Copper-Mediated Introduction of the CF2PO(OEt)2 Motif: Scope and Limitations

Article abstract of DOI:10.1002/chem.201703542

Herein, a general procedure to access CF₂PO(OEt)₂-containing molecules is reported. The reagent CuCF₂PO(OEt)₂ is accessible by a simple protocol and a broad range of substrates can be functionalised. The procedure allows the conversion of aryl diazonium salts, as well as aryl, heteroaryl, vinyl and alkynyl iodonium salts, into the corresponding fluorinated molecules at room temperature. Mechanistic studies were performed to gain a better understanding of the reaction pathway. Under similar conditions, vinyl and aryl iodides, allyl halides, and benzyl bromides were also functionalised, and the scope and limitations of the reaction were studied. Finally, the procedure was extended to disulfides to offer new access to SCF₂PO(OEt)₂-containing molecules.

Full text of DOI:10.1002/chem.201703542

A Journal of
Accepted Article
Title: Copper-Mediated Introduction of the CF2PO(OEt)2 Motif: Scope
and Limitations
Authors: Maria Ivanova, Alexandre Bayle, Tatiana Besset, Xavier
Pannecoucke, and Thomas Poisson
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To be cited as: Chem. Eur. J. 10.1002/chem.201703542
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10.1002/chem.201703542
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Copper-Mediated Introduction of the CF2PO(OEt)2 Motif: Scope
and Limitations
Maria V. Ivanova, Alexandre Bayle, Tatiana Besset, Xavier Pannecoucke, and Thomas Poisson*[a]
Abstract: Herein, we reported a general procedure to access
CF2PO(OEt)2-containing molecules. CuCF2PO(OEt)2 reagent is
accessible by a simple protocol and a broad range of substrates
could be functionalized. The procedure allowed to convert aryl
diazonium salts as well as aryl, heteroaryl, vinyl and alkynyl
iodonium salts into the corresponding fluorinated molecules at room
temperature. Mechanistic studies were performed to get a better
understanding of the reaction pathway. Using similar conditions,
vinyl and aryl iodides, allyl halides and benzyl bromides were also
functionalized and the scope and limitations of the reaction were
studied. Finally, the procedure was extended to disulfides to offer a
new access to SCF2PO(OEt)2-containing molecules.
phosphonic acid a close pKa to the phosphate (Scheme 1).
Taking into account the importance
difluoromethylphosphonate-containing molecules,
of
several
pathways were developed to introduce or build-up this key motif.
Prior to 2010, the main approaches were quite restricted and
relied on the nucleophilic fluorination of α-ketophosphonate,[9]
the electrophilic α,α-fluorination of phosphonate,[10] the
Michaelis-Becker or Arbuzov reactions,[11] the nucleophilic
addition of difluoromethylphosphonate anion[12] and the addition
of difluoromethylenephosphonyl radical or phosphonyl radical to
olefin or fluorinated olefins, respectively.[13] To tackle the
limitations of the above-mentionned strategies, like the use of
toxic reagent or harsh conditions, a renewal of interest was
observed after 2010 to develop more efficient methodologies to
access CF2PO(OEt)2-containing molecules.
Introduction
Bioisosteric relationships:
Organofluorine chemistry is a blossoming research field mainly
due to the impressive properties of the second smallest element
of the periodic table: the fluorine atom.[1] The propensity of this
atom to alter the physical and biological properties of a molecule
phosphate:
phosphonate:
1
1
2
.
1
1
8
.
1
O
P
°
7
O
P
OR2
OR2
°
OR2
OR2
R1
R1
O
H
H
gave it
a pivotal role in the discovery of drugs and
pharmaceuticals.[2] For instance, the appropriate introduction of
a fluorine atom on a molecule might change its affinity for a
biological receptor and modify its metabolic profile as well as its
lipophilicity.
R2 = H, pKa = 6.4
R2 = H, pKa = 7.6
difluoromethylphosphonate:
1
1
6
C-P bond strengh Apicophilicity
Isopolar
Similar pKa
.
5
O
P
°
OR2
OR2
Close geometry
R1
At last but not least, the fluorine atom or fluorinated groups are
often employed as a bioisoster of important functional group.[3]
As an example, the CF2H residue is widely used to mimic an
F
F
R2 = H, pKa = 5.4
alcohol or
a
thiol group.[4] In that context, the
Selected examples of proteine phosphatase inhibitors:
difluoromethylphosphonate residue is of prime importance, since
it behaves as an in vivo stable phosphate bioisoster. This
paradigm, firstly proposed by Blackburn more than thirty years
ago,[5] gave birth to a myriad of bioactive compounds and
particularly to protein phosphatase inhibitors.[6] This interest for
difluoromethylphosphonate-containing molecules arises from the
in vivo stability of this phosphate surrogate. Indeed, the
replacement of a labile O-P bond by a stronger C-P one
hampers a possible in vivo hydrolysis. In addition, this motif
presents electronic and structural similarities with the phosphate
unit[7] and the difluoromethylene has a comparable apicophilicity
(preference for the apical position) to an esterified oxygen.[8] All
these analogies provide to the phosphorus atom of the
difluoromethylphosphonate unit, a close geometry to the one of
the phosphate. Furthermore, the strong electron-withdrawing
character of the two fluorine atoms affords to the corresponding
CF2PO(OH)2
HO2C
NH2
CF2PO(OR)2
O
O
N
CO2H
O
NC
CF2PO(OR)2
CF2PO(OR)2
Br
Br
CF2PO(OR)2
Ph
N
PO3H2
N
OMe
N
N
Scheme 1. Bioisosteric relationships and difluoromethylphosphonate-
containing bioactive molecules.
[a]
M. V. Ivanova, Dr. A. Bayle, Dr. T. Besset, Prof. Dr. X. Pannecoucke
and Dr. T. Poisson.
Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR
6014), 76000 Rouen, France.
E-mail: thomas.poisson@insa-rouen.fr
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201703542
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New approaches using transition metals:
Zhang and co-workers:
Qing and co-workers:
Cu(I) (1 equiv), ligand (1 equiv)
X
CF2PO(OEt)2
Cu(I) (10 mol%), ligand (20 mol%)
B(OH)2
R
CF2PO(OEt)2
CF2PO(OEt)2
R
R
BrCF2PO(OEt)2, Zn (2-3 equiv)
dioxane, 60 °C
TMSCF2PO(OEt)2
CG
CG
Ag2CO3, pyridine, DMF, 45 °C
Cu(I) (1 equiv), ligand (1 equiv)
X = I or Br
B(OH)2 Pd(0) (5 mol%), Ligand (10 mol%)
CF2PO(OEt)2
R
H
R
R
BrCF2PO(OEt)2
TMSCF2PO(OEt)2
base, dioxane, 80 °C
tBuOK, DDQ, DMF, -15 °C
R2
R2
Pd(II) (5 mol%), Ligand (10 mol%)
H
CF2PO(OiPr)2
R1
R1
BrCF2PO(OiPr)2
K3PO4, DCE, 120 °C
R3
R3
New photocatalytic approaches:
Liu and co-workers:
fac-Ir(ppy)3 (3 mol%)
BrCF2PO(OEt)2
H
CF2PO(OEt)2
R
R
EDG
or
or
EDG
H
CF2PO(OEt)2
X
X
K3PO4, 450 nm, DCM, RT
Liu and Fu:
Hashmi and co-workers:
fac-Ir(ppy)3 (1-2 mol%)
BrCF2PO(OEt)2
[Au2-(dppm)2](OTf)2 (2 mol%)
O
N
O
R
BrCF2PO(OEt)2
R
N
H
N
N
R
R
base
visible or blue light
2,6-lutidine, 315-400 nm
MeCN, RT
N
CF2PO(OEt)2
R
CF2PO(OEt)2
NC
R
Scheme 2. State of the art. CG = coordinating group.
As part of this renewal, one should mention the impressive
contributions made by the group of Zhang, regarding the
development of new methodologies to introduce the
CF2PO(OR)2 moiety according to metal-catalyzed cross-coupling
reactions,[14] a strategy pioneered by Shibuya and co-workers in
1996.[15] Indeed, they developed accesses to aryl
difluoromethylphosphonates according to copper-catalyzed
Ullman-type cross-coupling reactions[14a,b] or palladium-catalyzed
Suzuki cross-coupling reactions.[14c,d] In addition, an access to
alkenyl difluoromethylphosphonates was reported by the same
group.[14e] In parallel, the group of Qing depicted oxidative cross-
coupling reactions to access either aryl or alkynyl
difluoromethylphosphonates.[16] More recently, Hashmi reported
the difluoromethylphosphonylation of hydrazines by using a
functionalization of various substrates: aryl diazonium salts,[20]
hypervalent iodine compounds,[21] vinyl and aryl halides, allylic
derivatives, benzyl halides and disulfides.
Results and Discussion
At the outset of the project we envisioned to develop a versatile
reactive species that might easily enable an efficient introduction
of the CF2PO(OEt)2 moiety on various classes of molecules. We
focused on the formation of the CuCF2PO(OEt)2 species, since
organocopper derivatives are well recognized as reactive
species in a broad range of transformations.[22] In addition,
copper is an attractive transition metal due to its low cost and
low toxicity compared to the other metals from the block d.[22e] It
is worth to mention that Burton and co-workers already reported
the formation of this species.[23] However its access required the
formation of the highly toxic cadmium derivatives prior to a
transmetallation reaction with a copper salt (eq. 1). In order to
avoid the use of cadmium, which hampered a wide application of
this reagent, we turned our attention to the TMSCF2PO(OEt)2 as
a precursor[24] of the corresponding copper derivative. Indeed,
inspired by the work from Gooβen and co-workers,[25] we
hypothesized the formation of the CuCF2PO(OEt)2 species from
the TMS derivative in the presence of an activator and a copper
salt (eq. 2). Note that this species was independently suspected
by Zhang[14a-b] and Qing[16] to be the active species in their
transformation. However no clear evidence of its involvement in
the transformations was reported.
gold-photocatalyst,[17] while the group of Liu developed
a
photocatalytic approach to aryl difluoromethylphosphonates and
6-difluoromethylphosphonylated phenanthridine derivatives.[18]
However, despite the real advances made through these reports,
it is worth to mention that all these methodologies required
specific optimized conditions for each class of substrate. As part
of our ongoing research program dedicated to the introduction of
fluorinated building blocks,[19] we report herein a full account of
our contribution toward the copper mediated synthesis of
difluoromethylphosphonate-containing
molecules.
In
that
purpose and taking into consideration the synthetic limitations of
the reported methodologies, we aimed at developing a general
manifold to introduce the CF2PO(OEt)2 motif onto various
scaffolds to broaden the current portfolio of transformations to
access this important class of compounds. By designing a
simple and practical way to produce the CuCF2PO(OEt)2
reagent, we described in this full paper its use toward the
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10.1002/chem.201703542
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Burton, 1999:
internal standard. [b] Isolated yields. NR = no reaction.
Cd(0)
CuBr
Br
PO(OEt)2
BrCd
PO(OEt)2
Cu
PO(OEt)2
eq.1
Pleasingly, we found that the use of CuSCN as a copper source
with 2.5 equiv of TMSCF2PO(OEt)2 in the presence of CsF
fluoride as an activator in MeCN allowed the formation of 2a in
73% NMR yield and 72% isolated yield. Within the optimization
of the reaction, it turned out that the use of CsF was crucial
since its replacement by other activators did not allow the
formation of the product (entries 2 and 3) or provided it in very
low yield (entry 4). The replacement of CuSCN by other copper
salts was deleterious toward the formation of 2a (entries 5 and
6), while a reduction of the amount of TMSCF2PO(OEt)2 gave
the product in a lower yield (entry 7). Finally, the use of MeCN
was crucial since DMF could not afford a better yield (entry 8).
Having optimized the reaction conditions regarding the formation
of the CuCF2PO(OEt)2 species and its reactivity toward 1a, we
sought to extend the scope of this transformation to other aryl
and heteroaryl diazonium salts (Scheme 5).[20]
F
F
F
F
F F
DMF, RT
DMF, 0 °C
90%
77%
This work:
TMS
Copper salt
activator
PO(OEt)2
Cu
PO(OEt)2
eq.2
F
F
F F
Scheme 3. Past method for the formation of CuCF2PO(OEt)2 species and
present strategy.
Pleasingly, after a screening of copper salts and activators, we
found that 2.5 equivalents of TMSCF2PO(OEt)2 in the presence
of 1 equivalent of CuSCN and CsF as an activator in MeCN at
40 °C furnished the CuCF2PO(OEt)2 species in a quantitative
yield according to 19F NMR (Scheme 4).
CuSCN (1 equiv)
TMS
PO(OEt)2
Cu
PO(OEt)2
CuSCN (1 equiv), CsF (3 equiv)
CF2PO(OEt)2
N2
F
F
F F
99%[a]
CsF (3 equiv), MeCN, 40 °C
BF4
R
R
2.5 equiv
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN, 0 °C to RT
1a-k
2a-k
Scheme 4. Formation of CuCF2PO(OEt)2 species monitored by 19F NMR. [a]
Determined by 19F NMR using α,α,α-trifluorotoluene as an internal standard.
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
MeO
OMe
2a, 72%[a]
CF2PO(OEt)2
2b, 60%
2c, 65%, 68%[b]
As a model reaction and in order to ascertain the formation of
the copper species, we decided to react the in situ formed
CuCF2PO(OEt)2 species in the reaction with aryl diazonium salt
1a (Table 1).[20] Indeed, due to the high reactivity of copper
species with diazonium salts, we assumed that a Sandmeyer
type reaction would be appropriate to demonstrate the reactivity
of the CuCF2PO(OEt)2 species.
MeO
BnO
CF2PO(OEt)2
CF2PO(OEt)2
OMe
2d, 40%
2e, 54%
2f, 60%
CF2PO(OEt)2
CF2PO(OEt)2
Br
CF2PO(OEt)2
F3C
Cl
2g, 37%
2h, 44%
2i, 36%
Table 1. Sandmeyer type reaction – effect of the reaction parameters.
CF2PO(OEt)2
CF2PO(OEt)2
CuSCN (1equiv.)
TMSCF2PO(OEt)2 (2.5 equiv)
CF2PO(OEt)2
N2
EtO2C
O2N
BF4
CsF (3 equiv)
MeCN, 0 °C to RT, overnight
2j, 35%
2k, 18%
MeO
MeO
1a
2a
Unreactive substrates:
Entry
Change from the standard conditions
Yield [%][a]
N2
N2
N2
BF4
BF4
BF4
1
2
3
4
5
6
7
8
No change
73 (72)[b]
NR
NR
23
S
CO2Me
N
N
KF instead of CsF
Scheme 5. Scope and limitations of the reaction of the CuCF2PO(OEt)2
species with aryl and heteroaryl diazonium salts, see ref 20. [a] The product
was contaminated with 7% of HCF2PO(OEt)2. [b] Reaction was performed on
a gram scale.
TMAF instead of CsF
Cs2CO3 instead of CsF
CuOAc instead of CuSCN
CuI instead of CuSCN
1.5 equiv of TMSCF2PO(OEt)2
DMF instead of MeCN
26
Aryl diazonium salts bearing an electron-donating group
30
furnished
the
corresponding
CF2PO(OEt)2–containing
53
derivatives in good yields. Indeed, the presence of a methoxy
substituent at the para- or meta-position gave the corresponding
products 2a and 2b in 72% and 60%, respectively. Noteworthy,
the reaction with para-methylphenyl diazonium salt 1c provided
24
[a] Yields were determined by 19F NMR using α,α,α-trifluorotoluene as an
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the product 2c in 65% yield and the reaction scale was
increased to the gram scale, without any loss of efficiency. The
reaction was then extended to aryl diazonium salts 1d, 1e and 1f
furnishing the targeted fluorinated products 2d-f in moderate to
good yields. Then, the reaction was applied to diazonium salts
bearing a halogen substituent, however the corresponding
products 2g and 2h were isolated in moderate yields, 37% and
44%, respectively. The use of aryl diazonium salts, bearing
electron-withdrawing group like a CF3, an ester or a nitro
synthesis, bench-stable, non toxic and easily prepared.[28]
Moreover, in contrast to the diazonium salts, alkenyl and alkynyl
iodonium species are stable and readily accessible. Therefore,
this class of compounds might offer an access to a broader
range of difluoromethylphosphonate-containing molecules. At
the initial stage of this project, we studied the reaction with the
commercially available diphenyl iodonium triflate 4a as a model
substrate.
substituent
(2i-k)
gave
the
corresponding
difluoromethylphosphate derivatives in low yields, which
represents a limitation of this Sandmeyer approach to introduce
the CF2PO(OEt)2 motif. Disappointingly, heteroaryl diazonium
salts were reluctant substrates and none of them furnished the
corresponding product.
Table 2. Effect of the reaction parameters with 4a as a reaction partner.
OTf
CuSCN (1 equiv), CsF (3 equiv)
CF2PO(OEt)2
I
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
4a
2l
Then, to confirm that the reaction proceeded according to a
classical Sandmeyer pathway involving a SET (single electron
transfert),[26] a radical clock experiment using the 2-(allyloxy)
diazonium salt 1l was performed (Scheme 6).
Entry
Change from the standard conditions
None
Yield [%][a]
1
2
3
4
5
6
91 (71)[b]
89
MeCN as a sole solvent
DMF as a sole solvent
CuOAc instead of CuSCN
KF instead of CsF
CF2PO(OEt)2
35
CuSCN (1 equiv), CsF (3 equiv)
N2
BF4
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN, 0 °C to RT
78
O
O
3,68%,[a] (84%)[b]
1l
64
Proposed mechanism:
PhI instead of 4a
NR
N2
N2
BF4
- N2
SET
O
[a] Yields were determined by 19F NMR using α,α,α-trifluorotoluene as an
O
O
internal standard. [b] Isolated yields. NR = no reaction.
1l
I
II
After a careful examination of the reaction parameters, we found
that the use of slightly modified reaction conditions furnished the
corresponding product 2l in 71% isolated yield and 91% NMR
yield. Indeed, the 1:1 mixture of MeCN/DMF was important to
ensure a decent conversion into the corresponding product. The
use of MeCN as a sole solvent provided 2l in 89% yield, while
DMF gave 2l in 35% yield (entries 2 and 3). The use of other
copper salts or activators furnished the product 2l in lower yields
(entries 4 and 5). A control experiment shown that phenyl iodide
was unreactive under our reaction conditions. This observation
assess that the reaction proceeded with the λ3 iodane rather
than with the aryl iodide that might arise from the decomposition
of the hypervalent iodine species (entry 6). Having demonstrated
the reactivity of the CuCF2PO(OEt)2 species toward 4a, we
sought to extend the scope of this transformation to other
iodonium salts. First, various symmetric and non-symmetric
diaryl iodonium salts were tested (Scheme 7).
Cu(I) CF2PO(OEt)2
Cu(II) CF2PO(OEt)2
Cu(II) CF2PO(OEt)2
Cu(II) CF2PO(OEt)2
CF2PO(OEt)2
O
O
3
III
Scheme 6. Radical clock experience – proposed mechanism. [a] Isolated yield.
[b] Yield was determined by 19F NMR using α,α,α-trifluorotoluene as an
internal standard.
Under standard conditions, the cyclized product 3 was isolated
in 68% yield, which confirmed the involvement of a radical
mechanism (Scheme 6). This observation was in line with the
previous reports depicting a Sandmeyer type reactions.[27],[25e]
Hence, the diazonium salt 1l performed a SET with the
CuCF2PO(OEt)2 reagent to provide the corresponding Cu(II)
species and the radical I. Then, a nitrogen extrusion provided
the aryl radical II, which underwent a radical cyclisation giving
the primary radical III. A final reaction with the Cu(II) species
furnished the cyclized product 3.
To address the limitations of the reaction between the
CuCF2PO(OEt)2 reagent and aryl diazonium salts and to extend
the scope of applications of this CuCF2PO(OEt)2 reagent, we
decided to investigate its reactivity toward hypervalent iodinated
species.[21] Indeed, λ3 iodanes are versatile reagents in organic
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CuSCN (1 equiv)
Phen (0-1 equiv), CsF (3 equiv)
X
OTf
I
CuSCN (1 equiv), CsF (3 equiv)
CF2PO(OEt)2
CF2PO(OEt)2
6a-e
I
Mes
R
Het
Ar
R
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
Het
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
4a-n
X= OTf or BF4
2
5a-e
Mes = mesityl
Ar = phenyl or mesityl
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
O
N
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
N
2l, 71%[a]
CF2PO(OEt)2
2c, 59%[a],[b]
2m, 53%
N
Cl
N
O
O
CF2PO(OEt)2
CF2PO(OEt)2
6a, 44%,[a] (89%)[b],[c]
6b, 57%[a],[c],[d]
CF2PO(OEt)2
6c, 34%, (74%)[b],[c]
O2N
MeO
Ph
2a, 68%[a]
CF2PO(OEt)2
2n, 65%
CF2PO(OEt)2
2o, 71%
CF2PO(OEt)2
CF2PO(OEt)2
6e, 76%, 66%[c],[d]
S
N
6d, 29%
F
Cl
Br
2p, 63%[a]
CF2PO(OEt)2
2g, 52%[a]
CF2PO(OEt)2
2q, 51%[a]
CF2PO(OEt)2
Scheme 8. Scope of the reaction with heteroaryl iodonium salts. [a] 1,10-
phenanthroline (Phen) was used. [b] Yields were determined by 19F NMR
using α,α,α-trifluorotoluene as an internal standard. [c] See ref 21. [d]
Reaction was performed on 3.4 mmol scale.
Cl
Cl
Br
EtO2C
2r, 77%
CF2PO(OEt)2
2h, 76%[a]
CF2PO(OEt)2
2j, 51%[a]
CF2PO(OEt)2
OHC
O
First, pyridine derivatives 6a and 6b were readily obtained in
moderate yields. Interestingly, the N,N-dimethyl uracil
derivatives 6c was obtained in a 74% NMR yield and isolated in
34% yield, while the quinoline derivative 6d was obtained in a
poor 29% yield. Finally, the thienyl difluoromethylphosphonate
6e was obtained in 76% yield and 66% yield on a gram scale,
demonstrating the synthetic utility of the process.
Subsequently, to further broaden the scope of our
transformation we expanded this process to the synthesis of
vinyl and alkynyl CF2PO(OEt)2 derivatives by using the
corresponding iodonium salts (Scheme 9).
O2N
2k, 68%[a]
2s, 70%[a]
2t, 57%[a]
Scheme 7. Scope of the reaction with diaryl iodonium salts. [a] See reference
21. [b] Symmetrical iodonium salt was used.
Aryl iodonium salts bearing electron-donating groups were
evaluated.
para-Alkyl
substituted
salts
provided
the
corresponding difluoromethylphosphonate derivatives 2c and
2m in good yields. The methoxy- and phenyl-substituted
iodonium salts were also compatible giving the products 2a and
2n in 68% and 65% isolated yields, respectively. Interestingly,
substrate 4o was reactive furnishing the biaryl ether derivative
2o in 71% isolated yield. Then, iodonium salts bearing a halogen
as a substituent were tested. Whatever, the substitution pattern,
fluoride, chloride and bromide substituents were tolerated giving
the corresponding products 2p, 2g, 2q, 2r and 2h in moderate to
good yields. Finally, electron-withdrawing groups like ester, nitro,
ketone and even aldehyde were compatible with our reaction
conditions and the corresponding fluorinated derivatives 2j, 2k,
2s and 2t were isolated in good yields. Remarkably, in the case
of 2s and 2t no addition product on the carbonyl groups was
detected in the reaction media proving the high selectivity of this
transformation.
BF4
CuSCN (1 equiv), CsF (3 equiv)
CF2PO(OEt)2
R1
I
R1
R2
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
R2
7a-f
8a-f
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
F
8c, 83%[a]
8b, 92%[a]
8a, 76%[a]
CF2PO(OEt)2
Ph
CF2PO(OEt)2
CF2PO(OEt)2
8d, 87%, 72%[a],[b]
8e, 94%[a]
8f, 67%[a]
Heteroaryl derivatives are important scaffolds in agrochemical
and pharmaceutical research. Hence, we then turned our
attention to the synthesis of heteroaryl derivatives bearing a
CF2PO(OEt)2 residue (Scheme 8).[21]
BF4
I
CuSCN (1 equiv), CsF (3 equiv)
CF2PS(OEt)2
Ph
Ph
Ph
TMSCF2PS(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
7a
9, 63%
O
CF2PO(OEt)2
O
standard
I
conditions
Ph-EBX
10, 64 %[a]
Scheme 9. Scope of the reaction with vinyl and alkynyl iodonium salts. [a] See
ref 21. [b] Reaction was performed on 3.4 mmol scale.
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First, iodonium salt bearing styryl substituents were tested. The
intervention of a possible free radical pathway. Then, during the
course of our investigations regarding the functionalization of
unsymmetrical iodonium salts, an interesting impact of the
addition of a ligand was observed on the selectivity of the
transformation (Scheme 12).
salts
7a-c
provided
the
corresponding
difluoromethylphosphonates 8a-c in good to excellent yields.
Then, alkyl-substituted olefins 8d and 8e were synthesized in
good yields and the reaction was scaled-up to 3.4 mmol as
demonstrated with 8d. Notably, internal olefin 8f was obtained in
67% isolated yield. In addition, this transformation was extended
to the introduction of the difluoromethylphosphonothioate motif.
Using a similar procedure to prepare the CuCF2PS(OEt)2
species, the reaction with vinyl iodonium salt 7a provided the
corresponding vinyl difluoromethylphosphonothioate 9 in 63%
yield. Finally, by using the Ph-EBX,[29] alkynyl derivatives 10 was
isolated in 64% yield.
O
N
OTf
I
O
N
CF2PO(OEt)2
CF2PO(OEt)2
standard
N
N
conditions
O
O
5c
A
B
without : 74%,[a] A:B = 73:27[b]
with:
73%,[a] A:B = 20:80[b]
1,10-phenanthroline
(1 equiv)
O
O
Then, to further showcase the synthetic utility of our procedure,
we carried out the introduction of the CF2PO(OEt)2 motif onto
biorelevant molecules (Scheme 10).
H
standard
CF2PO(OEt)2
H
Mes
H
H
conditions
H
H
Mes
I
CF2PO(OEt)2
OTf
13
D
C
without : 91%,[a] C:D = 50:50[b]
with:
75%,[a] C:D = 17:83[b]
1,10-phenanthroline
(1 equiv)
MeO2C
MeO2C
standard
AcHN
Mes
I
AcHN
conditions
CF2PO(OEt)2
Scheme 12. Mechanistic studies – ligand effect. [a] Yields were determined by
19F NMR using α,α,α-trifluorotoluene as an internal standard. [b] Ratios were
determined by 19F NMR on the crude reaction mixture.
BF4
12, 48%, (85%)[a]
11
O
O
H
H
H
standard
Indeed, when the reaction was carried with unsymmetrical
iodonium salt 5c, the mixture of compounds A and B was
obtained in 74% yield with a 73:27 ratio. Impressively, when
1,10-phenanthroline was added to the copper species prior to
the reaction with 5c, the reaction furnished the corresponding
mixture of products in 20:80 ratio and 73% yield. Similarly, with
iodonium salt 13, the impact of 1,10-phenanthroline on the
selectivity of the transfer was observed. Without the addition of
ligand an equimolar mixture of compounds C and D was
observed, while its addition provided a 17:83 ratio.
H
H
H
conditions
Mes
I
CF2PO(OEt)2
14, 37%
OTf
13
Scheme 10. Functionalization of biorelevant molecules. [a] Yields were
determined by 19F NMR using α,α,α-trifluorotoluene as an internal standard.
First, the iodonium salt 11 derived from iodotyrosine was used
as
a
substrate
and
the
corresponding
However, this significant ligand effect suggested that a copper
species is involved in the reaction mechanism (Scheme 13).
Therefore, the possible formation of a new λ3 iodane A resulting
from the replacement of the triflate by a CF2PO(OEt)2 residue
can be ruled out. With this information in hand, we suggested
the following reaction mechanism. First, the CuCF2PO(OEt)2
species reacted with the iodonium salt to form a putative Cu(III)
species B. The latter underwent a reductive elimination to
deliver the product 2.[31]
difluoromethylphosphonate 12 was isolated in 48% yield. This
compound is a synthetic intermediate toward the synthesis of a
potent phosphatase inhibitor.[30] Then, we applied our
methodology to the functionalization of the estrone derivative 13.
The iodonium salt was readily converted into the
difluoromethylphosphonate 14 in a moderate 37% yield.
Intrigued by the mechanism of this transformation, mechanistic
investigations were carried out.
OTf
CF2PO(OEt)2
standard
conditions
Formation of a new λ3 iodane:
none :
TEMPO: 59%[a]
72%[a]
I
Ar2IOTf
reductive
CF2PO(OEt)2
CuCF2PO(OEt)2
X
Ar CF2PO(OEt)2
I
TEMPO (1 equiv)
4a
2l
Ar
Ar
elimination
A
2
Scheme 11. Mechanistic studies. [a] Yields were determined by 19F NMR
using α,α,α-trifluorotoluene as an internal standard.
Proposed mechanism:
Ar2IOTf
reductive
Ar
CuIII CF2PO(OEt)2
CuCF2PO(OEt)2
Ar CF2PO(OEt)2
elimination
oxidative
addition
TfO
B
2
First, the reaction of 4a with CuCF2PO(OEt)2 was performed in
the presence of one equivalent of TEMPO ((2,2,6,6-
tetramethylpiperidin-1-yl)oxyl) (Scheme 11). The reaction
furnished the corresponding product 2l without a significant
decrease of the reaction yield. This result ruled out the
Scheme 13. Proposed mechanism.
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Then, we explored the reaction of the CuCF2PO(OEt)2 reagent
with vinyl halides (Scheme 14). Indeed, in 1996, Shibuya and
co-workers reported the reaction between XZnCF2PO(OEt)2 in
the presence of a stoichiometric amount of CuBr.[15] We thought
that the use of our protocol could avoid the use of Zn to prepare
the corresponding fluorinated organometallic species prior the
reaction.
Pleasingly, by using our standard conditions along with the
addition of 1,10-phenanthroline as a ligand, a broad range of
vinyl halides (bromide and iodide) were readily functionalized at
room temperature. First, (E)-β-bromostyrene 15a was engaged
under our reaction conditions providing the corresponding
fluorinated product 8a in 72% yield as a single (E)-isomer. When
the reaction was carried out with (Z)-β-iodostyrene 15b, the
reaction afforded the (Z)-isomer 8g in 79% isolated yield. This
result proved that the reaction proceeded with the retention of
the starting material geometry. Styryl derivatives bearing an
electron-donating or an electron-withdrawing group were
suitable substrates, as demonstrated with compounds 8h and 8i,
which were isolated in 82% and 63% yields, respectively.
corresponding (Z)-CF2PO(OEt)2-containing olefin 8l in 66% yield
as a single diastereoisomer. This result demonstrated that the
reaction conditions did not affect the stereochemistry of the
starting halo olefin. Similarly, methacrylonitrile derivative 15h
(2:1 E/Z mixture) was readily functionalized and the
corresponding product 8m was isolated in 57% yield as a
separable 2:1 mixture of diasteroisomers. Unfortunately, α-
bromo-propene, α-bromo-styrene as well as cyclic vinyl bromide
were unreactive under our reaction conditions. These examples
pointed out the limitation of the reaction, which was restricted to
terminal vinyl halides.
Aiming at developing a convenient method to introduce the
CF2PO(OEt)2 motif, we thought that our protocol to generate the
CuCF2PO(OEt)2 species might allow the Ullman cross-coupling
reaction with aryl iodides bearing a coordinating group (CG) at
the ortho-position (Scheme 15). Indeed, the group of Zhang
reported the copper catalyzed Ullman cross-coupling reaction
using in situ generated XZnCF2PO(OEt)2 on ortho-iodobenzoate
and ortho-iodo- and bromo-triazene derivatives.[14a,b]
CuCl (1 equiv), CsF (3 equiv)
1,10-phenanthroline (1 equiv)
CG
CG
I
CuSCN (1 equiv), CsF (3 equiv)
1,10-phenanthroline (1equiv)
R
R
R2
R2
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
CF2PO(OEt)2
17a-l
X
CF2PO(OEt)2
8
R1
15a-h
X = Br or I
R1
16a-m
CO2Et
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
COCH3
NO2
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
17c, 54%
CF2PO(OEt)2
17a, 84%, (25%)[a]
17b, 53%
CF2PO(OEt)2
MeO
CO2Me
8a, 72%, (99%)[a]
X= Br
8g, 79%
X= I
CO2Me
CO2Me
CF2PO(OEt)2
OMe
CF2PO(OEt)2
MeO
Cl
CF2PO(OEt)2
17e, 69%
CF2PO(OEt)2
CF2PO(OEt)2
17d, 61%
17f, 93%
O2N
MeO
CO2Me
CO2Me
Br
CO2Me
8h, 82%, (87%)[a]
8i, 63%, (80%)[a]
X = Br
X = Br
O2N
CF2PO(OEt)2
17g, 62%
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
17h, 68%
17i, 74%
I
CO2Me
CO2Me
8j, 62%, (94%)[a]
8k, 53%, (66%)[a]
X= I
X = I
CN
CF2PO(OEt)2
Cl
CF2PO(OEt)2
17k, 43%
CO2Et
CF2PO(OEt)2
17j, 56%
Me
CF2PO(OEt)2
CF2PO(OEt)2
8l, 66%, (70%)[a]
8m, 57%,[b] (66%)[a]
E:Z = 2:1
N
CF2PO(OEt)2
O2N
X = Br
2k, 47%
Unreactive substrates:
17l, 32%
X = Br, (15h, E:Z = 2:1)
Unreactive substrates:
Br
Br
Br
N
Ph
NHCOR
CN
I
CO2H
I
R = Me
R = Ph
R
I
I
R = CH3
R = CF3
Scheme 14. Functionalization of alkenyl halides. [a] Yields were determined
by 19F NMR using α,α,α-trifluorotoluene as an internal standard. [b] Combined
yield of the (E)- and (Z)-isomers.
Scheme 15. Synthesis of aryl-CF2PO(OEt)2 derivatives from aryl iodides. [a]
Ethyl ortho-bromobenzoate was used instead of 16a. CG = coordinating group.
Then, alkyl substituted vinyl iodides were smoothly reacted,
giving the vinyl-CF2PO(OEt)2 species 8j and 8k in moderate to
good yields (53% and 62%, respectively). Interestingly, (Z)-ethyl-
β-bromoacrylate 15g was reacted and provided the
By replacing CuSCN by CuCl along with the addition of 1,10-
phenanthroline as a ligand, the reaction with ethyl ortho-
iodobenzoate 16a afforded the corresponding product 17a in
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CuSCN (1 equiv), CsF (3 equiv)
1,10-phenanthroline (1 equiv)
84% isolated yield (Scheme 15). Note that, the use of ortho-
bromobenzoate instead of 16a, allowed the formation of 17a in a
lower yield (25%). Interestingly and in contrast to the previous
report on the Ullman cross-coupling reactions to introduce the
CF2PO(OEt)2 motif,[14a] our transformation proceeded at room
temperature. Then, the scope of the reaction was extended to
other aryl iodide bearing a coordinating group at the ortho-
position of the halide. Pleasingly, ketone and nitro groups could
be a suitable coordinating group to promote this transformation
since the corresponding products 17b and 17c were isolated in
53% and 54% yield. The reaction scope was further extended to
several ortho-iodobenzoate derivatives. First, benzoates bearing
an electron-donating group were tested. The sterically hindered
substrates 16d furnished the desired product 17d in a decent
61% yield, while the iodobenzoates 16e and 16f bearing
methoxy substituents were readily functionalized in 69% and
93% yields, respectively. A nitro substituent was also tolerated
since the product 17g was isolated in 62% yield. Then, ortho-
iodobenzoate derivatives bearing a halogen substituent were
evaluated. Pleasingly, chloro-, bromo- and even iodo-substituted
substrates were functionalized in good yields (17h-k).
Interestingly, in the case of 17j no functionalization was
observed at the meta-position, highlighting the high selectivity of
this process and the importance of a coordinating group at the
ortho-position of the halide in the Ullman cross-coupling reaction,
the so-called “ortho effect”.[32] Finally, the methodology was
applied to the functionalization of para-nitro iodobenzene and 2-
bromo-pyridine, albeit in moderate yields (47% and 32%,
respectively). Noteworthy, other coordinating groups like imine,
acetamide, trifluoroacetamide, as well as nitrile and carboxylic
acid were inefficient under our reaction conditions.
R
CF2PO(OEt)2
19a-g
CF2PO(OEt)2
R
Br
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
18a-g
CF2PO(OEt)2
Cl
19a, 91%, (96%)[a],[b] (60%)[a],[c]
19b, 62%
EtO2C
CF2PO(OEt)2
19d, 63%
CF2PO(OEt)2
19c, 61%
CF2PO(OEt)2
CF2PO(OEt)2
19f, 99%
19e, 98%
CF2PO(OEt)2
19g, 88%
Possible reaction pathway:
R
Br
CuCF2PO(OEt)2
18
Br
CF2PO(OEt)2
Br
CF2PO(OEt)2
Br
Cu
Cu
R
Cu
CF2PO(OEt)2
R
R
σ-allyl
π-allyl
σ-allyl
X
CF2PO(OEt)2
R
CF2PO(OEt)2
19
R
Unreactive substrates:
Br
R = NO2
R = OMe
R
Then, the functionalization of allyl halides was investigated to
access the allyl-CF2PO(OEt)2 derivatives (Scheme 16).
Scheme 16. Functionalization of allyl halide with the CuCF2PO(OEt)2 reagent.
[a] Yields were determined by 19F NMR using α,α,α-trifluorotoluene as an
internal standard. [b] Cinnamyl chloride was used instead of 18a. [c] Cinnamyl
diethyl phosphate was used instead of 18a.
First, (E)-cinnamyl bromide 18a was reacted under our standard
conditions affording the (E)-difluoromethylphosphonate 19a in
92% NMR yield. Pleasingly, the addition of 1,10-phenanthroline
as a ligand increased the reaction yield to 99% and the product
19a was isolated in 91% yield. Notably, cinnamyl chloride and
cinnamyl diethyl phosphate can also be used as starting
materials, since 19a was obtained in 96% and 60% NMR yields,
respectively. Then, to study the impact of our reaction conditions
on the stereochemical outcome, the reaction was carried out
using (Z)-cinnamyl bromide. Under the standard conditions, the
product with the (E)-configuration 19a was isolated in 51% yield.
This result was in agreement with the literature data, which
suggested the involvement of a π-allylcopper(III) in allylic
substitution.[33] The stereoselectivity of the reaction could be
explained by the formation of the π-allyl complex followed by an
isomerization step to form the σ-complex and a reductive
elimination to furnish the linear product 19. Interestingly, no
trace of the branched product was detected in the reaction
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CuCl (1 equiv), CsF (3 equiv)
1,10-phenanthroline (1 equiv)
mixture. Then, the reaction scope was extended to the para-
chloro cinnamyl derivatives 19b. Unfortunately, strong electron-
donating (OMe) and electron-withdrawing (NO2) groups at the
para-position of the aromatic ring were not tolerated. The α-
substitution did not have an impact on the reaction and the
corresponding products 19c and 19d were isolated in good
yields. Note that the presence of an ester group was tolerated.
Finally, prenyl, geranyl and farnesyl bromides were readily
functionalized giving the targeted difluoromethylphosphonate
derivatives 19e-g in good to excellent yields (98%, 99% and
88% respectively).
SCF2PO(OEt)2
R
S
R
S
R
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
22a-e
23a-e
SCF2PO(OEt)2
SCF2PO(OEt)2
SCF2PO(OEt)2
Me
MeO
23a, 49%, (50%)[a]
23b, 57%, (62%)[a]
23c, 48%, (61%)[a]
SCF2PO(OEt)2
SCF2PO(OEt)2
F
Cl
23d, 52%, (50%)[a]
23e, 57%, (71%)[a]
To further extend the reactivity and by analogy with the allyl
derivatives, benzyl bromide derivatives were then functionalized
(Scheme 17).
Unreactive substrates:
S
S
S
S
S
S
CuSCN (1 equiv), CsF (3 equiv)
1,10-phenanthroline (1 equiv)
Br
CF2PO(OEt)2
R
R
Scheme 18. Reaction of the CuCF2PO(OEt)2 with disulfides. [a] Isolated yields.
[b] Yields were determined by 19F NMR using α,α,α-trifluorotoluene as an
internal standard.
TMSCF2PO(OEt)2 (2.5 equiv)
MeCN/DMF, 0 °C to RT
20a-f
21a-f
CF2PO(OEt)2
CF2PO(OEt)2
CF2PO(OEt)2
Br
First, the phenyldisulfide 22a was used as a substrate and to our
delight the corresponding SCF2PO(OEt)2 derivative 23a was
obtained in 50% NMR yield and isolated with 49% yield. Then,
several disulfides were evaluated. The para-methyl and para-
methoxy disulfides reacted with the CuCF2PO(OEt)2 and
afforded the corresponding SCF2PO(OEt)2-containing aryls 23b
and 23c in 57% and 48% yields, respectively. Finally, the
disulfides bearing halogens at the para-position were also
readily converted into the targeted fluorinated molecules 23d
and 23e in moderate yields. Noteworthy, heteroaromatic
disulfide and aliphatic one were unreactive and did not provide
the desired fluorinated products.
21a, 87%
CF2PO(OEt)2
21b, 42%
CF2PO(OEt)2
21c, 74%
CF2PO(OEt)2
O
CN
I
21e, 36%, (65%)[a]
21d, 47%
21f, 48%
Unreactive substrates:
MeO
Br
Br
Cl
O2N
OMe
Scheme 17. Synthesis of benzyl CF2PO(OEt)2 derivatives. [a] Yield was
determined by 19F NMR using α,α,α-trifluorotoluene as an internal standard.
First, benzyl bromide 20a was reacted under the standard
conditions in the presence of 1,10-phenanthroline as a ligand
and the corresponding fluorinated product 21a was obtained in
87% isolated yield. Unfortunately, the reaction with benzyl
chloride did not afford trace of the corresponding product 21a.
Then para-substituted benzyl bromides were reacted and the
corresponding products 21b-d were isolated in good yields. The
reaction proved to be compatible with a bromide and a ketone
substituent. These examples demonstrated the selectivity of the
developed process. Then, ortho-substituted benzyl bromides
were tested and the cyano and iodide substituents were
tolerated giving the products 21e and 21f in moderate yields,
36% and 48% respectively. Note that the presence of an
electron-donating group on the aromatic ring was deleterious as
demonstrated with the dimethoxy substituted benzyl bromide
that did not afford the corresponding CF2PO(OEt)2 derivative.
Quite recently, our group shed light on the emergent
SCF2PO(OEt)2 fluorinated group.[34] Hence, we thought that the
reaction between the CuCF2PO(OEt)2 species and a disulfide
might offer a new synthetic access to this interesting sulfur-
containing fluorinated building block (Scheme 18).[35]
Conclusions
In summary, we reported herein
a full account of our
investigations toward the copper-mediated introduction of the
valuable phosphate bioisoster: the CF2PO(OEt)2 motif. Thanks
to a straightforward procedure to prepare the CuCF2PO(OEt)2
reagent from the readily available silylated precursor a broad
range of substrates were functionalized to access important
fluorinated building blocks bearing this particular motif. The
procedure allowed the functionalization of aryl diazonium salts,
aryl, heteroaryl, vinyl and alkynyl iodoniums salts. This protocol
was applied to the synthesis of biorelevant molecules. The
mechanism of the transformation using iodonium salts was
studied and an interesting ligand effect was observed. This
study suggested the involvement of a Cu(III) species as an
intermediate. Then, the methodology was extended to the
functionalization of vinyl halides (bromides and iodides) and aryl
iodides bearing a coordinating group at the ortho-position. The
corresponding products were obtained in good yields and the
developed methodology offered an interesting alternative to the
existing methods. By using our protocol to generate the
CuCF2PO(OEt)2 reagent, allyl halides and benzyl bromides were
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General procedures for the copper-mediated synthesis of
difluoromethylphosphonates from iodonium salts.
readily converted into the corresponding fluorinated compounds
at room temperature in moderate to good yields. Finally, we
demonstrated that our methodology afforded an interesting
pathway to access SCF2PO(OEt)2-containing molecules from
Method B:
disulfides. In conclusion, we developed
a straightforward
In a glove box, a tube was loaded with CuSCN (61 mg, 0.50 mmol) and
CsF (228 mg, 1.50 mmol) and sealed with a rubber septum. Dry
acetonitrile (1 mL) was added and the mixture was placed at 0 °C.
Diethyl [(trimethylsilyl)difluoromethyl]phosphonate (neat, 325 mg, 1.25
mmol) was added and the mixture was heated at 40 °C for 1 h, cooled to
0 °C and allowed to stir at this temperature for 1 h. The corresponding
iodonium salt (0.50 mmol) was added dropwise as a solution in DMF (1
mL). The rubber septum was removed, the tube was sealed and the
suspension was stirred for 16 h. The reaction mixture was diluted with
diethyl ether (30 mL) and filtered through a plug of Celite®. The organic
layer was washed with water (4 × 25 mL), brine (25 mL), dried over
MgSO4, and solvents were carefully removed under vacuum. Reverse
phase chromatography (H2O/CH3CN or MeOH, gradient: 9:1 to 0:1, rate:
1% CH3CN or MeOH per minute) gave the product.
manifold to access a braod range of CF2PO(OEt)2-containing
molecules at room temperature. We believe that this approach
will be useful to synthesize important building blocks and will be
applied to the synthesis of important biorelevant molecules.
Experimental Section
General: All reactions were carried out using oven dried glassware and
magnetic stirring under an atmosphere of argon unless otherwise stated.
Flash chromatography was performed with silica gel (0.040-0.060 nm).
Reverse phase chromatography was performed on a puriFlash®215
using a puriFlash® C18HP 15µm 55G Flash column. Analytical thin layer
chromatography was performed on silica gel aluminium plates with F-254
indicator and visualized by UV light (254 nm) and/or chemical staining
with a KMnO4 solution. 1H NMR spectra were recorded on a Bruker
DXP 300 at 300 MHz and a Bruker DXP 400 at 400 MHz, 13C NMR
Method C (with 1,10-phenanthroline):
In a glove box, a tube was loaded with CuSCN (61 mg, 0.50 mmol) and
CsF (228 mg, 1.50 mmol) and sealed with a rubber septum. Dry
acetonitrile (1 mL) was added and the mixture was placed at 0 °C.
Diethyl [(trimethylsilyl)difluoromethyl]phosphonate (neat, 325 mg, 1.25
mmol) was added and the mixture was heated at 40 °C for 1 h, cooled to
0 °C and allowed to stir at this temperature for 1 h. 1,10-Phenanthroline
spectra at 75 MHz and at 100 MHz, 19F NMR spectra at 282 MHz and 31
P
NMR at 121 MHz. Chemical shifts (δ) are quoted in parts per million
(ppm) relative to the residual solvent peak for CDCl3 (δH = 7.26 ppm;
δC = 77.16 ppm; or relative to external CFCl3: δ = 0 ppm), [D6]acetone (δH
= 2.05 ppm; δC = 29.84 ppm), CD3OD (δH = 3.31 ppm; δC = 49.00 ppm).
(90.1 mg, 1.00 mmol) was added followed by
a solution of the
The following abbreviations have been used: δ (chemical shift),
J
corresponding iodonium salt (0.50 mmol) in DMF (1 mL). The rubber
septum was removed, the tube was sealed and the suspension was
stirred for 16 h. The reaction mixture was diluted with diethyl ether (30
mL) and filtered through a plug of Celite®. The organic layer was washed
with water (4 × 25 mL), brine (25 mL), dried over MgSO4, and solvents
were carefully removed under vacuum. Reverse phase chromatography
(H2O/CH3CN or MeOH, gradient: 9:1 to 0:1, rate: 1% CH3CN or MeOH
per minute) gave the product.
(coupling constant), app. (apparent), br. (broad), s (singlet), d (doublet),
dd (doublet of doublets), ,t (triplet), td (triplet ou doublets), tq (triplet of
quadruplets) q (quartet), m (multiplet). High-resolution mass spectra
(HRMS) were recorded on Waters LCT Premier, IR spectra were
recorded on a PerkinElmer Spectrum 100.
Starting material synthesis:
Diethyl [difluoro(trimethylsilyl)methyl]phosphonate was synthesized
according to the procedure described by O’Hagan.[24] Diazonium salts
were prepared according to reported methods, see reference 25b and
references cited herein. Iodonium salts, 4, 5, 7, 11 and 13 were prepared
according to the literature.[36]
General procedures for the copper-mediated synthesis of
difluoromethylphosphonates from vinyl halides, allyl bromides and
benzyl bromides.
Method D:
General
procedure
for
copper-mediated
synthesis
of
In a glove box, a tube was loaded with CuSCN (61 mg, 0.50 mmol) and
CsF (228 mg, 1.50 mmol) and sealed with a rubber septum. Dry
acetonitrile (1 mL) was added and the mixture was placed at 0 °C.
Diethyl [(trimethylsilyl)difluoromethyl]phosphonate (neat, 325 mg, 1.25
mmol) was added and the mixture was heated at 40 °C for 1 h, cooled to
0 °C and allowed to stir at this temperature for 1 h. 1,10-Phenanthroline
difluoromethylphosphonates from aryl diazonium salts.
Method A:
In a glove box, a sealed tube was loaded with CuSCN (61 mg, 0.50
mmol) and CsF (228 mg, 1.50 mmol) and sealed with a rubber septum.
Dry acetonitrile (1 mL) was added and the mixture was placed at 0 °C.
Diethyl [(trimethylsilyl)difluoromethyl]phosphonate (325 mg, 1.25 mmol)
was added and the mixture was heated at 40 °C for 1h, cooled to 0 °C
and allowed to stirred at this temperature for 1 h. Unless otherwise noted,
the corresponding diazonium salt (0.50 mmol) was added dropwise as a
solution in acetonitrile (1 mL). The rubber septum was removed, the tube
was sealed and the suspension was stirred for 16 h. The reaction mixture
was diluted with diethyl ether (30 mL) and filtered through a plug of
Celite®. The organic layer was washed with water (4 × 10 mL), brine (2 ×
10 mL), dried over MgSO4, and solvents were carefully removed. Unless
otherwise noted, purification by flash chromatography on silica gel gave
the pure desired product.
(90.1 mg, 1.00 mmol) was added followed by
a solution of the
corresponding vinyl halide or allyl halide or benzyl bromide (0.50 mmol).
The rubber septum was removed, the tube was sealed and the
suspension was stirred for 16 h. The reaction mixture was diluted with
diethyl ether (30 mL), the organic layer was washed with water (4 × 25
mL), brine (25 mL), dried over Na2SO4, and solvent was carefully
removed under vacuum. Reverse phase chromatography (H2O/CH3CN,
gradient: 9:1 to 0:1, rate: 1% CH3CN per minute) gave the product.
General procedures for the copper-mediated synthesis of
difluoromethylphosphonates from iodoarenes
Method E:
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10.1002/chem.201703542
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In a glove box, a tube was loaded with CuCl (50 mg, 0.50 mmol) and CsF
(228 mg, 1.50 mmol) and sealed with a rubber septum. Dry acetonitrile (1
Diethyl [(p-tolyl)difluoromethyl]phosphonate 2с. Prepared following
the procedure A from p-tolyldiazonium tetrafluoroborate 1c with 65%
yield (90 mg, 0.5 mmol scale), 68% yield (680 mg, 3.6 mmol scale); the
procedure B from di(4-tolyl)iodonium trifluoromethanesulfonate 4c with
59% yield (82 mg, 0.5 mmol scale). Reverse phase chromatography
(H2O/MeCN). Yellow oil; 1H NMR (300 MHz, CDCl3): δ 7.48 (d, J = 7.7 Hz,
2H), 7.23 (d, J = 8.0 Hz, 2H), 4.28-4.05 (m, 4H), 2.37 (s, 3H), 1.29 (t, J =
7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 141.5 (dd, J = 4.1 and 2.1 Hz),
129.7 (td, J = 22.2 and 13.8 Hz), 129.2 (d, J = 1.3 Hz), 118.3 (td, J =
262.9 and 219.1 Hz), 64.8 (d, J = 6.7 Hz), 21.4, 16.4 (d, J = 5.6 Hz);
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ -108.5 (d, J = 118.0 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 6.5 (t, J = 118.0 Hz, 1P); IR (neat,
mL) was added and the mixture was placed at
0 °C. Diethyl
[(trimethylsilyl)difluoromethyl]phosphonate (neat, 325 mg, 1.25 mmol)
was added and the mixture was heated at 40 °C for 1 h, cooled to 0 °C
and allowed to stir at this temperature for 1 h. 1,10-Phenanthroline (90.1
mg, 1.00 mmol) was added followed by a solution of the corresponding
iodoarene (0.50 mmol). The rubber septum was removed, the tube was
sealed and the suspension was stirred for 16 h. The reaction mixture was
diluted with diethyl ether (30 mL), the organic layer was washed with
water (4 × 25 mL), brine (25 mL), dried over Na2SO4, and solvent was
carefully removed under vacuum. Reverse phase chromatography
(H2O/CH3CN, gradient: 9:1 to 0:1, rate: 1% CH3CN per minute) gave the
product.
cm−1
)
2985, 1617, 1515, 1260, 1011; HRMS (ESI+) calcd for
[M+H]+ C12H18F2O3P : 279.0962, found: 279.0957 (−1.8 ppm).
General procedures for the copper-mediated synthesis of diethyl
phosphono)difluoromethylthiolated derivatives
Diethyl
Prepared
[(3,5-dimethoxyphenyl)difluoromethyl]phosphonate
following the procedure from
2d.
3,5-
A
dimethoxybenzenediazonium tetrafluoroborate 1d. Reverse phase
chromatography (H2O/MeOH). Yield: 40% (65 mg, 0.5 mmol scale).
Yellow oil; 1H NMR (300 MHz, CDCl3): δ 6.74 (s, 2H), 6.53 (s, 1H), 4.27-
4.07 (m, 4H), 3.79 (s, 6H), 1.31 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3): δ 160.8 (d, J = 1.2 Hz), 134.6 (td, J = 22.1 and 14.1 Hz), 117.9
(td, J = 263.8 and 217.8 Hz), 104.3 (td, J = 7.1 and 2.3 Hz), 103.0 (dd, J
= 3.4 and 1.7 Hz), 64.9 (d, J = 6.7 Hz), 55.6, 16.4 (d, J = 5.6 Hz); 19F{1H}
NMR (CDCl3, CFCl3, 282 MHz) δ -108.5 (d, J = 115.5 Hz, 2F); 31P{1H}
NMR (CDCl3, 121 MHz) δ 6.2 (t, J = 115.6 Hz, 1P); IR (neat, cm−1) 2985,
1597, 1460, 1270, 1205, 1157, 1011; HRMS (ESI+) calcd for
[M+NH4]+ C13H23NF2O5P : 342.1282, found: 342.1274 (−2.3 ppm).
Method F:
In a glove box, a tube was loaded with CuSCN (61 mg, 0.50 mmol) and
CsF (228 mg, 1.50 mmol) and sealed with a rubber septum. Dry
acetonitrile (1 mL) was added and the mixture was placed at 0 °C.
Diethyl [(trimethylsilyl)difluoromethyl]phosphonate (neat, 325 mg, 1.25
mmol) was added and the mixture was heated at 40 °C for 1 h, cooled to
0 °C and allowed to stir at this temperature for 1 h. The corresponding
disulfide (0.50 mmol) was added. The rubber septum was removed, the
tube was sealed and the suspension was stirred for 16 h. The reaction
mixture was diluted with diethyl ether (30 mL), the organic layer was
washed with water (4 × 25 mL), brine (25 mL), dried over Na2SO4, and
solvent was carefully removed under vacuum. Reverse phase
chromatography (H2O/CH3CN, gradient: 9:1 to 0:1, rate: 1% CH3CN per
minute) gave the product.
Diethyl
[(3-benzyloxyphenyl)difluoromethyl]phosphonate
2e.
Prepared following the procedure A from 3-benzyloxybenzenediazonium
tetrafluoroborate 1e. Reverse phase chromatography (H2O/MeCN). Yield:
54% (100 mg, 0.5 mmol scale). Pale yellow oil; 1H NMR (300 MHz,
CDCl3): δ 7.36-7.25 (m, 5H), 7.17-7.12 (m, 3H), 6.99 (d, J = 8.1 Hz, 1H),
5.00 (s, 2H), 4.18-3.97 (m, 4H), 1.21 (t, J = 7.1 Hz, 6H); 13C NMR (75
MHz, CDCl3): δ 158.7 (d, J = 1.2 Hz), 136.6, 134.0 (td, J = 22.0 and 13.8
Hz), 129.7 (d, J = 1.2 Hz), 128.7, 128.2, 127.6, 118.8 (td, J = 6.9 and 2.3
Hz), 117.9 (td, J = 263.5 and 217.8 Hz), 112.6 (td, J = 7.1 and 2.3 Hz),
70.2, 64.9 (d, J = 6.7 Hz), 16.4 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3,
CFCl3, 282 MHz) δ -108.6 (d, J = 115.7 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 6.3 (t, J = 115.7 Hz, 1P); IR (neat, cm−1) 2985, 1587, 1442,
1268, 1012; HRMS (ESI+) calcd for [M+NH4]+ C18H25NF2O4P : 388.1489,
found: 388.1487 (−0.5 ppm).
Diethyl
[(4-methoxyphenyl)difluoromethyl]phosphonate
2a.
Prepared following the procedure A from 4-methoxybenzenediazonium
tetrafluoroborate 1a with 72% yield (106 mg, 0.5 mmol scale); the
procedure
B
from
di(4-methoxyphenyl)iodonium
trifluoromethanesulfonate 4a with 68% yield (100 mg, 0.5 mmol scale).
Reverse phase chromatography (H2O/MeCN). Yellow oil; 1H NMR (300
MHz, CDCl3): δ 7.56 (d, J = 8.3 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 4.49-
3.97 (m, 4H), 3.81 (s, 3H), 1.29 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3): δ 161.5 (dd, J = 3.6 and 1.7 Hz), 127.9 (td, J = 6.8 and 2.4 Hz),
124.6 (td, J = 22.7 and 14.0 Hz), 118.3 (td, J = 263.0 and 220.9 Hz),
113.9 (d, J = 1.2 Hz), 64.8 (d, J = 6.7 Hz), 55.4, 16.4 (d, J = 5.6 Hz);
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ -107.6 (d, J = 119.7 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 6.6 (t, J = 119.8 Hz, 1P); IR (neat,
Diethyl [(naphten-1-yl)difluoromethyl]phosphonate 2f. Prepared
following
the
procedure
A
from
naphthalene-1-diazonium
tetrafluoroborate 1f. Yield: 60% (94 mg, 0.5 mmol scale). Dark orange oil;
1H NMR (300 MHz, CDCl3): δ 8.45 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.2 Hz,
1H), 7.86 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.4 Hz, 1H), 7.59-7.48 (m, 3H),
4.29-4.01 (m, 4H), 1.25 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ
134.1 (d, J = 0.9 Hz), 132.1 (dd, J = 3.4 and 1.7 Hz), 129.9 (dd, J = 3.7
and 1.8 Hz), 128.6 (d, J = 2.5 Hz), 128.4 (td, J = 20.1 and 13.5 Hz),
126.9, 126.4 (td, J = 10.4 and 3.6 Hz), 126.3, 126.1 (td, J = 5.2 and 0.7
Hz), 124.4 (d, J = 1.7 Hz), 120.0 (td, J = 264.1 and 216.8 Hz), 64.8 (d, J
= 6.8 Hz), 16.3 (d, J = 5.6 Hz); 19F{1H} NMR (CDCl3, 282 MHz) δ -102.4
(d, J = 114.6 Hz, 2F); 31P{1H} NMR (CDCl3, CFCl3, 121 MHz) δ 6.7 (t, J =
114.7 Hz, 1P); IR (neat, cm−1) 2985, 1514, 1269; 1010; HRMS (ESI+)
calcd for [M+NH4]+ C15H21NF2O3P : 332.1227, found: 332.1233 (1.8 ppm).
cm−1
)
2985, 1614, 1515, 1250, 1011; HRMS (ESI+) calcd for
[M+H]+ C12H18F2O4P : 295.0911, found: 295.0906 (−1.7 ppm).
Diethyl
[(2-methoxyphenyl)difluoromethyl]phosphonate
2b.
Prepared following the procedure A from 2-methoxybenzenediazonium
tetrafluoroborate 1b. Yield: 60% (88 mg, 0.5 mmol scale). Yellow oil; 1H
NMR (300 MHz, CDCl3): δ 7.49 (d, J = 7.8 Hz, 1H), 7.41 (app. t, J = 7.9
Hz, 1H), 6.94-7.01 (m, 2H), 4.32-4.05 (m, 4H), 3.85 (s, 3H), 1.29 (t, J =
7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 157.8 (td, J = 3.3 and 2.0 Hz),
132.4 (dd, J = 3.2 and 1.6 Hz), 128.2 (td, J = 9.1 and 2.7 Hz), 120.9 (td, J
= 21.7 and 13.7 Hz), 120.4 (d, J = 0.8 Hz), 118.6 (td, J = 264.1 and 219.4
Hz), 112.2 (d, J = 0.9 Hz), 64.6 (d, J = 6.7 Hz), 55.9, 16.4 (d, J = 5.8 Hz);
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ -105.2 (d, J = 116.5 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 6.7 (t, J = 116.3 Hz, 1P); IR (neat,
cm−1) 2919, 1603, 1495, 1257, 1036, 1017; HRMS (ESI+) calcd for
[M+H]+ C12H18F2O4P : 295.0911, found: 295.0914 (1 ppm).
Diethyl [(4-chlorophenyl)difluoromethyl]phosphonate 2g. Prepared
following
tetrafluoroborate 1g with 37% yield (55 mg, 0.5 mmol scale); the
procedure from (4-chlorophenyl)(mesityl)iodonium
trifluoromethanesulfonate 4g with 52% yield (77 mg, 0.5 mmol scale).
the
procedure
A
from
4-chlorobenzenediazonium
B
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10.1002/chem.201703542
Chemistry - A European Journal
FULL PAPER
Reverse phase chromatography (H2O/MeCN). Dark yellow oil; 1H NMR
(300 MHz, CDCl3): δ 7.54 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 8.5 Hz, 2H),
4.29-4.08 (m, 4H), 1.30 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ
137.2 (dd, J = 4.7 and 2.4 Hz), 131.2 (td, J = 22.5 and 14.0 Hz), 128.9 (d,
J = 1.3 Hz), 127.8 (td, J = 6.8 and 2.3 Hz), 117.8 (td, J = 263.5 and 218.8
Hz), 65.0 (d, J = 6.8 Hz), 16.4 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3,
CFCl3, 282 MHz) δ -109.1 (d, J = 115.1 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 5.9 (t, J = 115.2 Hz, 1P); IR (neat, cm−1) 2986, 1602, 1492,
1270, 1256, 1012; HRMS (ESI+) calcd for [M+NH4]+ C11H18NF2O3PCl :
316.0681, found: 316.0675 (−1.9 ppm).
0.5 mmol scale). Orange oil; 1H NMR (300 MHz, CDCl3): δ 8.31 (d, J =
8.6 Hz, 2H), 7.81 (d, J = 7.9 Hz, 2H), 4.32-4.13 (m, 4H), 1.33 (t, J = 7.1
Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 149.5, 139.1 (td, J = 22.3 and 13.8
Hz), 127.8 (td, J = 6.7 and 2.2 Hz), 123.7 (d, J = 1.2 Hz), 117.3 (td, J =
264.3 and 216.3 Hz), 65.3 (d, J = 6.9 Hz), 16.5 (d, J = 5.4 Hz); 19F{1H}
NMR (CDCl3, CFCl3, 282 MHz) δ -110.1 (d, J = 110.8 Hz, 2F); 31P{1H}
NMR (CDCl3, 121 MHz) δ 5.1 (t, J = 110.9 Hz, 1P); IR (neat, cm−1) 2919,
1522, 1343, 1270, 1253, 1014;
[M+NH4]+ C11H18N2F2O5P : 327.0921, found: 327.0920 (−0.3 ppm).
HRMS (ESI+) calcd for
Diethyl
[2-(2,3-dihydrobenzofuran-3-yl)-1,1-
Diethyl [(3-bromophenyl)difluoromethyl]phosphonate 2h. Prepared
difluoromethyl]phosphonate 3. Prepared following the procedure A
from 2-(allyloxy)benzenediazonium tetrafluoroborate 1l. Reverse phase
chromatography (H2O/CH3CN). Yield: 68% (109 mg, 0.5 mmol scale).
Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.18-7.12 (m, 2H), 6.88 (dt, J =
7.5 and 0.9 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 4.74 (t, J = 9.0 Hz, 1H),
4.35-4.24 (m, 5H), 3.95-3.86 (m, 1H), 2.73-2.51 (m, 1H), 2.45-2.23 (m,
1H), 1.42-1.37 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 159.7, 128.9, 128.8,
124.2, 123.5 (td, J = 261.1 and 215.9 Hz), 120.8, 109.8, 64.8-64.7 (m),
38.7 (dt, J = 19.8 and 14.2 Hz), 35.5 (dt, J = 6.4 and 3.9 Hz),16.5 (d, J =
5.4 Hz), 1.15; 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −111.1 (dd, J =
298.2 and 105.4 Hz) and −113.3 (dd, J = 298.2 and 106.2 Hz); 31P{1H}
NMR (CDCl3, 121 MHz) δ 6.6 (t, J = 105.6 Hz, 1P); IR (neat, cm−1) ν:
2986, 1599, 1483, 1462, 1269, 1230, 1162,1013, 979; HRMS (ESI+)
calcd for [M+H]+ C14H20F2O4P: 321.1067, found: 321.1072 (1.6 ppm).
following
tetrafluoroborate 1h with 44% yield (75 mg, 0.5 mmol scale); the
procedure from (3-bromophenyl)(mesityl)iodonium
the
procedure
A
from
3-bromobenzenediazonium
B
trifluoromethanesulfonate 4h with 76% yield (129 mg, 0.5 mmol scale).
Reverse phase chromatography (H2O/MeCN). Orange oil; 1H NMR (300
MHz, CDCl3): δ 7.73 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.7 Hz,
1H), 7.32 (app. t, J = 7.9 Hz, 1H), 4.32-4.09 (m, 4H), 1.31 (t, J = 7.1 Hz,
6H); 13C NMR (75 MHz, CDCl3): δ 134.7 (td, J = 22.3 and 13.9 Hz), 134.0
(dd, J = 3.6 and 1.7 Hz), 130.2 (d, J = 1.3 Hz), 129.4 (td, J = 7.1 and 2.4
Hz), 125.1 (td, J = 6.7 and 2.2 Hz), 117.3 (td, J = 264.1 and 218.0 Hz),
65.1 (d, J = 6.8 Hz), 16.4 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3,
282 MHz) δ -109.4 (d, J = 113.9 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz)
δ 5.7 (t, J = 114.0 Hz, 1P); IR (neat, cm−1) 2985, 1574, 1476, 1270, 1242,
1012; HRMS (ESI+) calcd for [M79Br+NH4]+ C11H18NF2O3P79Br : 360.0176,
found: 360.0170 (−1.7 ppm).
Diethyl [(phenyl)difluoromethyl]phosphonate 2l. Prepared following
the procedure B from diphenyliodonium trifluoromethanesulfonate 4l.
Reverse phase chromatography (H2O/CH3CN). Yield: 71% (94 mg, 0.5
mmol scale). Caution: this compound is volatile. Pale yellow oil; 1H NMR
(300 MHz, CDCl3): δ 7.62 (d, J = 7.2 Hz, 2H), 7.47-7.45 (m, 3H), 4.28-
4.07 (m, 4H), 1.31 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 132.7
(td, J = 22.0 and 13.7 Hz), 130.8 (dd, J = 3.9 and 1.9 Hz), 128.5 (d, J =
1.3 Hz), 126.3 (td, J = 6.9 and 2.4 Hz), 118.1 (td, J = 263.1 and 218.2
Hz), 64.8 (d, J = 6.7 Hz), 16.4 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3,
CFCl3, 282 MHz) δ −109.0 (d, J = 116.3 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 6.4 (t, J = 116.3 Hz, 1P); IR (neat, cm−1) ν: 2986, 2917, 1452,
1257, 1011; HRMS (EI+) calcd for [M]+ C11H15F2O3P : 264.0727, found:
264.0726 (−0.2 ppm).
Diethyl [(4-{trifluoromethyl}phenyl)difluoromethyl]phosphonate 2i.
Prepared
following
the
procedure
A
from
4-
(trifluoromethyl)benzenediazonium tetrafluoroborate 1i. Yield: 36% (60
mg, 0.5 mmol scale). Orange oil; 1H NMR (300 MHz, CDCl3): δ 7.75-7.65
(m, 4H), 4.32-4.10 (m, 4H), 1.31 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3): δ 136.9-136.0 (m), 133.6-132.2 (m), 127.0 (td, J = 6.8 and 2.3
Hz), 125.6 (qd, J = 3.7 and 1.3 Hz), 120.1 (q, J = 272.7 Hz), 117.5 (td, J
= 263.6 and 217.3 Hz), 65.1 (d, J = 6.8 Hz), 16.4 (d, J = 5.5 Hz); 19F{1H}
NMR (CDCl3, CFCl3, 282 MHz) δ -63.5 (s, 3F), -109.9 (d, J = 112.8 Hz,
2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.6 (t, J = 112.8 Hz, 1P); IR (neat,
cm−1) 2992, 1414, 1266, 1127, 1066, 1013; HRMS (ESI+) calcd for
[M+NH4]+ C12H18NF5O3P : 350.0944, found: 350.0938 (−1.7 ppm).
Diethyl ((4-ethylphenyl)difluoromethyl)phosphonate 2m. Prepared
Ethyl 4-[(diethoxyphosphoryl)difluoromethyl]benzoate 2j. Prepared
following the procedure A from 4-(ethoxycarbonyl)benzenediazonium
tetrafluoroborate 1j with 35% yield (59 mg, 0.5 mmol scale); the
following the procedure
B
from (4-ethylphenyl)(mesityl)iodonium
trifluoromethanesulfonate 4m. Reverse phase chromatography
(H2O/CH3CN). Yield: 53% (78 mg, 0.5 mmol scale). Brown oil; 1H NMR
(300 MHz, CDCl3): δ 7.45 (d, J = 7.2 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H),
4.20-4.00 (m, 4H), 2.61 (q, J = 7.6 Hz, 2H), 1.26-1.21 (m, 6H), 1.17 (t, J =
7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 147.3 (dt, J = 2.0 Hz), 129.9
(dt, J = 22.2 and 13.6 Hz), 128.0 (d, J = 1.3 Hz), 126.3 (td, J = 7.0 and
2.4 Hz), 118.2 (td, J = 262.8 and 219.6 Hz), 64.7 (d, J = 6.7 Hz), 28.8,
16.4 (d, J = 5.7 Hz), 15.4; 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ
−108.3 (d, J = 118.6 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.6 (t, J
= 118.3 Hz, 1P); IR (neat, cm−1) ν: 2971, 2935, 1616, 1415, 1261, 1164,
1118, 1037, 1013, 976; HRMS (ESI+) calcd for [M+H]+ C13H20F2O3P:
293.1118, found: 293.1118 (0.0 ppm).
procedure
B
from
(((4-ethoxycarbonyl)phenyl)(mesityl)iodonium
trifluoromethanesulfonate 4j with 51% yield (86 mg, 0.5 mmol scale).
Reverse phase chromatography (H2O/MeCN). Yellow oil; 1H NMR (300
MHz, CDCl3): δ 8.11 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 4.38 (q,
J = 7.1 Hz, 2H), 4.27-4.07 (m, 4H), 1.39 (t, J = 7.1 Hz, 3H), 1.30 (t, J =
7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 165.8, 136.9 (td, J = 21.9 and
13.6 Hz), 132.8 (dd, J = 3.6 and 1.7 Hz), 129.7 (d, J = 1.3 Hz), 126.5 (td,
J = 6.8 and 2.3 Hz), 117.8 (td, J = 263.6 and 216.9 Hz), 65.0 (d, J = 6.8
Hz), 61.5, 16.4 (d, J = 5.5 Hz), 14.4; 19F{1H} NMR (CDCl3, CFCl3,
282 MHz) δ -109.9 (d, J = 113.5 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz)
δ
5.8 (t, J = 113.4 Hz, 1P); IR (neat, cm−1) 2985, 1719, 1270, 1107,
1011; HRMS (ESI+) calcd for [M+NH4]+ C14H23NF2O5P : 354.1282, found:
354.1291 (2.5 ppm).
Diethyl [(1,1'-biphenyl)-4-yldifluoromethyl]phosphonate 2n. Prepared
following the procedure
trifluoromethanesulfonate
B
from [1,1'-biphenyl]-4-yl(mesityl)iodonium
4n. Reverse phase chromatography
Diethyl [(4-nitrophenyl)difluoromethyl]phosphonate 2k. Prepared
(H2O/CH3CN). Yield: 65% (111 mg, 0.5 mmol scale). Brown oil; 1H NMR
(300 MHz, CDCl3): δ 7.72-7.66 (m, 4H), 7.61 (d, J = 7.7 Hz, 2H), 7.46 (t,
J = 7.0 Hz, 2H), 7.41-7.36 (m, 1H), 4.32-4.12 (m, 4H), 1.34 (t, J = 6.9 Hz,
6H); 13C NMR (75 MHz, CDCl3): δ 143.7 (dt, J = 2.1Hz), 140.1, 131.5 (dt,
J = 22.4 and 13.4 Hz), 131.4, 129.0, 128.1, 127.4-127.3 (m), 126.8 (td, J
= 6.8 and 2.1 Hz), 118.2 (td, J = 263.9 and 216.6 Hz), 64.9 (d, J = 6.8
following
tetrafluoroborate 1k with 18% yield (28 mg, 0.5 mmol scale); the
procedure from (4-nitrophenyl)(mesityl)iodonium
the
procedure
A
from
4-nitrobenzenediazonium
B
trifluoromethanesulfonate 4k with 68% yield (105 mg, 0.5 mmol scale);
the procedure E from 1-iodo-4-nitrobenzene 16k with 47% yield (72 mg,
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10.1002/chem.201703542
Chemistry - A European Journal
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Hz), 16.4 (d, J = 5.7 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ
−108.8 (d, J = 116.6 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.4 (t, J
= 116.4 Hz, 1P); IR (neat, cm−1) ν: 2984, 1611, 1394, 1267, 1166, 1114,
1013, 978; HRMS (ESI+) calcd for [M+NH4]+ C17H23NF2O3P: 358.1384,
found: 358.1383 (-0.3 ppm).
1164,
1124,
1013,
980;
HRMS
(ESI+)
calcd
for
[M+NH4]+ C11H17NCl2F2O3P: 350.0291, found: 350.0291 (0.0 ppm).
Diethyl [(4-acetylphenyl)difluoromethyl]phosphonate 2s. Prepared
following the procedure from (4-acetylphenyl)(mesityl)iodonium
B
tetrafluoroborate 4s. Reverse phase chromatography (H2O/MeOH).
Yield: 70% (107 mg, 0.5 mmol scale). Colourless oil; 1H NMR (300 MHz,
CDCl3): δ 8.01 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 4.28-4.09 (m,
4H), 2.61 (s, 3H), 1.30 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ
197.4, 138.9 (dd, J = 3.6 and 1.9 Hz), 137.1 (td, J = 21.9 and 13.6 Hz),
128.4 (d, J = 1.2 Hz), 126.7 (td, J = 6.7 and 2.2 Hz), 117.7 (td, J = 263.6
and 216.8 Hz), 65.0 (d, J = 6.8 Hz), 26.8, 16.4 (d, J = 5.5 Hz); 19F{1H}
NMR (CDCl3, CFCl3, 282 MHz) δ −105.3 (d, J = 115.3 Hz, 2F); 31P{1H}
NMR (CDCl3, 121 MHz) δ 5.9 (t, J = 115.0 Hz, 1P); IR (neat, cm−1) ν:
3670, 2988, 1689, 1613, 1407, 1264, 1011; HRMS (ESI+) calcd for
[M+H]+ C13H18F2O4P : 307.0911, found: 307.0900 (−3.6 ppm).
Diethyl [(3-(4-nitrophenoxy)phenyl)difluoromethyl]phosphonate 2o.
Prepared
following
the
procedure
B
from
mesityl(3-(4-
nitrophenoxy)phenyl)iodonium trifluoromethanesulfonate 4o. Reverse
phase chromatography (H2O/CH3CN). Yield: 71% (142 mg, 0.5 mmol
scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 8.24-8.19 (m, 2H), 7.55-
7.48 (m, 2H), 7.34 (s, 1H), 7.22-7.19 (m, 1H), 7.04-7.01 (m, 2H), 4.31-
4.11 (m, 4H), 1.32 (t, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 162.7,
154.9, 143.1, 135.3 (td, J = 22.7 and 14.0 Hz), 130.6 (d, J = 1.0 Hz),
126.1, 123.1 (dt, J = 6.7 and 2.3 Hz), 122.7 (d, J = 1.9 Hz), 118.5 (dt, J =
6.9 and 2.1 Hz), 117.7 (dt, J = 264.3 and 218.6 Hz), 117.5, 65.1 (d, J =
6.8 Hz), 16.4 (d, J = 5.3 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ
−109.1 (d, J = 114.0 Hz, 2F ); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.8 (t, J
= 113.8 Hz, 1P); IR (neat, cm−1) ν: 2986, 2917, 1583, 1517, 1487, 1442,
1343, 1263, 1237, 1163, 1111, 1013; HRMS (ESI+) calcd for
[M+NH4]+ C17H22F2N2O6P: 419.1184, found: 419.1183 (-0.2 ppm).
Diethyl [(3-formylphenyl)difluoromethyl]phosphonate 2t. Prepared
following the procedure
B
from (3-formylphenyl)(mesityl)iodonium
tetrafluoroborate 4t. Reverse phase chromatography (H2O/MeOH). Yield:
57% (83 mg, 0.5 mmol scale). Colourless oil; 1H NMR (300 MHz, CDCl3):
δ 10.04 (s, 1H), 8.10 (s, 1H), 7.99 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz,
1H), 7.62 (dd, J = 7.6 and 7.6 Hz, 1H), 4.29-4.10 (m, 4H), 1.30 (t, J = 7.1
Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 191.4, 136.6 (d, J = 0.7 Hz), 134.1
(td, J = 22.6 and 14.0 Hz), 132.2 (td, J = 6.5 and 2.0 Hz), 131.6 (m),
129.5 (d, J = 0.9 Hz), 127.9 (td, J = 6.8 and 2.3 Hz), 117.6 (td, J = 263.6
and 218.0 Hz), 65.2 (d, J = 6.8 Hz), 16.4 (d, J = 5.5 Hz); 19F{1H} NMR
(CDCl3, CFCl3, 282 MHz) δ −109.5 (d, J = 113.6 Hz, 2F); 31P{1H} NMR
(CDCl3, 121 MHz) δ 5.6 (t, J = 113.6 Hz, 1P); IR (neat, cm−1) ν: 3676,
2988, 1720, 1611, 1394, 1250, 1212, 1014, 577; HRMS (ESI+) calcd for
[M+H]+ C12H16F2O4P : 293.0754, found: 293.0740 (−4.8 ppm).
Diethyl [(4-fluorophenyl)difluoromethyl]phosphonate 2p. Prepared
following the procedure
trifluoromethanesulfonate
B
4p.
from (4-fluorophenyl)(mesityl)iodonium
Reverse phase chromatography
(H2O/CH3CN). Yield: 63% (44 mg, 0.25 mmol scale). Colourless oil; 1H
NMR (300 MHz, CDCl3): δ 7.64-7.59 (m, 2H), 7.16-7.11 (m, 2H), 4.29-
4.09 (m, 4H), 1.31 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 164.3
(m), 128.7 (m), 117.9 (td, J = 263.5 and 220.1 Hz), 115.8 (dd, J = 22.1
and 1.2 Hz), 65.0 (d, J = 6.8 Hz), 16.5 (d, J = 5.6 Hz); 19F{1H} NMR
(CDCl3, CFCl3, 282 MHz) δ −108.2 (d, J = 116.6 Hz, 2F), −109.9 (s, 1F);
31P{1H} NMR (CDCl3, 121 MHz) δ 6.1 (t, J = 116.0 Hz, 1P); IR (neat,
cm−1) ν: 2921, 2852, 1609, 1513, 1463, 1256, 1022; HRMS (ESI+) calcd
for [M+NH4]+ C11H18F3NO3P : 300.0976, found: 300.0970 (−2 ppm). Note
that despite a long acquisition time, the aromatic quaternary carbon
bearing the CF2 group is missing.
Diethyl [(pyridin-3-yl)difluoromethyl]phosphonate 6a. Prepared
following the procedure
trifluoromethanesulfonate
C
5a.
from (pyridin-3-yl)(mesityl)iodonium
Reverse phase chromatography
(H2O/MeOH). Yield: 44% (58 mg, 0.5 mmol scale). Caution: this
compound is volatile. Yellow oil; 1H NMR (300 MHz, CDCl3): δ 8.83 (br. s,
1H), 8.73 (d, J = 4.7 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.40 (dd, J = 8.0
and 4.9 Hz, 1H), 4.32-4.13 (m, 4H), 1.33 (2 × t, J = 7.1 Hz, 6H); 13C NMR
(75 MHz, CDCl3): δ 151.9 (dd, J = 4.0 and 2.0 Hz), 147.5 (td, J = 7.3 and
2.5 Hz), 134.3 (td, J = 6.5 and 2.0 Hz), 128.9 (td, J = 22.4 and 13.6 Hz),
123.2, 117.3 (td, J = 263.5 and 218.7 Hz), 65.1 (d, J = 6.9 Hz), 16.4 (d, J
= 5.4 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −110.4 (d, J = 112.8
Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.4 (t, J = 112.8 Hz, 1P); IR
(neat, cm−1) ν: 2987, 2915, 1594, 1480, 1422, 1263, 1011; HRMS (EI+)
calcd for [M]+ C10H14F2NO3P : 265.0679, found: 265.0684 (1.9 ppm).
Diethyl [(4-bromophenyl)difluoromethyl]phosphonate 2q. Prepared
following the procedure
trifluoromethanesulfonate
B
4q.
from (4-bromophenyl)(mesityl)iodonium
Reverse phase chromatography
(H2O/CH3CN). Yield: 51% (87 mg, 0.5 mmol scale). Yellow oil; 1H NMR
(300 MHz, CDCl3): δ 7.59 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H),
4.29-4.09 (m, 4H), 1.32 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ
131.8 (d, J = 1.3 Hz), 131.8 (td, J = 22.6 and 13.9 Hz), 128.0 (td, J = 6.8
and 2.3 Hz), 125.6 (m), 117.8 (td, J = 263.5 and 218.5 Hz), 65.0 (d, J =
6.8 Hz), 16.4 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ
−109.3 (d, J = 114.6 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.8 (t, J
= 114.9 Hz, 1P); IR (neat, cm−1) ν: 2921, 2853, 1464, 1378, 1280, 1242,
1060, 1021; HRMS (ESI+) calcd for [M+NH4]+ C11H18BrF2NO3P: 360.0176,
found: 360.0172 (−1.1 ppm).
Diethyl
following the procedure C from (6-chloropyridin-3-yl)(mesityl)iodonium
trifluoromethanesulfonate 5b. Reverse phase chromatography
[ (pyridin-3-yl)difluoromethyl]phosphonate 6b. Prepared
(H2O/MeOH). Yield: 57% (85 mg, 0.5 mmol scale). Note that the product
is contaminated with 10% of an unknown product. Yellow oil; 1H NMR
(300 MHz, CDCl3): δ 8.61-8.59 (m, 1H), 7.92-7.87 (m, 1H), 7.45-7.42 (m,
1H), 4.34-4.16 (m, 4H), 1.31 ( 2 × t, J = 7.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3): δ 154.2 (dd, J = 4.3 and 2.2 Hz), 147.7 (td, J = 7.4 and 2.6 Hz),
137.1 (td, J = 6.1 and 1.8 Hz), 128.0 (td, J = 22.9 and 13.9 Hz), 124.2 (d,
J = 1.1 Hz), 117.0 (td, J = 263.8 and 219.1 Hz), 65.3 (d, J = 6.9 Hz), 16.4
(d, J = 5.4 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −110.4 (d, J =
111.8 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.0 (t, J = 111.7 Hz,
1P); IR (neat, cm−1) ν: 2986, 2917, 1591, 1461, 1372, 1263, 1107, 1012,
575; HRMS (EI+) calcd for [M]+ C10H13ClF2NO3P : 299.0290, found:
299.0277 (−4.2 ppm).
Diethyl
[(3,4-dichlorophenyl)difluoromethyl)]phosphonate
2r.
Prepared following the procedure B from bis(3,4-dichlorophenyl)iodonium
tetrafluoroborate 4r. Reverse phase chromatography (H2O/CH3CN).
Yield: 77% (128 mg, 0.5 mmol scale). Brown oil; 1H NMR (300 MHz,
CDCl3): δ 7.68 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.4 and 0.6
Hz, 1H), 4.30-4.11 (m, 4H), 1.34-1.29 (m, 6H); 13C NMR (75 MHz,
CDCl3): δ 135.5 (dt, J = 2.3 Hz), 133.0 (d, J = 1.3 Hz), 132.7 (dt, J = 22.9
and 14.1 Hz), 130.7 (d, J = 1.3 Hz), 128.4 (td, J = 7.3 and 2.6 Hz), 125.7
(td, J = 7.3 and 2.6 Hz), 116.8 (td, J = 266.1 and 218.4 Hz), 65.0 (d, J =
6.9 Hz), 16.4 (d, J = 5.4 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ
−109.4 (d, J = 114.0 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.5 (t, J
= 113.9 Hz, 1P); IR (neat, cm−1) ν: 2985, 2932, 1470, 1385, 1271, 1237,
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10.1002/chem.201703542
Chemistry - A European Journal
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Diethyl [(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)difl
uoromethyl]phosphonate 6c. Prepared following the procedure B from
(1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)(phenyl)iodonium
trifluoromethane-sulfonate 5c. Reverse phase chromatography
(H2O/MeOH). Yield: 34% (55 mg, 0.5 mmol scale). Yellow oil; 1H NMR
(300 MHz, CD3OD): δ 7.94 (dd, J = 3.0 and 1.3 Hz, 1H), 4.33-4.21 (m,
4H), 3.41 (s, 3H), 3.21 (s, 3H), 1.32 (2 × t, J = 7.1 Hz, 6H); 13C NMR (75
MHz, CD3OD): δ 162.0 (m), 153.6, 147.5 (td, J = 10.7 and 3.8 Hz), 118.8
(td, J = 264.2 and 226.9 Hz), 107.0 (td, J = 22.9 and 14.9 Hz), 67.5 (d, J
= 7.0 Hz), 38.6, 29.0, 17.6 (d, J = 5.6 Hz); 19F{1H} NMR (CD3OD,
282 MHz) δ −107.7 (d, J = 116.7 Hz, 2F); 31P{1H} NMR (CD3OD,
121 MHz) δ 5.7 (t, J = 116.7 Hz, 1P); IR (neat, cm−1) ν: 2996, 1716, 1663,
1482, 1452, 1365, 1262, 1013; HRMS (ESI+) calcd for
[M+H]+ C11H18F2N2O5P: 327.0921, found: 327.0917 (−1.2 ppm).
methylstyryl)(phenyl)iodonium tetrafluoroborate 7b. Reverse phase
chromatography (H2O/CH3CN). Yield: 92% (140 mg, 0.5 mmol scale).
Colourless oil; 1H NMR (300 MHz, CDCl3): δ 7.48-7.46 (m, 1H), 7.37-7.29
(m, 1H), 7.24-7.16 (m, 3H), 6.27-6.12 (m, 1H), 4.37-4.20 (m, 4H), 2.38 (s,
3H), 1.38 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 136.7 (m),
135.1 (td, J = 10.7 and 6.1 Hz), 133.6 (m), 130.7, 129.4, 126.4, 126.2 (m),
120.2 (td, J = 21.1 and 12.9 Hz), 117.6 (td, J = 259.5 and 220.8 Hz), 64.8
(d, J = 6.7 Hz), 19.7, 16.5 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3,
282 MHz)
δ
−108.7 (d, J = 115.1 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 6.4 (t, J = 115.1 Hz, 1P); IR (neat, cm−1) ν: 2985, 1650, 1486,
1393, 1266, 1013, 750, 571; HRMS (EI+) calcd for [M]+ C14H19F2O3P :
304.1040, found: 304.1053 (4.3 ppm).
Diethyl [(E)-1,1-difluoro-3-(2-fluorophenyl)allyl]phosphonate 8c.
Prepared
following
the
procedure
B
from
(E)-(2-
Diethyl
following the procedure
trifluoromethanesulfonate
(
(quinolin-6-yl)difluoromethyl)phosphonate 6d. Prepared
fluorostyryl)(phenyl)iodonium tetrafluoroborate 7c. Reverse phase
chromatography (H2O/CH3CN). Yield: 83% (128 mg, 0.5 mmol scale).
Yellow oil; 1H NMR (300 MHz, CDCl3): δ 7.49-7.44 (m, 1H), 7.34-7.27 (m,
1H), 7.23-7.03 (m, 3H), 6.49-6.34 (m, 1H), 4.36-4.20 (m, 4H), 1.37 (t, J =
7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 161.0 (m), 131.0 (d, J = 8.7
Hz), 130.0 (m), 128.6 (m), 124.5 (d, J = 3.6 Hz), 122.4 (m), 121.6 (m),
117.4 (td, J = 259.9 and 220.3 Hz), 116.2 (d, J = 21.9 Hz), 64.9 (d, J =
6.8 Hz), 16.5 (d, J = 5.4 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ
−109.2 (d, J = 114.4 Hz, 2F), −116 (s, 1F); 31P{1H} NMR (CDCl3,
121 MHz) δ 6.2 (t, J = 114.4 Hz, 1P); IR (neat, cm−1) ν: 2918, 1654, 1613,
1580, 1489, 1267, 1012, 755; HRMS (EI+) calcd for [M]+ C13H16F3O3P :
308.0789, found: 308.0775 (−4.6 ppm).
B
5d.
from mesityl(quinolin-6-yl)iodonium
Reverse phase chromatography
(H2O/CH3OH). Yield: 29% (45 mg, 0.5 mmol scale). Brown oil; 1H NMR
(300 MHz, CDCl3): δ 8.99 (d, J = 3.2 Hz, 1H), 8.24 (d, J = 8.8 Hz, 1H),
8.18 (d, J = 9.0 Hz, 1H), 8.13 (s, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.47 (dd, J
= 8.2 and 4.4 Hz, 1H), 4.30-4.10 (m, 4H), 1.31 (t, J = 7.0 Hz, 6H); 13C
NMR (75 MHz, CDCl3): δ 152.2, 148.9 (d, J = 1.5 Hz), 137.1, 130.8 (dt, J
= 22.1 and 13.6 Hz), 130.1 (d, J = 0.8 Hz), 127.5 (d, J = 1.2 Hz), 126.8
(td, J = 7.5 and 3.2 Hz), 126.5 (td, J = 5.9 and 1.6 Hz), 122.1, 117.8 (dt, J
= 264.7 and 216.5 Hz), 65.0 (d, J = 6.8 Hz), 16.4 (d, J = 5.5 Hz); 19F{1H}
NMR (CDCl3, CFCl3, 282 MHz) δ −108.7 (d, J = 114.5 Hz, 2F ); 31P{1H}
NMR (CDCl3, 121 MHz) δ 6.1 (t, J = 115.0 Hz, 1P); IR (neat, cm−1) ν:
2985, 2934, 1501, 1464, 1444, 1393, 1370, 1268, 1245, 1179, 1121,
1012, 979; HRMS (ESI+) calcd for [M+H]+ C14H17F2NO3P: 316.0914,
found: 316.0912 (-0.6 ppm).
Diethyl [(E)-1,1-difluoro-3-cyclohexylallyl]phosphonate 8d. Prepared
following the procedure B from (E)-(2-cyclohexylvinyl)(phenyl)iodonium
tetrafluoroborate 7d. Reverse phase chromatography (H2O/CH3CN).
Yield: 87% (129 mg, 0.5 mmol scale), 72% (725 mg, 3.4 mmol scale).
Colourless oil; 1H NMR (300 MHz, CDCl3): δ 6.27-6.17 (m, 1H), 5.66-5.52
(m, 1H), 4.31-4.14 (m, 4H), 2.07 (app. br. s, 1H), 1.75-1.63 (m, 4H), 1.34
(t, J = 7.1 Hz, 6H), 1.25-1.04 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 145.3
(td, J = 9.7 and 5.8 Hz), 118.6 (td, J = 21.3 and 13.3 Hz), 117.3 (td, J =
258.8 and 220.2 Hz), 64.6 (d, J = 6.7 Hz), 40.2, 31.9 (m), 26.0, 25.8, 16.4
(d, J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −108.7 (d, J =
116.2 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.4 (t, J = 116.2 Hz,
1P); IR (neat, cm−1) ν: 2926, 1668, 1450, 1269, 1018, 972, 562; HRMS
(ESI+) calcd for [M+NH4]+ C13H27F2NO3P: 314.1697, found: 314.1687
(−3.2 ppm).
Diethyl [(phenyl)difluoromethyl]phosphonate 6e. Prepared following
the
trifluoromethanesulfonate
procedure
B
from
Reverse
phenyl(thiophen-2-yl)iodonium
phase chromatography
5e.
(H2O/MeOH). Yield: 76% (103 mg, 0.5 mmol scale), 66% (606 mg, 3.4
mmol scale). Pale yellow oil; 1H NMR (300 MHz, CDCl3): δ 7.47-7.45 (m,
2H), 7.07-7.04 (m, 1H), 4.30-4.11 (m, 4H), 1.30 (t, J = 7.1 Hz, 6H); 13C
NMR (75 MHz, CDCl3): δ 133.1 (td, J = 26.3 and 17.2 Hz), 128.1 (td, J =
6.4 and 3.1 Hz), 127.9 (dd, J = 4.0 and 2.0 Hz), 126.3 (d, J = 1.0 Hz),
115.6 (td, J = 261.1 and 224.9 Hz), 64.1 (d, J = 6.7 Hz), 16.4 (d, J = 5.5
Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −97.4 (d, J = 114.6 Hz,
2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.1 (t, J = 114.6 Hz, 1P); IR (neat,
cm−1) ν: 2920, 2847, 1431, 1271, 1240, 1011; HRMS (EI+) calcd for
[M]+ C9H13F2O3PS: 270.0291, found: 270.0286 (−2.0 ppm).
Diethyl [(E)-1,1-difluoro-4-phenylbut-2-en-1-yl)]phosphonate 8e.
Prepared following the procedure B from (E)-phenyl(3-phenylprop-1-en-
1-yl)-iodonium tetrafluoroborate 7e. Reverse phase chromatography
(H2O/CH3CN). Yield: 94% (72 mg, 0.25 mmol scale). Colourless oil; 1H
NMR (300 MHz, CDCl3): δ 7.37-7.29 (m, 3H), 7.22 (d, J = 7.2 Hz, 2H),
6.51-6.46 (m, 1H), 5.82-5.68 (m, 1H), 4.36-4.18 (m, 4H), 3.53 (app. br. s,
2H), 1.37 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 138.7 (td, J =
10.2 and 5.9 Hz), 138.0 (dd, J = 2.7 and 1.3 Hz), 128.7, 128.7, 126.7,
122.2 (td, J = 21.5 and 13.2 Hz), 117.0 (td, J = 259.0 and 220.0 Hz), 64.6
(d, J = 6.7 Hz), 38.4, 16.4 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3,
Diethyl [(E)-1,1-difluoro-3-phenylallyl]phosphonate 8a. Prepared
following the procedure
B from (E)-(2-phenylvinyl)(phenyl)iodonium
tetrafluoroborate 7a with 76% yield (110 mg, 0.5 mmol scale); the
procedure D from (E)-(2-bromovinyl)benzene 15a with 72% yield (104
mg, 0.5 mmol scale). Reverse phase chromatography (H2O/MeCN).
Colourless oil; 1H NMR (300 MHz, CDCl3): δ 7.47-7.43 (m, 2H), 7.40-7.34
(m, 3H), 7.12-7.04 (m, 1H), 6.37-6.23 (m, 1H), 4.37-4.20 (m, 4H), 1.37 (t,
J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 137.2 (td, J = 10.7 and 6.1
Hz), 134.5 (dd, J = 3.0 and 1.5 Hz), 129.6, 128.9, 127.5 (m), 118.9 (td, J
= 21.2 and 13.0 Hz), 117.6 (td, J = 259.7 and 221.1 Hz), 64.8 (d, J = 6.8
Hz), 16.5 (d, J = 5.4 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ
−108.8 (d, J = 114.7 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.4 (t, J
= 114.7 Hz, 1P); IR (neat, cm−1) ν: 2985, 1652, 1580, 1497, 1451, 1266,
1180, 1012, 749, 691; HRMS (ESI+) calcd for [M+NH4]+ C13H21F2NO3P:
308.1227, found: 308.1230 (1.0 ppm).
282 MHz)
δ
−109.3 (d, J = 114.8 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 6.5 (t, J = 114.8 Hz, 1P); IR (neat, cm−1) ν: 2986, 1669, 1604,
1497, 1455, 1268, 1016, 974, 700; HRMS (EI+) calcd for
[M]+ C14H19F2O3P : 304.1040, found: 304.1050 (3.4 ppm).
Diethyl [(1H-inden-2-yl)difluoromethyl]phosphonate 8f. Prepared
following the procedure
B
from (1H-inden-2-yl)(phenyl)iodonium
tetrafluoroborate 7f. Reverse phase chromatography (H2O/MeOH). Yield:
67% (101 mg, 0.5 mmol scale). Yellow oil; 1H NMR (300 MHz, CDCl3): δ
7.51-7.45 (m, 2H), 7.34-7.28 (m, 3H), 4.37-4.20 (m, 4H), 3.70 (br. s, 2H),
1.37 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3): δ 144.0, 142.8,
Diethyl [(E)-1,1-difluoro-3-(2-methylphenyl)allyl]phosphonate 8b.
Prepared
following
the
procedure
B
from
(E)-(2-
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10.1002/chem.201703542
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138.4 (m), 134.8 (td, J = 8.4, 5.8 Hz), 127.0, 126.7, 124.3, 122.8, 117.8
(td, J = 258.2, 220.7 Hz), 65.0 (d, J = 6.7 Hz), 38.3, 16.7 (d, J = 5.4 Hz);
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −105.3 (d, J = 115.2 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 5.9 (t, J = 115.3 Hz, 1P); IR (neat,
cm−1) ν: 2926, 1718, 1462, 1394, 1268, 1164, 1014; HRMS (ESI+) calcd
for [M+H]+ C14H18F2O3P: 303.0962, found: 303.0948 (−4.6 ppm).
(dt, J = 265.4 and 218.4 Hz), 64.8 (d, J = 6.7 Hz), 50.6, 48.0, 44.5, 37.9,
35.9, 31.6, 29.5, 26.4, 25.7, 21.7, 16.4 (d, J = 5.6 Hz), 13.9; 19F{1H}
NMR (CDCl3, CFCl3, 282 MHz) δ −108.4 (d, J = 117.9 Hz, 2F); 31P{1H}
NMR (CDCl3, 121 MHz) δ 6.5 (t, J = 117.8 Hz, 1P); IR (neat, cm−1) ν:
2933, 1737, 1259, 1123, 1015, 910, 727; HRMS (ESI+) calcd for
[M+NH4]+ C23H35NF2O4P: 458.2272, found: 458.2279 (1.5 ppm).
(E)-(diethoxy-λ4-sulfanylidene)(1,1-difluoro-3-phenylallyl)phosphane
9. Prepared following the procedure B from (E)-phenyl(styryl)iodonium
Diethyl [(Z)-1,1-difluoro-3-phenylallyl]phosphonate 8g. Prepared
following the procedure D from (Z)-(2-iodovinyl)benzene 15g. Reverse
phase chromatography (H2O/CH3CN). Yield: 79% (115 mg, 0.5 mmol
scale). Colourless oil; 1H NMR (300 MHz, CDCl3): δ 7.46 (d, J = 8.0 Hz,
2H), 7.35-7.28 (m, 3H), 6.93 (dt, J = 12.9 and 3.1 Hz, 1H), 5.84-5.67 (m,
1H), 4.29-4.16 (m, 4H), 1.32 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3): δ 139.1 (q, J = 6.6 Hz), 134.8 (d J = 1.4 Hz), 129.3 (dt, J = 3.9
and 1.2 Hz), 128.5, 127.9, 120.1 (td, J = 20.9 and 13.6 Hz), 117.6 (td, J
= 260.7 and 220.5 Hz), 64.8 (d, J = 6.5 Hz), 16.4 (d, J = 5.3 Hz); 19F{1H}
NMR (CDCl3, CFCl3, 282 MHz) δ −104.4 (d, J = 111.6 Hz, 2F); 31P{1H}
NMR (CDCl3, 121 MHz) δ 6.7 (t, J = 111.4 Hz, 1P); IR (neat, cm−1) ν:
2985, 2916, 1645, 1495, 1446, 1393, 1269, 1196, 1139, 1093, 1011,
977; HRMS (ESI+) calcd for [M+NH4]+ C13H21NF2O3P: 308.1227, found:
308.1215 (-3.9 ppm).
tetrafluoroborate
7a
and
O,O-diethyl
(difluoro(trimethylsilyl)methyl)phosphonothioate.
Reverse
phase
chromatography (H2O/CH3CN). Yield: 63% (48 mg, 0.25 mmol scale).
Yellow oil; 1H NMR (300 MHz, CDCl3): δ 7.48-7.45 (m, 2H), 7.41-7.36 (m,
3H), 7.08 (dq, J = 16.3 and 2.9 Hz, 1H), 6.40-6.26 (m, 1H), 4.32-4.21 (m,
4H), 1.35 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 137.1 (td, J =
10.4 and 6.5 Hz), 134.7 (d, J = 1.4 Hz), 129.6, 128.9, 127.6 (d, J = 1.0
Hz), 118.6 (td, J = 21.6 and 14.2 Hz), 118.4 (td, J = 264.6 and 183.9 Hz),
64.8 (d, J = 6.7 Hz), 16.3 (d, J = 6.2 Hz); 19F{1H} NMR (CDCl3, CFCl3,
282 MHz)
δ
−109.5 (d, J = 120.6 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 75.3 (t, J = 120.8 Hz, 1P); IR (neat, cm−1) ν: 2983, 2927,
1651, 1474, 1452, 1390, 1298, 1274, 1181, 1013, 961, 855; HRMS
(ESI+) calcd for [M+H]+ C13H18F2SO2P: 307.07332, found: 307.07202 (-
4.22 ppm).
Diethyl (E)-(1,1-difluoro-3-(4-methoxyphenyl)allyl)phosphonate 8h.
Prepared following the procedure
D from (E)-1-(2-bromovinyl)-4-
Diethyl
[1,1-difluoro-3-phenyl-2-propyn-1-yl]phosphonate
10.
methoxybenzene 15h. Reverse phase chromatography (H2O/CH3CN).
Yield: 82% (131 mg, 0.5 mmol scale). Brown oil; 1H NMR (300 MHz,
CDCl3): δ 7.40 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 14.5 Hz, 1H), 6.88 (d, J =
8.4 Hz, 2H), 6.16 (app. qt, 1H), 4.32-4.23 (m, 4H), 3.82 (s, 3H), 1.37 (t, J
= 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 160.8, 136.6 (td, J = 10.8
and 6.2 Hz), 129.0 (d, J = 0.9 Hz), 127.1 (d, J = 1.6 Hz), 118.0 (td, J =
257.3 and 222.2 Hz), 116.3 (td, J = 21.3 and 13.2 Hz), 114.3, 64.8 (d, J =
6.7 Hz), 55.5, 16.6 (d, J = 5.6 Hz); 19F{1H} NMR (CDCl3, CFCl3,
Prepared following the procedure
B
from 1-(phenylethynyl)-1,2-
benziodoxol-3(1H)-one. Reverse phase chromatography (H2O/CH3CN).
Yield: 64% (92 mg, 0.5 mmol scale). Yellow oil; 1H NMR (300 MHz,
CDCl3): δ 7.54-7.51 (m, 2H), 7.43-7.33 (m, 3H), 4.40-4.30 (m, 4H), 1.40
(m, 6H); 13C NMR (75 MHz, CDCl3): δ 132.4 (td, J = 2.7 and 1.8 Hz),
130.6, 128.7, 119.6 (td, J = 3.3 and 1.9 Hz), 109.6 (td, J = 253.2 and
229.6 Hz), 91.7 (dd, J = 14.2 and 7.4 Hz), 78.5 (td, J = 33.6 and 17.2 Hz),
65.6 (d, J = 6.6 Hz), 16.5 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3,
282 MHz) δ −96.8 (d, J = 107.8 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz)
δ 3.42 (t, J = 108.1 Hz); IR (neat, cm−1) ν: 2987, 2236, 1490, 1446, 1273,
1114, 1030, 757; HRMS (EI+) calcd for [M]+ C13H15F2O3P : 288.0727,
found: 288.0731 (1.4 ppm).
282 MHz)
δ
−108.3 (d, J = 116.4 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 6.5 (t, J = 116.6 Hz, 1P); IR (neat, cm−1) ν: 2963, 1652, 1606,
1514, 1252, 1172, 1098, 1013, 972, 791; HRMS (ESI+) calcd for
[M+NH4]+ C14H23NF2O4P: 338.1333, found: 338.1341 (2.4 ppm).
Diethyl
(E)-(1,1-difluoro-3-(4-nitrophenyl)allyl)phosphonate
8i.
Diethyl[((S)4-{2-acetamido-3-methoxy-3-oxopropyl}phenyl)difluorom
ethyl]phosphonate 12. Prepared following the procedure B from (S)-(4-
(2-acetamido-3-methoxy-3-oxopropyl)phenyl)(mesityl)iodonium
Prepared following the procedure
D
from (E)-1-(2-bromovinyl)-4-
nitrobenzene 15i. Reverse phase chromatography (H2O/CH3CN). Yield:
63% (106 mg, 0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ
8.19 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 12.8 Hz,
1H), 6.01-5.85 (m, 1H), 4.36-4.18 (m, 4H), 1.37 (t, J = 7.1 Hz, 6H); 13C
NMR (75 MHz, CDCl3): δ 147.5, 141.5, 136.5 (q, J = 6.9 Hz), 129.9 (dt, J
= 3.8 and 1.3 Hz), 123.4 (dt, J = 21.3 and 13.4 Hz), 123.2, 117.2 (td, J =
260.1 and 216.9 Hz), 65.0 (d, J = 6.9 Hz), 16.4 (d, J = 5.4 Hz); 19F{1H}
NMR (CDCl3, CFCl3, 282 MHz) δ −105.4 (d, J = 109.2 Hz, 2F); 31P{1H}
NMR (CDCl3, 121 MHz) δ 6.0 (t, J = 109.2 Hz, 1P); IR (neat, cm−1) ν:
2987, 2916, 1598, 1519, 1344, 1268, 1140, 1091, 1011, 857; HRMS
(ESI+) calcd for [M+NH4]+ C13H20F2N2O5P: 353.1078, found: 353.1081
(0.8 ppm).
tetrafluoroborate 11. Reverse phase chromatography (H2O/CH3CN).
Yield: 48% (39 mg, 0.2 mmol scale). Colourless oil; 1H NMR (300 MHz,
CDCl3): δ 7.53 (d, J = 7.4 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 6.07 (d, J =
7.7 Hz, 1H), 4.92-4.85 (m, 1H), 4.27-4.04 (m, 4H), 3.71 (s, 3H), 3.23-3.07
(m, 2H), 1.98 (s, 3H), 1.32-1.27 (m, 6H); 13C NMR (75 MHz, CDCl3): δ
171.9, 169.8, 139.2 (dd, J = 3.9 and 1.9 Hz), 131.6 (td, J = 22.3 and 13.9
Hz), 129.5 (d, J = 1.2 Hz), 126.6 (td, J = 6.7 and 2.3 Hz), 118.1 (td, J =
262.9 and 218.3 Hz), 64.9 (d, J = 6.6 Hz), 53.1, 52.5, 37.8, 23.2, 16.4 (d,
J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −108.8 (d, J =
116.2 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.2 (t, J = 116.1 Hz,
1P); IR (neat, cm−1) ν: 3290, 3026, 2924, 2852, 1744, 1660, 1542, 1493,
1452, 1373, 1260, 1123, 1017, 696;
[M+H]+ C17H25F2NO6P : 408.1388, found: 408.1384 (−1.0 ppm).
HRMS (ESI+) calcd for
Diethyl (E)-(1,1-difluoronon-2-en-1-yl)phosphonate 8j. Prepared
following the procedure D from (E)-1-iodooct-1-ene 15j. Reverse phase
chromatography (H2O/CH3CN). Yield: 62% (93 mg, 0.5 mmol scale).
Colourless oil; 1H NMR (300 MHz, CDCl3): δ 6.34-6.21 (m, 1H), 5.72-5.57
(m, 1H), 4.30-4.18 (m, 4H), 2.13 (s, 2H), 1.44-1.26 (m, 14 H), 0.87 (app. t,
3H); 13C NMR (75 MHz, CDCl3): δ 140.4 (td, J = 10.2 and 6.0 Hz), 120.7
(td, J = 21.2 and 13.1 Hz), 116.9 (td, J = 259.3 and 220.6 Hz), 64.6 (d, J
= 6.9 Hz), 32.2, 31.7, 28.8, 28.3 (d, J = 1.5 Hz), 22.6, 16.5 (d, J = 5.6 Hz),
14.1;1 9F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −108.6 (d, J = 115.7 Hz,
2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.8 (t, J = 116.0 Hz, 1P); IR (neat,
cm−1) ν: 2930, 2859, 1270, 1189, 1165, 1100, 1019, 969; HRMS (ESI+)
calcd for [M+H]+ C13H26F2O3P: 299.1588, found: 299.1589 (0.3 ppm).
Diethyl
[((estronyl)difluoromethyl]phosphonate
14.
Prepared
following
the procedure from mesityl(estronyl)iodonium
B
tetrafluoroborate 13. Reverse phase chromatography (H2O/CH3CN).
Yield: 37% (82 mg, 0.5 mmol scale). Yellow oil; 1H NMR (300 MHz,
CDCl3): δ 7.36 (s, 2H), 7.34 (s, 1H), 4.30-4.10 (m, 4H), 2.97-2.93 (m, 2H),
2.55-2.28 (m, 3H), 2.18-1.95 (m, 4H), 1.67-1.42 (m, 6H), 1.33 (m, 6H),
0.91 (s, 3H); 13C NMR (75 MHz, CDCl3): δ 220.7, 142.8 (d, J = 2.0 Hz),
136.9 (d, J = 1.4 Hz), 130.0 (dt, J = 22.2 and 13.6 Hz), 126.8 (dt, J = 6.7
and 2.5 Hz), 125.6 (d, J = 1.1 Hz), 123.5 (dt, J = 6.9 and 2.3 Hz), 118.5
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Diethyl (E)-(1,1-difluorohept-2-en-1-yl)phosphonate 8k. Prepared
following the procedure D from (E)-1-iodohex-1-ene 15k. Reverse phase
chromatography (H2O/CH3CN). Yield: 53% (72 mg, 0.5 mmol scale).
Colourless oil; 1H NMR (300 MHz, CDCl3): δ 6.35-6.22 (m, 1H), 5.73-5.57
(m, 1H), 4.31-4.18 (m, 4H), 2.15 (s, 2H), 1.42-1.29 (m, 10H), 0.89 (t, J =
7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 140.4 (td, J = 10.2 and 5.9 Hz),
120.8 (td, J = 21.2 and 13.2 Hz), 117.2 (td, J = 258.4 and 220.2 Hz), 64.5
(d, J = 6.6 Hz), 31.9, 30.4 (d, J = 1.5 Hz), 22.2, 16.5 (d, J = 5.5 Hz), 13.9;
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −108.6 (d, J = 115.4 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 6.8 (t, J = 115.4 Hz, 1P); IR (neat,
cm−1) ν: 2960, 2933, 2875, 1671, 1269, 1187, 1165, 1099, 1016, 974;
HRMS (ESI+) calcd for [M+H]+ C11H22F2O3P: 271.1275, found: 271.1268
(-2.6 ppm).
(CDCl3, 121 MHz) δ 5.8 (t, J = 112.6 Hz, 1P); IR (neat, cm−1) ν: 2984,
2920, 2852, 1732, 1445, 1392, 1368, 1263, 1141, 1095, 1012, 940, 761;
HRMS (ESI+) calcd for [M+H]+ C14H20F2O5P: 337.1016, found: 337.1022
(1.8 ppm).
Diethyl [(2-acetylphenyl)difluoromethyl]phosphonate 17b. Prepared
following the procedure E from ethyl 1-(2-iodophenyl)ethan-1-one 16b.
Reverse phase chromatography (H2O/CH3CN). Yield: 53% (81 mg, 0.5
mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.73 (d, J = 6.7 Hz,
1H), 7.55-7.47 (m, 2H), 7.26 (t, J = 5.9 Hz, 1H), 4.32-4.14 (m, 4H), 2.58
(s, 3H), 1.34 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 204.0,
141.6 (q, J = 3.4 Hz), 131.0 (d, J = 1.6 Hz), 129.2 (d, J = 1.6 Hz), 128.6
(dt, J = 7.3 and 1.2 Hz), 128.3 (dt, J = 21.7 and 15.2 Hz), 126.0, 118.6 (td,
J = 265.1 and 216.8 Hz), 65.1 (d, J = 6.9 Hz), 31.7 (t, J = 3.4 Hz), 16.4 (d,
J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −101.2 (d, J =
112.7 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.5 (t, J = 112.9 Hz,
1P); IR (neat, cm−1) ν: 2986, 2917, 1706, 1268, 1248, 1120, 1032, 1011,
939, 766; HRMS (ESI+) calcd for [M+H]+ C13H18F2O4P: 307.0911, found:
307.0909 (-0.7 ppm).
Ethyl
(Z)-4-(diethoxyphosphoryl)-4,4-difluorobut-2-enoate
8l.
Prepared following the procedure D from ethyl (Z)-3-bromoacrylate 15l.
Reverse phase chromatography (H2O/CH3CN). Yield: 66% (95 mg, 0.5
mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 6.24 (app. dd, 1H),
5.96 (app. ddt, 1H), 4.33-4.18 (m, 6H), 1.36 (t, J = 7.2 Hz, 6H), 1.28 (t, J
= 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 164.8 (d, J = 1.3 Hz), 128.6
(dd, J = 13.8 and 7.1 Hz), 127.5 (dt, J = 22.1 and 14.0 Hz), 116.4 (td, J =
262.5 and 217.0 Hz), 65.1 (d, J = 6.7 Hz), 61.4, 16.4 (d, J = 5.6 Hz),
14.1; 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −108.5 (d, J = 107.1 Hz,
2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.1 (t, J = 107.9 Hz, 1P); IR (neat,
cm−1) ν: 2987, 2919, 1736, 1658, 1446, 1396, 1270, 1212, 1149, 1095,
1010, 868, 795; HRMS (ESI+) calcd for [M+H]+C10H18F2O5P: 287.0860,
found: 287.0854 (-2.1 ppm).
Diethyl [(2-nitrophenyl)difluoromethyl]phosphonate 17c. Prepared
following the procedure E from ethyl 1-iodo-2-nitrobenzene 16c. Reverse
phase chromatography (H2O/CH3CN). Yield: 54% (83 mg, 0.5 mmol
scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.82-7.81 (m, 1H), 7.63-
7.61 (m, 3H), 4.35-4.17 (m, 4H), 1.34 (t, J = 7.0 Hz, 6H); 13C NMR (75
MHz, CDCl3): δ 148.8, 132.1 (d, J = 1.4 Hz), 131.4 (d, J = 1.1 Hz), 129.9
(td, J = 7.7 and 1.4 Hz), 125.4 (dt, J = 22.8 and 15.9 Hz), 124.0, 117.2 (td,
J = 266.7 and 216.9 Hz), 65.5 (d, J = 7.1 Hz), 16.4 (d, J = 5.4 Hz);
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −103.4 (d, J = 108.8 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 4.4 (t, J = 108.6 Hz, 1P); IR (neat,
cm−1) ν: 2988, 1541, 1370, 1270, 1036, 1012, 939; HRMS (ESI+) calcd
for [M+H]+ C11H15F2NO5P: 310.0656, found: 310.0665 (2.9 ppm).
Diethyl
(E)-(3-cyano-1,1-difluorobut-2-en-1-yl)phosphonate
8m.
Prepared following the procedure D from 3-bromo-2-methylacrylonitrile
(E/Z=1/0.7) 15m. Reverse phase chromatography (H2O/CH3CN). Yield:
38% (48 mg, 0.5 mmol scale). Colourless oil; 1H NMR (300 MHz, CDCl3):
δ 6.34-6.22 (m, 1H), 4.35-4.25 (m, 4H), 2.18-2.14 (m, 3H), 1.42-1.37 (m,
6H); 13C NMR (75 MHz, CDCl3): δ 135.1 (dt, J = 23.6 and 12.7 Hz), 120.9
(dt, J = 7.6 Hz), 118.7-118.6 (m), 116.4 (td, J = 261.6 and 217.7 Hz),
65.3 (d, J = 7.1 Hz), 17.2-17.1 (m), 16.5 (d, J = 5.5 Hz);19F{1H} NMR
(CDCl3, CFCl3, 282 MHz) δ −107.9 (d, J = 107.5 Hz, 2F); 31P{1H} NMR
(CDCl3, 121 MHz) δ 5.2 (t, J = 107.2 Hz, 1P); IR (neat, cm−1) ν: 2923,
1272, 1171, 1107, 1011, 950; HRMS (ESI+) calcd for
[M+NH4]+ C9H18F2N2O3P: 271.1023, found: 271.1026 (1.1 ppm).
Methyl
2-[(diethoxyphosphoryl)difluoromethyl]-3-methylbenzoate
from methyl 2-iodo-3-
17d. Prepared following the procedure
E
methylbenzoate 16d. Reverse phase chromatography (H2O/CH3CN).
Yield: 61% (103 mg, 0.5 mmol scale). Yellow oil; 1H NMR (300 MHz,
CDCl3): δ 7.37-7.29 (m, 2H), 7.21 (d, J = 6.7 Hz, 1H), 4.27-4.06 (m, 4H),
3.86 (s, 3H), 2.62 (t, J = 2.8 Hz, 3H), 1.31-1.26 (m, 6H); 13C NMR (75
MHz, CDCl3): δ 170.0, 139.3 (td, J = 3.9 and 1.4 Hz), 134.0 (d, J = 1.4
Hz), 133.7 (dt, J = 5.6 and 3.0 Hz), 130.3 (d, J = 1.2 Hz), 128.5 (dt, J =
20.5 and 15.2 Hz), 125.9, 119.6 (td, J = 267.6 and 213.7 Hz), 64.8 (d, J =
6.7 Hz), 52.7, 21.6 (t, J = 4.3 Hz), 16.4 (d, J = 5.5 Hz); 19F{1H} NMR
(CDCl3, CFCl3, 282 MHz) δ −98.1 (d, J = 112.5 Hz, 2F); 31P{1H} NMR
(CDCl3, 121 MHz) δ 6.6 (t, J = 112.3 Hz, 1P); IR (neat, cm−1) ν: 2953,
1735, 1587, 1435, 1392, 1370, 1290, 1269, 1147, 1061, 1011, 976;
HRMS (ESI+) calcd for [M+NH4]+ C14H23NF2O5P: 354.1282, found:
354.1286 (1.1 ppm).
Diethyl
(Z)-(3-cyano-1,1-difluorobut-2-en-1-yl)phosphonate
8m.
Prepared following the general procedure
D
from 3-bromo-2-
methylacrylonitrile (E/Z=1/0.7) 15m. Reverse phase chromatography
(H2O/CH3CN). Yield: 19% (24 mg, 0.5 mmol scale). Colourless oil; 1H
NMR (300 MHz, CDCl3): δ 6.27-6.17 (m, 1H), 4.41-4.20 (m, 4H), 2.16-
2.12 (m, 3H), 1.42-1.38 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 134.7 (dt,
J = 22.5 and 12.6 Hz), 117.5-117.3 (m), 115.7-115.6 (m), 115.3 (td, J =
262.4 and 218.5 Hz), 65.7 (d, J = 7.0 Hz), 22.5, 16.5 (d, J = 5.6 Hz);
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −109.8 (d, J = 107.9 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 4.3 (t, J = 107.7 Hz, 1P); IR (neat,
cm−1) ν: 2918, 2848, 1264, 1189, 1165, 1016; HRMS (ESI+) calcd for
[M+H]+ C9H15F2NO3P: 254.0758, found: 254.0770 (4.7 ppm).
Methyl 2-[(diethoxyphosphoryl)difluoromethyl]-4-methoxybenzoate
17e. Prepared following the procedure
E from methyl 2-iodo-4-
methoxybenzoate 16e. Reverse phase chromatography (H2O/CH3CN).
Yield: 69% (122 mg, 0.5 mmol scale). Brown oil; 1H NMR (300 MHz,
CDCl3): δ 7.54 (d, J = 8.7 Hz, 1H), 7.23 (s, 1H), 6.98 (ddd, J = 8.5 and
1.6 and 0.9 Hz, 1H), 4.27-4.12 (m, 4H), 3.85 (s, 3H), 3.83 (s, 3H), 1.32-
1.27 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 168.3, 160.9, 132.8 (dt, J =
21.7 and 15.5 Hz), 131.3, 124.1 (dt, J = 3.4 Hz), 117.9 (td, J = 265.1 and
215.0 Hz), 115.9 (d, J = 1.5 Hz), 113.9 (td, J = 8.6 and 1.6 Hz), 64.9 (d, J
= 6.8 Hz), 55.7, 52.6, 16.4 (d, J = 5.7 Hz); 19F{1H} NMR (CDCl3, CFCl3,
Ethyl 2-[(diethoxyphosphoryl)difluoromethyl]benzoate 17a. Prepared
following the procedure E from ethyl 2-iodobenzoate 16a. Reverse phase
chromatography (H2O/CH3CN). Yield: 84% (141 mg, 0.5 mmol scale).
Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.75-7.73 (m, 1H), 7.51-7.49 (m,
3H), 4.39-4.32 (m, 2H), 4.25-4.11 (m, 4H), 1.35 (t, J = 7.1Hz, 3H), 1.37-
1.27 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 168.5, 132.6 (q, J = 3.7 Hz),
130.7 (d, J = 1.6 Hz), 130.0 (d, J = 1.4 Hz), 129.9 (dt, J = 21.7 and 15.2
Hz), 128.7 (dd, J = 7.5 and 1.4 Hz), 128.6, 118.2 (td, J = 265.5 and 215.8
Hz), 64.9 (d, J = 6.7 Hz), 61.9, 16.4 (d, J = 5.5 Hz), 14.1; 19F{1H} NMR
(CDCl3, CFCl3, 282 MHz) δ −102.0 (d, J = 112.1 Hz, 2F); 31P{1H} NMR
282 MHz)
δ
−101.1 (d, J = 111.7 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 6.1 (t, J = 111.1 Hz, 1P); IR (neat, cm−1) ν: 2986, 1733, 1609,
1576, 1505, 1435, 1268, 1130, 1209, 1130, 1097, 1013, 985; HRMS (EI+)
calcd for [M]+ C14H19F2O6P: 352.08873, found: 352.08840 (-0.95 ppm).
This article is protected by copyright. All rights reserved.

10.1002/chem.201703542
Chemistry - A European Journal
FULL PAPER
Methyl
2-[(diethoxyphosphoryl)difluoromethyl]-3,5-
mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.87 (d, J = 7.9 Hz,
2H), 7.46 (d, J = 8.2 Hz, 1H), 4.25-4.11 (m, 4H), 3.89 (s, 3H), 1.34-1.29
(m, 6H); 13C NMR (75 MHz, CDCl3): δ 167.1, 139.3 (d, J = 1.4 Hz), 137.5,
133.5 (q, J = 3.6 Hz), 130.1 (dt, J = 6.4 and 1.6 Hz), 129.9 (dt, J = 22.2
and 15.4 Hz), 118.1 (td, J = 264.5 and 216.0 Hz), 97.0 (dt, J = 2.2 Hz),
65.1 (d, J = 6.9 Hz), 53.0, 16.4 (d, J = 5.4 Hz); 19F{1H} NMR (CDCl3,
CFCl3, 282 MHz) δ −102.9 (d, J = 111.4 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 5.3 (t, J = 111.0 Hz, 1P); IR (neat, cm−1) ν: 2918, 1738, 1585,
1562, 1436, 1393, 1289, 1259, 1155, 1125, 1098, 1039, 1013, 965, 938;
HRMS (ESI+) calcd for [M+NH4]+ C13H20NF2IO5P: 466.0092, found:
466.0103 (2.4 ppm).
dimethoxybenzoate 17f. Prepared following the procedure E from
methyl
2-iodo-3,5-dimethoxybenzoate
16f.
Reverse
phase
chromatography (H2O/CH3CN). Yield: 93% (178 mg, 0.5 mmol scale).
Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.17 (s, 1H), 6.98 (s, 1H), 4.26-
4.02 (m, 4H), 3.87 (s, 3H), 3.86 (s, 3H), 3.82 (s, 3H), 1.29-1.24 (m, 6H);
13C NMR (75 MHz, CDCl3): δ 168.5, 150.1 (d, J = 1.2 Hz), 150.0 (d, J =
1.2 Hz), 124.9 (q, J = 3.9 Hz), 123.7-122.7 (m), 117.9 (td, J = 264.6 and
219.1 Hz), 111.6, 110.9 (td, J = 7.8 and 1.1 Hz), 64.9 (d, J = 7.2 Hz),
56.2, 56.1, 52.7, 16.4 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3,
282 MHz)
δ
−100.7 (d, J = 114.2 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 6.2 (t, J = 114.2 Hz, 1P); IR (neat, cm−1) ν: 2941, 2852, 1733,
1605, 1525, 1464, 1435, 1356, 1271, 1205, 1165, 1129, 1090, 1007,
974; HRMS (ESI+) calcd for [M+H]+ C15H22F2O7P: 383.1071, found:
383.1081 (2.6 ppm).
Methyl
4-chloro-2-[(diethoxyphosphoryl)difluoromethyl]benzoate
from methyl 4-chloro-2-
17k. Prepared following the procedure
E
iodobenzoate 16k. Reverse phase chromatography (H2O/CH3CN). Yield:
43% (76 mg, 0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ
7.62 (s, 1H), 7.54 (dd, J = 8.3 and 1.9 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H),
4.43-4.24 (m, 4H), 3.88 (s, 3H), 1.41-1.36 (m, 6H); 13C NMR (75 MHz,
CDCl3): δ 167.8, 136.6 (d, J = 1.5 Hz), 132.6 (dt, J = 22.1 and 15.3 Hz),
130.9 (d, J = 1.5 Hz), 130.6-130.4 (m), 130.4, 128.7 (td, J = 8.3 and 1.4
Hz), 117.5 (td, J = 266.0 and 216.1 Hz), 65.2 (d, J = 6.7 Hz), 52.9, 16.4
(d, J = 5.7 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −102.3 (d, J =
110.2 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.4 (t, J = 110.7 Hz,
1P); IR (neat, cm−1) ν: 2988, 1738, 1596, 1435, 1393, 1290, 1261, 1224,
1112, 1013, 983; HRMS (ESI+) calcd for [M+H]+ C13H17ClF2O5P:
357.0470, found: 357.0458 (-3.4 ppm).
Methyl 2-[(diethoxyphosphoryl)difluoromethyl]-4-nitrobenzoate 17g.
Prepared following the procedure E from methyl 2-iodo-4-nitrobenzoate
16g. Reverse phase chromatography (H2O/CH3CN). Yield: 62% (114 mg,
0.5 mmol scale). Yellow oil; 1H NMR (300 MHz, CDCl3): δ 8.56 (s, 1H),
8.35 (dd, J = 8.5 and 1.2 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 4.33-4.20 (m,
4H), 3.94 (s, 3H), 1.35 (t, J = 7.2, 6H); 13C NMR (75 MHz, CDCl3): δ
166.9, 148.5, 137.6 (q, J = 3.3 Hz), 132.7 (td, J = 23.1 and 15.5 Hz),
130.2, 125.5 (d, J = 1.4 Hz), 124.0 (dt, J = 7.9 and 1.3 Hz), 117.4 (td, J =
266.2 and 218.1 Hz), 64.4 (d, J = 6.9 Hz), 53.3, 16.4 (d, J = 5.6 Hz);
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −103.3 (d, J = 109.1 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 4.7 (t, J = 108.8 Hz, 1P); IR (neat,
cm−1) ν: 2988, 1740, 1614, 1592, 1532, 1436, 1352, 1278, 1259, 1089,
1012, 951; HRMS (ESI+) calcd for [M+H]+ C13H17NF2O7P: 368.0711,
found: 368.0713 (0.5 ppm).
Diethyl [(pyridin-2-yl)difluoromethyl]phosphonate 17l.
Prepared
following the procedure E from 2-bromopyridine 16l. Reverse phase
chromatography (H2O/CH3CN). Yield: 32% (43 mg, 0.5 mmol scale).
Brown oil; 1H NMR (300 MHz, CDCl3): δ 8.68 (d, J = 4.3 Hz, 1H), 7.81 (t,
J = 8.1 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.39 (t, J = 6.3 Hz, 1H), 4.32-
4.25 (m, 4H), 1.33 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 151.7
(dt, J = 23.8 and 14.4 Hz), 149.6, 137.2, 125.4 (d, J = 1.4 Hz), 121.8 (app.
dt), 116.5 (td, J = 264.1 and 216.8 Hz), 65.0 (d, J = 6.6 Hz), 16.4 (d, J =
5.6 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −111.0 (d, J = 108.8
Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 5.5 (t, J = 108.8 Hz, 1P); IR
(neat, cm−1) ν: 3505, 2987, 1589, 1437, 1370, 1266, 1132, 1101, 1012,
944; HRMS (ESI+) calcd for [M+H]+C10H15NO3F2P: 266.0758, found:
266.0764 (2.3 ppm).
Methyl
5-chloro-2-[(diethoxyphosphoryl)difluoromethyl]benzoate
from methyl 5-chloro-2-
17h. Prepared following the procedure
E
iodobenzoate 16h. Reverse phase chromatography (H2O/CH3CN). Yield:
68% (121 mg, 0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ
7.70-7.66 (m, 1H), 7.50-7.48 (m, 2H), 4.29-4.10 (m, 4H), 3.88 (s, 3H),
1.33-1.28 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 167.3, 137.1 (q, J = 1.9
Hz), 133.7 (q, J = 3.7 Hz), 130.4 (d, J = 1.4 Hz), 130.1 (td, J = 7.8 and
1.4 Hz), 128.8, 128.7 (td, J = 22.4 and 15.4 Hz), 117.8 (td, J = 265.5 and
216.7 Hz), 65.0 (d, J = 6.8 Hz), 52.9, 16.3 (d, J = 5.5 Hz); 19F{1H} NMR
(CDCl3, CFCl3, 282 MHz) δ −102.4 (d, J = 110.8 Hz, 2F); 31P{1H} NMR
(CDCl3, 121 MHz) δ 5.4 (t, J = 111.1 Hz, 1P); IR (neat, cm−1) ν: 2988,
1741, 1596, 1569, 1436, 1393, 1293, 1263, 1152, 1118, 1090, 1014,
968; HRMS (ESI+) calcd for [M+NH4]+ C13H20NClF2O5P: 374.0736, found:
374.0738 (0.5 ppm).
Diethyl
(E)-(1,1-difluoro-4-phenylbut-3-en-1-yl)phosphonate
19a
Prepared following the procedure
F
from (E)-(3-bromoprop-1-en-1-
yl)benzene 18a with 91% yield (139 mg, 0.5 mmol scale); the procedure
F from (Z)-(3-bromoprop-1-en-1-yl)benzene with 51% yield (76 mg, 0.5
mmol scale). Reverse phase chromatography (H2O/CH3CN). Colourless
oil; 1H NMR (300 MHz, CDCl3): δ 7.39 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.5
Hz, 2H), 7.28-7.25 (m, 1H), 6.60 (d, J = 16.4 Hz, 1H), 6.21 (dt, J = 15.8
and 7.1 Hz, 1H), 4.33-4.23 (m, 4H), 3.10-2.92 (m, 2H), 1.37 (t, J = 7.1 Hz,
6H); 13C NMR (75 MHz, CDCl3): δ 136.6, 136.0, 128.6, 127.8, 126.3,
119.7 (td, J = 262.6 and 213.8 Hz), 118.3 (dt, J = 11.0 and 5.7 Hz), 64.4
(d, J = 6.4 Hz), 38.0 (td, J = 21.1 and 16.3 Hz), 16.3 (d, J = 5.6 Hz);
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −110.7 (d, J = 107.9 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 6.9 (t, J = 107.5 Hz, 1P); IR (neat,
cm−1) ν: 2985, 1497, 1268, 1163, 1014, 957, 745; HRMS (ESI+) calcd for
[M+Na]+ C14H19F2O3 NaP: 327.0938, found: 327.0936 (-0.6 ppm).
Methyl
5-bromo-2-[(diethoxyphosphoryl)difluoromethyl]benzoate
from methyl 5-bromo-2-
17i. Prepared following the procedure
E
iodobenzoate 16i. Reverse phase chromatography (H2O/CH3CN). Yield:
74% (149 mg, 0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ
7.66-7.58 (m, 3H), 4.27-4.12 (m, 4H), 3.88 (s, 3H), 1.33-1.28 (m, 6H); 13
C
NMR (75 MHz, CDCl3): δ 167.3, 133.8 (q, J = 3.6 Hz), 133.4 (d, J = 1.4
Hz), 131.7, 130.3 (td, J = 7.6 and 1.3 Hz), 129.4 (dt, J = 22.1 and 15.4
Hz), 125.3 (dt, J = 1.9 Hz), 117.7 (td, J = 265.4 and 216.4 Hz), 65.1 (d, J
= 6.9 Hz), 53.0, 16.4 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3,
282 MHz)
δ
−102.6 (d, J = 110.8 Hz, 2F); 31P{1H} NMR (CDCl3,
121 MHz) δ 5.3 (t, J = 111.0 Hz, 1P); IR (neat, cm−1) ν: 2989, 2954, 1740,
1591, 1566, 1436, 1390, 1291, 1260, 1153, 1124, 1102, 1012, 965, 938;
HRMS (ESI+) calcd for [M+NH4]+ C13H20NBrF2O5P: 420.0210, found:
420.0225 (3.6 ppm).
Diethyl
yl)phosphonate 19b. Prepared following the procedure F from (E)-1-(3-
bromoprop-1-en-1-yl)-4-chlorobenzene 18b. Reverse phase
(E)-(4-(4-chlorophenyl)-1,1-difluorobut-3-en-1-
chromatography (H2O/CH3CN). Yield: 62% (105 mg, 0.5 mmol scale).
Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.22 (app. t, 4H), 6.46 (d, J =
15.7 Hz, 1H), 6.11 (dt, J = 15.9 and 7.1 Hz, 1H), 4.24-4.15 (m, 4H), 3.00-
2.83 (m, 2H), 1.29 (t, J = 7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ
Methyl 2-[(diethoxyphosphoryl)difluoromethyl]-5-iodobenzoate 17j.
Prepared following the procedure E from methyl 2,5-diiodobenzoate 16j.
Reverse phase chromatography (H2O/CH3CN). Yield: 56% (125 mg, 0.5
This article is protected by copyright. All rights reserved.

10.1002/chem.201703542
Chemistry - A European Journal
FULL PAPER
135.2, 134.9, 133.5, 128.8, 127.7, 119.9 (td, J = 261.0 and 215.2 Hz),
119.0 (q, J = 5.7 Hz), 64.5 (d, J = 6.6 Hz), 38.1 (dt, J = 21.4 and 15.6 Hz),
16.4 (d, J = 5.5 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −111.2 (d,
J = 107.9 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.8 (t, J = 107.4 Hz,
1P); IR (neat, cm−1) ν: 2992, 2915, 1491, 1456, 1266, 1093, 1011, 967,
794; HRMS (ESI+) calcd for [M+NH4]+ C14H22ClNF2O3P: 358.0964, found:
358.0966 (0.6 ppm).
Diethyl
[(3E,7E)-1,1-difluoro-4,8,12-trimethyltrideca-3,7,11-trien-1-
yl]phosphonate 19g. Prepared following the procedure F from farnesyl
bromide 18g. Reverse phase chromatography (H2O/CH3CN). Yield: 88%
(172 mg, 0.5 mmol scale). Colourless oil; 1H NMR (300 MHz, CDCl3): δ
5.22-5.18 (m, 1H), 5.08-5.06 (m, 2H), 4.28-4.18 (m, 4H), 2.84-2.71 (m,
2H), 2.05-1.94 (m, 8H), 1.74-1.57 (m, 12H), 1.35 (t, J = 7.1 Hz, 6H); 13C
NMR (75 MHz, CDCl3): δ 141.6 (d, J = 3.4 Hz), 135.4 (d, J = 9.5 Hz),
131.5 (d, J = 21.8 Hz), 124.6, 124.3 (d, J = 4.6 Hz), 123.8, 120.5 (td, J =
260.1 and 215.6 Hz), 112.2 (ddt, J = 9.0 and 1.6 Hz), 64.4 (d, J = 6.7
Hz), 40.2, 39.8 (d, J = 7.9 Hz), 33.0 (dt, J = 20.9 and 14.8 Hz), 32.0 (app.
d), 26.8-26.6 (app dt), 26.4-26.3 (app dt), 25.7 (d, J = 2.2 Hz), 17.7 (d, J
= 3.9 Hz), 16.5 (d, J = 5.7 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ
−111.5 (d, J = 109.3 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 7.4 (t, J
= 109.3 Hz, 1P); IR (neat, cm−1) ν: 2968, 2916, 1444, 1375, 1269, 1162,
1016, 977, 899 HRMS (ESI+) calcd for [M+Na]+ C20H35F2O3 NaP:
415.2190, found: 415.2193 (0.7 ppm).
Diethyl
(1,1-difluoro-3-methylbut-3-en-1-yl)phosphonate
19c.
Prepared following the procedure F from 3-bromo-2-methylprop-1-ene
18c. Reverse phase chromatography (H2O/CH3CN). Yield: 61% (74 mg,
0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 5.02 (s, 1H),
4.92 (s, 1H), 4.30-4.21 (m, 4H), 2.77 (td, J = 20.3 and 4.9 Hz, 2H), 1.84
(s, 3H), 1.37 (t, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 135.9 (dt, J
= 3.3Hz), 119.9 (td, J = 262.2 and 216.1 Hz), 117.9, 64.5 (d, J = 6.7 Hz),
41.7 (dt, J = 20.7 and 14.8 Hz), 23.7, 16.5 (d, J = 5.5 Hz); 19F{1H} NMR
(CDCl3, CFCl3, 282 MHz) δ −111.1 (d, J = 107.8 Hz, 2F); 31P{1H} NMR
(CDCl3, 121 MHz) δ 7.0 (t, J = 108.1 Hz, 1P); IR (neat, cm−1) ν: 2986,
1652, 1446, 1394, 1269, 1164, 1099, 1014, 977; HRMS (ESI+) calcd for
[M+NH4]+C9H21F2O3PN: 260.1227, found: 260.1227 (0.0 ppm).
Diethyl [1,1-difluoro-2-phenylethyl]phosphonate 21a. Prepared
following the procedure G from benzyl bromide 20a. Reverse phase
chromatography (H2O/CH3CN). Yield: 87% (121 mg, 0.5 mmol scale).
Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.31 (s, 5 H), 4.25-4.11 (m, 4H),
3.44-3.29 (td, J = 20.2 and 5.8 Hz, 2H), 1.30 (t, J = 7.1 Hz, 6H); 13C NMR
(75 MHz, CDCl3): δ 131.0, 130.9-130.7 (m), 128.4, 127.7, 119.5 (td, J =
262.6 and 213.3 Hz), 64.5 (d, J = 7.1 Hz), 40.3 (dt, J = 21.4 and 15.9 Hz),
16.4 (d, J = 5.6 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −111.1 (d,
J = 107.6 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.9 (t, J = 107.5 Hz,
1P); IR (neat, cm−1) ν: 2985, 1497, 1456, 1269, 1164, 1081, 1028, 977,
886; HRMS (ESI+) calcd for [M+NH4]+ C12H21NF2O3P: 296.1227, found:
296.1224 (-1.0 ppm).
Ethyl
19d. Prepared following the procedure
(bromomethyl)acrylate 18d. Reverse phase
4-(diethoxyphosphoryl)-4,4-difluoro-2-methylenebutanoate
F
from ethyl 2-
chromatography
(H2O/CH3CN). Yield: 63% (95 mg, 0.5 mmol scale). Colourless oil; 1H
NMR (300 MHz, CDCl3): δ 6.44 (s, 1H), 5.85 (s, 1H), 4.28-4.20 (m, 6H),
3.14 (dt, J = 19.7 and 3.8 Hz, 2H), 1.37 (dt, J = 7.1 and 1.8 Hz, 6H), 1.29
(dt, J = 7.1 and 1.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 166.3, 131.3,
130.9 (dt, J = 3.6 Hz), 119.2 (td, J = 262.6 and 217.7 Hz), 64.7 (d, J = 6.7
Hz), 61.3, 35.1 (td, J = 20.8 and 15.7 Hz), 16.5 (d, J = 5.6 Hz), 14.2;
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −112.3 (d, J = 106.8 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 6.5 (t, J = 107.6 Hz, 1P); IR (neat,
cm−1) ν: 2985, 1718, 1635, 1273, 1155, 1012, 799; HRMS (ESI+) calcd
for [M+Na]+ C11H19F2O5 NaP: 323.0836, found: 323.0834 (-0.6 ppm).
Diethyl (1,1-difluoro-2-(p-tolyl)ethyl)phosphonate 21b. Prepared
following the procedure G from 1-(bromomethyl)-4-methylbenzene 20b.
Reverse phase chromatography (H2O/CH3CN). Yield: 42% (61 mg, 0.5
mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.20 (d, J = 7.7 Hz,
2H), 7.14 (d, J = 7.7 Hz, 2H), 4.29-4.10 (m, 4H), 3.40-3.25 (td, J = 20.0
and 5.3 Hz, 2H), 2.33 (s, 3H), 1.31 (t, J = 7.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3): δ 137.4, 130.9, 129.1, 127.6 (dt, J = 6.3 and 3.9 Hz), 119.7 (td, J
= 261.1 and 215.0 Hz), 64.5 (d, J = 6.9 Hz), 39.8 (dt, J = 20.8 and 15.4
Hz), 21.2, 16.4 (d, J = 5.6 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ
−111.3 (d, J = 107.4 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 7.1 (t, J
= 107.5 Hz, 1P); IR (neat, cm−1) ν: 2985, 2932, 1516, 1269, 1165, 1033,
1012, 978, 769; HRMS (ESI+) calcd for [M+H]+ C13H20F2O3P: 293.1118,
found: 293.1114 (-1.4 ppm).
Diethyl
(1,1-difluoro-4-methylpent-3-en-1-yl)phosphonate
19e.
Prepared following the procedure F from 1-bromo-3-methylbut-2-ene 18e.
Reverse phase chromatography (H2O/CH3CN). Yield: 98% (126 mg, 0.5
mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 5.18 (dt, J = 7.3
and 1.2 Hz, 1H), 4.28-4.18 (m, 4H), 2.82-2.67 (m, 2H), 1.73 (s, 3H), 1.63
(s, 3H), 1.34 (t, J = 7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 138.1,
120.7 (td, J = 261.2 and 214.9 Hz), 112.6 (dt, J = 5.5 and 5.3 Hz), 64.3 (d,
J = 6.7 Hz), 33.2 (dt, J = 21.2 and 15.4 Hz), 25.9, 18.1, 16.4 (d, J = 5.5
Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −111.4 (d, J = 108.7 Hz,
2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 7.4 (t, J = 109.1 Hz, 1P); IR (neat,
cm−1) ν: 2985, 2917, 1444, 1393, 1261, 1162, 1091, 1014, 977; HRMS
(ESI+) calcd for [M+H]+C10H20F2O3P: 257.1118, found: 257.1107 (-4.3
ppm).
Diethyl
Prepared
(bromomethyl)benzene.
(2-(4-bromophenyl)-1,1-difluoroethyl)phosphonate
21c.
1-bromo-4-
chromatography
following
the
20c
procedure
Reverse
G
phase
from
(H2O/CH3CN). Yield: 74% (132 mg, 0.5 mmol scale). Brown oil; 1H NMR
(300 MHz, CDCl3): δ 7.43 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H),
4.24-4.13 (m, 4H), 3.37-3.23 (td, J = 19.5 and 5.3 Hz, 2H), 1.30 (t, J = 7.3
Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 132.6, 131.5, 129.8 (dt, J = 6.4
and 3.9 Hz), 121.9, 119.1 (td, J = 261.4 and 214.6 Hz), 64.6 (d, J = 6.9
Hz), 39.7 (dt, J = 21.0 and 15.3 Hz), 16.3 (d, J = 5.6 Hz); 19F{1H} NMR
(CDCl3, CFCl3, 282 MHz) δ −111.4 (d, J = 106.0 Hz, 2F); 31P{1H} NMR
(CDCl3, 121 MHz) δ 6.6 (t, J = 106.1 Hz, 1P); IR (neat, cm−1) ν: 2985,
2915, 1490, 1268, 1164, 1032, 1011, 979; HRMS (ESI+) calcd for
[M+NH4]+ C12H20BrNF2O3P: 374.0332, found: 374.0319 (-3.5 ppm).
Diethyl [(E)-1,1-difluoro-4,8-dimethylnona-3,7-dien-1-yl]phosphonate
19f. Prepared following the procedure F from geranyl bromide 19f.
Reverse phase chromatography (H2O/CH3CN). Yield: 99% (161 mg, 0.5
mmol scale). Colourless oil; 1H NMR (300 MHz, CDCl3): δ 5.18 (t, J = 6.4
Hz, 1H), 5.04 (s, 1H), 4.26-4.17 (m, 4H), 2.82-2.69 (m, 2H), 2.00 (s, 4H),
1.71 (d, J = 4.2 Hz, 1H), 1.62 (d, J = 6.7 Hz, 5H), 1.55 (s, 3H), 1.33 (t, J =
7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 141.7, 124.1, 131.8, 120.2 (td,
J = 260.0 and 214.7 Hz), 112.3 (q, J = 5.6 Hz), 64.4 (d, J = 6.7 Hz), 39.9,
33.2 (dt, J = 20.7 and 15.4 Hz), 26.6, 26.4, 25.8, 17.8, 16.5 (d, J = 5.7
Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −111.5 (d, J = 109.3 Hz,
2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 7.4 (t, J = 109.3 Hz, 1P); IR (neat,
cm−1) ν: 2982, 2916, 1444, 1371, 1262, 1162, 1016, 977; HRMS (ESI+)
calcd for [M+Na]+ C15H27F2O3 NaP: 347.1564, found: 347.1566 (0.6 ppm).
Diethyl
Prepared
(2-(4-acetylphenyl)-1,1-difluoroethyl)phosphonate
following the procedure from
21d.
1-(4-
G
(bromomethyl)phenyl)ethan-1-one 20d. Reverse phase chromatography
(H2O/CH3CN). Yield: 47% (75 mg, 0.5 mmol scale). Brown oil; 1H NMR
(300 MHz, CDCl3): δ 7.94-7.90 (app. dt, 2H), 7.41 (d, J = 8.3 Hz, 2H),
4.30-4.12 (m, 4H), 3.50-3.35 (td, J = 19.6 and 5.3 Hz, 2H), 2.59 (s, 3H),
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10.1002/chem.201703542
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1.32 (t, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 197.9, 136.6, 136.3
(dt, J = 6.4 and 3.7 Hz), 131.3, 128.4, 119.2 (td, J = 262.1 and 215.7 Hz),
64.7 (d, J = 6.9 Hz), 40.2 (dt, J = 21.0 and 15.5 Hz), 26.8, 16.4 (d, J = 5.6
Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −111.2 (d, J = 106.3 Hz,
2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.6 (t, J = 106.5 Hz, 1P); IR (neat,
cm−1) ν: 2986, 1683, 1610, 1360, 1267, 1165, 1089, 1033, 1011, 979,
957; HRMS (ESI+) calcd for [M+NH4]+ C14H23NF2O4P: 338.1333, found:
338.1333 (0.0 ppm).
Diethyl (difluoro((4-methoxyphenyl)thio)methyl]phosphonate 23c.
Prepared
methoxyphenyl)disulfide
following
the
22c.
procedure
Reverse
H
phase
from
chromatography
1,2-bis(4-
(H2O/CH3CN). Yield: 48% (78 mg, 0.5 mmol scale). Brown oil; 1H NMR
(300 MHz, CDCl3): δ 7.57-7.52 (m, 2H), 6.93-6.88 (m, 2H), 4.35-4.23 (m,
4H), 3.81 (s, 3H), 1.40-1.35 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 161.7,
138.9, 124.6 (td, J = 266.6 and 216.3 Hz), 115.2-115.1 (m), 114.8, 65.4
(d, J = 6.6 Hz), 55.5, 16.4 (d, J = 5.7 Hz); 19F{1H} NMR (CDCl3, CFCl3,
282 MHz) δ −85.4 (d, J = 101.3 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz)
δ 4.2 (t, J = 101.3 Hz, 1P); IR (neat, cm−1) ν: 2987, 1591, 1495, 1464,
1394, 1274, 1250, 1175, 1164, 1115, 1015, 981; HRMS (ESI+) calcd for
[M+H]+ C12H18F2O4PS: 327.0631, found: 327.0634 (0.9 ppm).
Diethyl
(2-(2-cyanophenyl)-1,1-difluoroethyl)phosphonate
21e.
Prepared following the procedure G from 2-(bromomethyl)benzonitrile
20e. Reverse phase chromatography (H2O/CH3CN). Yield: 36% (55 mg,
0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.68 (d, J = 7.7
Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.3
Hz, 1H), 4.34-4.24 (m, 4H), 3.69-3.55 (app. t, 2H), 1.37 (t, J = 7.2 Hz,
6H); 13C NMR (75 MHz, CDCl3): δ 134.5 (dt, J = 7.5 and 2.9 Hz), 133.1,
132.7, 132.3, 128.5, 118.5 (td, J = 262.0 and 214.4 Hz), 117.8, 114.9,
65.0 (d, J = 6.8 Hz), 38.4 (dt, J = 20.9 and 15.9 Hz), 16.5 (d, J = 5.5 Hz);
19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −111.6 (d, J = 104.9 Hz, 2F);
31P{1H} NMR (CDCl3, 121 MHz) δ 5.9 (t, J = 104.5 Hz, 1P); IR (neat,
cm−1) ν: 2987, 2228, 1270, 1163, 1028, 1010, 762; HRMS (ESI+) calcd
for [M+NH4]+ C13H20F2N2O3P: 321.1180, found: 321.1191 (3.4 ppm).
Diethyl
[((4-fluorophenyl)thio)difluoromethyl]phosphonate
23d.
Prepared following the procedure H from 1,2-bis(4-fluorophenyl)disulfide
22d. Reverse phase chromatography (H2O/CH3CN). Yield: 52% (82 mg,
0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.64-7.59 (m,
2H), 7.11-7.02 (m, 2H), 4.35-4.20 (m, 4H), 1.39-1.35 (m, 6H); 13C NMR
(75 MHz, CDCl3): δ 164.3 (d, J = 250.6 Hz), 139.2 (d, J = 8.8 Hz), 124.7
(td, J = 297.1 and 219.0 Hz), 119.7-119.5 (m), 116.5 (d, J = 22.0 Hz),
65.5 (d, J = 6.6 Hz), 16.4 (d, J = 5.7 Hz); 19F{1H} NMR (CDCl3, CFCl3,
282 MHz) δ −85.2 (d, J = 101.0 Hz, 2F) and -110.2 (s,1F); 31P{1H} NMR
(CDCl3, 121 MHz) δ 3.8 (t, J = 101.4 Hz, 1P); IR (neat, cm−1) ν: 2987,
2918, 1590, 1491, 1397, 1371, 1273, 1225, 1159, 1118, 1010, 913;
HRMS (ESI+) calcd for [M+NH4]+ C11H18NF3O3PS: 332.0697, found:
332.0696 (- 0.3 ppm).
Diethyl
(1,1-difluoro-2-(2-iodophenyl)ethyl)phosphonate
21f.
Prepared following the procedure
G
from (1-(bromomethyl))-2-
iodobenzene 20f. Reverse phase chromatography (H2O/CH3CN). Yield:
48% (97 mg, 0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ
7.88 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H),
6.98 (t, J = 7.5 Hz, 1H), 4.35-4.26 (m, 4H), 3.63 (t, J = 19.9 Hz, 2H), 1.39
(t, J = 7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3): δ 139.9, 134.7 (dt, J = 8.4
and 2.5 Hz), 132.0, 129.5, 128.3, 119.2 (td, J = 261.7 and 214.9 Hz),
102.5, 64.8 (d, J = 6.7 Hz), 43.7 (dt, J = 20.1 and 16.1 Hz), 16.6 (d, J =
5.6 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −111.6 (d, J = 106.1
Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 6.6 (t, J = 106.4 Hz, 1P); IR
(neat, cm−1) ν: 2984, 1474, 1438, 1267, 1163, 1030, 1008, 741; HRMS
(ESI+) calcd for [M+NH4]+ C12H20INF2O3P: 422.0194, found: 422.0186 (-
1.9 ppm).
Diethyl
[((4-chlorophenyl)thio)difluoromethyl]phosphonate
23e.
Prepared following the procedure H from 1,2-bis(4-chlorophenyl)disulfide
22e. Reverse phase chromatography (H2O/CH3CN). Yield: 57% (94 mg,
0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.56 (m, 2H),
7.36 (m, 2H), 4.38-4.23 (m, 4H), 1.39-1.35 (m, 6H); 13C NMR (75 MHz,
CDCl3): δ 138.2, 137.2, 129.5, 124.6 (td, J = 298.6 and 219.7 Hz), 122.8
(td, J = 4.4 and 2.9 Hz), 65.5 (d, J = 6.5 Hz), 16.4 (d, J = 5.6 Hz); 19F{1H}
NMR (CDCl3, CFCl3, 282 MHz) δ −84.9 (d, J = 100.1 Hz, 2F); 31P{1H}
NMR (CDCl3, 121 MHz) δ 3.7 (t, J = 100.1 Hz, 1P); IR (neat, cm−1) ν:
2986, 2934, 1574, 1477, 1391, 1274, 1163, 1118, 1092, 1010, 910;
HRMS (ESI+) calcd for [M+NH4]+ C11H18NClF2O3PS: 348.0402, found:
348.0414 (3.4 ppm).
Diethyl [(phenylthio)difluoromethyl]phosphonate 23a. Prepared
following the procedure H from 1,2-diphenyldisulfide 22a. Reverse phase
chromatography (H2O/CH3CN). Yield: 49% (72 mg, 0.5 mmol scale).
Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.65-7.63 (m, 2H), 7.48-7.35 (m,
3H), 4.36-4.23 (m, 4H), 1.40-1.35 (m, 6H); 13C NMR (75 MHz, CDCl3): δ
137.0, 130.5, 129.2, 124.7 (td, J = 299.7 and 217.2 Hz), 124.4 (m), 65.4
(d, J = 6.6 Hz), 16.4 (d, J = 5.6 Hz); 19F{1H} NMR (CDCl3, CFCl3,
282 MHz) δ −84.6 (d, J = 100.7 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz)
δ 4.0 (t, J = 100.9 Hz, 1P); IR (neat, cm−1) ν: 2986, 2933, 1488, 1476,
1442, 1394, 1273, 1162, 1115, 1011, 982, 910; HRMS (ESI+) calcd for
[M+NH4]+ C11H19NF2O3PS: 314.0791, found: 314.0787 (- 1.3 ppm).
Acknowledgements
This work was partially supported by INSA Rouen, Rouen
University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-0029)
and Région Normandie (Crunch Network). M.V.I. thanks the
MESR for a doctoral fellowship. A.B. thanks the Labex SynOrg
(ANR-11-LABX-0029) and the Région Normandie for
postdoctoral fellowship.
a
Diethyl [((4-methylphenyl)thio)difluoromethyl]phosphonate 23b.
Prepared following the procedure H from 1,2-bis(4-methylphenyl)disulfide
22b. Reverse phase chromatography (H2O/CH3CN). Yield: 57% (88 mg,
0.5 mmol scale). Brown oil; 1H NMR (300 MHz, CDCl3): δ 7.51 (d, J = 8.0
Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 4.35-4.23 (m, 4H), 2.36 (s, 3H), 1.39-
1.34 (m, 6H); 13C NMR (75 MHz, CDCl3): δ 140.9, 137.0, 130.0, 130.4-
130.0 (m), 124.5 (td, J = 300.6 and 215.4 Hz), 65.4 (d, J = 6.5 Hz), 21.4,
16.4 (d, J = 5.7 Hz); 19F{1H} NMR (CDCl3, CFCl3, 282 MHz) δ −84.9 (d, J
= 101.1 Hz, 2F); 31P{1H} NMR (CDCl3, 121 MHz) δ 4.1 (t, J = 101.4 Hz,
1P); IR (neat, cm−1) ν: 2986, 2926, 1493, 1445, 1395, 1371, 1273, 1164,
1116, 1014, 981, 911; HRMS (ESI+) calcd for [M+H]+ C12H18F2O3PS:
311.0682, found: 311.0683 (0.3 ppm).
Keywords: fluorine • copper • phosphate mimic • synthetic
method
[1]
[2]
D. O'Hagan, Chem. Soc. Rev. 2008, 37, 308–319.
a) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev.
2008, 37, 320–330; b) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C.
del Pozo, A. E. Sorochinsky, S. Fustero, V. A. Soloshonok, H. Liu,
Chem. Rev. 2014, 114, 2432–2506; c) E. P. Gillis, K. J. Eastman, M. D.
Hill, D. J. Donnelly, N. A. Meanwell, J. Med. Chem. 2015, 58, 8315–
8359; d) E. A. Ilardi, E. Vitaku, J. T. Njardarson, J. Med. Chem. 2014,
57, 2832–2842 ; e) H.-J. Böhm, D. Banner, S. Bendels, M. Kansy, B.
This article is protected by copyright. All rights reserved.

10.1002/chem.201703542
Chemistry - A European Journal
FULL PAPER
Kuhn, K. Müller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5,
J. Org. Chem. 2012, 77, 2080–2086; h) M. Obayashi, K. Kondo,
Tetrahedron Lett. 1982, 23, 2327-2328.
637–643.
[3]
[4]
a) N. A. Meanwell, J. Med. Chem. 2011, 54, 2529–2591; b) E.
Schweizer, A. Hoffmann-Röder, K. Schärer, J. A. Olsen, C. Fäh, P.
Seiler, U. Obst-Sander, B. R. Wagner, M. Kansy, F. O. Diederich,
ChemMedChem 2006, 1, 611–621.
[13] For selected examples, see: a) S. Murakami, H. Ishii, T. Tajima, T.
Fuchigami, Tetrahedron 2006, 62, 3761-3769; b) C. De Schutter, E.
Pfund, T. Lequeux, Tetrahedron 2013, 69, 5920-5926; c) Z. Y. Yang, D.
J. Burton, Tetrahedron Lett. 1991, 32, 1019–1022; d) S. Pignard, C.
Lopin, G. Gouhier, S. R. Piettre, J. Org. Chem. 2006, 71, 31-37; e) S. R.
Piettre, Tetrahedron Lett. 1996, 37, 2233-2236; f) R. N. Haszeldine, D.
L. Hobson, D. R. Taylor, J. Fluorine Chem. 1976, 8, 115-124; g) T. F.
Herpin, J. S. Houlton, W. B. Motherwell, B. P. Roberts, J. -M. Weibel,
Chem. Commun. 1996, 613-614; h) T. F. Herpin, W. B. Motherwell, B.
P. Roberts, S. Roland, Tetrahedron 1997, 53, 15085-15100.
a) C. D. Sessler, M. Rahm, S. Becker, J. M. Goldberg, F. Wang, S. J.
Lippard, J. Am. Chem. Soc. 2017, 139, 9325–9332; b) Y. Zafrani, D.
Yeffet, G. Sod-Moriah, A. Berliner, D. Amir, D. Marciano, E. Gershonov,
S. Saphier, J. Med. Chem. 2017, 60, 797–804; c) M. D. Martinez, L.
Luna, A. Y. Tesio, G. E. Feresin, F. J. Duran, G. Burton, J. Pharm.
Pharmacol. 2016, 68, 233–244.
[5]
[6]
a) G. M. Blackburn, D. E. Kent, F. Kolkmann, J. Chem. Soc., Chem.
Commun. 1981, 1188–1190; b) M. V. Ivanova, A. Bayle, T. Besset, X.
Pannecoucke, T. Poisson, Chem. Eur. J. 2016, 22, 10284–10293.
For reviews, see: a) A. P. Combs, J. Med. Chem. 2010, 53, 2333–2344;
b) L. Bialy, H. Waldmann, Angew. Chem. Int. Ed. 2005, 44, 3814–3839;
For selected examples, see: c) C. Dufresne, P. Roy, Z. Wang, E.
Asante-Appiah, W. Cromlish, Y. Boie, F. Forghani, S. Desmarais, Q.
Wang, K. Skorey, D. Waddleton, C. Ramachandra, B. P. Kennedy, L.
Xu, R. Gordon, C.-C. Chan, Y. Leblanc, Bioorg. Med. Chem. Lett. 2004,
14, 1039–1042; d) Y. Han, M. Belley, C. I. Bayly, J. Colucci, C.
Dufresne, A. Giroux, C. K. Lau, Y. Leblanc, D. McKay, M. Therien, M.-
C. Wilson, K. Skorey, C.-C. Chan, G. Scapin, B. P. Kennedy Bioorg.
Med. Chem. Lett. 2008, 18, 3200–3205; e) D. Patel, M. Jain, S. R.
Shah, R. Bahekar, P. Jadav, B. Darji, Y. Siriki, D. Bandyopadhyay, A.
Joharapurkar, S. Kshirsagar, H. Patel, M. Shaikh, K. V. V. M. Sairam,
P. Patel, ChemMedChem 2011, 6, 1011–1016; f) M. Bahta, G. T.
Lountos, B. Dyas, S.-E. Kim, R. G. Ulrich, D. S. Waugh, T. R. Burke Jr.,
J. Med. Chem. 2011, 54, 2933–2943; g) P. Morlacchi, P. K. Mandal, J.
S. McMurray, ACS Med. Chem. Lett. 2014, 5, 69–72; h) P. K. Mandal,
F. Gao, Z. Lu, Z. Ren, R. Ramesh, J. S. Birtwistle, K. K. Kaluarachchi,
X. Chen, R. C. Bast Jr., W. S. Liao, J. S. McMurray, J. Med. Chem.
2011, 54, 3549–3563.
[14] a) Z. Feng, F. Chen, X. Zhang, Org. Lett. 2012, 14, 1938–1941; b) Z.
Feng, Y.-L. Xiao, X. Zhang, Org. Chem. Front. 2014, 1, 113–116; c) Y.-
L. Xiao, W.-H. Guo, G.-Z. He, Q. Pan, X. Zhang, Angew. Chem. Int. Ed.
2014, 53, 9909–9913; d) Z. Feng, Q.-Q. Min, Y.-L. Xiao, B. Zhang, X.
Zhang, Angew. Chem. Int. Ed. 2014, 53, 1669–1673; e) Z. Feng, Y.-L.
Xiao, X. Zhang, Org. Chem. Front. 2016, 3, 466–469.
[15] a) T. Yokomatsu, K. Suemune, T. Murano, S. Shibuya, J. Org. Chem.
1996, 61, 7207–7211; b) T. Yokomatsu, T. Murano, K. Suemune, S.
Shibuya, Tetrahedron 1997, 53, 815–822.
[16] a) X. Jiang, L. Chu, F.-L. Qing, Org. Lett. 2012, 14, 2870–2873; b) X.
Jiang, L. Chu, F.-L. Qing, New J. Chem. 2013, 37, 1736–1741.
[17] a) J. Xie, T. Zhang, F. Chen, N. Mehrkens, F. Rominger, M. Rudolph, A.
S. K. Hashmi, Angew. Chem. Int. Ed. 2016, 55, 2934–2938; For related
results, see: b) J. Xie, J. Li, V. Weingand, M. Rudolph, A. S. K. Hashmi,
Chem. Eur. J. 2016, 22, 12646–12650; c) J. Xie, J. Yu, M. Rudolph, F.
Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2016, 55, 9416–
9421; d) J. Xie, M. Rudolph, F. Rominger, A. S. K. Hashmi, Angew.
Chem. Int. Ed. 2017, 56, 7266–7270; e) J. L. T. W. V. W. H.-L. S. F. R.
M. R. A. S. K. H. Jin Xie, Org. Chem. Front. 2016, 3, 841–845.
[18] a) L. Wang, X.-J. Wei, W.-L. Lei, H. Chen, L.-Z. Wu, Q. Liu, Chem.
Commun. 2014, 50, 15916–15919; b) S. Wang, W.-L. Jia, L. Wang, Q.
Liu, Eur. J. Org. Chem. 2015, 6817–6821; for a related process, see: c)
M. Zhu, W. Fu, G. Zou, C. Xu, Z. Wang, J. Fluorine Chem. 2015, 180,
1–6.
[7]
[8]
[9]
D. O'Hagan, H. S. Rzepa, Chem. Commun. 1997, 645–652.
G. Thatcher, A. S. Campbell, J. Org. Chem. 1993, 58, 2272–2281.
For selected examples, see: a) M. S. Smyth, H. Ford, T. R. Burke,
Tetrahedron Lett. 1992, 33, 4137-4140; b) F. Benayoud, G. B.
Hammond, Chem. Commun. 1996, 1447-1448; c) D. Solas, R. L. Hale,
D.V. Patel, J. Org. Chem. 1996, 61, 1537-1539.
[19] a) Q. Zhao, V. Tognetti, L. Joubert, T. Besset, X. Pannecoucke, J.-P.
Bouillon, T. Poisson, Org. Lett. 2017, 19, 2106–2109; b) I. Fabre, T.
Poisson, X. Pannecoucke, I. Gillaizeau, I. Ciofini, L. Grimaud, Catal.
Sci. Technol. 2017, 7, 1921–1927; c) Q. Zhao, T. Besset, T. Poisson,
J.-P. Bouillon, X. Pannecoucke, Eur. J. Org. Chem. 2016, 76–82 ; d)
M.-C. Belhomme, A. Bayle, T. Poisson, X. Pannecoucke, Eur. J. Org.
Chem. 2015, 1719–1726; e) M.-C. Belhomme, T. Poisson, X.
Pannecoucke, J. Org. Chem. 2014, 79, 7205–7211; f) M.-C. Belhomme,
D. Dru, H.-Y. Xiong, D. Cahard, T. Besset, T. Poisson, X. Pannecoucke,
Synthesis 2014, 46, 1859–1870; g) C. Q. Fontenelle, M. Conroy, M.
Light, T. Poisson, X. Pannecoucke, B. Linclau, J. Org. Chem. 2014, 79,
4186–4195; h) G. Caillot, J. Dufour, M.-C. Belhomme, T. Poisson, L.
Grimaud, X. Pannecoucke, I. Gillaizeau, Chem. Commun. 2014, 50,
5887–5890; i) M.-C. Belhomme, T. Poisson, X. Pannecoucke, Org. Lett.
2013, 15, 3428–3431.
[10] a) E. Differding, R. O. Duthaler, A. Krieger, G. M. Rüegg, C. Schmit,
Synlett 1992, 395-396; b) S. D. Taylor, F. Mirzaei, A. Sharifi, S. L.
Bearne, J. Org. Chem. 2006, 71, 9420–9430.
[11] For selected examples, see: a) D. J. Burton, R. M. Flynn, J. Fluorine
Chem. 1980, 15, 263–266; b) D. J. Burton, R. M. Flynn, J. Fluorine
Chem. 1977, 10, 329–332; c) R. Waschbüsch, M. Samadi, P. Savignac,
J. Organomet. Chem. 1997, 529, 267–278; d) D. E. Bergstrom, P. W.
Shum, J. Org. Chem. 1988, 53, 3953–3958; e) C. F. Bigge, J. T.
Drummond, G. Johnson, Tetrahedron Lett. 1989, 30, 7013–7016; f) M.
Obayashi, E. Ito, K. Matsui, K. Kondo, Tetrahedron Lett. 1982, 23,
2323–2326.
[12] For selected examples, see: a) S. F. Martin, D. W. Dean, A. S.
Wagman, Tetrahedron Lett. 1992, 33, 1839-1842; b) D. B. Berkowitz, D.
Bhuniya, G. Peris, Tetrahedron Lett. 1999, 40, 1869-1872; c) D. B.
Berkowitz, M. J. Eggen, Q. Shen, J. Org. Chem. 1993, 58, 6174-6176;
d) D. B. Berkowitz, M. J. Eggen, Q. Shen, J. Org. Chem. 1996, 61,
4666-4675; e) T. Delaunay, T. Poisson, P. Jubault, X. Pannecoucke, J.
Fluorine Chem. 2015, 171, 56-59; f) P. Cherkupally, P. Beier, J.
Fluorine Chem. 2012, 137, 34-43; g) G.-V. Roschenthaler, V. P. Kukhar,
M. Y. Belik, K. I. Mazurenko, A. E. Sorochinsky, Tetrahedron 2006, 62,
9902–9910; d) K. Blades, D. Lapôtre, J. M. Percy, Tetrahedron Lett.
1997, 38, 5895–5898; e) T. Lequeux, J. M. Percy, Synlett 1995, 361-
362; f) M. Das, D. F. O’Shea, Chem. Eur. J. 2015, 21, 18717-18723; g)
M. D. Kosobokov, A. D. Dilman, M. I. Struchkova, P. A. Belyakov, J. Hu,
[20] A. Bayle, C. Cocaud, C. Nicolas, O. R. Martin, T. Poisson, X.
Pannecoucke, Eur. J. Org. Chem. 2015, 3787–3792.
[21] M. V. Ivanova, A. Bayle, T. Besset, T. Poisson, X. Pannecoucke,
Angew. Chem. Int. Ed. 2015, 54, 13406–13410.
[22] a) Copper-Mediated Cross-Coupling Reactions, G. Evano, N.
Blanchard, Eds.; Wiley, 2013; b) E. Nakamura, S. Mori, Angew. Chem.
Int. Ed. 2000, 39, 3750–3771; c) G. Evano, N. Blanchard, M. Toumi,
Chem. Rev. 2008, 108, 3054–3131; d) F. Monnier, M. Taillefer, Angew.
Chem. Int. Ed. 2009, 48, 6954–6971; e) K. S. Egorova, V. P. Ananikov,
Angew. Chem. Int. Ed. 2016, 55, 12150–12162.
[23] R. D. Guneratne, D. J. Burton, J. Fluorine Chem. 1999, 98, 11–15.
[24] TMSCF2PO(OEt)2 is commercially available, but quite expensive. It can
be readily prepared from BrCF2PO(OEt)2, see: J. Nieschalk, A. S.
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Batsanov, D. O’Hagan, J. A. K. Howard, Tetrahedron 1996, 52, 165-
176.
M. A. McClinton, R. J. Blade, J. Chem. Soc., Chem. Commun. 1988,
638–639; e) J. H. Clark, J. E. Denness, M. A. McClinton, J. Fluorine
Chem. 1990, 50, 411–426; f) A. I. Konovalov, A. Lishchynskyi, V. V.
Grushin, J. Am. Chem. Soc. 2014, 136, 13410–13425; g) A.
Lishchynskyi, M. A. Novikov, E. Martin, E. C. Escudero-Adán, P. Novák,
V. V. Grushin, J. Org. Chem. 2013, 11126-11146.
[25] a) C. Matheis, V. Wagner, L. J. Gooßen, Chem. Eur. J. 2015, 22, 79–
82; b) C. Matheis, K. Jouvin, L. J. Gooßen, Org. Lett. 2014, 16, 5984–
5987; c) B. Bayarmagnai, C. Matheis, E. Risto, L. J. Gooßen, Adv.
Synth. Catal. 2014, 356, 2343–2348; d) G. Danoun, B. Bayarmagnai, M.
F. Gruenberg, L. J. Gooßen, Chem. Sci. 2014, 5, 1312–1316; e) G.
Danoun, B. Bayarmagnai, M. F. Grünberg, L. J. Gooßen, Angew. Chem.
Int. Ed. 2013, 52, 7972–7975.
[33] a) J.-B. Langlois, A. Alexakis, Top. Organomet. Chem. 2011, 38, 235–
268 and references cited herein; b) E. R. Bartholomew, S. H. Bertz, S.
Cope, M. Murphy, C. A. Ogle, J. Am. Chem. Soc. 2008, 130, 11244–
11245.
[26] The coupling of such diazonium salts can also proceed via a cationic
mechanism for other elements of the copper triaded, see: a) S. Witzel,
J. Xie, M. Rudolph, A. S. K. Hashmi, Adv. Synth. Catal. 2017, 359,
1522–1528; b) L. Huang, F. Rominger, M. Rudolph, A. S. K. Hashmi,
Chem. Commun. 2016, 52, 6435–6438; c) L. Huang, M. Rudolph, F.
Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2016, 55, 4808–
4813.
[34] a) H.-Y. Xiong, A. Bayle, X. Pannecoucke, T. Besset, Angew. Chem. Int.
Ed. 2016, 55, 13490–13494; b) M. V. Ivanova, A. Bayle, T. Besset, X.
Pannecoucke, T. Poisson, Angew. Chem. Int. Ed. 2016, 55, 14141–
14145; c) M. V. Ivanova, A. Bayle, X. Pannecoucke, T. Besset, T.
Poisson, Eur. J. Org. Chem. 2017, 2475–2480.
[35] H.-Y. Xiong, X. Pannecoucke, T. Besset, Chem. Eur. J. 2016, 22,
16734–16749.
[27] a) J. K. Kochi, J. Am. Chem. Soc. 1956, 79, 2942–2948.; b) C. Galli,
Chem. Rev. 1988, 88, 765–792; c) A. Lishchynskyi, G. Berthon, V. V.
Grushin, Chem. Commun. 2014, 50, 10237-10240.
[36] a) H. Huang, G. Zhang, L. Gong, S. Zhang, Y. Chen, J. Am. Chem Soc.
2014, 136, 2280-2283; b) N. Ichiishi, A. F. Brooks, J. J. Topczewski, M.
E. Rodnick, M. S. Sandford, P. J. H. Scott, Org. Lett. 2014, 16, 3224-
3227; c) M. Bielawski, J. Malmgren, L. M. Pardo, Y. Wikmark, B.
Olofsson, ChemistryOpen 2014, 3, 19-22; d) M. Bielawski, M. Zhu, B.
Olofsson, Adv. Synth. Catal. 2007, 349, 2610-2618; e) M. Bielawski, B.
Olofsson, Chem. Commun. 2007, 2521-2523; f) M. D. Hossain, T.
Kitamura, Tetrahedron 2006, 62, 6955-6960; g) S. Thielges, P. Bisseret,
J. Eustache, Org. Lett. 2005, 7, 681-684; h) K. R. Roh, J. Y. Kim, Y. H.
Kim, Tetrahedron Lett. 1999, 40, 1903-1906; i) D. -W. Chen, M. Ochiai,
J. Org. Chem. 1999, 64, 6804-6814; j) M. Ochiai, M. Toyonari, T.
Nagaoka, D.-W. Chen, Tetrahedron Lett. 1997, 38, 6709-6712; k) T.
Kitamura, J. Matsuyuki, K. Nagata, R. Furuki, H. Taniguchi, Synthesis
1992, 945-946; l) P. Nikolaienko, T. L. Yildiz, M. Rueping, Eur. J. Org.
Chem. 2016, 1091–1094; m) T. E. Storr, M. F. Greaney, Org. Lett. 2013,
15, 1410–1413; n) Z. Huang, Q. P. Sam, G. Dong, Chem. Sci. 2015, 6,
5491–5498.
[28] a) P. J. Stang, V. V. Zhdankin, Chem. Rev. 1996, 96, 1123–1178; b) V.
V. Zhdankin, P. J. Stang, Chem. Rev. 2002, 102, 2523–2584; c) V. V.
Zhdankin, P. J. Stang, Chem. Rev. 2008, 108, 5299–5358; d) E. A.
Merritt, B. Olofsson, Angew. Chem. Int. Ed. 2009, 48, 9052–9070; e) A.
Yoshimura, V. V. Zhdankin, Chem. Rev. 2016, 116, 3328–3435.
[29] a) V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, J. T. Bolz, A. J.
Simonsen, J. Org. Chem. 1996, 61, 6547–6551; b) S. Nicolai, C.
Piemontesi, J. R. M. Waser, Angew. Chem. Int. Ed. 2011, 50, 4680–
4683.
[30] T. R. Burke, M. S. Smyth, A. Otaka, M. Nomizu, P. P. Roller, G. Wolf, R.
Case, S. E. Shoelson, Biochemistry 1994, 33, 6490–6494.
[31] a) T. P. Lockhart, J. Am. Chem. Soc. 1983, 105, 1940–1946; b) A.
Casitas, X. Ribas, Chem. Sci. 2013, 4, 2301–2318; c) A. J. Hickman,
M. S. Sanford, Nature 2012, 484, 177–185; d) M. N. Fananas-Mastral,
Synthesis 2017, 49, 1905–1930.
[32] a) C. E. Castro, R. Havlin, V. K. Honwad, J. Am. Chem. Soc. 1969, 91,
6464–6470; b) A. Bruggink, A. McKillop, Tetrahedron 1975, 31, 2607–
2619; c) J. Lindley, Tetrahedron 1984, 40, 1433–1456; d) J. H. Clark,
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