Copper accelerated one-pot sequential tandem synthesis of tetrahydropurinoisoquinoline derivatives

Article abstract of DOI:10.3987/COM-17-13694

Copper catalyzed efficient and operationally simple tandem synthesis of purino[8,9-a]isoquinolinedione from 5,6-diamino-1,3-dimethyluracil and in situ generated alkenyl aldehyde has been described. In this cascade reaction C-C and C-N bonds are formed through Sonogashira coupling, 5-endo cyclization, and 6-endo cyclization in a same reaction vessel.

Full text of DOI:10.3987/COM-17-13694

Supporting information
EXPERIMENTAL
Melting points were determined in an open capillary and are uncorrected. IR spectra were
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recorded on a Perkin-Elmer spectrum II spectrometer on KBr disks. H and 13C NMR spectra
were recorded at 300 and 75 MHz respectively in CDCl3 (chemical shift in δ) with TMS as
internal standard. Mass spectra were recorded on a TOF MASS ES+ instrument respectively.
Silica gel [(60-120 mesh), spectrochem, India] was used for chromatographic separation. Silica
gel G [E-Merck (India)] was used for TLC. Petroleum ether refers to the fraction boiling between
60 °C-80 °C.
GENERAL PROCEDURE
A mixture of 2-bromobenzaldehyde (1mmol), CuI (2 mol%) and Pd(PPh3)2Cl2 (2 mol%) in DMF
(5 mL) was degassed for 5 min under N2 atmosphere. Then the corresponding alkyne (1.5 equiv)
along with 2 mL of triethylamine was added to this mixture and allowed to stir at room
temperature under N2 atmosphere for 2 h. After completion of the reaction indicated by TLC,
5,6-diamino-1,3-dimetyluracil hydrate (1 mmol) and additional (2 mol%) of CuI was added to
this mixture in the same reaction vessel. Then the mixture was allowed to reflux for 3-4 h at
120 °C in open air and progress of the reaction was monitored by TLC. After completion of the
reaction, solvent was removed under reduced pressure. The organic layer extracted with EtOAc
(3X10 mL) and washed with brine water, dried over Na2SO4. The organic extract was
concentrated under reduced pressure. The crude product was purified by column chromatography
with EtOAc: petroleum ether (3:7) as eluent to get the desired compound.
3a. Yield: 85%, mp 180 °C, IR (KBr): 1663, 1703 cm-1, 1H NMR (CDCl3, 300 MHz) δ: 3.26 (s,
3H), 3.79 (s, 3H), 7.19 (s, 1H), 7.46-7.56 (m, 5H), 7.68-7.73 (m, 2H), 7.78-7.81 ( m, 1H), 8.72
(t,1H, J = 9Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ = 28.62, 30.13, 104.83, 116.24, 121.16,
124.78, 126.81, 127.44, 128.15, 128.24, 129.21, 130.57, 131.54, 136.58, 137.73, 147.92, 151.33,
151.82. MS m/z = 379 (M+ + Na), Anal. Calcd for C21H16N4O2: C, 70.77; H, 4.53; N, 15.72.
Found: C, 70.78; H, 4.51; N, 15.80.
3b. Yield: 89%, mp 258 °C, IR (KBr): 1665, 1701 cm-1, 1H NMR (CDCl3, 300 MHz) δ: 2.47 (s,
3H), 3.27 (s, 3H), 3.78 (s, 3H), 7.15 (s, 1H), 7.27 (d, J = 8.1 Hz, 2H ), 7.46 (d, J = 8.1 Hz, 2H),
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7.66-7.73 (m, 2H), 7.77-7.94 (m, 1H), 8.71 (t, J = 9 Hz, 1H); C NMR (CDCl3, 75 MHz) δ:

21.65, 28.64, 30.12, 116.18, 121.08, 124.77, 126.76, 127.15, 128.09, 128.89, 130.52, 131.66,
133.85, 137.92, 139.05, 148.02, 151.36, 151.88, 153.16. MS m/z = 393 (M++ Na), Anal. Calcd
for C22H18N4O2: C, 71.34; H, 4.90; N, 15.13. Found: C, 71.33; H, 4.82; N, 15.22.
3c. Yield: 86%, mp 276 °C, IR (KBr): 1667, 1702 cm-1, 1H NMR (CDCl3, 300 MHz) δ: 1.34 (t, J
= 7.5 Hz, 3H), 2.75 (q, J = 7.5 Hz, 2H), 3.26 (s, 3H), 3.78 (s, 3H), 7.16 (s, 1H), 7.29 (d, J = 7.8
Hz, 2H), 7.45 (d, J = 7.8 Hz, 2H), 7.66-7.73 (m, 2H), 7.76- 7.79 (m, 1H), 8.72 (t, J = 9 Hz, 1H);
13CNMR (CDCl3,75 MHz) δ: 15.27, 28.80, 28.81, 30.11, 116.19, 121.10, 124.76, 126.76, 127.22,
127.63, 128.08, 130.51, 131.67, 137.96, 145.27, 148.02, 151.36, 151.90. MS m/z = 407 (M++
Na), Anal. Calcd for C23H20N4O2: C, 71.86; H, 5.25; N, 14.57. Found: C, 71.89; H, 5.16; N,
14.65.
3d. Yield: 90%, mp 252 °C, IR (KBr): 1666, 1702 cm-1, 1H NMR (CDCl3, 300 MHz) δ: 1.41 (s,
9H), 3.25 (s, 3H), 3.79 (s, 3H), 7.48 (s, 4H), 7.17 (s, 1H), 7.68-7.71 (m, 2H), 7.76-7.79 (m, 1H),
8.72 (t, J = 9 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ: 28.46, 30.07, 31.30, 34.81, 104.88, 116.12,
121.08, 124.71, 125.0, 126.73, 126.96, 128.03, 130.45, 131.63, 133.68, 137.91, 147.94, 151.28,
151.90, 152.13, 152.97. MS m/z = 435 (M++ Na), Anal. Calcd for C25H24N4O2: C, 72.80; H,
5.86; N, 13.58. Found: 72.77; H, 5.81; N, 13.61.
3e. Yield: 95%, mp 120 °C, IR (KBr): 1710, 1725 cm-1, 1H NMR (CDCl3 , 300 MHz) δ: 0.85 ( t,
J = 6.9 Hz, 3H), 1.25 (m, 4H), 1.40-1.47 (m, 2H), 1.62-1.78 (m, 2H), 3.49 (s, 3H), 3.68 (t, J =
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7.2 Hz, 2H), 3.76 (s, 3H), 7.01 (s, 1H), 7.58-7.71 (m, 3H), 8.62 (d, J = 7.8 Hz, 1H); C NMR
(CDCl3, 75 MHz): δ = 14.16, 22.65, 28.65, 29.01, 29.13, 30.23, 31.82, 34.78, 105.34, 113.0,
120.87, 124.96, 125.92, 130.50, 131.81, 140.44, 148.20, 151.46, 151.64, 154.15. MS m/z = 387
(M+ + Na), Anal. Calcd for C21H24N4O2: C, 69.21; H, 6.64; N, 15.37. Found: C, 69.17; H, 6.55;
N, 15.45.
3f. Yield: 92%, mp 182 °C, IR (KBr): 1648, 1691cm-1, 1H NMR (CDCl3, 300 MHz) δ: 1.00 (t, J
= 7.2 Hz, 3H), 1.66 (q, J = 7.5 Hz, 2H), 3.49 (s, 3H), 3.63 (t, J = 7.5 Hz, 2H), 3.75 (s, 3H), 7.00
(s, 1H) 7.57-7.70 (m, 3H), 8.61 (d, J = 7.8 Hz, 1H); 13C NMR (CDCl3,75 MHz) δ: 14.06, 22.59,
25.23, 29.18, 30.11, 31.53, 115.51, 123.47, 124.27, 132.93, 133.85, 150.08, 150.89, 153.79,
155.87, 159.68, 165.20. MS m/z = 345 (M++ Na), Anal. Calcd for C18H18N4O2: C, 67.07; H,
5.63; N, 17.38. Found: C, 67.01; H, 5.72; N, 17.42.
3g. Yield : 94%, mp 234 °C, IR (KBr): 1638, 1701 cm-1, 1H NMR (CDCl3 , 300 MHz) δ: 3.28 (s,
3H), 3.79 (s, 3H), 3.90 (s, 3H), 7.01 (d, J = 8.7 Hz, 2H), 7.14 (s, 1H), 7.50 (d, 2H, J = 8.7 Hz),

7.65-7.79 (m, 3H), 8.73 (d, 1H, J = 9.3 Hz); 13C NMR (CDCl3, 75 MHz) δ: 22.62, 28.61, 30.09,
31.55, 55.24, 104.88, 113.50, 115.98, 121.01, 124.76, 126.67, 127.99, 128.68, 129.22, 130.50,
131.70, 137.73, 148.07, 151.38, 151.85, 153.13, 160.19. MS m/z = 387 (M++ H), Anal. Calcd for
C22H18N4O3: C, 68.38; H, 4.70; N, 14.50 Found: C, 68.32; H, 4.78; N, 14.62.
4a. Yield: 47%, mp 278 °C, IR (KBr): 1708, 1649 cm-1, 1H NMR (CDCl3, 300 MHz) δ: 3.59 (s,
3H), 3.80 (s, 3H), 7.23 (s, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.26 (m, 3H),
7.80 (m, 2H), 7.92 (d, J = 8.4 Hz, 1H), 9.92 (s, 1H), MS m/z = 356 (M+), Anal. Calcd for
C21H16N4O2: C, 70.77; H, 4.53; N, 15.72. Found: C, 70.65; H, 4.61; N, 15.63.
4b. Yield: 45%, mp 274 °C, IR (KBr): 1651, 1648 cm-1, 1H NMR (CDCl3, 400 MHz) δ: 2.53 (s,
3H), 3.57 (s, 3H), 3.78 (s, 3H), 7.23 (m, 1H), 7.41 (m, 3H), 7.60 (d, J = 8.8 Hz, 1H), 7.71 (d, J =
8 Hz, 2H), 7.89 (d, J = 8.4 Hz, 1H), 9.87 (s, 1H), MS m/z = 370 (M+), Anal. Calcd for
C22H18N4O2: C, 71.34; H, 4.90; N, 15.13. Found: C, 71.26; H, 4.85; N, 15.26.
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4c. Yield: 60%, mp 280°C, IR (KBr): 1699, 1641 cm-1, H NMR (CDCl3, 400 MHz) δ: 1.14 (s,
9H), 3.58 (s, 3H), 3.80 (s, 3H), 7.27 (m, 1H), 7.42 (m, 1H), 7.61 (m, 3H), 7.77 (q, 2H), 7.91 (d, J
= 8 Hz, 1H), 9.91 (s, 1H), MS m/z = 412 (M+), Anal. Calcd for C25H24N4O2: C, 72.80; H, 5.86;
N, 13.58. Found: C, 72.89; H, 5.81; N, 13.65.

1H NMR Data: Compound 3a

Compound 3b:

Compound 3c:

Compound 3d

Compound 3e:

Compound 3f:

Compound 3g:

Compound 4a:

Compound 4b:

Compound 4c:

13C NMR data: Compound 3a

Compound 3b:

Compound 3c:

Compound 3d:

Compound 3e:

Compound 3f:

Compound 3g: