Cobalt-Catalyzed Oxidative Phosphonylation of α-Amino Acid Derivatives and α-Amino Ketones for α-Aminophosphonates

Article abstract of DOI:10.1021/acs.joc.8b02680

A novel and efficient direct oxidative phosphonylation of α-amino ketones and α-amino acid derivatives with dialkyl phosphites by the catalysis of a cobalt salt under air is disclosed. A variety of α-amino ketones and α-amino acid derivatives underwent th

Full text of DOI:10.1021/acs.joc.8b02680

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Note
Cobalt-Catalyzed Oxidative Phosphonylation of #-Amino Acid
Derivatives and #-Amino Ketones for #-Aminophosphonates
Zhi-Qiang Zhu, Li-Jin Xiao, Dong Guo, Xu Chen, Jiu-Jian Ji, Xiao Zhu, Zong-Bo Xie, and Zhang-Gao Le
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02680 • Publication Date (Web): 12 Dec 2018
Downloaded from http://pubs.acs.org on December 12, 2018
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Cobalt-Catalyzed Oxidative Phosphonylation of α-Amino Acid
Derivatives and α-Amino Ketones for α-Aminophosphonates
8
9
Zhi-Qiang Zhu,*,†,‡ Li-Jin Xiao,‡ Dong Guo,‡ Xu Chen,‡ Jiu-Jian Ji,‡ Xiao Zhu,‡ Zong-Bo Xie,‡ and
Zhang-Gao Le*,†,‡
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†State Key Laboratory of Nuclear Resources and Environment, and ‡School of Chemistry, Biology and Material Science,
East China University of Technology, Nanchang 330013, P. R. China
ABSTRACT: A novel and efficient direct oxidative phosphonylation of α-amino ketones and α-amino acid derivatives with dialkyl
phosphites by the catalysis of a cobalt salt under air was disclosed. A variety of α-amino ketones and α-amino acid derivatives
underwent the reaction well with dialkyl phosphites to produce the desired α-aminophosphonates. This protocol not only provides
an alternative synthetic route for the preparation of diverse α-aminophosphonates, but also avoids the use of potentially explosive
peroxide agents.
O
O
H
H
O
N
R2
N
Co(ClO4)2 6H2O (10 mol %)
MeCN, 80 oC, air
R2
P OR3
OR3
R1
H
R1
O
OR3
P
R3O
H
up to 95% yield
24 examples
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C-P bond formation reactions has drawn considerable attention due to the
prevalence of organophosphorus compounds in pharmaceutical chemicals,
phosphine-containing ligands, organic synthesis blocks, and materials science.1 In
particular, forging C-P bonds to α-aminophosphonic acids and α-aminophosphonates
is considered as a significantly important conversion, because these compounds
exhibit many different biological properties such as antitumor,2 antibacterial,3
antifungal,4 catalytic antibody activities5 and others.6 Typical approaches for their
preparations are the Kabachnik-Fields reaction and the Pudovik reaction involving the
reaction of dialkylphosphites with imines, which are prepared by the condensation of
carbonyl compounds (aldehydes or ketones) and amines.7 Then, a great number of
studies by using Lewis acid catalyst and catalyst-free systems have been developed to
promote the synthesis of these high-value compounds.8 Despite these achievements,
exploring more greener and efficient pathways for the preparation of biologically
important α-aminophosphonate derivatives is still highly desired.
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Direct phosphorylation of C-H bond is undoubtedly the most straightforward and
attractive strategy for the generation of C-P bond.9 In recent years, remarkable works
have been conducted on the phosphonylation of C(sp3)-H bonds adjacent to nitrogen
with H-phosphonates to produce α-aminophosphonates.10-12 However, direct
phosphonylation of C(sp3)-H of α-amino acid derivatives with H-phosphonates to
provide the corresponding α-aminophosphonates remains rare.12 For example, in 2013,
Yang and coworkers revealed a copper-catalyzed oxidative phosphonation reaction of
α-amino ketones with diphenylphosphine oxide to give imidoylphosphonates by using
tert-butyl hydroperoxide (TBHP) as an oxidant.12a In 2016, Li et al. described a novel
cross-dehydrogenative-coupling (CDC) reaction between glycine amides and
H-phosphonates with CuI/TBHP catalysis system.12b Although N-(4- or
2-methoxyphenyl)glycine amides underwent the reaction readily, related α-amino
esters could not lead to the desired products at all. In consideration of the biological
importance of α-aminophosphonates, and as part of our effort in CDC reactions,13 we
herein report a novel cobalt-catalyzed selective phosphonation reaction with α-amino
ketones and α-amino acid derivatives for the assembly of α-aminophosphonates
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Importantly, the use of cobalt salt as a practical, cost-efficient catalyst and
atmospheric air as an environmentally benign oxidant makes this transformation
particularly attractive.
9
Table 1. Optimization of the reaction conditionsa
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O
H
O
N
H
O
[M] / Oxidant
OEt
N
O
H P OEt
OEt
OEt
P
Solvent, Temp.
EtO
OEt
3aa
1a
2a
Entry
1
Catalyst
CuO
Oxidant
Solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
Yield (%)b
Air
Air
22
10
36
8
2
CuCl2
Cu(OTf)2
CoO
3
Air
4
Air
5
CoCl2
Air
12
23
38
0
6
Co(ClO4)2·6H2O
Co(OAc)2
Air
7
8c
Air
--
Air
9
Co(OAc)2
DTBP
TBHP
DCP
K2S2O8
O2
32
33
35
30
37
0
10
11
12
13
14d
15e
16e
17e
18e
19e,g
20e,h
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
--
Co(OAc)2
Air
72
83(82)f
52
68
63
80
Co(ClO4)2·6H2O
Co(ClO4)2·6H2O
Co(ClO4)2·6H2O
Co(ClO4)2·6H2O
Co(ClO4)2·6H2O
Air
Air
Air
Toluene
MeCN
MeCN
Air
Air
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), catalyst (10 mol %), solvent (2 mL) at 80 C under air or
oxidant (2 equiv) for 12 h. b Isolated yield based on 1a. c In the absence of a catalyst. d Under N2 atmosphere. e 2a
(1.4 mmol). f 2a (1.6 mmol). g At 60 oC. h At 100 oC.
o
In the preliminary studies, we chose N-4-methylphenylglycine ester 1a and
diethyl phosphonate 2a as model substrates in the CDC reaction for their optimization
investigation. When the model reaction was proceeded under the conditions of 10 mol
o
% CuO in acetonitrile (CH3CN) at 80 C under air, we were pleased to find that the
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desired α-aminophosphonate 3aa was obtained in 22% yield (entry 1, Table 1). Next,
a series of transition-metal salts such as CuCl2, Cu(OTf)2, CoO, CoCl2, Co(OAc)2,
and Co(ClO4)2·6H2O were probed (entries 2-7, Table 1), we found that Co(OAc)2
gave rise to the best yield of 3aa (compare entries 1-6 with entry 7, Table 1; also see
the Supporting Information (SI)). Control experiment results demonstrated that no
desired product 3aa was formed in the absence of a catalyst (entry 8, Table 1). When
other oxidants were employed, lower or no formation of 3aa was observed (compare
entries 9-13 with entry 7, Table 1; also see SI). The reaction did not occur at all under
nitrogen atmosphere, this result attested clearly that air was crucial to this
transformation (entry 14, Table 1). The usage amount of diethyl phosphite 2a was
also examined, and we found that Co(ClO4)2·6H2O displayed better catalytic
efficiency for the yield of 3aa than Co(OAc)2 when 7 eq. diethyl phosphite 2a was
employed (compare entry 15 with entry 16, Table 1). Among various solvents
screened, MeCN proved to be the most efficient solvent to give 3aa in 83% yield
(compare entries 17-18 with entry 16, Table 1; also see SI). Lowering or raising the
reaction temperature led to a reduction in the yield of 3aa (compare entries 19-20 with
entry 16, Table 1).
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On the basis of the above discussion, it can be concluded that the optimized
reaction should be proceeded under the conditions of 10 mol % of Co(ClO4)2·6H2O in
o
MeCN at 80 C under air. With optimal reaction conditions in hand, various glycine
esters 1 and phosphonates 2 were investigated in the CDC reaction. Different from
reported protocol,12b an array of N-arylglycine esters 1a-i performed the reaction
readily with diethyl phosphite 2a to provide the corresponding α-aminophosphonates
3aa-ia in 40-90% yields (Table 2). Glycine esters 1a-c wtih electron-rich groups on
N-benzene rings reacted more smoothly with diethyl phosphite 2a than those 1d-e
with electron-poor groups on N-benzene rings. However, N-2-methylphenylglycine
ester with diethyl phosphite 2a afforded a complex mixture of unidentified
compounds. In addition, N-methyl, N-Boc or N-Cbz protected glycine esters were also
examined. The reaction did not proceed at all with those substrates under the standard
conditions. Nevertheless, N-arylglycine esters 1f-i bearing a number of different alkyl,
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such as methyl, isopropyl, tert-butyl, and benzyl groups in the activating ester moiety
were found to be suitable coupling partners, giving rise to the corresponding products
3fa-ia in 61-80% yields. Moreover, a range of different dialkyl phosphites 2b-d were
also able to react well with N-4-methylphenylglycine ester 1a, delivering the expected
products 3ab-ad in 62-95% yields. Unfortunately, no desired product was observed
when diphenylphosphine oxide was employed instead of dialkyl phosphites. To
evaluate the the practicability of this method, N-4-methylphenylglycine ester 1a (6.5
mmol) with diethyl phosphite 2a was performed in gram-scale, and the desired
α-aminophosphonate 3aa was obtained in 80% yield (1.71 g).
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Table 2. CDC reaction between N-arylglycine esters 1a-i and dialkyl phosphites
2a-da,b
O
H
O
N
H
O
P
Co(ClO4)2 6H2O (10 mol %)
MeCN, 80 oC, air
R2
N
R1
OR3
R2
O
OR3
H
R1
P
OR3
R3O
3aa-ia
3aa-ad
1a-i
2a-d
O
H
O
O
H
N
H
N
N
O
O
P
O
O
O
O
O
O
P
P
MeO
O
O
Ph
O
O
c
3ba
90%
O
3ca
3aa
65%
O
83% (80%)
O
H
N
H
N
H
N
O
O
O
O
P
O
P
O
P
O
O
Br
O
O
Cl
O
O
3da
41%
O
3fa
78%
O
3ea
40%
O
H
N
H
N
H
N
O
O
O
O
O
O
P
O
O
P
P
O
O
O
O
3ga
3ha
3ia 80%
61%
O
67%
O
H
O
H
N
H
N
N
O
O
O
O
P
O
P
O
O
P
O
O
O
O
O
3ab
95%
3ad
62%
3ac
76%
1 (
) 2
Reaction Conditions: (a) 0.2 mmol , (1.4 mmol), Co(ClO4)2 6H2O (10 mol %), MeCN (2 mL),
o
1
3aa
was obtained in 1.71g.
at 80 C under air for 12 h. (b) Isolated yield based on . (c) Product
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For further examining the generality of the present protocol, glycine amides and
α-amino carbonyl compounds 1 were also investigated in this CDC reaction with
diethyl phosphite 2a. A variety of glycine amides and α-amino ketones 1j-u
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Table 3. CDC reaction between glycine amides 1j-l or α-amino acketones 1m-u and
diethyl phosphite 2a by cobalt catalysisa,b
O
O
H
N
H
O
P
R2
Co(ClO4)2 6H2O (10 mol %)
MeCN, 80 oC, air
N
R2
R2
H
OEt
O
R1
P
OEt
EtO
OEt
3ja-ua
1j-u
2a
O
O
O
H
H
N
H
N
N
N
N
N
H
O
O
O
O
H
H
O
O
P
P
P
O
O
O
3ka
3ja
87%
95%
3la
76%
O
O
O
H
H
N
H
N
N
O
O
O
O
O
P
P
P
O
O
F
O
O
3na
3oa
93%
92%
O
3ma
91%
O
O
H
H
N
H
N
N
O
O
O
O
O
O
P
P
P
Cl
O
O
OMe
O
3pa
3qa
90%
83%
O
3ra
79%
O
O
H
N
H
N
H
N
O
P
O
O
O
P
P
O
O
Br
O
F
O
O
Cl
3ta
3ua
89%
81%
3sa
77%
1 (
) 2a
(1.4 mmol), Co(ClO4)2 6H2O (10 mol %), MeCN
Reaction Conditions: (a) 0.2 mmol ,
o
1
.
(2 mL), at 80 C under air for 12 h. (b) Isolated yield based on
performed this reaction well with diethyl phosphite 2a to produce the corresponding
α-aminophosphonates 3ja-ua in 76-95% yields (Table 3). Glycine amides 1j-l bearing
various amino substituents in the amide moiety, such as methylamino, ethylamino,
and benzylamino were good candidates in the present protocol, giving rise to the
desired α-aminophosphonates 3ja-la in satisfactory yields. Surprisingly, tertiary
amide,
N,N-dimethyl-2-(p-tolylamino)acetamide and simple dipeptide, ethyl
p-tolylglycylglycinate did not undergo the desired phosphorylation reaction with
diethyl phosphite 2a under the standard reaction conditions. Besides, a wide range of
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α-amino ketones 1m-u underwent the reaction well with diethyl phosphite 2a to
generate the expected products 3ma-ua in good to excellent yields. For example,
when different functional groups such as methyl, halogen groups were connected on
the para-position of amino unit on the N-benzene ring, the expected products 3na-pa
were isolated in high yields. The aryl groups connected with carbonyl groups were
also evaluated, and both electron-rich and electron-deficient substituents on the
benzene rings in α-amino ketones 1qa-ua led to the corresponding products 3qa-ua in
good yields.
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To investigate the mechanism of this transformation, some control experiments
were carried out, and the experimental results were depicted in Scheme 1. When the
radical
inhibitor
2,6-di-tert-butyl-4-methylphenol
(BHT)
or
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) existed, the reaction was suppressed
completely (eq 1). This observation implies that the reaction may undergo a radical
process. Next, in the absence of diethyl phosphonate 2a, glycine imine 5 was formed
in 53% yield by the oxidation of glycine ester 1a under the standard conditions (eq 2).
Then, the reaction between glycine imine 5 and diethyl phosphite 2a was examined,
and the expected α-aminophosphonate 3aa was generated in 88% yield (eq 3). These
results revealed that glycine imine 5 was the key intermediate in this cobalt-catalyzed
CDC reaction.
Scheme 1. Control Experiments
O
H
O
Co(ClO4)2 6H2O (10 mol %)
BHT or TEMPO (2 eq)
MeCN, 80 oC, air, 12 h
N
H
O
P
OEt
N
OEt
OEt
H
OEt
(1)
(2)
(3)
P
EtO
OEt
OEt
2a
O
1a
3aa
0%
O
O
N
H
OEt
Co(ClO4)2 6H2O (10 mol %)
MeCN, 80 oC, air, 12 h
N
5
53% yield
1a
O
H
O
N
O
P
OEt
N
Co(ClO4)2 6H2O (10 mol %)
MeCN, 80 oC, air, 12 h
H
OEt
OEt
P
EtO
OEt
OEt
O
5
3aa
2a
88% yield
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Based on the above experimental results and previous reports,12,14 a possible
mechanism of this conversion is illustrated as follows (Scheme 2). Firstly, Co(II)
activates oxygen in the air to generate a Co(III) peroxy radical,10e,14 which may
abstract a hydrogen radical of glycine ester 1a to produce radical 4. Subsequently,
radical 4 undergoes a single electron transfer (SET) by the high valent Co(III) to give
glycine imine 5, and regenerate Co(II).15 Finally, the attack of reactive diethyl
phosphonate 2a on the glycine imine 5 provides the desired α-aminophosphonate 3aa.
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Scheme 2. Plausible mechanism
Co(II)
O
O2
O
H
H
N
SET
Co(III)
N
O
Co(III)OO
O
Co(II)
Co(III)
4
1a
O
P
H
OEt
2a
OEt
O
OEt
H
O
N
HO
P OEt
N
O
O
O
O
P
O
5
3aa
In summary, a convenient and efficient cobalt-catalyzed oxidative
phosphonylation of α-amino acid derivatives and α-amino carbonyl compounds for
the preparation biologically important α-aminophosphonates has been developed.
Various glycine derivatives and α-amino ketones could proceed the reaction well
with diakyl phosphonates to furnish the desired α-aminophosphonates in
satisfactory yields. This approach not only provides an excellent step- and
atom-economy synthetic route for the preparation of diverse α-aminophosphonates,
but also uses atmospheric air as an environmentally benign oxidant.
EXPERIMENTAL SECTION
General Information. Unless otherwise indicated, all reagents were purchased
1
13
from commercial distributors and used without further purification. H NMR and C
NMR were recorded at 400 MHz and 100 MHz respectively, using tetramethylsilane
as an internal reference. High-resolution mass spectra (HRMS) were measured on a
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quadrupole time-of-flight (Q-TOF) mass spectrometer instrument with an electrospray
ionization (ESI) source. Melting points were uncorrected. Flash column
chromatography was performed over silica gel 200-300 mesh. Thin-layer
chromatography (TLC) was carried out with silica gel GF254 plates. N-arylglycine
derivatives and α-amino ketones 1 were prepared according to the previous reported
protocols.12-13
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General procedure for the synthesis of α-aminophosphonates 3. To a solution
of α-amino derivatives or α-amino ketones 1 (0.2 mmol) in MeCN (2 mL) was
added diakyl phosphonates 2 (1.4 mmol) and Co(ClO4)2·6H2O (7.3 mg, 0.02
o
mmol). Then, the reaction mixture was stirred at 80 C under air for 12 hrs.
After the reaction was completed, the resulting mixture was concentrated under
vacuum and the residue was subjected to column chromatography (silica gel,
8:1 petroleum ether/ethyl acetate as an eluent) to afford the desired
α-aminophosphonates 3.
Ethyl 2-(diethoxyphosphoryl)-2-(p-tolylamino)acetate (3aa):16 Yield 83% (54.6
mg); light yellow solid; mp 75.2-76.4 °C; 1H NMR (400 MHz, CDCl3): δ 7.00 (d, J =
6.4 Hz, 2H), 6.61 (dd, J = 5.4 Hz, J = 1.4 Hz, 2H), 4.47 (d, J = 18.4 Hz, 1H),
4.27-4.17 (m, 6H), 2.24 (s, 3H), 1.36-1.31 (m, 6H), 1.27 (t, J = 5.6 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 168.5 (d, J = 2.4 Hz), 143.8 (d, J = 9.0 Hz), 129.8, 128.8,
114.2, 64.2 (d, J = 4.5 Hz), 63.6 (d, J = 4.7 Hz), 62.2, 56.8 (d, J = 118.0 Hz), 20.5,
16.5 (d, J = 4.8 Hz), 16.4 (d, J = 5.4 Hz), 14.1; HRMS (ESI) calcd for C15H25NO5P
(M+H)+ 330.1465, found 330.1467.
Ethyl 2-(diethoxyphosphoryl)-2-((4-methoxyphenyl)amino)acetate (3ba):16
Yield 90% (62.1 mg); yellow oil; 1H NMR (400 MHz, CDCl3): δ 6.78 (d, J = 7.2 Hz,
2H), 6.66 (d, J = 7.2 Hz, 2H), 4.43 (d, J = 18.4 Hz, 1H), 4.27-4.18 (m, 6H), 3.74 (s,
3H), 1.37-1.31 (m, 6H), 1.27 (t, J = 5.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
168.7 (d, J = 1.8 Hz), 153.4, 140.2 (d, J = 10.3 Hz), 115.7, 114.8, 64.1 (d, J = 5.7 Hz),
63.5 (d, J = 6.0 Hz), 62.2, 57.5 (d, J = 118.2 Hz), 55.7, 16.5 (d, J = 4.8 Hz), 16.4 (d, J
= 4.7 Hz), 14.1; HRMS (ESI) calcd for C15H23NO6P (M-H)- 344.1269, found
344.1257.
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Ethyl 2-([1,1'-biphenyl]-4-ylamino)-2-(diethoxyphosphoryl)acetate (3ca): Yield
65% (50.9 mg); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 7.52 (dd, J = 6.8 Hz,
J = 0.8 Hz, 2H), 7.45 (dd, J = 5.2 Hz, J = 1.6 Hz, 2H), 7.39 (t, J = 6.2 Hz, 2H),
7.29-7.26 (m, 1H), 6.76 (dd, J = 5.2 Hz, J = 1.6 Hz, 2H), 4.68 (brs, 1H), 4.56 (d, J =
18.4 Hz, 1H), 4.31-4.18 (m, 6H), 1.36 (t, J = 5.6 Hz, 3H), 1.33 (t, J = 5.6 Hz, 3H),
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1.29 (t, J = 5.6 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 168.4 (d, J = 1.6 Hz),
145.6 (d, J = 8.3 Hz), 140.9, 132.4, 128.7, 128.0, 126.5, 114.3, 64.2 (d, J = 4.7 Hz),
63.7 (d, J = 6.1 Hz), 62.4, 56.8 (d, J = 117.3 Hz), 20.5, 16.5 (d, J = 5.3 Hz), 16.4, 14.2;
HRMS (ESI) calcd for C20H27NO5P (M+H)+ 392.1621, found 392.1627.
Ethyl 2-((4-chlorophenyl)amino)-2-(diethoxyphosphoryl)acetate (3da):16 Yield
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41% (28.6 mg); light yellow solid; mp 80.2-81.5 °C; H NMR (400 MHz, CDCl3): δ
7.15 (dd, J = 9.2 Hz, J = 2.4 Hz, 2H), 6.61 (dd, J = 9.2 Hz, J = 2.4 Hz, 2H), 4.62 (brs,
1H), 4.45 (d, J = 18.0 Hz, 1H), 4.29-4.14 (m, 6H), 1.35 (t, J = 5.8 Hz, 3H), 1.32 (t, J =
5.8 Hz, 3H), 1.28 (t, J = 5.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.2 (d, J
= 1.6 Hz), 144.8 (d, J = 8.6 Hz), 129.2, 124.1, 115.1, 64.1 (d, J = 5.6 Hz), 63.7 (d, J =
5.4 Hz), 62.4, 56.4 (d, J = 118.9 Hz), 16.5 (d, J = 4.9 Hz), 16.4, 14.1; HRMS (ESI)
calcd for C14H20ClNO5P (M-H)- 348.0773, found 348.0767.
Ethyl 2-((4-bromophenyl)amino)-2-(diethoxyphosphoryl)acetate (3ea):16 Yield
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40% (31.4 mg); light yellow solid; mp 75.2-76.4 °C; H NMR (400 MHz, CDCl3): δ
7.27 (dd, J = 5.8 Hz, J = 1.4 Hz, 2H), 6.56 (dd, J = 5.6 Hz, J = 1.6 Hz, 2H), 4.65-4.62
(m, 1H), 4.44 (dd, J = 18.6 Hz, J = 7.2 Hz, 1H), 4.29-4.14 (m, 6H), 1.38-1.25 (m,
9H); 13C{1H} NMR (100 MHz, CDCl3): δ 168.1 (d, J = 1.5 Hz), 145.2 (d, J = 9.4 Hz),
132.1, 115.1, 111.3, 64.1 (d, J = 5.2 Hz), 63.7 (d, J = 5.4 Hz), 62.4, 56.8 (d, J = 118.0
Hz), 16.4 (d, J = 5.2 Hz), 16.3 (d, J = 5.0 Hz), 14.1; HRMS (ESI) calcd for
C14H20BrNO5P (M-H)- 392.0268, found 392.0258.
Methyl 2-(diethoxyphosphoryl)-2-(p-tolylamino)acetate (3fa): Yield 78% (49.2
mg); light yellow solid; mp 73.5-74.8 °C; 1H NMR (400 MHz, CDCl3): δ 7.00 (d, J =
6.8 Hz, 2H), 6.60 (d, J = 6.8 Hz, 2H), 4.50 (d, J = 18.8 Hz, 1H), 4.27-4.17 (m, 4H),
3.78 (s, 3H), 2.24 (s, 3H), 1.35 (t, J = 5.2 Hz, 3H), 1.32 (t, J = 5.2 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 169.5 (d, J = 2.4 Hz), 143.8 (d, J = 9.6 Hz), 129.9, 128.9,
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114.2, 64.1 (d, J = 4.7 Hz), 63.7 (d, J = 5.4 Hz), 56.6 (d, J = 119.0 Hz), 53.0, 20.4,
16.4 (d, J = 6.4 Hz), 16.3; HRMS (ESI) calcd for C14H23NO5P (M+H)+ 316.1308,
found 316.1311.
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Isopropyl 2-(diethoxyphosphoryl)-2-(p-tolylamino)acetate (3ga): Yield 61%
(41.9 mg); light yellow solid; mp 76.0-77.5 °C;1H NMR (400 MHz, CDCl3): δ 7.00
(d, J = 6.4 Hz, 2H), 6.60 (d, J = 6.0 Hz, 2H), 5.11-5.07 (m, 1H), 4.44 (d, J = 18.4 Hz,
1H), 4.25-4.20 (m, 4H), 2.24 (s, 3H), 1.35 (t, J = 5.4 Hz, 3H), 1.32 (t, J = 5.6 Hz, 3H),
1.27 (d, J = 5.2 Hz, 3H), 1.27 (d, J = 4.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3):
δ 168.0 (d, J = 2.0 Hz), 143.9 (d, J = 9.0 Hz), 129.8, 128.7, 114.3, 70.0, 64.0 (d, J =
6.2 Hz), 63.4 (d, J = 5.7 Hz), 56.9 (d, J = 118.1 Hz), 21.8, 21.6, 20.5, 16.5 (d, J = 4.1
Hz), 16.4 (d, J = 5.2 Hz); HRMS (ESI) calcd for C16H27NO5P (M+H)+ 344.1621,
found 344.1619.
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tert-Butyl 2-(diethoxyphosphoryl)-2-(p-tolylamino)acetate (3ha): Yield 67%
(47.9 mg); light yellow oil;1H NMR (400 MHz, CDCl3): δ 7.00 (d, J = 6.4 Hz, 2H),
6.61 (d, J = 6.0 Hz, 2H), 4.37 (d, J = 18.0 Hz, 1H), 4.26-4.12 (m, 4H), 2.24 (s, 3H),
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1.46 (s, 9H), 1.36 (t, J = 5.8 Hz, 3H), 1.31 (t, J = 5.6 Hz, 3H); C{1H} NMR (100
MHz, CDCl3): δ 167.4 (d, J = 1.3 Hz), 144.2 (d, J = 8.2 Hz), 129.8, 128.5, 114.2, 83.1,
63.9 (d, J = 5.9 Hz), 63.3 (d, J = 6.0 Hz), 57.5 (d, J = 119.2 Hz), 27.9, 20.5, 16.5 (d, J
= 4.4 Hz), 16.4 (d, J = 5.4 Hz); HRMS (ESI) calcd for C17H29NO5P (M+H)+
358.1778, found 358.1776.
Benzyl 2-(diethoxyphosphoryl)-2-(p-tolylamino)acetate (3ia): Yield 80% (62.6
mg); light yellow oil;1H NMR (400 MHz, CDCl3): δ 7.33-7.30 (m, 5H), 6.98 (d, J =
6.8 Hz, 2H), 6.59 (d, J = 6.8 Hz, 2H), 5.24-5.16 (m, 2H), 4.54 (d, J = 18.8 Hz, 1H),
4.23-4.06 (m, 4H), 2.23 (s, 3H), 1.26 (t, J = 5.6 Hz, 3H), 1.25 (t, J = 5.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 168.5 (d, J = 2.5 Hz), 143.8 (d, J = 10.0 Hz),
135.1, 129.9, 128.9, 128.5, 128.4, 114.3, 67.8, 64.3 (d, J = 6.1 Hz), 63.7 (d, J = 5.8
Hz), 62.2, 56.8 (d, J = 118.4 Hz), 20.5, 16.4 (d, J = 4.0 Hz), 16.3 (d, J = 3.9 Hz);
HRMS (ESI) calcd for C20H27NO5P (M+H)+ 392.1621, found 392.1621.
Ethyl 2-(dimethoxyphosphoryl)-2-(p-tolylamino)acetate (3ab): Yield 95% (57.2
mg); light yellow solid; mp 69.2-70.1 °C; 1H NMR (400 MHz, CDCl3): δ 7.01 (d, J =
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6.4 Hz, 2H), 6.61 (dd, J = 6.8 Hz, 2H), 4.52 (d, J = 19.2 Hz, 1H), 4.30-4.23 (m, 2H),
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3.86 (s, 3H), 3.84 (s, 3H), 2.24 (s, 3H), 1.28 (t, J = 6.4 Hz, 3H); C{1H} NMR (100
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MHz, CDCl3): δ 168.3 (d, J = 2.6 Hz), 143.7 (d, J = 9.4 Hz), 129.9, 129.0, 114.3, 62.4,
56.5 (d, J = 119.4 Hz), 54.5 (d, J = 4.6 Hz), 53.9 (d, J = 5.3 Hz), 20.5, 14.1; HRMS
(ESI) calcd for C13H19NO5P (M-H)- 300.1006, found 300.1003.
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Ethyl 2-(diisopropoxyphosphoryl)-2-(p-tolylamino)acetate (3ac): Yield 76%
1
(54.3 mg); light yellow solid; mp 67.9-68.6 °C; H NMR (400 MHz, CDCl3): δ 6.99
(d, J = 6.4 Hz, 2H), 6.59 (dd, J = 8.8 Hz, J = 2.0 Hz, 2H), 4.85-4.76 (m, 2H), 4.41 (d,
J = 19.2 Hz, 1H), 4.22 (q, J = 6.4 Hz, 2H), 2.23 (s, 3H), 1.36 (d, J = 5.2 Hz, 6H), 1.33
(d, J = 5.2 Hz, 3H), 1.30 (d, J = 5.2 Hz, 3H), 1.26 (t, J = 6.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 168.8 (d, J = 1.6 Hz), 144.1 (d, J = 10.6 Hz), 129.8, 128.6,
114.2, 72.9 (d, J = 6.3 Hz), 72.4 (d, J = 5.8 Hz), 61.9, 57.3 (d, J = 119.6 Hz), 24.3 (d,
J = 3.3 Hz), 24.0 (d, J = 2.9 Hz), 23.8 (d, J = 4.3 Hz), 23.7 (d, J = 3.5 Hz), 20.5, 14.1;
HRMS (ESI) calcd for C17H29NO5P (M+H)+ 358.1778, found 358.1776.
Ethyl 2-(dibutoxyphosphoryl)-2-(p-tolylamino)acetate (3ad): Yield 62% (47.8
1
mg); light yellow oil; H NMR (400 MHz, CDCl3): δ 6.99 (d, J = 6.4 Hz, 2H), 6.60
(dd, J = 8.8 Hz, J = 2.0 Hz, 2H), 4.48 (d, J = 18.8 Hz, 1H), 4.23 (d, J = 6.4 Hz, 2H),
4.19-4.05 (m, 4H), 2.23 (s, 3H), 1.71-1.61 (m, 4H), 1.46-1.28 (m, 4H), 1.26 (t, J = 5.6
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Hz, 3H), 0.96-0.89 (m, 6H); C{1H} NMR (100 MHz, CDCl3): δ 168.6 (d, J = 1.8
Hz), 143.9 (d, J = 10.1 Hz), 129.8, 128.7, 114.2, 67.7 (d, J = 6.1 Hz), 67.1 (d, J = 5.8
Hz), 65.5 (d, J = 5.1 Hz), 62.1, 56.7 (d, J = 118.7 Hz), 32.5 (d, J = 5.6 Hz), 32.4 (d, J
= 5.0 Hz), 20.4, 18.7, 18.6 (d, J = 1.4 Hz), 14.1, 13.5; HRMS (ESI) calcd for
C19H31NO5P (M-H)- 384.1945, found 384.1942.
Diethyl (2-(methylamino)-2-oxo-1-(p-tolylamino)ethyl)phosphonate (3ja): Yield
95% (59.7 mg); light yellow solid; mp 110.3-110.9 °C; 1H NMR (400 MHz, CDCl3):
δ 7.02 (d, J = 6.8 Hz, 2H), 6.94 (brs, 1H), 6.59 (d, J = 6.4 Hz, 2H), 4.72 (d, J = 6.0
Hz, 1H), 4.25-4.14 (m, 5H), 2.82 (d, J = 3.6 Hz, 3H), 2.25 (s, 3H), 1.34 (t, J = 6.4 Hz,
3H), 1.33 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.6, 144.1 (d, J
= 9.3 Hz), 129.9, 129.2, 114.1, 64.2 (d, J = 5.6 Hz), 63.6 (d, J = 5.3 Hz), 58.3 (d, J =
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112.8 Hz), 26.5, 20.4, 16.4, 16.3 (d, J = 6.4 Hz); HRMS (ESI) calcd for C14H24N2O4P
(M+H)+ 315.1468, found 315.1466.
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Diethyl (2-(ethylamino)-2-oxo-1-(p-tolylamino)ethyl)phosphonate (3ka): Yield
87% (57.1 mg); light yellow solid; mp 99.7-101.3 °C; 1H NMR (400 MHz, CDCl3): δ
7.01 (d, J = 6.8 Hz, 2H), 6.98 (brs, 1H), 6.59 (d, J = 6.4 Hz, 2H), 4.76 (brs, 1H),
4.25-4.15 (m, 5H), 3.34-3.27 (m, 2H), 2.24 (s, 3H), 1.34 (t, J = 5.8 Hz, 3H), 1.33 (t, J
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= 5.6 Hz, 3H), 1.10 (t, J = 5.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 166.8,
144.2 (d, J = 8.8 Hz), 129.8, 129.0, 114.1, 64.1 (d, J = 5.5 Hz), 63.6 (d, J = 6.4 Hz),
58.3 (d, J = 112.0 Hz), 34.6, 20.4, 16.4, 16.3 (d, J = 4.2 Hz), 14.6; HRMS (ESI) calcd
for C15H24N2O4P (M-H)- 327.1479, found 327.1482.
Diethyl (2-(benzylamino)-2-oxo-1-(p-tolylamino)ethyl)phosphonate (3la): Yield
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76% (59.3 mg); light yellow solid; mp 92.4-93.6 °C; H NMR (400 MHz, CDCl3): δ
7.29-7.29 (m, 6H), 7.01 (d, J = 6.8 Hz, 2H), 6.60 (d, J = 6.8 Hz, 2H), 4.55-4.38 (m,
2H), 4.24-4.12 (m, 5H), 2.26 (s, 3H), 1.31 (t, J = 5.6 Hz, 3H), 1.29 (t, J = 5.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 167.0, 144.1 (d, J = 8.7 Hz), 137.7, 129.9, 129.2,
128.6, 127.6, 127.4, 114.2, 64.1 (d, J = 5.7 Hz), 63.7 (d, J = 5.6 Hz), 58.4 (d, J =
112.8 Hz), 43.6, 20.4, 16.4 (d, J = 4.6 Hz), 16.3 (d, J = 5.2 Hz); HRMS (ESI) calcd
for C20H26N2O4P (M-H)- 389.1636, found 389.1638.
Diethyl (2-oxo-2-phenyl-1-(phenylamino)ethyl)phosphonate (3ma): Yield 91%
(63.2 mg); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 8.06 (dd, J = 6.0 Hz, 2H),
7.61 (t, J = 5.8 Hz, 1H), 7.50 (t, J = 6.2 Hz, 2H), 7.18 (t, J = 6.2 Hz, 2H), 6.79-6.76
(m, 3H), 5.56 (d, J = 17.2 Hz, 1H), 4.17-4.00 (m, 4H), 1.17 (t, J = 5.6 Hz, 3H), 1.14
(t, J = 5.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 194.6 (d, J = 2.0 Hz), 146.5
(d, J = 6.3 Hz), 135.5, 134.0, 129.4, 129.1, 128.6, 119.2, 114.3, 64.0 (d, J = 5.7 Hz),
63.7 (d, J = 5.9 Hz), 59.3 (d, J = 118.0 Hz),16.3 (d, J = 4.4 Hz), 16.2 (d, J = 5.4 Hz);
HRMS (ESI) calcd for C18H23NO4P (M+H)+ 348.1460, found 348.1460.
Diethyl (2-oxo-2-phenyl-1-(p-tolylamino)ethyl)phosphonate (3na): Yield 93%
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(67.1 mg); light yellow oil; H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 6.4 Hz, 2H),
7.60 (t, J = 6.0 Hz, 1H), 7.48 (t, J = 6.2 Hz, 2H), 6.98 (d, J = 6.4 Hz, 2H), 6.68 (d, J =
6.8 Hz, 2H), 5.52 (d, J = 17.6 Hz, 1H), 415-3.99 (m, 4H), 2.22 (s, 3H), 1.18 (t, J = 5.6
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Hz, 3H), 1.14 (t, J = 5.8 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 194.9, 144.2
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(d, J = 7.4 Hz), 135.6, 133.9, 129.9, 129.8, 129.1, 128.6, 114.6, 64.0 (d, J = 5.6 Hz),
63.7 (d, J = 5.5 Hz), 59.8 (d, J = 117.8 Hz), 20.5, 16.3 (d, J = 4.5 Hz), 16.2 (d, J = 4.9
Hz); HRMS (ESI) calcd for C19H25NO4P (M+H)+ 362.1515, found 362.1514.
Diethyl (1-((4-fluorophenyl)amino)-2-oxo-2-phenylethyl)phosphonate (3oa):
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Yield 92% (67.2 mg); light yellow oil; H NMR (400 MHz, CDCl3): δ 8.05 (dd, J =
6.4 Hz, J = 0.8 Hz, 2H), 7.63-7.60 (m, 1H), 7.50 (t, J = 6.0 Hz, 2H), 6.88 (t, J = 7.0
Hz, 2H), 6.73-6.70 (m, 2H), 5.48 (d, J = 17.6 Hz, 1H), 4.14-3.99 (m, 4H), 1.17 (t, J =
5.6 Hz, 3H), 1.15 (t, J = 5.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 194.6 (d, J
= 2.2 Hz), 156.7 (d, J = 188.4 Hz), 142.8 (d, J = 7.2 Hz), 135.5, 134.1, 129.1, 128.6,
115.8 (d, J = 17.3 Hz), 115.5 (d, J = 5.6 Hz), 64.0 (d, J = 5.9 Hz), 63.8 (d, J = 5.9 Hz),
60.0 (d, J = 117.7 Hz), 16.2 (d, J = 5.1 Hz), 16.1 (d, J = 5.5 Hz); HRMS (ESI) calcd
for C18H20FNO4P (M-H)- 364.1120, found 364.1117.
Diethyl (1-((4-chlorophenyl)amino)-2-oxo-2-phenylethyl)phosphonate (3pa):
Yield 90% (68.6 mg); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 5.6
Hz, 2H), 7.62 (t, J = 5.8 Hz, 1H), 7.50 (t, J = 6.2 Hz, 2H), 7.12 (d, J = 6.8 Hz, 2H),
6.69 (d, J = 7.2 Hz, 2H), 5.49 (d, J = 17.6 Hz, 1H), 5.11 (brs, 1H), 4.13-3.99 (m, 4H),
1.16 (t, J = 5.6 Hz, 3H), 1.14 (t, J = 5.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
194.2 (d, J = 1.5 Hz), 145.0 (d, J = 6.6 Hz), 135.4, 134.1, 129.2, 129.1, 128.6, 123.8,
115.4, 63.9 (d, J = 5.9 Hz), 63.8 (d, J = 6.1 Hz), 59.3 (d, J = 118.3 Hz), 16.2 (d, J =
5.5 Hz), 16.3 (d, J = 4.0 Hz); HRMS (ESI) calcd for C18H22ClNO4P (M+H)+
382.0970, found 382.0966.
Diethyl (2-oxo-2-(p-tolyl)-1-(p-tolylamino)ethyl)phosphonate (3qa): Yield 83%
1
(62.3 mg); light yellow solid; mp 123.8-124.9 °C; H NMR (400 MHz, CDCl3): δ
7.96 (d, J = 6.8 Hz, 2H), 7.28 (t, J = 6.4 Hz, 2H), 6.97 (d, J = 6.4 Hz, 2H), 6.67 (d, J =
6.8 Hz, 2H), 5.49 (d, J = 17.6 Hz, 1H), 4.15-4.00 (m, 4H), 2.42 (s, 3H), 2.21 (s, 3H),
1.19 (t, J = 5.6 Hz, 3H), 1.16 (t, J = 6.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
194.2 (d, J = 1.4 Hz), 145.0, 144.3 (d, J = 7.5 Hz), 133.1, 129.8, 129.3, 128.5, 114.5,
63.9 (d, J = 5.5 Hz), 63.7 (d, J = 5.6 Hz), 59.6 (d, J = 117.8 Hz), 21.8, 20.4, 16.3 (d, J
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= 5.1 Hz), 16.2 (d, J = 4.0 Hz); HRMS (ESI) calcd for C20H27NO4P (M+H)+
376.1672, found 376.1675.
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Diethyl (2-(4-methoxyphenyl)-2-oxo-1-(p-tolylamino)ethyl)phosphonate (3ra):
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1
Yield 79% (61.8 mg); light yellow solid; mp 77.8-78.2 °C; H NMR (400 MHz,
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CDCl3): δ 8.06 (d, J = 5.6 Hz, J = 1.2 Hz, 2H), 6.98 (t, J = 6.8 Hz, 2H), 6.96 (d, J =
5.6 Hz, J = 1.2 Hz, 2H), 6.67 (d, J = 6.8 Hz, 2H), 5.45 (d, J = 17.2 Hz, 1H), 4.19-4.02
(m, 4H), 3.88 (s, 3H), 2.22 (s, 3H), 1.20 (t, J = 5.6 Hz, 3H), 1.18 (t, J = 5.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 192.8 (d, J = 1.7 Hz), 164.2, 144.4 (d, J = 7.5
Hz), 131.6, 129.8, 128.5, 128.4, 114.5, 113.7, 63.9 (d, J = 6.0 Hz), 63.6 (d, J = 6.0
Hz), 59.4 (d, J = 118.4 Hz), 55.6, 20.4, 16.3 (d, J = 5.5 Hz), 16.2 (d, J = 5.1 Hz);
HRMS (ESI) calcd for C20H27NO5P (M+H)+ 392.1621, found 392.1625.
Diethyl (2-(4-fluorophenyl)-2-oxo-1-(p-tolylamino)ethyl)phosphonate (3sa):
1
Yield 77% (58.4 mg); light yellow oil; H NMR (400 MHz, CDCl3): δ 8.12-8.09 (m,
2H),7.15 (t, J = 6.8 Hz, 2H), 6.98 (d, J = 6.8 Hz, 2H), 6.67 (d, J = 6.8 Hz, 2H), 5.45
(d, J = 17.6 Hz, 1H), 4.16-4.03 (m, 4H), 2.22 (s, 3H), 1.20 (t, J = 5.8 Hz, 3H), 1.17 (t,
J = 5.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 193.3 (d, J = 1.2 Hz), 166.2 (d,
J = 204.4 Hz), 144.2 (d, J = 7.2 Hz), 132.0, 131.9 (d, J = 6.6 Hz), 129.9, 128.7, 115.7
(d, J = 7.1 Hz), 114.5, 64.1 (d, J = 5.7 Hz), 63.8 (d, J = 6.1 Hz), 59.8 (d, J = 117.6
Hz), 20.4, 16.3 (d, J = 3.9 Hz), 16.2 (d, J = 4.7 Hz); HRMS (ESI) calcd for
C19H22FNO4P (M+H)+ 378.1276, found 378.1272.
Diethyl (2-(4-chlorophenyl)-2-oxo-1-(p-tolylamino)ethyl)phosphonate (3ta):
Yield 81% (64.0 mg); light yellow oil; 1H NMR (400 MHz, CDCl3): δ 8.01 (d, J = 6.8
Hz, 2H), 7.46 (d, J = 7.2 Hz, 2H), 6.98 (d, J = 6.8 Hz, 2H), 6.66 (d, J = 6.4 Hz, 2H),
5.45 (d, J = 18.0 Hz, 1H), 4.17-4.04 (m, 4H), 2.22 (s, 3H), 1.21 (t, J = 5.8 Hz, 3H),
13
1.18 (t, J = 5.6 Hz, 3H); C{1H} NMR (100 MHz, CDCl3): δ 193.8 (d, J = 1.1 Hz),
144.0 (d, J = 7.8 Hz), 140.5, 133.9, 130.5, 129.9, 128.9, 128.8, 114.5, 64.1 (d, J = 5.9
Hz), 63.8 (d, J = 5.9 Hz), 59.9 (d, J = 117.2 Hz), 20.4, 16.3 (d, J = 4.9 Hz), 16.2 (d, J
= 4.1 Hz); HRMS (ESI) calcd for C19H24ClNO4P (M+H)+ 396.1126, found 396.1120.
Diethyl (2-(4-bromophenyl)-2-oxo-1-(p-tolylamino)ethyl)phosphonate (3ua):
1
Yield 89% (78.2 mg); light yellow solid; mp 103.2-104.6 °C; H NMR (400 MHz,
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CDCl3): δ 7.93 (dd, J = 5.6 Hz, J = 1.6 Hz, 2H), 7.63 (d, J = 6.8 Hz, 2H), 6.98 (d, J =
6.8 Hz, 2H), 6.65 (d, J = 6.8 Hz, 2H), 5.43 (d, J = 17.6 Hz, 1H), 4.17-4.03 (m, 4H),
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8
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2.22 (s, 3H), 1.21 (t, J = 5.8 Hz, 3H), 1.18 (t, J = 5.6 Hz, 3H); C{1H} NMR (100
9
MHz, CDCl3): δ 194.1 (d, J = 2.3 Hz), 144.1 (d, J = 7.9 Hz), 134.3, 131.9, 130.6,
129.9, 129.3, 128.8, 114.5, , 64.1 (d, J = 5.5 Hz), 63.8 (d, J = 5.4 Hz), 59.9 (d, J =
117.8 Hz), 20.4, 16.3 (d, J = 4.7 Hz), 16.2 (d, J = 4.7 Hz); HRMS (ESI) calcd for
C19H24BrNO4P (M+H)+ 440.0621, found 440.0616.
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ASSOCIATED CONTENT
Supporting Information
Optimization of reaction conditions, 1H NMR and 13C NMR spectra of all products. This material is available free
of charge via the internet at http://pubs.acs.org.).
AUTHOR INFORMATION
Corresponding Author
*E-mail: zhqzhu@hotmail.com; zhuzq@ecit.edu. cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (21602027, 11765003), the Natural Science
Foundation of Jiangxi Province (20171BAB213006), the Foundation of Jiangxi Educational Committee
(GJJ170458), the China Postdoctoral Science Foundation (2018M632595) and the Scientific Research Foundation
of East China University of Technology (DHBK2016112) for financial support.
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