A novel and efficient synthesis of phenanthrene derivatives via palladium/norbornadiene-catalyzed domino one-pot reaction

Article abstract of DOI:10.3762/bjoc.15.26

Herein we report a novel palladium-catalyzed reaction that results in phenanthrene derivatives using aryl iodides, ortho-bromoben-zoyl chlorides and norbornadiene in one pot. This dramatic transformation undergoes ortho-C–H activation, decarbonylation and subsequent a retro-Diels–Alder process. Pleasantly, this protocol has a wider substrate range, shorter reaction times and higher yields of products than previously reported methods.

Full text of DOI:10.3762/bjoc.15.26

A novel and efficient synthesis of phenanthrene derivatives
via palladium/norbornadiene-catalyzed domino
one-pot reaction
Yue Zhong1, Wen-Yu Wu2, Shao-Peng Yu1, Tian-Yuan Fan1, Hai-Tao Yu1,
Nian-Guang Li*1, Zhi-Hao Shi*3, Yu-Ping Tang1,4 and Jin-Ao Duan1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 291–298.
1National and Local Collaborative Engineering Center of Chinese
doi:10.3762/bjoc.15.26
Medicinal Resources Industrialization and Formulae Innovative
Medicine, Jiangsu Collaborative Innovation Center of Chinese
Medicinal Resources Industrialization, Jiangsu Key Laboratory for
High Technology Research of TCM Formulae, Nanjing University of
Chinese Medicine, Nanjing 210023, China, 2Department of Nuclear
Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing
Received: 18 October 2018
Accepted: 18 January 2019
Published: 31 January 2019
Associate Editor: I. Marek
21006, China, 3Department of Organic Chemistry, China
Pharmaceutical University, Nanjing 211198, China and 4College of
Pharmacy and Shaanxi Collaborative Innovation Center of Chinese
Medicinal Resources Industrialization, Shaanxi University of Chinese
Medicine, Xi’an 712046, Shaanxi Province, China
© 2019 Zhong et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Nian-Guang Li* - linianguang@njucm.edu.cn; Zhi-Hao Shi* -
sszh163@163.com
*
Corresponding author
Keywords:
C–H activation; norbornadiene; palladium; phenanthrene derivatives
Abstract
Herein we report a novel palladium-catalyzed reaction that results in phenanthrene derivatives using aryl iodides, ortho-bromoben-
zoyl chlorides and norbornadiene in one pot. This dramatic transformation undergoes ortho-C–H activation, decarbonylation and
subsequent a retro-Diels–Alder process. Pleasantly, this protocol has a wider substrate range, shorter reaction times and higher
yields of products than previously reported methods.
Introduction
Phenanthrene is a polycyclic aromatic hydrocarbon which lactam Ia [2] and (−)-R-tylophorine [3] (Figure 1). Meanwhile,
contains three benzene rings. The phenanthrenes can be used as they also demonstrate a wide range of biological activities in-
fundamental building blocks or intermediates in the synthesis of cluding anticancer [4], anti-HIV [5], antibacterial [6], anti-in-
complex natural products such as tuberosinone [1], aristo- flammatory [7] and so on.
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Beilstein J. Org. Chem. 2019, 15, 291–298.
Figure 1: Representative natural products containing a phenanthrene moiety.
During the past decades, numerous methods for the preparation reaction were difficult to obtain, which limited the develop-
of phenanthrene derivatives have been developed. In 2003, ment of this approach. Moreover, the ultraviolet light (UV) used
Gabriel Tojo’s group reported a base-catalyzed photochemical in this reaction may cause skin damage to experimenters. Alter-
synthesis of phenanthrene derivatives [8] through intramolecu- natively, alkynes (Scheme 1b) played an important role in the
lar aromatic coupling (Scheme 1a). Although this method synthesis of phenanthrene scaffolds under transition metal catal-
offered an atom-economic and easier strategy for the construc- ysis [9]. However, this protocol required complicated proce-
tion of phenanthrene derivatives, the starting materials in this dures, harsh reaction conditions and was incompatible with
Scheme 1: Different methods for the synthesis of phenanthrene derivatives.
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Beilstein J. Org. Chem. 2019, 15, 291–298.
many functional groups. Subsequently, facile one-pot ation of arenes [18]. Recently, our group also achieved aromat-
approaches had been realized via norbornene-mediated palla- ic ketones [19] and 2-alkynyl aromatic ketones [20] successful-
dium-catalyzed Catellani reaction by Lautens’ group [10] ly through ortho-acylation and ipso-Suzuki coupling or alkynyl-
(
Scheme 1c). Though this strategy was superior to previous ation for the aryl iodides. In this paper, we developed an effi-
methods in terms of mildness of the reaction conditions, it had a cient domino reaction of aryl iodides with ortho-bromobenzoyl
limited substrate scope and relatively low reaction efficiency. chlorides and norbornadiene leading to phenanthrene deriva-
Very recently, Fuk Yee Kwong and co-workers (Scheme 1d) tives, which could be widely used in the synthesis of vital inter-
developed a straightforward one pot π-extension method using mediates for functional materials, pharmaceutical agents and
norbornadiene instead of norbornene as directing group to natural products.
afford the phenanthrenes [11]. However, ortho-haloaryl
carboxylic acids employed in this approach had low reactivity, Results and Discussion
which needed higher reaction temperatures and longer reaction We initiated our investigations by evaluating the three-compo-
time. Therefore, the development of novel, efficient, and highly nent cross-coupling reaction of 2-iodotoluene (1a), ortho-
functional group tolerant methods for the synthesis of phenan- bromobenzoyl chloride (2a) and norbornadiene, and we opti-
threne derivatives is still desirable.
mized the reaction conditions [21]. Firstly, the reaction took
place under Pd(PPh3)4/PPh3 as the catalyst, Cs2CO3 as
Domino reactions such as norbornene-mediated palladium-cata- base, and dimethyl formamide (DMF) as solvent at 105 °C for
lyzed Catellani reactions, which were originally discovered by 10 h under N2 atmosphere. Meanwhile, different pallladium
Catellani in the 1990s [12] and further developed by groups of species were tested in this reaction system. It was found that
Catellani and Lautens et al. [13-17], hold great potential for not Pd(OAc)2 was the most effective palladium catalyst, and the
only settling the sequential reactions in one pot, but also provid- desired product y-1 was obtained in 98% yield (Table 1, entries
ing access to multisubstituted arenes. In the previous work, we 1–4). Next, we studied the influence of different ligands in
innovatively developed a strategy for the remote C–H alkyl- terms of electron-rich, electron-deficient substituents and steric
Table 1: Optimization of the reaction conditions.a
entry
catalyst
ligand
base
solvent
yield [%]b
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
PdCl2
PPh3c
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
DMF
86
75
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
DMF
98
PPh3
DMF
82
TFPd
DMF
95
diethyl maleate
X-PHOSe
PPh3
DMF
94
DMF
96
DMF
95
PPh3
CsOAc
Et3N
DMF
62
10
11
12
13
14
15
16
PPh3
DMF
trace
trace
N.D.
64
PPh3
DIPEA
DMF
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
MeCN
toluene
1,4-dioxane
THF
PPh3
PPh3
68
PPh3
trace
92
PPh3
DMAC
aReaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a (0.36 mmol, 1.2 equiv), norbornadiene (0.6 mmol, 2.0 equiv), Pd (5 mol %), ligand (12.5 mol %),
base (0.675 mmol, 2.25 equiv), solvent (4 mL), 105 °C for 10 h under N2. bYield of isolated product. N.D. = not determined. cPPh3 = triphenylphos-
phine. dTFP = tris(2-furyl)phosphine. eX-PHOS = 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl.
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hindrance. The results suggested that different ligands had little ence in this process. The reaction of methoxy-, 2-ethyl-, 2-iso-
effect on this reaction (Table 1, entries 5–7). After a further propyl, and 2-phenyliodobenzenes in this procedure afforded
opimization of various bases, we found that K2CO3 owned a the desired products in excellent yields (y-3, y-5, y-6 and y-4),
slimilar reactivity as Cs2CO3, while CsOAc with weaker alka- while 1-iodonaphthalene gave a relative low yield of 64% (y-2).
linity showed a lower activity than K2CO3, giving a yield of Gratifyingly, the reaction of disubstituted iodine substrates
6
2% (Table 1, entries 8 and 9). Besides, organic bases such as proceeded smoothly to deliver targeted compounds y-7, y-8,
Et3N and N,N-diisopropylethylamine (DIPEA) were not effec- y-14 and y-15 as well. Introducing electron-withdrawing groups
tive for this reaction (Table 1, entries 10 and 11). Furthermore, at the ortho-position of aryl iodides, such as nitro, fluorine,
different solvents were then tested, including MeCN, toluene, chlorine, trifluoromethyl and ester, gave 75–95% yields of the
1
,4-dioxane, tetrahydrofuran (THF), and dimethylacetamide corresponding products y-9–y-13, which were precursors for
DMAC), and we found the yield of y-1 was inferior to that further transition metal-catalyzed cross-coupling reactions.
done by DMF (Table 1, entries 12–16).
(
To further explore the generality of this reaction, different
With the optimum reaction conditions in hand (Table 1, entry substituted ortho-bromobenzoyl chlorides were then tested
), we expanded the aryl iodide substrates of this reaction (Scheme 3). The ortho-bromobenzoyl chlorides possessing
Scheme 2). As a result, it was found that both electron-defi- electron-donating groups, such as methyl and methoxy, were
3
(
cient and electron-rich aryl iodides progressed well in the trans- well tolerated in this transformation, and the targeted compo-
formation, and the yield of relevant phenanthrene derivatives nents were acquired in excellent yields (z-1 and z-2). Notably,
y-2–y-15 was quite well. Therefore, it is speculated that the ortho-bromobenzoyl chlorides with electron-withdrawing sub-
intrinsic electronic properties of aryl iodides makes no differ- stituents were also compatible substrates, which afforded the
Scheme 2: Substrate scope with various aryl iodides. Reaction conditions: 1 (0.3 mmol, 1.0 equiv), 2a (0.36 mmol, 1.2 equiv), norbornadiene
(0.6 mmol, 2.0 equiv), Pd(OAC)2 (5 mol %), PPh3 (12.5 mol %), Cs2CO3 (0.675 mmol, 2.25 equiv), DMF (4 mL), 105 °C for 10 h under N2.
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Beilstein J. Org. Chem. 2019, 15, 291–298.
Scheme 3: Scope of the reaction in terms of ortho-bromobenzoyl chlorides. Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2 (0.36 mmol, 1.2 equiv),
norbornadiene (0.6 mmol, 2.0 equiv), Pd(OAC)2 (5 mol %), PPh3 (12.5 mol %), Cs2CO3 (0.675 mmol, 2.25 equiv), DMF (4 mL), 105 °C for 10 h
under N2.
corresponding products in 82–87% yield (z-3–z-5). At the same Based on the above experimental results and the use of norbor-
time, a disubstituted substrate was tolerated well to this conver- nadiene in Catellani reactions followed by retro-Diels–Alder
sion (z-6). However, the substrates containing ortho-substitu- reaction firstly reported by Lautens et al. [22-24], which is
ents were disadvantageous for this reaction, and none of the mentioned in recent works [11], a proposed mechanism for this
desired products was obtained, which indicated that the reac- domino reaction is presented in Scheme 5. As is commonly
tion was strongly influenced by steric hindrance.
considered, the aryl-PdII complex A is formed by oxidative ad-
dition of aryl iodide to the Pd0 complex, which is followed by
It was noteworthy that this sequential one-pot reaction could be the insertion of norbornadiene to the C–Pd bond of A to
carried out on the gram scale (Scheme 4). We selected produce B. Then, an ortho-C–H activation reaction occurs to B,
2
-iodotoluene and 2-bromo-4,5-dimethoxybenzoyl chloride as which offers compound C with a five-membered palladacycle.
substrates. When the reaction of 2-iodotoluene (1a, 3.0 mmol, C undergoes the process of oxidative addition with ortho-
.0 equiv, 0.654 g), 2-bromo-4,5-dimethoxybenzoyl chloride bromobenzoyl chloride to give the PdIV intermediate D, and E
3.6 mmol, 1.2 equiv, 1.006 g), and norbornadiene (6.0 mmol, can be obtained via a reductive elimination reaction. A novel
.0 equiv, 0.553 g) was performed in the presence of 0.15 mmol aryl-PdII species F is formed through removing carbon mon-
of Pd(OAc)2, 0.375 mmol of PPh3 and 6.75 mmol of Cs2CO3 at oxide from E. Ultimately, G will experience immediate retro-
05 °C in DMF under N2 for 30 h, the desired compound z-6 Diels–Alder reaction after the catalytic cycle to afford the target
1
(
2
1
was isolated in 88% yield.
product while taking off cyclopentadiene.
Scheme 4: Gram scale synthesis of z-6.
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Beilstein J. Org. Chem. 2019, 15, 291–298.
Scheme 5: Proposed mechanism for the formation of phenanthrene derivatives.
Conclusion
by standard techniques without special instructions. Thin-layer
In summary, we have developed a novel and efficient protocol chromatography (TLC) was performed on GF254 plates, and
which allows us to construct a variety of phenanthrene deriva- the spots were monitored through UV light. Flash chromatogra-
tives starting from aryl iodides, ortho-bromobenzoyl chlorides phy was carried out on silica gel 300–400 mesh. 1H and
and norbornadiene in one pot. A wide range of functional 13C NMR spectra were recorded in CDCl3 at 500 and 126 MHz,
groups are compatible with the reaction, including both elec- respectively, using the solvents as internal standards. High-reso-
tron-withdrawing and electron-donating groups. Compared with lution mass spectra were taken on Waters Synapt MS. The peak
previous work for the synthesis of the phenanthrenes, this patterns are indicated as follows: s, singlet; d, doublet; t, triplet;
method shows higher reactivity, shorter reaction times, and m, multiplet; q, quartet. The coupling constants (J) are offered
higher yields of the target compounds. Meanwhile, these flex- in Hz. The ortho-bromobenzoyl chlorides 2a–f were synthe-
ible approaches to the phenanthrene derivatives would be ex- sized using the known method [25,26].
pected to provide significant references to material chemistry,
General procedure for the preparation of
pharmaceutical agents and natural product synthesis.
products
Experimental
A dried round-bottomed flask was charged with aryl iodide
General remarks
(0.30 mmol, 1.0 equiv), ortho-bromobenzoyl chlorides
All reactions were carried out under a nitrogen atmosphere (0.36 mmol, 1.2 equiv), norbornadiene (0.60 mmol, 2.0 equiv),
unless otherwise stated and commercially available reagents Pd(OAc)2 (5 mol %), triphenylphosphine (12.5 mol %),
were used without further purification. Solvents were purified Cs2CO3 (0.675 mmol, 2.25 equiv), and DMF (4 mL). The mix-
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Beilstein J. Org. Chem. 2019, 15, 291–298.
7
.
.
Wen, T.; Wang, Z.; Meng, X.; Wu, M.; Li, Y.; Wu, X.; Zhao, L.;
ture was stirred at 105 °C under nitrogen atmosphere for 10 h.
After cooling to room temperature, the mixture was diluted with
ethyl acetate (5 mL) and brine (10 mL), and extracted with ethyl
acetate (3 × 10 mL). The combined organic phase was washed
with brine, dried with anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The crude product was purified
by column chromatography on silica gel (petroleum ether/ethyl
acetate as eluent) to afford the target compounds.
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