Visible-Light-Induced External Oxidant-Free Oxidative Phosphonylation of C(sp2)-H Bonds

Article abstract of DOI:10.1021/acscatal.7b02418

Considering the synthetic value of phosphonates, developing powerful catalytic methods for the phosphonylation of C(sp²)-H bonds is important. Herein, we achieve a visible-light-induced external oxidant-free oxidative phosphonylation of C(sp

Full text of DOI:10.1021/acscatal.7b02418

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Letter
Visible Light-induced External Oxidant-free
Oxidative Phosphonylation of C(sp2)-H Bonds
Linbin Niu, Jiamei Liu, Hong Yi, Shengchun Wang, Xing-
An Liang, Atul Kumar Singh, Chien-Wei Chiang, and Aiwen Lei
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02418 • Publication Date (Web): 27 Sep 2017
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ACS Catalysis
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Visible Light-Induced External Oxidant-Free Oxidative
Phosphonylation of C(sp2)-H Bonds
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Linbin Niu,1 Jiamei Liu,1 Hong Yi,1 Shengchun Wang,1 Xing-An Liang,1 Atul Kumar Singh,1 Chien-
Wei Chiang,1 and Aiwen Lei1,2*
1. College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan, Hubei
430072, P. R. China.
2. State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China.
ABSTRACT: Considering the synthetic value of phosphonates, developing powerful catalytic methods for the phosphonylation of
C(sp2)-H bonds is important. Herein, we achieve a visible light-induced external oxidant-free oxidative phosphonylation of C(sp2)-H
bonds via the combination of photocatalysis and proton-reduction catalysis. Mechanistic studies indicate visible light-induced
electron-rich arene radical cation is the key reactive intermediate. The synthetic application of this approach is demonstrated in the
late-stage functionalization of pharmaceutical molecules. This study may have significant implications for the functionalization of
C(sp2)-H bonds, especially for those which are sensitive to oxidative conditions.
KEYWORDS: Photocatalysis, External oxidant-free, Proton-reduction catalysis, Phosphonylation, C(sp2)-H bonds, Radical
cation
Due to aryl and vinyl phosphonates being incorporated into a
vast number of structural diverse molecules which involve in
organic synthesis, agrochemical, material chemistry, and
biochemistry,1 mild and sustainable catalytic phosphonylation
strategies are considered highly desirable. The pioneering work
of constructing C(sp2)-P bonds by palladium-catalyzed cross
coupling of an aryl halide with H-phosphonate was reported by
Hirao et al.2 Since then, transition-metal-catalyzed
phosphonylation of various C(sp2)-X has been served as a
general route to forge C(sp2)-P bonds.3 In spite of possessing
regiospecificity, the key limitation of the method is in need of
pre-functionalized starting material. There is no doubt that
oxidative phosphonylation of C(sp2)-H bonds is the most direct
method for C(sp2)-P bonds construction.
demonstrate
an
external
oxidant-free
oxidative
phosphonylation of C(sp2)-H bonds (methylarenes, anisoles,
polycyclic aromatic hydrocarbons, heteroaromatics, anilines
and olefins derivatives) with no need for excess
phosphonylation reagents by merging visible-light photoredox
with cobalt catalysis. By adopting this strategy, the late-stage
functionalization of the pharmaceutical molecules can be
successfully carried out.
Scheme 1. The oxidative phosphonylation of C(sp2)-H bonds
under visible light-induced external oxidant-free conditions.
Various strategies for oxidative phosphonylation of C(sp2)-H
bonds have been developed in recent years. Transition-metal-
catalyzed and chemical oxidants dominating the oxidative
C(sp2)-H bonds phosphonylation are regarded as important
synthetic advances.4 However, these transformations regularly
require directing groups, stoichiometric oxidants or inevitably
rigorous reaction temperature. Recently, photochemistry has
been an attractive way to realize some challenging chemistry
conversions.5 Particularly, visible light-induced oxidative
phosphonylation of C(sp2)-H bonds by photo/oxidant catalytic
system has provided an efficient access to C(sp2)-P bonds.6
Even so, the introduction of stoichiometric quantities of
oxidants as dehydrogenation agent and electron acceptor limits
its application, especially causing the circumscribed functional
group compatibility and oxidative side reactions.6b Having
recognized the importance of aryl and vinyl phosphonates, and
the limitation of previous reports about oxidative
phosphonylation of C(sp2)-H bonds, we hope to develope a
noble metal-free, external oxidant-free and harsh temperature-
free oxidative phosphonylation method for C(sp2)-H bonds.
Inspired by the photoinduced oxidative cross-coupling between
two nucleophiles under the oxidant-free condition,7 herein, we
Our strategy for phosphonylation of C(sp2)-H bonds is based
on the capture of the crucial arenes and olefins radical cations
(Scheme 1). Simple arenes and olefins can undergo a single
electron transfer (SET) step with some excited photocatalysts
whose oxidative ability are strong under light irradiation.7 The
generated radical cation species can be trapped by phosphites,
and followed by another SET step and the subsequent
deprotonation step, delivering the cation intermediate. Finally,
the nucleophilic displacement step gives the final captured
product.4b
To this end, after optimization, a satisfactory yield 92% (3a)
of the oxidative C(sp2)-H phosphonylation was reaped with the
p-xylene (1a) and triethyl phosphite (2a) by merging
photoredox and cobalt catalysis, whereas the benzyl group was
unaffected (Table 1, entry 3). To unambiguously develop this
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phosphonylativon protocol (Table S1),8 the investigation of With the suitable condition in hand, all kinds of C(sp2)-H
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photocatalyst was carried out primarily. As we can see, the
failure that no phosphonylation product was obtained when
Ru(bpy)3(PF6)2 and Eosin Y were employed as the
photocatalyst (Table 1, entries 1 and 2), contrastively revealed
that an adequately high oxidizing capability of the excited
bonds were extended to the phosphonylation protocol. In
consideration of methylarenes as versatile building blocks in
organic synthesis,10 various alkyl-substituted benzenes were
firstly investigated. As shown in Scheme 2, what’s particularly
noteworthy was the perfect chemoselectivity that only C(sp2)-
H phosphonylation occurred regardless of the existence of the
sensitive benzyl C(sp3)–H bond, when benzene ring bears
isopropyl substituent (3b). What's more, 1-(tert-butyl)-4-
methylbenzene delivered the targeted aryl phosphonates
product in single site-selectivity (3c). In spite of the bulky steric
hindrance that the polyalkyl-substituted benzenes possess, the
reaction was still processed with high efficiency (3d and 3e).
Likewise, anisole derivatives with different functional groups
were probed to show good functional group tolerance. It was
notable that 1-(tert-butyl)-4-methoxybenzene behaved a good
yield with excellent selectivity (3f). Notably, the
phosphonylation of 1-allyl-4-methoxybenzene was carried out
with sole chemoselectivity and site-selectivity (3g). We were
delighted that meta-substituted anisole was phosphonylated in
satisfying regioselectivity (3h). Importantly, π-extended aryl
ether and derivatives could be well tolerable and provide an
opportunity for the modification of some drug molecules which
contain naphthalene skeleton (3i and 3j). We then chose 2-
methoxynaphthalene (1i) to scale up this phosphonylation
protocol, which was smoothly amenable to gram-scale
synthesis in a good yield 83%, providing a promising synthetic
route for phosphonylation of C(sp2)-H bonds (Figure S3).
photocatalyst to induce a SET step is the crucial requirement.
7d
Due to the volatility of the arene,9,
the yield for the
phosphonylation product dropped to 61% when the
concentration of arene was lowered to one stoichiometric level
(Table 1, entry 4). In absence of photocatalyst, cobalt catalyst
or light, the reaction couldn't be promoted, indicating that all
the components are essential for this visible light-induced
external oxidant-free phosphonylation protocol (Table 1,
entries 5, 6 and 7). Meanwhile, ammonium acetate was
necessary which might act as a nucleophile to facilitate the
nucleophilic displacement (Table 1, entry 8).4b It was
noteworthy that phosphonylation of C(sp2)-H bonds showed
extremely poor reactivity due to the overoxidation of
methylarenes and phosphites, when the reaction was mediated
by O2 or stoichiometric oxidants such as sodium persulfate
(Na2S2O8) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) (Table 1, entries 9, 10 and 11, see Supporting
Information for details, Table S2). In comparison to
photo/oxidant catalytic system, this visible light-induced
external oxidant-free oxidative phosphonylation protocol
overcomes the limitation of overoxidation and provides an ideal
alternative for the synthesis of aryl phosphonates.
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Table 1. Investigation of the reaction conditions.a
Unfortunately,
there
was
no
reactivity for
4-
(trifluoromethyl)anisole due to the difficulty of being oxidized
by excited photocatalyst (3k).
Scheme 2. Substrate scope for the oxidant-free
phosphonylation of methylarenes and anisoles with
P(OEt)3.a
Entry
1
Photocatalyst
Co catalyst
Yield (%)b
n.d.
Ru(bpy)3(PF6)2
Co(dmgH)(dmgH2)Cl2
2
3
Eosin Y
Co(dmgH)(dmgH2)Cl2
Co(dmgH)(dmgH2)Cl2
Co(dmgH)(dmgH2)Cl2
Co(dmgH)(dmgH2)Cl2
-
n.d.
92 (92)c
61
Acr+-Mes ClO4
Acr+-Mes ClO4
-
-
4d
5
-
n.d.
n.d.
n.d.
trace
14
-
-
-
-
-
-
6
Acr+-Mes ClO4
Acr+-Mes ClO4
Acr+-Mes ClO4
Acr+-Mes ClO4
Acr+-Mes ClO4
Acr+-Mes ClO4
7e
8f
9
Co(dmgH)(dmgH2)Cl2
Co(dmgH)(dmgH2)Cl2
O2 instead
10
11
Na2S2O8 instead
DDQ instead
15
10
aConditions: 1a (0.4 mmol), 2a (0.2 mmol), photocatalyst (7 mol%),
Co catalyst (8 mol%), 0.5 eq. CH3COONH4 in 3.0 mL CH3CN under a
nitrogen atmosphere, irradiated by 3 W blue LEDs, r.t., 24 h; bGC
yields with naphthalene as the internal standard; cisolated yield within
parentheses; d1.0 equiv. arene was used; ewithout light; fwithout
CH3COONH4.
aConditions: 1 (0.4 mmol), 2a (0.2 mmol), Acr+-Mes ClO4- (7 mol%),
Co(dmgH)(dmgH2)Cl2 (8 mol%), 0.5 eq. CH3COONH4 in 3.0 mL
CH3CN under a nitrogen atmosphere, irradiated by 3 W blue LEDs, r.t.,
24 h; isolated yields. The ratio of the isomers was determined by NMR.
The unprecedented reactivity encouraged us to explore the
phosphonylation of more general and valuable C(sp2)-H bonds
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ACS Catalysis
(Scheme 3). Indeed, the high-yield phosphonylation of
phosphonylation were successfully achieved (8 and 10).
Simultaneously, the highly reactive benzyl C(sp3)-H bonds
were preserved. The pioneering result is expected to bring about
the late-stage phosphonylation of more complex and
meaningful molecules.
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heterocycles, olefins and anilines derivatives with good
selectivity still remain rare. Notably, the procedure can be
expanded to quinoline bearing electron-releasing substitution
(5a). Electron-rich thiophene compounds such as 2-
phenylthiophene and trimethyl(thiophen-2-yl)silane were
successfully phosphonylated in satisfactory yield and modest
selectivity (5b and 5c). It was disappointed that the
phosphonylation of indoles failed under the standard condition.
Biphenyl displayed a good reaction activity but the inseparable
isomers were obtained (5d). Even acetyl-protected aniline was
still a competent substrate, because the single selectivity
seemed to be effortlessly obtained (5e). Significantly, the
phosphonylation product serves as a key intermediate to access
to GPAT inhibitor.11 It is important that olefins were also
suitable for this system and achieved the desired products with
the sole chemoselectivity (5f and 5g), which further
demonstrated the universality of this novel and powerful
phosphonylation method. Unfortunately, the not-styrene-based
olefin like cyclohexene couldn’t be phosphonylated due to the
Scheme 4. Late-stage functionalization of drug-like
molecules.
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The detailed mechanistic studies was demonstrated to reveal
some important hints of this visible light-induced external
oxidant-free phosphonylation protocol. In the presence of
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO, 2 equiv.) or 2,6-
di-tert-butyl-4-methylphenol (BHT, 2 equiv.), the inhibition of
the reaction efficiency indicated that a radical process might be
involved (Figure S4).
high oxidation potential (E1/2
= +2.37 V vs SCE).12
ox
Additionally, we also made our attempts to use other different
phosphites to achieve the phosphonylation of C(sp2)-H bonds
under this catalytic system. For trialkyl phosphites, P(OMe)3
provided a modest yield (5h) and P(OiPr)3 was a satisfactory
phosphonylation reagent despite of the possible steric bulk (5i).
Moreover, excellent reactivity was demonstrated when tris(2-
chloroethyl) phosphite was applied (5j).
Thereafter, we designed the intermolecular kinetic isotope
effect experiment, which afforded the KIE value in 1.25 (Figure
1), revealing that the rate-determining step might not take place
in the cleavage of C(sp2)-H (see Supporting Information for
details, Figure S5 and S6). Simultaneously, no O18 labeling aryl
phosphonate was detected in H2O18 labeling experiment, which
excluded the participation of water in the reaction pathway
(Figure S7).
Scheme 3. Substrate scope for the oxidant-free
phosphonylation of other extended C(sp2)-H bonds.a
Figure 1. The intermolecular kinetic of isotopic effect
experiment.
From the outset, we anticipated that the initial SET step is
originated from the single electron oxidation of C(sp2)-H bonds
by excited photocatalyst. With the aim of gaining convincing
evidence,
a
series of photoluminescence quenching
experiments were designed (see Supporting Information for
details ， Figure S8). The photoluminescence of the
-
photocatalyst Acr+-Mes ClO4 was obviously quenched by
methylarenes, anisoles, anilines and olefins derivatives. In
contrast, nearly no quenching was behaved when P(OEt)3 2a
was employed as
a quencher. Moreover, P(OPh)3 2k
-
aConditions: 4 (0.4 mmol), 2 (0.2 mmol), Acr+-Mes ClO4 (7 mol%),
decomposed into phenol 6 under this reaction condition, failing
to produce any corresponding phosphonylated products 5k
(Figure S11). This is why the arene and olefin radical cations
were considered as the critical reaction intermediates.
Co(dmgH)(dmgH2)Cl2 (8 mol%), 0.5 eq. CH3COONH4 in 3.0 mL
CH3CN under a nitrogen atmosphere, irradiated by 3W blue LEDs, r.t.,
b
24 h; isolated yields. 4.0 mL of CH3CN was used. The ratio of the
isomers was determined by NMR.
Additionally, the late-stage functionalization of several drug-
like molecules (7 and 9) were designed to highlight the
synthetic value of our catalytic strategy (Scheme 4). Not only
the good efficiency but also the aim of site-selective
Based on the experimental results of mechanistic
investigation, we presumed that the arene or olefin radical
cations are pivotal intermediates for the phosphonylation of
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C(sp2)-H bonds. Taking p-xylene 1a as an example, a plausible
Notes
mechanistic cycle for this C(sp2)-H phosphonylation was
outlined in Figure 2. Initially, the excited state acridinium
photocatalyst13 excited by the irradiation of commercial
available blue LEDs is capable of oxidizing p-xylene 1a,
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4
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6
7
8
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the 973 Program (2011CB808600,
2012CB725302, 2013CB834804), the National Natural Science
Foundation of China (21390400, 21272180, 21302148, 2109343
and 21402217), and the Research Fund for the Doctoral Program
of Higher Education of China (20120141130002) and the Ministry
of Science and Technology of China (2012YQ120060) and the
Program for Changjiang Scholars and Innovative Research Team
in University (IRT1030). The Program of Introducing Talents of
Discipline to Universities of China (111 Program) is also
appreciated.
-
generating the Acr+-Mes ClO4 radical and the corresponding
arene radical cation 11. Herein, we believe that the P(OEt)3 2a
acts as a nucleophile to capture the arene radical cation, and
delivers the adduct 12. Then, the proton-reduction Co(III)
catalyst is responsible for producing the intermediate 13 by a
single electron transfer, which oneself be reduced to give the
Co(II). A rapid deprotonation affords the phosphorus cation
intermediate 14. With the help of the additive CH3COONH4
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leading
a
nucleophilic displacement step,4b the aryl
phosphonium salt 14 is converted into the final phosphonylation
product 3a.14 It is considered that the regeneration of the
photocatalyst is resulted from the oxidation by Co(II) and
generates Co(I). As a result, the protonation of Co(I) affords
Co(III)-H15 and H2 can be released by the protonation of
Co(III)-H to accomplish the Co catalytic cycle.
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Figure 2. Proposed mechanism for visible light-induced
oxidant-free oxidative C(sp2)-H phosphonylation (PC:
-
photocatalyst Acr+-Mes ClO4 ; Co: Co(dmgH)(dmgH2)Cl2
catalyst).
In conclusion, we have demonstrated
a mild and
chemoselective nature of visible light-induced external oxidant-
free oxidative phosphonylation of C(sp2)-H bonds. Various
kinds of C(sp2)-H bonds including methylarenes, anisoles,
polycyclic aromatic hydrocarbons, heteroaromatics, anilines
and olefins derivatives can be phosphonylated efficiently,
making it appealing for late stages of synthesis programs.
Moreover, mechanistic studies show that the single electron
oxidation of electron-rich aromatic rings or olefins is the key
reaction step for this phosphonylation conversion. The
development of related functionalization of C(sp2)-H bonds is
underway in our laboratory.
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́
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge via the
Internet at http://pubs.acs.org, which included NMR data; extended
data about mechanism study, condition investigation, and
characterization (PDF)
̈
̈
AUTHOR INFORMATION
Corresponding Author
* Corresponding author, E-mail: aiwenlei@whu.edu.cn.
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C.; Li, Y.; Dou, B.; Singh, A. K.; Lei, A. Angew. Chem., Int. Ed. 2017,
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(8) The conversion yields of the condition investigation were provided
in the SI. In addition, the excess of arenes were recovered, and related
byproducts weren’t observed under this oxidant-free condition.
(9) Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.;
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(13) Romero, N. A.; Nicewicz, D. A. J. Am. Chem. Soc. 2014, 136,
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(14) The further phosphonylation of products weren’t detected by LC-
MS because the electron-rich arenes are excess and the phosphite esters
are limited. Moreover, the cyclic voltammetry experiments of
representative products were shown in SI.
(15) (a) Artero, V.; Chavarot-Kerlidou, M.; Fontecave, M. Angew.
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