Synthesis of functionalized 6(5H)-phenanthridinones based on a [3+3]-cyclocondensation/lactamization strategy

Article abstract of DOI:10.1016/j.tetlet.2008.05.067

Functionalized 6(5H)-phenanthridinones (dibenzo[b,d]pyrid-6-ones) were prepared by [3+3]-cyclocondensation of 1-trimethylsilyloxy-1,3-butadienes with nitro-substituted 1-aryl-1-silyloxy-1-en-3-ones and subsequent reductive lactamization.

Full text of DOI:10.1016/j.tetlet.2008.05.067

Tetrahedron Letters 49 (2008) 4467–4469
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Synthesis of functionalized 6(5H)-phenanthridinones based
on a [3+3]-cyclocondensation/lactamization strategy
Mirza A. Yawer a, Ibrar Hussain a, Inam Iqbal a, Anke Spannenberg b, Peter Langer a,b,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Functionalized 6(5H)-phenanthridinones (dibenzo[b,d]pyrid-6-ones) were prepared by [3+3]-cyclocon-
densation of 1-trimethylsilyloxy-1,3-butadienes with nitro-substituted 1-aryl-1-silyloxy-1-en-3-ones
and subsequent reductive lactamization.
Received 9 April 2008
Revised 8 May 2008
Accepted 13 May 2008
Available online 16 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
6(5H)-Phenanthridinones (dibenzo[b,d]pyrid-6-ones) are phar-
macologically important molecules which occur in a variety of nat-
ural products. This includes, for example, sanguinarinone which
shows antiparasitic activity against the dog roundworm, anticoag-
ulant activity, and antiproliferative activity against leukemia HL-60
cells.1 Oxotoddaline has been reported to possess anti-proliferative
report what is, to the best of our knowledge, the first synthesis
of 6(5H)-phenanthridinones by application of a [3+3]-cyclocon-
densation/lactamization strategy. Notably, the products are
formed with very good regioselectivity and are not readily avail-
able by other methods.
The LDA-mediated condensation of acetone (1a) and pentan-2-
one (1b) with benzoyl chlorides 2a–c afforded the nitro-substi-
tuted benzoylacetones 3a–d which were transformed into the
1-aryl-1-silyloxy-1-en-3-ones 4a–d (Scheme 1, Table 1). The
TiCl4-mediated cyclization of 4a–d with 1,3-bis(trimethylsilyl-
oxy)-1,3-butadienes 5a–f, readily available in two steps from the
corresponding b-ketoesters,13 afforded the novel nitro-substituted
biaryls 6a–n (Scheme 1, Table 2).14 All cyclizations proceeded with
very good regioselectivity. During the optimization, it proved to be
important to carry out the reactions in a highly concentrated solu-
tion. The structures of all products were established by spectro-
scopic methods. The structure of 6m was independently
confirmed by X-ray crystal structure analysis (Fig. 1).15
The regioselective formation of products 6a–n can be explained,
following a mechanism first suggested by Chan,13a by TiCl4-medi-
ated isomerization of 4 into intermediate type A, TiCl4-mediated
attack of the terminal carbon atom of 1,3-bis(silyl enol ether) 5
onto the carbon located next to substituent R1 to give intermediate
type B (conjugate addition), cyclization (intermediate type C), and
subsequent aromatization (Scheme 1).
activity against P-388 and human colon carcinoma HT-29 cells.2
A
number of other pharmacologically active natural products, for
example, cytotoxic oxynitidine,3 have been reported.4,5 6(5H)-Phe-
nanthridinones have been prepared by reductive cyclization of 2-
nitro-20-alkoxycarbonyl-biphenyls under various conditions
(including Fe/AcOH, Fe/THF, Zn/HOAc, Raney-Ni, and H2-Pd/C).6
The corresponding biaryls have been prepared by Ullmann-type
reactions and by nucleophilic aromatic substitutions.7 An alterna-
tive approach relies on the nitration of appropriate biphenyls.8
The scope of these reactions is limited by the harsh reaction condi-
tions and by steric effects. In fact, sterically encumbered and highly
functionalized derivatives are not readily available by this ap-
proach. In addition, the synthesis of the starting materials, highly
functionalized arenes, is often not an easy task. These problems
can be circumvented by application of a ‘building block approach’.
To the best of our knowledge, only a single application of this strat-
egy has been reported to date. Ashburn and coworkers reported
the synthesis of 2-nitro-20-alkoxycarbonyl-biphenyls based on
[4+2]-cycloadditions.9
Chan and coworkers were the first to report a convenient
synthesis of functionalized phenols by TiCl4-mediated [3+3]-
cyclization10 of 1,3-bis(trimethylsilyloxy)-1,3-butadienes11 with
3-silyloxy-2-en-1-ones. In recent years, we studied the application
of this reaction to the synthesis of various functionalized arenes.
Recently, we reported the synthesis of dibenzo[b,d]pyran-6-ones
based on a [3+3]-cyclization/lactonization strategy.12 Herein, we
The Pd/C-catalyzed hydrogenation of 6a–h directly afforded the
6(5H)-phenanthridinones 7a–h (Scheme 2, Table 3). The products
are formed by transformation of the nitro into an amino group
and subsequent spontaneous lactamization.16
The hydrogenation of 3-nitro-30-hydroxy-biphenyls 6j and 6k
afforded the 3-amino-30-hydroxy-biphenyls 8a and 8b (Scheme
3). Notably, 3-amino- and 3-nitro-30-hydroxy-biphenyls are of con-
siderable current interest, due to their wide range of pharmacolog-
ical properties. This includes, for example, antimalarial activity,
binding affinity to C5a receptor (human monocyte cell line
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.067

4468
M. A. Yawer et al. / Tetrahedron Letters 49 (2008) 4467–4469
O
O
OH
Cl
O
R2
i
+
R3
R5
R2
R3
R5
R4
2a-c
R4
3a-d
1a,b
ii
Me3SiO OSiMe3
R1
O
OH
R1
R2
OSiMe3
R3
O
OR
OR
R4
5a-f
R2
iii
R5
6a-n
R3
R5
R4
4a-d
TiCl4
O
O
R1
R2
Me3SiO
R2
O
Figure 1. Ortep plot of 6m.
OR
OTiCl3
R3
R5
R3
O
OH
R4
OH
O
C
A
R5
R1
R2
R1
H
R4
OR
N
i
5a-f
TiCl4
Me3SiCl
R2
_
(Me3Si)2O
O2N
O
7a-h
6a-h
Me3SiO
R1
OR
Scheme 2. Synthesis of 7a–h. Reagents and condition: (i) H2, Pd/C (10 mol %),
20 °C, 48 h.
OTiCl3
R2
Me3SiO
Table 3
Synthesis of 7a–h
R3
R5
R4
B
6, 7
R
R1
R2
% (7)a
Scheme 1. Synthesis of 6a–n. Reagents and conditions: (i) LDA (1.5 equiv), THF; (ii)
(1) NEt3 (1.6 equiv), Me3SiCl (1.8 equiv), C6H6, 20 °C, 3 d; (iii) TiCl4, CH2Cl2, ꢀ78?
20 °C, 18 h.
a
b
c
d
e
f
Me
Me
Et
Me
Me
Me
Et
Me
Me
Me
Me
nPr
nPr
nPr
nPr
H
Me
Et
nOct
H
Me
Et
64
52
70
69
56
50
63
74
Table 1
Synthesis of 3a–d
g
h
1
2
3
R2
R3
R4
R5
% (3)a
% (4)a
Me
nHex
a
b
a
a
a
a
b
c
a
b
c
Me
nPr
Me
Me
NO2
NO2
H
H
H
NO2
H
H
H
H
NO2
54
45
34
43
91
88
90
92
a
Yields of isolated products.
d
H
a
Yields of isolated products.
O
OH
OH
O
R1
R1
OR
OR
Table 2
Synthesis of 6a–n
i
Me
Me
4
5
6
R
R1
R2
R3
R4
R5
% (6)a
a
a
a
a
b
b
b
b
c
c
c
d
d
d
a
b
c
d
a
b
c
e
a
b
c
a
b
f
a
b
c
d
e
f
g
h
i
j
k
l
m
n
Me
Me
Et
Me
Me
Me
Et
Me
Me
Me
Et
Me
Me
Me
H
Me
Et
nOct
H
Me
Et
nHex
H
Me
Et
H
Me
Et
Me
Me
Me
Me
nPr
nPr
nPr
nPr
Me
Me
Me
Me
Me
Me
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
NO2
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
36
41
35
40
48
38
37
25
32
50
37
36
46
33
NO2
NH2
8a (R = Me, R1 = Me, 81%)
8b (R = Et, R1 = Et, 78%)
6j,k
Scheme 3. Synthesis of 8a,b. Reagents and condition: (i) H2, Pd/C (10 mol %),
MeOH, 20 °C, 48 h.
U937), inhibition of cyclic nucleotide phosphorodiesterases (PDEs),
activity for topoisomerases I and II-mediated DNA cleavage, and
anti-hepatitis activity.17
In conclusion, we have reported a regioselective approach
to functionalized 6(5H)-phenanthridinones by application of a
NO2
NO2
NO2
H
a
Yields of isolated products.

M. A. Yawer et al. / Tetrahedron Letters 49 (2008) 4467–4469
4469
13. (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534; (b)
Brownbridge, P.; Chan, T.-H.; Brook, M. A.; Kang, G. J. Can. J. Chem. 1983, 61,
688.
[3+3]-cyclization/lactamization strategy. The products are not
readily available by other methods.
14. General procedure for the synthesis of salicylates 6a–bf n: To a CH2Cl2 solution of
silyl enol ether 4 (1.0 equiv) and 1,3-bis(silyl enol ether) 5 (1.1 equiv) was
dropwise added TiCl4 (1.1 equiv) at ꢀ78 °C under argon atmosphere. The
solution was stirred at ꢀ78 °C for 30 min and then allowed to warm to 20 °C
during 18 h. To the solution was added hydrochloric acid (10%). The organic
layer was separated and the aqueous layer was repeatedly extracted with
CH2Cl2. The combined organic layers were dried (Na2SO4) and filtered. The
filtrate was concentrated in vacuo and the residue was purified by
chromatography (silica gel, n-hexane/EtOAc) to give salicylates 6. Synthesis of
methyl 3-hydroxy-5-methyl-2’-nitro[1,10-biphenyl]-2-carboxylate (6a). Starting
with 5a (1.145 g, 4.4 mmol), TiCl4 (0.835 g, 4.4 mmol), CH2Cl2 (6 mL), and 4a
(1.117 g, 4.0 mmol), 6a was isolated (0.420 g, 36%) as a yellowish oil. 1H NMR
(CDCl3, 250 MHz): d = 2.21 (s, 3H, CH3), 3.33 (s, 3H, OCH3), 6.35 (d, 4J = 1.9 Hz,
1H, CHAr), 6.74 (d, 4J = 1.4 Hz, 1H, CHAr), 7.10–7.13 (m, 1H, CHAr), 7.36 (ddd,
3J = 7.4 Hz, 3J = 7.2 Hz, 4J = 1.4 Hz, 1H, CHAr), 7.47 (ddd, 3J = 7.5 Hz, 3J = 7.4 Hz,
4J = 1.5 Hz, 1H, CHAr), 7.92 (dd, 3J = 8.0 Hz, 4J = 1.5 Hz, 1H, Ar), 11.10 (s, 1H, OH).
13C NMR (CDCl3, 75 MHz): dC = 21.6 (CH3), 51.9 (OCH3), 108.4 (CAr), 118.0,
122.5, 123.6, 127.8, 131.1. 132.4 (CHAr), 138.2, 140.2, 145.6, 147.8, 162.4 (CAr),
170.4 (C@O). GC–MS (EI, 70 eV): m/z (%) = 287 ([M]+, 26), 255 (100), 227 (27),
197 (5), 181 (11), 152 (30), 115 (5), 76 (7). HRMS (EI): calcd for C15H13NO5:
287.07882; found: 287.07873.
Acknowledgment
Financial support by the State of Pakistan (HEC scholarships for
I.H., M.A.Y, and I.I.) and by the State of Mecklenburg-Vorpommern
is gratefully acknowledged.
References and notes
1. (a) Castedo, L.; Lopez, S.; Rodriguez de Lera, A.; Villaverde, C. Phytochemistry
1989, 28, 251; (b) Satou, T.; Akao, N.; Matsuhashi, R.; Koike, K.; Fujita, K.;
Nikaido, T. Biol. Pharm. Bull. 2002, 25, 1651; (c) Chen, J.-J.; Chang, Y.-L.; Teng,
C.-M.; Lin, W.-Y.; Chen, Y.-C.; Chen, I.-S. Planta Med. 2001, 67, 423.
2. (a) Chen, J.-J.; Fang, H.-Y.; Duh, C.-Y.; Chen, I.-S. Planta Med. 2005, 71, 470; (b)
Tsai, I.-L.; Wun, M.-F.; Teng, C.-M.; Ishikawa, T.; Chen, I.-S. Phytochemistry 1998,
48, 1377; (c) Ng, K. M.; Gray, A. I.; Waterman, P. G. Phytochemistry 1987, 26,
3251.
3. (a) Chou, H.-C.; Chen, J.-J.; Duh, C.-Y.; Huang, T.-F.; Chen, I.-S. Planta Med. 2005,
71, 1078; (b) Vardamides, J. C.; Dongmo, A. B.; Meyer, M.; Ndom, J. C.; Azebaze,
A. G. B.; Zounda, M. R. S.; Sielinou, V. T.; Ndemangou, B.; Nkengfack, A. E.;
Ngando, T. M.; Fomum, Z. T. Chem. Pharm. Bull. 2006, 54, 1034; (c) Tsai, I.-L.;
Wun, M.-F.; Teng, C.-M.; Ishikawa, T.; Chen, I.-S. Phytochemistry 1998, 48, 1377;
(d) Tsai, I.-L.; Fang, S.-C.; Ishikawa, T.; Chang, C.-T.; Chen, I.-S. Phytochemistry
1997, 44, 1383.
15. CCDC-684633 (6m) contains the supplementary crystallographic data for this
Letter. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
16. General procedure for the synthesis of 6(5H)-phenanthridinones 7a–h: To
a
stirred methanol suspension (25 mL) of Pd/C (10 mol %) was added 6a–h
(1.0 equiv). The mixture was set under a hydrogen atmosphere. After stirring
for 48 h at 20 °C, the reaction mixture was filtered (celite) and the filtrate was
concentrated in vacuo. The residue was purified by chromatography (silica gel,
hexanes?hexanes/EtOAc = 2:1). Synthesis of 7-hydroxy-9-methyl-6(5H)-
phenanthridinone (7a). Starting with 6a (0.429 g, 1.65 mmol), 7a was isolated
(0.237 g, 64%) by column chromatography (silica gel, heptanes/
4. Llabres, J. M.; Viladomat, F.; Bastida, J.; Codina, C.; Rubiralta, M. Phytochemistry
1986, 25, 2637.
5. For synthetic work, see: (a) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7,
4777; (b) Torres, J. C.; Pinto, A. C.; Garden, S. J. Tetrahedron 2004, 60,
9889.
EtOAc = 30:1?20:1) as
a
colorless solid. 1H NMR (DMSO-d6, 250 MHz):
6. (a) Elango, S.; Srinivasan, Panayencheri C. Tetrahedron Lett. 1993, 34, 1347; (b)
Dow, R. L.; Chou, T. T.; Bechle, B. M.; Goddard, C.; Larson, E. R. J. Med. Chem.
1994, 37, 2224; (c) Mohanakrishnan, A. K.; Srinivasan, P. C. J. Org. Chem. 1995,
60, 1939; (d) Kleppinger, R.; Lillya, C. P.; Yang, C. Angew. Chem. 1995, 107, 1762;
(e) Kleppinger, R.; Lillya, C. P.; Yang, C. J. Am. Chem. Soc. 1997, 119, 4097; (f)
Kanojia, R. M.; Ohemeng, K. A.; Schwender, C. F.; Barrett, J. F. Tetrahedron Lett.
1995, 36, 8553; (g) Li, J.-H.; Serdyuk, L.; Ferraris, D. V.; Xiao, G.; Tays, K. L.;
Kletzly, P. W.; Li, W.; Lautar, S.; Zhang, J.; Kalish, V. J. Bioorg. Med. Chem. Lett.
2001, 11, 1687; (h) Goerlitzer, K.; Trittmacher, J.; Jones, P. G.; Frohberg, P.;
Drutkowsi, G. Pharmazie 2003, 58, 776; (i) Banwell, M. G.; Lupton, D. W.; Ma, X.;
Renner, J.; Sydnes, M. O. Org. Lett. 2004, 6, 2741; (j) Zhang, W.; Wilke, B. I.;
Zhan, J.; Watanabe, K.; Boddy, C. N.; Tang, Y. J. Am. Chem. Soc. 2007, 129, 9304.
7. (a) Poesche, W. H. J. Chem. Soc. C 1966, 890; (b) Forrest, J. J. Chem. Soc. 1960,
589; (c) Helmchen, G.; Prelog, V. Helv. Chim. Acta 1972, 55, 2599; (d) Suzuki, H.;
Enya, T.; Hisamatsu, Y. Synthesis 1997, 1273; (e) Bell, Anthony J.; Read, R. W.
Aust. J. Chem. 1987, 40, 1813; (f) Take, K.; Okumura, K.; Takimoto, K.; Kato, M.;
Ohtsuka, M.; Shiokawa, Y. Chem. Pharm. Bull. 1991, 39, 2915. See also Ref. 6h.
8. Kleppinger, R.; Lillya, C. P.; Yang, C. J. Am. Chem. Soc. 1997, 119, 4097. See also
Ref. 6b.
d = 2.45 (s, 3H, CH3), 6.82 (s, 1H, CHAr), 7.27–7.30 (m, 1H, CHAr), 7.33–7.41
(m, 1H, CHAr), 7.49–7.55 (m, 1H, CHAr), 7.76 (m, 1H, CHAr), 8.34 (d, 3J = 7.9 Hz,
1H, CHAr), 12.02 (br, 1H, NH), 13.25 (s, 1H, OH). 13C NMR (DMSO-d6, 62 MHz):
dC = 21.8 (CH3), 107.9 (CAr), 113.1 115.0, 116.6 (CHAr), 118.0 (CAr), 123.2, 123.6,
128.4 (CHAr), 129.8, 135.6, 146.0, 159.4 (CAr), 165.7 (C@O). MS (EI 70 eV): m/z
(%) = 225 ([M]+, 100), 206 (10), 196 (16), 99 (14), 73 (16), 57 (27), 43 (52).
HRMS (EI): calcd for C14H11NO2: 225.07853; found: 225.07843.
17. (a) Werbel, L. M.; Cook, P. D.; Elslager, E. F.; Hung, J. H.; Johnson, Judith L. J. Med.
Chem. 1986, 29, 924; (b) Take, K.; Okumura, K.; Takimoto, K.; Kato, M.; Ohtsuka,
M.; Shiokawa, Y. Chem. Pharm. Bull. 1991, 39, 2915; (c) Astles, P. C.; Brown, T. J.;
Cox, P.; Halley, F.; Lockey, P. M. Bioorg. Med. Chem. Lett. 1997, 7, 907; (d) Ukita,
T.; Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Takahashi, M. J. Med. Chem. 1999, 42,
1293; (e) Sun, L.; Tran, N.; Liang, C.; Tang, F.; Rice, A.; Schreck, R.; Waltz, K.;
Shawver, L. K.; McMahon, G.; Tang, C. J. Med. Chem. 1999, 42, 5120; (f) Poupart,
M.-A.; Cameron, D. R.; Chabot, C.; Ghiro, E.; Goudreau, N.; Goulet, S.; Poirier,
M.; Tsantrizos, Y. S. J. Org. Chem. 2001, 66, 4743; (g) Parikh, V.; Welch, W. M.;
Schmidt, A. W. Bioorg. Med. Chem. Lett. 2003, 13, 269; (h) Wang, L.; Wang, G. T.;
Wang, X.; Tong, Y.; Sullivan, G.; Park, D.; Leonard, N. M.; Li, Q.; Cohen, J.; Gu,
W.-Z.; Zhang, H. J. Med. Chem. 2004, 47, 612; (i) Sheppard, G. S.; Kawai, M.;
Craig, R. A.; Davidson, D. J.; Majest, S. M.; Bell, R. L.; Henkin, J. Bioorg. Med.
Chem. Lett. 2004, 14, 965; (j) Mor, M.; Rivara, S.; Lodola, A.; Plazzi, P. V.; Tarzia,
G.; Duranti, A.; Tontini, A.; Piersanti, G.; Kathuria, S.; Piomelli, D. J. Med. Chem.
2004, 47, 4998; (k) Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.;
Naruto, S.; Sugano, Y. Bioorg. Med. Chem. Lett. 2004, 14, 4383.
9. Ashburn, B. O.; Carter, R. G.; Zakharov, L. N. J. Am. Chem. Soc. 2007, 129, 9109.
10. For a review of [3+3]-cyclizations, see: Feist, H.; Langer, P. Synthesis 2007, 327.
11. For a review of 1,3-bis(silyl enol ethers), see: Langer, P. Synthesis 2002, 441.
12. (a) Nguyen, V. T. H.; Langer, P. Tetrahedron Lett. 2005, 46, 1013; (b) Hussain, I.;
Nguyen, V. T. H.; Yawer, M. A.; Dang, T. T.; Fischer, C.; Reinke, H.; Langer, P.
J. Org. Chem. 2007, 72, 6255.