Transition Metal-Free Synthesis of α-Aminophosphine Oxides through C(sp3)?P Coupling of 2-Azaallyls

Article abstract of DOI:10.1002/adsc.201901553

Radical reactions have been widely applied in C?P bond-forming strategies. Most of these strategies require initiators, transition metal catalysts, or organometallic reagents. Herein, a transition metal-free C(sp³)?P bond formation to prepare α

Full text of DOI:10.1002/adsc.201901553

Title: Transition Metal-Free Synthesis of α-Aminophosphine Oxides
through C(sp3)−P Coupling of 2-Azaallyls
Authors: Jin Wang, Guogang Deng, Chunxiang Liu, Zhuo Chen, Kaili
Yu, Wen Chen, Hongbin Zhang, and Xiaodong Yang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901553
Link to VoR: http://dx.doi.org/10.1002/adsc.201901553

10.1002/adsc.201901553
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.2019#####
Transition Metal-Free Synthesis of α-Aminophosphine Oxides
through C(sp3)−P Coupling of 2-Azaallyls †
Jing Wang, Guogang Deng, Chunxiang Liu, Zhuo Chen, Kaili Yu, Wen Chen, Hongbin
Zhang,* and Xiaodong Yang*
Key Laboratory of Medicinal Chemistry for Natural Resources, Ministry of Education and Yunnan Province, School of
Chemical Science and Technology, Yunnan University, Kunming, 650091, P. R. China
Fax: (+86)-871-65035538; e-mail: xdyang@ynu.edu.cn; zhanghb@ynu.edu.cn
Received: December ##, 2019; Revised: January ##, 2020; Published online: January ##, 2020
Supporting information for this article can be found under https://dx.doi.org/10.1002/adsc.2019#####.
Abstract. Radical reactions have been widely applied in
C−P bond-forming strategies. Most of these strategies
require initiators, transition metal catalysts, or
organometallic reagents. Herein, a transition metal-free
C(sp3)−P bond formation to prepare α-aminophosphine
oxides via deprotonative radical coupling processes of
2-azaallyls with chlorodiphenylphosphine oxides was
presented. Deprotonation of N-benzyl imines may
generate super-electron-donor (SED) 2-azaallyl anions
that reduced chlorodiphenylphosphine oxides to
phosphine oxide radicals. Single-electron transfer (SET)
process transformed the 2-azaallyl anions into 2-azaallyl
radicals, which may couple with phosphine oxide radicals
to construct C−P bonds. The deprotonative radical
coupling approach enables the synthesis of
α-aminophosphine oxides bearing various functional
groups under mild conditions and without precious
transition metal catalysts or oxidants.
Keywords: Radical coupling; α-Aminophosphine;
C(sp3)−P bond formation; Azaallyl anions;
Super-electron-donor
Organic phosphorus compounds, such as phosphine
oxides, have attracted tremendous attention due to
their wide applications as catalysts and ligands in
synthetic chemistry and their significant biological
and pharmacological characteristics.[1] A subclass of
these, α-aminophosphine oxides, have gained interest
because they exhibit particularly interesting biological
properties such as antitumor, anti-HIV, antibacterial
and antituberculosis activities.[2] They are also widely
Scheme 1. Synthetic Strategies toward α-aminophosphine
oxides.
used in agrochemicals, such as herbicides and plant
virucides.[3]
Consequently,
efficient
and
straight-forward approaches for the construction of
α-aminophosphine oxides remain in demand.
catalysts and stoichiometric quantities of oxidants.
Representative studies by Wang[6] described a
Cu-catalyzed α-amination of phosphine oxides with
Since the pioneering studies of Genet[4], various
transition metal catalysts, including Pd, Cu, Fe, Ag,
Rh, Ru and Co, using to access α-aminophosphine
oxide derivatives have been reported (Scheme 1a).[5]
Their synthesis is generally limited by the harsh
reaction conditions and the addition of toxic metal
o-benzoylhydroxylamines
via
an
organozinc
intermediate, which showed a novel attractive
protocol for α-aminophosphine oxides in one step
(Scheme 1b). Furthermore, an α-aminophosphonate
cation equivalent reacted with organoboranes to yield
1
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10.1002/adsc.201901553
Advanced Synthesis & Catalysis
α-aminophosphine oxides.[7] Lately, ultrasound entries
1–6).
Among
them,
LiN(SiMe3)2,
irradiation[8] and electrochemical approach[9] for NaN(SiMe3)2, KN(SiMe3)2 afforded coupling product
α-aminophosphine oxide derivatives have been 3aa in 9%, 62% and 78% assay yields (AY,
1
developed. Over the past decade, radical reactions determined by H NMR integration of the product
have been widely applied in C−P bond-forming against an internal standard), while other bases
strategies.[10] The uses of visible-light activated (LiOtBu, NaOtBu and KOtBu) led to no reaction.
photo-catalysis (Scheme 1c) [11], cobalt catalysis[12] Using KN(SiMe3)2, we next studied the effect of
and 2,2,6,6-tetromethyl-1-piperidinyloxy (TEMPO)[13] solvent. No improvement of yield was observed when
to generate radicals have been found applications in switching other ethereal or non-polar solvents to
the synthesis of α-aminophosphine oxides. Most of DME (dimethoxyethane), CPME (cyclopentyl methyl
these processes, however, require organometallic ether),
toluene,
dioxane,
DMF,
DMA
reagents, transition metal catalysts, or initiators.
(N,N-dimethylacetamide), DMSO or MTBE (methyl
tert-butyl ether) all led to lower AY’s (0–70%, entries
as 7–14). The study of reaction time indicated that the
Recently, 2-azaallyl anions
Super-electron-donor (SED, pioneered by the yield dropped to 74% (entry 15) at 3 h, but slightly
Murphy[14]) was deeply studied by organic increased to 80% at 1 h, with 75% isolated yield
chemists such as Walsh[15] and Chruma[16]. We (entries 16). Raising the reaction temperature to 60 oC
helped to develop the SED radical coupling and 80 oC resulted in decreases to 69% and 65% AY,
processes
for
the
transition
metal-free respectively (entries 17 and 18). The reaction proved
C(sp3)−C(sp3) and C(sp3)−C(sp2) bonds formation to be relatively sensitive to concentration. With
enabled by 2-azaallyl anions.[17] Specifically, the KN(SiMe3)2 as base in THF, the concentration was
2-azaallyl anion reacted with aryl iodides or alkyl varied from 0.3 M and 0.1 M resulted in a lower yield
iodides/bromides through single-electron transfer to the original 0.2 M concentration, with 69% and
(SET) process to generate the 2-azaallyl radical 71% AY (entries 19 and 20). Based on this
and aryl or alkyl radicals. Then, radical-radical optimization, the standard conditions for the
coupling reactions led to C–C bonds formation. deprotonative radical coupling reaction that will be
This unique strategy was also applied to the used for the remainder of the study are those in entry
synthesis of benzofuran and isochromene 16 of Table 1.
derivatives
through
cascade
radical
Table 1: Optimization of deprotonative coupling of
N-benzyl ketimine 1a and chlorodiphenylphosphine
cyclization/radical-radical coupling.[17] On the
basis of the strategy, we want to use this radical
coupling approach to the synthesis of
α-aminophosphine oxides. Thus, in the present
oxide 2a [a,b]
.
work
we
hypothesized
the
use
of
chloro-diphenylphosphine oxides as radical
precursors (Scheme 1d). Deprotonation of
N-benzyl imines may generate 2-azaallyl anions
that reduced chlorodiphenylphosphine oxides to
phosphine oxide radicals, and Single-electron
transfer (SET) process transformed the 2-azaallyl
Time
[h]
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
Temp.
[oC]
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
Conc.
[M]
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.3
0.1
Yield
[%]
9
62
78
0
Entry
Base
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
LiOtBu
THF
THF
THF
THF
THF
anions
into
2-azaallyl
radicals.
Then,
NaOtBu
0
0
radical-radical coupling between the phosphine
oxide radicals and 2-azaallyl radicals was
expected to lead to α-aminophosphine oxides.
Herein, we report the first deprotonative radical
coupling processes between 2-azaallyl anions and
chlorodiphenylphosphine oxides to prepare
α-aminophosphine oxides. This approach enables
the synthesis of α-aminophosphine oxides bearing
various functional groups without radical
initiators or transition metal catalysts (21
examples, up to 83% yield).
KOtBu
THF
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
KN(SiMe3)2
DME
CPME
PhMe
Dioxane
DMF
DMA
DMSO
MTBE
THF
THF
THF
THF
THF
70
60
52
55
33
24
0
60
74
80 (75)[c]
69
65
69
71
1
1
1
1
rt
60
80
rt
THF
1
rt
[a]Reactions conditions: 1a (0.2 mmol, 2.0 equiv), 2a
We initiated our reaction optimization by using
(0.1 mmol, 1.0 equiv), base (3.0 equiv). [b]Assay yields
benzyl
ketimine
1a
and
commercial
1
chlorodiphenylphosphine oxides 2a as the model
substrates in the presence of base in THF at room
temperature for 2 h. At the outset, a variety of bases
including LiN(SiMe3)2, NaN(SiMe3)2, KN(SiMe3)2,
LiOtBu, NaOtBu and KOtBu were examined (Table 1,
determined by H NMR spectroscopy of the crude
reaction mixtures using CH2Br2 as an internal standard
.
Yields represent mean values of three independent
determinations. [c]Yield of isolated product after
chromatographic purification.
2
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10.1002/adsc.201901553
Advanced Synthesis & Catalysis
and 3.0 equiv base at 0.2 M. [b]Yield of isolated product
after chromatographic purification.
Encouraged by the potential synthetic utility of
this deprotonative coupling, we first explored the
scope of ketimines (Table 2). Generally, the
optimized reaction conditions accommodated
ketimines possessing various substituted aryl groups
in moderate to good yields. N-Benzyl groups bearing
alkyl substituents 4-Me (1b), 3,4-di-Me (1c) and
4-tBu (1d) afforded α-aminophosphine oxides 3ba,
3ca and 3da in 69%, 70% and 67% yields,
respectively. Electron donating substrates (1e, 4-OMe)
led to product 3ea in 60ꢀ% yield. N-Benzyl groups
with electron-withdrawing substituents, such as 4-F
(1f), 4-Cl (1g), 4-Br (1h), 3-CF3 (1i) and 3,5-di-F (1j),
afforded the desired products 3fa, 3ga, 3ha, 3ia and
3ja in 72%, 68%, 65%, 63% and 69% yields,
respectively. Reaction with ketimine possessing
biphenyl group (1k) generated the product 3ka in
62% yield. Interestingly, a heterocyclic ketimine
possessing a piperonyl group (1l) was also a suitable
coupling partner, generating the product 3la in 64%
yield. Unfortunately, N-benzyl groups with
ortho-substituents (2-Br) or ketimines with other
heteroaromatic groups (pyridine, thiazole, oxazole)
led to the products in trace yields (< 5%) or no
reaction. Meanwhile, when the imines bearing
We next investigated the ability of the
deprotonative coupling to accommodate various aryl
substituents on the chlorodiarylphosphine oxides
(Table 3). Most of chlorodiarylphosphine oxides were
easily prepared using the method of Han[18] by
reaction of the corresponding aryl bromide with
diethyl phosphate (57–72% yields, see Supporting
Information). In this study, chlorodiarylphosphine
oxides possessing two substituent aryls on the
phosphorus, such as two 4-methylphenyl (2b),
3,5-dimethylphenyl (2c), 4-tert-butylphenyl (2d) or
4-methoxyphenyl (2e) were coupled with N-benzyl
ketimine 1a. Under the optimized conditions,
α-aminophosphine oxides 3ab, 3ac, 3ad and 3ae were
isolated in 51%, 72%, 60% and 67% yields,
respectively.
Furthermore,
various
chlorodiarylphosphine oxides underwent coupling
with N-4-methylbenzyl ketimine 1b following the
standard procedure to generate the desired products
3bb, 3bc, 3bd and 3be were isolated in 55%, 80%,
45% and 83% yields, respectively. However,
chlorodiarylphosphine oxides with ortho-substituents
(such as 2-ethylphenyl) on both aryl groups generated
the product in trace yield (< 5%), which was probably
due to the effect of steric hindrance. Additionally,
phosphine oxide Ph(EtO)P(O)Cl coupled with
N-benzyl ketimine 1a afforded the desired product
3af only in 20% yield, and (EtO)2P(O)Cl led to no
reaction.
prop-2-en-1-amine
(CH=CH−CH2−NH2)
or
aliphaticamine (CH3−CH2−NH2) were employed, the
C−P coupling led to no reaction.
Table 2: Scope of N-benzyl ketimines.[a,b]
Table 3: Scope of chlorodiarylphosphine oxides.[a,b]
[a]Reactions were conducted on a 0.4 mmol scale using 2.0
equiv ketimine 1, 1.0 equiv diphenylphosphinic chloride 2a,
[a]Reactions were conducted on a 0.4 mmol scale using 2.0
equiv ketimine 1, 1.0 equiv chlorodiarylphosphine oxide 2,
3
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10.1002/adsc.201901553
Advanced Synthesis & Catalysis
and 3.0 equiv base at 0.2 M. [b]Yield of isolated product
after chromatographic purification.
We next studied the scalability and utility of the
deprotonative coupling reaction. For this, the
coupling process was carried out on gram-scale
through a telescoped method that first prepared the
ketimine, as shown in Scheme 2. Thus, treatment of
the benzophenone imine (10 mmol) with benzyl
o
amine (10 mmol) in THF at 70 C for 12 h was
followed by removing solvent under reduced pressure
to yield N-benzyl ketimine 1a. The unpurified
ketimine was coupled with chlorodiphenylphosphine Scheme 3. Control experiments.
oxide 2a under the standard conditions. After 1 h at
room temperature, workup, and purification on silica
In summary, we present a transition metal-free
gel led to 1.60 g of 3aa (68% over 2 steps). Moreover, C(sp3)−P
bond
formation
to
prepare
compound 3aa was characterized by X-ray α-aminophosphine oxides via deprotonative radical
crystallography, confirming its structure (CCDC coupling processes of 2-azaallyls. In this method,
1964234).[19] Furthermore, hydrolysis of the product deprotonation of imines may generate SED 2-azaallyl
3aa generated the corresponding α-aminophosphine anions that reduced chlorodiphenylphosphine oxides
oxide 4aa in 95% yield.
to phosphine oxide radicals. SET process transformed
the 2-azaallyl anions into 2-azaallyl radicals, which
may couple with phosphine oxide radicals to
construct C−P bonds. This process just needs
commercially available base, which enables the
synthesis of α-aminophosphine oxides bearing various
functional groups under mild conditions. A gram
scale telescoped α-aminophosphine oxide synthesis
was conducted that showed the potential synthetic
utility. Notably, this method avoids addition of
precious transition metal catalysts or oxidants and
separation of trace transition metal impurities, which
is significant in the pharmaceutical industry.[22]
Scheme 2. Gram scale telescoped α-aminophosphine
oxide synthesis and product hydrolysis.
Experimental Section
Finally, to obtain some information of the
mechanism, radical inhibition control experiments
were conducted.[20] No desired product 3aa was
detected following the standard procedure when 2.5
General Methods
All air- and moisture-sensitive solutions and
chemicals were handled under a nitrogen atmosphere
of a glovebox and solutions were transferred via
“Titan” brand pipettors. Anhydrous solvents,
equiv
of
2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) was added as radical scavenger, only
radical coupling product 5aa and 6aa were observed
with 55% and 10% yield. Moreover, compound 6aa
was characterized by X-ray crystallography,
confirming its structure (CCDC 1976111)[21] (Scheme
3a). Notably, radical coupling product 6aa was not
detected when 2.5 equiv TEMPO was added without
N-benzyl ketimine 1a under standard conditions
(Scheme 3b). Meanwhile, adjunction of butylated
hydroxytoluene (BHT) resulted in a quite low yield of
3aa (10%) (Scheme 3c). These results indicated that
the reaction may take place through a radical pathway,
which provided support for the key radical coupling
step proposed in Scheme 1d.
including
DME
(dimethoxyethane),
CPME
(cyclopentyl methyl ether), MTBE (methyl tert-butyl
ether), toluene, THF (tetrahydrofuran), and
1,4-dioxane were purchased from Sigma-Aldrich and
used without further purification. Unless otherwise
stated, all reagents were commercially available and
used as received without further purification.
Chemicals were obtained from Sigma-Aldrich, Acros,
TCI and Alfa-Aesar. TLC was performed with Merck
TLC Silica gel60 F254 plates with detection under
UV light at 254 nm. Silica gel (200-300 mesh,
Qingdao) was used for flash chromatography.
Deactivated silica gel was prepared by addition of 15
mL Et3N to 1 L of silica gel. The products were
purified with XDB-C18 (9.4 × 250 mm, 5 μm)
1
column on an Agilent HPLC 1260 system. H NMR,
13C NMR, 31P NMR and 19F NMR spectra were
4
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10.1002/adsc.201901553
Advanced Synthesis & Catalysis
obtained using a Bruker DRX 400 spectrometer at
400 MHz, 100 MHz, 162 MHz and 376 MHz
respectively. Chemical shifts are reported in units of
parts per million (ppm) downfield from
tetramethylsilane (TMS), and all coupling constants
are reported in hertz. The infrared (IR) spectra were
measured on a Nicolet iS10 FTIR spectrometer with 4
cm−1 resolution and 32 scans between wavenumber of
4000 cm−1 and 400 cm−1. High Resolution Mass
spectra were taken on AB QSTAR Pulsar mass
spectrometer. Melting points were obtained on a XT-4
melting-point apparatus and were uncorrected.
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General Procedure for Radical Coupling of
ketimines and phosphorous oxychloride.
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Under a nitrogen atmosphere in a glove box, an
oven-dried reaction vial equipped with a stir bar was
charged with diphenylphosphinic chloride 2 (0.2
mmol) and 1.0 mL dry THF was added to the vial by
a “Titan” brand 1000 μL pipettor, then added the
N-benzyl ketamine 1 (0.4 mmol) and pure (solid)
KN(SiMe3)2 (0.6 mmol). The reaction mixture turned
dark purple on addition of the base. The vial was then
sealed with a cap, removed from the glove box, and
stirred for 1 h at room temperature. The reaction
mixture was then opened to air, quenched with three
drops of H2O, diluted with 5 mL of ethyl acetate, and
filtered over a 2 cm pad of MgSO4 and silica. The pad
was rinsed with ethyl acetate (3 X 5 mL), and the
combined solutions were concentrated in vacuo. The
crude material was loaded onto a deactivated silica
gel column and separated by flash chromatography
(petroleum ether: ethyl acetate = 10:1 to 5:1). Further
purification was performed on an Agilent HPLC 1260
system using acetonitrile:H2O (75:25 vol./vol.) as
mobile phase and flow rate of 3.5 mL/min at 254 nm
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to
give
(((diphenylmethylene)amino)(phenyl)methyl)dipheny
lphosphine oxide.
Acknowledgements
This work was supported by grants from the NSFC
(21662043, 21572197 and U1702286), the Program
for Changjiang Scholars and Innovative Research
Teams in Universities (IRT17R94) and IRTSTYN, the
NSF of Yunnan Province (2019FY003010), the
DongLu Scholar and the YunLing Scholar Program.
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10.1002/adsc.201901553
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