c (300 MHz, CDCl3)
N
NO
O
CF3
1.9
91
5
0.9
69
8
2.0
41
6
2.0
10
8
1.9
76
2
6.0
31
7
0.9
41
2
1.9
47
7
Inte
gra
l
8.0
76
58
.04
91
7.8
42
17
.77
82
7.7
50
87
.68
08
7.6
56
47
.61
07
7.5
86
47
.51
64
7.4
92
07
.46
77
7.4
49
47
.42
50
7.4
03
77
.37
63
7.3
15
47
.26
06
6.8
64
96
.83
75
(ppm)
6.87.07.27.47.67.88.08.2
1.9
91
5
0.9
69
8
2.0
41
6
2.0
10
8
1.9
76
2
6.0
31
7
0.9
41
2
1.9
47
7
3.0
00
0
Inte
gra
l
8.0
76
58
.04
91
7.8
42
17
.77
82
7.7
50
87
.68
08
7.6
56
47
.61
07
7.5
86
47
.51
64
7.4
92
07
.46
77
7.4
49
47
.42
50
7.4
03
77
.37
63
7.3
15
47
.26
06
6.8
64
96
.83
75
3.8
26
6
-0.0
00
1
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
N
N O
O
CF3
16
0.7
77
41
60
.19
86
14
8.7
14
51
46
.58
22
14
3.3
53
31
40
.61
17
14
0.0
93
91
33
.42
28
13
1.6
25
51
31
.22
95
13
0.8
03
11
30
.55
94
12
9.1
27
71
28
.76
21
12
8.1
52
91
27
.87
87
12
7.2
08
61
27
.02
58
12
6.9
64
91
26
.23
38
12
4.9
54
41
13
.98
82
10
1.2
55
2
77
.58
65
77
.16
00
76
.73
35
55
.47
13
(ppm)
102030405060708090100110120130140150160170180
61
1H and
13C Spectra of compound 8d (300 MHz, CDCl3).
5.11 4.033.94 3.002.32 2.031.99
0.0
0
1.5
7
2.4
4
3.6
9
3.9
0
3.9
5
4.0
7
4.1
2
6.8
9
6.9
2
7.0
8
7.1
0
7.1
6
7.2
6
7.3
1
7.3
4
7.3
5
7.3
7
7.5
2
7.5
4
7.8
6
7.8
9
7.9
3
7.9
6
N
N
O
CH3
5e
21
.60
41
.27
76
.64
77
.07
77
.49
10
0.4
6
12
5.2
6
12
6.0
8
12
6.2
3
12
6.6
3
12
7.6
9
12
8.1
8
12
8.4
3
12
8.9
4
12
9.8
3
13
1.9
3
13
3.7
3
13
6.2
2
13
9.9
7
14
0.7
9
14
8.4
4
15
0.4
8
15
4.7
5
16
0.5
9
N
N
O
CH3
5e
62
1H and
13C Spectra of compound 9a (300 MHz, CDCl3).
N
NO
O
O
1.9
344
1.9
660
5.0
626
6.0
000
0.9
811
2.0
305
2.1
178
6.5
241
Inte
gra
l
8.1
041
8.0
736
7.9
031
7.8
757
7.2
638
7.0
324
7.0
203
7.0
050
6.9
868
3.8
937
3.8
876
2.6
638
2.6
516
2.6
394
2.6
212
1.8
875
1.8
601
1.7
322
1.7
140
1.7
018
1.5
496
1.3
334
0.0
000
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
N
N O
O
O
16
1.4
78
01
61
.05
15
16
0.4
11
8
15
3.6
79
8
14
8.3
18
5
13
9.9
72
01
33
.91
02
13
1.1
07
71
29
.98
06
12
9.1
88
61
28
.73
17
12
7.3
00
0
12
1.5
12
2
11
4.5
67
01
14
.07
96
11
3.3
48
5
99
.15
34
79
.71
88
77
.58
65
77
.16
00
76
.73
35
55
.44
08
31
.98
53
29
.91
39
25
.89
30
24
.91
82
(ppm)
0102030405060708090100110120130140150160170180
63
1H and
13C Spectra of compound 9b (300 MHz, CDCl3).
N
NO
O
Me1.9
60
0
2.0
29
3
1.9
81
7
2.0
45
9
3.0
19
1
1.9
92
5
Inte
gra
l
8.1
61
98
.13
45
7.9
03
17
.87
57
7.4
43
47
.41
60
7.3
61
27
.33
38
7.2
60
87
.17
86
7.1
51
27
.06
90
7.0
41
6
(ppm)
7.27.68.0
1.9
60
0
2.0
29
3
1.9
81
7
2.0
45
9
3.0
19
1
1.9
92
5
3.0
00
0
2.0
15
9
2.9
86
5
3.0
80
7
Inte
gra
l
8.1
61
98
.13
45
7.9
03
17
.87
57
7.4
43
47
.41
60
7.3
61
27
.33
38
7.2
60
87
.17
86
7.1
51
27
.06
90
7.0
41
6
3.9
12
0
2.7
70
42
.74
30
2.7
18
62
.69
42
2.3
77
6
1.3
15
21
.29
08
1.2
63
4
-0.0
00
0
(ppm)
0.01.02.03.04.05.06.07.08.09.010.011.0
N
NO
O
Me
161.4
139
160.6
219
149.0
769
147.3
406
139.9
689
139.3
901
133.6
938
131.7
442
131.1
655
129.2
159
128.6
676
126.2
611
125.7
433
119.2
549
113.4
977
100.1
555
93.1
797
77.4
310
77.0
046
76.5
781
55.4
072
28.9
055
21.6
252
15.3
196
-0.0
026
(ppm)
020406080100120140160180200220
64
1H and
13C Spectra of compound 9c (300 MHz, CDCl3).
N
NO
O
1.9
349
2.0
448
2.0
615
2.1
092
4.0
768
4.2
675
1.2
107
2.0
711
Inte
gra
l
8.1
741
8.1
436
8.0
553
8.0
279
7.7
692
7.7
387
7.6
748
7.6
504
7.5
591
7.5
530
7.5
408
7.5
287
7.5
104
7.4
891
7.4
617
7.4
252
7.4
008
7.3
795
7.3
734
7.3
643
7.2
608
7.2
425
7.0
842
7.0
568
(ppm)
6.87.27.68.08.4
1.9
349
2.0
448
2.0
615
2.1
092
4.0
768
4.2
675
1.2
107
2.0
711
3.0
000
Inte
gra
l
8.1
741
8.1
436
8.0
553
8.0
279
7.7
692
7.7
387
7.6
748
7.6
504
7.5
591
7.5
530
7.5
408
7.5
287
7.5
104
7.4
891
7.4
617
7.4
252
7.4
008
7.3
795
7.3
734
7.3
643
7.2
608
7.2
425
7.0
842
7.0
568
3.9
181
(ppm)
2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
16
0.9
90
61
60
.83
83
15
4.1
36
71
49
.59
79
14
3.3
53
31
40
.03
30
13
9.9
41
61
33
.78
83
13
1.9
60
61
31
.35
14
12
9.7
97
81
29
.21
91
12
9.0
97
21
28
.57
94
12
8.1
52
91
27
.81
78
12
7.6
65
51
27
.17
81
12
6.2
33
81
22
.42
61
11
3.6
83
6
10
1.0
11
5
93
.06
10
88
.46
13
77
.58
65
77
.16
00
76
.73
35
55
.56
27
(ppm)
0102030405060708090100110120130140150160170180
N
NO
O
65
1H and
13C Spectra of compound 10a (300 MHz, CDCl3).
N
N O
Cl
S
S
1.1
595
1.1
714
1.2
993
1.6
618
7.2
797
2.0
000
Inte
gra
l
8.3
354
8.3
263
7.9
792
7.9
610
7.6
718
7.6
657
7.4
860
7.4
739
7.4
678
7.4
586
7.3
582
7.3
399
7.3
125
7.3
064
7.2
882
7.2
608
4.3
960
(ppm)
2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0
66
1H and
13C Spectra of compound 10b (300 MHz, CDCl3).
N
N O
Cl
S
Me
0.7
82
3
0.8
82
0
2.0
71
0
1.2
32
2
7.2
19
2
1.5
99
8
3.0
00
0
Inte
gra
l
8.3
32
47
.99
45
7.9
76
27
.54
39
7.5
16
57
.48
30
7.4
70
97
.46
48
7.4
55
67
.43
13
7.3
79
57
.35
52
7.3
33
97
.31
25
7.2
85
17
.27
30
7.2
36
47
.21
82
7.1
93
8
4.3
96
1
2.3
99
0
0.0
00
0
(ppm)
0.01.02.03.04.05.06.07.08.09.0
N
N O
Cl
S
Me
15
7.8
53
1
15
3.0
09
61
52
.76
59
14
7.9
53
01
45
.36
38
13
9.4
23
71
39
.14
96
13
8.4
48
91
37
.38
28
13
2.0
21
51
31
.83
88
13
0.5
28
91
29
.40
18
12
9.3
40
91
29
.21
90
12
8.7
31
71
26
.99
53
12
6.7
82
11
25
.71
60
11
9.5
62
7
98
.87
92
98
.30
04
77
.58
65
77
.16
00
76
.73
35
41
.33
70
21
.71
97
(ppm)
102030405060708090100110120130140150160
67
1H and
13C Spectra of compound 10c (300 MHz, CDCl3).
N
N O
Cl
O
F
1.8
96
9
1.9
78
7
1.0
56
1
0.9
97
0
2.0
02
2
3.0
00
0
1.9
60
0
2.1
51
5
3.0
99
7
4.2
24
1
3.4
81
4
Inte
gra
l8
.16
19
8.1
37
58
.12
23
7.8
63
57
.83
62
7.5
28
77
.50
74
7.5
01
37
.48
00
7.4
73
97
.45
26
7.2
63
87
.21
51
7.2
09
07
.18
77
7.1
81
67
.16
03
7.1
54
27
.04
77
7.0
17
2
5.3
00
2
3.8
93
7
2.6
60
82
.63
64
2.6
15
1
1.7
93
11
.76
88
1.7
20
11
.69
57
1.5
73
91
.54
65
1.3
70
01
.35
78
0.9
40
70
.91
94
0.8
95
0
0.0
00
0
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0
N
N O
Cl
O
F
164.5
546
161.2
952
160.8
383
158.9
801
152.9
792
147.0
696
144.1
148
139.0
277
131.5
341
130.5
898
128.7
621
122.2
129
117.6
131
113.8
054
113.2
571
102.3
214
77.5
560
77.1
600
76.7
335
69.1
790
55.5
322
31.4
979
28.9
087
28.4
517
22.6
945
20.3
489
14.1
957
(ppm)
102030405060708090100110120130140150160170
68
1H and
13C Spectra of compound 11a (300 MHz, CDCl3).
N
N O
O
0.9
699
1.9
399
3.9
500
1.0
169
0.9
742
Inte
gra
l
8.6
033
7.7
144
7.6
870
7.6
109
7.5
865
7.5
652
7.5
348
7.4
160
7.3
886
7.3
612
7.2
547
6.9
746
6.9
685
6.9
442
(ppm)
6.07.08.09.0
0.9
699
1.9
399
3.9
500
1.0
169
0.9
742
2.0
000
1.0
012
6.3
726
2.0
146
12.0
40
Inte
gra
l
8.6
033
7.7
144
7.6
870
7.6
109
7.5
865
7.5
652
7.5
348
7.4
160
7.3
886
7.3
612
7.2
547
6.9
746
6.9
685
6.9
442
4.1
555
4.1
342
4.1
099
4.0
855
3.6
776
3.6
502
3.6
228
3.5
954
3.5
649
2.1
128
2.0
945
2.0
702
2.0
458
1.9
971
1.9
788
1.9
636
1.7
475
1.7
383
1.7
231
1.4
765
1.4
552
1.4
308
1.3
943
-0.0
000
(ppm)
0.01.02.03.04.05.06.07.08.09.010.0
163.7
931
159.5
589
154.2
586
150.6
641
149.6
893
140.8
250
138.9
668
134.6
108
130.0
111
129.0
363
127.4
218
125.8
378
119.5
932
116.0
901
114.9
325
113.6
836
77.5
865
77.1
600
76.7
335
63.7
264
37.8
339
34.8
182
32.5
031
31.4
979
26.5
022
14.9
877
(ppm)
020406080100120140160180200220
N
N O
O
69
1H and
13C Spectra of compound 11b (300 MHz, CDCl3).
N
N OS
Me
O
1.9
55
5
2.8
76
0
4.0
65
2
1.9
71
0
5.6
64
3
2.0
16
2
3.0
00
0
9.3
77
4
Inte
gra
l
8.0
52
38
.02
49
7.8
42
27
.83
01
7.8
02
7
7.4
43
47
.43
43
7.3
15
67
.24
86
7.2
39
57
.21
51
7.1
93
87
.17
25
7.1
29
97
.10
55
4.3
35
2
2.6
33
4
1.3
60
8
-0.0
00
0
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.5
N
N OS
Me
O
197.8
493
153.5
884
152.2
481
151.8
826
151.6
693
148.0
139
139.4
542
136.6
822
136.2
252
135.3
419
130.5
594
130.2
547
129.3
104
129.0
058
128.9
144
128.5
184
126.7
517
126.4
166
126.1
729
125.4
113
115.0
848
77.5
865
77.1
600
76.7
335
41.2
761
34.8
182
31.5
284
31.4
674
26.8
068
(ppm)
0102030405060708090100110120130140150160170180190200
70
1H and
13C Spectra of compound 11c (300 MHz, CDCl3).
N
N OMe
Me
O
F
10
.65
2
2.1
52
7
2.9
41
9
3.0
41
4
3.0
69
2
Inte
gra
l
7.6
17
07
.58
65
7.5
56
17
.55
00
7.5
31
77
.52
56
7.5
01
37
.48
91
7.4
64
77
.43
73
7.4
19
17
.39
47
7.3
70
47
.33
38
7.3
15
67
.29
12
7.2
60
87
.23
34
7.2
24
27
.19
07
7.1
63
36
.85
89
6.8
31
5
3.7
71
9
2.6
09
0
2.2
68
0
(ppm)
2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0
N
N OMe
Me
O
F
16
1.7
21
71
59
.16
29
15
8.4
31
81
54
.95
92
15
4.4
10
91
46
.97
82
14
6.1
86
21
38
.17
48
13
2.0
52
01
31
.04
68
13
0.9
55
41
30
.65
07
13
0.5
28
91
30
.19
38
12
9.9
50
11
27
.69
60
12
7.4
82
71
26
.14
24
12
4.4
67
01
22
.79
16
11
7.3
69
41
15
.99
87
11
5.6
94
11
14
.20
14
77
.58
65
77
.16
00
76
.73
35
55
.28
85
22
.29
85
22
.23
75
20
.37
94
(ppm)
0102030405060708090100110120130140150160170180
71
1H and
13C Spectra of compound 11d (300 MHz, CDCl3).
N
NO
S
O
Me
Me
2.0
565
2.9
644
4.1
142
8.8
873
1.9
985
3.0
000
3.1
081
Inte
gra
l
8.0
980
8.0
706
7.7
966
7.7
692
7.5
043
7.4
769
7.4
465
7.3
308
7.3
217
7.2
943
7.2
729
7.2
608
7.2
090
7.1
816
4.5
422
2.6
668
2.3
929
-0.0
000
(ppm)
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0
N
NO
S
O
Me
Me
197.8
493
152.9
792
152.8
878
152.4
309
139.7
588
139.3
323
138.5
403
136.9
563
136.1
034
134.8
849
131.9
606
130.3
461
130.2
548
129.4
018
129.2
191
129.0
667
128.7
317
126.9
040
126.8
126
126.6
603
126.0
815
119.1
058
114.7
802
94.8
583
86.5
117
77.5
865
77.1
600
76.7
335
41.9
463
26.8
677
21.7
502
(ppm)
102030405060708090100110120130140150160170180190200
72
1H and
13C Spectra of compound 12a (300 MHz, CDCl3).
1.9
58
8
1.9
84
9
4.0
24
8
3.0
00
0
0.9
88
0
6.7
26
6
Inte
gra
l
7.8
60
77
.84
24
7.8
30
27
.81
50
7.5
89
77
.57
15
7.5
59
37
.54
41
7.2
60
97
.20
61
7.1
87
97
.17
87
7.1
60
57
.14
83
7.1
33
1
2.6
45
7
2.3
74
82
.35
65
2.3
41
32
.32
91
1.3
61
01
.35
19
1.3
45
81
.33
66
1.2
57
51
.18
44
1.1
75
31
.15
70
1.1
47
9
(ppm)
1.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0
N
N OMe
F
F
N
N OMe
F
F
16
4.5
54
61
63
.91
49
16
1.2
64
81
60
.62
51
15
9.8
63
5
15
2.8
26
9
14
9.5
97
9
14
3.9
93
01
38
.66
22
13
5.6
16
01
31
.44
28
13
1.3
51
41
30
.77
26
13
0.6
81
2
12
6.5
38
4
11
6.0
29
11
15
.75
50
11
5.5
11
31
15
.23
71
11
5.1
45
7
77
.58
65
77
.16
00
76
.73
35
23
.30
37
9.5
04
68
.86
49
(ppm)
102030405060708090100110120130140150160170180