Novel silver tetrafluoroborate catalyzed electrophilic cascade cyclization reaction: A facile approach to the synthesis of halo-substituted benzo[a]fluorenols

Article abstract of DOI:10.1021/ol301153t

A facile and novel silver tetrafluoroborate catalyzed electrophilic cascade cyclization reaction to generate halo-substituted benzo[a]fluorenols under mild conditions is disclosed. Good chemical selectivity and mild reaction conditions were involved in the transformation. The halide-containing benzo[a]fluorenols could be further elaborated via palladium-catalyzed cross-coupling reactions to introduce complexity.

Full text of DOI:10.1021/ol301153t

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3588–3591
Novel Silver Tetrafluoroborate Catalyzed
Electrophilic Cascade Cyclization
Reaction: A Facile Approach to the
Synthesis of Halo-Substituted
Benzo[a]fluorenols
Zhiyuan Chen,* Mengjing Zeng, Jianjun Yuan, Qin Yang, and Yiyuan Peng*
Key Laboratory of Functional Small Organic Molecules, Ministry of Education and
College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang,
Jiangxi 330022, China
zchenjx@yahoo.cn; yiyuanpeng@yahoo.com
Received April 28, 2012
ABSTRACT
A facile and novel silver tetrafluoroborate catalyzed electrophilic cascade cyclization reaction to generate halo-substituted benzo[a]fluorenols
under mild conditions is disclosed. Good chemical selectivity and mild reaction conditions were involved in the transformation. The halide-
containing benzo[a]fluorenols could be further elaborated via palladium-catalyzed cross-coupling reactions to introduce complexity.
Transition-metal-catalyzed or electrophile-promoted
carbocyclization reactions with tethered alkynes have pro-
ven to be powerful methods for the selective generation of
functionalized cyclic compounds that are generally not
easily accessible via classical pericyclic reactions.1,2 How-
ever, there are only limited reports concerning the combi-
nation of a transition metal and an electrophile to produce
complex carbocyclic ring systems in a cascade fashions in
the literature.3 Transition-metal-catalyzed electrophilic
cascade cyclization reactions show undeniable benefits,
such as good chemo- or regioselectivity, mild conditions,
as well as high economical and ecological merits.
On the other hand, it is well-known that fused fluorene
derivatives are widely applied in optoelectronic materials
or devices because of their highly conjugated rigid sys-
tems.4 In addition, they have been widely found in numer-
ous natural products that exhibit interesting biological
activities.5 For instance, kinamycin D,5a which was pro-
duced by Streptomyces murayamaensis and recognized as
5-diazobenzo[b]fluorene, is a naturally occurring diazo
(1) For selected reviews on transition-metal-catalyzed cyclizations,
see: (a) Larock, R.; In Acetylene Chemistry. Chemistry, Biology, and
Material Science; Diederich, F., Stang, P., Tykwinski, R., Eds.; Wiley-VCH:
New York, 2005; Chapter 2, pp 51À99. (b) Nicolaou, K.; Edmonds, D.;
Bulger, P. Angew. Chem. 2006, 118, 7292. Angew. Chem., Int. Ed. 2006,
(4) (a) Shimizu, A.; Tobe, Y. Angew. Chem., Int. Ed. 2011, 50, 6906.
(b) Liu, T.; Xing, C.; Hu, Q. Angew. Chem., Int. Ed. 2010, 49, 2909.
(c) Allard, S.; Forster, M.; Souharce, B.; Thiem, H.; Scherf, U. Angew.
Chem., Int. Ed. 2008, 47, 4070.
(5) (a) Gould, S.; Melville, C.; Cone, M.; Chen, J.; Carney, J. J. Org.
Chem. 1997, 62, 320. (b) Gould, S.; Tamayo, N.; Melville, C. R.; Cone,
M. C. J. Am. Chem. Soc. 1994, 116, 2207. (c) Mithani, S.; Weeratunga,
G.; Taylor, N. J.; Dmitrienko, G. I. J. Am. Chem. Soc. 1994, 116, 2209.
(d) Omura, S.; Nakagawa, A.; Yamada, H.; Hata, T.; Furusaki, A.;
Watanabe, T. Chem. Pharm. Bull. 1973, 21, 931. (e) Furusaki, A.;
Matsui, M.; Watanabe, T.; Omura, S.; Nakagawa, A.; Hata, T. Isr. J.
Chem. 1972, 10, 173. (f) Gould, S.; Melville, C. Bioorg. Med. Chem. Lett.
1995, 6, 51.
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45, 7134. (c) Michelet, V.; Toullec, P. Y.; Genet, J. Angew. Chem., Int.
Ed. 2008, 47, 4268. (d) Yu, Z.; Wang, Y.; Wang, Y. Chem. Asian J. 2010,
5, 1072. (e) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.;
Simonneau, A. Chem. Rev. 2011, 111, 1954.
(2) For selected reviews on electrophilic cyclization, see: (a) Rodrıguez,
F.; Fananas, F. J. In Handbook of Cyclization Reactions; Ma, S., Ed.;
Wiley-VCH: New York, 2010; Vol. 2, p 951. (b) Godoi, B.; Schumacher,
R.; Zeni, G. Chem. Rev. 2011, 111, 2937.
(3) For a Brønsted acid promoted electrophilic cascade cyclization to
generate heterocyclic compounds, see:Ali, S.; Li, Y.; Anwar, S.; Yang,
F.; Chen, Z.; Liang, Y. J. Org. Chem. 2012, 77, 424.
r
10.1021/ol301153t
Published on Web 07/11/2012
2012 American Chemical Society

compound that possesses modest antitumor properties and
antibiotic activity against Gram-positive organisms.5b,c
The kinobscurinone, benzo[b]fluorenone, was recently
shown to be a more advanced intermediate in kinamycin
biosynthesis.5f Thus, there has been increased interest in
aimed at determining the reaction outcomes and optimiz-
ing the reaction conditions.11 Unfortunately, no reaction
was occurred in the presence of 1.0 equiv of FeCl3 or a
catalytic amount of FeCl3 6H2O or CuI as indicated by
3
crude NMR analysis. However, to our delight, when the
starting materials were treated with 10 mol % of Cu(OTf)2
under N2, a product was isolated in 36% yield, which was
identified as the iodo-substituted benzo[a]fluorenol 2a.
The structure of 2a was verified by X-ray diffraction
analysis (see the Supporting Information). No reaction
occurred when a hard Lewis acid, such as In(OTf)3 or
NiCl2(PPh3)2, was employed as the catalyst in the reaction.
Further screening of the catalysts demonstrated that
AgOTf was a choice for this transformation, while a
cocatalyst system of PPh3AuCl and AgOTf was examined
to be less reactive. Moreover, the significance of silver salts
as catalysts revealed that AgBF4 was shown to be the best
catalyst as compared with the other silver salts such as
Ag2CO3, AgF, AgNO3, and AgSbF6, and the yield could
be improved to 76% when the reaction was performed in
dichloromethane.
ꢀ
the synthesis of the fused benzofluorenes. Recently, Saa
and co-workers reported the thermal cycloaromatization
of aryldiacetylenes such as nonconjugated benzotriynes
and benzodiynes to produce benzo[b]fluorene and benzo-
[c]fluorene skeletons (Scheme 1, eq 1).6 In 2009, Zhang
reported a four-example reaction of gold-catalyzed tan-
dem reactions to afford benzo[a]fluorenols in moderate to
good yields.7 These achievements, however, often suffered
from harsh reaction conditions, tedious separation proce-
dures of the isomers, or limited examples.
In the context of our ongoing interest in transition-metal-
catalyzed tandem reactions,8 as well as our efforts to
develop efficient methodologies in electrophilic cycliza-
tion reactions,9 we envisioned that under a suitable Lewis
acid catalyst the 1,6-diyn-4-en-3-ols 1a might react with
an electrophile to give a fused benzofluorene under envi-
ronmentally benign conditions. Herein, we disclose the first
transition-metal-catalyzed electrophilic cascade cyclization
reaction of benzodiyne 1 with an halogen-containing elec-
trophile, which affords the unexpected halo-containing
benzo[a]fluorenols 2 at room temperature in moderate to
good yields (Scheme 1, eq 2).10 The obtained halogen-contain-
ing benzo[a]fluorenols could be decorated to more complex
products via palladium-catalyzed cross-coupling reactions.
Surprisingly, the Lewis acid catalyst was found to be
crucial for the transformation. Brønsted acids, such as
TsOH H2O and CF3COOH, or in the absence ofa catalyst
3
were proved to be inert for the product generation.11 No
improvements of the yield were observed when water or
˚
4 A MSaswellasaninorganicbasewereaddedasadditives
into the reaction. The amount of catalyst was examined as
well. On decreasing the catalyst loading to 2 mol %, the
reaction time was prolonged but the yield was decreased
dramatically(32% yield). Furtherevaluationofthesolvent
effects revealed that dichloromethane (DCM) was the
solvent of choice, and other organic solvents such as
CHCl3, CH3CN, MeOH, toluene, or THF did not facil-
itate the formation of 2a. Elevating the reaction tempera-
ture to 30 °C could slightly shorten the reaction time to
about 10 h but resulted in a lower yield.
Scheme 1. Research Design
As for the electrophilic reagent screening, we were
pleased to find that the N-bromosuccinimide (NBS)
worked as an electrophile and could also be involved in
the transformation. For the reaction of N-chlorosuccini-
mide (NCS) with 1,6-diyn-4-en-3-ols 1, the starting mate-
rials could also be consumed, but the reaction became
complex and some unidentified compounds were isolated.
In addition, we found that in the presence of 2.5 equiv of
Initial investigations using 1,6-diyn-4-en-3-ols 1a and an
electrophile, N-iodosuccinimide (NIS), as substrates were
(9) (a) Chen, Z.; Ding, Q.; Yu, X.; Wu, J. Adv. Synth. Catal. 2009,
351, 1692. (b) Chen, Z.; Yu, X.; Su, M.; Wu, J. Adv. Synth. Catal. 2009,
351, 2702. (c) Chen, Z.; Su, M.; Yu, X.; Wu, J. Org. Biomol. Chem. 2009,
7, 4641. (d) Chen, Z.; Pan, X.; Wu, J. Synlett 2011, 964. (e) Ding, Q.;
Chen, Z.; Yu, X.; Peng, Y.; Wu, J. Tetrahedron Lett. 2009, 50, 340.
(10) For a recent iodocyclization reaction of 1,6-diyn-4-en-3-ols 1
with ICl to produce 1,3-diiodinated naphthalene derivatives, see: (a)
Wang, L.; Zhu, H.; Lu, L.; Yang, F.; Liu, X.; Liang, Y. Org. Lett. 2012,
14, 1990. For recent examples on gold-catalyzed cyclizations of benzo-
diyne 1, see: (b) Chen, Y.; Chen, M.; Liu, Y. Angew. Chem., Int. Ed. 2012,
51, 6181. (c) Chen, Y.; Chen, M.; Liu, Y. Angew. Chem., Int. Ed. 2012,
51, 6493.
ꢀ
(6) (a) Rodrıguez, D.; Castedo, L.; Domınguez, D.; Saa, C. Tetra-
hedron Lett. 1999, 40, 7701. (b) Rodrıguez, D.; Navarro, A.; Castedo, L.;
Domınguez, D.; Saa, C. Org. Lett. 2000, 2, 1497. (c) Rodrıguez, D.;
ꢀ
ꢀ
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Navarro-Vazquez, A.; Castedo, L.; Domınguez, D.; Saa, C. Tetrahedron
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Lett. 2002, 43, 2717. (d) Rodrıguez, D.; Quintas, D.; Garcıa, A.; Saa, C;
Domınguez, D. Tetrahedron Lett. 2004, 45, 4711.
(7) (a) Liu, L.; Zhang, J. Angew. Chem., Int. Ed. 2009, 48, 6093.
(b) Liu, L.; Wei, L.; Zhang, J. Adv. Synth. Catal. 2010, 352, 1920.
(8) (a) Chen, Z.; Gao, L.; Ye, S.; Ding, Q.; Wu, J. Chem. Commun.
2012, 48, 3975. (b) Gao, L.; Ye, S.; Ding, Q.; Chen, Z.; Wu, J.
Tetrahedron 2012, 68, 2765. (c) Ye, C.; Chen, Z.; Wang, H.; Wu, J.
Tetrahedron 2012, 68, 5197. (d) Chen, Z.; Ye, C.; Gao, L.; Wu, J. Chem.
Commun. 2011, 47, 5623. (e) Chen, Z.; Zheng, D.; Wu, J. Org. Lett. 2011,
13, 848. (f) Chen, Z.; Wu, J. Org. Lett. 2010, 12, 4856. (g) Chen, Z.; Yu,
X.; Wu, J. Chem. Commun. 2010, 46, 6356. (h) Yu, X.; Chen, Z.; Yang,
X.; Wu, J. J. Comb. Chem. 2010, 12, 374. (i) Chen, Z.; Yang, X.; Wu, J.
Chem. Commun. 2009, 3469.
(11) For details, see the Supporting Information.
(12) (a) Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9, 5259. (b) Shi, M.;
Horn, M.; Kobashiya, S.; Mayr, H. Chem.ÀEur. J. 2009, 15, 8533.
(13) (a) Kitamura, T.; Kobayashi, S.; Taniguchi, H.; Rappoport, Z.
J. Org. Chem. 1982, 47, 5003. (b) Chen, X.; Lu, P.; Wang, Y. Chem.ÀEur. J.
2011, 17, 8105.
Org. Lett., Vol. 14, No. 14, 2012
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NaHCO3, electrophiles such as iodine, bromine, or ICl
could also be reactive under the AgBF4-catalyzed electro-
philic cascade cyclization reactions. Although all of the
iodine-, bromine-, or ICl-mediated tandem electrophlic
cyclizations generally have lower yields than those of
the corresponding outcomes when using NIS or NBS
as substrates, these reactions, however, could also
serve as an alternative method for the generation of
halo-substituted benzo[a]fluorenols. For details, see
the Supporting Information.
With the optimized conditions [AgBF4 (5 mol %), DCM,
10 °C] in hand, we next explored the generality of
the reaction, and the results are summarized in Table 1.
For all cases, 1,6-diyn-4-en-3-ols 1 reacted with NXS
(X = I, Br) leading to the corresponding iodo- or bromo-
substituted benzo[a]fluorenols 2 in moderate to good yields.
Table 1. Sequential Electrophilic Cyclization Reaction to Halogen-Substituted Benzo[a]fluorene Derivatives
a Isolated yield based on 1,6-diyn-4-en-3-ols 1. b PMP = 4-MeO-Ph.
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Org. Lett., Vol. 14, No. 14, 2012

For example, good results were obtained when an electron-
withdrawing group was linked on the R1 position; the 4-F
substituted compound 1b reacted with NIS or NBS gave the
corresponding iodo- or bromo-substituted benzo[a]fluorenols
2c or 2d in 63% or 61% yield, respectively (Table 1, entries 3
and 4). The structure of 2c was confirmed by X-ray
diffraction analysis as well (Supporting Information). A
good result (2e, 78% yield) was obtained when 5-NO2 was
attached on the R1 ring (Table 1, entry 5). The reaction
got complex when two electron-donating group substi-
tuted compound 1d was involved in the reaction, which
might be because the two electron-rich triple bonds
became too reactive for the silver-catalyzed electrophilic
cascade cyclization reaction, thus leading less chemos-
electivity under the reaction conditions (Table 1, entry 6).
Good yields were observed when electron-donating
groups such as MeO- or Et- were linked on the R3 position
(Table 1, entries 7À10). While for the F-substitued starting
material 1g reacted with NIS and NBS, the corresponding
halo-substitued benzo[a]fluorenols 2j and 2k could be
isolated in 45% and 50% yield, respectively (Table 1,
entries 11 and 12). However, an inferior yield was dis-
played when 4-CON(nPr)2-substituted benzodiyne 1h was
employed in the reaction (35% yield, Table 1, entry 13).
The reaction was complex when 4-NH2- or 4-N(Boc)2-
substituted benzodiyne was employed, and an unknown
molecular could be isolated from the reaction of
4-COOMe-substituted benzodiyne with NIS (data not
shown in Table 1).
For various substituents attached on the R2 aromatic
ring, it could be noticed from Table 1 that generally
moderate yields were obtained whether electron-donating
or -withdrawing groups were attached. For example, the
R2 = 3-F-substituted benzodiyne 1i reacted with NIS and
NBS to give the corresponding products 2m and 2n in 42%
and 43% yield, respectively (Table 1, entries 14 and 15).
For the reaction of substrate 1j (R2 = 4-MeO) with NIS,
the desired benzo[a]fluorenol product 2m could be formed
in 35% yield under the standard conditions (Table 1, entry 16),
whereas a complex reaction was observed for the sub-
strate 1k substituted with two strong electron-donating
groups (Table 1, entry 17). For further examination of
other R2 = 4-F- or 3-F-substituted substrates 1lÀn, the
reactions also proceeded smoothly to give the desired
products in moderate yields (Table 1, entries 18À21).
On the basis of the above observations, we proposed a
plausible mechanism for the silver tetrafluoroborate cata-
lyzed electrophilic cascade cyclization reaction (Scheme 2).
We envisioned that in the presence of a Lewis acid catalyst
one of the triple bonds was easily converted to iodonium
intermediate A, which could be electrophilically attacked
by the other triple bond through an intramolecular 6-endo
cyclization to produce a vinylic carbocation B.12 Subse-
quently, intramolecular FriedelÀCrafts cyclization oc-
curred, and then the proton was released to produce an
intermediate D.13 Finally, the hydroxy group, which
could be activated by the Lewis acid, would be released
and the positive ion intermediate E would undergo an
intramolecular tautomerization to produce the tertiary
carbonium F, and 2a was produced.
Scheme 2. Plausible Mechanism for the Silver Tetrafluorobo-
rate Catalyzed Sequential Electrophilic Cyclization Reaction
As mentioned above, the halo-substituted benzo[a]
fluorenols 2 could be easily elaborated via known
palladium-catalyzed cross-coupling reactions.9a,c Thus,
the palladium-catalyzed SuzukiÀMiyaura cross-coupling
reactionofcompound 2awith4-methylphenylboronicacid
in DMFÀH2O at 50 °C proceeded smoothly to give the
corresponding product 3a in a quantitative yield. In the
Sonogashira coupling reaction, compound 2a reacted with
4-methylphenylacetylene to give rise to the desired product
4a in 83% yield.
In summary, we have described a novel silver tetrafluo-
roborate catalyzed electrophilic cascade cyclization reac-
tion of benzodiyne with electrophiles for the construction
of halo-substituted benzo[a]fluorenols, which could be
further elaborated via palladium-catalyzed cross-coupling
reactions to introduce complexity. The reaction features high
chemoselectivity and mild reaction conditions toward the
starting benzodiynes, introducing the possibility of preparing
a tetracyclic nucleus scaffold from which a library of opto-
electronically or biologically interesting compounds could be
constructed. More detailed mechanistic studies and further
application of this chemistry are underway in our laboratory.
Acknowledgment. We thank the National Natural
Science Foudation of China (No. 21162012) and the
Jiangxi Provincial Education Department (GJJ12192) for
financial support. Support from Jiangxi Normal Univer-
sity is gratefully acknowledged.
Supporting Information Available. Experimental pro-
cedure, characterization data, 1H and 13C NMR spectra
of compounds 2, and X-ray data for compounds 2a and
2c (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
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