Metal-free cycloisomerizations of: O -alkynylbiaryls

Article abstract of DOI:10.1039/c8cc05484c

We describe a novel and highly efficient metal-free strategy to construct 9,9-disubstituted fluorenes and phenanthrenes via the TfOH-catalyzed cycloisomerizations of o-alkynylbiaryls. Notably, the significant effects of the electronic properties and steric hindrance of the alkyne terminus on the reaction selectivity have been observed.

Full text of DOI:10.1039/c8cc05484c

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Metal-free cycloisomerizations of
o-alkynylbiaryls†
Cite this: Chem. Commun., 2018,
54, 12455
Jingyi Zhang,a Siqi Li,a Yan Qiao,b Cheng Peng,a Xiao-Na Wang *a and
Junbiao Chang*a
Received 7th July 2018,
Accepted 11th October 2018
DOI: 10.1039/c8cc05484c
rsc.li/chemcomm
We describe a novel and highly efficient metal-free strategy to
construct 9,9-disubstituted fluorenes and phenanthrenes via the
TfOH-catalyzed cycloisomerizations of o-alkynylbiaryls. Notably,
the significant effects of the electronic properties and steric
hindrance of the alkyne terminus on the reaction selectivity have
been observed.
The cycloisomerization of o-alkynylbiaryls is a powerful tool for
the construction of fused five- and six-membered ring systems.
Although the thermal cycloisomerization of o-ethynylbiphenyl
provides
a straightforward access to phenanthrene, this
method suffers from high reaction temperature (700 1C) and
a tedious isolation procedure caused by the benzazulene
byproduct.1 Therefore, transition-metal catalysts have been
sought to promote the cycloisomerization of o-alkynylbiaryls
under mild conditions. Palladium-catalyzed exclusive 5-exo-dig
cyclization of o-alkynylbiaryls possessing aryl or ethoxycarbonyl
terminal groups on the alkyne moiety (TG = aryl or CO2Et)
was first reported by Gevorgyan and co-workers (Scheme 1a),2
but this cyclization preferred electron-deficient substrates and
no other new methods about 5-exo-dig cyclization of o-alkynyl-
biaryls have been developed.
In striking contrast, the transition-metal-catalyzed exclusive
or predominant 6-endo-dig cycloisomerization of o-alkynyl-
biaryls possessing electron-rich aryl rings (R2 = electron-donating
groups) was first demonstrated by Fu¨rstner et al. (Scheme 1b).3
Since the pioneering report from Fu¨rstner’s group, this method
Scheme 1 Cycloisomerizations of o-alkynylbiphenyls.
a Collaborative Innovation Center of New Drug Research and Safety Evaluation,
Henan Province, Key Laboratory of Advanced Drug Preparation Technologies,
Ministry of Education, School of Pharmaceutical Sciences, and College of
Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001,
P. R. China. E-mail: wangxn@zzu.edu.cn, changjunbiao@zzu.edu.cn
b School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001,
P. R. China
has been extensively applied to the syntheses of polyaromatic
molecules,4–6 natural products, and bioactive molecules.7 Mean-
while, since the electron-deficient o-alkynylbiaryls are essentially
incompatible with the reaction conditions, and the cyclization of
unsymmetrically substituted substrates suffers from poor regio-
selectivity, new methods have been developed to solve these
limitations (Scheme 1b). For instance, Fe(OTf)3-catalyzed 6-endo-
dig cyclization of electron-deficient biarylalkynes has been achieved,
even though the alkyne moiety is limited to those possessing a
† Electronic supplementary information (ESI) available: Experimental procedures,
characterization data, crystallographic data in CIF and NMR spectra. CCDC
1847362 (7ee). For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c8cc05484c
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Table 1 Cycloisomerization of o-ethynylbiarylsa,b
phenyl terminal (TG = Ph).8 In(OTf)3 or AuCl(IPr)/AgSbF6-catalyzed
6-endo-dig cyclization of biarylalkynes possessing a phenylselenyl
terminal (TG = SePh) was successfully performed irrespective of the
substitution pattern on the aryl rings involved in the C–C bond
formation.9 Furthermore, Pt(II), Au(I), or Ru(II)-catalyzed 6-endo-dig
cyclizations of diverse o-ethynylbiaryls were described.10 And it was
mentioned that the selectivity and efficiency for the cycloisomeriza-
tion of o-alkynylbiaryls should be controlled by the judicious choice
of neutral/cationic metal–ligand combinations.10c
In regard to the metal-free cycloisomerization of o-alkynyl-
biphenyls,11,12 to the best of our knowledge, only one strategy
has been realized via the DBU-catalyzed 6-endo-dig cyclization
of o-alkynylbiphenyls possessing n-butyl or benzyl terminal
(TG = n-Bu or Bn). However, this protocol is limited to the alkyl
terminal groups on the alkyne moiety since the cyclization
proceeds via an allene intermediate (Scheme 1c).12 Herein, a
metal-free exclusive 5-exo-dig cycloisomerization of o-ethynyl-
biaryls for efficient synthesis of 9,9-disubstituted fluorenes is
described. Further study on the cyclization of the terminally
substituted o-alkynylalkynes was achieved, and we found that
the reaction selectivity is controlled by the properties of the
terminal groups on the alkyne moiety. Furthermore, the metal-
free intramolecular cyclization in a 6-endo mode enables highly
selective and orthogonal access to phenanthrenes as well
(Scheme 1d).
We initiated our investigation by the reaction of o-ethynyl-
biphenyl 1a in various solvents under the catalyst TfOH.
After condition optimization (see ESI† for details), the scope
and generality of this cyclization have been assessed (Table 1).
It was found that a variety of o-ethynylbiaryls 1 bearing electron-
neutral, electron-deficient, and even more surprisingly electron-
a
Reactions were carried out using 1 (0.20 mmol) and 2 (0.50 mL) with
b
TfOH (0.10 mmol) at 100 1C. Isolated yields.
rich aryl rings, underwent highly effective 5-exo-dig cyclization to And even more surprisingly, the phenethyl-terminated biaryl-
give 9,9-disubstituted fluorenes 3aa–nf in good to excellent yields. alkyne 5f efficiently provided a spirocyclic product 6f0, which
Various groups, such as OMe, Cl, F, CO2Me, Ac, and NO2, were may be formed via a Friedel–Crafts cyclization of 5f followed by
perfectly tolerated under the reaction conditions. Although the an intramolecular Friedel–Crafts alkylation reaction. Biarylalkyne
cyclizations of o-ethynylbiaryls 1 with toluene 2a exhibited not 5g possessing a trimethylsilyl terminal worked well, affording
high regioselectivity (3aa–ea), significant effects of the nature of R2 the desilication product fluorene 6g in high yield, albeit with
on o-ethynylbiaryl 1 have been observed. The regioselectivity could poor diastereoselectivity. And we were especially excited by the
be improved by increasing steric or electron-donating effect of R2. discovery that the biarylalkyne 5h bearing a cyclopropyl terminal
Remarkably, cyclization of all o-ethynylbiaryls 1a–n with anisole underwent selective 6-endo-dig cycloisomerization followed by
2f proceeded with high para-selectivity, merely providing an intermolecular Friedel–Crafts alkylation reaction, leading to
PMP-substituted fluorenes, except that the nitro-substituted phenanthrene 7h in excellent yield with moderate diastereo-
o-ethynylbiaryl 1i (R2 = NO2) delivered small amount of selectivity. Subsequently, various aryl-terminated biarylalkynes
o-methoxyphenyl-substituted fluorene 3if–o. It should be noted 5i–s were tested and reacted smoothly with almost quantitative
that, besides the fluorene 3hf, the reaction of acetyl-substituted conversion. Meanwhile significant effects on the reaction selec-
o-ethynylbiaryl 1h (R2 = Ac) afforded the product 3(hf)0 due to tivity were observed. The transformation of the reaction selec-
the carbonyl group further taking part in the Friedel–Crafts tivity from 5-exo-dig to 6-endo-dig cyclization is most likely due to
alkylation reaction. It was noteworthy that o-ethynylbiaryls the increasing electron-donating property (5p–s vs. 5i–n) and
having 2-thienyl and 3-thienyl groups were compatible with steric hindrance (5o vs. 5m) of the terminal groups on the alkyne
the reaction conditions, leading to the desired geometrically moiety. Once again the interesting phenomenon has occurred,
pure fluorenes 3of and 3pf.
just as the nitro-substituted o-ethynylbiaryl 1i, the nitro-substituted
Subsequently, we assessed how terminally substituted biarylalkynes 5i and 5j (R1 = p-NO2C6H4) resulted small amount
biarylalkynes 5 behave under the reaction conditions (Table 2). of o-methoxyphenyl-substituted fluorenes 6i–o and 6j–o, and
Alkyl-terminated biarylalkynes 5a–e proceeded smoothly to give the 5-exo-dig cyclization of the other biarylalkynes with anisole
the 5-exo-dig cyclization products 6a–e in excellent yields even proceeded with high para-selectivity, merely providing PMP-
for the bulkier n-hexyl- and benzyl-substituted biarylalkynes. substituted fluorenes. In order to better verify the effect of the
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Table 2 Cycloisomerization of terminally substituted o-alkynylbiaryls
a
b
Unless otherwise noted, reactions were carried out using 5 (0.20 mmol) with TfOH (0.10 mmol) in anisole (0.50 mL) at 100 1C. Isolated yields.
Reactions were carried out using 5 (0.20 mmol) with TfOH (0.10 mmol) in CH2Cl2 (0.50 mL) at rt except for the synthesis of 7u using anisole as
c
solvent. TMS = trimethylsilyl.
electronic properties of the terminal groups (5, R1) on the an inverse aldol reaction and intermolecular Friedel–Crafts
reaction selectivity, we turned our attention to the cycloiso- alkylation reaction with anisole. On the contrary, due to the
merization of benzoyl-terminated biarylalkyne and biarylyn- electron-donating effect of the nitrogen lone pair, all of the
amides. As our proposed, due to the electron-withdrawing biarylynamides underwent highly effective 6-endo-dig cyclization
effect of the benzoyl group, biarylalkyne 5t (R1 = Bz) gave the to give 9-aminophenanthrenes with good to excellent yields.
cyclization product fluorene 6t0 with high yield, which was Various biarylynamides bearing electron-withdrawing, and
probably formed via a 5-exo-dig cyclization of 5t followed by electron-donating sulfonyl systems, were compatible with the
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powerful cycloisomerizations will be eagerly adopted into the
repertoire of synthetic chemistry.
We thank the National Natural Science Foundation of China
(No. 81330075 and 81803406), the China Postdoctoral Science
Foundation (No. 2015M570631 and 2016T90672), and the
Outstanding Young Talent Research Fund of Zhengzhou
University (No. 1621331003) for financial support and Professor
Richard P. Hsung of the University of Wisconsin–Madison for
invaluable discussions.
Conflicts of interest
There are no conflicts to declare.
Notes and references
Scheme 2 Proposed mechanisms for the cycloisomerizations.
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Calculations on this cycloisomerizations (see the ESI†) mapped
out the mechanisms in Scheme 2. The cycloisomerizations
are initiated by the formation of acetylene-cation A or C. For the
o-ethynylbiaryl
1 or o-alkynylbiaryl 5 possessing electron-
withdrawing terminal groups, the preferred electrophilic attack
of a carbon by the proton from catalyst TfOH gives A, which is
intercepted by the adjacent aromatic ring, a C–C bond formation
with concomitant release of the catalyst ensues to form 4.
A subsequent Friedel–Crafts reaction of 4 via the carbocation B
furnishes the final product 3 or 6; on the contrary, for the
o-alkynylbiaryl 5 possessing electron-donating or bulky terminal
groups, the preferred electrophilic attack of b carbon by the proton
gives C, which is intercepted by the adjacent aromatic ring with
concomitant release of the catalyst affording phenanthrene 7.
In conclusion, we have demonstrated the first example of
metal-free exclusive 5-exo-dig cycloisomerization of o-ethynylbiaryls,
and this method allows for efficient cyclization of a variety
o-ethynylbiaryls possessing electron-neutral, electron-rich, and
electron-deficient aryl rings into the corresponding fluorenes.
Further study on this metal-free cycloisomerization of the terminally
substituted biarylalkynes was achieved, and the significant effects of
the alkyne terminus on the reaction selectivity have been observed
for the first time. Furthermore, the metal-free intramolecular cycli-
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12458 | Chem. Commun., 2018, 54, 12455--12458
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