Phenanthrenes/dihydrophenanthrenes: The selectivity controlled by different benzynes and allenes

Article abstract of DOI:10.1039/d0cc06300b

A method for the intermolecular annulation of benzynes with allenes is disclosed. This protocol utilized allenes as an unconventional diene component for the selective synthesis of phenanthrenes and dihydrophenanthrenes under the control of different benzyne precursors, featuring high atom-economy and good functional group compatibility. Density functional theory (DFT) calculations reveal that different migratory routes of the aromatic C-H bond are crucial for the observed selectivity. This journal is

Full text of DOI:10.1039/d0cc06300b

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Phenanthrenes/dihydrophenanthrenes: the
selectivity controlled by different benzynes and
Cite this:DOI: 10.1039/d0cc06300b
allenes†
Received 18th September 2020,
Accepted 10th November 2020
Liangliang Yao, Bo Fang, Qiong Hu, Yu Lei, Li Bao and Yimin Hu
*
DOI: 10.1039/d0cc06300b
rsc.li/chemcomm
A method for the intermolecular annulation of benzynes with allenes is ortho-silyl aryltriflates) with an allene. Cheng and co-workers
disclosed. This protocol utilized allenes as an unconventional diene described NiBr2(PPh3)4-catalyzed co-cyclotrimerization of benzynes
component for the selective synthesis of phenanthrenes and dihydro- with allenes that afforded 10-methylene-9,10-dihydrophenanthrenes
phenanthrenes under the control of different benzyne precursors, in moderate yields.9a Li and co-workers developed a protocol for the
featuring high atom-economy and good functional group compatibility. selective synthesis of phenanthrene derivatives via palladium-
Density functional theory (DFT) calculations reveal that different migra- catalyzed annulation of benzynes with allenes.9b Nevertheless, the
tory routes of the aromatic C–H bond are crucial for the observed approaches used in these studies were catalyzed by transition
selectivity.
metals, and a 2 : 1 benzyne : allene adduct was isolated as the major
product. Hexadehydro-Diels–Alder (HDDA)-derived benzynes10 have
Phenanthrenes and dihydrophenanthrenes are valuable skeletons unique advantages in the construction of cyclic compounds with
found in many natural products and pharmaceutically active good regioselectivity.11
compounds1,2 such as gymnopusin,1a confusarin,1b halofantrine,1c
Herein, we developed a selective route controlled by different
lusianthridin,2d and orchinol,2e and display a broad spectrum of benzynes with the same allene for constructing different polycyclic
biological activities (e.g., antiviral and anticancer activities) aromatic compounds. HDDA-derived benzynes and allenes in
(Scheme 1a). Efficient synthesis of phenanthrenes and dihy- toluene typically yield multifunctional, fused dihydrophenanthrene
drophenanthrenes is constantly required by the pharmaceutical derivatives, whereas classical method-derived benzynes with allenes
industry, and represents the longstanding goal of organic in acetonitrile provide polysubstituted phenanthrene derivatives as
chemists. In this context, a variety of powerful methods have the major products (Scheme 1b). Although the closely related [4+2]
been established. These methods include the metal-catalyzed reactions of benzynes with styrene derivatives resulting in different
Ullman–McMurry reaction,3 Pschorr reaction,4 Mallory cycliza-
tion of stibenes,5 cyclization of alkynylated biaryls,6 and [4+2]
annulation of biphenyls.7 Although useful, these methods
often suffer from harsh reaction conditions and not available to
introduce new functional groups. Therefore, efficient methods
with a greater diversity of substituents for the synthesis of
functionalized phenanthrene derivatives are still highly desirable.
Benzynes have been recently employed in the construction of
cyclic compounds.8 Phenanthrenes and dihydrophenanthrenes
have been produced by trapping classical method-derived
benzynes (i.e., formed by fluoride-induced ortho-elimination of
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, China.
E-mail: yiminhu@ahnu.edu.cn
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization of all new compounds. CCDC 1966582, 1966583 and
Scheme 1 Selected natural and biologically active scaffolds containing
phenanthrene and dihydrophenanthrene and our work.
1966585. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/d0cc06300b
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Table 1 Preparation of fused dihydrophenanthrenes 4ab
products containing a phenanthrene/dihydrophenanthrene skeleton
are extensively studied,12 the selectivity is quite special as observed
for the formation of each product from different sources of
benzynes. The compounds prepared via these two reaction pathways
have multiple rings, variable structures, and wide application
prospects in pharmaceutical synthesis compared to general phenan-
threnes and dihydrophenanthrenes.
First, we used tetrayne (1a) as a precursor for an HDDA-
derived benzyne with ethyl 4-phenylbuta-2,3-dienoate (2a) to
optimize the reaction conditions. Several phenomena were
observed when the experimental conditions were modified.
Screening results demonstrated that the reaction temperature
affected the reaction. The yield of the target product 4a
was greatly enhanced to 80% upon increasing the reaction
temperature to 100 1C (8 h) with dry toluene as the solvent.
When the reaction was conducted at 120 1C for 8 h, the yield of
4a decreased to 71%. Investigation of catalysts indicated that
the Pd catalytic system was the most effective system in
cyclization, but the reaction proceeded well without metal
catalysts or other additives. We investigated the reactions in
acetonitrile, nitromethane and 1,4-dioxane and found that
toluene was most effective. Collectively, the optimal conditions
were identified as follows: 1.0 equiv. of tetraynes reacted with
1.1 equiv. of allenes in toluene at 100 1C for 8 h.
Having determined the optimal reaction conditions, the
scope of this reaction was further investigated (Table 1). Various
products (4a–4n) were readily isolated in good to excellent yields
(ranging from 68% to 87%) from the reactions of tetraynes with
ethyl 4-phenylbuta-2,3-dienoate. The effect of different tetrayne
substrates on the product yield was examined. Since tetrayne
substrates bearing different esters (OEt, OMe, and OiPr) were
well tolerated, the yields were almost the same (4a (80%), 4f
(78%), and 4i (80%)). By contrast, the substituted groups in
the aryl ring of tetraynes bearing electron-donating groups,
including meta-Me, para-Me, and para-Et (4d, 4g, and 4k),
exhibited higher yields than the electron-withdrawing groups,
such as para-Cl and para-F (4e and 4h), likely because the
electron-withdrawing groups decreased the reactivity. Com-
pound 4c was isolated with the highest yield (87%) among the
examined substrates. Furthermore, ethyl 4-(4-fluorophenyl)buta-
2,3-dienoate participated in the reaction to afford good yields of
4l (84%) and 4m (86%). Notably, the N-tetrayne substrate that
contained alkyl groups instead of phenyl or substituted phenyl
groups also generated products with good regioselectivity (4n (70%)).
These results demonstrated the potential of the direct functionaliza-
tion of HDDA-derived benzynes with allenes for the synthesis of
multifunctionalized dihydrophenanthrenes. The structures of 4a
and 4k were confirmed by X-ray diffraction.13
In contrast to the behavior of the HDDA-derived benzynes, the
classical method-derived benzynes provided a different outcome
when kept in toluene solution at 100 1C for 8 h. Only a trace amount
of the expected HDDA-derived benzyne cyclization product was
observed. Instead, ethyl 2-(phenanthren-9-yl)acetate 5a was isolated
as the principal product formed in this experiment. We presumed
a
Reaction conditions: tetraynes 1 (1.0 mmol), allenes 3 (1.1 mmol),
b
toluene (2 mL), stirred at 100 1C for 8 h. Yield of the isolated product
after flash column chromatography.
Given the interest in phenanthrene compounds, a reaction
that this result may be attributed to the different migratory routes of scheme for accessing classical method-derived benzynes
the aromatic C–H bond.
with allenes was designed. After a brief screening of different
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Table 2 Preparation of polysubstituted phenanthrenes 5ab
the synthesis of polysubstituted phenanthrenes. The structure of 5j
was confirmed by X-ray diffraction.13
A reaction mechanism was proposed and further elucidated
by density functional theory (DFT) calculations at the
B3LYP+D3(BJ)/6-311+G(2d,p) level of theory (see the ESI†) to
gain further insight into the reaction mechanisms and selec-
tivity in product distribution. We used a structurally simplified
HDDA-derived benzyne intermediate IN1 from 1a as the start-
ing point of this investigation. Intermolecular annulation of
IN1 with the allene derivative 3a resulted in adduct IN2.
Computational data suggested that this annulation reaction
should be a concerted process with the unique transition state
TS1. Subsequently, an intramolecular hydrogen transfer via TS2
afforded product 4a with high selectivity.14 The computed free-
energy variations validated the rationality of the proposed
reaction mechanism. The barrier height of IN2 generation
was 6.9 kcal molꢀ1, and that of the intramolecular hydrogen
transfer was 24.7 kcal molꢀ1. Both processes were feasible at
100 1C (Scheme 2).
Transformation of the benzyne intermediate into IN3
(Scheme 3) is predicted to occur through two individual steps
from 2a and CsF.15 Similarly, the in situ generated benzyne
undergoes intermolecular cycloaddition with 3a via TS3 to
produce IN4. On the one hand, the intermediate IN4 undergoes
intramolecular hydrogen transfer to generate IN6/5a by Path
A/Path B via TS4/TS5 which should overcome a considerably
high barrier (52.4 and 31.0 kcal molꢀ1). On the other hand, the
interaction of IN4 with Fꢀ formed a stable complex IN5 through
base-assisted intermolecular hydrogen transfer.16 Thus, the
thermodynamically and kinetically favorable formation of IN5
via Path C provided the observed phenanthrene product 5a via
a
Reaction conditions: classical method-derived benzyne precursors
2 (1.0 mmol), allenes 3 (1.1 mmol), CsF (3.0 equiv.), CH3CN (2 mL),
stirred at 60 1C for 12 h. Yield of the isolated product after flash
b
c
column chromatography. The regioisomer ratio of the crude mixture
was determined by 1H NMR.
reaction parameters, including fluoride source, solvent, tempera- TS6.
ture, and molar ratio of reactants, the optimal reaction conditions
In summary, we obtained polysubstituted phenanthrenes and
were identified as follows: allene derivative 3a (1.1 equiv.), classical dihydrophenanthrenes using different benzyne intermediates
method-derived benzyne precursor 2a (1.0 equiv.), and CsF trapped by the same allenes. In this reaction, allene was utilized
(3.0 equiv.) as the fluoride source in acetonitrile at 60 1C for 12 h. as an unconventional diene component in the intermolecular
As shown in Table 2, a series of products (5a–5j) were readily isolated annulation which was conducted without any catalyst but exhibited
from the reactions of allenes 3 with the classical method-derived high atom economy in producing different types of products. DFT
benzyne precursors 2, and the yields ranged from 58% to 80%. We
explored the substitution at R3 with R1 = H and found that the
reactions of nonsubstituted substrates 2a with 3b and 3c generated
products 5b and 5c, in 58% and 77% yields, respectively. The higher
yield of 5c is a consequence of an electron-withdrawing group that
increases the reactivity of phenyl allene. The naphthyl allene deri-
vative was successfully converted into the corresponding product 5d
with 63% yield. In addition, when unsymmetrical classical method-
derived benzyne precursors were used in these cyclizations, mixtures
of regioisomers ((5e/5e0)–(5h/5h0)) were obtained. It should be noted
that these mixtures were not separated into individual isomers,
and regioisomer ratios were determined by 1H NMR analysis.
Interestingly, when an ortho-OMe-substituted classical method-
derived benzyne precursor was employed, the corresponding
products 5i and 5j were isolated in 80% and 71% yields, respectively,
and with good regioselectivity likely because of steric hindrance.
These results demonstrated the potential of the direct functionaliza-
Scheme 2 DFT based mechanistic study of the HDDA-derived benzyne
tion of the existing classically generated benzynes with allenes for intermediate IN1 cyclization with allene 3a in CH3CN.
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