Photoinduced Transition-Metal-Free Cross-Coupling of Aryl Halides with H-Phosphonates

Article abstract of DOI:10.1021/acs.orglett.8b04081

Photoinduced transition-metal- and photosensitizer-free cross-coupling of aryl halides (including Ar-Cl, Ar-Br, and Ar-I) with H-phosphonates (including dialkyl phosphonates and diarylphosphine oxides) is reported. Various functional groups were tolerated, including ester, methoxy, dimethoxy, alkyl, phenyl, trifluoromethyl, and heterocyclic compounds. This simple and green strategy provides a practical pathway to synthesize arylphosphine oxides.

Full text of DOI:10.1021/acs.orglett.8b04081

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photoinduced Transition-Metal-Free Cross-Coupling of Aryl Halides
with H‑Phosphonates
Huiying Zeng,*,† Qian Dou,† and Chao-Jun Li*,†,‡
†The State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Road, Lanzhou 730000, People’s
Republic of China
‡Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke Street West,
Montreal, Quebec H3A 0B8, Canada
S
* Supporting Information
ABSTRACT: Photoinduced transition-metal- and photosensitizer-free cross-
coupling of aryl halides (including Ar−Cl, Ar−Br, and Ar−I) with H-
phosphonates (including dialkyl phosphonates and diarylphosphine oxides) is
reported. Various functional groups were tolerated, including ester, methoxy,
dimethoxy, alkyl, phenyl, trifluoromethyl, and heterocyclic compounds. This
simple and green strategy provides a practical pathway to synthesize
arylphosphine oxides.
hosphorus-containing compounds are important for
pharmaceuticals (Figure 1), agrochemicals, and flame-
Scheme 1. Methods for Cross-Coupling of Aryl Halides with
H-Phosphonates
P
Figure 1. Representative biologically active phosphorus-containing
compounds.
resistant materials.1 They are also important as ligands for
various transition-metal-catalyzed reactions. Because of their
functional and biological activities, C−P bond formation has
attracted significant interest from organic chemists.2 Tradi-
tionally, aryl phosphonates were synthesized from aryl halides
and H-phosphonates catalyzed by palladium.2a,3 Catalysts with
cheaper transition metals, such as copper4 and nickel,5 for this
transformation were developed subsequently (Scheme 1a).
Recently, Xiao’s group reported nickel and ruthenium dual-
catalyzed cross-coupling of aryl iodides with H-phosphonates
6
̈
upon irradiation by visible light (Scheme 1b). Konig’s group
reported the organic-photosensitizer-catalyzed Arbuzov reac-
tion of aryl bromides and trialkyl phosphites.7 Although great
advances have been achieved, the more active aryl iodides and
aryl bromides have been used as the substrates. For
photoredox reactions, only a few examples of aryl chlorides
were successful for the C−P bond formation.7 Photoinduced
and photosensitizer-free catalysis has been developed as a
greener pathway for carbon−heteroatom bond formation.8 It is
thus highly desirable to develop alternative photoinduced
methods for cross-coupling of aryl halides with H-phospho-
nates that do not use photosensitizers and transition metals.9
Herein we report a photoinduced photosensitizer- and
transition-metal-free cross-coupling of aryl halides (including
Ar−Cl, Ar−Br, and Ar−I) or heteroaryl halides with H-
phosphonates (including dialkyl phosphonates and diary-
lphosphine oxides) (Scheme 1c).
Our investigation commenced with the reaction of
bromobenzene (1a) and dimethyl phosphonate (2a) with
TMEDA (2.0 equiv) and sodium iodide (0.5 equiv) in
acetonitrile (1.0 mL) at room temperature under an argon
atmosphere in a quartz tube with irradiation by 254 nm light.
No desired product was detected (Table 1, entry 1). The same
Received: December 21, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04081
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
With the optimized reaction conditions in hand, the scope of
aryl halides was explored with 2.0 equiv of dimethyl
phosphonate at room temperature under an argon atmosphere
using 2.0 equiv of t-BuONa as the base in acetonitrile (1.0 mL)
under irradiation. As shown in Scheme 2, more reactive
Table 1. Screening of the Conditions
b
entry
base
solvent
CH3CN
additive
yield (%)
Scheme 2. Cross-Coupling of Different Aryl Halides with
Dimethyl Phosphonate
1
2
3
4
5
6
7
8
9
TMEDA
DABCO
K2CO3
K3PO4
NaOH
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
−
KI
LiI
I2
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
n.p.
n.p.
n.p.
n.p.
n.p.
17
9
64
52
68
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
H2O
Cs2CO3
EtONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
10
11
12
13
14
15
16
17
31
n.p.
80 (70)
<5
23
41
<5
73
78
<5
DMF
DMA
CH3CN/H2O
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
c
18
d
19
e
20
f
21
g
n.p.
n.p.
n.p.
22
h
23
a
General conditions: 1a (0.2 mmol), 2a (0.4 mmol), base (2.0 equiv),
additive (0.5 equiv), and solvent (1.0 mL) for 18 h under an argon
atmosphere at room temperature with UV light (254 nm).
Abbreviations: n.p., no product; DMF, N,N-dimethylformamide;
DMA, N,N-dimethylacetamide; TBAI, tetrabutylammonium iodide.
b
Determined by 31P NMR analysis using triethyl phosphate as an
c
internal standard; an isolated yield is shown in parentheses. TBAI
d
e
f
g
(0.2 equiv). TBAI (1.0 equiv). 405 nm. Blue LED. White light.
h
In the dark.
a
Method A for ArI: aryl iodide 1 (0.2 mmol), 2a (0.4 mmol), and t-
BuONa (0.4 mmol) in CH3CN (1.0 mL) irradiated by 405 nm light
at room temperature in a sealed quartz tube under an argon
atmosphere for 12 h. Isolated yields are shown. Method B for ArBr:
results were obtained with other organic and inorganic bases
(Table 1, entries 2−5). Fortunately, a small amount of the
desired product was obtained when cesium carbonate or
sodium ethoxide was used as the base (Table 1, entries 6 and
7). The best yield was obtained using the strong base
potassium tert-butoxide (Table 1, entry 8). In the absence of
sodium iodide additive, the yield was lowered to 52% (Table 1,
entry 9). With other iodide sources (Table 1, entries 10−
13),10 the highest yield was detected when TBAI was used
(Table 1, entry 13). With other solvents, such as water, DMF,
DMA, and an MeCN/H2O mixture, no improvement was
observed (Table 1, entries 14−17). When the amount of
additive was increased or reduced, the yield was slightly
lowered (Table 1, entries 18 and 19). Different light sources
were examined, such as 405 nm light, a blue LED, and white
light, and all showed lower efficiency than 254 nm light (Table
1, entries 20−22). These results indicate that the light source is
very important to this reaction. Since metal tert-butoxide can
promote the reaction of bromobenzene to form benzene free
radical without light,11 a control experiment was also carried
out under dark conditions, and no product was detected
(Table 1, entry 23).
b
aryl bromide 1 (0.2 mmol), 2a (0.4 mmol), TBAI (0.5 equiv), and t-
BuONa (0.4 mmol) in CH3CN (1.0 mL) irradiated by UV light (254
nm) at room temperature in a sealed quartz tube under an argon
c
atmosphere for 18 h. Isolated yields are shown. Method C for ArCl:
aryl chloride 1 (0.2 mmol), 2a (2.0 equiv), TBAI (0.2 equiv), and t-
BuONa (0.4 mmol) in CH3CN (1.0 mL) irradiated by UV light (254
nm) at room temperature in a sealed quartz tube under an argon
atmosphere for 24 h. Isolated yields are shown.
iodobenzene derivatives were irradiated with 405 nm light
(method A), while the less reactive bromobenzene derivatives
also worked very well upon addition of TBAI under irradiation
at 254 nm together with a prolonged reaction time of 18 h
(method B). Importantly, although chlorobenzene derivatives
are usually more inert for metal-catalyzed cross-coupling
reactions, they can also react smoothly upon irradiation at
254 nm with 0.2 equiv of TBAI (method C). A broad range of
aryl halides containing different functional groups proved to be
competent substrates. Aryl halides (including Ar−I, Ar−Br,
and Ar−Cl) substituted with a weak electron-withdrawing
B
DOI: 10.1021/acs.orglett.8b04081
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
group (e.g., methyl, tert-butyl, or phenyl) at different positions
reacted very well, generating the corresponding products 3a−e
in moderate to high yields. Even 2,4,6-trimethylbromobenzene,
with high steric hindrance, generated the cross-coupled
product 3f in moderate yield. Various aryl halides bearing a
strong electron-donating group at different positions were all
effective, forming the corresponding products 3g−k in good to
high yields. Substrates bearing different halides could be
selectively cross-coupled with dimethyl phosphonate, as shown
by the generation of fluorine-containing product 3l. Substrates
bearing strong electron-withdrawing groups also reacted
smoothly to afford products 3m and 3n. The reaction of
iodo- or bromonaphthalene generated the corresponding
products 3o and 3p. Heterocyclic products 3q−s were also
obtained by this method.
It is well-recognized that trace amounts of transition-metal
residue are highly undesirable in the pharmaceutical industry.
To demonstrate the advantage of this method, the calcium
antagonist 3ad was synthesized on a gram scale without the use
of any transition metal (Scheme 4).
Scheme 4. Application to the Synthesis of a Calcium
Antagonist on a Gram Scale
To investigate the reaction mechanism, radical trap
experiments were carried out (Scheme 5). Different amounts
To further investigate the scope of this reaction system,
different phosphonate esters were also tested (Scheme 3).
Scheme 5. Radical Trap Experiments
Scheme 3. Cross-Coupling of Aryl Halides with Different H-
Phosphonates
of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) were added
to the cross-coupling of bromobenzene with dimethyl
phosphonate under the standard reaction conditions. With
increasing amounts of TEMPO, the yield decreased accord-
ingly. When 2.0 equiv of TEMPO was added to the reaction
system, the cross-coupled product 3a was obtained in only 9%
yield. These experiments suggested that radicals may exist in
this reaction.
On the basis of those experimental results, a tentative
mechanism is proposed in Scheme 6. Aryl halide A is irradiated
Scheme 6. Tentative Mechanism
a
Method A for ArI: aryl iodide 1 (0.2 mmol), 2 (0.4 mmol), and t-
BuONa (0.4 mmol) in CH3CN (1.0 mL) irradiated by 405 nm light
at room temperature in a sealed quartz tube under an argon
b
atmosphere for 12 h. Isolated yields are shown. Method B for ArBr:
aryl bromide 1 (0.2 mmol), 2 (0.4 mmol), TBAI (0.5 equiv), and t-
BuONa (0.4 mmol) in CH3CN (1.0 mL) irradiated by UV light (254
nm) at room temperature in a sealed quartz tube under an argon
c
atmosphere for 18 h. Isolated yields are shown. DMF was used as the
solvent instead of CH3CN.
Diethyl and diisopropyl phosphonates and various substituted
diaryl phosphonates were successfully cross-coupled with aryl
halides. Diethyl phenylphosphonate (3t), diisopropyl phenyl-
phosphonate (3u), triphenylphosphine oxide (3v), phenyldi-p-
tolylphosphine oxide (3w), bis(4-methoxyphenyl)(phenyl)-
phosphine oxide (3x), and bis(4-fluorophenyl)(phenyl)-
phosphine oxide (3y) were obtained in good to high yields.
The method could also be applied to other substituted aryl
halides and heterocyclic halides to give the corresponding
products 3z−ac.
by light to form aryl free radical B and bromine free radical C
via homolytic cleavage of the C−X bond (path a). Phosphite D
tautomerizes with phosphonate E, which reacts with strong
base to form another tautomerization pair between anions F
and G. Then anion F or G is oxidized by bromine free radical
C via a single electron transfer (SET) process to generate
phosphonate free radical H, which cross-couples with aryl free
radical B to generate the product J. Alternatively, the aryl
C
DOI: 10.1021/acs.orglett.8b04081
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Experimental procedures, additional experimental data,
and compound characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zenghy@lzu.edu.cn.
*E-mail: cj.li@mcgill.ca.
ORCID
Huiying Zeng: 0000-0002-2535-111X
Chao-Jun Li: 0000-0002-3859-8824
Notes
The authors declare no competing financial interest.
(9) During the time of writing this article, a visible-light-promoted
transition-metal-free cross-coupling of heteroaryl halides with diary-
lphosphine oxides was reported. The substrates suffered from limited
scope of heteroaryl halides and diarylphosphine oxides. Aryl halide
substrates or dialkyl phosphonates were not successful under this
reaction system. See: Yuan, J.; To, W.-P.; Zhang, Z.-Y.; Yue, C.-D.;
Meng, S.; Chen, J.; Liu, Y.; Yu, G.-A.; Che, C.-M. Org. Lett. 2018, 20,
7816−7820.
(10) An iodide source was added to this reaction system for the
aromatic Finkelstein reaction. Upon UV irradiation, the aryl halides
(including Ar−Br and Ar−Cl) were exchanged for aryl iodide in situ
to increase the activity of the aryl halides. See refs 8k and 8n .
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ACKNOWLEDGMENTS
■
We thank the Recruitment Program of Global Experts (Short-
Term B to C.-J.L.), the Fundamental Research Funds for the
Central Universities (lzujbky-2018-62), the International Joint
Research Centre for Green Catalysis and Synthesis, Gansu
Provincial Sci. & Tech. Department (2016B01017,
18JR3RA284, and 18JR4RA003), and Lanzhou University for
support of our research. We also thank the Canada Research
Chair (Tier I) Foundation, the E.B. Eddy Endowment Fund,
the CFI, NSERC, and FQRNT (to C.-J.L). We thank Mr.
Dawei Cao in this group (Lanzhou University) for reproducing
the results presented for 3c, 3k, and 3s in Scheme 2 and 3ac in
Scheme 3.
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