Selective Synthesis of Phenanthrenes and Dihydrophenanthrenes via Gold-Catalyzed Cycloisomerization of Biphenyl Embedded Trienynes

Article abstract of DOI:10.1021/acs.orglett.0c03067

Readily available o′-alkenyl-o-alkynylbiaryls, a particular type of 1,7-enynes, undergo a selective cycloisomerization reaction in the presence of a gold(I) catalyst to give interesting phenanthrene and dihydrophenanthrene derivatives in high yields. The solvent used provokes a switch in the evolution of the gold intermediate and plays a key role in the reaction outcome.

Full text of DOI:10.1021/acs.orglett.0c03067

pubs.acs.org/OrgLett
Letter
Selective Synthesis of Phenanthrenes and Dihydrophenanthrenes
via Gold-Catalyzed Cycloisomerization of Biphenyl Embedded
Trienynes
́
́
́
Ana Milian, Patricia García-García,* Adrian Perez-Redondo, Roberto Sanz, Juan J. Vaquero,
́
and Manuel A. Fernandez-Rodríguez*
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ABSTRACT: Readily available o′-alkenyl-o-alkynylbiaryls, a particular
type of 1,7-enynes, undergo a selective cycloisomerization reaction in
the presence of a gold(I) catalyst to give interesting phenanthrene and
dihydrophenanthrene derivatives in high yields. The solvent used
provokes a switch in the evolution of the gold intermediate and plays a
key role in the reaction outcome.
regioselectively afford phenanthrenes substituted at the carbon
next to the arene that acts as a nucleophile (Ar1) in the catalytic
process (Scheme 1a).9 Herein, we describe that, in the presence
of cationic gold(I) catalysts,10 related o′-alkenyl-o-alkynylbiar-
yls, a particular type of 1,7-enynes,11 selectively react to
produce phenanthrenes substituted at the carbon bonded to the
henanthrenes and their dihydro derivatives have attracted
Pconsiderable attention due to their widespread occurrence
in natural products and pharmaceuticals with biological
activities, which have led to their application in the treatment
of microbial or viral infections, allergies, cancer, and malaria.1
Moreover, phenanthrenes, which are small polycyclic aromatic
hydrocarbons (PAHs),2 also exhibit outstanding electro-
chemical and photophysical properties with wide-ranging
applications in organic optical and electronic materials.3 As a
consequence, intensive efforts to construct phenanthrene
skeletons with different substitution patterns have been made.
The methods described include oxidative alkene-arene or
arene−arene couplings in vinyl biaryls and stilbenes;4 intra-
molecular McMurry coupling of suitable 2,2′-disubstituted
biaryls or related carbonyl or olefin metathesis and carbene
dimerizations;5 aryne annulations;6 metal- or visible-light-
induced intermolecular cyclizations of ortho-functionalized
biaryl derivatives with acetylenes;7 metal-catalyzed sequential
Csp2−Csp2 bond-forming reactions;8 and electrophilic cyclo-
isomerizations of o-alkynylbiaryls.9 However, these methods
require harsh reaction conditions, densely functionalized
starting materials, and multistep routes and/or display limited
substrate scope and tolerance to functionalities. In addition,
procedures to access nonsymmetric and/or selectively sub-
stituted phenanthrenes are scarce. As such, the development of
efficient methodologies to synthesize phenanthrenes, or their
derivatives, with selective substitution is highly desirable.
In these regard, metal-catalyzed 6-endo carbocyclizations of
biaryls bearing an internal alkyne, which is a general and
straightforward route to furnish the phenanthrene core,
Scheme 1. Regioselective Synthesis of Phenanthrenes by
Cycloisomerization of o-Alkynylbiaryls
Received: September 14, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03067
© XXXX American Chemical Society
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A

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arene (Ar2) originally linked to the triple bond (Scheme 1b).
Thus, the catalytic method developed provides a comple-
mentary synthetic strategy to the most common one depicted in
Scheme 1a that differs in the substitution pattern at the internal
cycle of the phenanthrene skeleton constructed. Moreover,
upon careful selection of the appropriate reaction conditions,
mainly the solvent, unsymmetrically (9,10)-disubstitued
dihydrophenanthrenes can also be prepared from the same
starting 1,3,5-trien-7-ynes (Scheme 1b).
Based on our experience in the electrophilic cycloisomeriza-
tion of o-alkynylstyrenes,12 we selected 2-(2-methylprop-1-en-
1-yl)-2′-(phenylethynyl)-1,1′-biphenyl (1a) as the model for
assessing the reactivity in the presence of gold catalysts. This
substrate possesses two nucleophilic entitiesan arene and the
olefinin suitable locations to react with the alkyne that would
render different cycloadducts. However, we envisioned that the
high substitution of the alkene would facilitate its selective 6-exo
nucleophilic addition to the metal-activated acetylene, thus
furnishing the desired phenanthrene skeleton. At the outset,
several gold-derived complexes as catalysts, and different
solvents, were studied, and the most significant results are
summarized in Table 1.
occurred when THF was employed as solvent and the reaction
was conducted for an extended reaction time (72 h). Thus,
under these conditions, dihydrophenanthrene 3a could be
selectively obtained in good yield (entry 3). Analogous
experiments in THF varying the gold catalyst gave varying
mixtures of 2a, 3a, and other unidentified products, whereas no
evolution was observed in other solvents such as acetonitrile or
DMF.13
The minimal influence of the nature of the cationic gold(I)
complex was determined from the outcome of the reactions
conducted in DCM. Thus, phenanthrene 2a was obtained
exclusively from model substrate 1a in quantitative yields with
most of the catalysts tested, including less active gold(III) salts
such as AuCl3 (entries 4−9). Of these gold complexes,
JohnPhosAu(MeCN)SbF6 exhibited a slightly improved
selectivity and no traces of the regioisomeric cycloadduct 3a
could be detected. Moreover, different temperatures or
concentrations resulted in a higher percentage of byproducts,
whereas a limited screening with silver salts showed no
beneficial effect or improvement in this process.13 Finally,
lowering the catalyst loading to 1 mol% or scaling the reaction
to 1 mmol had no impact on either the yield or the reaction
time (entry 10). In summary, an appropriate choice of catalyst
and solvent allows the selective formation of phenanthrene 2a
(entry 10) and dihydrophenanthrene 3a (entry 3).
a
Table 1. Optimization of Reaction Conditions
With these results in hand, and based on previous studies in
the cycloisomerization of 1,n-enynes,10,11c,12,14 we propose the
following mechanism that accounts for the formation of both
phenanthrene derivatives 2a and 3a (Scheme 2).
b
Scheme 2. Proposed Mechanism
entry
[Au]+
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
ArO3PAuCl/AgNTf2
tBu3PAuNTf2
XPhosAuNTf2
JohnPhosAu(MeCN)SbF6
IPrAuCl/AgNTf2
AuCl3
solvent
product
conv (%)
1
2
3
CH2Cl2
toluene
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2a
2a
3a
2a
2a
2a
2a
2a
2a
2a
100 (94)
c
70
d
100 (79)
e
c
4
5
6
7
8
9
100
80
100 (98)
100 (99)
100 (97)
100 (98)
f
g
10
JohnPhosAu(MeCN)SbF6
100 (99)
a
Reactions conducted using 0.05 mmol of 1a in 1 mL of solvent at 25
b
1
°C for 2 h. Conversion estimated by H NMR spectroscopy (300
Hz); isolated yield in parentheses for an experiment conducted with
0.2 mmol of 1a. < 5% of 3a was detected. Significant amounts of 3a
c
d
and other unidentified products were observed. Conducted for 72 h.
e
f
g
Ar = 2,4-(tBu)2C6H3. Conducted with 1.0 mol% of catalyst. Same
isolated yield was obtained in an experiment conducted with 1.0
mmol of 1a.
The reaction of 1a in the presence of 5 mol% PPh3AuNTf2 as
catalyst in dichloromethane at room temperature selectively
afforded the 9-substituted phenanthrene 2a in less than 2 h
(entry 1). Remarkably, the competitive pathway resulting from
addition of the arene to the alkyne, which would produce the
corresponding regioisomeric phenanthrene, described in
Scheme 1a, was not detected. Encouraged by this initial result,
the influence of the solvent on the cycloisomerization of 1a was
explored. Thus, the reaction conducted in toluene also gave 2a
as the major product, albeit with lower conversion and
selectivity (entry 2). From that crude mixture, the formation
of a disubstituted 9,10-dihydrophenanthrene 3a was deter-
mined. Interestingly, a complete switch in the regioselectivity
The reaction is initiated upon activation of the acetylene of
the starting enyne 1a upon coordination to the gold complex,
followed by an intramolecular 6-exo-dig nucleophilic addition of
the alkene moiety to give cationic intermediate I. This
intermediate can be described as the resonance hybrid of two
structures, namely the cyclopropylgold(I) carbene Ia and the
gold-stabilized homoallylic carbocation intermediate Ib, which
delocalizes the positive charge over the molecule. Cyclopropyl
ring expansion of Ia then furnishes the (η2-cyclobutene)gold(I)
complex II,15 which, after ring opening of the cyclobutene and
subsequent demetalation, would lead to phenanthrene 2a and
release the gold catalyst for a new cycle (path a). An alternative
pathway (a′) involving the direct transformation of inter-
B
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mediate I into the final phenanthrene, thus avoiding the
formation of cyclobutene species II, can also be envisioned.16
Both proposed pathways (a/a′) are consistent with the well-
documented gold-catalyzed, single-cleavage type rearrange-
ments of 1,n-enynes, which formally imply 1,3-migration of the
external carbon of the olefin to the acetylene terminal position
of the trienyne 1a.11c,14 On the other hand, intermediate I could
also undergo a proton elimination, thus giving rise to a
vinylgold species III (path b).12 This pathway is preferred if
THF is used as solvent, probably due to the stabilization of the
homoallyl cationic resonance structure Ib, which favors the
elimination event leading to 9,10-dihydrophenathrenes. Sub-
sequent protodemetalation would lead to dihydrophenanthrene
3a and regenerate the catalyst.
(1g), and alkyl groups (1h). However, complex mixtures were
observed with 1d bearing an o-tolyl substituent, and no
evolution was detected with trienyne 1j, which contain a bulkier
TIPS group, or quinoline-derived enyne 1f, under the
optimized reaction conditions or even after heating at reflux
in DCE for 24 h. The outcome for the latter starting material
can be rationalized in terms of consumption of the gold catalyst
by the nitrogenated heterocycle, thus preventing it from
participating in the catalytic cycle. The addition of 1 equiv of
PTSA to the reaction media avoided this catalytic inhibition but
also triggered the formation of 9,10-disubstituted phenanthrene
iso-3f instead of the expected 3f. Interestingly, reaction of
ethynyl-substituted biphenyl 1k occurred to give nearly
equimolecular mixtures of the corresponding phenanthrene
2k and dibenzocycloheptatriene 4k as a result of a formal 7-endo
cyclization (Scheme 4). After some experimentation, phenan-
Having established biphenyl embedded trienyne 1a as a
suitable precursor for the intended selective synthesis of
phenanthrene 2a, we explored the scope of this catalytic
transformation by varying the substitution at the main points of
diversity of the molecule (Scheme 3).
Scheme 4. Cycloisomerization of Terminal Substrate 1k
As shown, the process developed is tolerant to the presence
of a broad range of substituents at the alkyne terminus of the
polyunsaturated substrate 1, including aromatic (irrespective of
their electronic nature) (1a−c), heteroaromatic (1e), alkenyl
Scheme 3. Synthesis of Phenanthrene Derivatives 2*
a
Isolated yield of reaction performed using 0.4 mmol of 1k.
threne 2k could be obtained exclusively in excellent yield using
AuCl3 as catalyst, whereas no improvement in the selectivity for
4k could be achieved.13 Reaction of substrate 1i, which bears a
trimethylsilyl group, gave a mixture of the same compounds 2k
and 4k in a similar ratio, thus indicating that desilylation took
place prior to the cycloisomerization event.
Next, trienynes 1 with different substitution patterns and
electronic properties at the olefin, as well as at the biphenyl
core, were evaluated. Thus, we found that reactions of
substrates 1l−m, alkyl or aryl monosubstituted at the β carbon
of the styrene moiety, selectively produce the corresponding
phenanthrenes 2l−m in good to excellent yields with no 7-endo
adducts being detected, even with terminal trienyne 1n.
Moreover, phenanthrenes 2p−s, which bear electron-donating
or -withdrawing substituents at any of the external arenes of the
tricyclic skeleton, also proved to be accessible in high yields
using the developed methodology starting from appropriately
substituted conjugated enynes 1p−s. No competitive addition
of the arene that would give phenanthrenes with different
substitution patterns (see Scheme 1a), or dihydrophenanthrene
3 formation, was observed for any of the substrates tested, with
the sole exception of substrate 1f (see above). Furthermore, the
structural assignment for phenanthrenes 2, initially determined
on the basis of NMR studies, was confirmed by single-crystal X-
ray diffraction analysis of 2a and 2b (Scheme 3).
We also analyzed the applicability of this catalytic procedure
for the construction of unsymmetrically 9,10-disubstituted
phenanthrenes, which are not easily accessible using other
methods. To this end, less reactive α-disubstituted-β,β-
unsubstituted styrene substrate 1t was synthesized and
submitted to the optimized reaction conditions to afford
cyclobutene compound 5t after 24 h (Scheme 5).17 This
tetracyclic compound 5t, the structure of which was confirmed
*
Isolated yields from reactions performed using 0.4 mmol of 1.
a
b
Conducted in the presence of PTSA (1 equiv) for 24 h. Same dr of
the starting material, with the exception of 2n (1n dr > 10:1).
C
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possess an electron-rich (hetero)arene at the acetylene, led to
moderate yields and mixtures with their phenanthrene isomers
2. Moreover, in this case, substrate 1d, which bears an o-tolyl
group, efficiently evolved to the corresponding dihydrophenan-
threne 3d in good yield. Additionally, the structure of 3q was
confirmed by single-crystal X-ray diffraction analysis (Scheme
6).
Scheme 5. Cycloisomerization of α-Disubstituted-β,β-
unsubstituted Styrene Substrate 1t
In conclusion, we have developed an efficient and solvent-
controlled gold-catalyzed synthesis of phenanthrenes and
dihydrophenanthrenes from easily available biphenyl embed-
ded trienynes 1. These processes occur with good to excellent
yields, broad scope, and complete selectivity. Consequently, the
phenanthrene synthesis described here is complementary to the
well-developed strategy that produces regioisomeric phenan-
threnes resulting from the competitive nucleophilic addition of
biphenyl to the activated alkyne. Further studies on the
reactivity of biphenyl embedded trienynes that provide
straightforward access to other relevant policyclic scaffolds via
new and selective reaction pathways are currently underway in
our laboratories and will be reported in due course.
by single-crystal X-ray diffraction analysis, could be transformed
into the corresponding desired phenanthrene 2t simply by
heating at 90 °C. Moreover, 2t could be directly obtained from
1t by performing the catalytic reaction under the heating
conditions. These experiments both expand the scope of the
developed methodology to the preparation of unsymmetrically
9,10-disubstituted phenanthrenes and support the participation
of cyclobutene species II in the catalytic cycle (see Scheme 2).
Finally, using the optimized conditions for the preparation of
3a, a family of 9,10-dihydrophenanthrenes 3 that proved the
scope and usefulness of this catalytic procedure was synthesized
(Scheme 6). Thus, reactions of selected substrates with
different substitution at both the alkyne terminus and the
biphenyl moiety occurred to form the anticipated disubstituted
tricyclic compounds 3. The yield and selectivity were, in
general, very high when using the optimized conditions or
heating at 50 °C for some examples. Only enynes 1b,e, which
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03067.
Experimental details, NMR spectra for all new com-
pounds and X-ray crystallographic data for 2a,b, 3q, and
5t (PDF)
Accession Codes
CCDC 2011662−2011665 contain the supplementary crys-
tallographic data for this paper. These data can be obtained free
of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 6. Synthesis of Dihydrophenanthrenes 3*
AUTHOR INFORMATION
■
Corresponding Authors
́
́
Patricia García-García − Departamento de Quımica Organica y
́
́
́
́
́
Quımica Inorganica, Instituto de Investigacion Quımica “Andres
́
́
M. del Rıo” (IQAR), Universidad de Alcala (IRYCIS), 28805
Alcala de Henares, Madrid, Spain; orcid.org/0000-0003-
3671-5828; Email: patricia.garciagarci@uah.es
́
́
́
Manuel A. Fernandez-Rodríguez − Departamento de Quımica
́
́
́
́
Organica y Quımica Inorganica, Instituto de Investigacion
́
́
́
́
Quımica “Andres M. del Rıo” (IQAR), Universidad de Alcala
́
(IRYCIS), 28805 Alcala de Henares, Madrid, Spain;
orcid.org/0000-0002-0120-5599;
Email: mangel.fernandezr@uah.es
Authors
Ana Milian − Departamento de Quımica Organica y Quımica
́
́
́
́
́
́
́
́
Inorganica, Instituto de Investigacion Quımica “Andres M. del
́
́
́
Rıo” (IQAR), Universidad de Alcala (IRYCIS), 28805 Alcala
de Henares, Madrid, Spain
́
́
́
́
Adrian Perez-Redondo − Departamento de Quımica Organica
́
́
́
́
y Quımica Inorganica, Instituto de Investigacion Quımica
*
a
́
́
́
“Andres M. del Rıo” (IQAR), Universidad de Alcala (IRYCIS),
Isolated yields of reactions performed using 0.4 mmol of 1.
A
b
́
28805 Alcala de Henares, Madrid, Spain
mixture with 2b,e was obtained. Conducted at 50 °C.
D
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Letter
́
S.; Yan, X.; Cheng, Z.; Zhang, H.; Liu, Y.; Wang, Y. Highly efficient
near-infrared delayed fluorescence organic light emitting diodes using
a phenanthrene-based charge-transfer compound. Angew. Chem., Int.
Ed. 2015, 54, 13068−13072. (c) He, Z.; Xu, X.; Zheng, X.; Ming, T.;
Miao, Q. Conjugated macrocycles of phenanthrene: a new segment of
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(b) Niphakis, M. J.; Georg, G. I. Synthesis of Tylocrebrine and related
phenanthroindolizidines by VOF3-mediated oxidative aryl-alkene
́
́
Roberto Sanz − Area de Quımica Organica, Departamento de
́
Quımica, Facultad de Ciencias, Universidad de Burgos, 09001
Burgos, Spain; orcid.org/0000-0003-2830-0892
́
́
Juan J. Vaquero − Departamento de Quımica Organica y
́
́
́
́
́
Quımica Inorganica, Instituto de Investigacion Quımica “Andres
́
́
M. del Rıo” (IQAR), Universidad de Alcala (IRYCIS), 28805
́
Alcala de Henares, Madrid, Spain; orcid.org/0000-0002-
3820-9673
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03067
coupling. Org. Lett. 2011, 13, 196−199. (c) Wang, K.; Lu, M.; Yu,
̈
Notes
A.; Zhu, X.; Wang, Q. Iron(III) chloride catalyzed oxidative coupling
The authors declare no competing financial interest.
of aromatic nuclei. J. Org. Chem. 2009, 74, 935−938. (d) Almeida, J. F.;
́
Castedo, L.; Fernandez, D.; Neo, A. G.; Romero, V.; Tojo, G. Base-
ACKNOWLEDGMENTS
We are grateful to the Ministerio de Economıa y Compet-
itividad (MINECO), AEI and FEDER (projects CTQ2017-
85263-R and CTQ2016-75023-C2-1-P), Instituto de Salud
Carlos III (FEDER funds, ISCIII RETIC REDINREN RD16/
induced photocyclization of 1,2-diaryl-1-tosylethenes. A mechanisti-
cally novel approach to phenanthrenes and phenanthrenoids. Org. Lett.
2003, 5, 4939−4941.
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(5) (a) McAtee, C. C.; Riehl, P. S.; Schindler, C. S. Polycyclic
aromatic hydrocarbons via iron(III)-catalyzed carbonyl-olefin meta-
thesis. J. Am. Chem. Soc. 2017, 139, 2960−2963. (b) Xia, Y.; Liu, Z.;
Xiao, Q.; Qu, P.; Ge, R.; Zhang, Y.; Wang, J. Rhodium(II)-catalyzed
cyclization of bis(N-tosylhydrazone)s: an efficient approach towards
polycyclic aromatic compounds. Angew. Chem., Int. Ed. 2012, 51,
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(d) McMurry, J. E. Carbonyl-coupling reactions using low-valent
titanium. Chem. Rev. 1989, 89, 1513−1524.
́
0009/0015), Junta de Castilla y Leon and FEDER
(BU291P18), and University of Alcala (projects CCGP2017-
EXP/016 and CCG2018/EXP-008 and predoctoral contract
for A.M.) for financial support.
́
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