Copper-Mediated Formation of Aryl, Heteroaryl, Vinyl and Alkynyl Difluoromethylphosphonates: A General Approach to Fluorinated Phosphate Mimics

Article abstract of DOI:10.1002/anie.201507130

A general and efficient access to aryl, heteroaryl, vinyl and alkynyl difluoromethylphosphonates is described. The developed methodology using TMSCF₂PO(OEt)₂, iodonium salts and a copper salt provided a straightforward manifold to re

Full text of DOI:10.1002/anie.201507130

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International Edition: DOI: 10.1002/anie.201507130
German Edition: DOI: 10.1002/ange.201507130
Synthetic Methods
Copper-Mediated Formation of Aryl, Heteroaryl, Vinyl and Alkynyl
Difluoromethylphosphonates: A General Approach to Fluorinated
Phosphate Mimics
Maria V. Ivanova, Alexandre Bayle, Tatiana Besset, Thomas Poisson,* and Xavier Pannecoucke
Abstract: A general and efficient access to aryl, heteroaryl,
vinyl and alkynyl difluoromethylphosphonates is described.
The developed methodology using TMSCF2PO(OEt)2, iodo-
nium salts and a copper salt provided a straightforward
manifold to reach these highly relevant products. The reaction
proved to be highly functional group tolerant and proceeded
under mild conditions, giving the corresponding products in
good to excellent yields. This method represents the first
general synthetic route to this important class of fluorinated
scaffolds, which are well-recognized as in vivo stable phos-
phate surrogates.
Figure 1. Biorelevant compounds bearing a difluoromethylphosphinic
acid motif.
O
ver the last years, the demand of fluorinated molecules
lene residue provides to the phosphinic derivative a similar
pKa as the corresponding phosphonic acid.
has impressively increased. Indeed, the unique features of the
fluorine atom provide molecule-specific physical and biolog-
ical properties.[1] In particular, the propensity of the fluorine
atom or fluorinated groups to alter the lipophilicity, the
bioavailabilty and/or the metabolic stability of a molecule
afford it a pivotal role in the discovery of new pharmaceut-
icals.[2] Hence, the development of new methodologies to
access fluorinated molecules or building blocks has fascinated
the organic chemist community. While much efforts have
been devoted to the introduction of the fluorine atom or the
CF3 group,[3] the introduction of functionalized difluorome-
thylated residues has been far less explored.[4] This statement
is in sharp contrast with the high interest of the difluoro-
methyl motif, which can act as a remarkable bioisostere of an
oxygen atom or a carbonyl group, for instance. Among these
fluorinated groups, the difluoromethylphosphonate residue
(CF2PO(OR)2) is extremely appealing. Indeed, the CF2PO-
(OR)2 group can be considered as an in vivo stable surrogate
These difluoromethylated phosphonate-containing mole-
cules are usually obtained through the fluorination of the
corresponding keto- or methyl-phosphonate derivatives[6] or
through the introduction of the CF2PO(OR)2 residue. This
latter approach mainly relied on the Cu-mediated reaction of
metalated CF2PO(OR)2 derivatives with halogenated alke-
nes,[7a] alkynes,[7b,c] arenes bearing a coordinating group
(CG),[7d–f] or aryl diazonium salts.[7g] However, no general
method has emerged from these interesting reports and the
depicted methodologies remained restricted to a well-defined
class of substrates. Quite recently, the transition metal-
catalyzed or -promoted cross-coupling reactions with boronic
acids have been independently reported by Zhang[8a] and
Qing.[8b] In addition to these methods, this key motif has been
introduced through the copper-mediated oxidative coupling
of terminal alkynes with TMSCF2PO(OR)2[9] and the addition
of the difluoromethylphosphonyl radical to heteroarenes.[10] It
should be noted that these methods usually required the use
of moisture- and air-sensitive organometallic reagents, fine-
tuned coupling partners, or harsh reaction conditions
(Scheme 1). In this context, we aimed at offering a general
and straightforward method to access a wide range of
difluoromethylphosphonate derivatives under mild reaction
conditions. For this purpose, we envisioned the Cu-mediated
reaction of TMSCF2PO(OEt)2 (1) with various hypervalent
iodine species. We hypothesized the involvement of a CuIII
intermediate resulting from the oxidative addition of the CuI
intermediate with a l3 iodane as proposed by Barton and
others.[11] This process utilizing inexpensive and benign
copper salts as well as bench-stable and non-toxic hypervalent
iodinated compounds, would afford a synthetically useful
access to the highly relevant difluoromethylphosphonate
derivatives. Taking benefit from the versatility of iodonium
salts, this approach should offer a straightforward and robust
method to synthesize a large panel of difluoromethylphos-
À
of the phosphate group. The replacement of the O P bond by
the strongest C P bond suppresses potential metabolic
À
hydrolysis. It is important to mention that this concept,
proposed by Blackburn[5a–c] more than thirty years ago, has
been used to design biologically active compounds bearing
a difluoromethylphosphinic acid motif as a metabolically
stable residue (Figure 1).[5d,e] In addition, the difluoromethy-
[*] M. V. Ivanova,[+] Dr. A. Bayle,[+] Dr. T. Besset, Dr. T. Poisson,
Prof. Dr. X. Pannecoucke
Normandie Univ., COBRA, UMR 6014 et FR 3038,
Univ. Rouen, INSA Rouen, CNRS
1 rue Tesni›re, 76821 Mont Saint-Aignan Cedex (France)
E-mail: thomas.poisson@insa-rouen.fr
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507130.
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Table 1: Addition of CuCF2PO(OEt)2 to the aryl iodonium 2a.
Entry
Variation from standard conditions
Yield [%][a]
1
2
3
4
5
6
7
8
9
none
91 (71)[b]
CuOAc instead of CuSCN
CuI instead of CuSCN
MeCN as sole solvent
DMF as sole solvent
KF instead of CsF
1.5 equiv of TMSCF2PO(OEt)2
without CsF
78
45
89
35
64
28
0
PhI instead of 2a
0
[a] Yields determined by 19F NMR spectroscopy using a,a,a-trifluoro-
toluene as internal standard. [b] Yield of isolated products.
Scheme 1. Current state of the art and present strategy.
phonate compounds such as aryl, heteroaryl, vinyl and
alkynyl derivatives.
At the outset of the project, diphenyliodonium triflate 2a
was used as a model substrate. We first generated the
CuCF2PO(OEt)2 species from TMSCF2PO(OEt)2 (1) in the
presence of a copper salt and a Lewis base to promote the
transmetalation, which was reacted with the diphenyliodo-
nium salt 2a. After careful screening of the reaction
conditions we obtained the expected compound 3a in 91%
NMR yield and 71% isolated yield (Table 1, entry 1). Note
that the replacement of CuSCN by CuOAc or CuI furnished
lower yields (entries 2 and 3). The use of MeCN/DMF
mixture as solvent was found crucial (entries 4 and 5) and
a survey of Lewis bases confirmed the key role of CsF over
other activators to promote the Si–Cu transmetalation
(entry 6). Unfortunately, all our attempts to decrease the
stoichiometry of 1 failed, resulting in lower conversion to 3a
(entry 7). A set of control experiments confirmed the
importance of the presence of CsF and, most importantly,
when the reaction was carried out in the presence of phenyl
iodide instead of 2a, no reaction took place (entries 8 and 9).
This last result highlighted the prime importance of 2a as
a coupling partner.
Scheme 2. Scope of the reaction (0.25–0.5 mmol scale). [a] Yield of
isolated products. [b] NMR yields determined by using a,a,a-tri-
fluorotoluene as internal standard. [c] Reactions performed on
3.4 mmol scale. [d] 1,10-phenanthroline (1 equiv) was added. [e] Con-
taminated with 10% of an unknown product.
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Having established the optimized reaction conditions, we
sought to extend the scope of the reaction to aryl, vinyl,
alkynyl and heteroaryl iodonium salts (Scheme 2). First, the
para-tolyl-substituted iodonium salt 2b was coupled with the
CF2PO(OEt)2 moiety under standard conditions and the
corresponding difluoromethylated phosphonate 3b was
obtained in good yield. Electron-donating substituents (e.g.
OMe) were suitable as 3c was isolated in good yield (68%).
The reaction proved to be tolerant toward para- and meta-
halide-substituted iodonium salts. Indeed, iodonium salts with
fluorine, chlorine, and bromine as substituents afforded the
corresponding phosphonates 3d–g in good yields. Ester and
nitro groups were also well tolerated and the corresponding
difluoromethylated phosphonates 3h and 3i, respectively,
were isolated in good yields. To our delight, iodonium salts 2j
and 2k reacted readily to afford the corresponding products
3j and 3k without any trace of products resulting from the
addition of the difluoromethylphosphonate residue on the
ketone or aldehyde. These two examples highlight the
functional group tolerance of the process.[12] We then turned
our attention to the alkenyl iodonium salts 2l–q. Aryl- and
alkyl-substituted alkenes reacted smoothly to give the corre-
sponding products 3l–p in excellent yields (76–94%), while
the cyclic alkene 3q was isolated in a slightly lower yield
(67%). To demonstrate the synthetic utility of our process, we
performed a reaction on a larger scale with iodonium 2o and
the corresponding product 3o was isolated in 72% yield. In
addition, the reaction proved to be effective with alkynyl
derivative 2r, providing the difluoromethylphosphonate 3r in
moderate 64% yield. Due to the prime importance of
fluorinated heterocycles in the search for pharmaceuticals
and agrochemicals, the design of a straightforward method to
introduce the CF2PO(OR)2 moiety on these privileged
scaffolds is a matter of importance. Hence, we tested pyridine,
uracil and thiophene iodonium salts 2s–v. Pyridine derivatives
3s and 3t were isolated in good yields of 44% and 57%,
respectively. Interestingly, the uracil iodonium salt 2u was
also suitable, offering an efficient synthetic pathway to the
uracil difluoromethylphosphonate 3u in 34% yield. Finally,
the thiophene derivative 3v was isolated in a good 76% yield
and a larger scale reaction afforded 3v in 66% isolated yield
showcasing the versatility of the method.
To gain insight in the reaction mechanism, we first studied
the reaction competition between an electron-donating sub-
stituted aryl iodonium salt and an electron-withdrawing
substituted one (Scheme 4). The reaction carried out in the
Scheme 4. Mechanistic studies and proposed mechanism. [a] NMR
yields determined by using a,a,a-trifluorotoluene as internal standard.
[b] Ratio determined by 19F NMR spectroscopy.
presence of di-para-tolyl iodonium salt and the di-para-
chlorophenyl iodonium salt did not reveal a significant
selectivity for one of these substrates. In addition, we studied
the influence of the addition of a ligand with the iodonium salt
2u. Impressively, the addition of 1,10-phenanthroline
changed drastically the selectivity of the reaction. Without
ligand the uracyl ring was preferentially transferred, while the
addition of 1,10-phenanthroline reversed this selectivity
favoring the formation of 3a.[13] This intriguing result clearly
highlights the involvement of the copper species in the
reaction mechanism. Therefore, we can rule out the possible
formation of a potential l3-iodane (Ar2ICF2PO(OEt2)) in the
course of the reaction.[14]
Subsequently, we chose to apply our methodology to
a more complex structure to highlight the synthetic utility of
our approach (Scheme 3). We tested our reaction conditions
on the amino acid based iodonium salt 2w. Pleasingly, the
amino acid part was readily transferred and the corresponding
difluoromethylated phosphonate 3w was isolated in 48%
yield, thus providing a straightforward access to the corre-
sponding phosphatase inhibitor precursor.[5d]
If a new l3-iodane were involved as reaction intermediate,
the copper species should not have any influence on the
reaction outcome. In addition, the reaction performed in the
presence of TEMPO ((2,2,6,6-tetramethylpiperidin-1-
yl)oxyl) as radical inhibitor did not afford a significant drop
of the reactivity. This result precludes the involvement of
a free-radical pathway. Taking into account these data, we
propose the following mechanism to explain the reaction
outcome (Scheme 4). The copper species generated from
1 performs an oxidative addition reaction with the iodonium
salt to provide the CuIII species A. The latter undergoes
Scheme 3. Application of the methodology to biologically relevant
products. [a] Yield of isolated products. [b] NMR yield determined by
using a,a,a-trifluorotoluene as internal standard.
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phonate compounds 3, some key transformations were
carried out (Scheme 5). First, the difluoromethylphosphonate
3b was readily converted to the difluoromethylphosphinic
acid derivative 4 in 95% yield. Second, the alkenyl difluor-
omethylphosphonate 3o was smoothly reduced offering
hence an efficient pathway to the otherwise difficult to
access alkyl derivative 5 in 93% yield.
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Scheme 5. Synthetically useful transformations of the products.
In conclusion, we reported here the first general method
to access (hetero)aryl, vinyl and alkynyl difluoromethyl-
phosphonate derivatives by reacting TMSCF2PO(OEt)2 with
various iodonium salts in the presence of a copper salt. The
corresponding products were obtained in good to excellent
yields under mild conditions. The developed methodology
proved to be highly functional group tolerant and was applied
to a broad range of substrates including biologically relevant
molecules. This approach opens a new avenue to the synthesis
of phosphate mimics. Mechanistic studies supported a mech-
anism involving a CuIII intermediate. Finally, the synthetic
utility of the difluoromethylated phosphonates was demon-
strated.
Acknowledgements
This work was partially supported by INSA Rouen, Rouen
University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-
0029), and RØgion Haute-Normandie (Crunch Network).
M.V.I. thanks the MESR for a doctoral fellowship. A.B.
thanks Labex SynOrg for a postdoctoral fellowship (ANR-11-
LABX-0029).
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Keywords: copper · fluorine · iodonium salts ·
phosphate mimic · synthetic method
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13406–13410
Angew. Chem. 2015, 127, 13604–13608
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Received: July 31, 2015
Published online: September 11, 2015
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