Copper-Phosphine Mediated Oxidative Phosphorylation of Aromatic Amines and P(OR)3 under Aerobic Conditions

Article abstract of DOI:10.1002/ejoc.202100550

A copper-phosphine system (Cu(OAc)₂ and t-Bu₃P?HBF₄) was used to synthesize α-aminophosphonates and phosphoramides from various aromatic amines and trialkyl phosphites under oxygen atmosphere. With this Cu?P system, α-aminophosphonates containing C?P bonds were generated from N,N-dimethylanilines or N-methylanilines and trialkyl phosphites; phosphoramidates containing N?P bonds were produced from N-benzylanilines and trialkyl phosphites. This strategy provided a convenient and efficient method for the synthesis of phosphorous compounds. The compounds containing phosphoryl group attracted extensive attention due to their biological activities and wide applications.^[1,2] The α-aminophosphonates have been applied in medicine and agriculture such as anticancer drugs, antibiotics, antibacterial agents, and enzyme inhibitors.^[1] And phosphoramides could be served as antibiotics, prodrugs, flame retardants, and ligands.^[2].

Full text of DOI:10.1002/ejoc.202100550

Communications
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Copper-Phosphine Mediated Oxidative Phosphorylation of
Aromatic Amines and P(OR)3 under Aerobic Conditions
Shihaozhi Wang,[a] Shidi Ma,[a] Jiale Yang,[a] Wenshuang Li,[a] Dianjun Li,*[a] and Jinhui Yang*[a]
amines and trialkyl phosphites to synthesis α-aminophospho-
nates/phosphoramides under oxygen atmosphere.
A copper-phosphine system (Cu(OAc)2 and t-Bu3P·HBF4) was
used to synthesize α-aminophosphonates and phosphoramides
from various aromatic amines and trialkyl phosphites under
oxygen atmosphere. With this CuÀ P system, α-aminophospho-
nates containing CÀ P bonds were generated from N,N-dimeth-
ylanilines or N-methylanilines and trialkyl phosphites; phosphor-
amidates containing NÀ P bonds were produced from N-
benzylanilines and trialkyl phosphites. This strategy provided a
convenient and efficient method for the synthesis of phospho-
rous compounds. The compounds containing phosphoryl group
attracted extensive attention due to their biological activities
and wide applications.[1,2] The α-aminophosphonates have been
applied in medicine and agriculture such as anticancer drugs,
antibiotics, antibacterial agents, and enzyme inhibitors.[1] And
phosphoramides could be served as antibiotics, prodrugs, flame
retardants, and ligands.[2]
Based on previous reports, some transition metal catalysts
could activate C(sp3)-H bonds adjacent to nitrogen in tertiary
amines,[4–12,17] and we chose copper salts to produce α-amino-
phosphonates. N,N-dimethylaniline and triethyl phosphite were
selected as the model substrates. First, several copper salts
were tested to catalyze this reaction (Table S1, entries 1–4 in
the Supporting Information). To our delight, CuSO4 displayed
better catalytic ability in the presence of O2 (1 atm), and
product 3a was obtained in 36% yield (Table 1, entry 1). Then,
a series of ligands were evaluated (Table 1, entry 2; also see
Table S1, entries 5–11, in the Supporting Information), wherein
t-Bu3P·HBF4 significantly promoted the reaction (Table 1, en-
try 2). Next, we tested the yields of various copper salts in the
presence of ligands (Table 1, entries 2–5; also see Table S1,
entries 12–17, in the Supporting Information). Cu(OAc)2 was
proved to be the optimal catalyst which increased the yield to
75% (Table 1, entry 3). Obviously, t-Bu3P·HBF4 has better
promoting effect on this reaction than its analogues (Table 1,
entries 3, 6 and 7). Compared with phosphine salt ligands, the
During the past decades, the construction of CÀ P bond using
transition metals has been widely studied.[3] These metals
mainly include Cu,[4] Fe,[5] Co,[6] Mn,[7] Ru,[8] Au,[9] Pd,[10] Sb,[11] Ir,[12]
Ni,[13] Ag.[14] Among them, the synthesis of α-aminophospho-
nates by CDC (cross dehydrogenation coupling) reactions[15]
involving P(O)-H has been developed.[4–12] For example, Li
reported that copper salts catalyzed the synthesis of α-amino-
phosphonates from N-aryltetrahydroisoquinolines and dialkyl
phosphites[4a] (Scheme 1A). And the transition metal catalyzed
CDC reactions could also be applied for synthesis of
phosphoramides[16] containing NÀ P bonds. Hayes developed
the synthesis methodology of phosphoramides catalyzed by
Cu[16a] (Scheme 1B). In addition, Lei and coworkers reported a
visible light-mediated oxidative phosphorylation that used
trialkyl phosphites as phosphorus source to react with tertiary
amines (Scheme 1C), and this reaction was catalyzed by two
transition metals (Ru and Co).[8b] Because of the importance of
compounds containing phosphoryl groups, it is necessary to
establish a general protocol to synthesize α-aminophospho-
nates and phosphoramides. Herein, we developed a copper-
phosphine mediated oxidative phosphorylation of aromatic
Table 1. Optimization of reaction conditions.[a]
Entry
[Cu] [mol%]
Atmosphere
Ligand [mol%]
Yield[b]
[%]
1
2
3
4
5
6
7
8
CuSO4 (30)
CuSO4 (30)
Cu(OAc)2 (30)
CuCl (30)
CuBr2 (30)
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
Ar
Air
O2
O2
O2
O2
O2
O2
–
36
57
75
53
50
65
55
19
22
56
42
16
33
67
37
80
t-Bu3P·HBF4 (30)
t-Bu3P·HBF4 (30)
t-Bu3P·HBF4 (30)
t-Bu3P·HBF4 (30)
Cy3P·HBF4 (30)
n-Bu3P·HBF4 (30)
Cy3P (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
Cu(OAc)2 (50)
-
9
t-Bu3P (30)
10[c]
11[d]
12
13
14[e]
15[f]
16
17
18[g]
19[h]
t-Bu3P·HBF4 (30)
t-Bu3P·HBF4 (30)
t-Bu3P·HBF4 (30)
t-Bu3P·HBF4 (30)
t-Bu3P·HBF4 (30)
t-Bu3P·HBF4 (30)
t-Bu3P·HBF4 (50)
t-Bu3P·HBF4 (100)
–
[a] S. Wang, S. Ma, J. Yang, W. Li, Dr. D. Li, Prof. J. Yang
State Key Laboratory of High-efficiency Utilization
of Coal and Green Chemical Engineering,
College of Chemistry and Chemical Engineering,
Ningxia University,
76
16
Trace
–
Yinchuan 750021, China
[a] Reaction conditions: 1a (2 mmol), 2a (1 mmol), [Cu], Atmosphere
E-mail: jinhuiyang_nxdx@163.com
°
nxlidj@126.com
(1 atm), ligand, CH3CN (2 mL), 80 C for 18 h; [b] Isolated yield; [c] In DCE
°
°
(2 mL); [d] In THF (2 mL); [e] At 50 C; [f] At 100 C; [g] No ligand; [h] No Cu
(OAc)2 and ligand.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100550
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°
corresponding phosphine ligands (Cy3P and t-Bu3P) exhibited
much weaker catalytic ability (Table 1, entries 3, 6 and 8, 9).
Solvent screening was then performed. When acetonitrile was
replaced with DCE or THF, the yield decreased to 56% and
42%, respectively (Table 1, entries 10, 11). Control experiments
showed that molecular oxygen is critical to the transformation.
The yields in argon (16%) and air (33%) were much lower than
that in oxygen (Table 1, entries 12, and 13). Increasing or
decreasing the temperature was unfavorable to the reaction, so
the appropriate temperature was determined to be 80 C
(Table 1, entries 14, 15). Then, the amounts of catalyst and
ligand were examined (Table 1, entries 3, 16, 17), and a yield of
80% was obtained (Table 1, entry 16). In the condition control
experiment, when the ligand was removed, the yield was
decreased to 16% (Table 1, entry 18). In the absence of catalyst
and ligand, no product was obtained (Table 1, entry 19).
With the optimized conditions in hand, the scope of
phosphite was investigated (Scheme 2, 3a–3d). As shown in
Scheme 2, the yields of trialkyl phosphites (3a–3d) were better
than dialkyl phosphite (3a). For trialkyl phosphite, the yields
decreased with increasing alkyl chain length (Scheme 2, 3a–3c).
When triphenyl phosphite was used as phosphorus source, the
product was obtained in 24% (Scheme 2, 3d). Consequently,
we chose trimethyl phosphite as the phosphorus source in the
next steps of the study. Next, we studied different kinds of
tertiary amines under the optimized conditions. As shown,
various aromatic amines could be smoothly converted into the
corresponding α-aminophosphonates. When mono alkyl sub-
stituents (Me, t-Bu) or a phenyl moiety was present in the para-
position of N-phenyl ring, the expected products were obtained
in good yields (Scheme 2, 3e, 3j and 3k). Halogen atoms were
all well tolerated, showing their potential application in further
chemical transformations (Scheme 2, 3f-3i). The yields of
substrates with electron-donating substituents were higher
than that with electron-withdrawing substituents (Scheme 2,
3e, 3l). This is consistent with the fact that electron rich amines
were more facile to be oxidized. Alkyl groups in the meta-
position also provided the corresponding α-aminophospho-
nates in a good yield (Scheme 2, 3m and 3n). In addition, the
yields of para- and meta- substituted anilines were higher than
that of ortho-substituted anilines (Scheme 2, 3f and 3o, 3h and
3p, 3n and 3q, 3r). This difference is probably due to steric
hindrance. When methyl and other groups were attached to the
nitrogen atom, N-methyl was preferentially reacted and the
yields were low to medium (Scheme 2, 3s, 3t, 3u). Moreover, 1-
phenylpyrrolidine as substrate, the corresponding product was
obtained in 22% yield (Scheme 2, 3v). Obviously, naphthalene
ring was more unfavorable for the reaction (Scheme 2, 3w).
We also investigated the reaction of N-methylaniline and
trialkyl phosphite. As shown in Scheme 3, N-methylaniline
generated the same product 3a through intermolecular methyl
migration and N-methyl oxidative phosphorylation in moderate
yields might be due to low efficiency of methyl migration. With
an increased in the length of the carbon chain on trialkyl
phosphites, the yields of the reaction decreased (Scheme 3, 3a-
3c). In addition, substituents on the benzene ring were
unfavorable to the reaction (Scheme 3, 3e-3z).
Scheme 1. Reaction of phosphite with amine.
We next examined the applicability of this CuÀ P system in
the reaction of N-benzylanilines and trialkyl phosphites
(Scheme 4). Interestingly, phosphoramides were formed when
N-benzylanilines were treated with trialkyl phosphites using the
previously mentioned optimal conditions. Various substituted
N-benzylanilines bearing different substituents were converted
smoothly to the corresponding phosphoramides. Obviously,
with an increase in the electron-donating ability of the
substituents, the yield also increased (Scheme 4, 6d, 6f, 6k–
Scheme 2. Investigation of tertiary amine and phosphite.a,b [a] Reaction
conditions: 1 (2 mmol), 2 (1 mmol), Cu(OAc)2 (50 mol%), t-Bu3P·HBF4
°
(50 mol%), O2 (1 atm), CH3CN (2 mL), 80 C for 18 h; [b] Isolated yield; [c]
From HP(O)(OEt)2.
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Scheme 3. Substrate scope of N-methylaniline and trialkyl phosphite.a,b [a] Reaction conditions: 4 (4 mmol), 2 (1 mmol), Cu(OAc)2 (50 mol%), t-Bu3P·HBF4
°
(50 mol%), O2 (1 atm), CH3CN (2 mL), 80 C for 18 h; [b] Isolated yield.
Scheme 4. Substrate scope of N-benzylaniline and trialkyl phosphite.a,b [a] Reaction conditions: 5 (4 mmol), 2 (1 mmol), Cu(OAc)2 (50 mol%), t-Bu3P·HBF4
°
(50 mol%), O2 (1 atm), CH3CN (2 mL), 80 C for 18 h; [b] Isolated yield.
6n). However, the yields of methoxy-containing substituents
were moderate (Scheme 4, 6e and 6i). It was likely due to the
side reactions.
Several condition control experiments were carried out in
order to reveal the mechanism of these transformations
(Scheme 5). With the absence of O2 or t-Bu3P·HBF4, the
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Scheme 5. Mechanism experiment.a,b [a] Standard conditions: tertiary amine (2 mmol) or secondary amine (4 mmol), trialkyl phosphite (1 mmol), Cu(OAc)2
°
(50 mol%), t-Bu3P·HBF4 (50 mol%), O2 (1 atm), CH3CN (2 mL), 80 C for 18 h; [b] Isolated yield; [c] In Ar; [d] Without t-Bu3P·HBF4; [e] In Ar; [f] Without t-
Bu3P·HBF4; [g] Add TEMPO; [h] Add BHT.
Scheme 6. Proposed reaction mechanism.
corresponding products were obtained in low yields (Scheme 5,
A, B). These results showed that copper-phosphine-oxygen
system played crucial role in reaction processes. And the radical
inhibition experiments also exhibited that all reactions were
greatly inhibited in the presence of TEMPO or BHT, it implied
that the reaction might be carried out through a radical process
(Scheme 5, C, D). When the reaction was performed using
deuterated substrate, the corresponding methyl-deuterated
product was obtained (Scheme 5, E). It indicated that the N-
methyl group of product was derived from N-methylaniline
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[1] a) E. D. Naydenova, P. T. Todorov, K. D. Troev, Amino Acids 2010, 38, 23–
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generate N,N-dimethylaniline via intermolecular methyl migra-
tion.
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Some details of mechanism such were still uncertain up to
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as shown in Scheme 6. Initially, N-methylaniline 4 generated
N,N-dimethylaniline 1 via intermolecular methyl migration. After
that, N,N-dimethylaniline 1 produced iminium ion intermediate
A through SET (Single Electron Transfer), PT (Proton Transfer)
and SET process, and Cu(II) was reduced to Cu(I) at the same
time. Then, Cu(I) was oxidized to Cu(II) by oxygen and formed
water. Next, the intermediate B was formed by the coordination
of intermediate A, copper and ligand. Afterwards, P(OR)3 as a
nucleophilic reagent combined with intermediate B afforded
intermediate C. Finally, product 3 was produced by hydrolysis
of intermediate C, and the copper/ligand removed from the
substrate. For N-benzylaniline 5, similar to N,N-dimethylaniline
1, the iminium ion intermediate a was formed through SET, PT
and SET process. And Cu(I) was oxidized to Cu(II) by oxygen and
produced water. Next, intermediate b was generated by the
coordination of intermediate a, copper and ligand. And then,
P(OR)3 combined with intermediate b afforded intermediate c.
At last intermediate c hydrolyzed to generate product 6 and
the copper/ligand removed.
In summary, we have developed an efficient strategy of
various aromatic amines to synthesize compounds containing
phosphoryl group by using a copper and phosphine-ligand
(Cu(OAc)2 and t-Bu3P·HBF4) system under an aerobic atmos-
phere. Importantly, this method could be applied not only to
synthesis α-aminophosphonates (CÀ P bonds) but also to
produce phosphoramides (NÀ P bonds). Under this operationally
easy protocol, α-aminophosphonates were generated from
tertiary amines or secondary amines. In addition, phosphor-
amides were produced when N-benzylanilines were used as
substrates. Further studies on enantioselective copper-mediated
reactions are currently underway.
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This work was supported by the National Natural Science
Foundation of China (Grant no. 21861031, 21362025), Institute
local cooperation project of Chinese Academy of Engineering
(2019NXZD1), Key Research and Development project of Ningxia
(2019BDE03002), and the National First-rate Discipline Construc-
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(NXYLXK2017A04).
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Conflict of Interest
The authors declare no conflict of interest.
Keywords: α-Aminophosphonate · CÀ P bond formation · NÀ P
bond formation · Oxidative phosphorylation · Phosphoramide
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Manuscript received: May 3, 2021
Revised manuscript received: May 22, 2021
Accepted manuscript online: May 27, 2021
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S. Wang, S. Ma, J. Yang, W. Li, Dr. D.
Li*, Prof. J. Yang*
1 – 7
Copper-Phosphine Mediated
Oxidative Phosphorylation of
Aromatic Amines and P(OR)3
under Aerobic Conditions
A copper-phosphine system was
developed to promote the formation
of α-aminophosphonates and phos-
phoramides from various aromatic
amines and trialkyl phosphites under
aerobic conditions. Importantly, this
method could be applied not only to
the synthesis of α-aminophospho-
nates (CÀ P bonds) but also to
produce phosphoramides (NÀ P
bonds). This strategy provided a con-
venient and efficient method for the
synthesis of phosphorous
compounds.