Palladium-catalyzed allylic alkylation dearomatization of β-naphthols and indoles withgem-difluorinated cyclopropanes

Article abstract of DOI:10.1039/d0cc07529a

A palladium-catalyzed allylic alkylation dearomatization of β-naphthols and indoles withgem-difluorinated cyclopropanes has been developed. This reaction provided an efficient route to access 2-fluoroallylic β-naphthalenones and indolenines bearing quaternary carbon centers in good yields with highZ-selectivityviaC-C bond activation, C-F bond cleavage and the dearomatization process, benefiting from the wide substrate scope and good functional group tolerance. Moreover, 2-fluoroallylic furanoindoline and pyrroloindolines were achieved in good efficiencyviacascade allylic alkylation, dearomatization and cyclization processes in the presence of Et₃B.

Full text of DOI:10.1039/d0cc07529a

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DOI: 10.1039/D0CC07529A
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Palladium-catalyzed Allylic Alkylation Dearomatization of β-
Naphthols and Indoles with gem-Difluorinated Cyclopropanes
Zhiyuan Fu,‡ Jianping Zhu,‡ Songjin Guo,* and Aijun Lin*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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A Palladium-catalyzed allylic alkylation dearomatization of β- fragment to expand the diversity and utility of β-naphthols and
naphthols and indoles with gem-difluorinated cyclopropanes has indoles.
been developed. This reaction provided an efficient route to access
The incorporation of fluorine or fluorine-containing motifs
2-fluoroallylic β-naphthalenones and indolenines bearing into organic molecules brings about substantial improvement in
quaternary carbon centers in good yields with high Z-selectivity via bioactivity, and provides unique chemical and physical
C−C bond activation, C−F bond cleavage and dearomatization properties.9 Moreover, monofluoroalkenes have emerged as
process, benefiting from the wide substrate scope and good ideal peptide bond mimetics, which exhibit a similar steric and
functional group tolerance. Moreover, the 2-fluoroallylic electronic profile to amides, and have been extensively applied
furanoindolines and pyrroloindolines were achieved in good in the fields of medicinal chemistry and drug-discovery.10
efficiency via cascade allylic alkylation, dearomatization and Recently, gem-difluorinated cyclopropanes as fluoro-
cyclization process in the presence of Et3B.
alkenylating building blocks have attracted increasing attention
in the construction of functional monofluoroalkenes.11 Herein,
Naphthols and indoles are abundant and readily available
chemical feedstocks, which are widely used in organic synthesis
chemistry.1 The dearomatization of β-naphthols and indoles
we describe
a
palladium-catalyzed allylic alkylation
dearomatization of β-naphthols and indoles with gem-
difluorinated cyclopropanes to the synthesis of β-
naphthalenones and indolenines with 2-fluorinated allyl
scaffolds in good efficiency for the first time (Fig. 1b).
We started our studies with gem-difluorinated cyclopropane
1a and 1,3-dimethyl-2-naphthol 2a as the model substrates.
After a systematic survey of the reaction conditions (see the
Supporting Information (SI) for details), the desired product 3a
shows
a
great potential in rapidly accessing highly
functionalized β-naphthalenones and indolenines bearing
quaternary carbon centers,2 playing as pivotal scaffolds that are
frequently found in biologically active natural products and
pharmaceuticals.3 In the past decades, allylic esters and
carbonates,4 allylic alcohols,5 allylbenzenes6 and allenes7 have
been widely employed in transition-metal catalyzed allylic
alkylation dearomatization of β-naphthols and indoles (Fig. 1a).
Recently, our group described a redox-neutral palladium-
catalyzed allylic alkylation dearomatization of β-naphthols and
indoles with alkynes in high atom and step economy.8 Although
impressive results were achieved in previous works, it is worth
noting that the 2-position of the allyl framework in the products
was short of functional group. Thus, it is of great significance to
explore novel allylating reagents, which could enable
assembling some functional groups at the 2-position of the allyl
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal
Chemistry, School of Pharmacy, China Pharmaceutical University Nanjing 210009,
P. R. China
E-mail: yd1029820332@163.com; ajlin@cpu.edu.cn
†
Electronic Supplementary Information (ESI) available. CCDC 1974930 and CCDC
1974934. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/x0xx00000x
Fig. 1 Strategies for transition-metal-catalyzed allylic alkylation
dearomatization of β-naphthols or indoles.
‡
These authors contributed equally to this work.
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Table 1 Optimization of the reaction conditions
Table 2 Substrate scope of β-naphthols and gem-difluorinated
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cyclopropanesa,b
DOI: 10.1039/D0CC07529A
entry
1
deviation of standard conditionsa
None
yield/%b
92
2
Pd(OAc)2 instead of [η3-C3H5PdCl]2
Pd(OTFA)2 instead of [η3-C3H5PdCl]2
Pd2(dba)3 instead of [η3-C3H5PdCl]2
Pd(PPh3)4 instead of [η3-C3H5PdCl]2
Cy3P instead of XPhos
83
3
86
4
85
5
80
6
46
7
SPhos instead of XPhos
58
8
XantPhos instead of XPhos
tBu-XPhos instead of XPhos
DavePhos instead of XPhos
toluene instead of THF
37
9
15
10
11
12
13
14
15
40
87
mesitylene instead of THF
CH3CN instead of THF
90
33
1,4-dioxane instead of THF
without [η3-C3H5PdCl]2 or XPhos
74
n.r.
a Standard reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [η3-C3H5PdCl]2 (5.0
mol%), XPhos (10.0 mol%), LiOtBu (2.0 equiv), THF (2.0 mL), at 80 C under Ar
atmosphere for 18 h, sealed tube. b Isolated yield. n.r. = no reaction. Nap = 2-
naphthyl.
was obtained in 92% yield with 5 mol% [η3-C3H5PdCl]2 as the
catalyst, XPhos as the ligand and LiOtBu as the base in THF at
80 °C under Ar atmosphere for 18 h (Table 1, entry 1). Other
catalysts, such as Pd(OAc)2, Pd(OTFA)2, Pd2(dba)3 and Pd(PPh3)4
performed this reaction in 80-86% yields (Table 1, entries 2-5).
t
Other ligands, such as Cy3P, SPhos, XantPhos, Bu-XPhos and
DavePhos offered 3a in less efficiency (Table 1, entries 6-10).
Toluene and mesitylene offered 3a in 87 and 90% yields, while
CH3CN and 1,4-dioxane gave 3a in 33% and 74% yields,
respectively (Table 1, entries 11-14). No reaction occurred when
this transformation was conducted without the Pd catalyst or
the ligand (Table 1, entry 15).
Having optimized the reaction conditions, we then focused
on the substrate scope of this method (Table 2). Various gem-
difluorinated cyclopropanes were all allowed to react with 2a
well, and afforded the corresponding products 3a-3o in 63-93%
yields. The structure of 3l was confirmed on the basis of a single-
crystal X-ray crystallographic analysis (see the SI for details).
When 1p was employed as the substrate, the conjugated
fluorodiene 3p was obtained in 66% yield. The 1,1-disubstituted
a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), [η3-C3H5PdCl]2 (5.0 mol%), XPhos
(10.0 mol%), LiOtBu (2.0 equiv), THF (2.0 mL), 80 C, Ar atmosphere, 18 h, sealed
tube. b Isolated yields. c Mesitylene (2.0 mL) as solvent. d 1j (0.3 mmol ), 2a (0.2
mmol). e K3PO4 (2.0 equiv) as base, Mesitylene (2.0 mL) as solvent. f 100 C.
β-naphthols
2 were examined, and all of them performed
smoothly to deliver the products 3v-3ad in good efficiency.
Phenyl substituted β-naphthol gave 3z in 54% yield due to the
increased steric bulk. Notably, 1-methylnaphthalen-2-ol
converted to the product 3ad in 67% yield with good
regioselectivity.
After checking the reactivity of β-naphthols, we then
proceeded to explore the generality of indoles (Table 3). All 2,3-
disubstituted indoles were found to be compatible with the
reaction, and the products 5a-5g were formed in moderate to
good yields upon reaction with gem-difluorinated cyclopropane
1a employing Pd(XantPhos)Cl2 as the catalyst, XPhos as the
gem-difluorinated cyclopropanes (1q, 1r) could be converted to
the products 3q and 3r in low yields (see the SI for details), but
1,2-diphenyl substituted gem-difluorinated cyclopropane 1s
could not offer the desired product 3s. To further demonstrate
the potential utility of this reaction for the late-stage
modification of natural products, the estrone derivatives (1t, 1u)
were synthesized and tested, offering the products 3t and 3u in
o
ligand and LiOtBu as the base in toluene at 80 C for 24 h (see
the SI for details on the optimization of reaction conditions).
The structure of 5a was confirmed on the basis of a single-
crystal X-ray crystallographic analysis (see the SI for details).
good yields. Subsequently, the compatibility of
2 | J. Name., 2012, 00, 1-3
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Table
3 Substrate scope of indoles and gem-difluorinated
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DOI: 10.1039/D0CC07529A
cyclopropanes a,b
Scheme 2 Further study of the reaction
yield, and the relative configuration was confirmed by the NOE
spectra analysis (see the SI for details) (Scheme 2b). Product 5a
reacted with AcCl to deliver compound 8 in 94% yield. Bisindole
9
bearing an ethylene bridge, a potent antitumor activity
a Reaction conditions: 1 (0.2 mmol), 4 (0.3 mmol), Pd(XantPhos)Cl2 (10.0 mol%), skeleton,14 could be synthesized by Aldol-type condensation
XPhos (10.0 mol%), LiOtBu (2.0 equiv), toluene (2.0 mL), 80 C , Ar atmosphere, 24
(Scheme 2c).
h, sealed tube. b Isolated yields. c 1 (0.3 mmol), 4 (0.2 mmol), Et3B (1.1 equiv).
Based on the previous works,11 a plausible catalytic cycle of
this reaction was shown in Scheme 3. Initially, the activated
Pd(0) catalyst reacts with the gem-difluorinated cyclopropanes
Cyclic olefin-fused indoles could deliver the products 5i and 5j
in 62% and 65% yields. Moreover, gem-difluorinated
1
through oxidative addition to generate the four-membered
palladacycle intermediate , which undergoes β-F elimination
to form the π-allylpalladium species . Subsequent nucleophilic
attack of β-naphthols or indoles
hindered carbon atom of intermediate
fluoroallylic β-naphthalenones
regenerates Pd(0) catalyst to the next catalytic cycle.
In conclusion, we have developed a palladium-catalyzed
cyclopropanes were investigated upon reaction with 2,3-
dimethylindole, offering the products 5k-5r in moderate to
good yields. Polycyclic indoline fragments are prevalent in
natural products and biologically active molecules.12 Therefore,
tryptophol and tryptamines were then subjected to the reaction
with gem-difluorinated cyclopropane 1a. To our delight, the
A
B
2
4
B
at the sterically less
affords the products 2-
3
and indolenines 5, and
furanoindoline 6a and pyrroloindolines 6b-6d were achieved in
80-90% yields via cascade allylic alkylation, dearomatization and
cyclization process in the presence of Et3B (Scheme 1).13
To demonstrate the synthetic utility of this method, the scale-
up synthesis and further transformations of products were
conducted as shown in Scheme 2. Product 3a (1.62 g) was
achieved in 91% yield on 5.0 mmol scale under the standard
reaction conditions (Scheme 2a). The ketone group could be
selectively reduced by NaBH4 to afford compound 7 in 90%
allylic alkylation dearomatization of

-naphthols and indoles
Scheme 3 Proposed mechanism
Scheme 1 Construction of polycyclic indoline
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with gem-difluorinated cyclopropanes for the first time. This
reaction provided an efficient approach to prepare 2-
fluoroallylic β-naphthalenones and indolenines in good to
excellent yields. In addition, functional furanoindolines and
pyrroloindolines could also be synthesized via cascade allylic
alkylation, dearomatization and cyclization process from
tryptophol and tryptamines. Further study on the asymmetrical
process of this reaction is currently underway in our laboratory
(see the SI for details).
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The authors acknowledge generous financial support from
the National Natural Science Foundation of China
(NSFC22071267), Foundation of The Open Project of State Key
Laboratory of Natural Medicines (SKLNMZZ202023); the
Innovation Team of “the Double-First Class” Disciplines
(CPU2018GY35 and CPU2018GY04); the National Science &
Technology Major Project “Key New Drug Creation and
Manufacturing Program”, China (2020ZX09201015).
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