Phenanthrene Synthesis via Chromium-Catalyzed Annulation of 2-Biaryl Grignard Reagents and Alkynes

Article abstract of DOI:10.1021/acs.orglett.7b03342

A chromium/2,2′-bipyridine-catalyzed annulation reaction of 2-biarylmagnesium reagents with alkynes is reported. The reaction is applicable to a variety of aryl- and/or alkyl-substituted internal alkynes as well as 2-biaryl and related Grignard reagents, thus affording phenanthrene derivatives in moderate to good yields. The reaction proceeds at the expense of excess alkyne as a hydrogen acceptor and thus does not need an external oxidant. Deuterium-labeling experiments shed light on the reaction mechanism, which likely involves multiple intramolecular C-H activation processes on chromium.

Full text of DOI:10.1021/acs.orglett.7b03342

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Phenanthrene Synthesis via Chromium-Catalyzed Annulation of
2‑Biaryl Grignard Reagents and Alkynes
Jianming Yan and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
ABSTRACT: A chromium/2,2′-bipyridine-catalyzed annula-
tion reaction of 2-biarylmagnesium reagents with alkynes is
reported. The reaction is applicable to a variety of aryl- and/or
alkyl-substituted internal alkynes as well as 2-biaryl and related
Grignard reagents, thus affording phenanthrene derivatives in
moderate to good yields. The reaction proceeds at the expense
of excess alkyne as a hydrogen acceptor and thus does not need
an external oxidant. Deuterium-labeling experiments shed light on the reaction mechanism, which likely involves multiple
intramolecular C−H activation processes on chromium.
a
Table 1. Optimization of Reaction Conditions
henanthrene represents one of the simplest structural
Pelements in materials science based on polycyclic aromatic
Scheme 1. Annulation of 2-Functionalized Biaryl and Alkyne
to Phenanthrene via C−H Activation
b
b
entry
ligand
conv of 2a (%)
yield of 3aa (%)
1
2
3
4
5
6
none
100
100
100
100
51
19
2,2′-bipyridine (bpy)
1,10-phenanthroline
80 (78)
67
bathophenanthroline
57
terpyridine
dppe
bpy
15
85
30
c
7
100
9
21
d
8
e
bpy
16
9
bpy
76
56
a
Reaction conditions: 1a (prepared from 2-bromobiphenyl and Mg/
LiCl; 0.2 mmol in THF), 2a (0.4 mmol), CrCl2 (10 mol %), ligand
b
(20 mol %), THF, 80 °C, 18 h. Determined by GC using n-tridecane
as an internal standard. Isolated yield is shown in parentheses.
c
d
Norbornene (0.4 mmol) was added. 2,3-Dichlorobutane (0.5 mmol)
e
was added. The reaction was performed at room temperature.
functionalized biaryl and an alkyne via C−H activation is
attractive in terms of atom and step economy (Scheme 1a).4−6
Since the seminal works of Heck and Larock on the palladium-
catalyzed annulation of 2-iodobiaryl,4a,b annulation reactions
employing different biaryl substrates have been achieved under
palladium,4c iron,4d iridium,4e or rhodium4f catalysis. Among
them, Nakamura’s iron-catalyzed annulation of 2-biaryl
Grignard reagents using 1,2-dichloroisobutane as an oxidant
hydrocarbons (PAHs).1 The selective synthesis of substituted
phenanthrenes would be not only useful for the preparation of
phenanthrene-based materials2 but also promising, when
combined with other C−C coupling methods such as the
Scholl reaction, for the bottom-up construction of extended
polyaromatic systems.3 Among various approaches to phenan-
threne synthesis, transition-metal-catalyzed annulation of a 2-
Received: October 26, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03342
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of Alkynes
Scheme 3. Reaction of Different Grignard Reagents
a
Obtained as a mixture with the defluorinated product (i.e., 3aa; 11%).
At the outset, we explored the reaction between the 2-
biphenylmagnesium bromide−lithium chloride complex (1a),
prepared from 2-bromobiphenyl and Mg·LiCl,14 and dipheny-
lacetylene (2a, 2 equiv) (Table 1). In the presence of CrCl2 (10
mol %) in THF at 80 °C, the reaction afforded 9,10-
diphenylphenanthrene (3aa) in 19% GC yield (entry 1).
Upon ligand screening, 2,2′-bipyridine (bpy) was found to
dramatically improve the yield of 3aa to 80% (78% isolated
yield; entry 2). 1,10-Phenanthroline and bathophenanthroline
(bphen) also promoted the reaction in somewhat lower yields
(entries 3 and 4), while terpyridine and diphosphine ligands
such as dppe were much less effective (entries 5 and 6).
GCMS analysis of the CrCl2/bpy-catalyzed reaction
indicated the formation of (E)-stilbene (4) and 1,2,3-
triphenylnapthalene (5) as byproducts. While their origin was
probed later (vide infra), 4 and 5 appeared to be formed by
reduction of 2a and dimerization of 2a, respectively. The
consumption of 2a could not be suppressed by the addition of
norbornene as a hydrogen acceptor (entry 7). Unlike the iron-
catalyzed annulation,4d a dichloroalkane oxidant was only
detrimental (entry 8), causing substantial homocoupling of 1a.
Note that the present reaction took place even at room
temperature, albeit with lower conversion and yield (entry 9).
With the CrCl2/bpy system, the reaction of 1a with different
alkynes was explored (Scheme 2). A variety of diarylalkynes
participated in the annulation to afford 9,10-diarylphenan-
threnes 3ab−3ah in moderate to good yields. The reaction
became somewhat sluggish with CF3 groups on the para-
position (see 3ae and 3af). Di(2-thienyl)acetylene also afforded
the desired product 3ai in 49% yield. Aryl(alkyl)alkynes also
proved to be competent substrates, for which better yields were
achieved using bphen instead of bpy. Interestingly, the reaction
of phenyl(cyclopropyl)acetylene was accompanied by a partial
a
b
Bphen was used instead of bpy. Phenyl(cyclopropyl)acetylene was
used as the reactant, and an inseparable mixture of 3al and 3al′ was
obtained.
is notable for the low cost of the catalyst and the mild reaction
temperature.4d This reaction, however, requires 2 equiv of the
Grignard reagent, which can be more precious than the alkyne,
because 1 equiv is sacrificially consumed as a hydrogen
acceptor. Here, we report on a chromium-catalyzed annulation
reaction of a 2-biaryl Grignard reagent and an alkyne to form a
phenanthrene derivative. In contrast to iron catalysis, the
present reaction proceeds at the expense of excess alkyne as a
hydrogen acceptor.
The present study was prompted by our recent finding of a
chromium-catalyzed addition reaction of an aryl Grignard
reagent to a dialkylalkyne to afford an ortho-alkenylarylmagne-
sium species via a 1,4-chromium migration (Scheme 1b).7−10
During this study, we observed a small amount of 1,2,3,4-
tetraalkylnaphthalene, which appeared to be formed via
dehydrogenative annulation of the styrenylchromium or
ortho-alkenylarylchromium species with another molecule of
the alkyne via C(sp2)−H activation. Building on this
observation, and in light of recent progress in chromium
catalysis,11−13 we envisioned that the 2-biaryl Grignard reagent
could undergo annulation with an alkyne to form a
phenanthrene derivative.
B
DOI: 10.1021/acs.orglett.7b03342
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 4. Deuterium-Labeling Experiments
Scheme 5. Proposed Reaction Pathways
labeling experiments. First, the reaction between Grignard
reagent 1b and 2a, when quenched with D2O, afforded
phenanthrene 3ba, 4, and 5, with partial deuteration of the
ortho and olefinic positions of 4 (Scheme 4a). Second, the
reaction using pentadeuterated Grignard reagent 1a-d5
demonstrated partial deuterium transfer to the ortho and
olefinic positions of 4 and the 4- and 5-positions of 5 (Scheme
4b). Third, the reaction between Grignard reagent 1d and
decadeuterated diphenylacetylene (2a-d10) furnished the
phenanthrene 3da-d10 with slight deuteration of the less
hindered bay region (Scheme 4c). Finally, the treatment of
1d with a mixture of CrCl2 (30 mol %) and bpy (60 mol %),
upon quenching with D2O, resulted in partial deuteration of the
ortho positions of both the aryl rings (Scheme 4d).
To rationalize the lack of the regioselectivity in alkyne
insertion (Scheme 3b) and the results of the deuterium-labeling
experiments (Scheme 4), we propose reaction pathways (for 1a
and 2a) shown in Scheme 5 (see the Supporting Information
for further details). A 2-biarylchromium species A would
undergo intramolecular C−H oxidative addition to give a
metallafluorene hydride B. Migratory insertion of 2a into the
Cr−H bond of B would generate an alkenyl−metallafluorene
C, followed by isomerization to the trans isomer D presumably
via a zwitterionic carbene intermediate.15 The intermediate D
may undergo insertion of another molecule of 2a into the
biaryl−Cr bond (G), followed by reductive elimination to
afford 3aa along with a stilbenyl−Cr species H.6a Trans-
metalation between H and 1a would regenerate A and afford
stilbenyl−Mg species (RMgX). As judged from the H/D
scrambling results, D may also undergo sequential σ-bond
metathesis via a metallaindene species E, causing migration of
the chromium atom on the stilbenyl ligand. The resulting
intermediate F would also lead to 3aa via alkyne insertion/
reductive elimination. The annulation of metallaindene species
E or the stilbenyl−Cr species H with 2a would be responsible
for the formation of 5. The role of the bipyridine ligand
a
The yield was determined by GC for Scheme 5d. 1H NMR
integrations lower than that expected for nondeuterated compounds
are indicated.
cleavage of the cyclopropyl ring, affording a small amount of 9-
phenyl-10-propenylphenanthrene 3al′ along with the expected
product 3al. Dialkylalkynes such as 4-octyne and 4-methylpent-
2-yne also afforded the corresponding phenanthrene products
3ap and 3aq. Phenylacetylene failed to give the desired
phenanthrene but underwent dimerization, as judged from
GCMS analysis of the crude product.
Next, we subjected different 2-biaryl- and related Grignard
reagents to the annulation with 2a (Scheme 3a). 4-
Methoxyphenyl- and 4-fluorophenyl-substituted Grignard
reagents afforded the products 3ba and 3ca, respectively,
while the latter was accompanied by partial hydrodefluorina-
tion. 3-Tolyl-substituted Grignard reagent underwent regiose-
lective annulation at the less hindered ortho position (3da). The
steric hindrance of 2-tolyl- and 1-naphthyl-substituted Grignard
reagents could be tolerated (3ea and 3fa). 2-Thienyl- and 2-
alkenyl-substituted Grignard reagents also afforded the desired
products 3ga and 3ha in moderate to good yields. The reaction
between unsymmetrical Grignard reagent 1d and 1-phenyl-1-
propyne (2j) afforded regioisomers 3dj and 3dj′ in a ca. 1:1
ratio, demonstrating the lack of regioselectivity in the alkyne
insertion process (Scheme 3b).
To gain insight into the reaction mechanism and the origin
of the byproducts 4 and 5, we performed a series of deuterium-
C
DOI: 10.1021/acs.orglett.7b03342
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
H.; Takenouchi, K.; Hajjaj, F.; Fukushima, T. Nat. Commun. 2016, 7,
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(b) Tan, B.-H.; Yoshikai, N. Org. Lett. 2014, 16, 3392.
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remains unclear, while we suspect that it facilitates the reductive
elimination toward selective formation of 3aa.
In summary, we have developed a chromium-catalyzed
annulation reaction of 2-biarylmagnesium bromides and related
Grignard reagents with internal alkynes to form phenanthrene
derivatives. The reaction is mechanistically unique for the role
of excess alkyne as a hydrogen acceptor and the involvement of
multiple C−H activation processes. Further investigation into
chromium-catalyzed C−H activation/C−C bond formation is
underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03342.
Detailed experimental procedures and spectral data
(PDF)
(13) Zeng, X.; Cong, X. Org. Chem. Front. 2015, 2, 69.
(14) (a) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.;
Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 6802. (b) Dagousset, G.;
Francois, C.; Leon, T.; Blanc, R.; Sansiaume-Dagousset, E.; Knochel,
P. Synthesis 2014, 46, 3133.
(15) (a) Lin, P.-S.; Jeganmohan, M.; Cheng, C.-H. Chem. - Eur. J.
2008, 14, 11296. (b) Le, C. M.; Menzies, P. J. C.; Petrone, D. A.;
Lautens, M. Angew. Chem., Int. Ed. 2015, 54, 254.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nyoshikai@ntu.edu.sg.
ORCID
Naohiko Yoshikai: 0000-0002-8997-3268
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the Ministry of Education
(Singapore) and Nanyang Technological University (RG 3/
15, RG 114/15, and MOE2016-T2-2-043).
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DOI: 10.1021/acs.orglett.7b03342
Org. Lett. XXXX, XXX, XXX−XXX