Phenanthrene Synthesis by Palladium-Catalyzed Benzannulation with o-Bromobenzyl Alcohols through Multiple Carbon-Carbon Bond Formations

Article abstract of DOI:10.1021/acs.joc.7b00848

A palladium-catalyzed benzannulation with o-bromobenzyl alcohols enabled the facile construction of phenanthrene skeletons via the sequential multiple carbon-carbon bond formations. A variety of multisubstituted phenanthrenes were synthesized by the reaction of (Z)-β-halostyrenes with o-bromobenzyl alcohols as well as by the three-component coupling of alkynes, aryl bromides, and o-bromobenzyl alcohols. The electron-deficient phosphine ligand played an important role to control the sequential oxidative addition of two different organic halides employed, which realized the selective formation of the desired phenanthrenes in good yields. This synthetic protocol was also applicable to the synthesis of the highly fused polycyclic aromatic hydrocarbons such as tetraphenes.

Full text of DOI:10.1021/acs.joc.7b00848

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Article
Phenanthrene Synthesis by Palladium-Catalyzed Benzannulation with o-
Bromobenzyl Alcohols through Multiple Carbon–Carbon Bond Formations
Masayuki Iwasaki, Yasuhiro Araki, and Yasushi Nishihara
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 18 May 2017
Downloaded from http://pubs.acs.org on May 19, 2017
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The Journal of Organic Chemistry
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Phenanthrene Synthesis by Palladium-Catalyzed
Benzannulation with o-Bromobenzyl Alcohols
through Multiple Carbon–Carbon Bond Formations
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Masayuki Iwasaki,* Yasuhiro Araki, and Yasushi Nishihara*
Research Institute for Interdisciplinary Science, Okayama University,
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required)
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Abstract: A palladium-catalyzed benzannulation with o-bromobenzyl alcohols enabled the facile
construction of phenanthrene skeletons via the sequential multiple carbon–carbon bond formations. A
variety of multi-substituted phenanthrenes were synthesized by the reaction of (Z)--halostyrenes with
o-bromobenzyl alcohols as well as by the three-component coupling of alkynes, aryl bromides, and o-
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bromobenzyl alcohols. The electron-deficient phosphine ligand played an important role to control the
sequential oxidative addition of two different organic halides employed, which realized the selective
formation of the desired phenanthrenes in good yields. This synthetic protocol was also applicable to
the synthesis of the highly-fused polycyclic aromatic hydrocarbons such as tetraphenes.
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Introduction
Phenanthrenes have attracted much attention in the fields of materials science and medicinal
chemistry because of their unique physical properties and bioactivities. For instance, phenanthrene
skeletons are often incorporated in various organic functional materials, such as organic light-emitting
diodes and photoluminescence materials.1 Besides, phenanthrene derivatives are frequently found in
bioactive molecules, such as halofantrine and aristolochic acid.2 Therefore, their synthetic methods
have been well studied from old times.3 Although Mallory cyclization of stilbene derivatives represents
one of the most reliable methods, there are significant drawbacks.4 Oxidative cyclization of electron-
rich stilbenes proceeded well while the reaction of electro-poor substrates suffered from low yields. In
addition, the reaction required harsh reaction conditions, which led to low tolerance for functionalities.
Recently, transition-metal-catalyzed reactions have realized the phenanthrene synthesis under milder
reaction conditions (Figure 1). For example, cycloisomerization of o-alkynylbiphenyls5 and olefin
metathesis of 2,2’-divinylbiphenyls6 were well established for the efficient synthesis of phenanthrenes.
Moreover, several research groups reported the annulation of biphenyl derivatives with alkynes.7
Furthermore, sequential cross-coupling protocol has been developed to construct phenanthrene
skeletons.8 Benzannulation with arynes were also applied to phenanthrene synthesis.9 The reaction of
(Z)--iodostyrenes afforded the desired phenanthrenes in good yields. These synthetic methods have
the potential to expand the substrate scope significantly, but the starting substrates are difficult to
prepare in most cases, which resulted in the low overall yields of the target phenanthrenes.
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Figure 1. Conventional Synthesis of Phenanthrenes by Transition-Metal Catalysts
On the other hand, multi-component coupling has emerged in recent years as a powerful synthetic
method to construct the complex molecules from commercially available or easily accessible starting
materials in a single step.10 The reaction could avoid the bothering sequential multistep synthesis to
improve the total yields, which has made a significant contribution to combinatorial chemistry,
diversity-orientated synthesis, and high-throughput screening. Thus, the phenanthrene synthesis by
multi-component coupling is highly desirable.
We recently demonstrated that o-bromobenzyl alcohols could be utilized as the ideal annulating
reagents for benzannulation of aryl halides. Both a nucleophilic hydroxymethyl moiety and an
electrophilic bromo moiety in o-bromobenzyl alcohols resulted in the selective synthesis of the highly-
fused polycyclic aromatic hydrocarbons. In addition, the annulating reagents we developed are quite
stable in air and light, which can indeed be stored for several months. Moreover, ortho-substituted
benzyl alcohols are known to promote -carbon elimination,11 which is one of the key elementary steps
in palladium-catalyzed benzannulation of aryl halides. The reaction of o-iodobiphenyls with o-
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bromobenzyl alcohols provided a series of multisubstituted triphenylenes.12,13 We herein report the
facile construction of phenanthrene skeletons by palladium-catalyzed benzannulation of (Z)--
halostyrenes with o-bromobenzyl alcohols.14 Moreover, the optimized reaction conditions found to be
applied to the three-component coupling of aryl bromides, alkynes, and o-bromobenzyl alcohols. It is of
note that all of the reactants are commercially available or prepared in a single step. The present
palladium catalysis achieved the sequential multiple carbon–carbon bond formations.
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Results and Discussion
Benzannulation of (Z)--Halostyrenes with o-Bromobenzyl Alcohols. Prior to investigating the
three-component coupling, we examined the benzannulation of (Z)--halostyrenes 1 with o-
bromobenzyl alcohols 2. This is because the possible alkenylpalladium intermediate generated from 1
might also be readily formed by the reaction of aryl halides with alkynes.15 1-Bromo-1,2,2-
triphenylethene (1a) and o-bromobenzyl alcohol 2a were subjected to the various palladium-catalyzed
conditions (Table 1). In the presence of palladium/phosphine catalysts, the expected benzannulation
proceeded to give the desired phenanthrene 3a, while no reaction occurred without the catalyst. The
precise optimization of reaction conditions revealed that the choice of phosphine ligands was crucial.
The major byproduct in the reaction was the homo-coupled product of 2a, benzochromene 4.11a,c
Oxidative addition of 2a prior to 1a resulted in the undesired formation of 4. On the other hand, the
reaction of 1-iodo-1,2,2-triphenylethene with 2a afforded 3a in a lower yield along with undetermined
complex mixture. The catalytic activity of palladium species against 1a and 2a has to be controlled for
selective formation of phenanthrene 3a. The reaction gave 3a in 7% yield without any ligand (entry 1),
whereas the yield was improved with PPh3 (entry 2). The electron-donating ligands, such as P(4-
MeOC6H4)3 and XPhos (2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl), gave the lower yields,
in which highly active palladiums for oxidative addition might not distinguish the reactivity between
alkenyl bromide 1a and aryl bromide 2a (entry 3 and 4). However, the desired product 3a was obtained
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in a satisfactory yield when the electron-deficient P(4-CF3C6H4)3 was used (entry 5). The reaction
yielding 3a was retarded by applying too electron-poor ligand (entry 6). The bidentate ligands, such as
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4
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6
Xantophos
(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)
and
DPPF
(1,1’-
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9
bis(diphenylphosphino)ferrocene), were found to be ineffective (entries 7 and 8). The strong
coordination of the bidentate ligands would block the reaction cite of palladium to retard the course of
the reaction such as oxidative addition and migratory insertion steps.
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Table 1. Ligand Screening for Palladium-Catalyzed Benzannulation of 1-Bromo-1,2,2-triphenylethene
(1a) with o-Bromobenzyl Alcohol 2aa
NMR yieldb
entry
ligand
X (mol %)
3a (%)c
4
4 (%)d
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4
5
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8
none
-
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15
PPh3
66
0
P(4-MeOC6H4)3
XPhos
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P(4-CF3C6H4)3
P[3,5-(CF3)2C6H3]3
Xantophos
DPPF
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a1a (0.25 mmol), 2a (0.30 mmol), PdCl2(PhCN)2 (0.0125 mmol), ligand, Cs2CO3 (0.60 mmol) in
1
toluene (1 mL) at 110 ºC for 24 h. bDetermined by H NMR analysis of the crude mixture, using
c
d
dibenzyl ether as an internal standard. Based on 1a. Based on 2a.
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After the further fine modification of the reaction conditions, the yield of 3a was slightly increased
when 1.4 equivalent of 2a was employed (Table 2, entry 1). Under the optimized reaction conditions in
hand, a variety of (Z)--halostyrenes 1 were transformed to the corresponding multisubstituted
phenanthrenes 3 in good yields. The results were summarized in Table 2. Electron-rich alkenyl
bromides 1b and 1c underwent benzannulation with 2a to provide the products 3b and 3c in excellent
yields (entries 2 and 3). In addition, the reactions of electron-poor alkenyl bromides 1d and 1e
proceeded as well, giving phenanthrenes 3d and 3e in 95% and 65% yields, respectively (entries 4 and
5). The complexly-functionalized alkenyl bromide 1f was also applicable to the present reaction to
afford phenanthrene 3f substituted by two fluoro and one methoxy groups with functionalities remained
intact (entry 6). Substituents on alkenyl bromide 1 did not have to be aryl groups. Methyl-substituted
alkenyl bromide 1g smoothly reacted with 2a, yielding alkyl-substituted phenanthrene 3g (entry 7).
Notably, the corresponding iodide 1h gave the better results than 1g, while the reaction of triflate 1i
gave no product (entries 8 and 9). An electron-donating alkyl group on 1g might prevent the smooth
oxidative addition to palladium. Furthermore, -alkyl-substituted alkenyl halides 1j and 1k were
amenable to the reaction, in which the similar trend between bromide 1j and iodide 1k was observed
(entries 10 and 11). As a result of investigation with respect to the scope of o-bromobenzyl alcohol 2,
the benzannulation of 1a was achieved by using the functionalized annulating reagents 2b and 2c
(entries 12 and 13). Although the broad scope of substrates 1 and 2 clearly demonstrated high
generality of the present benzannulation, the preparation of (Z)--halostyrenes 1 needed several
synthetic steps, which resulted in low total yields of the desired phenanthrenes 3.
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Table 2. Palladium-Catalyzed Benzannulation of (Z)--Halostyrenes 1 with o-Bromobenzyl Alcohols
2a,b
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entry
yield (%)b
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a1 (1 equiv), 2 (1.4 equiv), PdCl2(PhCN)2b(5 mol %), P(4-CF3C6H4)3 (10 mol %), Cs2CO3 (2.4
equiv) in toluene (0.25 M) at 110 ºC for 24 h. Based on 1 after silica gel column chromatography.
Three-Component Coupling of Alkynes, Aryl Bromides, and o-Bromobenzyl Alcohols. The
promising results of benzannulation of (Z)--halostyrenes 1 with o-bromobenzyl alcohols 2 led us to
examine three-component coupling of alkynes 5, aryl bromides 6, and o-bromobenzyl alcohols 2 for the
efficient synthesis of multisubstituted phenanthrenes (Table 3). Under the identical reaction conditions,
treatment of diphenylacetylene (5a), ethyl 4-iodobenzoate (6a), and o-bromobenzyl alcohol 2a gave the
desired phenanthrene 3k in 17% yield, while most of 6a was consumed (entry 1). We then conducted
the reaction of less reactive ethyl 4-bromobenzoate (6b) with 5a and 2a. As we expected, the yield of
3k was improved to 41% (entry 2). Since 2a was totally consumed in the reaction of aryl bromide 6b, 2
equivalents of 2a was subjected to the reaction. Although the product yield was slightly improved, a
significant amount of byproduct 4 was formed (entry 3). In order to accelerate oxidative addition, the
amount of 6b was increased to 2-fold excess, giving 3k in 66% yield (entry 4). The continuous efforts
to improve the product yields revealed that 3k was isolated in 83% yield when the reaction with 6b (4
equiv) was performed in the presence of Cs2CO3 (2 equiv) at 120 ºC (entries 5–7).16
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Table 3. Palladium-Catalyzed Three-Component Coupling of Diphenylacetylene (5a), Ethyl 4-
Halobenzoate 6a or 6b, and o-Bromobenzyl Alcohols 2aa
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NMR yieldb
entry X (6) 6 (equiv) 2a (equiv)
Cs2CO3 (equiv)
2.4
temp. (ºC)
110
3k (%)c
4 (%)d
1
I (6a)
1
1
17
0
2
3
4
5
6
7
Br (6b)
Br (6b)
Br (6b)
Br (6b)
Br (6b)
Br (6b)
1
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2
2
4
4
1
2
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2
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2.4
2.4
2.4
2.4
2.4
2.0
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120
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66
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83
95 (83)
a5a (0.25 mmol), 6, 2a, PdCl2(PhCN)2 (0.0125 mmol), P(4-CF3C6H4)3 (0.025 mmol), Cs2CO3 in
toluene (1 mL) for 24 h. bDetermined by H NMR analysis of the crude mixture, using
1
dibromomethane as an internal standard. An isolated yield was shown in parentheses, based on 4a
c
d
after silica gel column chromatography. Based on 5a. Based on 2a.
The spectroscopic data for the product 3k was exactly consistent with the literature data, indicating
that triple carbon–carbon bond formations proceeded in a sequential manner. Namely, the formed
arylpalladium bromide A reacts with alkyne 5a, providing the corresponding alkenylpalladium species
B, followed by the reaction with 2a to yield the expected phenanthrene 3k (Scheme 1, path A). The
other possible pathway initiated by the reaction of A with 2a can completely be ruled out (path B)
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because the following reaction of the resulting palladium intermediate C with alkyne 5a provides the
regioisomer 3k’.
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Scheme 1. Selective Synthesis of Phenanthrenes through Sequential C–C Bond Formations
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We then turned our attention to examine the substrate scope of the present three-component coupling.
A wide range of aryl bromides 6 were subjected to the reaction with diphenylacetylene (5a) and o-
bromobenzyl alcohol 2a (Table 4). The reactions of electron-deficient aryl bromides 6b–6d, bearing
ethoxycarbonyl, chloro, or trifluoromethyl group, provided the corresponding phenanthrenes 3k–3m in
good yields (entries 1–3). In contrast, electron-donating 4-bromoanisole (6e) reacted with 5a and 2a,
giving the product 3n in modest yield (entry 4). The desired three-component coupling might be
retarded by the competing oxidative addition of 2a that leads to the formation of byproduct 4. The yield
of 3n was not improved even when 4-iodoanisole was used or the amount of 6e was increased. It is
notable that site-selective benzannulation proceeded by employing 2-bromonaphtharene (6f) which has
two different reaction sites. The bulky palladium would avoid the steric repulsion at 1-position of 6f.
Benzannulation occurred at the less hindered position to afford the tetraphene 3o in 68% yield as a sole
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product (entry 5). This example strongly showed the utility of the present protocol for the synthesis of
highly-fused PAHs. In the case of bromobenzene (6g), the reaction was not complete with 4 equivalents
of 6g. The reaction was conducted in a solvent amount of 6g (0.50 mL, 18 equiv) instead of toluene,
furnishing the product 3a in 86% yield (entry 6).
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Table 4. Scope of Aryl Bromides 6 in Reactions of Diphenylacetylene (5a) with o-Bromobenzyl
Alcohol 2aa
yield (%)b
entry
6
3
1
83
2c
82
60
3c
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6d
a5a (0.25 mmol), 6 (1.0 mmol), 2a (0.50 mmol), PdCl2(PhCN)2 (0.0125 mmol), P(4-CF3C6H4)3
(0.025 mmol), Cs2CO3 (0.50 mmol) in toluene (1 mL) at 120 ºC for 24 h. Based on 1a after silica gel
column chromatography. 6 (8 equiv). 6g (0.5 mL, 18 equiv) was used as solvent instead of toluene.
b
c
d
We then investigated the scope of the alkynes 5 in the three-component coupling (Table5). The
electronic properties of diarylacetylenes 5b–5d had only little influence on the reaction efficiency to
afford the corresponding phenanthrenes 3p–3r in moderate to good yields (entries 1–3). In addition, the
sterically bulky 5e could also be effectively converted into 3s in 54% yield (entry 4). Moreover, the
electronically-biased unsymmetrical alkynes 5f–5h underwent the benzannulation with 6g and 2a to
give the products 3c, 3d, and 3t, respectively (entries 5–7). Although several reactions of
unsymmetrical diarylacetylenes with 6b and 2a were conducted, poor regioselectivity was observed
only in the reaction of 5h, providing a 2:1 mixture of regioisomers 3u and 3u’ in 61% combined yields
(entry 8). However, the reaction of methylphenylacetylene (5i) with 6b and 2a proceeded with high
regioselectivity, furnishing a 10:1 mixture of regioisomers 3v and 3v’ in 54% combined yield (entry 9).
The regioselectivity can be rationalized as follows. During a migratory insertion step of alkyne 5h to an
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Ar–Pd bond, the palladium might favor to be located at the benzylic position to generate the relatively
stable alkenyl palladium species. The electronically-biased unsymmetrical alkynes increased the
selectivity of the reaction. On the other hand, the reaction of dialkylacetylenes and terminal alkynes
gave poor results. The reaction of 4-octyne gave no product, which would retard the migratory insertion
step. While the reaction of phenylacetylene affords the product in at most 15% NMR yield, but the
attempted isolation resulted in failure due to the contamination of unidentified byproducts.
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Table 5. Scope of Alkynes 5 in Reactions of Aryl Bromide 6b or 6g with o-Bromobenzyl Alcohol 2aa
yield (%)b
entry
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6b
a5 (0.25 mmol), 6b (1.0 mmol), 2a (0.50 mmol), PdCl2(PhCN)2 (0.0125 mmol), P(4-CF3C6H4)3 (0.025
b
mmol), Cs2CO3 (0.50 mmol) in toluene (1 mL) at 120 ºC for 24 h. Based on 5 after silica gel column
chromatography. 6g (0.5 mL, 18 equiv) was used as solvent instead of toluene. Determined by 1H
c
d
e
NMR analyses. Combined yields of two regioisomers.
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Finally, several o-bromobenzyl alcohols 2 were examined in the present three-component coupling
(Table 6). As a result, the annulating reagents 2b substituted by two methoxy groups and 2c having 1,3-
benzoxal skeletons found to be suitable for the benzannulation with diphenylacetylene (5a) and aryl
bromide 6b, giving the desired multisubstituted phenanthrenes 3w and 3x in 72% and 44% yields,
respectively (entries 1 and 2). Moreover, phenanthrene 3i was obtained in 67% yield from the three-
component coupling of readily available reagents 5a, 6g, and 2b (entry 3). Unfortunately, the reaction
with o-bromobenzyl alcohols bearing electron-withdrawing groups did not give the desired
phenanthrenes. When the difluorinated o-bromobenzyl alcohol was used, the corresponding product
was not obtained. Instead, a considerable amount of the homocoupled product derived from o-
bromobenzyl alcohol was formed probably because the undesired oxidative addition of o-bromobenzyl
alcohol was accelerated. Interestingly, the benzannulation of 5a and 6g with unsymmetrical o-
bromobenzyl alcohol 2d provided an unexpected mixture of regioisomers 3n and 3n’ in a 5:1 ratio
(entry 4).
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Table 6. Scope of o-Bromobenzyl Alcohols 2 in Reactions of Diphenylacetylene (5a) with Aryl
Bromide 6b or 6ga
yield (%)b
entry
6
2
3
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2c
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a5a (0.25 mmol), 6b (1.0 mmol), 2 (0.50 mmol), PdCl2(PhCN)2 (0.0125 mmol), P(4-CF3C6H4)3
(0.025 mmol), Cs2CO3 (0.50 mmol) in toluene (1 mL) at 120 ºC for 24 h. Based on 5a after silica gel
b
c
d
column chromatography. 0.125 mmol scale. 6g (0.5 mL, 18 equiv) was used as solvent instead of
toluene. Determined by 1H NMR analyses. Combined yields of two regioisomers.
e
f
We initially expected that phenanthrene 3n’ was solely obtained in the three-component coupling of
5a, 6g, and 2d, as shown in Scheme 2. After the alkenylpalladium species D is generated by oxidative
addition of 6g and the subsequent migratory insertion of alkyne 5a, the deacetonative coupling with o-
bromobenzyl alcohol 2d affords the intermediate E which leads to the formation of the desired
phenanthrene 3n’. On the other hand, prior to the reaction of D with 2d, 1,4-palladium migration from
D occurs to form arylpalladium species D’.17 The reaction of D’ with 2d affords the regioisomer 3n in
the same fashion through the intermediate E’. The predominant formation of 3n would be explained by
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the isomerization of alkenylpalladium species D to thermodynamically stable arylpalladium species D’,
from which the reaction with 2d would occur.18,19
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Scheme 2. 1,4-Palladium Migration from Alkenyl- to Arylplladium Species
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Several control experiments were conducted to gain some mechanistic insights into the above
mentioned 1,4-palladium migration in the reaction of 5a, 6g, and 2d. (Z)--Bromostyrene 1a which
might generate the same palladium intermediate also underwent the benzannulation with 2d to yield
phenanthrene 3n as the main product (Scheme 3a). In addition, under the identical reaction conditions,
the reaction of aryl bromide 7 also gave the similar results to that of 1a (Scheme 3b). The selectivity of
the reaction of 7 with 2d was slightly different from that of 1a with 2d and that of 5a and 6g with 2d,
which might result from the slower oxidative addition of aryl bromide 7. Three-component coupling
was lower yielding than both two-component couplings shown in Scheme 3a and 3b probably because
three different carbon–carbon bond formation reactions have to be catalyzed by the single catalyst.
Moreover, a stoichiometric reaction of 1a with Pd(PPh3)4 provided the 5:1 mixture of two palladium
complexes. 31P{1H} NMR spectrum of the obtained complexes shows two signals ( 19.6 and 20.5)
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assignable to D and D’ (Scheme 3c).16 The obtained palladium complexes were treated with 2a in the
presence of cesium carbonate to yield 3a quantitatively. These results strongly imply the existence of
the rapid equilibrium in 1,4-palladium migration between D and D’. At this stage, selective synthesis of
the desired phenanthrenes by the reaction with unsymmetrical o-bromobenzyl alcohols has yet to be
achieved although several experiments of different substrates with 2d were conducted. Further efforts
to synthesize the desired phenanthrenes with a perfect selectivity by tuning the phosphine ligands are
currently under investigation.
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Scheme 3. Control Experiments
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On the basis of the obtained results, a plausible reaction pathway for the palladium-catalyzed
benzannulation of (Z)--halostyrene 1a with o-bromobenzyl alcohol 2a and three-component coupling
of alkyne 5a, aryl bromide 6g, and o-bromobenzyl alcohol 2a is shown in Scheme 4. Initial
alkenylpalladium species D is generated by oxidative addition of alkenyl bromide 1a, or oxidative
addition of aryl bromide 6g and the sequential migratory insertion15 of alkyne 5a to arylpalladium
species F. The electron-deficient phosphine ligand, P(4-CF3C6H4)3, might suppress the reactivity of
palladium for oxidative addition of 2a, which leads to the undesired formation of benzochromene 4.8d,20
The formed alkenylpalladium D smoothly isomerizes to the relatively stable arylpalladium D’ by 1,4-
palladium migration.17 The following ligand exchange between D’ and o-bromobenzyl alcohol 2a is
facilitated by cesium carbonate to give the palladium intermediate G. Alkoxopalladium G undergoes -
carbon elimination12 with the release of acetone, providing the arylpalladium H, followed by reductive
elimination to yield aryl bromide 8 and regenerate the initial palladium species. Subsequently, the
smooth oxidative addition of 8 proceeds probably through ring-walking pathway21,22 to generate
arylpalladium species I, which undergoes the 6-endo-trig cyclization to furnish benzylpalladium
intermediate J. Finally, -hydrogen elimination23 from J releases the desired phenanthrene 3a, with the
initial palladium catalyst regenerated. The present reaction consists of two catalytic cycles;
deacetonative coupling and intramolecular cyclization. The first catalytic cycle might involve the rate-
determining step of the reaction because the intermediate 8 was not detected in the reaction mixture.
From the results of the reaction with unsymmetrical o-bromobenzyl alcohol, the minor pathway to give
the product 3a is considerable, which is initiated by the reaction of D with 2a. Aryl bromide 9 is
generated through ligand exchange, -carbon elimination, and reductive elimination. The following
palladium-catalyzed intramolecular cyclization of 9 affords 3a.
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Scheme 4. A Plausible Reaction Pathway
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The proposed reaction pathway shown in Scheme 4 was supported by the following experiment. The
possible intermediate 8 was independently prepared and reacted under the similar reaction conditions
(Scheme 5a). The desired phenanthrene 3a was obtained in 68% yield, which clearly suggested the
intermediacy of aryl bromide 8. As an alternative reaction mechanism, the pathway through the aryne
intermediate would be plausible, which might be generated from o-bromobenzyl alcohols. The reaction
of 1a with 2a in the presence of furan gave 3a in 84% yield while Diels–Alder reaction of benzyne with
furan did not proceed (Scheme 5b). In addition, Diels–Alder adduct was not detected at all in the
reaction of 2a with furan (Scheme 5c). On the basis of the obtained results, the reaction pathway via
aryne intermediates would be unlikely.
Scheme 5. Mechanistic Studies
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The obtained 9,10-diarylphenanthrenes 3 represent useful precursors of the highly-fused PAHs.
Oxidative cyclization of 3b by 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) in the presence of
methanesulfonic acid provided dibenzochrysene 10 in 50% yield (Scheme 6).24 The present
benzannulation-oxidation sequences demonstrated a powerful synthetic method of the functionalized
unsymmetrical PAHs which are difficult to be prepared by the conventional methods.
Scheme 6. Synthesis of Dibenzochrycene 10 by Oxidative Cyclization of 3b
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The present method by three-component coupling established the facile access to the desired
phenanthrenes from the commercially available substrates, which provided dramatically improvement
over two-component coupling. One example was shown in Scheme 7. When phenanthrene 3c was
synthesized by two-component coupling, the starting (Z)--halostyrene 1c had to be prepared by
dibromoolefination of benzophenone and the sequential cross-coupling with 4-methoxyphenylboronic
acid. Although the benzannulation of 1c with 2a yielded 3c in excellent yield, the overall yield was
35% yield in 3 steps. On the other hand, by using three-component coupling, 3c was obtained in 87%
overall yield in 2 steps since alkyne 5f employed can be available from the reliable Sonogashira–
Hagihara coupling of phenylacetylene with 4-iodoanisole.
Scheme 7. Synthetic Routes to Phenanthrene 3c
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Conclusions
In summary, we have developed the palladium-catalyzed benzannulation of (Z)--halostyrenes with o-
bromobenzyl alcohols and three-component coupling of alkynes, aryl bromides, and o-bromobenzyl
alcohols for the novel phenanthrene synthesis. Both reactions were efficiently catalyzed by a
palladium/phosphine complex through the multiple carbon–carbon bond formations. The present
protocol provided a variety of multisubstituted phenanthrenes with high functionalities, including a
highly-fused tetraphene derivative. The desired phenanthrene skeletons can be constructed in a single
step from the readily available starting materials, which represents the most advantageous point
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distinguished from the conventional synthesis. Further investigation to apply the palladium-catalyzed
benzannulation to the other PAH synthesis are ongoing in our laboratory.
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Experimental Section
9
General. High resolution mass spectra (HRMS) were obtained by fast atom bombardment (FAB)
using a double focusing magnetic sector mass spectrometer.
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Chemicals. Unless otherwise noted, materials obtained from commercial suppliers were used without
further purification. Alkynes 5a, 5i, and aryl halides 6a–6g were obtained from commercial suppliers.
(Z)-β-Halostyrenes 1a,25 1b,26 1c,27 1g,28 1h,29 1i,30 o-bromobenzyl alcohols 2a–2c,11a 2d,31
benzochromene 4,32 alkynes 5b,33 5c,34 5d,35 5e,34 5f,36 5g,37 5h,36 and chrysene 1038 were known
compounds.
Typical Procedure for Palladium-Catalyzed Benzannulation of (Z)-β-Halostyrenes 1 with o-
Bromobenzyl Alcohols 2: Synthesis of 9,10-diphenylphenanthrene (3a) is representative. Under an
argon atmosphere, cesium carbonate (196 mg, 0.60 mmol), bis(benzonitrile)dichloropalladium (4.8 mg,
0.0125 mmol), and tris(4-trifluoromethylphenyl)phosphine (11.7 mg, 0.025 mmol) were placed in a 20-
mL Schlenk tube. Toluene (1.0 mL), 1-bromo-1,2,2-triphenylethene (1a, 83.8 mg, 0.25 mmol) and 2-
(o-bromophenyl)-2-propanol (2a, 75.3 mg, 0.35 mmol) were added. The resulting mixture was stirred
at 110 ºC for 24 h. The mixture was then cooled to room temperature. Hydrochloric acid (1 M, 3 mL)
was added, and the product was extracted with dichloromethane (10 mL × 3). The organic layers were
dried over anhydrous sodium sulfate. After the volatile was evaporated, silica gel column purification
with hexane as an eluent afforded 9,10-diphenylphenanthrene (3a, 71.9 mg, 0.217 mmol, 87% yield).
Typical Procedure for Palladium-Catalyzed Three-Component Coupling of Aryl Bromides 5,
Alkynes 6, and o-Bromobenzyl Alcohols 2: Synthesis of 3-ethoxycarbonyl-9,10-diphenylphenanthrene
(3k) is representative. Under an argon atmosphere, cesium carbonate (163 mg, 0.50 mmol),
bis(benzonitrile)dichloropalladium (4.8 mg, 0.0125 mmol), and tris(4-trifluoromethylphenyl)phosphine
(11.7 mg, 0.025 mmol) were placed in a 20-mL Schlenk tube. Toluene (1.0 mL), diphenylacetylene (5a,
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44.6 mg, 0.25 mmol), ethyl 4-bromobenzoate (6a, 229 mg, 1.0 mmol), and 2-(o-bromophenyl)-2-
propanol (2a, 108 mg, 0.50 mmol) were added. The resulting mixture was stirred at 120 ºC for 24 h.
The mixture was then cooled to room temperature. Hydrochloric acid (1 M, 3 mL) was added, and the
product was extracted with dichloromethane (10 mL × 3). The organic layers were dried over
anhydrous sodium sulfate. After the volatile was evaporated, silica gel column purification
(hexane/ethyl acetate = 80:1) afforded 3-ethoxycarbonyl-9,10-diphenylphenanthrene (3k, 84.0 mg,
0.209 mmol, 83% yield).
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Characterization of Compounds.
Preparation of 1-Bromo-1-(4-fluorophenyl)-2,2-diphenylethene (1d)39: Under an argon
atmosphere, 1,1-dibromo-2,2-diphenylethene (338 mg, 1.0 mmol), 4-fluorophenylboronic acid (147 mg
1.05 mmol), tri(2-furyl)phosphine (34.8 mg, 0.15 mmol), and bis(dibenzylideneacetone)palladium (28.8
mg, 0.05 mmol) were placed in 50-mL of Schlenk tube. THF (4.9 mL), ether (2.1 mL), and a solution
of cesium carbonate (652 mg, 2.0 mmol) in water (2 mL) were then added. The reaction mixture was
stirred at reflux for 18 h. The product was extracted with ethyl acetate (30 mL × 3). The combined
organic layers were washed with brine (10 mL) and dried over anhydrous sodium sulfate. Evaporation
followed by silica gel column chromatography (hexane/ethyl acetate = 80:1) afforded 1d as orange solid
(157 mg, 0.444 mmol, 44%).
1
M.p. 113–114 ºC. IR (KBr) 3059 (w), 1647 (w), 1491 (m) cm–1. H NMR (600 MHz, CDCl3, rt):
6.88 (t, J = 9.0 Hz, 2H), 6.96–6.99 (m, 2H), 7.08–7.13 (m, 3H), 7.30–7.41 (m, 7H); 13C{1H} NMR (150
MHz, CDCl3, rt): δ 115.2 (d, 2JC–F = 21.9 Hz), 121.0, 127.3, 127.8, 128.1, 128.4, 129.6, 130.4, 132.3 (d,
3JC–F = 8.1 Hz), 137.3 (d, 4JC–F = 3.5 Hz), 141.0, 143.7, 144.1, 162.1 (d, 1JC–F = 248 Hz); 19F{1H} NMR
(376 MHz, CDCl3, rt): δ –113.0. Calcd for C20H14BrF: C, 68.01; H, 3.99%. Found: C, 67.80; H, 3.91%.
1-Bromo-1-(4-cyanophenyl)-2,2-diphenylethene (1e): The title compound was obtained as light-
yellow solid (90.3 mg, 0.251 mmol, 50%). M.p. 162–163 ºC. IR (KBr) 3061 (w), 2226 (w), 1682 (w),
1
1599 (m) cm–1. H NMR (600 MHz, CDCl3, rt): 6.93 (d, J = 8.4 Hz, 2H), 7.09–7.16 (m, 3H), 7.33–
7.37 (m, 3H), 7.39–7.41 (m, 4H), 7.47 (d, J = 8.4 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3, rt): δ
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111.4, 118.6, 119.2, 127.8, 128.2, 128.3, 128.4, 129.5, 130.4, 131.2, 131.9, 140.4, 143.0, 145.9, 146.1.
Calcd for C21H14BrN: C, 70.01; H, 3.92; N, 3.89%. Found: C, 69.81; H, 3.71; N, 3.76%.
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1-Bromo-2,2-di(4-fluorophenyl)-1-(4-methoxyphenyl)ethene (1f): The title compound was
obtained as light-yellow solid (79.9 mg, 0.199 mmol, 40%). M.p. 80–82 ºC. IR (KBr) 3044 (w), 2963
9
1
(w), 1655 (w), 1510 (m), 1225 (s), 1028 (s) cm–1. H NMR (600 MHz, CDCl3, rt):  3.78 (s, 3H), 6.72
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(d, 9.0 Hz, 2H), 6.78 (t, J = 9.0 Hz, 2H), 6.90 (dd, J = 8.4, 5.4 Hz, 2H), 7.06 (t, J = 9.0 Hz, 2H), 7.22 (d,
J = 9.0 Hz, 2H), 7.32 (dd, J = 8.4, 5.4 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3, rt): δ 55.4, 113.6,
115.1 (d, 2JC–F = 21.2 Hz), 115.4 (d, 2JC–F = 21.3 Hz), 123.0, 131.6 (d, 3JC–F = 8.0 Hz), 131.8, 132.2 (d,
3JC–F = 8.0 Hz), 133.2, 137.3 (d, 4JC–F = 3.5 Hz), 139.8 (d, 4JC–F = 3.5 Hz), 140.7, 159.4, 161.7 (d, 1JC–F
= 246 Hz), 162.2 (d, 1JC–F = 246 Hz); 19F{1H} NMR (376 MHz, CDCl3, rt): δ –114.5, –114.0. Calcd for
C21H15BrF2O: C, 62.86; H, 3.77%. Found: C, 63.02; H, 3.66%.
Preparation of (Z)-1-Bromo-1,2-diphenyl-1-hexene (1j)40: Under an argon atmosphere,
diphenylacetylene (891 mg, 5.0 mmol) was placed in 50-mL Schlenk tube. THF (6 mL) was then added.
n-Butyllithium (1.6 M hexane solution, 3.4 mL, 5.5 mmol) was added dropwise at –10 ºC. The reaction
mixture was stirred for 2 h. 1,2-Dibromoethane (0.57 mL, 6.6 mmol) was added at –78 ºC and the
reaction mixture was stirred for additional 30 min. After being cooled to 0 ºC, the reaction mixture was
poured into saturated ammonium chloride solution (20 mL), and extracted with diethyl ether (40 mL ×
3). The combined organic layers were washed with brine (10 mL) and dried over anhydrous sodium
sulfate. The volatiles were evaporated in vacuo. The product was chromatographed on silica gel
(hexane) to afford 1j as white solid (537 mg, 1.70 mmol, 34%).
1
M.p. 50–51 ºC. IR (KBr) 3076 (w), 2957 (m), 1597 (w), 1443 (m) cm–1. H NMR (400 MHz, CDCl3,
rt):  0.73 (t, J = 7.2 Hz, 3H), 1.11–1.28 (m, 4H), 2.33 (t, J = 7.2 Hz, 2H), 7.30–7.36 (m, 4H), 7.38–7.44
(m, 6H); 13C{1H} NMR (100 MHz, CDCl3, rt): δ 13.9, 22.4, 30.4, 36.0, 118.9, 127.3, 128.2, 128.3,
128.4, 128.5, 129.1, 141.0, 142.7, 143.7. Calcd for C18H19Br: C, 68.58; H, 6.07%. Found: C, 68.60; H,
5.98%.
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The Journal of Organic Chemistry
Preparation of (Z)-1-Iodo-1,2-diphenyl-1-hexene (1k)41: Under argon atmosphere, lithium granules
(694 mg, 100 mmol) was placed in 50-mL Schlenk tube. THF (24 mL) and trimethylstannyl chloride
(1.99 g, 10 mmol) was added and the reaction mixture was vigorously stirred at 0 ºC for 12 h. The
resulting dark green solution was transferred via a syringe to 20-mL Schlenk tube and the volatiles were
removed in vacuo. Hexane (18.2 mL) and diphenylacetylene (1.60 g, 9 mmol) were added at 0 ºC.
After the reaction mixture was stirred at 0 ºC for 3 h, 1-iodobutane (1.14 mL, 10 mmol) was added at 0
ºC. The reaction mixture was allowed to warm to room temperature and stirred for additional 3 h. The
volatiles were removed in vacuo. To the reaction mixture, were added dichloromethane (40 mL) and
iodine (4.57 g, 18 mmol). After being stirred at room temperature for 2 h, the reaction mixture was
poured into saturated sodium thiosulfate aqueous solution (20 mL). The product was extracted with
dichloromethane (40 mL × 3). The combined organic layers were washed with brine (20 mL) and dried
over sodium sulfate. After concentration in vacuo, purification by silica gel column chromatography
(hexane) affords 1k as white solid (1.66 g, 4.59 mmol, 51%).
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M.p. 67–68 ºC. IR (KBr) 3051 (w), 2959 (m), 1597 (w), 1441 (m) cm–1. H NMR (400 MHz, CDCl3,
rt):  0.71 (t, J = 7.2 Hz, 3H), 1.11–1.26 (m, 4H), 2.33 (t, J = 7.2 Hz, 2H), 7.24–7.30 (m, 2H), 7.33–7.44
(m, 8H); 13C{1H} NMR (100 MHz, CDCl3, rt): δ 13.9, 22.3, 30.6, 35.5, 97.6, 127.4, 127.8, 128.3,
128.36, 128.39, 128.7, 144.4, 146.2, 150.4. Calcd for C18H19I: C, 59.68; H, 5.29%. Found: C, 59.35; H,
5.16%.
9,10-Diphenylphenanthrene (3a): The reaction of 1a with 2a provided the title compound as white
solid (71.9 mg, 0.218 mmol, 87% yield). The reaction of 5a, 6g, and 2a provided the title compound as
1
white solid (71.0 mg, 0.215 mmol, 86% yield). H NMR (300 MHz, CDCl3, rt):  7.14–7.28 (m, 10H),
7.47–7.52 (m, 2H), 7.55–7.58 (m, 2H), 7.64–7.70 (m, 2H), 8.82 (d, J = 8.4 Hz, 2H). Compound 3a was
consistent with the literature data.42
9-Phenyl-10-(4-methylphenyl)phenanthrene (3b): The reaction of 1b with 2a provided the title
1
compound as white solid (105.2 mg, 0.305 mmol, 100%). H NMR (400 MHz, CDCl3, rt): δ 2.31 (s,
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