Phosphinoyl Radical Initiated Vicinal Cyanophosphinoylation of Alkenes

Article abstract of DOI:10.1021/acs.orglett.7b02621

A double-functionalization reaction of alkenes through Mn(OAc)₃-mediated phosphinoyl radical addition followed by CuCN-catalyzed cyanation is introduced. This one-pot reaction is performed under mild conditions to afford vicinal cyanophosphinoylation products.

Full text of DOI:10.1021/acs.orglett.7b02621

Letter
pubs.acs.org/OrgLett
Phosphinoyl Radical Initiated Vicinal Cyanophosphinoylation of
Alkenes
Pei-Zhi Zhang,† Ling Zhang,† Jian-An Li,† 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 double-functionalization reaction of alkenes through Mn-
(OAc)3-mediated phosphinoyl radical addition followed by CuCN-catalyzed
cyanation is introduced. This one-pot reaction is performed under mild
conditions to afford vicinal cyanophosphinoylation products.
rganophosphorus compounds have broad and desirable
The initial experiment was carried out using styrene 1a,
diphenylphosphine oxide (HPOPh2) 2, and trimethylsilylcya-
nide (TMSCN) as substrates, Mn(OAc)3 as an oxidant, and N-
methyl-2-pyrrolidinone (NMP) as a solvent. Only a trace
amount of product 3a was detected from a reaction at 55 °C for
3 h (Table 1, entry 1). Reactions using tetrabutylammonium
chemical,2 and biological properties.3 The
development of ionic4 and radical5 phosphinoylation reactions
has received much attention. Among them, radical-based vicinal
bifunctionalization of alkenes is attractive due to high synthetic
efficiency and structural diversity of products.6 Bifunctionaliza-
tion reactions such as oxyphosphinoylation,7 hydroxyphosphi-
noylation, acetoxyphosphinoylation,8 halophosphinoylation,9
and aminophosphinoylation10 have been reported in the
literature (Scheme 1a−c).
1
Ophysical,
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Phosphorus Radical-Based Bifunctionalizations
b
entry CN source cat. (20 mol %) solvent temp (°C) yield (%)
1
TMSCN
TBACN
CuCN
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
DMF
DMF
55
55
55
55
55
40
30
20
10
20
20
20
trace
c
2
ND
3
25
4
TBACN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
TMSCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
trace
27
5
6
33
7
41
8
47
9
29
10
11
12
70
d
86
trace
a
Styrene (0.4 mmol), HPOPh2 (0.6 mmol), CN source (0.8 mmol),
Mn(OAc)3·2H2O (1.0 mmol), CuCN (20 mol %), solvent (3 mL), 3 h
b
c
d
under argon. isolated yield. ND means none detected. HPOPh2
(0.8 mmol) and Mn(OAc)3·2H2O (1.2 mmol) were used.
cyanide (TBACN) or CuCN as a cyano source were conducted
(Table 1, entries 2 and 3). No product was detected from the
reaction with TBACN, while 25% of 3a was obtained from the
reaction using a stoichiometric amount of CuCN. Reactions
with 20 mol % of CuCN in combination with 2 equiv of
TMSCN or TBACN were conducted. Only a trace amount of
Cyano is a versatile group which can be converted to amines,
amides, acids, aldehydes, and heterocycles11 for the synthesis of
natural products and bioactive compounds.12 Our groups are
interested in exploring phosphorus radical reactions.8c,10b,13
Presented in this paper is our effort on the development of
cyanophosphinoylation as a new bifunctionalization reaction for
alkenes (Scheme 1d). To the best of our knowledge, there is no
such reaction in the literature.
Received: August 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02621
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3a was observed from the reaction of TBACN/CuCN system,
but 27% was obtained from the TMSCN/CuCN system (Table
1, entries 4 and 5). Replacing Mn(OAc)3 with other oxidants,
such as AgNO3/K2S2O8 and tert-butyl hydroperoxide (TBHP),
or using other copper salts did not give better results (see
Supporting Informtion, Tables S1 and S2). Reaction temper-
ature was found to be crucial. Upon lowering the temperature
from 55 to 20 °C, the yield of 3a steadily increased from 27%
to 47% but dropped to 29% at 10 °C (Table 1, entries 5−9).
Screening of solvents (see SI, Table S3) revealed that DMF
could give 3a in 70% yield (Table 1, entry 10). The optimized
conditions were found to be using 1:2:3 of alkene/HP(O)Ph2/
Mn(OAc)3 in DMF at 20 °C for 3 h under argon, which gave
3a in 86% yield (Table 1, entry 11). A control reaction without
using CuCN only gave a trace amount of product (Table 1,
entry 12).
processed well to give 3s and 3t in 88% and 63% yield,
respectively. Furthermore, the reaction of 2-vinylpyridine
afforded 3u in 75% yield. But no product was observed from
the reaction of 4-nitrostyrene due to the strong electron-
withdrawing effect of the nitro group.
Results obtained from the reactions of aryl alkenes
encouraged us to conduct reactions of aliphatic alkenes 4
(Scheme 3). In these cases, a mixture of desired bifunctional
a
Scheme 3. Reactions of Aliphatic Alkenes 4
The scope of this reaction with a number of substituted
styrenes was examined under the optimized reaction conditions
(Scheme 2). It was found that electron-donating groups (Me
a
Scheme 2. Reactions of Substituted Styrenes 1
a
Alkene 5 (0.4 mmol), HPOPh2 (0.8 mmol), TMSCN (0.8 mmol),
CuCN (20 mol %), Mn(OAc)3·2H2O (1.2 mmol), DMF (3 mL), 3 h
under argon, isolated yield.
products 5a−g (major) and phosphinoylation products 5a′−g′
(minor) were obtained due to competitive cyanation and
hydrogen abstraction of the intermediate radical. The cyanation
appears to be a predominant process except for the reactions of
cyclic alkenes for 5h and 5i. In reactions of aliphatic alkenes
without an aryl group, the amounts of phosphinoylation
products 5e′ and 5f′ were slightly increased. It was interesting
to find that reaction of vinyl acetate afforded 5g and 5g′ in 52%
and 32% yields, respectively. The reactions of other alkenes like
1,2-diphenylethylene, α-methylstyrene, 2-methylheptene, ethyl
acrylate, and 2-vinylthiophene with dialkylphosphites were also
performed, and no desired product was detected (see SI,
Scheme S1).
a
Alkene 1 (0.4 mmol), HPOPh2 (0.8 mmol), TMSCN (0.8 mmol),
CuCN (20 mol %), Mn(OAc)3·2H2O (1.2 mmol), DMF (3 mL) at 20
°C for 3 h under argon, isolated yield.
Several control reactions were carried out in order to have a
good understanding of the reaction mechanism. To confirm if
the reaction process involved a phosphinoyl radical, reactions
with radical trapping agents TEMPO and BHT were
performed. It was found that the cyanophosphinoylation was
suppressed and no expected product was detected, while radical
coupling product 6 was isolated from the reaction with BHT
and MeO), halogen atoms (F, Cl, and Br), and electron-
withdrawing groups (CN and CO2Me) at different positions of
benzene ring afforded products 3a−p in 65−90% yields. A
slightly lower yield (65%) of 3k probably resulted from the
steric hindrance of the o-bromo substituent. The reaction of β-
methylstyrene occurred smoothly to afford 3q in 80% yield.
However, the reaction of α-methylstyrene did not give the
desired product. The reaction of 2-vinylnaphthalene afforded 3r
in 87% yield. It was also found that reactions of cyclic alkenes
1
and characterized by H, 13C, 31P NMR and HRMS (Scheme
4a and 4b). No evidence indicates that CN radical was involved
in the reaction process since no CN radical was trapped by 1,1-
B
DOI: 10.1021/acs.orglett.7b02621
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
In summary, a new reaction for vicinal bifunctionalization of
alkenes is developed using Mn(OAc)3 as an oxidation agent to
generate phosphinoyl radical for addition followed by CuCN-
catalyzed cyanation. This one-pot reaction of readily available
reagents and starting materials, including aromatic and aliphatic
alkenes, is performed under mild conditions to afford vicinal
cyanophosphinoylation products regioselectively. The cyano
group in the cyanophosphinoylation products could be a
valuable synthon to access other functional groups with
synthetic or biological interests.
Scheme 4. Control Reactions
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.7b02621.
Experimental details and spectral data for compounds 3
and 5−8 (PDF)
a
Styrene (0.4 mmol), HPOPh2 (0.8 mmol), TMSCN (0.8 mmol),
CuCN (20 mol %), Mn(OAc)3·2H2O (1.2 mmol), DMF (3 mL) at 20
°C for 3 h under argon, isolated yield.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jpzou@suda.edu.cn.
diphenylethylene and BHT (see SI, Scheme S2). In addition,
the reaction of 1,1-diphenylethylene with HPOPh2 and
TMSCN only produced compound 7 in 35% yield (Scheme
4c). Furthermore, a reaction with 4.0 equiv of tetrabutylammo-
nium bromide (TBAB) provided product 3a and 8 in 35% and
15% yields, respectively. These results suggest that cyanation is
a cationic reaction.
A mechanism for cyanophosphinoylation of alkenes is
proposed on the basis of the results obtained from the control
reactions (Scheme 5). Phosphinoyl radical A, generated from
*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. acknowledges the generous financial support from the
National Natural Science Foundation of China (Nos. 21172163
and 21472133), the Priority Academic Program Development
of Jiangsu Higher Education Institutions (PAPD) & State, and
Local Joint Engineering Laboratory for Novel Functional
Polymeric Materials.
Scheme 5. Proposed Mechanism for Cyanophosphinoylation
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Org. Lett. XXXX, XXX, XXX−XXX