Proline/pipecolinic acid-promoted copper-catalyzed P-arylation

Article abstract of DOI:10.1021/jo060492j

We have developed a convenient and efficient approach for P-arylation of organophosphorus compounds containing P-H. Using commercially available and inexpensive proline and pipecolinic acid as the ligands greatly improved the efficiency of the coupling reactions, so the method can provide an entry to arylphosphonates, arylphosphinates and arylphosphine oxides.

Full text of DOI:10.1021/jo060492j

and its derivatives,2f ethylene glycol,5a diethylsalicylamide,5b
amino acids,6 oxime-type and Schiff base ligands,7 thiophene-
2-carboxylate,8 bidentate phosphines,9 diphosphinidenecy-
clobutene,10 and diphenyl pyrrolidine-2-phosphonate11 for N-
arylation of amines/amides and 1-naphthoic acid,2a 2,2,6,6-
tetramethylheptane-3,5-dione,2b phosphazene P4-t-Bu base,2c
N,N-dimethylglycine,2d 8-hydroxyquinoline,2e and salicylal-
doxime (Salox)2g for O-arylation of substituted phenol or
alcohol. Although arylphosphonates12 and phosphane oxides13
are of practical application, to the best of our knowledge,
examples of copper-mediated C-P bond formation are rare.14
Since proline is an efficient ligand for the copper-catalyzed
Ullmann coupling reactions,6i,15 here we report it and its
analogue pipecolinic acid as efficient bidentate ligands for the
formation of copper-catalyzed C-P bonds.
Proline/Pipecolinic Acid-Promoted
Copper-Catalyzed P-Arylation
Cheng Huang,† Xu Tang,† Hua Fu,*,† Yuyang Jiang,†,‡ and
Yufen Zhao†
Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua UniVersity, Beijing 100084, P. R. China,
and Key Laboratory of Chemical Biology, Guangdong ProVince,
Graduate School of Shenzhen, Tsinghua UniVersity, Shenzhen
518057, P. R. China
fuhua@mail.tsinghua.edu.cn
We initially optimized the catalysis conditions, including
copper source, base, solvent, amount of catalyst, and ligand
(proline or pipecolinic acid), to achieve good coupling yields
of aryl halides with organophosphorus compounds containing
P-H. The experimental results showed the catalyst system using
CuI as the catalyst, Cs2CO3 or DMAP as the base, and toluene
or DMF as the solvent could provide higher coupling yields
(see Table 1 for experimental details). However, no P-arylation
products were obtained when no catalyst or ligand was added
to the reaction system, which indicated that CuI/L could greatly
promote the reactivity of the substrates.
ReceiVed March 7, 2006
We have developed a convenient and efficient approach for
P-arylation of organophosphorus compounds containing
P-H. Using commercially available and inexpensive proline
and pipecolinic acid as the ligands greatly improved the
efficiency of the coupling reactions, so the method can
provide an entry to arylphosphonates, arylphosphinates and
arylphosphine oxides.
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Copper-catalyzed Ullmann coupling reactions have recently
attracted much attention, including N-arylation of amines/
amides1 and O-arylation of substituted phenol2 or alcohol.3 This
progress relied on the utilization of some special bidentate
additives, for example, aliphatic diamines,4 1,10-phenanthroline
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* To whom correspondence should be addressed. Fax: (+86) 10-62781695.
† Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology.
‡ Key Laboratory of Chemical Biology.
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10.1021/jo060492j CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/27/2006
5020
J. Org. Chem. 2006, 71, 5020-5022

TABLE 1. Proline- or Pipecolinic Acid-Promoted Copper-Catalyzed Coupling of Aryl Halides and Organophosphorus Compounds Containing
P-Ha
a Reaction conditions: 1 (1 mmol), 2 (1.1 mmol), CuI (10 mol %). b Proline. c Pipecolinic acid (40 mol %), base (2 mmol), and solvent (3 mL) at 110
°C under N2. d Isolated yield (average of two runs). e CuI (15 mol %), ligand (40 mol %) for entries 15 and 16. f 1 (3 mmol), 2 (1 mmol), DMAP (N,N-
dimethylaminopyridine) (4 mmol). g After reaction of 1 (1.2 mmol) with KI (1.2 mmol) for 24 h in the presence of CuI (20 mol %) and proline (40 mol %)
at 110 °C, the solution was cooled to room temperature, 2 (1 mmol) was added to the solution, add the solution was warmed to 110 °C and stirred for 36
h.
J. Org. Chem, Vol. 71, No. 13, 2006 5021

proline,or pipecolinic acid were added to a flask with Cs2CO3 or
DMAP and toluene or DMP (see Table 1 for the amounts of all
chemicals and solvents used), the mixture was stirred for 30 min
at room temperature under nitrogen atmosphere, and CuI was added
to the flask. The flask was immersed in an oil bath, and the reaction
mixture was stirred at the temperature and time indicated in Table
1. The reaction mixture was then allowed to cool to room
temperature, diluted with 10 mL of ethyl ether, and filtered, and
the filtrate was concentrated under vacuum. Purification by column
chromatography on silica gel (hexane-chloroform 4:1 to 100%
chloroform) afforded the desired pure product.
Proline-promoted copper-catalyzed coupling reactions of aryl
halides and organophosphorus compounds containing P-H were
carried out. As shown in Table 1, aryl iodides gave the good to
excellent yields. Unfortunately, aryl bromides were weak
substrates, and only a low yield of product was obtained even
if the reaction time was elongated (entry 2). The coupling
reactions of 1-bromo-4-iodobenzene with diethyl phosphite
(entry 8) and diphenylphospine oxide (entry 11) yielded the
target products 3e and 3h containing bromine on the benzene
ring, respectively, which also showed that aryl iodides were
much more reactive than aryl bromides. However, reaction of
aryl bromide with 2 equiv of KI for 24 h under our catalytic
conditions (see Table 1) provided the corresponding aryl
iodide,16 and when diethyl phosphite was added to the resulting
solution, the desired product 3c was obtained in a good yield
(entry 17), which is comparable with the yields in the reaction
of iodobenzene with diethyl phosphite (entry 5). In general, the
dialkyl phosphites and ethyl phenylphosphinate displayed higher
reactivity than diphenylphosphine oxides and hypophosphite,
and the former could provide higher yields in a short amount
of time. The aryl iodides containing electron-withdrawing groups
usually provided higher yields (compare entries 5, 7 and 8, 12,
13, and 14). Unexpectedly, 4-iodotoluene gave a higher yield
than phenyl iodide and 1-bromo-4-iodobenzene (compare entries
9-11), and 1-iodo-4-nitrobenzene provided product 3b in only
68% yield with some side products appearing. Reaction of
phenyl iodide with 1.1 equiv of ammonium hypophosphite led
to the functionalized monoarylphosphinic acid 3l (entry 15),
and disubstituted product 3m was obtained in 39% yield when
3 equiv of phenyl iodide relative to ammonium hypophosphite
was added to the reaction system (entry 16). The effect of bases
was investigated, and the experimental results showed that Cs2-
CO3 was most effective in the coupling reactions.
We also attempted pipecolinic acid-copper-catalyzed cou-
pling of aryl iodides with organophosphorus compounds con-
taining P-H under catalysis conditions similar to those shown
in Table 1, and the corresponding target products were obtained
in yields similar to those for proline-promoted copper-catalyzed
coupling reactions. All of the above results indicated that the
coupling reactions of aryl iodides with the organophosphorus
compounds provided an approach to arylphosphonates, arylphos-
phinates, and arylphosphine oxides.
A commercially available and inexpensive proline- or pipe-
colinic acid-promoted copper-catalyst system has been devel-
oped for the formation of arylphosphonates, arylphosphinates,
and arylphosphine oxides through P-arylation of organophos-
phorus compounds containing P-H, and the method can be of
practical application for the construction of biological molecules
and catalytic ligands containing phosphorus.
General Procedure for the Preparation of Compounds 3l-
m. Aryl iodide, ammonium hypophosphite, and proline or pipe-
colinic acid were added to a flask with DMAP in DMF (3 mL),
the mixture was stirred for 30 min at room temperature under
nitrogen atmosphere, and CuI was added to the flask (see Table 1
for the amounts of all chemicals used). The flask was immersed in
an oil bath, and the reaction mixture was stirred at 110 °C for the
time indicated in Table 1. The reaction mixture was then allowed
to cool to room temperature, evaporated, diluted with 10 mL of
water, washed with Et2O, and acidified with KHSO4 (1 M, saturated
with NaCl). The resulting aqueous phase was extracted with acetate
(3 mL × 4). The organic phase was combined, dried with MgSO4,
filtrated, and concentrated under vacuum to give the pure product.
Diisopropyl phenylphosphonate (3a):17 oil; 31P NMR (CDCl3,
1
121 MHz) δ 17.07; H NMR (CDCl3, 300 MHz) δ 7.83 (t, J )
7.58 Hz, 1H), 7.50 (d, J ) 7.89 Hz, 2H), 7.26-7.33 (m, 2H), 3.92-
3.95 (m, 2H), 1.36 (d, J ) 7.56 Hz, 12H); 13C NMR (CDCl3, 75
MHz) δ 136.3 (J ) 5.7 Hz), 134.0 (J ) 159 Hz), 132.1 (J ) 2.9
Hz), 129.2 (J ) 2.2 Hz), 71.3 (J ) 5.7 Hz), 24.4 (J ) 7.9 Hz);
HR-EI-MS M+ m/z calcd for C12H19O3P 242.1072, found 242.1077.
Phenylphosphinic acid (3l):18 oil; 31P NMR (CDCl3, 121 MHz)
1
δ 21.52; H NMR (CDCl3, 300 MHz) δ 11.28 (br, s, 1H), 7.75-
7.80 (m, 2H), 7.59 (d, J ) 7.56 Hz, 2H), 7.44-7.45 (m, 1H), 6.16
(d, J ) 566 Hz); 13C NMR (CDCl3, 75 MHz) δ 133.0 (J ) 3.7
Hz), 132.0 (J ) 3.6 Hz), 129.7 (J ) 185.7 Hz), 128.4 (J ) 13.6
Hz); HR-ESI-MS [M + H]+ m/z calcd for C6H8O2P 143.0262,
found 143.0256.
Acknowledgment. This work was supported by the Excel-
lent Dissertation Foundation of the Chinese Ministry of Educa-
tion (No. 200222), Program for New Century Excellent Talents
in University (NCET) in China, the Excellent Young Teacher
Program of MOE, P. R. C., the National Natural Science
Foundation of China (Grant No. 20472042), and the Key Subject
Foundation from Beijing Department of Education
(XK100030514).
Supporting Information Available: Gerneral experimental
procedures, characterization data and 31P, 1H, and 13C NMR spectra
for compounds 3a-m. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO060492J
Experimental Section
General Procedure for the Preparation of Compounds 3a-
k. Aryl halide, organophosphorus compound containing P-H, and
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5022 J. Org. Chem., Vol. 71, No. 13, 2006