An intramolecular arylation route to the kinafluorenones

Article abstract of DOI:10.1016/S0040-4039(00)00848-0

Intramolecular palladium-mediated arylation approaches to benzo[b]fluorenes have been investigated. The methodology has been applied in a short synthesis of kinafluorenone 2, providing an effective alternative to Friedel-Crafts-based approaches. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00848-0

Tetrahedron Letters 41 (2000) 5317±5320
An intramolecular arylation route to the kina¯uorenones
Ghassan Qabaja and Graham B. Jones*
Bioorganic and Medicinal Chemistry Laboratories, Department of Chemistry and Barnett Institute, 102 Hurtig Hall,
Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
Received 13 April 2000; accepted 17 May 2000
Abstract
Intramolecular palladium-mediated arylation approaches to benzo[b]¯uorenes have been investigated.
The methodology has been applied in a short synthesis of kina¯uorenone 2, providing an e€ective alter-
native to Friedel±Crafts-based approaches. # 2000 Elsevier Science Ltd. All rights reserved.
The search for new antibiotics continues at a steady pace, and quinonoid derived systems have
been the subject of a number of promising leads.1 Of the benzo[b]¯uorenone family, the natural
products stealthin C, 12and prekinamycin 33 have attracted considerable interest, and both are
accessible from the benzo[b]¯uorenone 2.4 Additionally, tetracycle 3 is a known intermediate in
the biosynthesis of the kinamycin family of antibiotics produced by Streptomyces murayamaensis,
and a number of these natural products show Gram positive and negative antibacterial properties,
and antitumoral activity.5
Though a number of di€erent approaches to the basic benzo[b]¯uorenone skeleton 4 have been
reported, most involve variants of Friedel±Crafts type closures of acylbiphenyls 5 (Scheme 1).6
Due to the versatility of transition metal-mediated arylations, we were interested to investigate
the potential for a Pd mediated closure from 6, which would o€er a complimentary strategy for
the production of analogs of the natural products.
To demonstrate the feasibility of the approach, appropriate model substrates were assembled,
either by coupling arene 7 with 2-iodobenzoic acid, or in the case of 10, acylation followed by Ti-
catalyzed ortho-Fries rearrangement (Scheme 2). Palladium-mediated closures on substrates 8
and the methyl ether of 11 were conducted using a variety of methods with limited success, but
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00848-0

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Scheme 1. Complimentary routes to the benzo[b]¯uorene skeleton
optimal conditions were eventually found, involving high temperature closure with Pd(OAc)2 in
dimethylacetamide (DMA), as had been previously demonstrated by Ames and Opalko in the
cyclization of substituted diphenylethers to dibenzofurans.7
Scheme 2. Model arylation route to benzo[b]¯uorenones
With the model study complete, we sought application in the synthesis of key structure 2.
Accordingly, dimethylanisole 13 was converted to iodoaldehyde 14 which was subjected to 1,2
addition with the lithioarene derived from aryl bromide 16, in turn prepared from methyljuglone
158 (Scheme 3). The resulting benzylic alcohol was oxidized (17), and the Pd mediated closure
attempted. Using identical conditions to the model substrates, low yields of 2 were isolated, sug-
gesting either the o-methoxy group exerts a subtle electronic in¯uence or else developing (repulsive)
interactions between the aryloxy groups in 2 retard product formation.
Scheme 3. Convergent synthesis of kina¯uorenone: (a) CCl4, NBS, then K2CO3, dioxane, 40%; (b) nBuLi, hexanes, I2
^78ꢀC, 80%; (c) COCl2, DMSO, 95%; (d) Na2S2O4, ether then Me2SO4, K2CO3 85%; (e) CCl4, Br2 99% then K2CO3,
Me2SO4 60%; (f) tBuLi, ether, ^78ꢀC (quant.); (g) PCC, CH2Cl2, 80%

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Complicating the process was product decomposition which ensued at the higher temperatures
and extended reaction times necessary to e€ect closure (Table 1). Since metal-catalyzed processes
are often ideal candidates for acceleration using microwaves,9,10 a reaction was conducted using
microwave irradiation (mW). Additionally, DMA, which has a dielectric constant of 37.8 D
would be expected to heat rapidly during the irradiation process. Accordingly, a sample of 17,
PdCl2(PPh3)2 and sodium acetate dissolved in DMA, in a round-bottomed ¯ask was placed in the
center of a conventional microwave oven and irradiated for 60 sec.11 During this period, the
solution temperature reached 140ꢀC, and gave a 53% yield of desired product 2, along with traces
of unreacted 17. E€orts to improve the product yields by extended thermolysis were unsuccessful,
and after 2 min the solution began to re¯ux, necessitating cessation of the reaction. Similarly,
microwave accelerated closures to model substrates 9 and 12 were successful, in both cases giving
comparable yields of product to the thermal process (Scheme 2) within 1 min.
Table 1
Attempted Pd-catalyzed arylation of 17
The speed and eciency of the mW accelerated coupling suggests additional applications in
transition metal-mediated processes may be forthcoming. The described synthesis of kina-
¯uorenone 2 is competitive with existing routes, and may allow development of additional ana-
logs of the natural product. The scope and limitations of the arylation process, together with
antitumoral and antibacterial data for synthetic analogs of 2 will be presented in a full account of
this work.
Microwave accelerated route to 2: A heavy walled (5 mm) boiling tube (100 ml) equipped with a
virgin septum and magnetic stir bar was ¯ame dried under a stream of nitrogen gas. Ketone 17
(92 mg, 0.18 mmol), sodium acetate (46 mg, 0.54 mmol) and dichlorobis(triphenylphosphine)-
palladium(II) (20 mg, 0.027 mmol) in dimethylacetamide (50 ml) were introduced and the mixture
degassed (N2) for 2 h. The tube was placed in a 100 ml beaker within the cavity of a domestic
microwave oven (450 W), and irradiated at full power for 60 sec. On cooling, the mixture was
poured into ether (100 ml) and washed with HCl (1M, 3Â30 ml). The combined organic extracts
were dried (MgSO4), condensed in vacuo, and the resulting residue puri®ed by ¯ash chromato-
graphy (5% EtOAc: 95% CH2Cl2) to give 2 (36 mg, 53%) isolated as an orange solid m.p. 110ꢀC
(dec.) and spectroscopically identical with authentic material.3
Acknowledgements
We thank the National Institute for General Medical Sciences (RO1GM57123) for generous
®nancial support.

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