Cu(I)-catalyzed cascade intramolecular cyclization of 2-propynol phenyl azides and diarylphosphine oxides for the synthesis of bisphosphorylated indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.09.006

The [Cu(OTf)]₂·C₆H₆ catalyzed cascade intermolecular addition–intramolecular cyclization reaction of easily prepared 2-propynol phenyl azides and diarylphosphine oxides was developed. This novel reaction leads to simultane

Full text of DOI:10.1016/j.tetlet.2018.09.006

Accepted Manuscript
Cu(I)-Catalyzed Cascade Intramolecular Cyclization of 2-Propynol Phenyl
Azides and Diarylphosphine Oxides for the Synthesis of Bisphosphorylated In-
dole Derivatives
Xian-Rong Song, Ren Li, Tao Yang, Jiang Bai, Ruchun Yang, Xi Chen, Haixin
Ding, Qiang Xiao, Yong-Min Liang
PII:
S0040-4039(18)31078-5
https://doi.org/10.1016/j.tetlet.2018.09.006
TETL 50245
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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29 July 2018
2 September 2018
3 September 2018
Please cite this article as: Song, X-R., Li, R., Yang, T., Bai, J., Yang, R., Chen, X., Ding, H., Xiao, Q., Liang, Y-
M., Cu(I)-Catalyzed Cascade Intramolecular Cyclization of 2-Propynol Phenyl Azides and Diarylphosphine Oxides
for the Synthesis of Bisphosphorylated Indole Derivatives, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.09.006
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Tetrahedron Letters
Cu(I)-Catalyzed Cascade Intramolecular Cyclization of 2-Propynol Phenyl Azides
and Diarylphosphine Oxides for the Synthesis of Bisphosphorylated Indole
Derivatives
Xian-Rong Song,a Ren Li,a Tao Yang,a Jiang Bai,a Ruchun Yang,a Xi Chen,a Haixin Ding,a Qiang Xiao*a
and Yong-Min Liangb
a Institute of Organic Chemistry, Jiangxi Science & Technology Normal University, Key Laboratory of Organic Chemistry, Jiangxi Province, Nanchang 330013,
China
bState Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The [Cu(OTf)]2. C6H6 catalyzed cascade intermolecular addition–intramolecular cyclization reaction
of easily prepared 2-propynol phenyl azides and diarylphosphine oxides was developed. This novel
reaction leads to simultaneous formation of one C—N and two C—P bonds in a single step to give
bisphosphorylatd indole derivatives under mild conditions in moderate to good yields.
Available online
.
Keywords:
2-Propynol Phenyl Azides
Bisphosphorylated Indoles
Copper-Catalyzed
Cascade Cyclization
Introduction
Functional indoles are widely spread in natural products and
synthetic molecules, which possess numerous
properties.1
particular,
derivatives screened
pharmaceutical
phosphinoylindole
In
were
3-
as
nonnucleoside reverse transcriptase inhibitors (NNTRI),
among which compound IDX-899 demonstrates high
activity against wild-type and NNRTI-resistant HIV-1.2 In
addition, 3-phosphinoylindoles were used as ligands in
cross-coupling reactions for the direct arylation of carbonyl
compounds.3 Owing to the significant pharmaceutical
activities of these compounds, as well as synthetic
relevance, great efforts have been devoted to develop
efficient approaches for their preparation.4 For example, Lu
and co-workers developed
a novel approach to 3-
Scheme 1 Previous works and our new attempt
phosphinoylindoles through metal-free electrophilic
phosphination of indoles.5 Very recently, Kozlowski and
Wang group reported Lewis acid-catalyzed phosphorylation
of 2-indolylmethanols for the synthesis of 3-
phosphinoylindoles.6 Despite the many advances in this field,
further exploration and development of more effective
protocol for their preparation are still extremely attractive
and desirable.
structural diversity.7 In this regard, applying propargylic
alcohols towards the phosphorus-containing compounds
have been developed. For example, the Zhao,8 Yang9 and
Han10 groups reported the metal-catalyzed dehydrative C
—P
coupling of propargylic alcohols with diarylphosphine
oxides leading to allenylphosphoryl compounds (Scheme 1-
1). Subsequently, Liang and our group have developed a
copper-catalyzed cascade cyclization of 2-propynolphenols
In the past decade, the Lewis acid-catalyzed cascade
transformation of propargylic alcohols has become an
efficient way to access various compounds with rich
with
diarylphosphine
oxides
to
form
3-

2
Tetrahedron
phosphinoylbenzofurans and 4-phosphorylated 2H-
conditions for all subsequent transformation were affirmed
as the use of [Cu(OTf)]2. C6H6 (20 mol%),
diphenylphosphine oxide (5.0 equiv) in DCE at 100 °C for
4.0 h under argon.
chromenes via the allenylphosphoryl intermediate,
respectively (Scheme 1-2).11 Base on the above results and
our continuous interest in the potential application of
propargylic alcohols for heterocycle synthesis,12 it was
reasoned that attacking the aromatic allenylphosphoryl
intermediate by an ortho-azide group would lead to the
phosphorylated N-containing heterocycle. To the best of our
knowledge, the cascade reaction of 2-propynol phenyl
azides to functional indoles has not been disclosed yet.
Herein, we reported our findings (Scheme 1-3).
Table 1 Optimization of reaction for synthesis of 3aa
Entry
Catalyst
Solvent
MeNO2
T[ºC Yield[
%]b
100 50
]
1
2
3
Cu(OTf)2
AgOTf
MeNO2
MeNO2
100 15
Cu(OAc)2
100 trace
4
5
[Cu(OTf)]2.C6H6
Cu(acac)2
MeNO2
MeNO2
100 60
100 <5
6
7
[Cu(OTf)]2. C6H6
[Cu(OTf)]2. C6H6
[Cu(OTf)]2. C6H6
[Cu(OTf)]2. C6H6
[Cu(OTf)]2. C6H6
[Cu(OTf)]2. C6H6
[Cu(OTf)]2. C6H6
[Cu(OTf)]2. C6H6
[Cu(OTf)]2. C6H6
[Cu(OTf)]2. C6H6
DCE
DCM
100 70
40
57
8
MeCN
1,4-dioxane
DCE
100 trace
100 <5
9
10c
11d
12e
13 e, f
14 e,
15 e
80
65
DCE
100 78
100 83
100 73
100 82
100 78
DCE
DCE
g
Figure 1 X-ray structure of 3a
DCE
,h
DCE
aUnless otherwise noted, all reactions were performed with 1a
(0.1 mmol), 2a (0.35 mmol), catalyst (20 mol%), and solvent (2.0
mL) at the indicated temperature for 4.0 h under argon. b Isolated
yields. c At 80 ºC . d 4.0 equiv. of 2a was used. e 5.0 equiv. of 2a
Results and Discussion
Our exploration was initiated by chosing 2-propynol
phenyl azides 1a and diphenylphosphine oxide 2a as model
substrates to study the possible reactivity. In a preliminary
experiment, the reaction was performed in CH3NO2 at 100
°C using Cu(OTf)2 (20 mol%) as catalyst. To our delight,
the reaction proceeded to give a new florescent compound in
50% yield (Table 1, entry 1). Its 31P NMR showed two 31P
signals having characteristic P-C chemical shifts. Further X-
ray crystallographic analysis unambiguously confirmed the
structure as unexpected bisphosphorylated indole 3a (Figure
1).13 To the best of our knowledge, this is the first reported
bisphosphorylated indole and also the first reported indole
synthesis from 2-propynol phenyl azide. Encouraged by this
result, different metal catalysts were investigated and
[Cu(OTf)]2. C6H6 was found to be the most efficient one
f
g
was used. Under air. 30 mol% of catalyst. h Using 15 mol% of
catalyst was used.
Having the optimized conditions in hand, we next
investigated Cu-catalyzed cascade cyclization of various 2-
propynol phenyl azides
1 with diarylphosphine oxides 2 to
explore the generality of the method, and the results are
summarized in Table 2. Upon repeating the reaction with
diphenylphosphine oxide 2a, substrates
1 with electron-
donating groups on the aryl ring of the benzyl alcohol
moiety all worked well, efficiently delivering the
corresponding functionalized indoles 3a-3c and 3e-3f in
moderate to excellent yields. Substrates with substituents at
ortho position could be transformed into the corresponding
products, which demonstrated that steric interaction did not
significantly affect the reactivity. However, substrates
bearing electron-withdrawing group 1d proved to be
ineffective for this transformation, possibly due to its
relative instability of the propargyl carbocation intermediate
(for details see the scheme 3). Furthermore, several multi-
substituted substrates were also compatible with this
protocol to generate the corresponding bisphosphorylated
indoles in excellent yields (3e−3f). Next, we further turned
our attention to evaluate substituents (R2) on another aryl
moiety under optimal conditions. Both electron-rich and
electron-deficient groups at the para position of the
substrates worked efficiently to give the desired products in
(Table 1, entries 1−5). Subsequently,
a variety of
representative solvents including MeCN, CH3NO2, DCM,
dioxane, were examined carefully, in which DCE gave the
highest yield of 70% (Table 1, entries 6−9). The reaction
was carried out under lower temperature and gave a
decreased yield of 3a, showing that 100 °C is the most
suitable reaction temperature. Changing the substrate ratio to
1:5 could improve the reaction conversion with 83% yield of
product 3a isolated (Table 1, entries 11-12). An additional
control experiment demonstrated that an argon atmosphere
was beneficial for this transformation. Furthermore, no
better result was obtained after increasing or decreasing the
catalyst loadings (Table 1, entries 14-15). After extensive
screening on other parameters, the optimum reaction

satisfactory yields (3g-3m). Additionally, a series of
halogen-containing substrates 2h-2j could be well
tolerated in this transformation. It was noteworthy that
substrates with strong electron-deficient groups (CN, CF3,
COOMe) also worked to give the corresponding products
(Scheme 2). When the reaction was carried out in the
presence of the radical scavenger TEMPO (2,2,6,6-
tetramethylpiperidine-1-oxyl) or BHT (2,6-di-tert-butyl-4-
methylphenol), these transformations were found to be
almost unaffected, indicating that the reaction might not
proceed through a radical pathway (Scheme 2-1). Moreover,
we assumed that one possible pathway would be a tandem
sequence involving the copper catalyst decomposes the
azide to copper nitrene intermediate. To verify this
(
)
(3k
-3m) in good yields. Moreover, the scope of diaryl
phosphine oxides
2
with 1a was further investigated under
optimal conditions. Diphenylphosphine oxides substituted
by F (2b), Cl (2c) or Me (2d) were tolerated as well, and the
corresponding products 3n-3p were obtained in moderate to
hypothesis, the alcohol protected 2-propynol phenyl azide 4
good yields. However, no desired product was isolated when
diethyl phosphite (2e) was employed under the optimal
conditions. Unfortunately, when the alkyl-substituted
substrate was performed under the optimal conditions, no
corresponding product 3r was isolated.
was prepared and used as starting material to undergo this
transformation under the optimal conditions; however, the
desired product 3a was not observed (Scheme 2-2). This
result clearly indicates that copper nitrene intermediate is
not involved in this novel transformation.
Table
2 Transformation of propargylic alcohols 1 to
bisphosphorylated indole derivatives 3a
Scheme 2 Control experiments
On the basis of the above detailed observation and
literature reports,11,14 a plausible mechanism for this cascade
reaction was proposed in Scheme 3. Initially, the hydroxyl
group is activated by copper catalyst and generates
propargylic cation intermediate
tautomerization to form allenic cation intermediate
A
, which followed through a
. The
was attacked by nucleophile 2a to give
, followed by nucleophilic attack of another
. Then, intermediate could
undergo 5-endo-trig cyclization to produce intermediate
B
intermediate
intermediate
B
C
2a to generate intermediate
D
D
E.
Finally, the desired product 3a was formed with the release
of a molecule of nitrogen gas.
a
Unless otherwise noted, all reactions were performed with
(0.1 mmol) and (0.5 mmol) in DCE (2.0 mL) at 100 °C
1
2
for 4.0 h. Isolated yields.
To gain further mechanistic insight into the
transformation, some control experiments were investigated
Scheme 3 Plausible mechanism

4
Tetrahedron
Jia, T.; Walsh, P. Org. Lett. 2013, 15, 4190; (e) Benincori, T.;
In summary, we have successfully developed a
copper-catalyzed bisphosphorylation/cascade cyclization of
2-propynol phenyl azides to construct series of
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4
a
bisphosphorylated indole derivatives. This transformation
proceeds with the formation of two C—P bonds and C—N
bond simultaneously in moderate to good yields. This novel
transformation applied diarylphosphine oxide as nucleophies
and avoided using ligands and oxidants. Although the
substituent effect exerts a clear influence on the reaction,
this is the first example to synthesize bisphosphorylated
indoles using propargylic alcohols,15 which was identified as
acceptable substrate compatibility, especially for electron-
donating groups. Further biological activity study of the
obtained bisphosphorylated indoles are underway in our
laboratory and will be reported in due course.
5
6
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8
9
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Acknowledgments
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L.-B. Adv. Synth. Catal. 2017, 359, 4417.
We acknowledge the National Science Foundation of China (No.
21676131 and No. 21462019), the Science Foundation of Jiangxi
Province
20143ACB20012), Jiangxi Science & Technology Normal
University (2017QNBJRC004 ， Doctor Startup Fund) for
financial support.
11 (a) Li, R.; Chen, X.; Song, X.-R.; Ding, H.; Wang, P.; Xiao, Q.;
Liang, Y.-M. Adv. Synth. Catal. 2017, 359, 3962; (b) Li, X.-S.;
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References and notes
13 CCDC 1836747 (compound 3a) contains the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
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Graphical Abstract
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Cu(I)-Catalyzed Cascade Intramolecular
Cyclization of 2-Propynol Phenyl Azides
and Diarylphosphine Oxides for the
Leave this area blank for abstract info.
Synthesis of Bisphosphorylated Indole Derivatives
Xian-Rong Song,a Ren Li,a Tao Yang,a Jiang Bai,a
Ruchun Yang,a Xi Chen,a Haixin Ding,a
Qiang Xiao*a and Yong-Min Liangb
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6
Tetrahedron
Highlights
Cu(I)-catalyzed cascade cyclization of easily prepared 2-
•
propynol phenyl azides to bisphosphorylated indoles .
• This is the first report about the construction of
bisphosphorylated indole derivatives.
•
This reaction occurred smoothly with formation one C-N bond
and two C-P bonds simultaneously.