Synthesis of pentacyclic 13-azadibenzo[a,de]anthracenes via anionic cascade ring closure

Article abstract of DOI:10.1021/jo0300340

Bromine-lithium exchange using tert-butyllithium at -78 °C initiates a cascade process whereby either xanthone derivatives or pentacyclic 13-azadibenzo[a,de]anthracenes are produced in high yields. The reaction proceeds via a sequential intramolecular trapping of organolithium intermediates.

Full text of DOI:10.1021/jo0300340

SCHEME 1. Synthesis of Xanthone Derivatives
Synthesis of Pentacyclic
13-Azadibenzo[a,de]anthracenes via
Anionic Cascade Ring Closure
3a-ca
Jesper L. Kristensen,* Per Vedsø,† and Mikael Begtrup
Department of Medicinal Chemistry, The Danish University
of Pharmaceutical Sciences, Universitetsparken 2,
2100 Copenhagen, Denmark
jekr@dfh.dk
Received January 27, 2003
Abstract: Bromine-lithium exchange using tert-butyl-
lithium at -78 °C initiates a cascade process whereby either
xanthone derivatives or pentacyclic 13-azadibenzo[a,de]-
anthracenes are produced in high yields. The reaction
proceeds via a sequential intramolecular trapping of orga-
nolithium intermediates.
a Key: (i) 1a: 2-bromophenol, K2CO3, DMF, 100 °C, 48 h; 1b:
2-bromothiophenol, K2CO3, DMF, 100 °C, 24 h; 1c: (1) 2-bromo-
aniline, KOtBu, DMSO, rt, (2) MeI; (ii) (1) t-BuLi, THF, -78 °C to
rt; (iii) 4 N HCl, 70 °C, 12 h; (iv) EtOCOCl.
The generation of a very reactive organometallic
intermediate via metalation or halogen-metal exchange
followed by an intramolecular ring closing reaction is a
powerful way of constructing complex polycyclic mol-
ecules.1 In this paper, we wish to report the design and
execution of a new anionic cascade reaction giving access
to pentacyclic 13-azadibenzo[a,de]anthracene derivatives
via a sequential intramolecular trapping of organolithium
intermediates. This class of compounds have been re-
ported as potent telomerase inhibitors with potential
applications within anti-cancer therapy.2
In connection with a recent program in our laboratories
directed toward the synthesis of a new class of azaxan-
thones, we reported that a cyano group functions as an
electrophile in the intramolecular trapping of metalated
pyrazole derivatives.3 In Scheme 1, the generalization of
this approach to the synthesis of xanthone derivatives
is outlined. Substrates 1a-c were prepared in one step
via nucleophilic aromatic substitution of the fluorine in
2-fluorobenzonitrile. 2-Bromophenol gave 1a in 95%
yield, and 2-bromothiophenol produced 1b in 99% yield.
FIGURE 1. Proposed cascade process. Key: (i) Br-Li ex-
change, (ii) intramolecular addition to CN, (iii) intramolecular
SNAR
.
mixture was allowed to warm to room temperature, the
intermediate cyclic lithio-imines 2a-c were formed via
bromine-lithium exchange followed by an intramolecular
attack on the cyano group.6 Subsequent hydrolysis of 2a
and 2b gave xanthone 3a and thioxanthone 3b in 82%
and 75% yield, respectively. Imine 2c proved extremely
sluggish toward hydrolysis, and instead 2c was reacted
with ethyl chloroformate to give 3c7 in 84% yield.
2-Bromoaniline gave 1c in 89% yield via a one-pot SNAR
/
alkylation procedure.4 When 1a-c were added to 2.1
equiv of tert-butyllithium5 at -78 °C and the reaction
† Current address: Novo Nordisk A/S, Medicinal Chemistry Re-
search, DK-2760 Måløv, Denmark.
(1) (a) Boatman, R. J.; Whitlock, B. J.; Whitlock, H. W. J. Am. Chem.
Soc. 1977, 99, 4822. (b) Parham, W. E.; Bradsher, C. K. Acc. Chem.
Res. 1982, 15, 300. (c) Bailey, W. F.; Jiang, X.-L.; McLeod, C. E. J.
Org. Chem. 1995, 60, 7791. (d) Familoni, O. B.; Ionica, I.; Bower, J.
F.; Snieckus, V. Synlett 1997, 1081. (e) Jamison, T. F.; Shambayati,
S.; Crowe, W. E., Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 4353.
(f) MacNeil, S. L.; Gray, M.; Briggs, L. E.; Li, J. L.; Snieckus, V. Synlett
1998, 419. (g) Poirier, M.; Chen, F.; Bernard, C.; Wong, Y.-S.; Wu, G.
G. Org. Lett. 2001, 3, 3795. (h) Mealy, M. J.; Bailey, W. F. J.
Organomet. Chem. 2002, 646, 59.
(5) A side product arising from the competing addition of the
organolithium to the nitrile could be detected in the crude products.
Other alkyllithiums, solvents, and temperatures were tested, but we
found that the best results were obtained using inverse addition of
the substrate to a solution af tert-butyllithium in THF at -78 °C. See
the following references for the use of tert-butylllithium in halogen-
lithium exchange reactions: (a) Seebach, D.; Neumann, H. Chem. Ber.
1974, 107, 847. (b) Bailey, W.; Punzalan, E. R. J. Org. Chem. 1990,
55, 5404. (c) Negishi, E.-I.; Swanson, D. R.; Rousset, C. J. J. Org. Chem.
1990, 55, 5406.
(6) GC-MS analysis of quenched aliquots showed full conversion of
the starting aryl bromides 1a-c and formation of the corresponding
imines as the major products.
(7) Kristan, P.; Berna´t, J.; Imrich, J.; Sedla´k, E.; Alfo¨ldi, J.;
Cˇ ornanicˇ, M. Heterocycles 2001, 55, 279.
(2) (a) Gime´nez-Arnau, E.; Missailidis, S.; Stevens, M. F. G. Anti-
Cancer Drug Design 1998, 13, 125. (b) Heald, R.; Modi, C.; Cookson,
J. C.; Hutchinson, I.; Laugthon, C. A.; Gowan, S. M.; Kelland, L. R.;
Stevens, M. F. G. J. Med. Chem. 2002, 45, 590 and references therein.
(3) Kristensen, J. L.; Vedsø, P.; Begtrup, M. Tetrahedron 2002, 58,
2397.
(4) Full experimental details are given in the Supporting Informa-
tion.
10.1021/jo0300340 CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/11/2003
J. Org. Chem. 2003, 68, 4091-4092
4091

SCHEME 2. Synthesis of Substrates 4a-c for
SCHEME 3. Synthesis of 13-Azadibenzo[a,de]-
anthracene 5a-c via Anionic Cascade Ring
Closurea
Anionic Ring Closurea
a Key: *isolated yield. Average of two runs.
a Key: (i) Pd(PPh3)4, 2 M K2CO3, EtOH/toluene, 80 °C, 63 h;
(ii) see the Supporting Information.
proposed sequence in Figure 1. Thus, the pentacyclic 13-
azadibenzo[a,de]anthracenes 5a-c were isolated in 74-
91% yield.
This demonstrated that the intermediate lithio-imines
could be trapped with electrophiles. We speculated that
if this observation was combined with our recently
reported protocol for the synthesis of 6-substituted
phenanthridines via intramolecular trapping of imine-
anions,8 this could lead to the pentacyclic systems 5a-c
from 4a-c via the cascade process indicated in Figure
1.
The required substrates 4a-c were prepared in two
steps, as summarized in Scheme 2. Suzuki-Miyaura
coupling9 of commercially available 2-chloro-6-fluoroben-
zonitrile with 2-fluoroarylboronic ester 610 gave biaryl 7
in 78% yield. Subsequent regioselective nucleophilic
aromatic substitution of the fluorine ortho to the activat-
ing cyano group, using the conditions developed for the
synthesis of 1a-c, gave 4a-c in 78-92% yield.
With the key substrates in hand, we set out to test the
hypothesis; see Scheme 3. Addition of 4a-c to 2.1 equiv
of tert-butyllithium in THF at -78 °C followed by
warming to room temperature did indeed induce the
In conclusion, we have developed a novel approach to
the synthesis of 13-azadibenzo[a,de]anthracene deriva-
tives via an anionic cascade ring-closing reaction. Previ-
ous methodologies rely on Grade-Uhlmann thermolysis
of benzotriazole derivatives at reflux in diphenyl ether
and other radical cyclizations.11 Our synthetic approach
proceeds in three steps from readily available starting
material in over all 48-65% yield and should offer rapid
access to substituted derivatives inaccessible via previ-
ously reported methodologies. We are currently exploring
the scope of the reaction with respect to the incorporation
of heterocycles in the pursuit of pyridoacridine alkaloid
analogues.12
Supporting Information Available: Detailed experi-
mental procedures and characterization of compounds 1a-c,
3a-c, and 6. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0300340
(8) Lyse´n, M.; Kristensen, J. L.; Vedsø, P.; Begtrup, M. Org. Lett.
2002, 4, 257.
(9) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(10) Kristensen, J.; Lyse´n, M.; Vedsø, P.; Begtrup, M. Org. Lett.
2001, 3, 1435.
(11) (a) Katritzky, A. R.; Du, W.; Matsukawa, Y.; Ghiviriga, I.;
Denisenko, S. N.; J. Heterocycl. Chem. 1999, 36, 927. (b) Ellis, M. J.;
Stevens, M. F. G. J. Chem. Soc., Perkin Trans. 1 2001, 3180.
(12) Molinski, T. F. Chem. Rev. 1993, 93, 1825.
4092 J. Org. Chem., Vol. 68, No. 10, 2003