Palladium-Catalyzed Tandem γ-Arylation/Aromatization of Cyclohex-2-En-1-One Derivatives: A Route to 3,4-Dihydroanthracen-1(2H)-Ones

Article abstract of DOI:10.1002/adsc.202001587

An intramolecular palladium-catalyzed tandem γ-arylation/aromatization reaction of cyclohex-2-en-1-one derivatives was developed. This work provides a simple and efficient approach for the construction of substituted 3,4-dihydroanthracen-1(2H)-ones in good yields with a broad substrate scope. (Figure presented.).

Full text of DOI:10.1002/adsc.202001587

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DOI: 10.1002/adsc.202001587
Palladium-Catalyzed Tandem γ-Arylation/Aromatization of
Cyclohex-2-En-1-One Derivatives: A Route to 3,4-
Dihydroanthracen-1(2H)-Ones
Yi-Kang Song,a Si-Yu Xu,a Shu-Sheng Zhang,a Jian-Guo Fu,a,*
Guo-Qiang Lin,a, b and Chen-Guo Fenga, b, c,
*
a
The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine Shanghai, University of
Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, People’s Republic of China
Fax: (+86) 21-5132-2416;
phone: (+86) 21-5132-2416
E-mail: fujg@shutcm.edu.cn; fengcg@shutcm.edu.cn
b
c
CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy
of Science, 345 Lingling Road, Shanghai 200032, People’s Republic of China
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, Shanghai Jiao Tong University, 800 Dongchuan Road,
Shanghai 200240, People’s Republic of China
Manuscript received: December 22, 2020; Revised manuscript received: March 21, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001587
also developed. Maier and co-workers reported a
Abstract: An intramolecular palladium-catalyzed
tandem γ-arylation/aromatization reaction of cyclo-
hex-2-en-1-one derivatives was developed. This
palladium-catalyzed γ-arylation/aromatization se-
quence of enones (Scheme 1b).[10] Imahori employed a
similar γ-arylation/aromatization strategy for the syn-
work provides a simple and efficient approach for
thesis of substituted phenols (Scheme 1b).[11] Recently,
the construction of substituted 3,4-dihydroanthra-
Liu and co-workers described an efficient palladium-
cen-1(2H)-ones in good yields with a broad sub-
strate scope.
catalyzed γ-arylation/aza-Michael addition cascade
(Scheme 1c).[12] Despite the achievement in intermo-
lecular γ-arylation, the corresponding intramolecular
process, which is potentially quite useful in the
construction of complex ring systems, has not been
reported yet.
3,4-Dihydroanthracen-1(2H)-one is an important
Keywords: palladium; γ-arylation; tandem reactions;
cyclization; dihydroanthracen-1(2H)-ones
tricyclic skeleton in many bioactive natural products,
Transition metal-catalyzed α-arylation of carbonyl like mithramycin,[13] aloesaponol I[14] and peroxisomi-
derivatives via enolates has become a powerful tool for cine A1 (Figure 1).[15] Although a few synthetic
the construction of carbon-carbon bonds.[1] In contrast, methods have been presented for this core structure,
the corresponding vinylogous γ-arylation of α,β-unsa- they often suffered from limited substrate scope,
turated carbonyl compounds via dienolates has re-
ceived less attention, which may be ascribed to several
obvious challenges, including the difficulty in control-
ling the regioselectivity between α-, β-, and γ-
arylation, the reduced nucleophilicity of dienolates
compared with enolates, and the side reactions through
self-condensation or Heck process.[2–4]
In 1998, Miura and co-workers described a palla-
dium-catalyzed γ-arylation of α,β-unsaturated alde-
hydes with aryl bromides.[5] Since then, a number of
α,β-unsaturated aldehydes,[6] ketones,[3b,7] amides[8] and
esters[9] were applied in such transformations (Sche-
Figure 1. Selected examples of bioactive natural products
containing 3,4-dihydroanthracen-1(2H)-one units.
me 1a). In the meantime, a few cascade reactions were
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Table 1. Optimization of the reaction conditions.[a]
Scheme 1. γ-Arylation of α,β-unsaturated carbonyl compounds.
tedious reaction procedure and poor regioselectivity.[16]
Therefore, more efficient synthetic methods are highly
desirable. We envision that an intramolecular γ-
arylation of cyclohex-2-en-1-one derivatives 1 can
afford tricyclic skeleton 2, which may subsequently
undergo a Pd-catalyzed dehydrogenation to produce
the desired 3,4-dihydroanthracen-1(2H)-ones
3
(Scheme 1d).[17]
With the above consideration in mind, we began
our investigation of this cascade process using aryl
bromide 1a as the model substrate (Table 1). In the
presence of palladium catalyst, the desired 3,4-
dihydroanthracen-1(2H)-one 3a was generated and the
intermediate enone 2 was not observed. The structure
of 3a was unambiguously confirmed by X-ray
crystallographic analysis.[18] Notably, the possible side
product from Heck pathway was also not observed,
and the most common and identifiable side reaction
was the debromination of 1a. Extensive screening of
reaction conditions led to the best isolated yield of
[a] Reaction conditions: 1a (0.20 mmol), Pd(TFA)2 (0.02 mmol),
L1 (0.02 mmol), CsOAc (0.40 mmol), TEMPO (0.20 mmol)
°
in DMF (2 mL) under N2 at 125 C for 12 h unless otherwise
noted.
[b] Determined by 1H NMR spectroscopy analysis using CH2Br2
as an internal standard.
72% for the desired product 3a (entry 1). The reaction (TEMPO) was not indispensable for this transforma-
could be promoted by both bisphosphine and mono- tion, but it had a strong beneficial effect on the reaction
phosphine ligands, however the electron-deficient yield (entry 16). Although the exact role of TEMPO
triarylphosphine ligand L6 resulted in a significant was unclear at this moment, we speculate that it may
decrease in reaction yield (entry 6). As expected, base act as a promoter in the dehydrogenative aromatization
was crucial for this transformation, and no desired step. Further attempts to improve the yield by temper-
product was generated without adding CsOAc (en- ature variation proved to be fruitless (entries 18 and
try 7). Other bases, CsOPiv and KOAc, were also 19).
workable, but less effective (entries 8 and 9). Solvent
With the optimized reaction conditions in hand, the
effects were also surveyed, and it was found that substrate scope was explored for this γ-arylation/
amide-group-containing polar solvents were essential aromatization cascade process (Table 2). Small fluctua-
for the efficient reaction (entries 10-12). Comparable tions in yield were observed when various substituents
results were obtained when precatalyst Pd(TFA)2 was were introduced to different positions of the phenyl
replaced by Pd(OAc)2, Pd(PPh3)2Cl2 or Pd2(dba)3 ring (3a–3h), and the yields did not show a clear
(entries 13-15). 2,2,6,6-Tetramethyl-1-piperidinyloxy relationship with the electronic or steric profiles of the
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by a ethyl group, the cascade process proceeded rather
sluggishly, and the generation of an inseparative poly-
substituted phenol was accompanied (see supporting
information for details).
Table 2. Palladium-catalyzed tandem γ-arylation/aromatization
of cyclohex-2-en-1-one derivatives.[a,b]
To demonstrate the utility of the cyclization
products, transformations of the product 3a were
conducted (Scheme 2). Chlorine atom could be in-
stalled at the α-position of carbonyl group by treatment
with N-chlorosuccinimide (NCS), providing a good
handle for further derivatization.[19] Friedländer con-
densation with 2-aminobenzyl alcohol furnished a
polycyclic compound 6.[20]
To gain insights into the reaction mechanism,
several control experiments were carried out. Upon
completion, hydrogen evolution was detected accord-
ing to GC analysis of the gas in the sealed reaction
tube (Scheme 3a). When palladium complex 7 was
prepared and subjected to the standard conditions, the
desired cyclization product could be obtained in 40%
yield (Scheme 3b). However, in the absence of CsOAc,
the product 3a was not generated at all (Scheme 3c).
Based on the above experimental observation, a
postulated mechanism is outlined in Scheme 4. First,
oxidative addition of aryl bromide to palladium(0)
generates the intermediate A, which can be deproto-
nated by CsOAc to provide dienolate B. Then, an
intramolecular nucleophilic substitution of the bromide
by enolate takes place, forming a seven-membered
[a] Reaction conditions: 1a (0.20 mmol), Pd(TFA)2 (0.02 mmol),
L1 (0.02 mmol), CsOAc (0.40 mmol), TEMPO (0.20 mmol)
°
in DMF (2 mL) under N2 at 125 C for 12 h.
[b] Isolated yields.
[c] A gram-scale reaction with 1a (1.112 g, 4.00 mmol) was
Scheme 2. Conversion of the obtained product 3a.
carried out.
substituents. Next, substituents at the β-position of
carbonyl group were also examined. For aryl substitu-
ents, the introduction of electron-withdrawing groups
or the steric hindrance (like ortho-methyl group) to the
phenyl ring showed detrimental effect on the reaction
yields (3i–3o). The replacement of phenyl ring with
naphthyl group was well tolerated (3p), giving the
desired product in 76% yield. As for aliphatic
substituents, an ethyl group at this position resulted in
some improvement in reaction yield (3q), but the
longer phenethyl chain brought the yield back to 67%
(3r). Notably, a comparable result was achieved for
the gram-scale synthesis of 3a. While the β-methyl
substitution in cyclohex-2-en-1-one 1a was replaced
Scheme 3. Mechanistic experiments.
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Science and Technology Commission of Shanghai Municipality
(18401933500 and 20XD1423400), the Shanghai Municipal
Education Commission (2019-01-07-00-10-E00072) for finan-
cial support. We thank Dr. Sheng Geng and Miss Yu Jiang from
Agilent Technologies (Shanghai) Co., Ltd. for assistance in H2
gas detection. We also thank Dr. Han-Qing Dong from Arvinas
Inc. for his help in the preparation of this manuscript.
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This work was supported by the National Natural Science
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Palladium-Catalyzed Tandem γ-Arylation/Aromatization of
Cyclohex-2-En-1-One Derivatives: A Route to 3,4-Dihy-
droanthracen-1(2H)-Ones
Adv. Synth. Catal. 2021, 363, 1–6
Y.-K. Song, S.-Y. Xu, S.-S. Zhang, J.-G. Fu*, G.-Q. Lin, C.-
G. Feng*