Efficient synthesis of 9-aryldihydrophenanthrenes by a cascade reaction involving arynes and styrenes

Article abstract of DOI:10.1021/ol4033094

A mild, general, and transition-metal-free protocol for the synthesis of 9,10-dihydrophenanthrenes is reported. The aryne generated by the fluoride-induced 1,2-elimination of 2-(trimethylsilyl)aryl triflates undergoes an efficient cascade reaction initiated by the Diels-Alder reaction with the differently substituted styrenes leading to the formation of 9-aryl-9,10-dihydrophenanthrene derivatives in moderate to good yields.

Full text of DOI:10.1021/ol4033094

Letter
pubs.acs.org/OrgLett
Efficient Synthesis of 9‑Aryldihydrophenanthrenes by a Cascade
Reaction Involving Arynes and Styrenes
Sachin Suresh Bhojgude,† Anup Bhunia,† Rajesh G. Gonnade,‡ and Akkattu T. Biju*,†
‡
†Organic Chemistry Division, and Center for Materials Characterization, CSIR-National Chemical Laboratory, Dr. Homi Bhabha
Road, Pune 411008, India
S
* Supporting Information
ABSTRACT: A mild, general, and transition-metal-free protocol
for the synthesis of 9,10-dihydrophenanthrenes is reported. The
aryne generated by the fluoride-induced 1,2-elimination of 2-
(trimethylsilyl)aryl triflates undergoes an efficient cascade
reaction initiated by the Diels−Alder reaction with the differently
substituted styrenes leading to the formation of 9-aryl-9,10-
dihydrophenanthrene derivatives in moderate to good yields.
a
Table 1. Optimization of the Reaction Conditions
9,10-Dihydrophenanthrene derivatives are common structural
units in various biologically active natural products.1 For
example, the natural product juncusol,2 isolated from the plant
Juncus roemerianus, has been reported to possess anticancer and
antimicrobial activity, lusianthridin3 isolated from the orchid
Lusia indiuisa has been found to show α,α-diphenyl-2-
piorylhydrasyl (DPPH) free-radical scavenging activity, and
orchinol4 isolated from Orchis militaris shows antifungal activity
(Figure 1). Due to their diverse biological activity, 9,10-
dihydrophenanthrenes are interesting synthetic targets. Con-
sequently, the search for efficient and flexible synthetic methods
toward this structural motif has attracted much attention in
synthetic organic chemistry.5
The synthesis of 9,10-dihydrophenanthrenes has been known
to utilize transition-metal-catalyzed cyclization reactions involv-
ing arynes.6,7 Based on our interest in the transition-metal-free
carbon−carbon and carbon-heteroatom bond-forming reactions
using arynes,8 we envisioned that the [4 + 2] cycloaddition
reaction between arynes generated by the fluoride induced 1,2-
elimination of 2-(trimethylsilyl)aryl triflates9 with styrenes
could result in a straightforward access to 9,10-dihydrophenan-
threnes. This will be interesting as the utility of styrenes as the
4π-component in Diels−Alder reactions utilizing a carbon−
carbon double bond, which is involved in aromaticity,10 can
also meet with problems involving polymerizations11 as side
reactions. Notably, the reaction of styrene with aryne generated
from 2-bromofluorobenzene leading to the formation of 9-
phenyl 9,10-dihydrophenanthrene was reported by Dilling as
early as 1966.12 However, this reaction is limited to only one
example. Subsequently, the reaction of aryne with α-methyl
F−
temp
(°C)
time
(h)
yield of 3a yield of 3a′
b b
entry source
solvent
(%)
(%)
1
2
3
4
5
6
CsF
CH3CN
THF
30
30
30
60
30
30
12
12
12
12
6
77 (73)
59
<5
21
<1
<5
<5
<5
c
KF
TBAF
CsF
CsF
CsF
THF
<1
CH3CN
CH3CN
CH3CN
71
69
d
12
74
a
Standard conditions: 1a (0.25 mmol), 2a (0.60 mmol), fluoride
b
source (4.8 equiv), solvent (1.0 mL), 30 °C, and 12 h. The yields
were determined by 1H NMR analysis of crude products using CH2Br2
as the internal standard. Isolated yield on 0.50 mmol scale in
c
d
parentheses. 4.8 equiv of 18-crown-6 was used as an additive. 2.0
equiv of 2a and 4.0 equiv of CsF was used.
styrene furnishing three products in low yields was developed
by Wolthuis and Cady.13 Moreover, the reaction of
tetrahalogenated arynes with styrenes leading to the Diels−
Alder adduct was reported by Heaney and co-workers.14
Intriguingly, in these reports, the substrate scope appears to be
very narrow, and the yields are relatively low and hence a
general system remains to be established. Herein, we report a
mild, general, and efficient reaction of arynes with styrenes
proceeding via a cascade reaction initiated by the Diels−Alder
reaction leading to the highly selective synthesis of 9-aryl-9,10-
dihydrophenanthrene derivatives in moderate to good yields
and with broad scope.
Received: November 15, 2013
Figure 1. Selected naturally occurring 9,10-dihydrophenanthrenes.
© XXXX American Chemical Society
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Scheme 1. Proposed Mechanism of the Reaction
Scheme 4. Reaction of Arynes with Substituted Styrenes
Scheme 2. Reaction in CD3CN
Scheme 3. Substrate Scope of the Cascade Reaction:
Variation of Styrenes
a
Table 2. Variation of the Aryne Moiety
a
a
General conditions: 1 (0.50 mmol), 2a (1.20 mmol), CsF (4.8
equiv), CH3CN (2.0 mL), 30 °C, and 12 h. Yields of the isolated
b
c
products are given. Determined by 1H NMR. Inseparable mixture of
d
regioisomers. 17% of 1:1 adduct was also isolated.
The present study commenced with the treatment of 1-
methyl-4-vinylbenzene 1a and the aryne generated in situ from
2-(trimethylsilyl)aryl triflate 2a9 using 4.8 equiv of CsF in
CH3CN as the solvent. Under these conditions, a facile reaction
occurred, leading to the formation of 9-phenyl-9,10-dihydro-
phenanthrene derivative 3a in 77% yield (73% isolated yield).15
Interestingly, the product 3a′ derived from the initial Diels−
Alder reaction followed by proton transfer was observed only in
trace amounts (based on 1H NMR spectroscopy, Table 1, entry
1). When the reaction was carried out using KF (in the
a
General conditions: 2a (1.20 mmol), 1 (0.50 mmol), CsF (4.8
equiv), CH3CN (2.0 mL), 30 °C and 12 h. Yields of the isolated
b
products are given. Reaction was run on 0.25 mmol scale.
presence of 18-crown-6) as the fluoride source, 3a was formed
in a reduced yield of 59%, whereas 3a′ was formed in 21%
(entry 2). The use of tetrabutylammonium fluoride (TBAF) as
fluoride source was not found to be beneficial (entry 3).
B
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Increasing the reaction temperature and reducing the reaction
time lowered the yield of 3a (entries 4 and 5). Lowering the
amount of 2a below 2.4 equiv lowered the yield of 3a (entry 6).
The mechanistic rationale for this cascade process is shown
in Scheme 1. The reaction of styrene with aryne generated from
2 lead to the generation of the adduct 4. This adduct 4 can add
to another molecule of electrophilic aryne in a concerted ene
reaction leading to the formation of the desired product 3.16
Alternatively, in a stepwise pathway, 4 can be deprotonated by
the basic medium followed by nucleophilic addition to another
molecule of aryne generating intermediate 5, which can be
protonated leading to the formation of 3.
An indication for the Diels−Alder/ene cascade reaction
comes from the fact that the reaction of 1b with 2a carried out
in CD3CN resulted in the smooth formation of the
corresponding protonated product 3b in 67% (Scheme 2).
The incorporation no deuterium in the product sheds light on a
concerted process.
Regarding the scope of this cascade reaction (Scheme 3), the
unsubstituted styrene worked well and various styrenes with
electronically dissimilar groups at the 4-position of the aromatic
ring of 1 were well tolerated, furnishing 9-aryl-9,10-
dihydrophenanthrene derivatives in good yields and excellent
selectivity for the cascade product (3a−e). Moreover,
substitution is tolerated at 2-position of the aromatic ring of
1 resulting in the desired product in moderate yield (3f). As
anticipated, styrenes with substituent at the 3-position of the
aromatic ring resulted in the formation of regioisomers. When
the substituent was −OMe, the regioisomers were separable by
column chromatography and the products 3g and 3gg were
isolated in 35% and 27% yield, respectively. However, when the
substituent was Br, the regioisomers 3h and 3hh were
inseparable and were observed in 50% overall yield and 3:1
ratio. Additionally, 3,4-disubstituted styrenes afforded regioiso-
meric products in moderate to good yields (3i, 3ii and 3j, 3jj).
The reaction of 1-vinylnaphthalene afforded the cascade
product 3k in 43% along with the 1:1 adduct 3k′ in 26%
yield. Interestingly, 2-vinylthiophene and 2-vinylbenzofuran
also furnished the desired product albeit in low to moderate
yields, further expanding the scope of this cascade reaction (3l,
3m). In addition, trans-stilbene afforded the 9,10-diaryl 9,10-
dihydrophenanthrene 3n in 70% along with the 1:1 adduct 3b
in 17% yield. Furthermore, β-methyl styrene underwent
efficient cascade reaction with arynes leading to the formation
of 9-methyl-10-phenyl-9,10-dihydrophenanthrene in 59% yield
and a good diastereomeric ratio of 15:1 in favor of the cis
isomer.
Notably, the reaction of aryne with styrenes having an
electron-withdrawing group at the 4-position of the ring
afforded the 1:1 adduct derived from the initial Diels−Alder
reaction followed by proton transfer in good yield (Scheme 4,
eq 1, 3p′−r′). In these cases, the cascade product was observed
in only <10% yield.17,18 Moreover, the reaction of 1,1-
diphenylethylene 1s with aryne furnished the 1:1 adduct 3b
in 73%. Furthermore, this reaction worked well with electroni-
cally different aryne precursors, and the desired dihydrophe-
nanthrenes were isolated in good yields (3s′−u′). Rather
unexpectedly, the reaction of aryne with 4-nitrostyrene resulted
in the formation of 3-nitrophenanthrene 3v′ in 72% yield
(Scheme 4, eq 2).19
furnished the 9-phenyl-9,10-dihydrophenanthrene derivatives
3w−y in moderate to good yields (entries 1−3). In the case of
3x, the structure was unequivocally confirmed by single-crystal
X-ray analysis.20 Notably, some of the fluorinated 9,10-
dihydrophenanthrenes are known to have potential applications
as liquid crystalline materials.21 Moreover, the 3,6-dimethyl-
substituted symmetrical aryne precursor 2e worked well to
afford the product 3z in 82% yield (entry 4). In addition, 3-
methoxyaryne generated from 2f furnished a separable mixture
of regioisomers 3α and 3αα in ∼3:1 ratio and overall yield of
67%, further expanding the scope of this reaction (entry 5).
Formation of two products in this case is due to the possibility
of two Diels−Alder adducts formed between styrene 1a and
aryne 2f.
In conclusion, we have developed a mild, general, and
efficient procedure for the synthesis of functionalized 9,10-
dihydrophenanthrenes by a unique cascade reaction involving
arynes and styrenes.22 The present method utilized styrenes as
an unconventional diene component in the Diels−Alder
reaction. The protocol presented herein is likely to find
application for the transition-metal-free synthesis of 9,10-
dihydrophenanthrene derivatives.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, single-crystal X-ray data of
3x, and characterization data of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: at.biju@ncl.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by CSIR-New Delhi (as part of the
XII Five Year plan programme under ORIGIN-CSC0108).
S.S.B. and A.B. thank CSIR-New Delhi for the award of Senior
Research Fellowships. We thank Ms. Ananya Panda (Raven-
shaw University, Odisha) for experimental support, Mr.
Digvijay Porwal (CSIR-NCL) for helpful discussions, and Dr.
P. R. Rajamohanan (CSIR-NCL) for the NMR spectra.
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