Dearylation of arylphosphine oxides using a sodium hydride-iodide composite

Article abstract of DOI:10.1039/c8cc00289d

A new protocol for the dearylation of arylphosphine oxides was developed using sodium hydride (NaH) in the presence of lithium iodide (LiI). The transient sodium phosphinite could be functionalized with a range of electrophiles in a one-pot fashion.

Full text of DOI:10.1039/c8cc00289d

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Dearylation of Arylphosphine Oxides by a Sodium Hydride‐Iodide
Composite
Received 00th January 20xx,
Accepted 00th January 20xx
Ciputra Tejo,a Jia Hao Pang,a Derek Yiren Ong,a Miku Oi,b,c Masanobu Uchiyama,b,c Ryo Takita*b
and Shunsuke Chiba*a
DOI: 10.1039/x0xx00000x
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A new protocol for dearylation of arylphosphine oxides was available arylphosphine oxides (Scheme 1b). Subsequent
developed using sodium hydride (NaH) in the presence of lithium reactions of the resulting sodium phosphinites with a range of
iodide (LiI).
The transient sodium phosphinite could be carbon‐electrophiles are able to furnish functionalized
functionalized with a range of electrophiles in one‐pot fashion.
phosphine oxides. The discovery, scope/limitation, and
mechanistic proposal of these processes are described.
Organophosphorus compounds have been utilized in
various applications as reagents for chemical synthesis1 and
privileged ligands for transition metal catalysts2 as well as in
medicinal chemistry,3 chemical biology,4 and materials
chemistry.5 Therefore, a variety of methods to construct
carbon‐phosphorus bonds have been developed for their
synthesis.6
Various covalent hydrides such as boranes/borohydrides,7
alanes/aluminum hydrides,8 hydrosilanes,9 and zirconium
hydrides (the Schwartz reagent)10 have been adopted as a
reagent of choice for reduction of phosphine oxides to
phosphines (Scheme 1a), whereas use of ionic hydrides has
remained elusive for transformation of phosphine oxides.11
We recently disclosed that unprecedented hydride donor
reactivity is installed onto sodium hydride (NaH) by its
solvothermal treatment with NaI or LiI in THF and the resulting
NaH‐iodide composites could be used for a series of hydride
reduction such as hydrodecyanation, reduction of amides into
aldehydes, and hydrodehalogenation of bromo‐ and
iodoarenes.12,13 In this context, we wondered if the NaH‐
iodide composites are capable of reducing phosphine oxides in
unique and unprecedented manners. Herein, we report use of
the NaH‐iodide composites to perform dearylation of readily
Scheme 1. Hydride reduction of phosphine oxides.
We commenced our studies with the reactions of
triphenylphosphine oxide (1a) (Scheme 2a, see the ESI for the
details on the optimization of the reaction conditions). We
were surprised to find that the treatment of 1a with NaH (2
equiv) and NaI (1 equiv) in THF at 60
C (for 24 h) followed by
aqueous work‐up gave dephenylated product,
a
diphenylphosphine oxide (2a) in 88% yield.14,15 Use of LiI (1
equiv) instead of NaI enhanced the reaction efficiency,
providing 2a in 98% yield with the reaction time of 13 h. This
hydrodephenylation of 1a should go through formation of
sodium phosphinite and its protonation. Almost no reaction
was observed from the reaction with NaH only, which
indicates unique feature of the NaH‐iodide composites. The
method could be extended for hydrodearylation of both
a. Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore.
electron‐rich (for 1b and 1c) and sterically hindered (for 1d
phosphine oxides to provide the corresponding
diarylphosphine oxides 2b 2d in good yields, while that of
electron‐deficient tris(4‐trifluoromethylphenyl)phosphine
)
b. Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable
Resource Science, and Elements Chemistry Laboratory, RIKEN, 2‐1 Hirosawa,
Wako‐shi, Saitama 351‐0198, Japan
‐
c. Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7‐3‐1
Hongo, Bunkyo‐ku, Tokyo 113‐0033, Japan
oxide (1e) became sluggish (Scheme 2b). It should be noted
that 1,3‐dimethoxybenzene was also isolated in 76% yield from
Electronic Supplementary Information (ESI) available: Electronic Supplementary
Information (ESI) available: Experimental details, including procedures, syntheses
and characterization of new compounds; 1H and 13C NMR spectra. See the reaction of 1c
.
DOI: 10.1039/x0xx00000x
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yet underutilized triphenylphosphine oxide (1a) to more
valuable monoalkyl‐diphenylphosphine oxides. We found the
scope of alkyl halides to be broad and versatile. The resulting
phosphinite intermediate derived from 1a could be quickly
functionalized by a series of primary alkyl bromides
incorporating wide range of functionalities such as
alkoxycarbonyl, acetal, alkenyl,16 alkynyl, and alkoxymethyl17
moieties. The method is amenable to use dibromides 3m 3p
as an electrophile for synthesis of bis‐phosphine oxides 4am
4ap Installation of secondary alkyl electrophiles required
higher reaction temperature (60 C) and/or use of more
reactive iodide (for 4aq 4ar).
We next examined use of
3,
a
‐
‐
.

‐

‐polar electrophiles 5 for the
functionalization of the transient sodium phosphinite derived
from triphenylphosphine oxide (1a) (Scheme 4). 1,2‐Addition
Scheme 2. Hydrodearylation of triarylphosphine oxides 1.
a The reactions were
conducted using 0.5 mmol of phosphine oxides
1 in THF (2.5 mL: 0.2 M) and
onto aldehydes 5a
the corresponding alcohols 6aa
‐
5b and aldimines 5c
‐
5e worked well to give
6ae
isolated yields of diarylphosphine oxides
2
were noted above. b 1H NMR yield. 1a
‐
6ab and amines 6ac
‐
,
c
d
was recovered in >95% yield. 4 equiv of NaH and 2 equiv of LiI were used.
1,3‐Dimethoxybenzene was also isolated in 76% yield.
respectively. Use of the Ellman’s t‐butanesulfinamides 5f and
5g18 offered diastereoselective addition of the phosphinite to
afford 6af and 6ag, respectively.
1,4‐Addition of the
phosphinite proceeded efficiently onto alkylidenemalonate 5h
,
whereas those onto acrylate derivatives were not successful.
It is worthy to note that installation of another aromatic ring
was enabled by ipso‐substitution with 4‐fluorobenzotrifluoride
(
5i) and 2‐chloropyridine (5j).
a
Scheme 3. Synthesis of mono‐alkyl diphenylphosphine oxides
4.
Unless
otherwise stated, the reactions were conducted using 0.5 mmol of
triphenylphosphine oxide (1a) with NaH (2 equiv) and LiI (1 equiv) in THF (2.5 mL:
0.2 M) at 60 °C for 13 h and then with alkyl bromides
3 (1.1 equiv). Isolated
b
c
yields of the products were noted above. Chlorides 3k and 3l were used.
5
Scheme 4 Reactions with
using 0.5 mmol of triphenylphosphine oxide (1a) with NaH (2 equiv) and LiI (1
equiv) in THF (2.5 mL: 0.2 M) at 60 °C for 13 h and then with ‐polar
electrophiles (1.1 equiv). Isolated yields of the products were noted above.
PMP = para‐methoxyphenyl.

‐polar electrophiles. a The reactions were conducted
mmol of 1a was used. d Iodocyclohexane (3r) was used.

5
We attempted further alkylation of the transient sodium
phosphinite intermediate with alkyl halides in one‐pot fashion
(Scheme 3). This strategy offers a facile way to convert cheap
2 | J. Name., 2012, 00, 1‐3
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The present protocol with the NaH‐LiI system was model reaction of triphenylphosphine oxide (1a) with a single
amenable to functionalize t‐butyldiphenylphosphine oxide (1f B97X‐D/6‐31+G* (scrf = pcm, THF)
molecule of NaH,24 at the
and adamantyldiphenylphosphine oxide 1g), offering
level of theory using Gaussian 16 software (Scheme 6b).25 We
synthetic route to unsymmetrical tertiary phosphine oxides found a sequential pathway, namely, nucleophilic attack of
(Scheme 5).19,20
More fascinatingly, the reactions of NaH on the P center, elimination of phenylsodium and
)

(
a
dibenzophosphole oxide 1h21 resulted in selective C(sp2)‐P diphenylphosphine oxide, and its deprotonation, as the most
bond cleavage to break the dibenzophosphole core, leading to probable mechanism. The addition of hydride onto the P
the formation of unsymmetrical phosphine oxides bearing a center affords a pentavalent intermediate IM‐1, with a
biphenyl moiety. Given that biarylphosphines have been reasonable activation barrier (∆G‡ = +14.5 kcal/mol). Through
utilized as a ligand for the transition metal catalysts in various the smooth flipping of Na cation on the hydride to the
chemical processes,22 the current method could offer an opposite phenyl side (i.e. IM‐1
opportunity to design and supply new types of unsymmetrical phenylsodium takes place via TS‐3, which requires the low
–TS‐2–IM‐2), the elimination of
tertiary biarylphosphine ligands.
activation energy (∆G‡ = +14.0 kcal/mol) for the single step to
form dipnehylphosphine (IM‐3). Subsequent deprotonation of
the P–H moiety by phenylsodium should lead to the formation
of sodium phosphinite (IM‐4).26 It should be noted that the
last step competes with deprotonation by co‐existing NaH,
which was indicated by the results of deuterium labeling
experiment with NaD,27 as well as the incomplete conversion
in use of less than 2 equiv of NaH (see the ESI for details).28
Scheme 5 Synthesis of unsymmetrical tertiary phosphine oxides. a The reactions
b
were conducted using 0.5 mmol of
1
in THF (0.2 M).
Dephenylation was
c
conducted using 3 equiv of NaH and 1.5 equiv of LiI at 60 °C for 16 h.
Dephenylation was conducted using 3 equiv of NaH and 1.5 equiv of LiI at 85 °C
for 12 h. d Dephenylation was conducted using 2 equiv of NaH and 1 equiv of LiI
at 60 °C for 6 h. The reaction conditions were stated in parentheses. [1,1'‐
biphenyl]‐2‐yl(phenyl)phosphine oxide (2h) was also isolated in 20% yield. 1‐Ad
= 1‐adamantyl.
e
f
To investigate the reaction mechanism especially
pertaining to the C(sp2)‐P bond breaking process in the present
dearylation, competition experiments were conducted using t‐
butyldiarylphosphine oxides 6fi, 7, and 8 (Scheme 6a). These
experiments unambiguously indicated that the C(sp2)‐P bond
cleavage preferentially takes place at the more electron‐
deficient aryl group.
Our recent work on materials characterization of the NaH‐
iodide composite indicated that a smaller nanometric unit of
NaH dispersed on NaI might be produced by solvothermal
treatment of NaH with NaI or LiI in THF, giving rise to unique
hydride donor reactivity.23 To seek for deeper insights on the
C(sp2)‐P bond breaking with the formation of the sodium
phosphinite intermediate, we conducted DFT calculations for a
Scheme 6 (a) Competition studies and (b) DFT calculation results for the reaction
pathaway with a single molecule of NaH. Energy changes and bond lengths at the

B97X‐D/6‐31+G* (scrf = pcm, THF) level of theory are shown in kcal/mol and Å,
respectively (see the ESI for the pathway with energy diagram).
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Z. Hong, D. Y. Ong, S. K. Muduli, P. C. Too, G. H. Chan, Y. L.
Tnay, S. Chiba, Y. Nishiyama, H. Hirao, H. S. Soo, Chem. Eur.
J., 2016, 22, 7108.
This work demonstrates new use of the NaH‐iodide
composite for dearylative functionalization of arylphosphine
oxides to prepare functionalized tertiary phosphine oxides in a
concise operation. Further investigation on use of the NaH‐
iodide composite to explore other types of reductive
molecular transformations is ongoing in our laboratory.
This work was financially supported by Nanyang
Technological University and the Singapore Ministry of
Education (Academic Research Fund Tier 1: RG10/17) for S.C.
and The Tokyo Biochemical Research Foundation for R.T.
13 For use of NaH‐iodide composites as the unprecedented
Brønsted bases, see: (a) A. Kaga, H. Hayashi, H. Hakamata,
M. Oi, M. Uchiyama, R. Takita, S. Chiba, Angew. Chem. Int.
Ed., 2017, 56, 11807; (b) Y. Huang, G. H. Chan, S. Chiba,
Angew. Chem. Int. Ed., 2017, 56, 6544.
14 For reports on C(sp2)‐P bond formation driven by Pd‐
catalyzed dephenylation from triarylphosphines, see: (a) K.
Baba, M. Tobisu, N. Chatani, Org. Lett., 2015, 17, 70; (b) K.
Baba, M. Tobisu, N. Chatani, Angew. Chem. Int. Ed., 2013, 52
11892.
,
15 For reports on aromatic substitution reactions of
arylphosphine oxides with alkyllithium or magnesium
reagents, see: (a) M. Stankevič, J. Pisklak, K. Włodarczyk,
Tetrahedron, 2016, 72, 810; (b) T. Shimada, H. Kurushima, Y.‐
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16 For use of allyl diphenylphosphineoxides for radical
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17 For use of alkoxymethylphosphine oxides such as 4ak and 4al
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19 The present protocol has thus far not proven successful with
primary‐ or secondary‐alkylphosphine oxides due to inherent
Brønsted basicity of NaH.
3
4
5
6
7
For reviews, see: (a) I. Wauters, W. Debrouwer, C. V.
Stevens, Beilstein J. Org. Chem., 2014, 10, 1064; (b) H.
20 For reports on synthesis of unsymmetrical tertiary phosphine
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Org. Lett., 2017, 19, 3899, and references therein.
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23 Our materials characterization (ref. 12c) also revealed that
solvothermal treatment of NaH and LiI induces counter ion
methathesis to form the activated NaH with NaI and LiH. No
reaction was observed with LiH only and the LiH‐LiI
composite (see the ESI for details).
24 NaH has ionic character with the cubic halite crystal
structure composed of sodium cations and hydride anions: a)
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26 The calculated deprotonation step by phenylsodium species
is described in the ESI.
27 The reaction of triarylphosphine oxide 1c with NaD‐LiI
followed by treatment with H2O gave diarylphosphine oxide
2c in 57% yield and 1,3‐dimethoxybenzene in 80% yield with
39% D‐incorporation (see the ESI).
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28 Another reaction pathway via nucleophilic aromatic
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estimated by the DFT calculation. See the ESI.
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A new protocol for dearylative functionalization of arylphosphine oxides was developed
using NaH in the presence of LiI.