Selective synthesis of 2-aryl-3-alkenylindoles and 2-aryl-3-alkynylindoles by palladium-catalyzed ligand-promoted annulative coupling of anilines and propargyl alcohols

Article abstract of DOI:10.1016/j.jorganchem.2021.121930

A palladium-catalyzed annulative reaction between aniline and propargyl alcohol has been developed. Propargyl alcohols act as internal or terminal alkynes in the reactions through C?H/C?C activation in the presence of Ac-Gly-OH or Xantphos as ligand, resulting in the formation of 3-alkenylindoles or 3-alkynylindoles respectively. The incorporated alkenyl and alkynyl groups could be engaged for further derivations to form versatile indole skeletons with potential applications.

Full text of DOI:10.1016/j.jorganchem.2021.121930

Journal of Organometallic Chemistry 948 (2021) 121930
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Selective synthesis of 2-aryl-3-alkenylindoles and
-aryl-3-alkynylindoles by palladium-catalyzed ligand-promoted
annulative coupling of anilines and propargyl alcohols
2
a
a
b,∗
b
a,∗
Qiang Li , Maoshuai Zhu , Xufei Yan , Ying Xia , Xiangge Zhou
a
College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
b
West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, P. R. China
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed annulative reaction between aniline and propargyl alcohol has been developed.
Propargyl alcohols act as internal or terminal alkynes in the reactions through C−H/C−C activation in
the presence of Ac-Gly-OH or Xantphos as ligand, resulting in the formation of 3-alkenylindoles or 3-
alkynylindoles respectively. The incorporated alkenyl and alkynyl groups could be engaged for further
derivations to form versatile indole skeletons with potential applications.
Received 25 January 2021
Revised 8 May 2021
Accepted 7 June 2021
Available online 10 June 2021
Keywords:
Palladium
Ligand
©
2021 Elsevier B.V. All rights reserved.
Catalysis
Annulative coupling
Indoles
Indole skeleton, ubiquitously existed in bioactive molecules and
approved drugs, has emerged as high-profile targets for facile syn-
thesis all along [1]. Besides ordinary Fischer, Bischler and Bartoli
indole synthetic approaches [2], transition-metal catalysis to elab-
orate a diverse collection of multi-functionalized indoles also draw
considerable attentions up to now [3]. Among different compounds
containing indole skeleton, 3-alkenylindoles has been well doc-
umented with biological properties such as potential anticancer
agent A and polymerase inhibitor B shown in Fig. 1 [4]. Normally,
[10]c. Despite of these protocols to construct functionalized in-
doles, there still exist a demand of concise and general synthetic
routes to achieve C2 and C3 functionalized indoles.
On the other hand, propargyl alcohol has been reported as a
versatile building motif incorporated in allene and alkyne transfor-
mation as well as ring expansion reactions [11]. Recently, we re-
ported γ -aryl propargyl alcohol as arylacetylene precursor through
β-C elimination process to form 2-arylindoles (Scheme 1a) [12].
In pursuit of further synthetic diversity to multi-functionalized in-
doles and our persistent work on heterocycle synthesis [13], herein
we disclosed palladium-catalyzed ligand-promoted annulation re-
actions between anilines and γ -aryl propargyl alcohols, affording
2-aryl-3-alkenylindoles and 2-aryl-3-alkynylindoles in the presence
of Ac-Gly-OH or Xantphos as ligand respectively (Scheme 1b).
Our investigation commenced with the reaction between N-
4-methylphenyl-2-animopyridine 1a and 2-methyl-4-phenylbut-3-
yn-2-ol 2a in DMF in the presence of 10 mol% Pd(OAc)2 and
2.0 equiv Cu(OAc)2 at 120 °C for 12 h under N2 atmosphere. As
shown in Table 1, the annulative coupling products 3a and 4a were
obtained in similar yields 22% and 25%, which involved internal
alkyne insertion or β-C elimination process respectively, indicating
the selectivity between internal or terminal alkynes derived from
3
-alkenylindoles can be derived from the existed indole molecules
by Wittig reaction [5], Heck or Stille type coupling reactions [6], di-
rect indole C3 alkenylation reaction [7], or cycloaddition of alkenyl
substituted anilines in the presence of palladium catalyst [8].
Analogously, 3-alkynylindoles such as tyrosine phosphatase in-
hibitor C and neuroprotective agent D (Fig. 1), which exhibit at-
tractive biological activities, can be accessed by two pathways:
transition-metal catalyzed cross coupling reaction of pre-existed
indoles [9]; and electrophilic cyclization and subsequent alkyny-
lation reaction with o-alkynylanilines [10]. Followed by the lat-
ter strategy, Jiang and co-workers successfully developed a facile
synthesis of 3-alkynylindoles with 2-alkynylanilines and terminal
alkynes with high atomic economy and broad substrate scope
2a might be the key challenge in this reaction (Table 1, entry 1).
Meanwhile, there existed byproduct 1,4-diphenylbuta-1,3-diyne 5
from Glaser coupling reaction of 2a in a yield around 30%. Fur-
ther experiments revealed that other metal salts including Co(II),
∗
Corresponding author.
E-mail addresses: yanxf92@scu.edu.cn (X. Yan), zhouxiangge@scu.edu.cn (X.
Zhou).
https://doi.org/10.1016/j.jorganchem.2021.121930
0
022-328X/© 2021 Elsevier B.V. All rights reserved.

Q. Li, M. Zhu, X. Yan et al.
Journal of Organometallic Chemistry 948 (2021) 121930
Fig. 1. Selected 3-alkenyl or 3-alkynyl indoles with bioactivities.
Scheme 1. Transition-metal catalyzed C−H/C−C activation to construct functional-
ized indoles with auxiliary directing group.
Ni(II), Ru(II) and Rh(III) were not suitable for this transformation
(
Table 1, entries 2-5). Then, different ligands were tested, which
exhibited significant effects on the results (Table 1, entries 6-13).
After comparison of different ligands, phosphine ligand Xantphos
with steric hindrance benefited for the formation of product 4a in
5
5% yield (Table 1, entries 6-10), while ligand Ac-Gly-OH favored
the transformation to 3a in 60% yield (Table 1, entries 11-13).
Table 1
Optimization of reaction conditionsa.
b
Entry
Metal salt
Ligand
Cu(II)
Yield (%)3a/4a
1
2
3
4
5
6
7
8
9
Pd(OAc)2
/
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
CuCl2
22/25
Co(OAc)2•4H2O
Ni(OAc)2•4H2O
/
0/0
/
5/3
[RuCl2(p-cymene)]2
/
0/0
Scheme 2. Scope of N-aryl-2-aminopyridinesa,b.
∗
[Cp RhCl2]2
/
8/5
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
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
X-Phos
Xantphos
PPh3
8/40
6/55(50)
22/28
After a series experiments of screening different Cu(II) salts,
bases [14] and solvents, the optimal reaction conditions for the for-
PCy3
25/25
1
1
1
1
1
1
1
1
1
1
2
0
1
2
3
4
5
6
dppe
20/33
mation of 3a was: 10 mol% Pd(OAc) , 20 mol% Ac-Gly-OH and 2.0
2
pyridine
1,10-Phen
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Ac-Gly-OH
Xantphos
Xantphos
5/trace
8/trace
60/8
equiv of CuSO4 in DMF (1.0 mL) at 120 °C for 12 h under N2 in 70%
isolated yield (Table 1, entry 17). And the optimal reaction condi-
42/trace
26/trace
22/trace
71(70)/ trace
38/trace
15/trace
47/trace
trace/23
trace/14
tions to form 4a was: 10 mol% Pd(OAc) , 20 mol% Xantphos and
2
2
5
.0 equiv Cu(OAc)2 in DMF (1.0 mL) at 120 °C for 12 h under N2 in
0% isolated yield (Table 1, entry 7).
CuBr2
7
8c
9d
0e
CuSO4
With the optimal reaction conditions established, the scope of
CuSO4
CuSO4
N-aryl-2-aminopyridines 1 was investigated to form 3 and 4 under
CuSO4
the two different catalytic systems respectively.
2 f
1
2g
Cu(OAc)2
Cu(OAc)2
As shown in Scheme 2, in the case of preparation of
3
2
with Ac-Gly-OH as ligand, N-aryl-2-aminopyridines 1 bearing
a
i
Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv), catalyst (10 mol%), Cu(II)
electron-donating moieties including -Me, - Pr, and -OMe groups
were found to give better results than those bearing electron-
withdrawing groups. It was worthy to note that chloro substituted
product 3g could be obtained by this transformation, and would
be easily further derived. Steric effects seemed to have few im-
pacts on the reaction, as ortho-, meta- and para-methyl substituted
substrates afforded the corresponding products 3n, 3k and 3a in
approximately moderate yields around 70%.
salts (2.0 equiv) and ligand (20 mol%) were stirred in the solvent (1.0 mL) at 120°C
for 12 h under N2.
b
NMR yields with CH2Br2 as internal standard and isolated yields were shown
in the parentheses.
c
1
,4-dioxane.
d
e
f
toluene.
MeCN.
Na2CO3 (2.0 equiv).
g
ꢀ
ꢀ
ꢀ
ꢀ
Cs2CO3 (2.0 equiv). X-Phos, dicyclohexyl(2 ,4 ,6 -triisopropyl- [1,1 -biphenyl]-2-
yl)phosphane; Xantphos, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; dppe,
,2-bis(diphenyl-phosphino)ethane; Ac-Gly-OH, N-acetylglycine.
On the other hand, in the case of preparation of 4 with Xant-
phos as ligand, electronic effects seemed to have few influences
1
2

Q. Li, M. Zhu, X. Yan et al.
Journal of Organometallic Chemistry 948 (2021) 121930
Fig. 2. ORTEP diagram of 3g and 4g with thermal ellipsoids showed at 20% proba-
bility.
on the results. For example, N-aryl-2-aminopyridines 1 containing
i
either electron-donating groups (-Me, - Pr and -OMe) or electron-
withdrawing groups (-Cl and -Br) were all capable of this annula-
tion/alkynylation process in moderate yields ranging from 48% to
5
4%. On the contrary, steric effects seemed to play a pivotal role,
as none of 4h was obtained in the case of ortho-methyl substituted
substrate. Of note that the structures of 3g (CCDC 2046561) and 4g
(CCDC 2046564) were confirmed by X-ray single crystal determina-
tion as shown in Fig. 2.
Scheme 4. A scale-up experiment and product transformations.
Next, γ -Aryl propargyl alcohols containing different sub-
stituents were also exploited as depicted in Scheme 3. Again,
electron-donating substituents seemed to be more suitable for
this reaction. And the highest yield 82% was obtained in the
case of para-methyl substituted substrate delivering 3q. However,
methoxyl group substituted γ -aryl propargyl alcohol afforded 3r in
a lower yield of 56% partially due to an easier competitive Glaser
coupling. The steric effect is almost negligible as ortho-, meta- and
para-methyl substituted γ -aryl propargyl alcohols resulted in the
formation of 3o, 3p and 3q in similar yields around 80%. Of note
that thiophene-containing substrate was also tolerated to elaborate
3x albeit in 55% yield. Meanwhile, using Xantphos as the ligand,
methyl, fluoro, chloro and dimethyl substituted γ -aryl propargyl
alcohols could be engaged in this cascade reaction to form prod-
uct 4 with yields ranging from 36% to 45%.
At last, several experiments were implemented to further cor-
roborate the utility of this reaction. As shown in Scheme 4, a scale-
up reaction to form 3b proceeded smoothly in 58% isolated yield.
Ortho-bromo substituted γ -aryl propargyl alcohol could also be ap-
plied in this transformation followed by an intramolecular Heck-
type cross coupling in a total yield 45% to form benzocarbazole 6,
which has potential applications in medicinal molecules and func-
tional materials. Considering alkynyl moiety as a flexible synthon,
a controllable oxidative reaction was conducted successfully in the
presence of KMnO4 to obtain an indole derivative 7 containing 1,2-
diones motif.
To gain more insights into the possible reaction pathway, a se-
ries of experiments were carried out as shown in Scheme 5. Firstly,
H/D exchange experiments of 1b with Ac-Gly-OH or Xantphos as
ligand were conducted, resulting in 28% or 32% D incorporated
into the ortho position, which revealed that ortho C−H cleavage
might be reversible during reaction (Scheme 5, eq 1). Then, par-
allel and intermolecular competitive experiments of 1b and [D ]-
6
1b in both catalytic systems gave the kinetic isotope effect (KIE)
values (k /k ) from 1.0 to 1.3, implying that ortho C−H activation
H
D
might not been involved in the rate-determining process in both
cases (Scheme 5, eqs 2-5).
Further experiments indicated 2-arylindole 8 not to be involved
during the reaction (Scheme 5, eqs 6 and 7).
More importantly, palladacycle 9 was successfully isolated from
the reaction between 1a and PdCl , and was characterized by NMR
2
and HRMS analysis (Scheme 5, eq 8). The application of 9 in the
catalytic or equivalent reactions gave considerable yields of the de-
sired product 3a, revealing the possible existence of six-membered
palladacycle during the catalysis (Scheme 5, eqs 9 and 10).
Based on our experimental results as well as literatures [15], a
possible catalytic pathway was proposed. As shown in Scheme 6,
firstly, ortho C−H cleavage of 1b occurred with Pd(OAc) to form
2
six-membered palladacycle IM1 or IM3. In the case of Ac-Gly-
OH as ligand, IM1 might be transformed to be a six-membered
palladacycle IM2 through migration insertion of 2a as internal
alkyne [15]. Later, reductive elimination followed by dehydration
occurred to form the desired product 2-aryl-3- alkenylindole 3, and
Scheme 3. Scope of γ -aryl propargyl alcoholsa,b
.
3

Q. Li, M. Zhu, X. Yan et al.
Journal of Organometallic Chemistry 948 (2021) 121930
Scheme 6. Proposed reaction pathways.
tially owing to a larger steric hindrance via migration insertion of
2a to IM3 and thus lead to β-C elimination/transmetalation pro-
cesses to form IM4 assisted by a bulky phosphine ligand Xantphos.
Next, IM4 would proceed reductive elimination/aminopalladation
transformation to be IM6. Transmetalation appeared once again in-
stead of protonation to form alkynyl-Pd(II) intermediate IM7. IM7
underwent another reductive elimination to deliver the final prod-
uct 2-aryl-3-alkynylindole 4. Analogously, Cu(OAc)2 would oxidize
Pd(0) to Pd(II) for the next catalytic cycle.
In conclusion, we have disclosed a novel and tuneable annu-
lative reaction to synthesize 2-aryl-3-alkenylindoles and 2-aryl-3-
alkynylindoles with anilines and propargyl alcohols as substrates
by utilizing pyridine as the directing group. Propargyl alcohols
could be engaged in migration insertion/annulation as internal
alkynes or β-C elimination/alkynylation as terminal alkynes with
the aid of Ac-Gly-OH or Xantphos as the ligand respectively.
Derivations of alkenyl and alkynyl motifs have also been imple-
mented to diverse functionalized indoles, illustrating the potential
utility of this selective annulative reactions.
Declaration of Competing Interest
The authors in the manuscript entitled “Selective Synthesis of
2-Aryl-3-Alkenylindoles and 2-Aryl-3-Alkynylindoles by Palladium-
Catalyzed Ligand-Promoted Annulative Coupling of Anilines and
Propargyl Alcohols” declare that they have no known competing
financial interests or personal relationships that could have ap-
peared to influence the work reported in this paper.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (grant no. 22071159) and the Sichuan Science and Technol-
ogy Program (No. 2018JY560) for financial support. X. Yan acknowl-
edges Public Health and Preventive Medicine Provincial Experi-
ment Teaching Center at Sichuan University for compound char-
acterization.
Scheme 5. Studies of the reaction pathways.
Pd(0) would be re-oxidized to be Pd(II) by CuSO4 to recover the
catalyst.
Supplementary materials
On the other hand, in the case of Xantphos as ligand, 2a would
go through a β-C elimination in the presence of Cu(OAc)2 and sev-
ered as phenylacetylene precursor with a sequence of transmeta-
lation to form IM4. The selectivity between IM2 and IM4 was par-
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.jorganchem.2021.
121930.
4

Q. Li, M. Zhu, X. Yan et al.
Journal of Organometallic Chemistry 948 (2021) 121930
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