Metal-free synthesis of 6-phosphorylated phenanthridines: Synthetic and mechanistic insights

Article abstract of DOI:10.1021/acs.orglett.6b02983

A novel and efficient method for the generation of phosphinoyl radicals from the combination of diphenyliodonium salt (Ph₂I⁺,^-OTf) with triethylamine (Et₃N) in the presence of secondary phosphine oxides is reported. By employing this practical and simple approach, a large variety of 6-phosphorylated phenanthridines have been synthesized through the addition of phosphinoyl radicals to isonitriles as radical acceptors. The reaction works smoothly in the absence of any transition metal or photocatalyst. On the basis of electron paramagnetic resonance (EPR) and density functional theory (DFT) calculations, the mechanism of this reaction is discussed.

Full text of DOI:10.1021/acs.orglett.6b02983

Letter
pubs.acs.org/OrgLett
Metal-Free Synthesis of 6‑Phosphorylated Phenanthridines:
Synthetic and Mechanistic Insights
Ludovik Noel-Duchesneau,† Elodie Lagadic,† Fabrice Morlet-Savary,‡ Jean-Franco
̧
is Lohier,†
Isabelle Chataigner,⊥ Martin Breugst,*,§ Jacques Lalevee,‡ Annie-Claude Gaumont,† and Sami Lakhdar*,†
̈
́
†Normandie Universite,
‡Institut de Science des Mater
France
⊥Normandie Universite,
§Department fur Chemie, Universitat zu Koln, Greinstraße 4, 50939 Koln, Germany
́
LCMT, ENSICAEN, UNICAEN, CNRS, 6, Boulevard Marec
́
hal Juin, Caen 14000 France
́
iaux de Mulhouse IS2M - UMR CNRS 7361 - UHA, 15, rue Jean Starcky, Mulhouse 68057 Cedex,
́
INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: A novel and efficient method for the generation
of phosphinoyl radicals from the combination of diphenylio-
donium salt (Ph2I+,−OTf) with triethylamine (Et3N) in the
presence of secondary phosphine oxides is reported. By
employing this practical and simple approach, a large variety of
6-phosphorylated phenanthridines have been synthesized
through the addition of phosphinoyl radicals to isonitriles as
radical acceptors. The reaction works smoothly in the absence
of any transition metal or photocatalyst. On the basis of
electron paramagnetic resonance (EPR) and density functional theory (DFT) calculations, the mechanism of this reaction is
discussed.
Scheme 1. Synthesis of 6-Phosphorylated Phenanthridines
sonitriles 1 are radical acceptors “par excellence”. Their
Isynthetic potential has been triggered by Curran, who
demonstrated that isonitriles can efficiently be employed for the
synthesis of nitrogen based heterocycles.1 While the develop-
ment of this chemistry has grown slowly, recent years have
witnessed remarkable interest in radical insertion reactions into
isonitriles.2 This has allowed construction of nitrogen hetero-
cycles such as phenanthridines, indoles, quinolines, quinoxa-
lines, and isoquinolines.3 This impressive development in the
field is obviously due to the discovery of efficient and mild
methods for the generation of radical species such as visible-
light photoredox catalysis.2,4 Among those heterocycles,
phenanthradines have recently emerged as an interesting
scaffold with promising applications in medicinal chemistry
and material sciences.2 In this context, Studer et al. have
reported an elegant method for the synthesis of 6-
phosphorylated phenanthridines 3 from the reactions of aryl
isonitriles 1 with secondary phosphine oxides 2 in the presence
of stoichiometric amounts of AgOAc (3 equiv) at 100 °C
(Scheme 1).5a The key step of this reaction involves the
addition of phosphinoyl radical to isonitrile as a radical
acceptor. Shortly thereafter, Wu et al. demonstrated that
stoichiometric manganese(III) acetate (3 equiv) can also afford
phosphorylated isonitriles 3 from the reaction of 1 and 2.6
During the preparation of this manuscript, Yan, Lu, et al.
showed that the same reaction can proceed through visible light
photoredox catalysis in the presence of K2S2O8 (3 equiv) and
CsF (2 equiv) at room temperature.7 Despite the robustness of
these methods, the use of stoichiometric or expensive transition
metals still remains a disadvantage. Therefore, the development
of a mild metal-free method for the synthesis of these
phosphorylated molecules that is mechanistically distinct from
the approaches mentioned above is highly appealing.
Design Plan. Given the accessible bond dissociation energies
(BDE ≈ 90 kcal mol−1) of the P−H bond of secondary
phosphine oxides and related structures,8 the use of
stoichiometric amounts of metal oxides (methods A and B,
Received: October 3, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02983
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1) or photocatalyst/K2S2O8 (method C) to generate
phosphinoyl radicals can be replaced by milder metal-free
conditions. Indeed, because open-shell species can be formed
when an electron donor−acceptor complex (EDA) undergeos a
single-electron-transfer event (SET),9 one can employ this
technology for the generation of phosphorus-centered radicals.
For instance, diaryliodonium ions (Ph2I+,−OTf) are now
recognized as suitable electron-acceptor substrates for the
formation of EDA complexes when combined with electron
donors.10 When these complexes undergo SET events
photochemically or thermally, they generate aryl radicals.11
While this strategy has been used for arylating radical reaction
in the past, one can envision taking advantage of the strong
hydrogen abstraction ability of this radical to generate
phosphinoyl radical from related phosphine oxides.12
which is less expensive, has been selected to study the scope of
the reaction. Among all tested solvents, dichloromethane has
been identified as optimal for the reaction (entry 12). Lastly,
optimization attempts showed that the temperature can be
decreased to 40 °C without any loss in efficiency (entry 15).
Varying the concentration of the mixture has almost no
influence on the reaction efficiency. Finally, we found that 2
equiv of Et3N allowed a further increase to a 74% conversion
(entry 16). A control experiment revealed the essential role of
the base as only trace amounts of 3a have been detected
without any base (entry 17).
On the basis of this hypothesis, we reacted isonitrile 1a with
diphenyl phosphine oxide 2a in the presence of Et3N, 5a, and
Ph2I+,−OTf, 4, under white light irradiation (26 W CF-lamp) at
rt in DMF (Table 1). The reaction proceeds smoothly,
Table 1. Optimization of the Radical Phosphorylation of
Isonitrile 3a
a
b
entry 5, electron donor (equiv)
solvent
temp (°C) 3a, yield (%)
c
e
1
5a, Et3N (1.3)
DMF
20
20
50
50
50
50
50
50
50
50
50
40
50
40
40
40
40
45
41
c
2
5a, Et3N (1.3)
DMF
c
3
5a, Et3N (1.3)
DMF
72
c
4
5b, NaOAc (1.3)
5c, KOH (1.3)
5d, NaHCO3 (1.3)
5e, K2CO3 (1.3)
5f, K3PO4 (1.3)
5g, Cs2CO3 (1.3)
5g, Cs2CO3 (1.3)
5g, Cs2CO3 (1.3)
5g, Cs2CO3 (1.3)
5g, Cs2CO3 (1.3)
5g, Cs2CO3 (2.0)
5a, Et3N (1.3)
DMF
31
c
5
DMF
45
c
6
DMF
62
c
7
DMF
66
c
8
DMF
67
c
9
DMF
68
c
10
11
12
13
14
15
16
17
THF
28
c
toluene
CH2Cl2
62
c
61
d
DMF
70
d
d
d
CH2Cl2
CH2Cl2
64
58
5a, Et3N (2.0)
CH2Cl2
74
trace
d
CH2Cl2
a
Reaction conditions: aryl isonitrile 1a (0.25 mmol; 1 equiv),
diphenylphosphine oxide 2a (2.5 equiv), diphenyliodonium triflate 4
b
(1.3 equiv), base 2 (x equiv), solvent (4 or 1 mL), 15 h. Determined
c
by 31P NMR using trioctylphosphine oxide as internal standard. [1a]
d
e
= 0.063 M. [1a] = 0.25 M. Irradiation with white LEDs.
furnishing 3a in 45% yield (entry 1). Remarkably, a control
experiment revealed that light is not required for the reaction, a
comparable result being observed in the dark (entry 2). This
suggests that the electron-transfer event within the EDA
complex is thermodynamically viable in the absence of
photochemical activation. The yield was further improved
upon gentle heating of the reaction mixture to 50 °C (72%;
entry 3). Interestingly enough, the reaction is compatible with a
wide range of bases (entries 5−9), including KOH (5c),
NaHCO3 (5d), K2CO3 (5e), K3PO4 (5f), Cs2CO3 (5g), and
Et3N (5a). Although the two latter gave similar results, Et3N,
Figure 1. Scope of EDA-mediated 6-phosphorylation of isonitriles 1.
Reaction conditions: Reactions were run on 0.5 mmol scale in 2 mL of
dichloromethane. Yields are obtained after isolation and purification.
See the Supporting Information.
B
DOI: 10.1021/acs.orglett.6b02983
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Organic Letters
Letter
Scheme 2. Proposed Mechanism Including Calculated Free Energies for the Synthesis of 6-Phosphorylated Phenanthridine 3a
With optimal conditions established, the scope of the
reaction was first explored with respect to the isocyanide
component. As shown in Figure 1, aryl isonitriles bearing
electron-donating or electron-withdrawing substituents at the
para position of the arene ring that does not carry the isonitrile
functionality furnished the desired heterocycles 3c−h,j in good
yields ranging from 72% to 89%. However, a moderate 43%
yield was obtained with isonitrile 1k bearing a naphthyl moiety.
This result remains comparable to that reported by Studer
under Ag-mediated conditions.5 Interestingly, while the
reaction of diphenylphosphine oxide 2a with 3-methyl-
substituted isocyanide 1l gave two regioisomers 3l and 3l′
(3:2) with 73% total yield, product 3i was obtained with
complete regiocontrol and in good yield (75%).
We have furthermore investigated the reaction with aryl
isonitriles bearing substituents at the arene carrying the
isonitrile functionality. As shown in Figure 1, the reaction
proceeds well, and the phenanthridines 3m−o were obtained in
good yields (76 to 82%). Remarkably, in contrast to the
conditions of Yan, Lu, et al.,7 where the reaction did not occur
when a strong electron-withdrawing group (F or CF3) is
located at the para position of isonitrile, the reaction proceeded
well under our conditions, leading to the formation of 3o in
76%. We finally extended the scope of our approach by
investigating the reactions of isocyanides with other pentavalent
phosphorus derivatives P(V). Interestingly, diarylphosphine
oxides bearing tert-butyl, trifluoromethyl, or methoxy at the
para positions of the aryl rings gave the desired P-substituted
phenanthridines 3p−r in decent yields (64 to 75%). The
reaction works smoothly with dicyclohexylphosphine oxide 3t,
dinaphthylphosphine oxide 3u, and dimesitylphosphine oxide
3s, furnishing the desired adducts in 58−73% yields (Figure 1).
To gain insights into the reaction mechanism, preliminary
mechanistic investigations have been undertaken. We first
conducted electron paramagnetic resonance EPR spin-trapping
experiments for the reaction of Ph2I+,−OTf 4 (1 equiv) with
Et3N 5a (1 equiv) in tert-butylbenzene in the presence of α-
phenyl-N-tert-butylnitrone (PBN) 6 at room temperature.
The EPR spectrum of this mixture reveals the clean
formation of the phenyl-PBN radical adduct, characterized by
typical hyperfine coupling constants (aN = 14.4 G and aH = 2.2
G) (Figure S1). These values perfectly match those reported
previously.12 The double integration of the EPR spectrum
(DIEPR) of the EDA complex 4−5a has been found to be
proportional to the free-radical concentration (Figure S2).
Importantly, in accordance with our observations gathered in
Table 1 (entry 2), the DIEPR experiment shows that the
phenyl radical is formed slowly and appeared for at least 72 h at
room temperature before reaching a plateau. This suggests that
the reduction of the iodonium salt 4 at room temperature goes
through a slow and irreversible process. Addition of
diphenylphosphine oxide 2a into this mixture resulted in the
formation of a new radical species 7 where the hyperfine
coupling constants (aN = 14.0 G, aH = 3.0 G, and aP = 18.4 G)
are in good agreement with those previously determined for the
PBN-diphenylphosphinoyl radical adduct 7 (Scheme 2).11
Furthermore, we employed density functional theory
[B3LYP-D3BJ/aug-cc-pVTZ/IEFPCM(CH2Cl2)//B3LYP-
D3BJ/6-31+G(d,p)] to investigate this transformation in more
detail. Based on the experimental and computational findings,
we now propose the reaction mechanism depicted in Scheme
2.13 The reaction begins with the association of NEt3 5a with
Ph2I+,−OTf 4 to form the corresponding EDA complex 4−5a.
Although all attempts to characterize this ground-state complex
1
failed, ROESY H NMR experiments in acetone-d6 at −40 °C
showed that both components are in close proximity in solution
(see the Supporting Information). It should be noted that Yu et
al. have recently demonstrated the formation of EDA complex
between hypervalent iodines such as Togni’s reagent and
tertiary amines, which has been employed for hydrotrifluor-
omethylation of unactivated alkenes and alkynes.14 Further-
more, our DFT calculations showed that the association of 4
and 5a is almost thermoneutral (Figure 2), which may explain
C
DOI: 10.1021/acs.orglett.6b02983
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ACKNOWLEDGMENTS
We thank the CNRS, Normandie Universite,
■
́
Labex Synorg
(ANR-11-LABX-0029), and the Fonds der chemischen
Industrie and the University of Cologne within the excellence
initiative for financial support and the Regional Computing
Center of the University of Cologne (RRZK).
Figure 2. Computed structures of selected intermediates (selected
bond lengths in angstroms).
DEDICATION
Dedicated to memory of Dr. Alain-Pierre Chatrousse.
■
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■
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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.6b02983.
́
Morlet-Savary, F.; Lohier, J.-F.; Lalevee, J.; Gaumont, A.-C.; Lakhdar,
S. J. Am. Chem. Soc. 2016, 138, 7436. For applications of
diaryliodonium salts in organic synthesis, see: (d) Olofsson, B. Top.
Curr. Chem. 2016, 373, 135. (e) Merritt, E. A.; Olofsson, B. Angew.
Chem., Int. Ed. 2009, 48, 9052.
Full experimental procedures, spectroscopic character-
izations, computational data, and NMR spectra; crystallo-
graphic data for compound 3j, 3h, and 3o (PDF)
(12) (a) Morlet-Savary, F.; Klee, J. E.; Pfefferkorn, F.; Fouassier, J.-P.;
́ ́
Lalevee, J. Macromol. Chem. Phys. 2015, 216, 2161. (b) Lalevee, J.;
Morlet-Savary, F.; Tehfe, M.-A.; Graff, B.; Fouassier, J.-P. Macro-
molecules 2012, 45, 5032.
AUTHOR INFORMATION
Corresponding Authors
■
(13) For details of the computational investigation, see the
*E-mail: mbreugst@uni-koeln.de.
*E-mail: sami.lakhdar@ensicaen.fr.
Notes
Supporting Information.
(14) Cheng, Y.; Yu, S. Org. Lett. 2016, 18, 2962.
(15) Fouassier, J.-P.; Lalevee
Scope, Reactivity and Efficiency; Wiley-VCH: Weinheim, 2012.
́
, J. Photoinitiators for Polymer Synthesis:
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.6b02983
Org. Lett. XXXX, XXX, XXX−XXX