1390
F. Hernández et al.
LETTER
169.4 (C-5), 168.3 (N-CO-Ar), 167.0 (C-2), 136.4 (C-2’),
135.9 (C-7a”), 131.6 (C-4’), 128.5 (C-6’), 128.3 (C-1’), 127.0
(C-3a”), 125.3 (C-2”), 125.0 (C-5’), 122.6 (C-6”), 120.1 (C-
5”), 118.9 (C-4”), 118.3 (C-3’), 111.2 (C-7”), 108.6 (C-3”),
58.7 (C-6), 45.0 (C-3), 28.5 (CH2-Ar). Anal. Calcd for
C20H16N6O3: C, 61.85; H, 4.15; N, 21.64. Found: C, 61.78; H,
4.21; N, 21.56.
(14) Aza-Wittig Cyclizations. General Procedure. A solution of
0.172 mmol of the acylated 2,5-piperazinedione (12 or 17a-d)
and Bu3P (0.172 mmol) in dry toluene (15 mL) was stirred at
room temperature for 16 h. After concentration, the residue
was purified by chromatography (25 g silica gel (230-400
mesh, Merck)) eluting with ethyl acetate (12 and 17a), ethyl
acetate/CH2Cl2 9/1 (17b), ethyl acetate/CH2Cl2 8/2 (17c
and17d).
(3R)-1-(o-Azidobenzoyl)-3-(3-indolylmethyl)-2,5-
piperazinedione (19a).: Mp 109-110 ºC; [ ]D25 = +13 (c 0.15,
CHCl3); max (NaCl) 3370, 1683 cm-1; H (250 MHz, CDCl3)
8.26 (br s, 1H, NH), 7.51 (dt, 1H, J = 1.6 and 8.0 Hz, H-4’),
7.49 (d, 1H, J = 7.7 Hz, H-4”), 7.38 (d, 1H, J = 7.9 Hz, H-7”),
7.32 (dd, 1H, J = 1.6 and 7.6 Hz, H-6’), 7.18 (m, 4H, H-
5”,6”,3’,5’), 7.07 (d, 1H, J = 2.3 Hz, H-2”), 6.39 (br s, 1H, H-
4), 4.39 (ddd, 1H, J = 2.4, 3.8 and 7.9 Hz, H-3), 4.27 (d, 1H,
J = 17.9 Hz, H-6), 3.78 (d, 1H, J = 17.9 Hz, H-6), 3.40 (dd,
1H, J = 3.8 and 14.7 Hz, CH2-Ar), 3.21 (dd, 1H, J = 7.9 and
14.7 Hz, CH2-Ar); C (62.5 MHz, CDCl3) 168.2, 168.0, 165.8,
136.5, 136.3, 131.7, 128.8, 128.2, 126.3, 125.0, 123.8, 122.9,
120.2, 118.3, 118.1, 111.5, 108.6, 56.3, 46.2, 29.6. Anal.
Calcd for C20H16N6O3: C, 61.85; H, 4.15; N, 21.64. Found: C,
61.36; H, 4.53; N, 21.12.
(4S)-4-Benzyl-2,4-dihydro-1H-pyrazino[2,1-
b]quinazoline-3,6-dione (15): Mp 172 ºC; [ ]D25 = +411 (c
0.54, CHCl3); max (NaCl) 2922, 2844, 2360, 2320, 1682,
1603, 1471, 1409, 1330, 1108 cm-1; H (250 MHz, CDCl3)
8.33 (dd, 1H, J = 1.3 and 8.0 Hz, H-7), 7.78 (ddd, 1H, J = 1.3,
7.2 and 8.4 Hz, H-9), 7.59 (d, 1H, J = 4.4 Hz, H-2), 7.57 (dd,
1H, J = 1.0 and 8.4 Hz, H-10), 7.52 (ddd, 1H, J = 1.0, 7.2 and
8.0 Hz, H-8), 7.21 (m, 3H, Ph), 6.95 (m, 2H, Ph), 5.59 (“t”,
1H, J = 4.3 Hz, H-4), 3.91 (dd, 1H, J = 4.4 and 16.9 Hz, H-1),
3.47 (dd, 1H, J = 4.3 and 14.4 Hz, CH2-Ar), 3.40 (dd, 1H,
J = 4.3 and 14.4 Hz, CH2-Ar), 2.76 (d, 1H, J = 16.9 Hz, H-1);
C (62.5 MHz, CDCl3) 168.5 (C-3), 160.4 (C-6), 148.0 (C-
11a), 147.0 (C-10a), 134.9 (C-9), 134.7 (C-1’), 129.7 (C-2’
and 6’), 128.9 (C-3’ and 5’), 127.9 (C-4’), 127.1 (C-8), 126.9
(C-7), 126.8 (C-10), 120.0 (C-6a), 56.9 (C-4), 44.4 (C-1), 37.0
(CH2-Ph). Anal. Calcd for C18H15N3O2: C, 70.81; H, 4.95; N,
13.76. Found: C, 71.20; H, 5.22; N, 14.08.
(3S,6R)-1-(o-Azidobenzoyl)-3-methyl-6-(3-indolylmethyl)-
2,5-piperazinedione (18b). Mp 89-91 ºC; [ ]D25 = -120 (c
0.34, CHCl3); max (NaCl) 3336, 1682 cm-1; H (250 MHz,
CDCl3) 8.36 (br s, 1H, NH), 7.66 (d, 1H, J = 7.7 Hz, H-4”),
7.44 (dt, 1H, J = 1.6 and 7.7 Hz, H-4’), 7.36 (dd, 1H, J = 1.4
and 7.7 Hz, H-6’), 7.30 (d, 1H, J = 7.9 Hz, H-7”), 7.19 (m, 2H,
H-6”, 5’), 7.12 (d, 1H, J = 7.5 Hz, H-3’), 7.08 (dt, 1H, J = 1.1
and 7.1 Hz, H-5”), 6.93 (d, 1H, J = 2.3 Hz, H-2”), 6.23 (br s,
1H, H-4), 5.22 (dd, 1H, J = 3.1 and 5.3 Hz, H-6), 3.70 (dd, 1H,
J = 3.1 and 14.9 Hz, CH2-Ar), 3.57 (dd, 1H, J = 5.3 and 14.9
Hz, CH2-Ar), 2.50 (q, 1H, J = 7.0 Hz, H-3), 1.06 (d, 3H,
J = 7.0 Hz, CH3); C (62.5 MHz, CDCl3) 170.3 (C-2), 169.4
(C-5), 168.6 (N-CO-Ar), 136.1 (C-2’), 135.9 (C-7a”), 131.5
(C-4’), 128.5 (C-6’), 127.1 (C-1’ and C-3a”), 125.1 (C-2”),
125.0 (C-5’), 122.5 (C-6”), 120.0 (C-5”), 118.9 (C-4”), 118.2
(C-3’), 111.2 (C-7”), 108.7 (C-3”), 59.3 (C-6), 50.3 (C-3),
28.3 (CH2-Ar), 18.4 (CH3). Anal. Calcd for C21H18N6O3: C,
62.68; H, 4.51; N, 20.88. Found: C, 62.53; H, 4.47; N, 20.76.
(3R,6S)-1-(o-Azidobenzoyl)-3-(3-indolylmethyl)-6-methyl-
2,5-piperazinedione (19b). Mp 74-76 ºC; [ ]D25 = +7 (c 0.13,
CHCl3); max (NaCl) 3364, 3016, 1698, 1689 cm-1; H (250
MHz, CDCl3) 8.51 (br s, 1H, NH), 7.53 (d, 1H, J = 7.7 Hz, H-
4”), 7.49 (dt, 1H, J = 1.6 and 7.9 Hz, H-4’), 7.38 (d, 1H,
J = 8.2 Hz, H-7”), 7.34 (dd, 1H, J = 1.6 and 7.9 Hz, H-6’),
7.22 (m, 2H, H-6”, 5’), 7.16 (d, 1H, J = 8.0 Hz, H-3’), 7.11 (d,
1H, J = 1.9 Hz, H-2”), 7.11 (dt, 1H, J = 1.1 and 7.0 Hz, H-5”),
6.35 (br s, 1H, H-4), 5.02 (dq, 1H, J = 0.8 and 7.2 Hz, H-6),
4.37 (dd, 1H, J = 3.5 and 10.2 Hz, H-3), 3.69 (dd, 1H, J = 3.5
and 14.8 Hz, CH2-Ar), 2.99 (dd, 1H, J = 10.2 and 14.8 Hz,
CH2-Ar), 1.58 (d, 3H, J = 7.2 Hz, CH3); C (62.5 MHz,
CDCl3) 169.4 (C-5), 168.5 (C-2), 168.2 (N-CO-Ar), 136.5 (C-
7a”), 136.3 (C-2’), 131.7 (C-4’), 128.8 (C-6’), 128.3 (C-1’),
126.4 (C-3a”), 125.0 (C-5’), 123.8 (C-2”), 122.7 (C-6”), 120.0
(C-5”), 118.3 (C-3’), 118.2 (C-4”), 111.6 (C-7”), 108.6 (C-
3”), 54.3 (C-3), 54.1 (C-6), 27.8 (CH2-Ar), 18.0 (CH3). Anal.
Calcd for C21H18N6O3: C, 62.68; H, 4.51; N, 20.88. Found: C,
62.75; H, 4.36; N, 21.04.
(1R,4S)-1-(3-Indolylmethyl)-4-methyl-2,4-dihydro-1H-
pyrazino[2,1-b]quinazoline-3,6-dione (21b). Mp 109-111
ºC; [ ]D25 = +31 (c 0.16, CHCl3); max (NaCl) 3282, 1684
cm-1; H (250 MHz, CDCl3/CD3OD) 8.17 (dd, 1H, J = 1.4
and 8.1 Hz, H-7), 7.74 (ddd, 1H, J = 1.4, 6.9 and 8.2 Hz, H-
9), 7.69 (dd, 1H, J = 1.1 and 8.2 Hz, H-10), 7.52 (d, 1H,
J = 8.0 Hz, H-4’), 7.45 (ddd, 1H, J = 1.1, 6.9 and 8.1 Hz, H-
8), 7.34 (d, 1H, J = 8.0 Hz, H-7’), 7.12 (dt, 1H, J = 1.0 and 8.0
Hz, H-6’), 7.11 (s, 1H, H-2’), 7.00 (dt, 1H, J = 1.0 and 8.0 Hz,
H-5’), 5.24 (q, 1H, J = 7.2 Hz, H-4), 4.82 (dd, 1H, J = 3.5 and
10.0 Hz, H-1), 4.11 (dd, 1H, J = 3.5 and 14.9 Hz, CH2-Ar),
3.10 (dd, 1H, J = 10.0 and 14.9 Hz, CH2-Ar), 1.47 (d, 3H,
J = 7.2 Hz, CH3); C (62.5 MHz, CDCl3) 169.0, 160.5, 149.8,
146.8, 136.7, 134.8, 127.3, 126.5, 124.0, 122.2, 120.2, 119.4,
118.0, 111.6, 108.2, 52.4, 52.1, 28.2, 16.7. Anal. Calcd for
C21H18N4O2: C, 70.38; H, 5.06; N, 15.63. Found: C, 69.95; H,
5.38; N, 15.89.
(15) In this case (17d), the isopropyl and the indolylmethyl chains,
both force the TMS groups to hinder their neighbouring
nitrogen.
(16) The enantiomeric purity was measured by chiral HPLC using
a Chiracel OD column (26 cm 0.25 mm), UV-detection at
254 nm, employing hexane/2-propanol 9/1 at 1 mL/min.
Retention times: (±)-15 = 19 and 20.5 min; (+)-15 = 20.5 min;
(±)-2 = 24.2 and 68.2 min; (-)-2 = 24.2 min; (-)-1 = 35.3 min;
(-)-3 = 41 min; (-)-4 = 10.8 min. Optical rotation data: (-)-1
[ ]D25 = -541 (c, 0.24 CHCl3); (-)-2 [ ]D25 = -471 (c, 0.47
CHCl3); (-)3 [ ]D25 = -411 (c, 0.37 CHCl3); {lit:7b (-)-1
[ ]D25 = -522 (c, 0.24 CHCl3); (-)-2 [ ]D25 = -516 (c, 0.74
CHCl3); (-)3 [ ]D25 = -463 (c, 0.62 CHCl3)}. In case of 2 and
3 the discrepancy of the rotation values compared to literature
is due to the small mass of the compounds and trace
impurities/solvent, since no peak of the other isomer was
detected at HPLC.
Article Identifier:
1437-2096,E;2001,0,09,1387,1390,ftx,en;G08701ST.pdf
Synlett 2001, No. 9, 1387–1390 ISSN 0936-5214 © Thieme Stuttgart · New York