Diphenyliodonium Ion/Et3N Promoted Csp2-H Radical Phosphorylation of Enamides

Article abstract of DOI:10.1021/acs.orglett.9b01963

This work reports a simple and efficient method for the direct phosphorylation of enamide under metal-free conditions. The P-centered radicals, derived from secondary phosphine oxides, are generated under mild reaction conditions in the presence of diphenyliodonium salt and Et₃N and are introduced onto a range of enamides in good isolated yields. The method features broad substrate scope, good functional group tolerance, and efficient scale-up.

Full text of DOI:10.1021/acs.orglett.9b01963

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diphenyliodonium Ion/Et3N Promoted Csp2‑H Radical
Phosphorylation of Enamides
Suman Pal,† Annie-Claude Gaumont,‡ Sami Lakhdar,*,‡ and Isabelle Gillaizeau*,†
†
́
́
̂
Institute of Organic and Analytical Chemistry, ICOA UMR 7311 CNRS, Universite d’Orleans, Pole chimie, rue de Chartres, 45100
́
Orleans, France
‡
́
́
LCMT, ENSICAEN, UNICAEN, CNRS, Normandie Universite, 6 Boulevard Marechal Juin, Caen 14000 France
S
* Supporting Information
ABSTRACT: This work reports a simple and efficient
method for the direct phosphorylation of enamide under
metal-free conditions. The P-centered radicals, derived from
secondary phosphine oxides, are generated under mild
reaction conditions in the presence of diphenyliodonium
salt and Et3N and are introduced onto a range of enamides in
good isolated yields. The method features broad substrate
scope, good functional group tolerance, and efficient scale-up.
Scheme 1. Manganese-Mediated (a) and (b) and Metal-Free
β-Phosphorylation of Enamides
he addition of radicals onto olefins is undoubtedly one of
Tthe most useful organic transformations in organic
synthesis.1 The impressive progress accomplished in this field
due to the discovery of practically simple and environmentally
benign approaches for the generation of radical species.2
Among them, P-centered radicals have recently attracted
increasing attention.3 Phosphorus-containing compounds
exhibit a broad range of applications in organic,4 material,5
and medicinal chemistry,6 triggering the development of many
methods for their preparation. Conventionally, C−P bond
formation was achieved using metal catalysis;7 however, most
of the reported procedures show drawbacks, which include the
use of noble metal catalysts (i.e., Pd, Rh, Ir) and precious
ligands and/or drastic conditions. Recent studies demonstrate
that radical mediated C−P bond formation can interestingly
emerge as a very useful tool to synthesize organophosphorus
compounds. The P-centered radicals can be obtained from the
cleavage of the H−P bond generated by various radical
initiators such as Ag(I),8 Mn(III),9 Cu(II),10 peroxides,11 or
under visible-light photocatalytic conditions.12 In addition,
although great progress has been made on C(sp2)-P bond
formation,13 the direct construction of a radical-mediated
C(sp2)-P bond from an enamide C−H bond is scarce. One of
our current research interests deals with the direct function-
alization of enamide C−H bonds. Enamides are stable enamine
surrogates and provide key intermediates for the synthesis of
small but complex nitrogen-containing compounds.14 The π-
donating ability of the nitrogen atom renders enamides more
electron-rich than simple alkenes, and they afford a means of
activating carbon−carbon double bonds.15 To the best of our
knowledge, only two examples for the synthesis of β-
phosphorylated enamides have been reported to date. Liu et
al. showed that β-phosphorylated acyclic enamides can be
obtained through manganese(III) mediated oxidative coupling
(Scheme 1);16 a Z-selectivity was observed. During the
preparation of this communication, Zeng et al. reported a
manganese(III) mediated method for the preparation of β-
phosphorylated enamides through the radical oxidative
phosphorylation of N-styrylamides.17 Despite these recent
advances, the development of a novel approach to access β-
phosphorylated enamides that proceeds under mild and metal-
free conditions is highly appealing.
Although the photophysical properties of EDA complexes
have been extensively studied,18,19 their use to allow organic
transformations is even less explored as electron transfers from
donors to acceptors are fast and reversible.20 A highly
anticipated application of this complex is the photochemical
Received: June 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
or thermal generation of reactive aryl radicals.12c,21 Indeed,
Kita et al. suggested the ability of diaryliodonium salts22 to
form EDA complexes with rich electron arenes and confirmed
the generation of aryl radicals by EPR spectroscopy.23
Control experiments revealed the essential role of the base
(entry 17) and of the iodonium salt (entry 4) in the reaction.
Attempts to reduce the amount of base, diphenylphosphine
oxide, or iodonium salt led to lower the yield significantly
(entries 6−9). A series of common solvents was next
examined, revealing that CH2Cl2 is best suited to the reaction
(entries 1, 5, 10−12). Other organic or inorganic bases also
worked well to deliver 4aa, albeit in lower yields (entries 13−
16). Incomplete conversion was observed with a shorter
reaction time or in the presence of air (entry 18).
Although this strategy has been frequently used in the
radical arylation reaction, its use as a hydrogen abstractor to
generate phosphinoyl radical from related phosphine oxides is
scarce. Prior to this work, we developed the synthesis of 6-
phosphorylated phenanthridines in the presence of phosphi-
noyl radicals from the combination of diphenyliodonium salt
(Ph2I+,−OTf), triethylamine (Et3N), and secondary phosphine
oxides.24 We consequently aimed at extending this approach to
consider the unprecedented transition-metal-free phosphinoyl-
functionalization of enamides. To the best of our knowledge,
the use of diphenyl iodonium ion/Et3N as radical initiator
system to promote Csp2-H phosphorylation of enamide,
otherwise inaccessible via conventional radical conditions, is
unprecedented. The phosphinoylation of enamides was first
investigated starting from 1a and diphenylphosphine oxide 2a,
selected as model substrates (Table 1). We surveyed the
With the optimized conditions in hand, we first explored the
scope of the reaction with respect to the enamide derivative
1b−u (Scheme 2). The reaction proceeded smoothly with a
a
Scheme 2. Scope of Enamides 1
Table 1. Optimization of the Reaction Conditions for the
a
Phosphorylation
b
entry
base (equiv)
solvent
temp (°C)
yield (%)
1
2
3
Et3N (2.0)
Et3N (2.0)
Et3N (4.0)
Et3N (2.0)
Et3N (2.0)
Et3N (2.5)
Et3N (1.5)
Et3N (2.0)
Et3N (2.0)
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
40
90
40
40
40
40
40
40
40
90
90
60
90
90
90
90
90
40
66
65
58
NR
70
68
15
46
35
46
57
53
60
51
37
44
NR
50
c
4
5
6
7
d
8
e
9
10
11
12
13
14
15
16
17
Et3N (2.0)
Et3N (2.0)
Et3N (2.0)
DMF
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
a
piperidine (2.0)
morpholine (2.0)
Cs2CO3 (2.0)
K2CO3 (2.0)
Reaction conditions: 1 (0.3 mmol), 2 (0.75 mmol), 3 (0.6 mmol),
base (0.6 mmol), CH2Cl2 (1.5 mL), 40 °C, 16 h under Ar.
wide functional group tolerance. The reaction of diphenyl-
phosphine oxide 2a with cyclic enamide 1b−e containing an
aryl group bearing strong electron donating (6-OMe, 5-OMe,
5,7-diMe) or withdrawing groups (7-F, 6-OAc) with different
substitution patterns afforded the corresponding phosphory-
lated products 4ba−4ea in moderate to good yields. In
addition, cyclic enamide bearing a methyl group at C4 position
reacted smoothly with 2a, leading to the hindered phosphory-
lated product 4fa in 55% yield. Similarly, 1-benzosuberone and
chromanone derived cyclic enamides were easily transformed
to the corresponding products 4ga−4ia in good to excellent
yields. Next, our method also proved to be applicable to the 6-,
7-, and 13-membered cyclic enecarbamates 4ja−ma. Interest-
ingly, enesulfonamide 1m led after N−S bond cleavage25 to the
β-phosphorylated secondary enamine 4ma isolated as a stable
product in 54% yield after purification on silica gel. This
method appears thus as a valuable alternative to the known
reported procedures.26 Our strategy was also amenable to the
f
18
Et3N (2.0)
a
Reaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), 3 (0.4 mmol),
b
c
base, solvent (1.0 mL) under Ar. Isolated yields. Reaction
performed in the absence of iodonium salt 3. Reaction performed
d
e
with 2 equiv of diphenylphosphine oxide 2a. Reaction performed
f
with 1.5 equiv of Ph2I+,OTf− 3. In the presence of air.
reaction parameters by using the diphenyliodonium salt 3 (2
equiv) and Et3N (2 equiv), as a sacrificial electron donor, at 40
°C in CH3CN under argon atmosphere. Fortunately, trapping
of the phosphinoyl radical by enamide 1a delivered the
phosphorylated product 4aa in 66% of isolated yield (Table 1,
entry 1). NMR and mass spectroscopy unambiguously
confirmed the structure of 4aa. No obvious improvement on
the reaction outcome was observed when the amount of base
or the reaction temperature was increased (entries 2−3).
B
DOI: 10.1021/acs.orglett.9b01963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
phosphinoyl-functionalization of endo-enamides bearing termi-
nal aryl (4na−ra) or ester (4sa) functional groups. In addition,
the electron-rich morpholinone-derived enamides 1t,u led to
the formation of the unexpected hydrophosphorylation
products 4ta−ua. While the hydrophosphorylation of an
electron-rich olefin such as glycal is already known,27 to the
best of our knowledge, in the case of enamide, this reaction has
been described only once as side traces.17 The formation of the
phosphinoyl morpholinones 4ta−ua can be rationally ex-
plained as follows: the phosphinoyl radical 7 formed added to
1t or 1u, giving the alkylradical 8 (see Scheme 5), which
subsequently abstracts a hydrogen atom from a hydrogen
donor such as 2a and affords the corresponding adduct 4ta−
ua.
These phosphinoyl lactams 4ta−ua can then be envisaged as
precursors of more complex compounds based on the
reactivity of the lactam or the phosphinoyl moiety. A variety
of phosphinoyl functionalized enamides was thus readily
furnished in synthetically useful yields. It is worth noting
that a complex mixture was unfortunately observed starting
from acyclic enamide.
Scheme 4. Gram-Scale Synthesis
reaction is depicted in Scheme 5. It starts with formation of
the electron donor−acceptor (EDA) complex between Et3N 5
Scheme 5. Postulated Reaction Mechanism for the β-
Phosphorylation of Enamide
Subsequently, we investigated furthermore the reactions of
enamide 1a with different secondary phosphine oxides
(Scheme 3). Various electronic properties and steric bulks
a
Scheme 3. Scope of Pentavalent Phosphorus Derivatives 2
and Ph2I+,−OTf 3. Consequently, a single electron transfer
process is initiated to generate the phenyl radical 6. This
radical abstracts a hydrogen from the secondary phosphine
oxide 2a to form the phosphinoyl radical 7. The latter adds
reversibly to the enamide 1a, generating the radical 8. The
oxidation of 8 with the diphenylidonium 3 give rise to the
radical cation 9, which yield the phosphorylated product 4aa
after deprotonation with Et3N.
In conclusion, we have successfully developed a novel and
new transition-metal-free C−P bond formation method
allowing the regioselective β-phosphorylation of cyclic and
acyclic enamides via a phosphinoyl radical. The transformation
features excellent functional group tolerance, simple operation,
and mild conditions. The scope of enamide and phosphine
oxide derivatives is broad. This strategy is anticipated to be an
important approach for the transition-metal-free functionaliza-
tion of enamides, precursors of more complex nitrogen-
containing molecules. Further studies to apply this strategy to
other reactions are ongoing in our laboratory.
a
Reaction conditions: 1 (0.3 mmol), 2 (0.75 mmol), 3 (0.6 mmol),
base (0.6 mmol), CH2Cl2 (1.5 mL), 40 °C, 16 h under Ar.
were tolerated. Diarylphosphine oxides bearing a t-Bu, NMe2,
or CF3 group at the C4 position of the aryl rings provided the
enamide adduct with good yields (4ab−ad). Diarylphosphine
oxides bearing a 3,5 disubstituted methyl group on the aryl ring
afforded the product (4ae) in 66% isolated yield. Unfortu-
nately, tert-butyl phosphine oxide proved to be unsuccessful in
our methodology. Then, we examined the scalability of the
process to demonstrate its practicability (Scheme 4). In this
context, more than 1 g of 1r and 2a was treated under similar
reaction conditions, and the corresponding product 4ra was
isolated in 56% yield (1.29 g, 2.8 mmol).
Radical trapping experiments using TEMPO or BHT were
conducted, confirming the free radical process for the
mechanism (see Supporting Information). On the basis of
these experiments and our previous mechanistic investigations,
a tentative reaction mechanism for this phosphorylation
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01963.
Experimental procedures and spectral data (PDF)
C
DOI: 10.1021/acs.orglett.9b01963
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: isabelle.gillaizeau@univ-orleans.fr.
*E-mail: sami.lakhdar@ensicaen.fr.
ORCID
Sami Lakhdar: 0000-0002-1168-7472
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the LABEX SynOrg (ANR-11-LABX-0029) for
financial support.
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DOI: 10.1021/acs.orglett.9b01963
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