Proton-Coupled Electron Transfer Enables Tandem Radical Relay for Asymmetric Copper-Catalyzed Phosphinoylcyanation of Styrenes

Article abstract of DOI:10.1021/acs.orglett.9b01607

A tandem radical relay strategy was realized for the first Cu(I)-catalyzed enantioselective phosphinocyanation of styrenes. In this reaction, ^tBuOOSiMe₃ generated in situ from ^tBuOOH serves as a radical initiator to trigger t-butoxy radical production upon oxidization of L?Cu(I) species via proton-coupled-electron transfer (PCET) pathway, which leads to sequential phosphinoyl radical and benzyl radical formations. The resultant β-cyanodiarylphosphine oxides could be easily converted to a series of chiral ?-amino phosphine ligands.

Full text of DOI:10.1021/acs.orglett.9b01607

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Proton-Coupled Electron Transfer Enables Tandem Radical Relay for
Asymmetric Copper-Catalyzed Phosphinoylcyanation of Styrenes
Guoyu Zhang,† Liang Fu,‡ Pinhong Chen,‡ Jianping Zou,*,† and Guosheng Liu*,‡,§
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Soochow University,
Suzhou, Jiangsu 215123, China
‡State Key Laboratory of Organometallic Chemistry, and §Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A tandem radical relay strategy was realized for
the first Cu(I)-catalyzed enantioselective phosphinocyanation
t
of styrenes. In this reaction, BuOOSiMe3 generated in situ
t
from BuOOH serves as a radical initiator to trigger t-butoxy
radical production upon oxidization of L*Cu(I) species via
proton-coupled-electron transfer (PCET) pathway, which
leads to sequential phosphinoyl radical and benzyl radical
formations. The resultant β-cyanodiarylphosphine oxides
could be easily converted to a series of chiral γ-amino
phosphine ligands.
rganophosphorus compounds can be frequently found in
Omedicinal chemistry, agrochemistry, and material
science;1 in addition, optically pure organophosphines bearing
a chiral β-functional group are widely used as organocatalysts
and ligands in asymmetric catalysis.2 Therefore, considerable
efforts have been made toward their synthesis. Among them,
radical phosphinoylation reactions serve as an efficient and
powerful tool,3 and a series of phosphinoylation-based
difunctionalizations of alkenes have been developed.4 Despite
these advances, the involvement of highly reactive carbon-
centered radical intermediates makes an asymmetric version
extremely difficult to accomplish. To the best of our
knowledge, no such asymmetric reactions have been
documented to date.
In our continuing efforts to develop asymmetric radical
transformations (ARTs),5 we have recently developed a
copper-catalyzed radical relay process for the enantioselective
cyanation,6 arylation,7 and alkynylation8 of styrenes (Scheme
1a). Critical to the success is that a key benzylic radical
intermediate is enantioselectively trapped by chiral (L*)-
CuII(Nu) species. Moreover, the benzylic radical was generated
by radical (Y) addition to styrenes, and the Y radical was
directly derived from electrophiles X-Y (e.g., NFSI and NFAS
for the generation of nitrogen-centered radicals, Togni [CF3]+
reagent for producing a CF3 radical) through a single electron
transfer (SET) process. We thus hypothesized that, if a
phosphinoyl radical could be generated for the similar
asymmetric radical reaction, it would provide an efficient and
straightforward approach to gain access to valuable chiral
organophosphine oxides. However, to the best of our
knowledge, the lack of P-based electrophiles for the generation
of phosphinoyl radicals impedes the development of the
asymmetric phosphinoyl radical-initiated reactions (Scheme
1a, i).9 Therefore, we envisaged that tandem radical relay
processes, namely, two sequential radical relay steps, by
introducing an additional radical relay step, in which
phosphinoyl radicals could be generated from R2P(O)H
through a hydrogen atom abstraction (HAA) process by Z
radical (e.g., tert-butoxy radical) generated from easily available
electrophiles X-Z (e.g., BuOOH or BuOOBut) and L*Cu(I)
catalysts, would be a reasonable strategy to solve the
aforementioned problem and greatly expand copper-catalyzed
asymmetric radical transformations (Scheme 1a, ii). Notably,
in this tandem radical relay process, the resulting Z radical
should react favorably with R2P(O)H rather than undergo
radical addition to styrenes. In addition, the rate for hydrogen
atom abstraction (HAA) should be much faster than that of a
combination of the Z radical with Cu(I) species, avoiding the
termination of the copper catalyst.10 Herein, we disclose a
novel proton-coupled-electron transfer (PCET) mechanism to
generate tert-butoxy radical from unusual tert-butyl peroxide
silane (TNPS) reagent, which allows generation of phosphi-
noyl radical from the seqential HAA of R2P(O)H. This tandem
radcal relay is compatible with the sequential asymmetric
t
t
Received: May 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Asymmetric Radical Phosphinoylation of Alkenes
Scheme 2. Optimization of the Reaction Conditions
a
The reaction was run on a 0.1 mmol scale, Cu(CH3CN)4PF6 (5 mol
%), ligand (6 mol %), 1a (0.1 mmol), 2a (0.2 mmol), TMSCN (0.2
mmol), and oxidant (0.2 mmol) in DCE (1 mL) at room temperature
under N2. b1H NMR yield using CH2Br2 as an internal standard.
cEnantiomeric excess (ee) value was determined by HPLC on a chiral
stationary phase. d3a′ as racemate. etBuOOH in water was used.
g
fTMSCN (3.0 equiv). At −10 °C.
cyanation, which enables highly chemo- and enantioselective
phosphinoylcyanation of alkenes (Scheme 1b).
for the reaction, employing an equimolar or more TMSCN
than tBuOOH led to the desired product 3a as a major product
t
Stoichiometric amounts of metal salts (e.g., Mn(OAc)3,
AgNO3, etc.) are often used as oxidants to generate
phosphinoyl radicals by oxidizng R2P(O)H;4 as we expected,
they proved to be incompatible to the asymmetric reaction to
in 92% ee (entries 6−7), while using more BuOOH than
TMSCN resulted in the predominant ether peroxide product
3a′ in 78% yield (entry 8), which was similar to the reaction
using tBuOOH in water (entry 1). Notably, the ether peroxide
product 3a′ obtained as racemate in these reactions (entries
1−8) was completely inhibited at −10 °C (entry 9).
t
give racemic product. Alternatively, BuOOH is also consid-
ered as an efficient oxidant to react with R2P(O)H to generate
the phosphinoyl radicals under metal or metal-free con-
ditions.11 Owing to its inexpensive and easily available
t
t
t
Compared to BuOOH, both BuOOBut and BuOOBz were
ineffective (entry 10); in addition, NFSI and PhI(OAc)2 used
in our previous studies were also ineffective.5
t
properties, BuOOH was selected to examine the asymmetric
phosphinoylcyanation reaction via tandem radial relay.
However, a tert-butyl peroxyl radical was likely to be generated,
and underwent cross coupling with carbon-centered radicals to
give ether peroxides as reported in difunctionalizations of
alkenes.12 In fact, tBuOOH in water or decane was respectively
employed for the reaction of 4- bromostyrene 1a with
diphenylphosphine oxide 2a using Cu(CH3CN)4PF6 and
bisoxazoline (Box) ligand L1 as catalyst; it was surprising
that the opposite results were obtained. The ether peroxide
product 3a′ was indeed obtained as the predominant product
With the optimal reaction conditions in hand, the substrate
scope of this enantioselective copper-catalyzed phosphinocya-
nation of styrenes was then investigated. As shown in Scheme
3, styrenes bearing electron-donating and withdrawing groups
on the benzene ring were suitable for the reaction, giving the
desired products 3a−3q in good yields with excellent
enantioselectivities (60−96% yields and 76−97% ee). Notably,
various functional groups, such as halide, ester, ether, and CF3,
could be well tolerated under our current mild conditions. In
addition, reactions of naphthalene-derived substrates also
worked well to give the desired products 3r−3t in good yields
with excellent enantioselectivities. Furthermore, vinyl hetero-
arene 1u and estrone-derived styrene 1v could also be
employed as substrates to afford the corresponding products
3u and 3v in good yields with excellent enantioselectivities.
Notably, the model reaction could be performed on a 10 mmol
scale without loss of reaction efficiency and enantioselectivity.
The absolute structure of (S)-3a was unambiguously
determined by the X-ray crystallography.
t
using BuOOH in water as the oxidant, along with a small
amount of the desired phosphinoylcyanation product 3a with
71% ee (Scheme 2, entry 1). Fortunately, the desired
asymmetric phosphinoylcyanation became a major pathway
t
when using BuOOH in decane, which gave the desired
product 3a with the same enantioselectivity (entry 2). Further
ligand screening revealed that gem-disubstituted Box ligands
played a significant role in enhancing both reactivities and
enantioselectivities (entries 3−6), and L5 with sterically bulky
gem-dibenzylic groups gave 3a with 92% ee (entry 6). In
The phosphorus substrate scope was also investigated, as
shown in Scheme 4. Diarylphosphorous oxides bearing
t
addition, the ratio of BuOOH to TMSCN was also essential
B
DOI: 10.1021/acs.orglett.9b01607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b c
, ,
electron-rich groups at the para or meta position of the
aromatic ring reacted smoothly with styrenes to deliver the
desired products 4a−4h in good yields (70−87%) with
excellent enantioselectivities (86−96% ee). In addition,
di(thiophen-2-yl)phosphine oxide was also suitable for the
reaction to afford the product 4i in 82% yield with 96% ee.
To showcase the synthetic utility of the method, the
optically pure phosphinocyanated product 3e after recrystal-
lization could be converted into the Boc-protected amine 5 in
85% yield with 99% ee in a one-pot fashion (Scheme 5). In
Scheme 3. Scope of Akenes
Scheme 5. Synthetic Transformations
addition, the phosphine oxide 3e could also be selectively
reduced to afford the chiral phosphine 6 bearing β-cyano
group in 75% yield with 99% ee,13 which could be further
reduced to give the chiral amine-based phosphine 7 in 82%
yield with 98% ee. Importantly, compound 7 was easily
converted to the corresponding chiral phosphine ligands 8 and
9 in moderate yields, which are a new class of potential chiral
organocatalysts in asymmetric catalysis.2b,d,14
a
Reaction conditions: 1 (0.2 mmol), Cu(CH3CN)4PF6 (5 mol %), L5
(6 mol %), 2a (0.4 mmol), TMSCN (0.4 mmol), tBuOOH in decane
(0.4 mmol) in DCE (2 mL) at −10 °C under N2. Isolated yield and
ee value was determined by HPLC on a chiral stationary phase. On a
b
c
10 mmol scale.
t
As mentioned above, BuOOH to TMSCN ratio was
a b
,
Scheme 4. Scope of Phosphorous Substrates
essential for the phosphinoylcyanation reaction, and using
t
more BuOOH than TMSCN resulted in the predominant
phosphinoyl-oxygenation product 3a′ (Scheme 2, entries 6 vs
8). To elucidate this outcome, a series of control experiments
t
were conducted. The reaction of BuOOH in decane with
t
TMSCN gave BuO2SiMe3 and HCN in quantitative yields
immediately, while no reaction occurred in the case of
tBuO2SiMe3 and HCN (Scheme 6a). In addition, a reaction
using a premixed solution of tBuOOH in decane and TMSCN
gave similar results as the standard reaction furnishing the
phosphinoylcyanation product 3a (Scheme 6b). However,
when BuO2SiMe3 was synthesized15 and tested for the
t
reaction of 1a and 2a with TMSCN, no reaction occurred at
all, and tBuOOSiMe3 and Ph2P(O)H 2a were almost
quantitatively recovered (>95%, Scheme 6c, left), whereas
upon treatment of TMSCN with water,16 the resultant HCN
t
reacted with BuO2SiMe3 under the same reaction conditions
to give the desired product 3a in good yield and excellent
enantioselectivity (Scheme 6c, right). These results revealed
that HCN rather than TMSCN acted as a real cyanide source
to participate in the cyanation of benzylic radicals and
excessive amounts of HCN did not poison copper catalysts
presumably due to a small dissociation constant of HCN
(HCN in H2O, pKa = 9.2), which were distinctly different from
our previous studies of the cyanide effect.6b
a
Reaction conditions: 1 (0.2 mmol), Cu(CH3CN)4PF6 (5 mol %), L5
t
(6 mol %), 2 (0.4 mmol), TMSCN (0.4 mmol), BuOOH in decane
(0.4 mmol) in DCE (2 mL) at −10 °C under N2. Isolated yield and
ee value was determined by HPLC on a chiral stationary phase.
b
C
DOI: 10.1021/acs.orglett.9b01607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
an absorption band of the colorless mixture (L5)Cu(I) at 235
nm decayed and a new absorption band at 295 nm emerged,
but no significant change to the spectrum was observed when
more than 1 equiv of tBuOOSiMe3 was added. Meanwhile, the
absorption band at 590 nm significantly increased after adding
tBuOOSiMe3. These observations suggested that a remarkable
Scheme 6. Control experiments
t
interaction between BuOOSiMe3 and (L5)Cu(I) indeed
occurred, and the titration experiment revealed that there
t
was only a BuOOSiMe3 molecule connecting to a copper
t
center (Figure 1a). Furthermore, the interaction of BuOO-
SiMe3 with (L5)Cu(I) was monitored by EPR spectroscopy.
t
To our surprise, the single electron transfer between BuOO-
SiMe3 and (L5)Cu(I) did not occur (Figure 1b, red line);
however, a Cu(II) signal was immediately detected by EPR
spectroscopy after adding HCN (Figure 1b, purple line), but
no Cu(II) signals were detected using TMSCN (blue line).
This, along with the reaction outcomes in Scheme 3c,
prompted us to conclude that the single electron oxidation
t
of (L5)Cu(I) with BuOOSiMe3 only occurred through a
possible PCET process in the presence of HCN (Scheme 4c,
right), rather than TMSCN, to deliver tert-butoxy radical and
(L5)Cu(II) species which were key intermediates for the
asymmetric phosphinoylcyanation.
a
*tBuOOSiMe3 was synthesized; HCN** was generated from
Although the interaction between tBuOOtBu and (L5)Cu(I)
was also observed with a small reaction constant (see
TMSCN and H2O.
t
Figure.S4), the single electron oxidation of BuOOBut with
(L5)Cu(I) did not occur in the presence of TMSCN or HCN
To provide more insight into the possible mechanism,
additional experiments were carried out. A colorless solution of
(see Figure 1c), which agreed with the ineffective tBuOOtBu in
t
t
the catalytic reaction. Thus, BuOOSiMe3 exhibited a unique
(L5)Cu(I) in CH2Cl2 turned blue immediately after BuOO-
t
reactivity toward the (L5)Cu(I) oxidation.
SiMe3 was added (Figure 1a), and a mixture of BuOOSiMe3
Based on these experiments and our previous studies,6 a
plausible radical mechanism is described in Scheme 7. At the
beginning, TBHP reacted with TMSCN to generate the real
and (L5)Cu(I) was then analyzed by UV spectrum. As shown
17
t
in Figure 1a, when 0−1.0 equiv of BuOOSiMe3 was
individually added to the solution of (L5)Cu(I) in CH2Cl2,
t
reactive oxidant BuOOSiMe3 (TBPS) and HCN (Scheme 7a,
eq 1). Then, the resulting tBuOOSiMe3 initially coordinated to
(L5)CuI(CN) to form int-I which underwent PCET to give
Scheme 7. Proposed Mechanism
Figure 1. Studies on the single electron oxidation of Cu(I)/L5 with
tBuOOSiMe3 (TBPS) by UV (a) and EPR spectrum (b); and with
tBuOOBut (DTBP) by EPR spectrum (c).
D
DOI: 10.1021/acs.orglett.9b01607
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Cu(II) species int-II and tert-butoxy radical in the presence of
HCN (eqs 2−3), possibly triggered by a hydrogen bonding
effect (Scheme 7c, right). Subsequently, the Cu(II) species int-
II reacted with HCN to yield active (L5)CuII(CN)2 species.
Meanwhile, the tert-butoxy radical could abstract the hydrogen
of Ph2P(O)H to give phosphinoyl radicals,11b,c which
sequentially added to styrenes. Eventually, the resultant
benzylic radical int-IV was enantioselectively trapped by
(L5)CuII(CN)2 to give the enantiomerically enriched
phosphinoylcyanation products.
21532009, 21790330, and 21821002 for GL, 21472133 for
JZ), the Science and Technology Commission of Shanghai
Municipality (Nos. 17XD1404500, 17QA1405200, and
17JC1401200), and the strategic Priority Research Program
(No. XDB20000000) and the Key Research Program of
Frontier Science (QYZDJSSWSLH055) of the Chinese
Academy of Sciences. JZ thanks the support from the Priority
Academic Program Development of Jiangsu Higher Education
Institutions (PAPD). GL thanks Prof. Liang Deng @ SIOC,
and Prof. Hairong Guan @ University of Cincinnati for the
helpful discussion.
In addition, when an excessive amount of tBuOOH was used
for the reaction, the reaction of 1a with 2a gave the major
product 3a′ (Scheme 2, entry 8). Previous studies demon-
strated that an alkylperoxo Cu(II) complex (CuII−OOR)
could be converted into peroxyl radicals.18 Therefore, we
reasoned that tBuOOH could react quickly with Cu(II) species
int-II to provide int-III which released the peroxyl radical to
couple with benzylic radicals to give racemic product 3′
(Scheme 7b).12,19
In summary, we have developed the first copper-catalyzed
enantioselective phosphinocyanation of alkenes via a tandem
radical relay, which allows for the straightforward and efficient
synthesis of various phosphine-containing alkylnitriles in good
yields with excellent enantioselectivities under very mild
conditions. Preliminary mechanistic studies reveal that the in
situ generated tert-BuOOSiMe3 acts as an oxidant and HCN is
the real cyanide source, which provides a potential protocol for
introducing 11CN into molecules by using 11C-labeled HCN.
Further applications of this method are in progress.
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ASSOCIATED CONTENT
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Synthetic procedures, characterization, and X-ray data
(PDF)
NMR spectra and HPLC analysis (PDF)
Accession Codes
CCDC 1915903 contains the supplementary crystallographic
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: jpzou@suda.edu.cn.
*E-mail: gliu@mail.sioc.ac.cn.
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Guosheng Liu: 0000-0003-0572-9370
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We are grateful for financial support from the National Basic
Research Program of China (973-2015CB856600), the
National Nature Science Foundation of China (Nos.
E
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t
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t
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F
DOI: 10.1021/acs.orglett.9b01607
Org. Lett. XXXX, XXX, XXX−XXX