Redox-Neutral Atom-Economic Pd(0)-Catalyzed Dearomatization of β-Naphthols with Alkynes toward Naphthalenones

Article abstract of DOI:10.1021/acs.orglett.8b00662

A dearomative coupling of β-naphthols with alkynes via Pd hydride catalysis has been developed. This redox-neutral strategy provides a straightforward platform to access diverse naphthalenones bearing congested quarternary stereocenters with excellent atom and step economy since no leaving groups are needed to preinstall on the allylic reagents. The overall utility of this protocol is exemplified by broad functional group compatibility and gram-scale capacity.

Full text of DOI:10.1021/acs.orglett.8b00662

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Redox-Neutral Atom-Economic Pd(0)-Catalyzed Dearomatization of
β‑Naphthols with Alkynes toward Naphthalenones
Xinxin Fang, Yuye Zeng, Qiuyu Li, Zijun Wu, Hequan Yao,* and Aijun Lin*
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal Chemistry, School of Pharmacy, China
Pharmaceutical University, Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: A dearomative coupling of β-naphthols with
alkynes via Pd hydride catalysis has been developed. This
redox-neutral strategy provides a straightforward platform to
access diverse naphthalenones bearing congested quarternary
stereocenters with excellent atom and step economy since no
leaving groups are needed to preinstall on the allylic reagents.
The overall utility of this protocol is exemplified by broad
functional group compatibility and gram-scale capacity.
aphthols are readily available raw materials and possess
multiple reactive sites, which makes them versatile
Scheme 1. Transition-Metal-Catalyzed Dearomative Allylic
Alkylation of β-Naphthols
N
precursors for the synthesis of biologically active natural
products and pharmaceuticals.1 The dearomatization of
naphthols has received great attention2 because this trans-
formation represented an ideal method for the rapid
construction of densely functionalized naphthalenones, which
are important components of natural products and therapeutic
reagents (Figure 1).3 Well-designed strategies such as
regard, we envisioned building a general catalytic platform for
site-specific dearomative allylic alkylation of naphthols with
easily prepared materials and further promoting atom and step
economy.
Electrophilic π-allylmetal complexes are important inter-
mediates in transition-metal-catalyzed allylic alkylation reac-
tions.10 Compared with various activated precursors of π-allyl
fragments (allyl halides, alcohols, esters, and carbonates, etc.),
alkynes possess inherent advantages for the redox-neutral
process, exhibiting high atom and step economy since no
leaving groups are needed to preinstall on the allylic reagents.13
Combined with our previous work on the hydrofunctionaliza-
tion of alkynes via Pd hydride catalysis,14 herein we present our
latest work on Pd(0)-catalyzed site-specific dearomative allylic
alkylation of β-naphthols with alkynes to construct allyl-
substituted naphthalenones bearing congested quarternary
stereocenters (Scheme 1b).
Figure 1. Natural products and bioactive compounds containing
naphthalenones bearing α-quarternary stereocenters.
alkylation,4 arylation,5 alkenylation,6 amination,7 and halogen-
ation8 of naphthols as well as hypervalent iodine or transition-
metal-catalyzed oxidation9 have been elegantly unveiled to
target these frameworks. Recently, transition-metal-catalyzed
allylic substitution reactions10 have emerged as an alternative
method to realize dearomatization of naphthols with allyl
carbonates or alcohols as the allylic reagents (Scheme 1a).11
However, due to the competitive O-alkylation or Friedel−
Crafts alkylation reaction pathways, it is still challenging to
develop an efficient intermolecular dearomative cross-coupling
reaction with high control of chemoselectivity.11c,12 In this
We initiated our study with 1,3-dimethyl-2-naphthol 1a and
phenylpropyne 2a as the model substrates (Table 1). When the
reaction was performed in the presence of Pd(PPh3)4 (10.0 mol
Received: February 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a,b
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope of Alkynes
b
entry
ligand
PPh3
base
T (°C)
yield (%)
1
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Cs2CO3
K2CO3
Na2CO3
KHCO3
K3PO4
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
35
52
2
3
dppb
trace
trace
63
4
dppm
DPEPhos
XantPhos
Cy3P
5
6
nr
7
76
8
Cy-JohnPhos
Cy3P
trace
trace
82
9
10
11
12
13
Cy3P
Cy3P
86
Cy3P
96
Cy3P
42
c
14
Cy3P
K3PO4
nr
15
Cy3P
nr
d
16
Cy3P
KHCO3
KHCO3
85
17
Cy3P
80
82
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd(PPh3)4 (10.0
mol %), ligand (20.0 mol %), PhCO2H (20.0 mol %), and base (2.0
equiv) in toluene (2.0 mL) at 100 °C for 12 h under argon
b
c
d
atmosphere. Isolated yield. Without palladium catalyst. Pd(PPh3)4
(5.0 mol %) and ligand (10.0 mol %) were used. nr = no reaction.
%), PhCO2H (20.0 mol %), and Li2CO3 (2.0 equiv) in toluene
at 100 °C for 12 h, the desired product 3aa could be obtained
in 35% isolated yield (Table 1, entry 1). The yield of 3aa
increased to 52% when PPh3 was employed as the ligand
(Table 1, entry 2). In the subsequent investigation of
phosphine ligands (Table 1, entries 3−8), Cy3P exhibited
best performance, offering 3aa in 76% isolated yield. Screening
the bases revealed that KHCO3 was an ideal choice, resulting
3aa in 96% isolated yield, while other bases such as Cs2CO3,
K2CO3, and K3PO4 exhibited in low efficiency (Table 1, entries
7 and 9−13). Control experiments indicated that the palladium
catalyst and base were both essential to the transformation
(Table 1, entries 14 and 15). Reducing the amount of
Pd(PPh3)4 or lowering the temperature impacted the reaction
efficiency (Table 1, entries 16 and 17).
To demonstrate the generality of this reaction, we then
examined the substrate scope of alkynes and the results are
shown in Scheme 2. 1-Aryl-1-propynes with electron-donating
groups or electron-withdrawing groups at the C4-position of
the phenyl ring delivered 3ab−ae in 71−93% yields. Although
substrates bearing 4-CN (2f) and an acetal group (2g) were
less reactive under standard conditions, the desired products
3af and 3ag could be obtained in good yields under a
Pd(dppf)Cl2·CH2Cl2/DavePhos catalytic system at 80 °C. The
steric hindrance of alkynes did not significantly influence the
reactivity and offered 3ah in 85% yield by prolonging the
reaction time, and m-methyl-substituted 2i afforded 3ai in 89%
yield under standard conditions. When the phenyl group was
replaced with naphthyl, indolyl, and thiophene groups, the
reaction proceeded smoothly, leading to 3aj−al in moderate to
good yields. Finally, this method allowed the late-stage
modification of estrone 2m, affording 3am in 54% yield.
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(PPh3)4 (10.0
mol %), Cy3P (20.0 mol %), PhCO2H (20.0 mol %), and KHCO3 (2.0
equiv) in toluene (2.0 mL) at 100 °C for 12 h under argon
b
c
atmosphere. Isolated yields. Pd(dppf)Cl2·CH2Cl2 (10.0 mol %),
DavePhos (20.0 mol %), 80 °C, 12 h. 24 h. 80 °C. The dr value was
determined by H NMR and HPLC analysis.
d
e
f
1
Aliphatic alkynes, e.g., 2n, were unreactive under standard
conditions.
After the substrate scope of alkynes was investigated, various
β-naphthols (1b−m) were chosen to react with phenylpropyne
(2a) to further examine the generality of this reaction (Scheme
3). When the methyl group in the 1-position of β-naphthol was
replaced by ethyl and phenyl groups, 3ba and 3ca were
achieved in 90% and 75% yields. 1-Methyl-2-naphthol
derivatives bearing 3-ethyl (1d), 3-allyl (1e), 3-benzyl (1f), 3-
chloro (1g), and 3-phenyl (1h) groups occurred smoothly to
deliver the corresponding products 3da−ha in 63−91% yields.
Moreover, 1,3-dimethyl-2-naphthols bearing different substitu-
ents, such as 7-OMe, 7-Ph, and 6-Ph on the aromatic ring, were
all well tolerated, affording 3ia−ka in 66−82% yields. It was
noteworthy that the present system could also be applicable to
simple 1-substituted β-naphthol substrates (1l and 1m),
realizing 3la and 3ma in moderate yields with excellent
chemoselectivity and regioselectivity.
To demonstrate the utility of the reaction, the gram-scale
experiments and further transformations of the naphthalenones
were carried out. The reaction of 1a (860 mg, 5.0 mmol) with
2a (1.16 g, 10.0 mmol) afforded 3aa (1.33 g) in 93% yield
under standard conditions. Reducing the amount of catalyst to
5.0 mol %, the reaction of 1a (5.0 mmol) could still afford 3aa
B
DOI: 10.1021/acs.orglett.8b00662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
this reaction was carried out, but only moderate yield and low
ee value were detected (see the SI for more details).
Scheme 3. Substrate Scope of β-Naphthols
To gain insight into the mechanism of this reaction, we
prepared phenyl allene 4 and tested its reactivity with 1a under
the standard conditions, which could deliver 3aa in 65% yield
(Scheme 3a).13d This result suggested that the phenyl allene
could be involved in the reaction process. Given that the allene
could transform to allylic ester in the presence of Pd catalyst
and acid,15 the control study with cinnamyl benzoate 5 was
then tested to provide insight on the involvement of its
intermediacy. When 2.0 equiv of cinnamyl benzoate 5 was used
as the substrate with or without PhCO2H as the additive, only a
trace of product was detected (Scheme 5b). This result
Scheme 5. Mechanistic Insights
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(PPh3)4 (10.0
mol %), Cy3P (20.0 mol %), PhCO2H (20.0 mol %), and KHCO3 (2.0
equiv) in toluene (2.0 mL) at 100 °C for 12 h under argon
b
atmosphere. Isolated yields.
(1.22 g) in 85% yield by prolonging the reaction time to 48 h
(Scheme 4a). Branched allylic product 4aa could be achieved
Scheme 4. Further Study of Pd-Catalyzed Dearomative
Allylic Alkylation of β-Naphthols with Alkynes
suggested that cinnamyl benzoate was not the main
intermediate of the reaction, which may be attributed to the
significant effect of leaving groups in transition-metal-catalyzed
allylic substitution reactions and the poor leaving ability of
benzoate.16 Combined with the previous work,17 a plausible
mechanism was proposed (Scheme 5c). First, ligand exchange
of Pd(PPh3)4 with Cy3P produces the active palladium catalyst
A, and oxidation of A with benzoic acid delivers the
hydridopalladium species B. Syn-migratory insertion of B to
2a affords the adduct C, and then β-hydrogen elimination of C
forms the phenyl allene D and regenerates intermediate B
(catalytic cycle I). Migratory insertion of B to D produces the
π-allyl-Pd intermediate E. The intermediate E could be trapped
by 1a assisted by the base to deliver 3aa directly, and the active
catalyst A is regenerated to enter the next catalytic cycle
(catalytic cycle II).
through Wittig reaction of 3aa and subsequent intramolecular
Cope rearrangement in one pot. The ketone group could be
selectively reduced by NaBH4 to afford the allylic alcohol 4la in
excellent yield with high diastereoselectivity, and the relative
configuration was confirmed by the NOE spectra (see the
Supporting Information for details) (Scheme 4b). Next, an
initial attempt for the development of an asymmetric version of
In summary, we have demonstrated a redox-neutral
dearomative coupling of β-naphthols with alkynes via Pd
hydride catalysis. This strategy provided straightforward access
to diverse naphthalenones bearing congested quarternary
stereocenters with excellent chemoselectivity. The reaction
C
DOI: 10.1021/acs.orglett.8b00662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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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.8b00662.
1H and 13C NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ajlin@cpu.edu.cn.
*E-mail: hyao@cpu.edu.cn, cpuhyao@126.com.
ORCID
Hequan Yao: 0000-0003-4865-820X
Aijun Lin: 0000-0001-5786-4537
Notes
́
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Generous financial support from the National Natural Science
Foundation of China (NSFC21502232 and NSFC21572272) is
gratefully acknowledged.
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