Palladium-Catalyzed α-Arylation of Silylenol Ethers in the Synthesis of Isoquinolines and Phenanthridines

Article abstract of DOI:10.1021/acs.orglett.7b03776

A diverse array of isoquinolines and phenanthridines have been accessed by developing a two-step, one-pot method constituting regioselective palladium-catalyzed Kuwajima-Urabe α-arylation of silylenol ethers and acid-mediated deprotection, annulation, and aromatization. Structural diversity in the silylenol ethers leads to three different classes of isoquinolines and phenanthridines from which related natural products can be derived. The synthetic utility of this method by the quick assembly of the natural product trispheridine is also demonstrated.

Full text of DOI:10.1021/acs.orglett.7b03776

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed α‑Arylation of Silylenol Ethers in the Synthesis
of Isoquinolines and Phenanthridines
Gaurav Saini, Pravin Kumar, Gangam Srikanth Kumar, Arun Raj Kizhakkayil Mangadan,
and Manmohan Kapur*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Bhopal Bypass Road, Bhauri, Bhopal 462066,
MP, India
S
* Supporting Information
ABSTRACT: A diverse array of isoquinolines and phenan-
thridines have been accessed by developing a two-step, one-pot
method constituting regioselective palladium-catalyzed Kuwaji-
ma−Urabe α-arylation of silylenol ethers and acid-mediated
deprotection, annulation, and aromatization. Structural diversity
in the silylenol ethers leads to three different classes of
isoquinolines and phenanthridines from which related natural
products can be derived. The synthetic utility of this method by
the quick assembly of the natural product trispheridine is also
demonstrated.
he isoquinoline core is one of the most significant
scaffolds in biologically active N-heterocycles and a wide
indoles.17 Herein we report a two-step, one-pot method
involving palladium-catalyzed α-arylation of silylenol ethers of
enones, ketones, and aldehydes, followed by a Brønsted acid
mediated deprotection, annulation, and aromatization for
accessing three different classes of isoquinolines and phenan-
thridines (Scheme 1). By simply varying the silyl-enol ethers
T
array of natural products.1,2 Apart from synthetic applications in
pharmaceuticals, isoquinolines also play an important role in
material sciences, paints, and dye industries (Figure 1).3
Scheme 1. Our Approach toward the Synthesis of
Isoquinolines and Phenanthridines
and utilizing protected 2-bromobenzylamines as the coupling
partner, we can access phenanthridines, 3-alkenyl isoquinolines,
3-arylisoquinolines, and 4-arylisoquinolines. In addition to this
diversity, the highlight of this work is a unique α-arylation
reaction of the silyl-enol ethers of terminal aldehydes which, to
the best of our knowledge, is the first report of its kind.
Our initial studies commenced with palladium-catalyzed α-
arylation of silyl-enol ether 2aa with 2-bromobenzylamine, but
the reaction failed, which could be attributed to the poisoning
of the catalyst by the free amine. We then proceeded with the
investigation of N-protected-2-bromobenzylamines, which
included Ac, Fmoc, Boc, and Tr as the protecting groups
(Table 1). The α-monoarylation was more efficient with Boc
(entry 3, Table 1) as compared to trityl (entry 4, Table 1), but
we also observed some amount of diarylation as well as the
Figure 1. Isoquinolines and phenanthridine based natural products.
Traditional methods for accessing substituted isoquinolines
include Bischler−Napieralski, Pictet−Spengler, and Pomeranz−
Fritsch reactions among others as critical approaches.4
Numerous methods involving metal-catalyzed photoredox
reaction, C−H activation, and cycloadditions have also been
developed for achieving these N-heterocycles.5−9
Transition-metal-catalyzed α-arylation is an efficient method
for functionalizing the acidic α-C−H bonds of carbonyl
compounds with aryl groups.10−13 Recently, we had employed
Hartwig’s modification14 of the Kuwajima−Urabe method-
ology15 in the regioselective C(sp3) arylation of enones,16
which we then extended to the synthesis of substituted
Received: December 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of α-Arylation of Silyl-Enol Ether of
Enone
Table 2. Optimization of the Deprotection, Annulation, and
Aromatization
temp
(°C)
yield
a
temp
(°C)
a
entry
reaction condition
solvent
time
(%)
entry
R =
ligand
time
yield (%)
1
2
3
TFA
HCl
DCM
dioxane
THF
rt
6 h
30
0
1
Ac
DtBPF
85
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
2 h
2 h
2 h
2 h
2 h
2 h
complex mixture
2
Fmoc
Boc
DtBPF
85
complex mixture
reflux
rt
12 h
8 h
b
Amberlyst-15, DDQ,
4 Å MS
91
3
DtBPF
85
55
4
Tr
tBu imine
DtBPF
85
32
4
5
Amberlyst-15, 10% Pd/C,
4 Å MS
THF
reflux
reflux
24 h
10 h
76
83
5
DtBPF
85
complex mixture
6
Boc
Xanthphos
X-phos
Davephos
tBu-Xphos
DtBPF
85
0
Amberlyst-15, DDQ,
4 Å MS
dioxane
7
Boc
85
16
6
7
8
Amberlyst-15, 4 Å MS
DDQ, 4 Å MS
THF
reflux
reflux
reflux
10 h
36 h
11 h
0
0
8
Boc
85
complex mixture
THF
9
Boc
85
complex mixture
c
PTSA, DDQ, 4 Å MS
dioxane
86
10
11
12
13
14
15
16
Boc
85
33
49
DtBPF
100
100
100
135
100
a
b
Boc
Isolated yields. Amberlyst-15 (5 equiv (w/w)), DDQ (2 equiv).
PTSA (6 equiv), DDQ (3 equiv). See Supporting Information for full
optimization.
c
b
Boc
DtBPF
75
bc
,
Boc
DtBPF
41
bd
,
Boc
DtBPF
complex mixture
e
Scheme 2. α-Arylation Approach toward Synthesis of
Isoquinolines and Phenanthridines
Boc
DtBPF
55
f
Boc
DtBPF
100
c
2 h
d
0
a
b
e
Isolated yield. DtBPF (5 mol %). PhCF3. Xylene. Pd(OAc)2 (3
f
mol %), DtBPF (di-tert butyl phosphinoferrocene) (3 mol %). In
absence of Bu3SnF.
protodehalogenation of the starting material. We screened
other bidentate as well as monodentate ligands (entries 6−9),
but the α-arylation was expectedly best only with the electron-
rich and sterically encumbered DtBPF ligand.14−17 Decreasing
the ligand loading as well as the reaction time and
simultaneously increasing the temperature led exclusively to
α-arylation (entries 11−12). Other solvents had no substantial
impact on the reaction (entries 13−14). Further diminishing
the catalyst and ligand loading was not beneficial for the
reaction (entry 15).
After optimizing the α-arylation, we next attempted to
perform the removal of the Boc group followed by annulation
and aromatization in a single step to access the substituted
isoquinolines. Initially, we screened the reaction of 3aa with
TFA in DCM (entry 1, Table 2) which resulted in the desired
isoquinoline 4aa in a rather low yield.
The reaction with HCl in dioxane (entry 2, Table 2) was not
fruitful either. The combination of Amberlyst-15, DDQ, and 4
Å MS in THF led to exclusive formation of the desired
isoquinoline (entry 3, Table 2). The absence of any one of
these reagents did not lead to the isoquinoline (entries 6−7).
After optimizing both of the steps individually, we then aimed
to develop the entire transformation as a one-pot process and
obtained a satisfactory success. With the optimized conditions
in hand, we examined the substrate scope of our methodology
by first accessing 3-alkenylisoquinolines (Scheme 2A). The
TES-enol ether 2a coupled efficiently with electron-rich and
-deficient aryl bromides to afford 4aa−4ad in good to moderate
yields with the exception of 4ac. TES-enol ether of electron-
neutral aromatic enone also reacted smoothly to give 4ae−4ag.
TES-enol ether of dimethoxy substituted aromatic enone
provided 4ah when reacted with an electron-rich bromide.
The silylenol ether of an aliphatic enone reacted less efficiently
than aromatic enones to give 4ai whereas the silylenol ether of
a
b
Amberlyt-15, DDQ, 4 Å MS, THF. PTSA, DDQ, 4 Å MS, dioxane.
c
d
10% Pd/C (5 mol %), xylene, reflux, 8 h. Amberlyt-15, 10% Pd/C
e
(0.5 equiv) 4 Å MS, THF, reflux, 24 h. Reaction performed on 1
mmol scale.
a π-extended enone underwent an efficient transformation to
afford 4aj. We also extended the substrate scope with the
formation of 3,4-disubstituted isoquinoline 4ak by the reaction
with an α-substituted TES-enol ether partner.
Phenanthridines are important scaffolds in the synthesis of
natural products. We demonstrated the utility of our method-
ology by developing an easy access to phenanthridines in
moderate to good yields (Scheme 2B). The TES-enol ether of
B
DOI: 10.1021/acs.orglett.7b03776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cyclohexenone reacted with electron-rich and -deficient aryl
bromides to provide 4ba−4bc in moderate yield. Monosub-
stituted 3-methyl and 3-ethoxy cyclohex-2-enone as well as the
disubstituted 3,5-dimethyl cyclohex-2-enone reacted with
substituted aryl bromides to afford 4bd−4bi. We investigated
the substrate scope with benzo-fused cyclohex-2-enones (silyl
ethers of α-naphthols) but these reacted poorly to give 4bj and
4bk. Changing the electronic nature of the naphthols did not
help (4bl−4bo, Scheme 2).
Scheme 4. Synthesis of the Natural Product Trispheridine
3-Arylisoquinolines are synthons in many bioactive mole-
cules and medicinally important natural products. We also
examined the substrate scope of the transformation in the
synthesis of 3-arylisoquinolines (Scheme 3A). The TES-enol
A plausible mechanism for the transformation is depicted in
Scheme 5. In situ generated Pd(0) undergoes oxidative addition
a
Scheme 5. Plausible Mechanism
Scheme 3. Our Approach toward Synthesis of 3-Aryl and 4-
Arylisoquinolines
a
Representative mechanism for the synthesis of 4-arylisoquinolines.
followed by transmetalation with reactive stannyl-enol ether
(7d′−7d) of the enone to give organopalladium species 6a′−
6a. Reductive elimination affords the arylated product which
under protic conditions results in the isoquinolines via
sequential deprotection, annulation, and aromatization.
In summary, we have developed a palladium-catalyzed two-
step, one-pot process for direct access to different classes of
substituted isoquinolines and phenanthridines via the α-
arylation of preformed silylenol ethers with bromobenzyl-
amines. By the simple variation of the silylenol ether of enones,
we demonstrated the utility of our method by synthesizing 3-
alkenylisoquinolines and phenanthridines. Switching between
3-aryl and 4-arylisoquinolines could be obtained by choosing
the appropriate silylenol ethers. This also amounts to the first
report of palladium-catalyzed α-arylation of preformed enol
ethers of aldehydes. We also demonstrated the synthetic utility
of the method by the quick assembly of the alkaloid
trispheridine.
a
b
Amberlyt-15, DDQ, 4 Å MS, THF. PTSA, DDQ, 4 Å MS, dioxane.
ether of acetophenone reacted with differently substituted
bromides to yield 4ca−4cd. Moreover, silylenol ethers of p-
fluoroacetophenone and m-nitroacetophenone reacted
smoothly to produce 4ce−4ci in decent yields. This method-
ology provides a strategy for easy access to pharmaceutically
important 3-arylated isoquinolines.
The most attractive aspect of this methodology was the
development of a new approach for the synthesis of 4-
arylisoquinolines, which are a common building constituent in
several isoquinoline-based natural products (Scheme 3B). The
TES-enol ethers of substituted phenyl acetaldehydes reacted
with substituted bromides to afford 4-arylisoquinolines 4da−
4dk. It is noteworthy that from a single bromobenzyl amine we
can access 3-aryl as well as 4-arylisoquinolines in moderate
yields just by switching the silyl-enol ethers.
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.7b03776.
Experimental details and spectral characterization of all
new compounds (PDF)
We also demonstrated the synthetic utility of this method-
ology by the quick synthesis of alkaloid trispheridine18 in
moderate yield (Scheme 4). Other amaryllidaceae alkaloids,
bicolorine and N-methylcrinasiadine, can be accessed from
trispheridine using literature reports.19,20
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mk@iiserb.ac.in.
C
DOI: 10.1021/acs.orglett.7b03776
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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Med. Chem. Res. 2016, 25, 2959−2964.
Manmohan Kapur: 0000-0003-2592-6726
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding from DST-India (SB/S1/OC-10/2014) and CSIR-
India (02(205)/14/EMR-II) is gratefully acknowledged. G.S.
and A.R.K.M. both thank IISERB for a Research Fellowship and
BS-MS Fellowship, respectively, and P.K. thanks UGC-India for
a Research Fellowship. G.S.K. thanks CSIR-India for a Research
Fellowship. We thank CIF (IISERB) for the spectral data. We
also thank Director, IISERB for funding and infrastructural
facilities.
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