Fused benzo[b]fluorenols: Palladium-catalyzed intramolecular dehydroaromatization and carbonyl reduction

Article abstract of DOI:10.1002/adsc.201200108

Benzo[b]fluorenols were prepared by a new palladium-catalyzed one-pot reaction of en-one-ynes with 3-bromoprop-1-yne through intramolecular dehydroaromatization and carbonyl reduction. Copyright

Full text of DOI:10.1002/adsc.201200108

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DOI: 10.1002/adsc.201200108
Fused Benzo[b]fluorenols: Palladium-Catalyzed Intramolecular
Dehydroaromatization and Carbonyl Reduction
Quansheng Zhao,a Qiong Hu,a Lei Wen,a Min Wu,a and Yimin Hua,*
a
Laboratory of Functional Molecular Solids, Ministry of Education; Anhui Key Laboratory of Molecular-Based Materials;
School of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, Peopleꢀs Republic of China
Fax : (+86)-553-388-3517; e-mail: yiminhu@mail.ahnu.edu.cn
Received: February 9, 2012; Revised: May 24, 2012; Published online: July 29, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200108.
À
Abstract: Benzo[b]fluorenols were prepared by
a new palladium-catalyzed one-pot reaction of en-
one-ynes with 3-bromoprop-1-yne through intramo-
lecular dehydroaromatization and carbonyl reduc-
tion.
ladium-catalyzed processes and direct C H function-
alization,[10] we performed the palladium-catalyzed re-
actions of 1a to 1y (Table 1) with 3-bromoprop-1-yne,
providing a direct, efficient, and economical method-
ology for the construction of fused benzo[b]fluorenol
compounds through intramolecular dehydroaromati-
zation and carbonyl reduction.[11]
Keywords: benzo[b]fluorenols; dehydroaromatiza-
tion; domino reactions; hydrogen-transfer reduc-
tion; palladium
A survey of the reaction conditions using (E)-3-
phenyl-1-(2-(phenylethynyl)phenyl)prop-2-en-1-one
(1a), 3-bromoprop-1-yne or allyl bromide (2a to 2d),
as a test experiment was performed (Scheme 1). The
efficiency of the domino reaction can be enhanced
considerably by increasing the reaction temperature
Fused benzo[b]fluorenols are important classes of to 1308C. The additive bases play an important role
chiral alcohols that possess a broad range of biologi- in the overall efficiency of this domino reaction, thus
cal and pharmaceutical activities.[1] Molecules contain- simple variation of the base from potassium carbon-
ing fluorenol have been the subject of considerable ate to tributylamine under otherwise identical condi-
interest as potent antitumor, antimicrobial, and antivi- tions, as well as furnishing the unexpected benzo[b]-
ral agents.[2] Recently, dehydrogenation strategies for fluorenol 3a in 84% yield, also produced a small
the preparation of aromatic scaffolds have produced quantity of benzo[b]fluorenone (4a). Among the cata-
significant synthetic challenges.[3] Stahl reported on an lysts investigated, the palladium(II) acetate/(3-bromo-
unconventional ortho-dimethylaminopyridine ligand- prop-1-yne) catalytic system was found to be the most
mediated conversion of substituted cyclohexanones
into the corresponding phenols.[4] Grꢁtzmacher re-
ported on the domino rhodium-/palladium-catalyzed
dehydrogenation reactions of alcohols to acids.[5]
Maier demonstrated the convenient synthesis of 7-ar-
yltetralones using a novel arylation–dehydroaromati-
zation sequence.[6] Beckhaus described the dehydroar-
omatization of quinoxalines through three-fold dehy-
[7]
À
drogenative C C coupling. Carbonyl reduction has
become increasingly involved in biological systems in
which the reduction of a ketone leads to secondary al-
cohol.[8] In the current study, novel domino methods[9]
and hydrogen transfer reactions were developed to
synthesize fused benzo[b]fluorenol compounds
through intramolecular dehydroaromatization and
carbonyl reduction, which led directly to a secondary
alcohol through transformation of the linear en-one-
yne. As this study focuses on the development of pal- Scheme 1. Strategy for the synthesis of benzo[b]fluorenol.
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Quansheng Zhao et al.
Table 1. Palladium-catalyzed dehydroaromatization and carbonyl reduction for the formation of fused PAHs.[a,b]
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3a (84%)
3g (77%)
3m (85%)
3b (75%)
3h (80%)
3n (76%)
3c (86%)
3i (80%)
3o (85%)
3d (88%)
3j (75%)
3p (89%)
3e (73%)
3k (83%)
3q (75%)
3f (65%)
3l (85%)
3r (68%)
3s1 (45%)
3s2 (38%)
3t (60%)
3u (66%)
3v (70%)
3w (62%)
3x (59%)
3y (65%)
[a]
General conditions: 1a–1y (1.0 equiv.), C3H3Br (1.2 equiv.), PdACHTNUGTRENUNG(OAc)2 (2 mol%), (n-Bu)3N (2 equiv.), DMF 10 mL, 1308C.
Yield given for isolated product.
[b]
effective in cross-coupling screens. DMF proved to be 3-bromoprop-1-yne or allyl bromide on the outcome
a better solvent than toluene. Benzo[b]fluorenol com- of the reactions and on the formation of the final
pound 3a was only isolated in yields of 66% and 35%, products. Thus, the following standard reaction condi-
respectively, when 1-bromobut-2-yne or allyl bromide tions were used to carry out the following studies:
was employed as a reactant, indicating the effects of 1 equiv. of 1a was reacted with 1.2 equiv. of 3-bromo-
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Adv. Synth. Catal. 2012, 354, 2113 – 2116

Fused Benzo[b]fluorenols: Palladium-Catalyzed Intramolecular Dehydroaromatization
prop-1-yne in the presence of 2 mol% palladium(II) mensional (COSY) NMR spectral analyses, and ele-
catalyst and 2 equiv. of (n-Bu)3N as an additive in mental or HR-MS analyses, respectively. The struc-
DMF at 1308C.
ture of 3o was confirmed independently through an
Illustrative examples of the scope are shown in X-ray crystal structure analysis (Figure 1).[12] Further
Table 1. Interestingly, various intramolecular en-yn- details can be found in the Supporting Information
ones are compatible with this palladium-catalyzed de- (see also the Experimental Section).
hydroaromatization and carbonyl reduction. A range
In conclusion, a one-pot synthesis of fused ben-
of 5-phenyl-11H-benzo[b]fluoren-11-ol compounds zo[b]fluorenols through aryl-substituted en-one-yne
were readily isolated in good to excellent yields, with systems via domino reactions was reported. To the
the exception of 3t or 3x, when 3-phenyl-1-[2-(phenyl- best of our knowledge, there have been no reports
ethynyl)phenyl]prop-2-en-1-one was employed with thus far on such a domino process, a topic which
a variety of substituted groups. The substituted groups could be of general interest. The dihydronaphthalene
could be para-, ortho-, or meta- substituted groups on is then oxidized into the fully aromatic system and
the benzene ring (i.e., chloro, fluoro, methyl, methoxy the hydrogen transferred to the keto group to give
and benzo). Using 3-bromoprop-1-yne with en-yn-one the benzo[b]fluorenols. The hydrogen transfer pattern
substrates (a, c, d, h, i, k–m, o, and p), the reaction of the products is not readily available when other
gave 5-phenyl-11H-benzo[b]fluoren-11-ols 3a, 3c, 3d, methods are used. The generality of this process
3h, 3i, 3k, 3l, 3m, 3o, and 3p, respectively, in yields makes the reaction highly valuable in view of the syn-
beyond 80%. The yields of compounds 3d and 3p thetic and medicinal importance of these kinds of
were the highest at 88% and 89%. Simultaneously, PAHs. The mechanism is not clear so far. Further
when 3-bromoprop-1-yne was used in the reaction mechanistic and synthetic studies are in progress.
with b, e–g, j, n, q, r, u–w, the desired phenanthridines
were obtained in good yields ranging from 62% to
77% (3b, 3e–3g, 3j, 3n, 3q, 3r, 3u–3w, and 3y). Inter- Experimental Section
estingly, the comparison of the products 3s1 and 3s2 in-
dicates that the electronic properties of the substrates Typical procedure
À
also influenced the regioselectivity of the C H bond
functionalization because the en-yno-nes reacted with
Substrate 1a (1.0 mmol), 3-bromoprop-1-yne (1.2 mmol),
and PdACTHUNTGRNE(UNG OAc)2 (2 mol%) were added to a degassed solution
the same 3-bromoprop-1-yne but produced different
of (n-Bu)3N (2 mmol) in DMF (10 mL). and the mixture
was stirred at room temperature for half an hour, and then
heated at 1308C for 18 h. The reaction mixture was cooled,
and then quenched with water and extracted with EtOAc
(3ꢃ5 mL). The combined organic layers were washed with
hydrochloric acid (5%), sodium carbonate (5%), and satu-
rated sodium chloride solution. After separation, the organic
layer was dried over MgSO4 and then concentrated. The res-
idue was loaded onto a silica gel column and purified by
flash chromatography (eluent: petroleum ether/ethyl ace-
tate=10:1) to give the corresponding product 3a; yield:
84%.
À
C H bond functionalization products. Results indi-
cate that 3s1 and 3s2 gave good yields at 43% and
38%, respectively.
All the resulting tetracyclic and pentacyclic com-
pounds were confirmed by one- (1H, 13C) and two-di-
Acknowledgements
The authors are grateful to the National Science Foundation
of China (21072003, 20872002), and Department of Human
Resources of Anhui Province for financial support. The au-
thors also thank Dr. Yun Wei and Prof. Xiaolong Mu for X-
ray crystallography.
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