Expedient synthesis of phenanthrenes via In(III)-catalyzed 6-exo-dig cycloisomerization

Article abstract of DOI:10.1021/ol400073s

This paper documents the first example of In(III)-catalyzed selective 6-exo-dig hydroarylation of o-propargylbiaryls and their subsequent double-bond migration to obtain functionalized phenanthrenes. Electron-rich biaryl substrates undergo hydroarylation

Full text of DOI:10.1021/ol400073s

ORGANIC
LETTERS
2013
Vol. 15, No. 4
920–923
Expedient Synthesis of Phenanthrenes via
In(III)-Catalyzed6-Exo-Dig Cycloisomerization
Yongseok Kwon,† Hyunkyung Cho,† and Sanghee Kim*,†
College of Pharmacy, Seoul National University, San 56-1, Shilim, Kwanak,
Seoul 151-742, Korea
pennkim@snu.ac.kr
Received January 10, 2013
ABSTRACT
This paper documents the first example of In(III)-catalyzed selective 6-exo-dig hydroarylation of o-propargylbiaryls and their subsequent double-
bond migration to obtain functionalized phenanthrenes. Electron-rich biaryl substrates undergo hydroarylation more effectively, and the
substrates with various types of substituents on the alkyne can also be smoothly and selectively converted to phenanthrenes.
Phenanthrenes are of widespread interest because of
their versatile physicochemical properties, such as photo-
conduction and electroluminescence.1 In addition to their
potential applications in materials science, they are present
within a large number of natural products and synthetic
compounds that exhibit diverse biological activities.2 Con-
sequently, many synthetic routes have been developed for
their preparation.3,4
captured attention because of its ability to create a large
variety of polysubstituted phenanthrenes. Examples of
either base- or metal cation-mediated carbocyclization of
o-alkynylbiaryls are known in the literature (Scheme 1). In
the base-catalyzed cyclization, the base induces the iso-
merization of alkynylbiaryls to the allene intermediate,
which then undergoes a 6π cycloaddition and subsequent
aromatization at very high temperatures (Scheme 1, eq 1).5
In the metal-catalyzed process, metal ion coordination to
the triple bond renders it susceptible to nucleophilic attack
by the aromatic ring under relatively mild conditions.
Although the metal-catalyzed cyclization of o-alkynylbiar-
yls potentially allows for substantial structure variations,
and it can be applied in the related heterocyclic series, it
inherently possesses a regioselectivity problem: the com-
petition between 6-endo-dig and 5-exo-dig cyclization path-
ways. The selectivity between these two cyclization modes
varies depending on the metal catalysts employed as well as
the substrate type. For example, the 6-endo cyclization of
o-alkynylbiaryls is preferred when transition-metal catalysts,
such as Fe(OTf)3, PtCl2, AuCl3, or GaCl3 (Scheme 1, eq 2),
are employed.6 Substrates with an electron-withdrawing
Among the various synthetic approaches to phenanthrenes,
the intramolecular hydroarylation of o-alkynylbiaryls has
ꢀ
(1) (a) Machado, A. M.; Munaro, M.; Martins, T. D.; Davila,
L. Y. A.; Giro, R.; Caldas, M. J.; Atvars, T. D. Z.; Akcelrud, L. C.
Macromolecules 2006, 39, 3398. (b) Liu, R.; Farinha, J. P. S.; Winnik,
M. A. Macromolecules 1999, 32, 3957. (c) Lewis, F. D.; Burch, E. L.
J. Phys. Chem. 1996, 100, 4055.
(2) (a) Banwell, M. G.; Bezos, A.; Burns, C.; Kruszelnicki, I.; Parish,
C. R.; Su, S.; Sydnes, M. O. Bioorg. Med. Chem. Lett. 2006, 16, 181.
ꢀ
(b) Schmidt, J. M.; Mercure, J.; Tremblay, G. B.; Page, M.; Kalbakji, A.;
Feher, M.; Dunn-Dufault, R.; Peter, M. G.; Redden, P. R. J. Med.
Chem. 2003, 46, 1408. (c) Gellert, E. J. Nat. Prod. 1982, 45, 50.
(3) For reviews, see: (a) Jørgensen, K. B. Molecules 2010, 15, 4334.
(b) Li, Z.; Jin, Z.; Huang, R. Synthesis 2001, 16, 2365. (c) Floyd, A. J.;
Dyke, S. F.; Ward, S. E. Chem. Rev. 1976, 76, 509.
(4) For recent representative examples, see: (a) Xia, Y.; Liu, Z.; Xiao,
Q.; Qu, P.; Ge, R.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2012, 51,
5714. (b) Bera, K.; Sarkar, S.; Jalal, S.; Jana, U. J. Org. Chem. 2012, 77,
8780. (c) Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc.
2011, 133, 6557. (d) Chen, Y.; Li, G.; Liu, Y. Adv. Synth. Catal. 2011,
353, 392. (e) Kuninobu, Y.; Tatsuzaki, T.; Matsuki, T.; Takai, K. J. Org.
Chem. 2011, 76, 7005. (f) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. T.;
Heo, J.-N. J. Org. Chem. 2008, 73, 495.
(5) Wang, Y.; Burton, D. J. Org. Lett. 2006, 8, 5295.
€
(6) (a) Furstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264.
€
(b) Mamane, V.; Hannen, P.; Furstner, A. Chem.;Eur. J. 2004, 10,
4556. (c) Komeyama, K.; Igawa, R.; Takaki, K. Chem. Commun. 2010,
46, 1748.
r
10.1021/ol400073s
Published on Web 02/01/2013
2013 American Chemical Society

group on the alkyne show a pronounced preference for
5-exo cyclization to give the fluorene framework.6a,b The
electron-neutral and electron-deficient o-alkynylbiaryls
undergo palladium-catalyzed 5-exo-dig cyclization, pre-
sumably via a mechanism involving CꢀH activation
(Scheme 1, eq 3).7
to curtail the influence of substituents on the reactivity of
the alkyne group. The o-propargylbiaryl 1a was prepared
via the addition of lithium acetylide to the readily available
o-bromomethylbiaryl.11 Various alkynophilic transition
metal catalysts (10 mol %) were screened in toluene
(0.05 M) at 80 °C (oil bath) to test the viability of the
cycloisomerization. The representative results are sum-
marized in Table 1. AuCl3, AuCl, AgOTf, Pd(OAc)2,
and [Ru(CO)3Cl2]2 failed to give the desired product,
resulting in the recovery of unreacted starting material or
decomposition products. When PtCl2 or PtCl4 was em-
ployed, the desired product 2a was formed in low conver-
sion and yield (entries 1 and 2). Substantial amounts of the
starting material remained even after 40 h. The 7-endo-dig
product, dibenzo[a,c]cycloheptene 3a, was also formed as a
minor component in a 3ꢀ4:1 ratio.12 The reaction using
GaCl3 as the catalyst resulted in good conversions and gave
appreciable yield. However, the regioselectivity was poor,
resulting in a mixture of 2aand 3a in a ca. 4:1 ratio (entry 3).
Among the tested metal species, In(III) salts most
efficiently induced the desired 6-exo-dig hydroarylation
and subsequent double-bond migration. The reactions
with InCl3 and InBr3 resulted in rapid, efficient (1 h at
80 °C), and extremely regioselective conversions that
resulted in phenanthrene 2a in 91% and 89% yields,
respectively (entries 4 and 5). Upon changing the solvent
to 1,2-dichloroethane (1,2-DCE), the yield improved to
94% with little effect on the reaction rate (entry 6).
Remarkably, we found that the In(III)-promoted reaction
was not air and moisture sensitive. The reaction also
proceeded in the presence of water and air to give the
product in 91% yield (entry 7). When the reaction was
conducted in the presence of D2O, two deuterium
atoms were incorporated at the benzylic position (66%,
d-incorporation) in the phenanthrene product 2a.
When the InCl3 loading was reduced to 5 mol %
(entry 8) or the temperature was lowered to 50 °C
(entry9), thereaction timeincreasedbutthe yieldremained
almost the same. Under these milder conditions, we could
identify the intermediate that was gradually converted to
phenanthrene 2a. The identity of this intermediate was
revealed to be a nonaromatized intermediate 4a.12 Heating
of the isolated 4a in 1,2-DCE at 80 °C for 1 h in the
presence of InCl3 resulted in the aromatized product 2a,
while performing the same reaction without the InCl3 did
not yield 2a. The identification of intermediate4a strength-
ened our mechanistic hypothesis that the phenanthrene
framework was formed from o-propargylbiaryl substrates
via 6-exo-dig intramolecular hydroarylation and subsequent
exo-endo double bond migration as shown in Scheme 2.
Another possible mechanistic path via an allene inter-
mediate 5a (Scheme 2) was considered.13 However, this
Scheme 1. Cycloisomerizations of o-Alkynylbiaryls and
o-Propargylbiaryls
We envisioned that the intramolecular hydroarylation
of o-propargylbiaryls would offer an alternative opportu-
nity for the synthesis of phenanthrenes (Scheme 1, eq 4).
Both possible competing cyclization modes of o-propar-
gylbiaryls, 6-exo-dig and 7-endo-dig, are favored by Bald-
win’s rules.8 The selectivity between these two cyclization
modes is influenced by many factors including the stereo-
electronic properties and the enthalpy of the transition
state.8,9 On the basis ofentropic considerations, which play
an important role in the kinetics of ring closure,10 the for-
mation of a six-membered ring is predicted to be faster than
the formation of seven-membered ring. Thus, we anticipated
that the carbocyclization of o-propargylbiaryls would pre-
ferentially afford a phenanthrene framework. Herein, we
report the first example of an In(III)-catalyzed selective
6-exo-dig hydroarylation of o-propargylbiaryls and a sub-
sequent double-bond migration that forms phenanthrenes.
The electron-rich propargylbiaryl 1a (Table 1) was
initially chosen as the model substrate to test the viability
of the envisioned cycloisomerization process. A simple
primary alkyl group was attached to the alkyne terminus
(7) (a) Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130,
5636. (b) Chernyak, N.; Gevorgyan, V. Adv. Synth. Catal. 2009, 351, 1101.
(8) (a) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
(b) Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111, 6513.
(9) For selected examples of 6-exo-dig/7-endo-dig cyclization, see:
(a) Girard, A.-L.; Enomoto, T.; Yokouchi, S.; Tsukano, C.; Takemoto,
Y. Chem. Asian J. 2011, 6, 1321. (b) Ramana, C. V.; Induvadana, B.;
Srinivas, B.; Yadagiri, K.; Deshmukh, M. N.; Gonnade, R. G. Tetrahedron
2009, 65, 9819. (c) Liu, B.; De Brabander, J. K. Org. Lett. 2006, 8, 4907.
(10) Iluminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(11) See the Supporting Information for synthesis details.
(12) The mixture was virtually inseparable by thin-layer chromato-
graphy. The separation was achieved by HPLC.
(13) For recent examples of allene-mediated construction of phenan-
threnes from the propargylic substrates, see: (a) Saifuddin, M.; Agarwal,
P. K.; Kundu, B. J. Org. Chem. 2011, 76, 10122. (b) Spencer, W. T.;
Frontier, A. J. J. Org. Chem. 2012, 77, 7730.
Org. Lett., Vol. 15, No. 4, 2013
921

Table 1. Screening of the Transition-Metal Catalysts for the
Cycloisomerization of Substrate 1a
Scheme 2. Plausible Mechanism for the Cycloisomerization of
o-Propargylbiaryl
catalyst
temp time
(°C) (h) 2a:3aa
yieldb
(%)
entry (10 mol %) solvent
1
2
3
4
5
6
7
8
9
PtCl2
PtCl4
GaCl3
InCl3
InBr3
InCl3
InCl3
toluene
toluene
toluene
toluene
toluene
1,2-DCE
80 40
80 40
74:26
80:20
82:18
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
23 (38)
32 (60)
86
80
80
80
80
6
1
1
1
3
6
4
91
89
94
1,2-DCE/H2Oc 80
91
d
InCl3
InCl3
toluene
80
50
89
terminal alkyne 1b underwent smooth cycloisomerization
to afford the desired phenanthrene 2b in nearly quantita-
tiveyield. Thesilyl-substitutedalkynes, 1cand 1d, afforded
the same product 2b also in excellent yield. This product
was presumably formed via a protodesilylation of the
initially generated vinylsilane intermediate.15 The reaction
of alkyne 1e bearing a secondary alkyl group produced the
corresponding product in high yield. The aryl-substituted
alkyne 1f readily produced 2f in 80% yield. Substrate 1g
containing an electron-withdrawing ester group afforded
the cyclization product 2g in nearly quantitative yield.
Interestingly, the reaction of propargyl alcohol 1h did
not afford the expected alcoholic product, but instead
resulted in the formation of the dehydrated olefinic prod-
uct 2h in 70% yield. The cycloisomerization of olefin-
substituted alkyne 1i resulted in the double-bond migration
product 2i in 86% yield, presumably via a [1,5] hydride shift.
1,2-DCE
91
a Determined by 1H NMR analysis. b Isolated yield of the mixture of
2a and 3a. The values in parentheses indicate the yield of recovered
starting material. c Ratio of 1,2-DCE/H2O = 10:1. d Using 5 mol % of
catalyst.
pathway is less likely because such an intermediate was not
detected when the reaction of 1a was analyzed. In addition,
the In(III) catalyzed reaction of o-propargylbiaryl sub-
strate 6e (vide infra), which is less reactive in hydroaryla-
tion than 1a, resulted in nearly quantitative recovery of the
starting material under the reaction conditions described
in entry 6 of Table 1. This result again implies that the
alkyneꢀallene isomerization is not feasible under the
above conditions and that an allene intermediate is not
involved in the mechanism.14 Furthermore, our experiments
with allene 5a11 gave rise to different reaction outcomes when
compared to those with 1a. For example, the exo-double
bond intermediate 4a was not observed when 5a was sub-
jected to the mild conditions used in entry 8. Phenanthrene
product 2a was formed from allene 5a under the conditions
stated in entry 6. However, the yield (71%) and conversion
rate (4 h) were lower compared with those from the pro-
pargylic substrate 1a. These results also support our mechan-
istic rationale that an allene intermediate is not involved.
Encouraged by the remarkable results of In(III)-
mediated cycloisomerization of 1a, we next investigated
analogouspropargylbiarylshavingafunctionalizedalkyne
group. The results are summarized in Scheme 3. Remark-
ably, all compounds investigated showed an exclusive
preference for the 6-exo-dig hydroarylation over the con-
ceivable 7-endo mode. Under the conditions described in
entry 6 (Table 1) (10 mol % of InCl3, 1,2-DCE, 80 °C),
Scheme 3. In(III)-Catalyzed Cycloisomerization
(14) The alkyneꢀallene isomerization occurs generally under the
catalysis of base. The acid-catalyzed isomerization is rare.
922
Org. Lett., Vol. 15, No. 4, 2013

To further explore the reaction scope, the cycloisome-
rization chemistry has been extended to other biaryl
systems (Scheme 4). In general, substrates bearing elec-
tron-donating groups on the upper ring of the biaryl
backbone underwent effective 6-exo-dig carbocyclization
to give phenanthrenes after isomerization. Under the stan-
dard conditions (10 mol % of InCl3, 1,2-DCE, 80 °C,
method A), the 3,4-dimethoxy- or 3,4-methylenedioxy-
substituted substrates 6a and 6b smoothly afforded the
corresponding phenanthrene products 7a and 7b in high
yield. However, the reaction required longer time com-
pared with that of the 3,5-dimethoxy substrate 1a. The
cycloisomerization of the 3-methoxy functionalized 6c
afforded a 5:1 regiochemical mixture of 6-exo-dig products
7c and 7c0, with more favorable cyclization to the less
hindered position. Substrate 6d with 2-methoxy group and
substrate 6e with unfunctionalized biaryl backbone failed
to produce the desired phenanthrene products, under the
standard reaction conditions. We hypothesize this result is
because of the lower nucleophilicity of their aryl ring
moieties. Most of the starting material was recovered un-
changed. However, under the more forcing reaction con-
ditions (20 mol % of InBr3, toluene, reflux, method B),
these substrates produced the corresponding products 7d
and 7e, albeit in low yield. Interestingly, changing the propyl
group of 6e to an alkyne-activating group such as phenyl or
ester group dramatically increased the yield (7f and 7g vs 7e).
In summary, the electrophile-promoted nucleophilic
cyclization of o-propargylbiaryls was investigated as an
alternative and selective path for synthesizing phenan-
threnes. Environmentally benign In(III) efficiently in-
duced the desired hydroarylation and subsequent double-
bond migration. In the In(III)-catalyzed reactions, the
complete regioselectivity of intramolecular hydroaryla-
tion for six- over seven-membered rings is noteworthy.
Similar to the other electrophile-promoted hydroaryla-
tion reactions, the electron-rich biaryl substrates undergo
hydroarylation more effectively. Unlike hydroarylation of
o-alkynylbiaryl systems, diverse substituent groups are
Scheme 4. Scope of Cycloisomerization of o-Propargylbiaryls
tolerated on the alkynyl carbon of o-propargylbiaryl sys-
tem without affecting the regioselectivity. This efficient
synthetic protocol for securing functionalized phenan-
threnes might be applied to the synthesis of related hetero-
cyclic series.
Acknowledgment. This work was supported by Midca-
reer Researcher Program (KRF-2010-0027312) and the
World Class University Program (R32-2008-000-10098-0)
of the National Research Foundation of Korea (NRF)
grant funded by the Korean Government (MEST). This
work was also supported by NRF (NRF-2012-Fostering
Core Leaders of the Future Basic Science Program).
Supporting Information Available. 1H and 13C NMR
spectra of all new compounds and preparation of starting
materials. This material is available free of charge via the
Internet at http://pubs.acs.org.
(15) The 1-(trialkylsilyl)acetylene systems were found to be stable
under the conditions employed.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
923