Tandem Oxidative C?H Amination and Iodization to Synthesize Difunctional Atropoisomeric P-Stereogenic Phosphinamides

Article abstract of DOI:10.1002/chem.201700218

An efficient metal-free tandem intramolecular oxidative C?H amination and iodization of phosphinamide was performed and a series of new phosphorus heterocyclic compounds was obtained. This method provides a concise and highly valuable pathway for the synthesis of difunctional atropoisomeric P-stereogenic phosphinamides.

Full text of DOI:10.1002/chem.201700218

A Journal of
Accepted Article
Title: Tandem Oxidative C-H Amination and Iodization to Synthesize
Difunctional Atropoisomeric P-Stereogenic Phosphinamides
Authors: Shangdong Yang, Yan-Na Ma, and Xi Zhang
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COMMUNICATION
DOI: 10.1002/chem.200((will be filled in by the editorial staff))
Tandem Oxidative C-H Amination and Iodization to Synthesize Difunctional Atropoisomeric P-
Stereogenic Phosphinamides
Yan-Na Ma,[a] Xi Zhang,[a] and Shang-dong Yang*[a][b]
C-H activation using an atom-efficient phosphamide precursor
has become an increasingly common topic for research. Recently,
Abstract:
An
efficient
metal-free
tandem
Duan and Liu groups almost simultaneously report a Pd-catalyzed
enantioselective intramolecular C-H arylation to synthesize chiral
phosphinic amide (A, Scheme 1).8 Moreover, subsequent studies
by Han and coworkers demonstrated the enantioselective
synthesis of P-stereogenic phosphinamides through Pd-catalyzed
desymmetric ortho C-H arylation of diarylphosphinamides with
boronic acids (B, Scheme 1).9 Chang and coworkers have
developed the direct C-H amidation of arylphosphoryl compounds
by using an IrIII catalyst system under mild conditions.10 Very
recently, Cramer group discloses an enantioselective synthesis of
cyclic phosphinamides with a P-stereogenic phosphorus (V) atom
catalyzed by a CpxRhIII complex (C, Scheme 1).11 These
significant advances towards chiral phosphinamides have been
driven by the transition metals to activate C-H bonds. To the best
of our knowledge, no example involves in preparation of chiral
phosphinamides via the metal free oxidative asymmetric C-H
amination, which avoids the employment of expensive transition
metal and chiral ligand, and promises a potential for large-scale
preparations. If the key challenge of overcoming the conflict
between enantioselectivity with metal free C-H functionalization
could be addressed, such sequence would offer great advantages.
In the last year, by using the chiral phosphrous oxide as directing
group, we have succeeded to achieve the Pd(II)-catalyzed
asymmetric C-H activation via dynamic kinetic resolution.12 We
have questioned whether chiral phosphinamide and metal free
direct oxidative C-H amination might be successfully combined to
create a new pattern for the synthesis of compounds containing
both axial chirality and a P-stereogenic in large-scale through
dynamic kinetic resolution or desymmetrisation proccess (D,
Scheme 1).
With this design principles in mind, we have firstly
synthesized the chiral phosphinic amide 1a through our previous
Pd-catalyzed cascade asymmetric cross-coupling reaction and
further reacted with lithium methylamide in high yield with
excellent enantioselectivity,13 and wished to achieve the
asymmetric synthesis of atropoisomeric azaphosphaannulation
compounds under metal free reaction conditions. We initially
studied the asymmetric metal free C-H amination reaction of 1a
with different oxidants in CH3CN (Table 1, entries 1-5). To our
delighted, when NIS was used, the desired azaphosphaannulated
product 2a with iodization at 5’ position was obtained in 31%
yield with good diastereoselectivity through desymmetrisation
process. In many metal free oxidative C-H amination reactions,
hypervalent iodine(III) species possessing an iodine-nitrogen
bond are efficient reagents in oxidative C-H amination of
nonprefunctionalized arenes and heteroarenes.14 Encouraged by
intramolecular oxidative C-H amination and iodization
of phosphinamide has been performed and a series of
novel phosphorus heterocyclic compounds was
obtained. This method provides a concise and highly
valuable pathway for the synthesis of difunctional
atropoisomeric P-stereogenic phosphinamides.
Selective C-H bond amination has emerged as a powerful
tool for the synthesis of complex nitrogen-containing molecules.1
This methodology allows one to bypass the installation and
subsequent removal of classical leaving groups and to reduce
wastes and synthetic steps. Therefore, C-H bond amination has
attracted a growing amount of attention in the past decades. In
general, C-H amination has been propelled by transition metals to
activate C-H bonds.2 Additionally, metal free catalyzed direct
oxidative C-H amination by different oxidants has also provide a
concise and efficient pathway.3 Because chiral amine compounds
are powerful pharmacophore for defining new pharmaceutical and
pivotal synthon for synthesis of chiral alkaloids and N-hybridize
ligands.4 Thus, the exploration and establishment of the novel and
high effective methods of the asymmetric C-H amination become
a challenging task.
Chiral aminophosphines are versatile building blocks that
have been employed in modular syntheses of chiral ligands and
organocatalysts.5 Especially these ligands possessing both axial
chirality and a P-stereogenic were proven very efficient and
stereochemically stable.6 However, catalytic asymmetric methods
for highly enantioselective synthesis of P-stereogenic phosphines,
especially the methods for P-stereogenic phosphorus heterocycles,
remain very rare.7 As an alternative strategy, selective asymmetric
[a]
[b]
Y. Ma, X. Zhang and Prof. S. Yang
State Key Laboratory of Applied Organic Chemistry, Lanzhou
university, Lanzhou 73000, P.R. China
Fax: (+) 86-931-8912859
E-mail: yangshd@lzu.edu.cn
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Lanzhou 730000, P. R. China
((Note: If Supporting Information is submitted, please include the following
line:))
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201xxxxxx.
1
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while no product was obtained when KI, NaI, NH4NI, Bu4NI were
used (entries 12-15). Results of solvents screening indicated that
the reaction could proceed smoothly in almost all of the solvents
and showed good reactivity (entries 16-21). Finally, we selected
CH3CN as the solvent which exhibited the best reactivity when
other substrates were used and the optimized reaction conditions
are as follows: I2 as the iodine source, PhI(OAc)2 as the oxidant in
CH3CN at 80 oC under air atmosphere.
With the optimized reaction conditions in hand, we firstly
examined the N-protecting group. When N-alkyl or N-benzyl
phosphinic amides were used, the desired products were obtained
in good yields with excellent diastereoselectivities (Table 2, 2a-
2d). Meanwhile the free phosphinic amide can also been used into
this reaction and the desired product was obtained in 27% yield
with good selectivity (2e). While when the protecting group was
electronic-withdrawing tosyl or pentafluorobenzyl, we only got
the racemic substrates. When these two substrates were used, we
obtained the intramolecular C-H hydroxylation product and the
iodine atom didn’t been introduced (3). Base on these results,
different substituted phosphinic amides were screened under
metal free reaction conditions to demonstrate the scope and
limitations of this reaction. For the 2′-substituted biphenyl-2-yl
phosphinic amides, we want to achieve the synthesis of axially
chiral azaphosphaannulated product through dynamic kinetic
resolution process, while we didn′t obtain the pure product which
illustrated that the steric effect impacted the reactivity. So we
trained our attention to the asymmetric C-H amination through
desymmetrisation process. For our reaction, the dynamic kinetic
resolution mainly toward the 2′-substituted biphenyl-2-yl
phosphinic amides, which can easily take racemization under the
reaction conditions. The desymmetrisation process mainly toward
the substrates with no substituents at the 2‘ position and the
Scheme 1. Various Strategies for Synthesis of Chiral
Phosphinamides
this result, we further optimized the reaction conditions and
screened other hypervalent iodine catalytic system. When we used
PhI(OAc)2+I2 to prompt this reaction, the desired product was
improved to 75% yield with good diastereoselectivity (entry 6).
Based on this result, the influence of other oxidants was also
examined, BPO, mCPBA, K2S2O8, (NH4)2S2O8 could also
propelled the reaction and the desired product was obtained in
different yields with good dr value with I2 as the iodine sources
(entries 7-11). Next, we have evaluated other iodine sources,
Table 1. Reaction Conditions Screening.[a]
Table 2. Scope of the Metal Free C-H Amination.[a]
[a] Reaction conditions: 0.2 mmol of 1a, 0.4 mmol of oxidants and 0.4 mmol
iodine sources in different solvents (2.0 mL) under air atmosphere. [b] Isolated
yields. [c] The values of p/o and dr were determined by 1H NMR and 31P NMR.
[d] BPO = Benzoperoxide.
[a] Reaction conditions: 0.5 mmol of 1, 1.0 mmol of PhI(OAc)2 and 1.0 mmol
I2 in different CH3CN (5.0 mL) under air atmosphere. [b] Isolated yields. [c]
1
The values of p/o and dr were determined by H NMR and 31P NMR. [d] 0.5
mmol 1h and 1.25 mmol NIS in DCM at 70 oC.
2
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10.1002/chem.201700218
Chemistry - A European Journal
symmetry will be broken when the C-H amination occurred. To
our delight, the 6′-substituented substrates showed good reactivity
and diastereoselectivity through desymmetrisation process (2f and
2g). When the phenyl group was replaced by thiophene, the
corresponding poly heterocycle product 2h and 2i was obtained
with good yield and excellent selectivity which was confirmed by
single-crystal X-ray crystallography (2h). For the substrates with
the substituted group lies on the meta-position of the phosphinic
amide group, good results were obtained (2j-2l). Moreover, the
4’-substituted phosphinic amides also exhibited good activity
accompanying with excellent selectivities (2g and 2m). Finally,
we also extended this method to modify estrone and afforded
chiral atropoisomeric product 2n in moderate yield with high
diastereoselectivity, which is an important steroid.
an electron-rich arene which can immediately occur iodization
under the reaction conditions to give the desired product 2a.
Scheme 4. A Plausible Mechanism.
To demonstrate the versatility of iodinated products in cross-
coupling reactions, we explored various coupling reactions with
2a (Scheme 5). Suzuki-Miyaura coupling with phenylboronic acid
afforded triaryl derivative 6a in quantitative yield. Reacting with
NaN3 gave the azide compound 7a in 68% yield.16 The
phosphinated product 8a was achieved in 76% yield with
Pd(OAc)2 as the catalyst.17 Heck coupling with ethyl acrylate
gave the vinylation derivative 9a in 86% yield.18.
In light of the above results, we next changed the iodine
sources to other halogenation reagents and anticipated to achieve
the bromination and chlorination. Firstly, KBr was used instead of
I2 to the bromination reaction with 1a as the model substrate. As
we expected, the desired bromination product 4a was obtained in
62% yield with excellent selectivity when toluene/H2O (4:1) was
used as the solvent (eq 1, Scheme 2). A higher yield of 82% was
gained if the PhI(OAc)2 was changed to oxone. While when NaCl
was used, we only obtained the N-chlorination compound 5a as
the N-Cl bond was relatively stable which indicated that the N-X
compounds were the reaction intermediate (eq 2, Scheme 2).
Scheme 2. Intramolecular Metal Free C-H Amination
Bromination.
Scheme 5. The Coupling Reactions of 2a.
Next, the reaction mechanism was studied, when free radical
scavengers TEMPO or BHT were added to the reaction mixture,
no product was detected. So we proposed that the reaction went
The “click chemistry” has recently emerged to become one of
the most powerful tools in drug discovery, chemical biology, and
proteomic applications. Herein, we also selected the product 2a as
starting material to undergo the click chemistry with 5'-azido-5'-
deoxythymidine 12 by the Cu(II)-catalyzed 1,3-dipolar azide-
alkyne cycloaddition (CuAAC) reactions (Scheme 6). Firstly, 2a
was installed the terminal alkyne through the Sonogashira
coupling reaction and removal of trimethylsilyl to obtain 11 in
96% yield.19 Following a “click” reaction,20 compound 11 was
reacted with 5'-azido-5'-deoxythymidine 12 to afford the desired
cycloaddition product 13 in 93% yield with excellent dr value.
through
a radical process. Meanwhile the intramolecular
amination compound 3a was subjected to the reaction conditions
and the desired iodization product 2a was obtained in 88% yield
(Scheme 3). So we suggested that 3a was initially formed as an
intermediate.
Scheme 3. Study of Mechanism.
On the basis of these results and previous reports,15 a plausible
mechanism is shown in Scheme 4. Firstly, the N-I bond is formed
under the effect of Ph(OAc)2 and I2 which is very unstable, and
easily undergoes thermal homolytic cleavage to generate the
phosphonamidyl radical B. Then the radical is trapped by the
arene to give intermediate C. Rearomatization of C under the
PhI(OAc)2 to provide intermediate 3a. As the intermediate 3a is
Scheme 6. Click chemistry with 2a.
3
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Chemistry - A European Journal
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bond cleavage of 6a was examined using nBuLi as the
nucleophilic reagent.8a The dr values of the ring-opening product
were 84:16 under -78 oC and 1.2:1 when the temperature was
increased to room temperature (Scheme 7). As the ring-opening
compound 14a only contain two substituents at the axis, so the
axial chirality cannot be keeped at room temperature and took
racemization. While for the cyclization products, the biaryl axis
cannot rotate easily. This maybe attribute to the rigid structure of
the 6-membered N,P-heterocycle. So we think our products exist
axial chirality.
Scheme 7. The experiment to certify the existence of axial
chirality.
In summary, we have described a metal-free radical tandem
oxidative C-H amination and iodization reaction under mild
reaction conditions. With this method, we achieved the synthesis
of azaphosphaannulation compounds with iodization or
bromination at 5’ position in good yield and selectivity and the
iodization product can be further used into various coupling
reactions and the “click chemistry” to modify the
pharmacologically relevant molecules.
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A solution of 154 mg (0.5 mmol, 1.0 equiv) 1a, 322 mg (1.0 mmol, 2.0 equiv)
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concentrated in vacuo. The crude reaction mixture was purified by flash
chromatography on silica gel to give the pure product 2a (162 mg, 75%, dr >
20:1, ee = 99%).
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Acknowledgements
We are grateful for the NSFC (Nos. 21472076 and 21532001) and Program for
Changjiang Scholars and Innovative Research Team in University (IRT_15R28)
financial support, and the Fundamental Research Funds for the Central Universities
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Keywords: Metal free • Oxidative C-H Amination • Iodization • P-
Stereogenic Phosphinamides
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10.1002/chem.201700218
Chemistry - A European Journal
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Catch Phrase 
Yan-Na Ma,[a] Xi Zhang,[a] and
Shang-dong Yang*[a][b]………...…
Page – Page
Tandem Oxidative C-H
Amination and Iodization to
Synthesize Difunctional
Atropoisomeric P-Stereogenic
Phosphinamides
An efficient metal-free tandem intramolecular oxidative C-H amination and
iodization of phosphinamide has been performed and a series of novel
phosphorus heterocyclic compounds was obtained. This method provides a
concise and highly valuable pathway for the synthesis of difunctional
atropoisomeric P-stereogenic phosphinamides.
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