Synthesis of acylphosphonates by a palladium-catalyzed phosphonocarbonylation reaction of aryl iodides with phosphites

Article abstract of DOI:10.1002/asia.201403260

Acylphosphonates are conveniently synthesized from aryl iodides by a palladium-catalyzed reaction with dialkyl phosphites under an atmospheric pressure of carbon monoxide. The reaction demonstrates the first example of the use of phosphorus nucleophiles in related metal-catalyzed carbonylation reactions.

Full text of DOI:10.1002/asia.201403260

DOI: 10.1002/asia.201403260
Communication
Homogeneous Catalysis
Synthesis of Acylphosphonates by a Palladium-Catalyzed
Phosphonocarbonylation Reaction of Aryl Iodides with Phosphites
Yusuke Masuda, Naoki Ishida, and Masahiro Murakami*[a]
Table 1. Phosphonocarbonylation of phenyl iodide (1a)[a]
Abstract: Acylphosphonates are conveniently synthesized
from aryl iodides by a palladium-catalyzed reaction with
dialkyl phosphites under an atmospheric pressure of
carbon monoxide. The reaction demonstrates the first ex-
ample of the use of phosphorus nucleophiles in related
metal-catalyzed carbonylation reactions.
Carbon monoxide is readily available from industrial sources
and one of the most inexpensive C1 feedstock. It is generated
along with the production of hydrogen gas from fossil fuels,
Entry
Ligand
Yield [%][b]
and it is becoming even more desired to utilize carbon monox-
ide as the carbonyl source. On the other hand, numerous aryl
halides are available from commercial sources or from parent
arenes by conventional halogenation methods. Thus, a diverse
range of transition metal-catalyzed carbonylation reactions of
aryl halides have been developed, and are utilized for the pro-
duction of various carbonyl compounds.[1,2] For example, car-
boxylic esters are synthesized by a palladium-catalyzed alkoxy-
carbonylation reaction of aryl halides with alcohols under an
atmosphere of carbon monoxide.[3] The carbonylation reaction
has been extended to the synthesis of amides,[4] aldehydes,[5]
and related acid derivatives.[1,6–10] Yet, there have been no ex-
amples reported for the use of phosphorus nucleophiles in re-
lated carbonylation reactions.
2a
3a
1
2
3
4
5
6
7
PPh3
P(tBu)3
tBuXPhos
DPPB
DPPF
nd
nd
nd
nd
<5
nd
8
nd
nd
nd
nd
nd
nd
<5
11
BINAP
DPEPHOS
XANTPHOS
XANTPHOS
8
9[c]
60
96(84[d]
)
<5
[a] Reaction conditions: 1a (0.20 mmol), diethyl phosphite (0.24 mmol,
1.2 equiv), Pd2(dba)3·CHCl3 (5.0 mmol; 5 mol% Pd), ligand (12 mol% for
monophosphines and 6 mol% for diphosphines), CO (balloon), (iPr)2NEt
(2 equiv), THF (1 mL), RT, 16 h. [b] Determined by 1H NMR analysis of the
crude reaction mixture. [c] 1 equiv of (iPr)2NEt was used. [d] Yield of iso-
lated product. tBuXPhos=2-di-(tert-butyl)phosphino-2’4’6’-tri-(iso-propyl)-
biphenyl, DPPB=1,4-bis(diphenylphosphino)butane, DPPF=1,1’-bis(di-
phenylphosphino)ferrocene, BINAP=2,2’-bis(diphenylphosphino)-1,1’-bi-
naphthyl, DPEPHOS=bis[2-(diphenylphosphino)phenyl] ether, XANT-
PHOS=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.
An acylphosphonate skeleton is a key structural motif com-
monly found in inhibitors of benzoylformate decarboxylase in
an acid form,[11,12] photoactive bioisosters of phosphotyrosine
residues,[13] and photoinitiators of polymerization of alkenes.[14]
Acylphosphonates also act as the intermediates for enantiose-
lective syntheses of various a-functionalized phosphonates.[15]
Conventionally, they are synthesized by a reaction of acid
chlorides with trialkylphosphites (Michaelis–Arbuzov reac-
tion)[16] or by an addition reaction of dialkyl phosphites to alde-
hydes followed by oxidation.[17] We report herein an alternative
method to synthesize acylphosphonate esters from aryl io-
dides, carbon monoxide, and dialkyl phosphites by a palladi-
um-catalyzed phosphonocarbonylation reaction.
Phenyl iodide (1a) was treated with diethyl phosphite under
an atmospheric pressure of carbon monoxide in the presence
of Pd/phosphine catalysts. The results using various phosphine
ligands are listed in Table 1. Monodentate phosphines such as
PPh3 and P(tBu)3 failed to promote the reaction (Table 1, en-
tries 1–3). Whereas typical diphosphine ligands like BINAP gave
almost no acylphosphonate 2a (Table 1, entries 4–6), XANT-
PHOS, a diphosphine with a large bite angle,[18] was uniquely
effective for the phosphonocarbonylation reaction (Table 1,
entry 8). Diphosphonated product 3a was formed as the by-
product when two equivalents of (iPr)2NEt was used as the
base. Interestingly, the use of one equivalent of (iPr)2NEt af-
forded 2a selectively (Table 1, entry 9). Whereas the resulting
2a is prone to hydrolysis upon treatment with standard silica
[a] Y. Masuda, Dr. N. Ishida, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University
Katsura, Kyoto 615-8510 (Japan)
E-mail: murakami@sbchem.kyoto-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/asia.201403260.
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palladium–phosphonate complex 6 was not observed. Instead,
a mixture of acyl phosphonate 2a (47% yield) and decarbony-
lated phosphonate 7 (39% yield) was directly produced.[21,22]
On the other hand, an analogous reaction of 5 under an at-
mosphere of carbon monoxide suppressed the formation of 7
and selectively afforded 2a in 82% yield. These results suggest
that the retro-insertion of carbon monoxide (reversion from 5
to 4) takes place competitively with exchange of the iodide
ligand with phosphite (5 to 6). Once the palladium–phospho-
nate complex 6 is generated, reductive elimination immediate-
ly follows to afford 2a.
A wide variety of aryl iodides were successfully converted
into the corresponding acylphosphonates under the optimized
reaction conditions (Table 2).[23] Whereas 4-tolyl iodide afforded
Table 2. Scope of aryl iodides.[a]
Scheme 1. Plausible mechanism.
gel, the use of diol-modified silica gel allowed chromatograph-
ic isolation of 2a in 84% yield.
We propose a mechanism shown in Scheme 1 for the forma-
tion of acylphosphonate 2a from 1a. Initially, oxidative addi-
tion of 1a to palladium(0) generates phenylpalladium iodide 4.
Then, carbon monoxide inserts into the carbon–palladium
bond to produce acylpalladium species 5. The iodo ligand is
exchanged with a phosphonate anion to furnish phosphonate
complex 6, which subsequently undergoes reductive elimina-
tion to give acylphosphonate 2a with regeneration of the pal-
ladium(0) catalyst. The diphosphonated product 3a is formed
by a base-mediated nucleophilic addition reaction of diethyl
phosphite to 2a followed by rearrangement.[19]
Notably, the mechanistic scheme proposed above could be
traced step-by-step by the corresponding stoichiometric reac-
tions (Scheme 2). Initially, the phenylpalladium complex 4 was
[a] Reaction conditions: aryl iodide
1 (0.20 mmol), diethyl phosphite
(0.24 mmol; 1.2 equiv), (iPr)2NEt (0.20 mmol; 1 equiv), Pd2(dba)3·CHCl3
(5.0 mmol; 5 mol% Pd), XANTPHOS (0.012 mmol; 6 mol%), THF (1.0 mL),
RT, 16 h. Isolated yields after flash-column chromatography on diol-modi-
fied silica gel were shown. [b] 408C. [c] 608C.
acylphosphonate 2b (89%), 2-tolyl iodide produced a mixture
of acylphosphonate and arylphosphonate (the product without
incorporation of CO). The reaction of 4-(N,N-dimethylamino)-
phenyl iodide required heating at 608C. Although the reaction
of 4-acetylphenyl iodide suffered from the concomitant forma-
tion of the corresponding arylphosphonate, the acetal-protect-
ed substrate efficiently incorporated CO to produce acyl-
phosphonate 2g (80%). A bromo group remained intact under
the reaction conditions. Alkenyl and alkynyl groups, which are
potentially liable to hydrophosphonation, were tolerated (2h–
Scheme 2. Stoichiometric studies.
prepared from Pd2(dba)3·CHCl3 (dba=1,5-diphenyl-1,4-penta-
dien-3-one), XANTPHOS (1 equiv), and 1a (1 equiv) according
to the reported method.[20] Treatment of a CD2Cl2 solution of 4
with carbon monoxide gave rise to benzoylpalladium iodide 5
in quantitative yield, as previously reported.[8] When the ben-
zoylpalladium complex 5 was treated with diethyl phosphite at
room temperature under a nitrogen atmosphere, the expected
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Table 3. Scope of phosphites.[a]
Keywords: carbonylation
·
homogeneous catalysis
·
palladium · phosphorus · synthetic methods
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[a] Reaction conditions: aryl iodide (1a, 0.20 mmol), PH (0.24 mmol;
1.2 equiv), (iPr)2NEt (0.20 mmol; 1 equiv), Pd2(dba)3·CHCl3 (5.0 mmol;
5 mol% Pd), XANTPHOS (0.012 mmol; 6 mol%), THF (1.0 mL), RT, 16 h. Iso-
lated yields after flash-column chromatography on diol-modified silica gel
were shown. [b] Isolated by GPC. [c] 40 h.
k). Even heteroaromatics such as thiophene and indole could
be incorporated into the acylphosphonates (2l, m).
The reaction scope of phosphites was also examined
(Table 3). n-Butyl and iso-propyl esters could be employed in
place of ethyl esters. Ethyl phenylphosphinate efficiently react-
ed to give 2p in 84% yield. However, the reaction with di-
phenyl phosphine oxide failed to incorporate CO, and triphenyl
phosphine oxide was formed as the major product.
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In summary, we have described the palladium-catalyzed
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method of acylphosphonates. The reaction demonstrates the
first example of the use of phosphorus nucleophiles in the
metal-catalyzed carbonylation reactions.
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Experimental Section
To an oven-dried flask equipped with a stirrer bar was added
Pd2(dba)3·CHCl3 (5.2 mg, 5.0 mmol) and XANTPHOS (6.9 mg,
12 mmol). The flask was capped with a rubber septum, evacuated
and refilled with argon three times. Dry THF (1 mL) was added by
syringe. After being stirred at room temperature for 1 h, the reac-
tion mixture was cooled to À788C. Then, phenyl iodide (1a,
40.8 mg, 0.20 mmol), diethyl phosphite (33.1 mg, 0.24 mmol), and
(iPr)2NEt (34.8 mL, 0.20 mmol) were added. The reaction mixture
was evacuated and refilled with carbon monoxide three times.
After being stirred at room temperature for 16 h, the resulting mix-
ture was passed through a pad of Celite and eluted with diethyl
ether. The filtrate was concentrated under reduced pressure. The
residue was purified by flash column chromatography on diol-
modified silica gel MB 100-40/75 (FUJI SILYSIA) (eluent: hexane/
ethyl acetate=3:1) to give 2a as colorless oil (40.4 mg, 0.17 mmol,
84%).
Acknowledgements
This work was supported in part by a Grant-in-Aid for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis”, a Grant-in-Aid for Scientific
Research (B) from MEXT, and the ACT-C program of the JST.
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XANTPHOS complex under an argon atmosphere. For palladium-cata-
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[23] Phenyl bromide and triflate failed to undergo the phosphonocarbonyla-
tion reaction at room temperature, probably because their oxidation
addition was slower. A mixture of 2a, 3a, and 7 was obtained when
phenyl bromide was reacted at 608C.
[20] V. V. Grushin, W. J. Marshall, J. Am. Chem. Soc. 2006, 128, 12644–12645.
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Received: November 4, 2014
[22] Although decarbonylation of 2a is also conceivable for the formation
of 7, no reaction took place when 2a was treated with the palladium-
Published online on && &&, 0000
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COMMUNICATION
&
Homogeneous Catalysis
Yusuke Masuda, Naoki Ishida,
Masahiro Murakami*
CO Confidential: Acylphosphonates are
conveniently synthesized from aryl io-
dides by a palladium-catalyzed reaction
with dialkyl phosphites under an atmos-
pheric pressure of carbon monoxide.
The reaction demonstrates the first ex-
ample of the use of phosphorus nucleo-
philes in analogous metal-catalyzed car-
bonylation reactions.
&& – &&
Synthesis of Acylphosphonates by
a Palladium-Catalyzed
Phosphonocarbonylation Reaction of
Aryl Iodides with Phosphites
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