Controllable Pd-Catalyzed Allylation of Indoles with Skipped Enynes: Divergent Synthesis of Indolenines and N-Allylindoles

Article abstract of DOI:10.1021/acs.orglett.8b02481

An unprecedented acid- and ligand-controlled divergent allylation of indoles with unactivated skipped enynes via Pd hydride catalysis has been disclosed. This redox-neutral transformation went through multiple hydropalladation insertion, β-hydrogen elimin

Full text of DOI:10.1021/acs.orglett.8b02481

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Controllable Pd-Catalyzed Allylation of Indoles with Skipped
Enynes: Divergent Synthesis of Indolenines and N‑Allylindoles
Xinxin Fang, Qiuyu Li, Rui Shi, 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: An unprecedented acid- and ligand-controlled divergent allylation of indoles with unactivated skipped enynes via
Pd hydride catalysis has been disclosed. This redox-neutral transformation went through multiple hydropalladation insertion, β-
hydrogen elimination, π−σ−π isomerization, and allylic substitution steps. This method not only provides a platform for
synthesizing indolenines and N-allylindoles but also allows facile access to functional 1,3-dienes with high atom and step
economy.
he indole scaffolds play a vital role in drug discovery and
The past decades have witnessed great success in the field of
transition-metal-catalyzed allylic substitution7 and allylic C−H
oxidation8 allowing the construction of allyl compounds;
however, the catalytic synthesis of versatile 1,3-diene motifs9
remains underdeveloped.10 Polyenyl esters10a,b and 1,4-
pentadienes10c−f have been developed to construct 1,3-dienes,
while the further development of these synthetic platforms was
impeded by the multistep synthesis and prefunctionalization of
the allylic substrates, formation of valueless byproducts and/or
employment of extra oxidants. Herein, we describe the
generality of Pd hydride catalysis for the divergent allylation
of indoles (C3 and N1) with unactivated skipped enynes to
furnish functional 1,3-dienes, featuring high atom and step
economy (Scheme 1c). The high chemoselectivity was made
feasible by a delicate choice of acids and ligands.
T
agrochemical development due to their prevalence in
natural products and biologically active structures.1 They also
serve as privileged building blocks in synthetic chemistry.2 It
has been well documented that the C3-position of indole was
the most reactive site among the three positions (N1, C2, C3)
(Scheme 1a), and the majority of reactions of indoles focused
Scheme 1. Chemoselective Allylation of Indoles
Our studies commenced by employing 5-methoxy-2,3-
dimethylindole 1a and pent-4-en-1-yn-1-ylbenzene 2a as the
model substrates (Figure 1). When the reaction was performed
in the presence of Pd(PPh3)4 (10.0 mol %), PPh3 (20.0 mol
%), and PivOH (20.0 mol %) as a catalytic system in toluene at
100 °C, the C3-allylation of indole was successfully realized
through a dearomatizaton process with high chemoselectivity,
yielding 3aa in 15%. To increase the yield of 3aa, various acids
were then tested, and 2,4,6-trimethylbenzoic acid (A5,
MesCOOH) could provide 3aa in 62% yield. Further
screening of acids revealed that the chemoselectivity was
completely switched to the formation of the N-allylation
product 4aa when (PhO)2POOH or p-TsOH·H2O was used
(see the SI for more details). Given that the specific structure
on the C3-position.3 In contrast, the selective N-functionaliza-
tion of indoles,4 especially the direct N-allylation reaction,5
remains difficult due to the weaker nucleophilicity of N1
relative to that of the C3-position (Scheme 1b). Therefore,
developing efficient protocols to control the chemoselectivity
and enable divergent synthesis or modification of indoles is still
highly desirable, yet challenging, in organic synthesis.6
Received: August 3, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02481
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Letter
a,b
Scheme 2. Substrate Scope of C3-Allylation of Indoles
Figure 1. Optimization of reaction conditions. Reaction conditions:
1a (0.2 mmol), 2a (0.4 mmol), Pd(PPh3)4 (10.0 mol %), ligand (20.0
mol %), and acid (20.0 mol %) in toluene (2.0 mL). (a) Isolated
yields of two products and the yields are reported as a mixture of E
and Z isomers. (b) C/N refers to the ratio of 3aa:4aa. (c) Ratios of
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(PPh3)4 (10.0
mol %), PCy3 (20.0 mol %), and MesCOOH (20.0 mol %) in toluene
b
(2.0 mL). Isolated yields and the yields are reported as a mixture of
1
2E/2Z were determined by H NMR. nr = no reaction.
E and Z isomers. The ratios of 2E/2Z were determined by 1H NMR.
c
d
e
120 °C. After recrystallization. 1.1 equiv of Et3B was added.
of ligands may have an enormous impact on stability, reactivity,
and selectivity of the transition-metal complexes,11 an
extensive ligand screening for C3-allylation of indoles was
examined and is listed in Figure 1b. Diphosphine ligands L1−
L4 exhibited low reactivity and selectivity, whereas mono-
phosphine ligands L5−L9 performed well. Based on the
evaluation of the monophosphine ligands, we observed a close-
knit relationship between the ligand cone angle and the
reactivity and selectivity. Monophosphine ligands with cone
angles in the range of 131−183° showed good efficiency, and
the best result was observed when PCy3 was adopted with an
optimal cone angle of 144°. Further increasing the cone angle
of ligands (L10 and L11) resulted in a dramatic decrease in
reactivity.
With the optimized conditions in hand, we then examined
the substrate scope of C3-allylation of indoles, and the results
are shown in Scheme 2. Methoxy, methyl, and isopropyl
groups installed at the C5-position of indoles (1a−c) provided
3aa−ac in 67−71% yields. 2,3-Dimethylindole 1d gave 3ad in
73% yield. Products 3ae and 3af with halogen groups (−Cl,
−F) at the C5-position were achieved in 44% and 54% yields.
Indoles bearing strong electron-withdrawing groups (−NO2
and −CF3) were found to be incompatible. C4-OMe-
substituted indole 1i afforded 3ai in 75% yield. In addition,
7-methyl- and 4,6-dimethyl-substituted indoles (1j and 1k)
and 1,2-dimethyl-3H-benzo[e]indole 1l could furnish 3aj−al in
55−81% yields. The reaction was amenable to scale-up,
providing 3aj in 73% yield on a 5.0 mmol scale. By changing
the C3-methyl group to an ethyl group or a benzyl group, 3am
and 3an were obtained in 65% and 69% yields. 1,2,3,4-
Tetrahydrocarbazole 1o delivered 3ao in 65% yield.
Furanoindoline 3ap and pyrroloindoline 3aq were achieved
in good yields with tryptamine and tryptophol as substrates via
cascade dearomatization/allylation/cyclization.12 2-Methylin-
dole 1r and 5-methoxyindole 1s could offer C3-allylated
indoles in moderate yields. However, 3-methylindole 1t and
2,5-dimethylpyrrole 1u gave trace or none products under the
standard conditions. Skipped enynes bearing both electron-
donating groups (−Me, −OMe) and electron-withdrawing
groups (−Cl, −F, −CF3) on the phenyl ring provided 3ba−ia
in moderate to good yields. When the phenyl group was
replaced with naphthyl and thiophene groups (2j and 2k), the
B
DOI: 10.1021/acs.orglett.8b02481
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a,b
reaction could also proceed efficiently as well. Alkyl- or ester-
substituted skipped enynes (2l and 2m) were invalid.
Scheme 4. Substrate Scope of Naphthols
After examining the scope of C3-allylation of indoles, we
then turned to the selective N-allylation of indoles (Scheme 3).
a,b
Scheme 3. Substrate Scope of N-Allylation of Indoles
a
Reaction conditions: 4 (0.2 mmol), 2a (0.4 mmol), Pd(PPh3)4 (10.0
mol %), A6 (30.0 mol %), and KHCO3 (2.0 equiv) in toluene (2.0
b
mL). Isolated yields and the yields are reported as a mixture of E and
Z isomers. The ratios of 2E/2Z were determined by H NMR.
1
Scheme 5. Synthetic Applications
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(PPh3)4 (10.0
mol %), CyJohnPhos (20.0 mol %), and (PhO)2POOH (20.0 mol %)
b
in toluene (2.0 mL). Isolated yields and the yields are reported as a
mixture of E and Z isomers. The ratios of 2E/2Z were determined by
c
1H NMR. 120 °C.
The combination of (PhO)2POOH and CyJohnPhos was
found to be an ideal catalytic system (see the SI for more
details). Various N−H indoles bearing sterically modified
substituents could efficiently convert into N-allylindoles 4aa
and 4ad−ai with high chemoselectivity. Moreover, natural
product rutecarpine could be successfully modified to provide
4aj in 51% yield. Aryl-substituted skipped enynes were
competent reagents, which offered 4ak−ao in good yields,
while alkyl- or ester-substituted skipped enynes were
unsuccessful substrates (4ap and 4aq). Indoles bearing strong
electron-withdrawing groups, 2-methylindole, 5-methoxyin-
dole, and 3-methylindole failed to give the desired N-
allylindoles (4ab, 4ac, and 4ar−at).
Naphthols are readily available materials and possess
multiple reactive sites. Recently, the dearomatization of
naphthols has received great attention because this trans-
formation represents an ideal method for the rapid
construction of functionalized cyclohexadienones.13 In our
Pd hydride catalysis, the cyclohexadienones 5a−d bearing 1,3-
diene motifs could be easily accessed through the addition of
various β-naphthol and phenol derivatives to skipped enyne 2a
with high chemoselectivity (C/O > 20:1) (Scheme 4).
To demonstrate the utility of the reaction, further trans-
formations of the products were carried out. An olefin cross-
metathesis of 3aj with tert-butyl acrylate in the presence of
Grubbs II catalyst occurred smoothly to furnish indolenine 6 in
80% yield (Scheme 5). Indolenine 7 bearing a long-chain alkyl
group could be obtained through catalytic hydrogenation.
Bisindole 8, a structural motif known for its presence in potent
antitumor agents,14 could be easily obtained by Aldol-type
condensation. Treatment of 3aj with acetyl chloride in the
presence of triethylamine provided the corresponding β-
enaminone 9 in 52% yield.15 The N-allylindole 4aa underwent
a cycloaddition reaction with N-phenylmaleimide, producing
polycyclic compound 10 in 65% yield.
To gain some insight into the mechanism of this reaction,
we prepared phenyl allene 11 and tested its reactivity with 1a
under slightly modified conditions,16 which delivered 3aa in
61% yield (Scheme 6a). This result indicated that the phenyl
allene could be involved in the reaction process. On the basis
of previous reports,17 the above result, and deuterium-labeling
experiment (see the SI for details), a plausible catalytic cycle
for the C3-allylation of indoles was proposed as shown in
Scheme 6b. First, oxidation of Pd(PPh3)4 with MesCOOH
initials the catalytic cycles and affords the hydridopalladium
species A. Hydropalladation of 2a with A affords the vinyl
palladium intermediate B. β-Hydrogen elimination of B
produces the phenyl allene C and intermediate A (catalytic
cycle I). Next, hydropalladation of A with phenyl allene C
C
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Scheme 6. Mechanism Study
ACKNOWLEDGMENTS
■
Generous financial support from the National Natural Science
Foundation of China (NSFC21572272 and NSFC21502232)
is gratefully acknowledged.
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ASSOCIATED CONTENT
* Supporting Information
■
S
1H and 13C NMR spectra for all new compounds (PDF).
Experimental procedures and spectroscopic characterization
data. The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02481.
Experimental procedures and spectroscopic character-
1
ization data; H 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
The authors declare no competing financial interest.
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