Ligand-free copper-catalyzed denitrogenative arylation of phosphorylamides with arylhydrazines

Article abstract of DOI:10.1080/00397911.2020.1725577

A straightforward arylation of phosphorylamides with arylhydrazines hydrochloride was herein demonstrated. The protocol proceeded in the presence of a catalytic loading of Cu(OAc)₂ as the catalyst, DTBP as the external oxidant and Cs₂CO₃ as the base, but without any ligands. And a series of N-aryl phosphorylamides were successfully obtained in high efficiency (up to 93% yields) with good substituents compatibility (up to 30 examples). Free radical mechanism was proposed for the facile methodology based on the results of control reactions and literature explorations.

Full text of DOI:10.1080/00397911.2020.1725577

Synthetic Communications
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Ligand-free copper-catalyzed denitrogenative
arylation of phosphorylamides with arylhydrazines
Qiao Zhu, Shiying Che, Zhenghong Luo & Zijian Zhao
To cite this article: Qiao Zhu, Shiying Che, Zhenghong Luo & Zijian Zhao (2020): Ligand-free
copper-catalyzed denitrogenative arylation of phosphorylamides with arylhydrazines, Synthetic
Communications, DOI: 10.1080/00397911.2020.1725577
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https://doi.org/10.1080/00397911.2020.1725577
Ligand-free copper-catalyzed denitrogenative arylation of
phosphorylamides with arylhydrazines
Qiao Zhua,b,c, Shiying Chea,b,c, Zhenghong Luob,c, and Zijian Zhaoa,b,c
aCollege of Pharmacy, Shaanxi University of Chinese Medicine, Xi’an-Xianyang New Ecomic Zone,
b
Xianyang, Shaanxi, P. R. China; School of Chemistry and Materials Science, Huaihua University, Hunan,
c
Huaihua, P. R. China; Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of
Hunan Province, Huaihua University, Hunan, Huaihua, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 6 December 2019
A straightforward arylation of phosphorylamides with arylhydrazines
hydrochloride was herein demonstrated. The protocol proceeded in
the presence of a catalytic loading of Cu(OAc)2 as the catalyst, DTBP
as the external oxidant and Cs2CO3 as the base, but without any
ligands. And a series of N-aryl phosphorylamides were successfully
obtained in high efficiency (up to 93% yields) with good substituents
compatibility (up to 30 examples). Free radical mechanism was pro-
posed for the facile methodology based on the results of control
reactions and literature explorations.
KEYWORDS
Arylhydrazines; copper
catalysis; denitrogenative
arylation; ligand-free;
phosphorylamides
GRAPHICAL ABSTRACT
Introduction
Extraordinary biological properties,[1] broad applications in synthetic chemistry and material
science[2] ensured the popularity of the organophosphorus compounds in the field and long-
standing attention has been paid on the derivation of the versatile molecules. Among phos-
phorylamides which possessed a P–N bond within the molecules, have gained more and
more research interests for the special architecture, as well for the versatile roles in medicinal
chemistry[3] and catalysts design.[4] Thus, sacrifice have been paid for the readily transforma-
tions of the expedient molecules with excellent biological and clinical properties.[5,6] For
example, synthesis of benzazaphosphole-1-oxides and phosphaisoquinolin-1-oxides has been
successfully realized by inter/intra-molecular annulation reactions in the presence of different
transition metal catalysts.[6] However, the topic remained underdeveloped and novel meth-
ods for the enrichment of the diversity of the –P(¼O)–N– backboned molecules are still
CONTACT Zhenghong Luo
2447151770@qq.com; Zijian Zhao
zjzhao@163.com
School of Chemistry and
Materials Science, Huaihua University, Huaidong Rd. 180, Huaihua 418000, Hunan, P. R. China.AQ1
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
Q. ZHU ET AL.
highly desired for the further development of the topic. For instance, firstly reported by
Guo,[7] arylation method of phosphinamides was demonstrated and different aryl groups
were successfully installed on the amino groups, which was provided by aryl iodides, in the
presence of CuI as catalyst and ( )-trans-cyclohexane-1,2-diamine as ligand. Successively, An
and coworkers disclosed a general arylation protocol of phosphorylamides with the assistance
of catalytic loading of Cu(OAc)2 and TBAF (tetrabutylammonium fluoride), in which aryl
siloxanes was applied as the aryl donators, forming a plenty of N-aryl phosphorylamides in
high efficiency and functional group tolerance.[8] Then, the same products were successfully
synthesized with aryl boronic acids in the presence of Cu(OAc)2 from the same group.[9]
Arylhydrazines, which was normally utilized as synthetic modules and identification reagents
for the advantages including low-cost, high reactivity and easy availability,[10] came to our
awareness as an efficient arylation reagent, which were able to supply different aryl groups
through the C-N bonds cleavage with emission of N2 and H2O via the aryldiazene intermedi-
ate under oxidative conditions, leading to the formations of kinds of chemical bonds. For
example, carbon-carbon bond construction, which was pioneered by Loh,[11] was successfully
realized by transition metallic catalyzed systems, or even under metal-free conditions. Other
carbon-hetero bonds, such as C-P[12] and C-S[13] bonds were readily formed through the
denitrogenative mechanism, giving an access to arylphosphonates and diarylsulfides success-
fully. For example, recently, reactions between arylhydrazines and trialkylphosphites were
described in the presence of CuO, providing arylphosphonates without any external reduc-
tants or ligands,[14] which shed light on that it was reasonable to exploit novel methods for
the formation of C-N bond. Within this context, Co/Cu-cocatalyzed system was created for
the arylation of anilines through the denitrogenative pathway.[15] Successively, An’s groups
also disclosed a new arylation protocol on NH-sulfoximines and sulfonamides under mild
conditions (room temperature or 60 ꢀC) in a similar manner.[16] Within this background, we
wished to reported a general arylation method for the preparation of N-aryl phosphoryla-
mides, which was also catalyzed by simple Cu(OAc)2 salt without any organic ligands.
Discussion
Firstly, reactions between model substrates P,P-diphenyl phosphinamide (1a) and phe-
nylhydrazine hydrochloride (2a) were carried out to investigate the optimal conditions
of the arylation protocol, as summarized in Table 1. In the presence of di-tert-butyl per-
oxide (DTBP) and Na2CO3, activities of different palladium catalysts were tested in 1,2-
dichloroethane at 80 ꢀC for 6 hours. To our satisfactory, PdCl2 was capable to make the
reaction happen smoothly, and 32% of N,P,P-triphenyl phosphinamide (3aa) was suc-
cessfully isolated after column chromatography (entry 1). Other palladium catalysts,
such as Pd(OAc)2 and Pd(PPh3)2Cl2, ensured the occurrence of the transformation in
36 and 30% yields, respectively (entries 2 and 3). However, silver salts, like AgNO3,
AgOTf, AgOAc failed to make the protocol take place and no reaction was detected
(entries 4–6). Then, various Cu(I)- and Cu(II) catalysts were logically examined in the
system and it was found that Cu(I) salts offered general inferior performance to that
Cu(II) catalysts did in the system (entries 7–14). Among all the Cu(II) salts tested,
Cu(OAc)2 (entry 12) gave the desired N-aryl phosphinamide 3aa in 82% yield, which
was distinguished from the others, like CuCl2, CuBr2, Cu(OTf)2 and CuSO4 (entries 10,

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Table 1. Conditions optimizationa.
Entry
[M]
[O]
Base
Sol.
Yieldb
1
2
3
4
5
6
7
8
PdCl2
Pd(OAc)2
Pd(PPh3)2Cl2
AgNO3
AgOTf
AgOAc
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
DCP
m-CPBA
K2S2O8
TBHP
TBHP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
DMF
DMSO
Toluene
32%
36%
30%
n.d.
n.d.
n.d.
25%
32%
40%
48%
trace
82%
78%
70%
60%
58%
64%
62%
trace
80%
n.d.
CuCl
CuBr
CuI
CuCl2
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25c
26
27
28
29
30
31
CuBr2
Cu(OAc)2
Cu(OTf)2
CuSO4
FeCl2
FeBr2
FeCl3
FeBr3
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
n.d.
70%
58%
91%
n.d.
KOAc
Cs2CO3
Et3N
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
n.d.
84%
trace
trace
n.d.
aReaction conditions: 1a (0.3 mmol), 2a (0.6 mmol, 3 portions at 2 hours intervals), Cat. (10 mol%), [O] (0.6 mmol), Base
(0.6 mmol) under air in Sol. (1.5 mL) at 80ꢀC for 6 h.
bIsolated yields.
cThe optimal conditions represented in bold.
dFor not detected.
11, 13, and 14). Iron catalysts, for example, FeCl2, FeBr2, FeCl3 and FeBr3 made the
reaction happen readily; however, lower efficiency were observed for up to 64% yield of
3aa was isolated after the completion of the reaction (entries 15–18). Next, different oxi-
dants were also subjected to the reactions for screening. Tert-Butyl hydroperoxide failed
to make the reaction happen while dicumyl peroxide rendered the formation of 3aa in
80% yield (entries 19 and 20). No reaction was detected in the presence of m-chloroper-
benzoic acid (m-CPBA) and K2S2O8 (entries 21 and 22). Amongst all the bases tested,
inorganic bases, such K2CO3, KOAc, Cs2CO3, and organic bases, like Et3N and DBU
(1,8-Diazabicyclo[5.4.0]undec-7-ene), Cs2CO3 showed superior performance in the sys-
tem to the others and the highest 91% yield was observed (entries 23–27). For organic

4
Q. ZHU ET AL.
Table 2. Scope of phosphoryl amidesa.
O
O
P
Ph
NH
Cu(OAc)2, Cs2CO3
P
NH2
+
PhNHNH2·HCl
O
DTBP, DCE, 80 oC, 6 h
O
R
R
1b - 1q
2a
3ba - 3qa
3ba, 85%
3ea, 80%
3ca, 88%
3fa, 82%
3da, 85%
3ga, 78%
3ha, 82%
3ia, 83%
3ja, 87%
3ka, 88%
3la, 89%
3ma, 75%
3na, 79%
3qa, 48%
3oa, 80%
3pa, 81%
aReaction conditions: 1 (0.3 mmol), 2a (0.6 mmol, 3 portions at 2 hours intervals), Cu(OAc)2 (10 mol%), DTBP
(0.6 mmol), Cs2CO3 (0.6 mmol) under air in DCE (1.5 mL) at 80 ꢀC for 6 h.
solvents, similar efficiency was observed in acetonitrile (84% yield for entry 28), better
than other solvents examined, like DMF, DMSO and toluene (entries 29–31).
Now that with the optimal reaction conditions in hands, examination of the substrate
scope was successively carried out, which was shown in Table 2. P-Phenyl-P-methyl
phosphonamide (1b) and P-Phenyl-P-ethyl phosphonamide (1c) reacted with phenylhy-
drazine hydrochloride in the catalytic system, offering the arylated product 3ba and 3ca
in good yields, up to 88%. Other long chained alkyl substituted substrates were also

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Table 3. Scope of arylhydrazine hydrochloridesa.
O
O
P
Ar
NH
Cu(OAc)2, Cs2CO3
P
NH2
+
ArNHNH 2·HCl
DTBP, DCE, 80 oC, 6 h
1a
2b - 2n
3ab - 3an
3ab, 82%
3ae, 86%
3ah, 93%
3ac, 88%
3af, 88%
3ai, 77%
3al, 56%
3ad, 90%
3ag, 90%
3aj, 78%
3am, 82%
3ak, 81%
3an, 80%
aReaction conditions: 1a (0.3 mmol), 2 (0.6 mmol, 3 portions at 2 hours intervals), Cu(OAc)2 (10 mol%), DTBP (0.6 mmol),
Cs2CO3 (0.6 mmol) under air in DCE (1.5 mL) at 80 ꢀC for 6 h.
compatible in the system, and in a similar manner, P-isopropyl- and P-n-butyl-phos-
phonamides 3da and 3ea were successfully isolated in 85% and 80% yields, respectively.
P-(1-methoxyethyl)- and P-(1-chloropropyl)- phosphonamide 3fa and 3ga were also
obtained in 82 and 78% yields, separately. Surprisingly, cyclo-alkyl groups, which was
exemplified by the employment of P-phenyl-P-cyclohexylmethyl phosphonamide (1h) in
the transformation, forming the desired phenylated product 3ha in 82% yield. Then, the
activities of arylated alkyl groups, for example, phenylethyl group was well tolerated in
the protocol and the corresponding phosphonamide 3ia was readily arylated by the
Cu(OAc)2-mediated system, in 83% yield. Other unsaturated substituents were also
compatible in the transformation and N,P-diphenyl phosphonamidic-(E)-cinnamyl ester

6
Q. ZHU ET AL.
(3ja) and phosphonamidic-2-butynyl ester (3ka) were isolated with good efficiency,
in up to 88% yields. Benzyl groups decorated phosphonamides, such as P-benzyl- (1l),
P-3-fluorobenzyl- (1m), P-2-chlorobenzyl- (1n), P-4-chlorobenzyl- (1o) and P-2-bromo-
benzyl- (1p) were furnished smoothly in yields from 75 to 89%. Worthy of note that
the positions of the halo atoms on the benzyl groups did not affect the efficiency of the
transformation significantly, and comparison of the formation of 3na and 3pa, in 79
and 81% yields, respectively. Beyond our expectations, N-(p-tolyl)-P-(4-morpholinyl)-P-
phenyl phosphinamide (3qa) was gained in moderate yield, up to 48%.
Successively, the examination of the substrate scope was logically extended to the
arylhydrazines hydrochlorides, as shown in Table 3. Different tolylhydrazine hydro-
chloride salts were firstly tested in the system. Worthy of note, the positions of the
methyl groups did not affect the efficiency of the transformation significantly, and the
corresponding products 3ab–3ad were isolated in yields from 82 to 90%. Similarly, ethyl
group substituted arylhydrazine hydrochlorides, were also subjected to the optimal reac-
tion conditions and the desired arylated products were furnished in 86 and 88% yields,
respectively. Electron sufficient phenyl groups, which possessed a methoxy group on the
either the meta- or the para- positions, offering the best performance in the arylation
protocol and methoxyphenyl decorated phosphoryl amides were successfully produced
in excellent yields, up to 93%. Halo atoms on the para-positions of the arylhydrazine
hydrochlorides, such as 4-fluorophenylhydrazine hydrochloride (2i), 4-chlorophenylhy-
drazine hydrochloride (2j), 4-bromophenylhydrazine hydrochloride (2k) gave the ary-
lated phosphoryl amides in a range of 77–81% yields, lower than that alkyl and alkoxyl
groups offered in the system. Logically, electron-deficient phenylhydrazine hydrochlor-
ides gave inferior effects to the catalytic transformation and para-nitrophenylhydrazine
hydrochloride (2l) and para-trifluoromethylphenylhydrazine hydrochloride (2m) ary-
lated the phosphinamide successfully in the Cu(II)-mediated transformation, allowing
the formation of the corresponding N-aryl phosphinamides in 56 and 82% yields,
respectively. Finally, polyarylhydrazine hydrochloride, which was exemplified by 2-naph-
thylhydrazine hydrochloride (2n), showed good compatibility in the system and N-(2-
naphthyl) phosphinamide (3an) was isolated successfully in 80% yield.
To take a deeper insight into the mechanism of the arylation protocol, control reac-
tion was conducted in the presence of different radical scavengers, as shown in
Scheme 1. For example, addition of TEMPO or BHT was conducted to the reaction
mixture under the standard conditions. However, no free radical-TEMPO or BHT
adducts were detected or isolated, and the yield of the denitrogenative transformation
was dramatically depressed and only trace of the desired product was observed by TLC
analysis. The results indicated the reaction might take place in the free radical pathway.
Scheme 1. Control reactions with additions of TEMPO or BHT.

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7
Scheme 2. Proposed mechanism of the denitrogenative arylation protocol.
Successively, analysis on EPR (Electron Paramagnetic Resonance)[17] was carried out
to obtain more information on the possible free-radical transformation, as exemplified
by the reaction between 1a and 2a. To our satisfactory, 2a gave expected signal in the
presence of Cu(OAc)2 (0.1 equiv.), Cs2CO3 (2.0 equiv.) and DTBP (2.0 equiv.) in DCE
at 80 ꢀC, giving a ge factor as 2.0024 (in a range of 2.0020–2.0025 for aryl radicals),
while 1a offered no any signal under the same conditions.
Thus, based on the EPR analysis and literature explorations, the illation would easily
come into our mind that the denitrogenative arylation protocol likely took place via an
aryl radical intermediate, which was generated in situ from arylhydrazine hydrochloride
under the oxidative surroundings. As shown in Scheme 2, the possible mechanism of
the transformation was proposed based on the literature explorations and results of
above-mentioned experiments. Starting with the treatment of phenylhydrazine hydro-
chloride with the base (Cs2CO3), corresponding phenylhydrazine was formed, which
could offer another key intermediate phenyldiazene (A) upon the interaction with oxi-
dant DTBP, along with the formation of a molecular of H2O. With the assistance of the
oxidant, the key intermediate A was transformed quickly into phenyldiazene radical B.
Along the emission of a dinitrogen molecule, formation of phenyl radical particle C was
realized and successive coupling with the Cu(II)-phosphorylamide complex took place
easily to afford the desired product 3aa and Cu(I) species. Then, the Cu(I) species was
reoxidized in the presence of DTBP for the next catalytic circle.
Conclusions
In conclusion, we have demonstrated an easy-operated N-arylation of phosphorylamides
with arylhydrazine hydrochlorides in the presence of Cu(OAc)2 under oxidative condi-
tions. The protocol feathered for generality in the synthesis of N-aryl phosphorylamides
with high efficiency. And further explorations for the synthetical and clinical applica-
tions of the products were still on-going in our laboratory.

8
Q. ZHU ET AL.
Experimental
Typical synthetic procedure of N-aryl phosphoryl amides 3
Under the air atmosphere, a Schlenk tube (35 mL) equipped with a magnetic bar, aryl-
hydrazine hydrochloride 2 (0.6 mol in three portions at the interval of 2 hours) was
added to the mixture of phosphoryl amide 1 (0.3 mmol), Cu(OAc)2 (10 mol%), DTBP
(0.6 mmol), Cs2CO3 (0.6 mmol) in dry DCE (3.0 mL). Then, the reaction mixture was
allowed to stir at 80 ꢀC for 6 hours. After the consumption of 1, as monitored by TLC
analysis, the mixture was filtered through a short celite pad and washed with methane
(15 mL ꢁ 3). The filtrate was concentrated, and the oily crude product was purified by
column chromatography using silica gel (200–300 mesh) as stationary phase and a mix-
ture of n-hexane and ethyl acetate (ca. 5:1) as eluent to give the corresponding arylated
products 3 (Rf¼ca.0.3 otherwise noted).
Spectra data of P,P,N-triphenyl phosphorylamide (3aa)
White solid (111.4 mg, 76% yield). m.p. 230–232 ꢀC. 1H NMR (400 MHz, CDCl3):
d ¼ 7.89 (dd, J ¼ 12.3, 7.5 Hz, 4H), 7.53 (t, J ¼ 7.0 Hz, 2H), 7.49–7.43 (m, 4H), 7.14 (t,
J ¼ 7.5 Hz, 2H), 6.98 (d, J ¼ 7.8 Hz, 2H), 6.89 (t, J ¼ 7.3 Hz, 1H), 5.35 (d, J ¼ 9.2 Hz, 1H)
(ppm). 13C NMR (CDCl3, 100 MHz): d ¼ 140.5, 132.4 (JC–P¼3.0 Hz), 132.1
(JC–P¼10.0 Hz), 132.1 (JC–P¼129.0 Hz), 129.0 (JC–P¼13.0 Hz), 129.4, 122.0, 118.7
(JC–P¼7.0 Hz) (ppm). 31P NMR (CDCl3, 160 MHz): d ¼ 18.4 ppm. IR (in KBr): ꢀ ¼
3111, 3070, 2960, 2930, 2890, 1600, 1494, 1434, 1408, 1270, 1184, 1100, 1031, 930, 803,
748 (cmꢂ1). MS (ESI): m/z (%)¼218.1, 294.1 (100). HRMS (ESI): m/z calcd for
[M þ H]þ: 294.1042; found: 294.1051.
Full experimental details, 1H and 13C NMR spectra are accessible via the
“Supplementary Content” section of this article’s webpage.
Funding
The authors are grateful for the financial support from the Fundamental Research Funds for the
Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan
Province [No. YYZW2018-9] and the financial support from the Huaihua University Program
[No. ZWX2016-11].
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