A copper-catalyzed variant of the Michaelis-Arbuzov reaction

Article abstract of DOI:10.1002/cctc.201301029

As part of our studies on copper-catalyzed arylation of nucleophiles, we report on Michaelis-Arbuzov reactions with a novel catalytic system, featuring a copper(I) salt as precatalyst without any additional ligand. This procedure is an interesting alternative to the use of expensive and toxic transition metals (nickel, palladium) traditionally used as catalysts in Michaelis-Arbuzov reactions. Our approach allows the synthesis from triethylphosphite, diethyl aryl phosphonite, and diaryl ethylphosphinite of various aryl phosphonates, aryl phosphinates, and aryl phosphine oxides, respectively. These families of compounds are essential owing to their respective importance in bioorganic and medical chemistry, their applicability as flame retardants, and their usability in coordination chemistry and catalysis. Copper load of this! The first copper-catalyzed Michaelis-Arbuzov reactions are described. The methodology is ligand-free and allows the direct synthesis of various aryl phosphonates, aryl phosphinates, and aryl phosphine oxides from aryl iodides.

Full text of DOI:10.1002/cctc.201301029

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DOI: 10.1002/cctc.201301029
A Copper-Catalyzed Variant of the Michaelis–Arbuzov
Reaction
Jorge Ballester,[a] Jꢀrꢀmie Gatignol,[b] Guntram Schmidt,[a] Carole Alayrac,[b] Annie-
Claude Gaumont,*[b] and Marc Taillefer*[a]
As part of our studies on copper-catalyzed arylation of nucleo-
philes, we report on Michaelis–Arbuzov reactions with a novel
catalytic system, featuring a copper(I) salt as precatalyst with-
out any additional ligand. This procedure is an interesting al-
ternative to the use of expensive and toxic transition metals
(nickel, palladium) traditionally used as catalysts in Michaelis–
Arbuzov reactions. Our approach allows the synthesis from
triethylphosphite, diethyl aryl phosphonite, and diaryl ethyl-
phosphinite of various aryl phosphonates, aryl phosphinates,
and aryl phosphine oxides, respectively. These families of com-
pounds are essential owing to their respective importance in
bioorganic and medical chemistry, their applicability as flame
retardants, and their usability in coordination chemistry and
catalysis.
synthesis of the corresponding phosphonates and phosphi-
nates. There remained, however, large shortcomings in the
range of substrates and the alloy had to be employed stoichio-
metrically. The first catalytic Michaelis–Arbuzov reactions were
reported in 1970.[25] They allowed the conversion of further
substituted aryl and vinyl halides, but were dependent on the
usage of toxic nickel salt catalysts and high temperatures
(1608C). There were also sporadic reports on palladium cata-
lysts but these were limited to singular reactions.[26–28] Further
developments in Michaelis–Arbuzov reactions involving copper
suffered the disadvantages of dependence on stoichiometric
amounts of copper and harsh reaction conditions.[29–31]
As part of our studies on the copper-catalyzed arylation of
nucleophiles,[32] we report herein Michaelis–Arbuzov reactions
with a novel catalytic system that features a copper(I) salt as
precatalyst without any additional ligand. Our approach allows
the synthesis of various aryl phosphonates, aryl phosphinates,
and aryl phosphine oxides.[33]
The Michaelis–Arbuzov reaction, discovered by A. Michaelis in
1898[1] and explored soon thereafter by A. Arbuzov,[2–4] has
been widely used for the synthesis of various phosphonates,
phosphinates, phosphine oxides, and phosphines.[5–8] Nowa-
days, these compound families are essential owing to their im-
portance in bioorganic and medical chemistry,[9–12] their applic-
ability as flame retardants,[13–15] and their usability in coordina-
tion chemistry and catalysis,[16–19] respectively. The Michaelis–
Arbuzov protocol has been limited for a long time to reactions
between nucleophilic phosphites and electrophilic alkyl hal-
ides, resulting in the formation of the corresponding alkyl
phosphonates. Thus, the classical method did not allow con-
version of aryl halides into aryl phosphonates and derivatives,
which are valuable intermediates in organic synthesis[20,21] and
of great importance in polymer chemistry.[22,23] In 1967 Tavs
and Korte described the first Michaelis–Arbuzov reactions in-
volving a copper–tin alloy.[24] The range of possible substrates
was thus extended, enabling the use of aryl halides for the
Ligand-free copper(I) iodide was chosen as the catalyst for
the reactions and the reaction conditions were optimized by
using the model substrates iodobenzene and triethylphos-
phite. Several solvents were tested at reflux but no product
formation was observed (Table 1, entry 1) unless cesium car-
bonate was added to the system, which led to the formation
Table 1. Ligand-free copper-catalyzed Michaelis–Arbuzov reaction be-
tween phenyl iodide and triethylphosphite: parametric study.[a]
Entry Solvent (2 mL)
Base [equiv.]
Yield [%][b]
1
toluene, CH3CN, DMSO, EtOH, THF –
–
2
toluene
Cs2CO3 (1)
20
3
4
5
6
7
8
9
10
11
12
toluene
toluene
toluene
toluene
DMF
CH3CN
EtOH, THF, H2O, dioxane
toluene
toluene
Cs2CO3 (2)
Cs2CO3 (3)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
Cs2CO3 (4)
CsOH (4), K2CO3 (4)
Et3N (4), pyridine (4)
K3PO4 (4)
50
73
95, 92[c]
4[d]
[a] J. Ballester, G. Schmidt, Dr. M. Taillefer
CNRS, UMR 5253, Institut Charles Gerhardt Montpellier
ENSCM, 8, rue de l’Ecole Normale, 34296 Montpellier (France)
Fax: (+33)467-144-319
40
E-mail: marc.taillefer@enscm.fr
75, 72[c]
4–16
–
[b] J. Gatignol, Dr. C. Alayrac, Prof. A.-C. Gaumont
Laboratoire de Chimie Molꢀculaire et Thio-organique
CNRS, UMR 6507, INC3M FR3038,
–
15
ENSICAEN & Universitꢀ de Caen Basse-Normandie
6 Boulevard du Marꢀchal Juin, 14050 Caen (France)
Fax: (+33)231-452-877
toluene
[a] Reaction performed with 1 equiv. of PhI, 1 equiv. of P(OEt)3, 10 mol%
of CuI (99.9999%, Alfa), and 0–4 equiv. of base in a sealed tube at reflux.
[b] GC yield determined with 1,3-dimethoxybenzene as standard. [c] Iso-
lated yield. [d] Reaction performed at 1008C.
E-mail: annie-claude.gaumont@ensicaen.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cctc.201301029.
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of small amounts of phenyl phosphonate 1a (entry 2). Increas-
ing the quantity of cesium carbonate to 4 equivalents with tol-
uene as the solvent under reflux conditions led to quantitative
product formation (entries 3–5). This phosphonylation was
straightforward and only traces of triethylphosphate as the oxi-
dation side product were found. Lowering the reaction tem-
perature to 1008C resulted in very low yields (entry 6), even in
the presence of additional ligands such as N,N’-dimethylethyle-
nediamine, phenanthroline, proline, or diketones.
Table 2. Synthesis of aryl phosphonates 1 by the ligand-free copper-cata-
lyzed Michaelis–Arbuzov reaction between various aryl iodides and
triethylphosphite.[a]
Entry
1
ArI
ArP(O)(OEt)2
Yield [%][b]
92, 72[c]
Replacing toluene by DMF resulted in only moderate yields
(Table 1, entry 7). By changing the solvent to acetonitrile, good
yields were obtained despite the low reflux temperature
(entry 8). With all other solvents, no satisfying product forma-
tion could be achieved. We also studied the influence of base
on the reaction. Neither organic (triethylamine, pyridine) nor
inorganic bases (CsOH, K2CO3) promote the reaction (entries 10
and 11), except K3PO4 (entry 12), albeit with a poor yield of
15% compared to the reaction with Cs2CO3. Finally, under the
best conditions as described in entry 5, no reaction was ob-
served if bromobenzene was used in place of iodobenzene.
To investigate the functional group tolerance of our catalytic
system, we tested several differently substituted aryl iodides
under the optimized reaction conditions (Table 1, entry 5).
Good yields for the phosphonylation are obtained with elec-
tron-donating substituents (p-OMe, m/p-Me, Table 2, entries 2–
5). Electron-withdrawing substituents in para positions, such as
À(CO)Me, ÀNO2, ÀCN and ÀPh enable product formation in
very high yields (Table 2, entries 7–10). The strongly activated
p-nitrophenyl iodide also gives high yields if the reaction is
conducted at lower temperatures (entry 7). The reaction from
iodohalobenzenes is chemoselective with respect to a singular
iodo substitution (entries 11–14), which is also the case if
2 equivalents of P(OEt)3 are employed in the reaction. This se-
lectivity may allow further functionalizations of the remaining
halide position and, in the case of phenol derivative 1 f, of the
remaining hydroxide function (Table 2, entry 6). If the ortho po-
sition of the aryl iodide was substituted with a methyl group,
we did not observe any reaction (entry 15). Finally, as for the
bromobenzene, the very low reactivity of aryl bromides or aryl
chlorides, substituted by electron withdrawing or donating
groups, did not allow the formation of the expected phospho-
rus products.
PhI
1a
1b
1c
2
3
78, –[d]
74
4
5
1d
1e
63
71
6
1 f
1g
1h
1i
84
7
90,[d] 27[e]
8
80
9
83, –[d]
78
10
11
12
13
14
15
1j
1k
1l
72
76
1m
1n
1o
80
81
0
[a] Reaction performed with 1 equiv. of ArI, 1 equiv. of P(OEt)3, 10 mol%
of CuI (99.9999%, Alfa), and 4 equiv. of base (Cs2CO3, 99.995%, Acros) in
toluene in a sealed tube at reflux. [b] Isolated yield. [c] Reaction per-
formed in CH3CN. [d] Reaction performed at 1008C. [e] Reaction per-
formed at 908C.
We then tested our conditions with other phosphorus deriv-
atives. Thus, a phosphinylation of substituted aryl iodides with
PhP(OEt)2 was tested under the reaction conditions developed
for the phosphonylation (Table 1, entry 5). The reaction pro-
ceeded very smoothly with the aryl iodide with an electron
withdrawing group (p-CN, Table 3, entry 6) and counterparts
with electron donating groups (p-OCH3, m/p-CH3, entries 2–4)
proceeded equally well. As was already the case for the syn-
thesis of the aryl phosphonates, the reaction from fluoro-,
chloro-, bromo-, or iodobenzene was fully chemoselective,
leading efficiently to the corresponding halophosphinates (en-
tries 7–10). Again, the halophosphinates and the hydroxyphos-
phinate (entry 5) possessed functional groups accessible to fur-
ther functionalization. Most of the synthesized aryl phosphi-
nates were previously unknown to the chemical literature and
their full characterizations have been provided in the Support-
ing Information. Notably, the formation of the phosphorus de-
rivatives was not observed from o-iodotoluene, p-bromo- or p-
chlorotoluene, or p-bromo- or p-chlorobenzonitrile.
Finally, we applied our catalytic system to the synthesis of
phosphine oxides from aryl iodides and Ph2POEt. By using the
same reaction conditions as outlined before (Table 1, entry 5),
we synthesized Ph3PO in very good yields (Table 4, entry 1).
Furthermore, we also obtained the corresponding phosphine
oxides from aryl iodides with electron donating substituents
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Table 3. Synthesis of aryl phosphinates 2 by the ligand-free copper-cata-
lyzed Michaelis–Arbuzov reaction between various aryl iodides and dieth-
yl phenyl phosphonite.[a]
Table 4. Synthesis of phosphine oxides 3 by ligand-free copper-catalyzed
Michaelis–Arbuzov reaction between aryl iodides and ethyl diphenyl
phosphinite.[a]
Entry
1
ArI
ArPhP(O)OEt
Yield [%][b]
87
Entry
1
ArI
ArPh2P(O)
Yield [%][b]
81[c]
PhI
2a
2b
2c
PhI
3a
3b
3c
3i
2
3
87
71
2
3
4
5
79
71
81
62
4
2d
69
3j
5
2 f
2i
78
82
77
85
90
82
[a] Reaction performed with 1 equiv. of ArI, 1 equiv. of Ph2POEt, 10 mol%
of CuI (99.9999%, Alfa), and 4 equiv of base (Cs2CO3, 99.995%, Acros) in
toluene in a sealed tube at reflux. [b] Yield determined by 31P NMR
(Ph3PO as external standard). [c] Isolated yield.
6
7
2k
2l
alyzed Michaelis–Arbuzov reactions,[8,34] we identified two pos-
sible catalytic pathways (A and B, Figure 1).
8
For cycle A, the first step would be the formation of a cop-
per(I) complex A1 from CuI and 2 equivalents of P(OEt)3. This
would be followed by an oxidative addition of the iodoben-
zene to yield the copper(III) complex A2. A quasiphosphonium
salt could then be liberated by reductive elimination to pro-
duce the copper(I) complex A3, which may be stabilized by an
addition of P(OEt)3. The quasiphosphonium salt is a well-
known intermediate of the Michaelis–Arbuzov reactions that,
by intramolecular rearrangement, would decompose into ethyl
iodide and the desired phosphonate. In the cycle B, the same
catalytically active species B1 (equivalent to A1) would first un-
dergo a rearrangement (nucleophilic attack of the ethoxy by
the iodide), thus enabling the activation of the aryl iodide (oxi-
dative addition) to give a new copper(III) intermediate B2,
9
2m
2n
10
[a] Reaction performed with 1 equiv. of ArI, 1 equiv. of PhP(OEt)2,
10 mol% of CuI (99.9999%, Alfa), and 4 equiv. of base (Cs2CO3, 99.995%,
Acros) in toluene in a sealed tube at reflux. [b] Isolated yield.
(p-OMe, p-Me, entries 2–3) and electron withdrawing substitu-
ents (p-CN, p-Ph, entries 4–5) in good yields. Aryl bromides or
chlorides were unreactive in these conditions.
We investigated the possibility
of in situ reductions of the phos-
phine oxides by using Si2Cl6. The
liquid phase of the above reac-
tion was thus subjected to
a treatment with 1.5 equivalents
of Si2Cl6. We confirmed the
quantitative formation of the
phosphines by NMR analysis,
with coaddition of authentic
samples as internal standards.
In recognition of the proposed
catalytic cycles for the nickel cat- Figure 1. Possible mechanisms.
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We gratefully acknowledge financial support from the Agence
Nationale de la Recherche, project no. ANR-09-CP2D-13-Phoscat,
the Ministꢁre de la Recherche et des Nouvelles Technologies,
CNRS (Centre National de la Recherche Scientifique), the Rꢀgion
Basse-Normandie and the European Union (FEDER Funds). COST
ACTION CM0802 “PHOSCINET” is also acknowledged for support.
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Keywords: arylation
· copper · homogeneous catalysis ·
synthetic methods · phosphorus
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Received: December 4, 2013
Published online on && &&, 0000
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Copper load of this! The first copper-
catalyzed Michaelis–Arbuzov reactions
are described. The methodology is
ligand-free and allows the direct synthe-
sis of various aryl phosphonates, aryl
phosphinates, and aryl phosphine
oxides from aryl iodides.
J. Ballester, J. Gatignol, G. Schmidt,
C. Alayrac, A.-C. Gaumont,* M. Taillefer*
&& – &&
A Copper-Catalyzed Variant of the
Michaelis–Arbuzov Reaction
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemCatChem 0000, 00, 1 – 4
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