Phosphinoyl Radical-Initiated α,β-Aminophosphinoylation of Alkenes

Article abstract of DOI:10.1021/acs.orglett.7b02183

A new double functionalization reaction of alkenes through AgNO₃-mediated phosphinoyl radical addition followed by Cu(II)-catalyzed amination is introduced. This one-pot, three-component reaction is performed under mild conditions to afford α,β-aminophosphinoylation products.

Full text of DOI:10.1021/acs.orglett.7b02183

Letter
pubs.acs.org/OrgLett
Phosphinoyl Radical-Initiated α,β-Aminophosphinoylation of Alkenes
Jian-An Li,† Pei-Zhi Zhang,† Kui Liu,† Adedamola Shoberu,† Jian-Ping Zou,*,† and Wei Zhang*,‡
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow University,
Jiangsu 215123, China
‡Department of Chemistry, University of Massachusetts Boston, Massachusetts 02125, United States
S
* Supporting Information
ABSTRACT: A new double functionalization reaction of alkenes through
AgNO3-mediated phosphinoyl radical addition followed by Cu(II)-catalyzed
amination is introduced. This one-pot, three-component reaction is performed
under mild conditions to afford α,β-aminophosphinoylation products.
tions13c,14c encouraged us to explore aminophosphinoyl
nique chemical, biological, and physical properties
Uassociated with organophosphorus compounds have reactions. Introduced in this paper is a AgNO3-mediated
found broad applications as agricultural chemicals,1 drug and
phosphinoyl radical addition followed by Cu(II)-catalyzed
drug candidates for HIV,2 chronic inflammation,3 type 2
amination for bifunctionalization of alkenes (Scheme 1f). The
diabetes mellitus,4 glucocorticoid receptor antagonists,5 ligands
intramolecular aminophosphinoylation reaction is reported
(Scheme 1e).17 To the best of our knowledge, there is no
intermolecular aminophosphinoylation reaction in the liter-
ature.
Substrates styrene 1a, Ph2P(O)H 2a, and aniline 3a were
used for the development of reaction conditions. The
phosphinoyl radical could be readily generated from the
oxidation of HP(O)Ph2 with AgNO3,12 but a catalyst for
sequential amination is key for aminophosphinoylation.
Reactions with CuBr as a catalyst in different solvents revealed
that CH3CN is a good choice which gave product 4a in 51%
yield (Table 1, entries 1−3). Screening of different copper salts
and organocatalysts,6 essential synthetic building blocks,7,8 drug
release nanomaterials,9 degradable polymers,10 and fire
retardant materials.11 Bifunctional α,β-aminophosphinoyl com-
pounds also possess special biological activities.2−4 Synthetic
methods for α,β-aminophosphinoylated compounds are limited
to the reactions of cyanobenzene or β-carbonylphosphinoyl
compounds which are not readily available, and the reaction
processes could be tedious.4a,7a−c Phosphorus radical-based
reactions have been developed as a powerful method12 for
oxyphosphinoylation,13 hydroxyphosphinoylation, acetoxy-
phosphinoylation,14 halophosphinoylation,15 and other bifunc-
tionalization reactions of alkenes (Scheme 1a−d).16 Our recent
success in the development of oxyphosphinoylation reac-
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Phosphorus Radical-Initiated Bifunctionalization
b
entry
solvent
temp (°C)
Cu cat. (mol %)
yield (%)
1
CH3CN
DMF
40
40
40
40
40
40
40
40
60
40
40
40
CuBr (40)
CuBr (40)
CuBr (40)
CuI (40)
51
37
19
43
37
36
45
68
53
2
3
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
4
5
CuCl (40)
CuO (40)
Cu(OAc)2 (40)
CuBr2 (40)
CuBr2 (20)
−
6
7
8
9
c
10
11
ND
CuBr2 (20)
68
d
12
CuBr2 (20)
47
a
Conditions: 1a (1.0 mmol), 2a (1.5 mmol), 3a (3.0 mmol), AgNO3
(2.0 mmol), CuBr2 (20 mol %) in CH3CN (5 mL) at 40 °C, 5 h under
b
c
d
Ar. Isolated yield. ND means none detected. Under air.
Received: July 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02183
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
indicated that CuBr2 afforded an increased yield of 68% (Table
1, entries 4−8), whereas a control reaction without a Cu-
catalyst gave no product (Table 1, entry 10). Further exploring
the reaction conditions by changing the loading of CuBr2 (10−
40 mol %), the amount of aniline (2−4 equiv), and reaction
temperature (25−60 °C) and time (3−8 h) gave the optimized
conditions which include using 1:1.5:3 of 1a:2a:3a with 2.0
equiv of AgNO3 and 20 mol % of CuBr2 (see Supporting
Information (SI)). The reaction in CH3CN at 40 °C for 5 h
under argon gave 4a in 68% yield (Table 1, entry 11). It was
confirmed that AgNO3 is a good oxidant (see SI) and the
reaction has to be performed under air-free conditions (Table
1, entry 12).
with aniline. It is worth noting that dialkylphosphites (R = OEt
or OiPr) were amenable to this reaction to give α,β-
aminophosphonated products 5h and 5i in synthetically useful
yields.
Reactions of different anilines were also performed (Scheme
t
4). Products 6a−e bearing Me, Et, and Bu as the R3 group
a b
,
Scheme 4. Reactions of 1a, 2a with Different Anilines 3
Reactions with different styrenes 1 were conducted under the
optimized conditions (Scheme 2). Small alkyl and alkoxy
Scheme 2. Reactions of Different Styrenes 1 with 2a and
a b
,
3a
a
The reaction condition is similar to that shown in Scheme 2.
Isolated yield.
b
were obtained in 23−71% yields. No product 6f was obtained
from the 2,6-ditBu-substituted aniline. Reactions of 2- or 3-
methoxyanilines afforded 6g and 6h in 79% and 43% yields,
respectively. The reaction 4-methoxyaniline gave no product 6i,
but rather the oxidation product of 4-methoxyaniline. Halogen-
substituted anilines at the 3- or 4-position gave corresponding
products 6j−m in 43−70% yields. Anilines with 4-nitro and 4-
cyano groups failed to give products 6n and 6o.
To understand if the α,β-aminophosphinoylation process
involved radicals, two control reactions using TEMPO or BHT
as the radical tracking agent were carried out under the
standard conditions described in Scheme 5. In both cases, the
a
Reaction conditions: 1 (1.0 mmol), 2a (1.5 mmol), 3a (3.0 mmol),
AgNO3 (2.0 mmol), CuBr2 (20 mol %) in CH3CN (5 mL), 40 °C, Ar,
b
5 h. Isolated yield.
groups as well and halogen groups on the benzene gave
corresponding products 4 in satisfactory yields except for the
groups at the ortho-position (4b, 4g, 4h, 4k) due to steric
effects. No product 4o was detected from the reaction of 4-
nitrostyrene. Reactions of α- or β-substituted styrenes could
afford products 5a−c in 33−78% yields depending on the steric
effect of the R2 group (Scheme 3). However, no products were
obtained for 5d−e due to the presence of phenyl and bromo
groups as the R2 group at the 1- or 2-position of the styrenes.
The reaction of nonconjugated allylbenzene failed to give
product 5g probably due to the intermediate carbon radical
without phenyl group conjugation being too unstable to react
Scheme 5. Control Reactions with Radical Tracking Agents
a b
,
Scheme 3. Reactions of Alkenes 1 with 2 and 3a
formation of 4a was completely suppressed, and only radical
coupling products 7 and 8 were obtained. Based on these
results, a mechanism was proposed for the α,β-amino-
phosphinoylation reaction (Scheme 6). The phosphinoyl
radical generated from the oxidation of 2a with AgNO3 adds
to styrene to form radical 9 which coordinates with Cu(II)-
aniline complex 10 to form Cu(III) complex 11.18 Reductive
elimination of 11 affords α,β-aminophosphinoylation products
4−6.
In summary, we have developed a new alkene bifunctional-
ization reaction using AgNO3 to generate a phosphinoyl radical
from diarylphosphine oxides followed by CuBr2-catalyzed
amination with anilines to afford α,β-aminophosphinoylation
products. This three-component, one-pot reaction is performed
under mild conditions. The reaction scope for different
a
The reaction conditions are similar to those shown in Scheme 2.
Isolated yield.
b
B
DOI: 10.1021/acs.orglett.7b02183
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02183.
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Experimental details and spectral data for compounds
4−8 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jpzou@suda.edu.cn.
*E-mail: wei2.zhang@umb.edu.
ORCID
Jian-Ping Zou: 0000-0002-8092-9527
Wei Zhang: 0000-0002-6097-2763
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
J.-P.Z. is thankful for generous financial support from National
Natural Science Foundation of China (Nos. 21172163,
21472133), the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD) & State, and
Local Joint Engineering Laboratory for Novel Functional
Polymeric Materials.
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Chem. 2014, 79, 1449. (b) Sun, W. B.; Zhang, P. Z.; Jiang, T.; Li, C.
K.; An, L. T.; Shoberu, A.; Zou, J. P. Tetrahedron 2016, 72, 6477.
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DOI: 10.1021/acs.orglett.7b02183
Org. Lett. XXXX, XXX, XXX−XXX