LETTER
Michael Addition of Quinones to Nitroolefins
1401
58, 3015. (d) Barcia, J. C.; Cruces, J.; Estévez, J. C.;
Estévez, R. J.; Castedo, L. Tetrahedron Lett. 2002, 43,
5141. (e) Fernández, M.; Barcia, C.; Estévez, J. C.; Estévez,
R. J.; Castedo, L. Synlett 2004, 267. (f) Otero, J. M.; Barcia,
J. C.; Estévez, J. C.; Estévez, R. J. Tetrahedron: Asymmetry
2005, 16, 11.
of an enamine, followed by addition of the amino group to
the quinone system and oxidation. The validity of this ap-
proach was established from a similar transformation of
10b into 15b, via compounds 11b and 12b, 13b and 14b.
The work here reported clearly constitutes novel chemis-
try in the indole field, which should have great scope.
Routes in Scheme 1 and Scheme 2 could be amenable to
combinatorial chemistry protocols. Accordingly, the ste-
reoselective addition of quinones 4 to a panel of nitrocy-
clohexanes 5 derived from the plethora of aldohexoses
together with the controlled regiochemical heteroannula-
tion of compounds 7 should provide panels of novel high-
ly functionalized D-ring indolequinones 8 and 9 of
potential biological interest, on account of their dual char-
acter as quinones and sugar mimics. On the other hand,
extension of the route in Scheme 2 to the appropriate pan-
el of nitrocyclohexenes should provide a divergent access
to the novel highly functionalized N-cyano indoloquino-
nes 2a–f and to kinamycins 3a–f by convenient heteroan-
nulation or carboannulation of the common intermediates
14. In particular, the synthesis of compounds 2a–f for
chemical and biological studies is of great interest be-
cause the structural similarity of these compounds with in-
doloquinones 1 and with kinamycins strongly suggests
that they should show similar biological properties to
those of the two latter compounds.
(8) Corey, E. J.; Estreicher, H. J. Am. Chem. Soc. 1978, 100,
6294.
(9) All new compounds gave satisfactory analytical and
spectroscopic data. Selected physical and spectroscopic data
follow.
Compound 6: mp 181–183 °C (MeOH). IR (NaCl): n = 1673
(C=O), 1644 (C=O), 1540 (NO2), 1367 (NO2) cm–1. 1H
NMR (CDCl3): d = 1.38–1.64 (m, 2 H, CH2), 1.73–2.08 (m,
5 H, 2 × CH2 and CHH), 2.33–2.51 (m, 1 H, CHH), 3.71 (td,
J = 11.6, 4.0 Hz, 1 H, CH), 5.40 (td, J = 11.6, 4.0 Hz, 1 H,
CHNO2), 7.67 (td, J = 7.6, 1.5 Hz, 1 H, ArH), 7.76 (td,
J = 7.6, 1.5 Hz, 1 H, ArH), 8.05 (dd, J = 7.6, 1.5 Hz, 1 H,
ArH), 8.11 (dd, J = 7.6, 1.5 Hz, 1 H, ArH) ppm. 13C NMR
(CDCl3): d = 24.2 (CH2), 25.0 (CH2), 28.4 (CH2), 32.1
(CH2), 38.5 (CH), 85.9 (CHNO2), 121.6 (C), 126.2 (CH),
127.0 (CH), 129.0 (C), 132.7 (C), 133.1 (CH), 135.2 (CH),
153.4 (C), 181.0 (C=O), 183.7 (C=O) ppm. MS–FAB: m/z
(%) = 302 (12) [MH+], 137 (100).
Compound 8: IR (NaCl): n = 2935 (NH), 1681 (C=O) cm–1.
1H NMR (DMSO): d = 1.16–2.27 (m, 8 H, 4 × CH2), 2.50–
2.65 (m, 1 H, CH), 3.43–3.59 (m, 1 H, CH), 7.57–7.94 (m, 4
H, 4 × ArH), 9.21 (br s, 1 H, NH) ppm. 13C NMR (DMSO):
d = 24.3 (CH2), 25.3 (CH2), 28.4 (CH2), 30.0 (CH2), 47.5
(CH), 67.7 (CH), 115.7 (C), 124.2 (CH), 127.4 (C), 127.7
(CH), 131.5 (C), 131.6 (CH), 133.9 (CH), 161.1 (C), 171.2
(C=O), 183.6 (C=O) ppm. MS: m/z (%) = 253 (63) [M+], 195
(100).
Work on all these aspects is currently in progress.7f
Compound 9: IR (NaCl): n = 2931 (NH), 1670 (C=O), 1628
(C=O) cm–1. 1H NMR (acetone): d = 1.28–1.92 (m, 6 H,
3 × CH2), 2.20–2.31 (m, 1 H, CH), 2.56–2.74 (m, 2 H, CH2),
3.19–3.33 (m, 1 H, CH), 6.65 (br s, 1 H, NH), 7.68 (td, 1 H,
J = 7.5, 1.6 Hz, ArH), 7.76 (td, 1 H, J = 7.5, 1.6 Hz, ArH),
7.91–7.99 (m, 2 H, 2 × ArH) ppm. 13C NMR (acetone): d =
26.3 (CH2), 27.6 (CH2), 30.6 (CH2), 32.7 (CH2), 50.7 (CH),
70.3 (CH), 124.5 (C), 127.0 (CH), 127.1 (CH), 133.6 (CH),
135.8 (C), 135.9 (CH), 136.2 (C), 156.4 (C), 181.5 (C=O),
182.0 (C=O) ppm. MS: m/z (%) = 253 (91) [M+], 224 (100).
Compound 11a: mp 120–122 °C (MeOH). 1H NMR
(CDCl3): d = 1.45–2.18 (m, 6 H, 3 × CH2), 2.28–2.47 (m, 1
H, CHH), 2.53–2.74 (m, 1 H, CHH), 3.59 (dt, J = 13.0, 3.9
Hz, 1 H, CHAr), 3.91 (s, 3 H, OCH3), 3.96 (s, 3 H, OCH3),
5.07–5.16 (m, 1 H, CHNO2), 6.67 (s, 1 H, ArH), 7.43–7.59
(m, 2 H, 2 × ArH), 8.02 (d, J = 8.0 Hz, 1 H, ArH), 8.23 (d,
J = 7.3 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3): d = 19.9
(CH2), 25.1 (CH2), 25.5 (CH2), 30.5 (CH2), 39.0 (CH), 55.6
(OCH3), 62.3 (OCH3), 86.1 (CHNO2), 102.6 (CH), 121.9
(CH), 122.4 (CH), 125.3 (CH), 125.9 (C), 126.5 (CH), 127.9
(C), 128.6 (C), 146.7 (C), 151.9 (C) ppm. MS: m/z (%) = 315
(100) [M+].
Acknowledgment
We thank the Spanish Ministry of Science and Education for a grant
to José M. Otero and the Xunta de Galicia for financial support and
for a grant for José C. Barcia.
References and Notes
(1) (a) Barret, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86,
751. (b) Nitroalkanes and Nitroalkenes in Synthesis, In
Tetrahedron Symposia-in-Print; Barret, A. G. M.,
Ed.Tetrahedron 1990, 46, 7313. (c) Noboru, O. In The
Nitro Group in Organic Synthesis; Feuer, H., Ed.; Organic
Nitro Chemistry Series, Wiley-VCH: New York, 2001.
(2) (a) The Chemistry of Functional Groups: The Chemistry of
The Quinoid Compounds; Patai, S.; Rappoport, Z., Eds.;
Wiley: New York, 1988. (b) Thomson, R. H. Naturally
Occurring Quinones, 4th ed.; Chapman and Hall: London,
1997.
(3) Cheng, C. C. Structural Aspects of Antineoplastic Agents –
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1988, pp 35–83.
(4) (a) Gould, S. J. Chem. Rev. 1997, 97, 2499. (b) Marco-
Contelles, J.; Molina, M. Curr. Org. Chem. 2003, 7, 1433.
(5) Harwood, J. S.; Harwood, C. A. J. Org. Chem. 2004, 69,
5128.
Compound 11b: mp 109–110 °C (MeOH). 1H NMR
(CDCl3): d = 1.42–2.14 (m, 6 H, 3 × CH2), 2.28–2.44 (m, 1
H, CHH), 2.50–2.69 (m, 1 H, CHH), 3.53 (dt, J = 13.1, 3.9
Hz, 1 H, CHAr), 3.85 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3),
3.95 (s, 3 H, OCH3), 5.06–5.13 (m, 1 H, CHNO2), 6.69 (s, 1
H, ArH), 6.84 (d, J = 7.9 Hz, 1 H, ArH), 7.40 (t, J = 7.9 Hz,
1 H, ArH), 7.62 (d, J = 7.9 Hz, 1 H, ArH) ppm. 13C NMR
(CDCl3): d = 19.8 (CH2), 25.0 (CH2), 25.4 (CH2), 30.5
(CH2), 38.9 (CH), 56.3 (OCH3), 56.8 (OCH3), 62.0 (OCH3),
85.9 (CH-NO2), 105.3 (CH), 106.2 (CH), 114.7 (CH), 117.8
(C), 126.6 (CH), 129.3 (C), 130.7 (C), 146.7 (C), 153.4 (C),
157.3 (C) ppm. MS: m/z (%) = 346 (94) [MH+], 299 (100).
(6) Yu, M.; Malinakova, H. C.; Stagliano, K. N. J. Org. Chem.
2006, 71, 6648.
(7) (a) Estévez, J. C.; Estévez, R. J.; Castedo, L. Tetrahedron
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(c) Cruces, J.; Martínez, E.; Treus, M.; Martínez, L. A.;
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Synlett 2007, No. 9, 1399–1402 © Thieme Stuttgart · New York