Rh(III)-Catalyzed Phosphine Oxide Migration Reactions: Selective Synthesis of 3-Phosphinoylindoles

Article abstract of DOI:10.1002/asia.201800516

3-Phosphinoylindoles are important components of biological active natural products and materials in pharmaceuticals. Herein, a new approach for the synthesis of 3-phosphinoylindoles has been established by a Rh(III)-catalyzed cyclization from readily acc

Full text of DOI:10.1002/asia.201800516

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Accepted Article
Title: Rh(Ⅲ)-Catalyzed Phosphine Oxide Migration Reactions:
Selective Synthesis of 3-Phosphinoylindoles
Authors: Shangdong Yang and Chunhai Wang
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Rh(Ⅲ)-Catalyzed Phosphine Oxide Migration Reactions: Selective
Synthesis of 3-Phosphinoylindoles
Chun-Hai Wang, [a] Shang-Dong Yang*[a, b]
Abstract: 3-Phosphinoylindoles are important components both of
biological active nature products and materials in pharmaceuticals.
Herein, a new approach for the synthesis of 3-phosphinoylindoles
has been established through Rh(Ⅲ)-catalyzed cyclization from the
designed, readily accessible (2-azidostyryl)diphenylphosphine
oxides. This intramolecular transformation occurs through unique
phosphine oxide group migration and offers a straightforward route
to rebuild sp2 C-P bond and construct the indole ring in single step.
complex functionalized products. Inspired by Driver’s work, we
questioned whether it would be possible to form 3-
phosphinoylindoles through the intramolecular reaction involving
the selective migration of phosphine oxide group process.
Herein, we report our initial studies that Rh(Ⅲ)-catalyzed
cyclization
to
form
3-phosphinoylindoles
from
(2-
azidostyryl)diphenylphosphine oxides (d, Scheme 1). This
intramolecular transformation occurs through unique phosphine
oxide group migration and offers a straightforward route to
rebuild sp2 C-P bond and construct the indole ring in single step,
Indole skeletons are basic elementary components both of
biological active natural products and materials in
pharmaceuticals.1 Since the discovery of Fischer indole
synthesis,2 a plethora of methods have been reported for the
preparation of indole and its derivatives.3 Among them, styryl
azides, acting as the ideal nitrogen precursors, have attracted
much attention due to the fact that thermolysis or photolysis of
azides produce nitrenes,4 which can react with neighboring C-H
bonds to construct N-heterocycle compounds.5 Meanwhile,
metal-mediated nitrogen atom transfer reactions from organo
azides are well-known to create new C-N bonds.6 Aside from the
seminal reports on the nitrene transformation from an initially
generated metallonitrenoid to the target C-H bonds to produce
the C-N bonds were developed effecitively.7 In 2011, Driver et al.
reported the method to selectively form 3-nitroindoles from β-
nitro stryl azides catalyzed by Rh(Ⅱ) complexes.6e Recently, the
synthesis of indolyl-backbone phosphines, especially for 3-
phosphinoylindoles is a hot topic due to their unique roles as
ligands and pharmaceutical drugs.8 To the best of our
knowledge, besides the traditional stoichiometric Grignard
reaction (a, Scheme 1),8a only two methods were developed for
the synthesis of 3-phosphinoylindoles. In 2014, our group
thereby providing
phosphinoylindoles formation.
a
new synthetic method for 3-
reported
a
copper-catalyzed cross-coupling reaction by
hydrogen(H2) removal for the stereoselective synthesis of 3-
phosphoindoles between the 2-substituted indoles and P(O)H
compounds (b, Scheme 1).9 In 2016, Zhao et al. reported a
cascade phosphinoylation, cyclization, desulfonylation approach
for the synthesis of 3-phosphindoles by using N-Ts-2-
alkynylanilines and diphenylphosphine oxide (c, Scheme 1).10
These intermolecular reactions to form 3-phosphinoylindoles are
highly efficient. However, intramolecular reactions that
containing a selective migration event can transform simple
designed, readily accessible starting materials into more
Scheme 1. Route to 3-phosphinoylindoles.
At first,
a variety of transition-metal complexes were
examined for their potential to form 3-diphenylphosphinoylindole
(Table 1). To our surprise, exposure of 1 to Rh2(OAc)4 (2.5
mol %) formed 3-diphenylphosphinoylindole as the only product
[a]
[b]
Dr. C. H. Wang and Prof. S. D. Yang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Address Lanzhou 730000, P. R. China
Fax: (+) 86-931-8912859
E-mail: yangshd@lzu.edu.cn
Prof. S. D. Yang
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Lanzhou 730000, P. R. China
with 13% isolated yield (entry 1), the other known N-atom
11d
transfer catalysts (such as [Ir(cod)OMe]2,6c FeBr2,11a,
and
((2-
11b
CoI2
)
could only give the NH2-product,
3
aminostyryl)diphenylphosphine oxide) (entries 3-5, Table 1).6c, 11
No reaction was observed when the RuCl3xH2O acts as the
catalyst (entry 2).11c Then we investigated the oxidation state of
rhodium, the results showed that the Rh(Ⅰ) complex–
Rh(CO)H(PPh3)3 only gave the NH2-product (entry 6) either,12
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
but exposure of
1
to Rh(OAc)3xH2O formed 3-
diphenylphosphinoylindole with 82% isolated yield and avoided
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the NH2-product completely (entry 7). These results emphasize
the importance of the oxidation state of rhodium to achieve this
transformation to form 3-diphenylphosphinoylindole. Next, we
examined the influences of the solvents, expect for the more
polar protic solvent HFIP could give the target product in good
yield (60%; entry 10), many solvents (such as CH3CN, THF and
DCE) could not tolerate this transformation effectively. Exposure
of this transformation under air atmosphere, the isolated yield
was lowered to 47% (entry 13), and the Rh2(esp)2 failed to react
with the (2-azidostyryl)diphenylphosphine oxide (entry 12).6e, 6g
Finally, the optimal reaction condition was obtained by using
Rh(OAc)3xH2O (2.5 mol%) as catalyst, TFE (1.0 mL) as the
solvent for 1a (0.1 mmol) at 80 ℃ under argon (details please
see the Table S1 in Supporting Information (SI).
indoles (e.g., 2h, Table 2), which cannot be made regioselectively
by using the Fischer indole reaction.13 Moreover, we found that the
substrate with R1 substituent on either the orth-position of the
azide group or alkenylphosphine group could affect the formation
of 3-phosphinoylindoles, yields of 52% and 46% were obtained
(2n and 2o, Table 2). Also, the electronic nature of group on
phosphorus could affect the reaction either. When changing the
phenyl group on phosphorus to the ethoxy group, the diethyl(2-
azidostyryl)phosphonate did not result in diethyl (1H-indol-3-
yl)phosphonate formation with the full recovery of 1q (Table 2).
While the strong electron-withdrawing group (CF3) was introduced
to the meta-position of azide in 1p, the diethyl (6-(trifluoromethyl)-
1H-indol-3-yl)phosphonate could be obtained in 37% yield (2p,
Table 2). These results re-emphasize that the electronic nature of
the aryl azide substrates strongly effect the cyclization process
and may also support the hypothesis that the C-N bond formation
occurs via an electrocyclization process.6f
Table 1. Optimization of Reaction Conditionsa
Table 2. Scope of Rh( Ⅲ )-catalyzed Phosphine oxide Shift
Reactionsa
Entry
Cat. [2.5 mol %]
Solvent Yield [%]
2a:3
1
2
Rh2(OAc)4
RuCl3xH2O
[Ir(cod)OMe]2
FeBr2
TFE
TFE
13
0
100/0
n.a.b
3
TFE
trace
19
0/100
0/100
0/100
0/100
100/0
100/0
mixc
4
TFE
5
CoI2
TFE
12
6
Rh(CO)H(PPh3)3
Rh(OAc)3xH2O
Rh(OAc)3xH2O
Rh(OAc)3xH2O
Rh(OAc)3xH2O
Rh(OAc)3xH2O
Rh2(esp)2
TFE
13
7
TFE
CH3CN
THF
HFIP
DCE
TFE
82
8
trace
trace
60
9
10
11
12
13d
100/0
100/0
n.a.
trace
0
TFE
47
100/0
Rh(OAc)3xH2O
[a] All reactions were carried out with 1a (0.1 mmol), catalyst (2.5 mmol %),
solvent (1.0 mL), 80 ℃, argon atmosphere, 14 h. Yield of isolated product are
given. bn.a.= no reaction. c2a and 3 were obtained together and the ratio was not
determined. dReaction was carried out under air atmosphere.
Using our optimized conditions, the substrate scope was
investigated (Table 2). A series of 3-phosphinoylindoles were
produced from substrates bearing
a
range of R1 and R2
substituents (2a-2p, Table 2). Our data demonstrated that the
electronic nature of the aryl substrates can affect the formation of
6f
3-phosphinoylindoles to different degrees.6c,
When R1
substituent on the para-position of the azide group, the reaction
was influenced by the electronic nature of the substrates largely
and correspondingly, 2b-2f were obtained in 42-91% yield. With
R1 substituent on the meta-position of the azide group, the
reaction tolerated both electron-withdrawing groups and electron-
donating groups very well. Moderate or excellent yields of 54-85%
were obtained in this case(2g-2m, Table 2, the structure of 2l was
confirmed by X-ray crystallographic analysis; see the Supporting
Information (SI). Our method was also able to form 6-substituted
[a] The reactions were carried out with substrates (0.1 mmol), catalyst (2.5
mmol %), TFE (1.0 mL), 80 ℃, argon atmosphere, 14 h. Yields of isolated
products are given.
Afterwards, to further confirm our method could be used to
form 3- phosphinoylindoles from either E-isomer or Z-isomer (2-
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azidostyryl)diphenylphosphine oxides. The variable-temperature Next, radical trapping experiments were conducted by employing
experiments were investigated under the Rh(Ⅲ)-catalyzed 2,6-di-tert-butyl-4-methylphenol (BHT), 1,1-diphenylethylene and
cyclization conditions by using a sealed NMR tube. When the 2,2,6,6-tetramethylpiperidinooxy
(TEMPO).15
All
reactions
temperature was warmed to 323 K, the two isomers had become generated the 3-phosphindoles with different yields when these
one intermediate according to the P-NMR (Figure 1). This result radical trapping reagents were added in the reaction under the
indicated that this transformation is not influenced by the optimal conditions (Scheme 3, eq 3). These results indicated this
stereochemical structure of substrates.
transform is not occurred through a radical pathway. Furthermore,
when changing the phenyl to aliphatic azide, the reaction was not
proceeded that maybe due to the fact that the aromaticity of azide
substrate was broken (1r, Scheme
3
,
eq 4). Thus,
Rh(OAc)3xH2O may react first with the aryl azide to form the
rhodium nitrene A by loss of N2.16
Based on the experiment data above and previous mechanistic
studies,5, 14, 16 we proposed that the cyclization occured from a
common catalytic intermediate,7 (Figure 2). Rh(OAc)3xH2O could
function as a nitrogen atom transfer reagent.5a, 14 In the proposed
mechanism, exposure of 1a to Rh(OAc)3xH2O induces loss of N2
to form rhodium nitrene A.5a Subsequently, a four π-electron, five
atom electrocyclization constructs the C-N bond and generates a
carboncation at C3 in B.6f After dearomatization of B to C,
dissociation of the Rh(Ⅲ) acetate to form D.6e Then, phosphine
oxide group shift of D could occur to form E under the force of
revovery of armoaticity. Next, deprotonation to produce the final
product 2a.6
Figure 1. Variable-Temperature Experiments of P-NMR.
For reason that several mechanisms could explain this
transformation according to the literatures,5, 6, 14 so some control
experiments were implemented to explore our mechanistic
hypothesis. Firstly, we synthesized deuterium-labeled substrates
1a-d1 and 1a-d2 and let them run the reaction. Both deuterium
experiments further confirmed that only the phosphine oxide group
shift occur through this transformation (Scheme 3, eq 1 and eq 2).
Figure 2. Protential Mechanism of Phosphine oxide Shift.
In conclusion, we have demonstrated that Rh(OAc)3xH2O
catalyzed cyclization to enable the formation of 3-
phosphinoylindoles from (2-azidostyryl)diphenylphosphine oxides.
This intramolecular transformation occurs through unique
phosphine oxide group migration, and offers a straightforward
route to rebuild sp2 C-P bond and construct the indole ring in
single step, thereby providing a new synthetic method for forming
3-phosphinoylindoles, which is important frameworks in
pharmaceuticals and ligands.
Experimental Section
Representative procedure for the Rh(OAc)3xH2O catalyzed
cyclization to enable the formation of 3-phosphinoylindoles
In
a
sealed tube containing
a
magnetic stir bar, (2-
azidostyryl)diarylphosphine oxide (0.1 mmol) was added to a mixture of
Scheme 3. Mechanistic studies.
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Rh(OAc)3xH2O (2.5 mol %) in TFE (1.0 mL) under argon atmosphere.
The reaction mixture was stirred for 14 h at 80 ℃ in an oil bath. The
residue was purified by chromatography on silica gel (petroleum
ether/isopropanol, 20:1) to afford the product of 3-phosphinoylindole.
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http://dx.doi.org/10.1002/asia.201xxxxxx.
Acknowledgements
[7]
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We are grateful for the NSFC (Nos. 21472076 and 21532001)
and International Joint Research Centre for Green Catalysis and
Synthesis, Gansu provincial Sci. & Tech. Department (No.
2016B01017) for financial support.
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Keywords: Rhodium • Phosphine oxide Migration • C-N Bond
Formation • 3-Phosphinoylindole
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Chun-Hai Wang, Shang-Dong Yang *
Page No. – Page No.
Rh( Ⅲ )-Catalyzed Phosphine Oxide
Migration
Reactions:
Selective
Synthesis of 3-Phosphinoylindoles
A new approach for the synthesis of 3-phosphinoylindoles through Rh(III)-catalyzed
cyclization has been developed. This intramolecular transformation occurs through
unique phosphine oxide group migration, therefore offers a straightforward route to
rebuild sp2 C-P bond and construct the indole ring from the designed and readily
accessible (2-azidostyryl)diphenylphosphine oxides substrates in one single step.
For internal use, please do not delete. Submitted_Manuscript
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