Cross-coupling hydrogen evolution by visible light photocatalysis toward C(sp2)-P formation: Metal-free C-H functionalization of thiazole derivatives with diarylphosphine oxides

Article abstract of DOI:10.1021/acs.orglett.5b03497

Visible light along with 5 mol % eosin B catalyzed the first direct C-H phosphorylation of thiazole derivatives with diarylphosphine oxides by a photoredox process in the absence of an external oxidant. The scope of thiazoles and phosphine oxides was further investigated, as was functional group tolerance. The general and operational simplicity provides a novel metal and oxidant-free alternative for the formation of heteroaryl-P bonds, and only molecular hydrogen is generated as a byproduct.

Full text of DOI:10.1021/acs.orglett.5b03497

Letter
pubs.acs.org/OrgLett
Cross-Coupling Hydrogen Evolution by Visible Light Photocatalysis
Toward C(sp2)−P Formation: Metal-Free C−H Functionalization of
Thiazole Derivatives with Diarylphosphine Oxides
Kai Luo,†,‡,§ Yao-Zhong Chen,†,‡,§ Wen-Chao Yang,† Jie Zhu,† and Lei Wu*,†
†Jiangsu Key Laboratory of Pesticide Science and Department of Chemistry, College of Sciences, Nanjing Agricultural University,
Nanjing 210095, China
‡College of Plant Protection, Nanjing Agricultural University, Nanjing 210095, China
S
* Supporting Information
ABSTRACT: Visible light along with 5 mol % eosin B catalyzed the first direct C−H phosphorylation of thiazole derivatives
with diarylphosphine oxides by a photoredox process in the absence of an external oxidant. The scope of thiazoles and phosphine
oxides was further investigated, as was functional group tolerance. The general and operational simplicity provides a novel metal
and oxidant-free alternative for the formation of heteroaryl-P bonds, and only molecular hydrogen is generated as a byproduct.
n the past decades, organophosphorus compounds have
emerged as a flourishing research area owing to their wide
including furan, thiophene, and pyrrole with aryl diazonium salts
through a photoredox process using eosin Y (Scheme 1a).11a In
2013, Wu et al. described the first C(sp2)−C(sp3) cross-coupling
hydrogen evolution reaction from indoles with tetrahydroiso-
quinoline derivatives by combining eosin Y and graphene-
supported RuO2 nanocomposite as the photosensitizer.12a
Furthermore, although significant progress has been made in
C−X bond formation, examples for the C(sp2)−P formation by
photocatalysis are still scarce.13 One was developed by Toste et
al. through the P-arylation of aryldiazonium salts with H-
phosphonates via dual gold and ruthenium photoredox catalysis
(Scheme 1b).13a Recently, Xiao and co-workers demonstrated
another dual-catalytic C(sp2)−P formation reaction of diphe-
nylphosphine oxide with aryl iodides by combining nickel
catalyst and ruthenium complex (Scheme 1b).13b Inspired by
these leading researches, we hypothesized that P-centered radical
might be able to couple with heteroarenes via synergistic
interactions of visible light stimulation and organic dye
sensitization. As part of our continuing interest in synthesis
and application of organophosphorus chemistry,14 herein, we
report a mild and efficient direct C−H functionalization of
thiazole derivatives with diarylphosphine oxides by photoredox
process (Scheme 1c). To the best of our knowledge, this is the
first example of direct C−H phosphorylation of heteroarenes via
cross-coupling hydrogen evolution by organic dye-sensitized
photocatalysis without metal, oxidant, or additive.15
I
applications in biochemistry, material chemistry, organic syn-
thesis, and catalysis.1 Generally, phosphorus substituents
regulate important biological, medicinal, and material functions;
they perform as ligands or directing group for transition metal
catalysis.2 As such, the introduction of organophosphorus
functionalities in convenient means continues to motivate the
research for methods for their synthesis. Of these methods,
coupling of phosphonate esters or phosphine oxides with
electrophiles catalyzed by transition metals has been recognized
as one of the most efficient and promising approaches for
C(sp2)−P bond formation. Palladium, nickel, copper, rhodium,
silver, etc., were extensively applied to enable the phosphor-
ylation of alkynes,3 propargylic derivatives,4 styrenes,5 arylbor-
onic acids,6 aryl(pseudo) halides,7 and (hetero)arenes.8
However, these transformations are associated with one or
more limitations such as expensive, toxic or stoichiometric
transition metals, air-sensitive ligands, additives/oxidants,
elevated temperatures, and so on.
Intriguingly, the practices in visible light photocatalysis have
actively responded to the demands of reaction economics,
operational simplicity, and environmental friendliness. Great
efforts have been devoted to the development of visible-light-
mediated C−C and C−X formations.9 Notably, direct C−H
functionalization has become an increasing significant sub-
ject.10−12 Among which, organic dye-type photocatalysts
exhibited superiority to their transition metal counterparts,
such as ruthenium and iridium complexes, with regard to the
aforementioned criteria. For representative examples, Konig
reported a direct intermolecular C−H arylation of heteroarenes
Received: December 8, 2015
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© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03497
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Letter
a
Scheme 1. (a) Representative C(sp2)−H Functionalization of
Heteroarenes by Organic Dyes under Visible Light; (b)
C(sp2)−P Formation by Photoredox/Metal Dual Catalysis;
(c) This Work
Table 1. Optimization of the Reaction Conditions
b
entry
organic dye
Eosin Y
solvent
yield (%)
1
THF
N.R.
N.R.
N.R.
69
2
Eosin Y
DMF
3
Eosin Y
CH3CN
toluene
H2O
4
Eosin Y
5
Eosin Y
67
6
Eosin Y
DMSO
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
83
7
Eosin Y
86
8
Eosin Y disodium
Eosin B
75
9
87
10
11
12
13
14
Fluorecein
Rhodamine B
Alizarin Red S
Rose Bengal
Ru(bpy)3Cl2, i-PrNEt2
Eosin B
33
22
25
trace
9
c
15
77%
58%
N.R.
N.R.
d
16
Eosin B
e
17
Eosin B
f
18
Eosin B
a
Reagents and conditions: 0.2 mmol benzothiazole, 0.6 mmol
diphenylphosphine oxide, 5 mol % organic dye, 1.5 mL of solvent,
With benzothiazole (1a), diphenylphosphine oxide (2a) as the
model substrates, and a 11 W white LED bulb as the visible light
source, we discovered that the desired phosphorylation product
(3aa) was produced in 69% isolated yield in toluene at room
temperature with organic dye eosin Y under a nitrogen
atmosphere for 24 h. Reactions in THF, DMF, and acetonitrile
left the reactants intact; in sharp contrast, DMSO as solvent
enabled the C−H phosphorylation to a good yield of 83%.
Interestingly, heterogeneous reaction in water performed
smoothly with medium yield of 67%. When chloroform was
further applied as the solvent, the substrate consumed
completely, yielding of the product with 86% (Table 1, entry
7). Subsequently, other organic dyes including eosin Y disodium,
eosin B, Fluorescein, Rhodamine B, Alizarin Red S, and Rose
Bengal were evaluated. To our delight, investigations revealed
that the yield of 3aa could be improved to 87% when eosin B was
employed as the photocatalyst (entry 9). As a comparison, the
classical ruthenium-pyridyl complex afforded merely 9% under
standard conditions (entry 14), which evidenced the superiority
of organic dyes over the transition metal-derived counterpart in
this type of C−H functionalization. Quite interestingly, sacrificial
oxidants, such as air or molecular oxygen, which are recognized
to accelerate the dehydrogenation process, led to significant
reduction or complete inhibition of reactivity in the present
conditions (entry 16 and 17). Moreover, no conversion could be
observed when the reactions were conducted in the dark (entry
18). These results indicate that light, eosin B, and protecting
atmosphere are all essential to achieve the reaction.
b
c
d
11 W white LED, N2, 24 h. Isolated yields. 3 mol % catalyst. Under
air. In oxygen atmosphere. Reaction in the dark.
e
f
were remarkably sensitive to the electron density of substitutions
on phenyl moiety. Arylthiazoles bearing electron-donating
groups, such as methoxy, methyl, and phenyl, were coupled
with 2a affording the corresponding adducts in medium to good
yields (Scheme 2, compounds 3ba−3ea). However, the
reactivity was dramatically increased when arylthiazole contain-
ing electron-withdrawing groups such as -F, -Cl, -Br were used
(Scheme 2, compounds 3fa−3ja). Notably, strong withdrawing
group (nitro) impaired the reactivity to afford medium yield of
3ka. Interestingly, ethyl 4-methyl thiazole-5-carboxylate and
methyl 4-methyl thiazole-5-carboxylate could also react under
the standard conditions affording the products 3la and 3ma in
yields of 82% and 64%, respectively. Unfortunately, 4,5-
dimethylthiazole (3na) was inapplicable even after systematic
screening, which might be attributed to the necessity of
conjugation on substrates. Meanwhile, benzoxazole derivatives
and dialkylphosphites were left intact under standard conditions.
Next, the scope of diarylphosphine oxides was examined. As
shown in Scheme 3, diarylphosphine oxides bearing electron-
donating or withdrawing groups at their para-positions, including
methoxy, t-butyl, methyl, fluoro, and trimethylfluoro, were
applicable to the coupling with medium to excellent yields
(compounds 3ab−3ad, 3ah, 3aj, 3ld, and 3lh). It is worthy to
mention that substitutions on meta-positions also proceeded
efficiently with yields ranged from 44% to 75% (compounds 3ae,
3ag, and 3ai). However, ortho-methyl substitution led to less
On the basis of this success, we evaluated the nature of thiazole
derivatives that could participate in the photoredox cross-
coupling with diphenylphosphine oxide. In general, the reactions
B
DOI: 10.1021/acs.orglett.5b03497
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Letter
a
(detected by gas chromatography, see details in Supporting
Information). When deuterated 1a and 2a were employed under
the standard conditions, D2 was observed instead of H2, which
suggested that the protons were released from the substrates.
The above results coupled with previous reports11,13 collectively
point to a plausible mechanism shown in Scheme 4. The
Scheme 2. Substrates Scope on Thiazole Derivatives
Scheme 4. Plausible Mechanism
a
Reagents and conditions: 0.2 mmol benzothiazole, 0.6 mmol
diphenylphosphine oxide, 5 mol % Eosin B, 1.5 mL of solvent, 11
W white LED, N2, 24 h.
a
Scheme 3. Substrates Scope on Diarylphosphine Oxides
photocatalytic cycle starts with reductive quenching of excited
state Eosin B+• with phosphinous acid A to yield the P-centered
radical 2′ after deprotonation of radical-cation intermediate B.
Then the nucleophilic addition of the radical diphenylphosphine
oxide to thiazole 1 leads to intermediate 3′. Finally, the
deprotonation of this species furnish the desired product 3.
Meanwhile, the dissociated hydrogen radicals combine to
produce H2.
In summary, we have reported the first example of direct C−H
phosphorylation of heteroarenes via cross-coupling hydrogen
evolution by organic dye-sensitized photocatalysis without metal,
oxidant, or additive. The reaction tolerates various functional
groups including bromides, ethers, and esters and furnishes the
coupling products in medium to excellent yields. Further
investigations of utilizing light-generated hydrogen are ongoing
in our laboratory.
a
Reagents and conditions: 0.2 mmol benzothiazole, 0.6 mmol
diphenylphosphine oxide, 5 mol % Eosin B, 1.5 mL of solvent, 11
W white LED, N2, 24 h.
ASSOCIATED CONTENT
* Supporting Information
■
S
reactivity, with only 35% yield of 3af isolated. The steric
hindrance effect of di(2,4,6-trimethylphenyl)phosphine oxide
was found to be extremely detrimental, and no product was
detected at all. In addition, dialkylphosphine oxides exhibited no
reactivity toward the standard conditions.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03497.
Experimental procedures and spectral data for all new
compounds (PDF)
More experiments were subsequently designed and conducted
for understanding the related mechanisms. Initially, TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy), a well-known radical
scavenger, was found to inhibit the reaction process, which
indicated that the reaction may occur through a radical
mechanism. Since that no sacrificial oxidant was employed in
our work, molecular hydrogen could be the only byproduct.
Thus, we carried out experiments with deuterated substrates and
solvents to identify the release and source of H2 in the reaction
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rickywu@njau.edu.cn.
Author Contributions
§These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b03497
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (NSFC, Grant No. 21372118), the
Foundation Research Project of Jiangsu Province (The Natural
Science Foundation No. BK20141359), and “333 High Level
Talent Project” of JiangSu Province.
(11) For selected C−H functionalization via organic dye-mediated
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