Direct Aminophosphonylation of aldehydes catalyzed by cyclopentadienyl ruthenium(II) complexes

Article abstract of DOI:10.1016/j.tet.2018.02.047

This work reports a novel method for the direct aminophosphonylation of aldehydes catalyzed by cyclopentadienyl ruthenium(II) complexes. The system HP(O)(OEt)₂/[CpRu(PPh₃)₂Cl] was very efficient for the aminophosphonylatio

Full text of DOI:10.1016/j.tet.2018.02.047

Accepted Manuscript
Direct Aminophosphonylation of aldehydes catalyzed by cyclopentadienyl
ruthenium(II) complexes
Ivânia R. Cabrita, Sara C.A. Sousa, Pedro R. Florindo, Ana C. Fernandes
PII:
S0040-4020(18)30192-3
10.1016/j.tet.2018.02.047
TET 29318
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 December 2017
Revised Date: 5 February 2018
Accepted Date: 20 February 2018
Please cite this article as: Cabrita IvâR, Sousa SCA, Florindo PR, Fernandes AC, Direct
Aminophosphonylation of aldehydes catalyzed by cyclopentadienyl ruthenium(II) complexes,
Tetrahedron (2018), doi: 10.1016/j.tet.2018.02.047.
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ACCEPTED MANUSCRIPT
Graphical abstract
Direct Aminophosphonylation of Aldehydes Catalyzed by Cyclopentadienyl
Ruthenium(II) Complexes
Ivânia R. Cabrita, Sara C. A. Sousa, Pedro R. Florindo and Ana C. Fernandes

ACCEPTED MANUSCRIPT
Aminophosphonylation of Aldehydes
Cyclopentadienyl Ruthenium(II) Complexes
Direct
Catalyzed
by
Ivânia R. Cabrita, Sara C. A. Sousa, Pedro R. Florindo and Ana C. Fernandes*
Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av.
Rovisco Pais, 1049-001 Lisboa, Portugal, Tel: 351 218419264; Fax: 351 218464455,
anacristinafernandes@tecnico.ulisboa.pt
Abstract: This work reports a novel method for the direct aminophosphonylation of
aldehydes catalyzed by cyclopentadienyl ruthenium(II) complexes. The system
HP(O)(OEt)2/[CpRu(PPh3)2Cl] was very efficient for the aminophosphonylation of
aldehydes with primary and secondary amines, producing the corresponding α-
aminophosphonates in good to excellent yields. This novel method has several
advantages including the use of a small amount of catalyst (0.5 mol%), high
chemoselectivity, solvent-free conditions and application of the catalyst
[CpRu(PPh3)2Cl] for at least 12 cycles with excellent activity.
Keywords: aminophosphonylation, aldehydes, α-aminophosphonates, ruthenium
complexes
1.Introduction
α-Aminophosphonates and α-aminophosphonic acids1 are structurally analogous to α-
amino acids and constitute an important class of compounds with diverse biological
activities and potential to be employed as enzyme inhibitors,2,3 antibiotics,4 and
antitumor agents.5,6 They also have a wide range of antiviral7 and antifungal properties
and are extensively used as insecticides and herbicides.8 Thus, a number of methods
have been developed for the synthesis of α-aminophosphonates both in racemic and in
optically active forms.9-15 Among the available synthetic methods for α-
aminophosphonates, the three-component reaction of aldehyde, amine, and phosphite,
also known as Kabachnik–Fields reaction, has gained much attention due to its one-pot
manner and convenience of synthesis of these compounds.16,17 Different catalysts have
been employed for the synthesis of α-aminophosphonates including SnCl2.2H2O,18
1

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ZnBr2,19 HfCl4,20 lanthanide triflate,21 Yb(PFO)3,22 SmI2,23 TaCl5,24 Cd(ClO4)2ꢀxH2O,25
28
BiCl3,26 LiClO4,27 FeCl3 or MoO2Cl2.29 In the last years, several methods for the
synthesis of α-aminophosphonates have also been developed using microwaves
radiations.30-34 However, the use of ruthenium complexes as catalysts for the synthesis
of α-aminophosphonates has never been studied. In this work we reported the first
method for the synthesis of -aminophosphonates with high yields catalyzed by
cyclopentadienyl ruthenium(II) complexes.
2.Results and discussion
The catalytic activity of several cyclopentadienyl ruthenium(II) complexes was
evaluated in the aminophosphonylation of 4-(methylthio)benzaldehyde with aniline and
HP(O)(OEt)2 under solvent-free conditions in air atmosphere (Table 1). All the catalysts
were very efficient, producing the α-aminophosphonate in excellent yields. The best
result (95%) was obtained in the presence of 0.5 mol% of [CpRu(PPh3)2Cl] after 15 min
(Table 1, entry 1). Using 0.25 mol% of this catalyst the reaction required 1h and the α-
aminophosphonate was isolated in only 51% yield (Table 1, entry 2). The reaction
carried out at room temperature afforded the product in only 42% yield after 24 h (Table
1, entry 3). The catalysts [CpRu(PPh3)(2,2′-bipy)][PF6] 2, [CpRu(dppe)Cl] 3 and
[CpRu(PPh3)(phen)][PF6] 4 were also very efficient, giving excellent yields of α-
aminophosphonate (Table 1, entries 4-6). The reactions carried out with the complexes
containing a carbohydrate moiety derived from xylose and fructose also produced
excellent yields of the product (Table 1, entries 7 and 8). Finally, in the absence of
catalyst only 19% of product was obtained after 1 h (Table 1, entry 9).
Fig. 1. Structure of catalysts 1-6.
2

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Table 1
Direct aminophosphonylation of aldehydes catalyzed by CpRu(II) complexesa
Catalyst Temp. (ºC)
Yield
(%)b
95
Entry Catalyst
Time
(mol%)
1
2
3
4
5
6
7
8
9
[CpRu(PPh3)2Cl] 1
0.5
0.25
0.5
0.5
0.5
0.5
80
80
r.t.
80
80
80
80
80
80
15 min
1 h
[CpRu(PPh3)2Cl] 1
51
42
94
93
91
95
92
19
[CpRu(PPh3)2Cl] 1
24 h
[CpRu(PPh3)(2,2′-bipy)][PF6] 2
[CpRu(dppe)Cl] 3
30 min
40 min
50 min
40 min
20 min
1 h
[CpRu(PPh3)(phen)][PF6] 4
[CpRu(PPh3)2(NCXylAc)][PF6] 5 0.5
[CpRu(PPh3)2(Fru)][PF6] 6
0.5
Without catalyst
−
a All reactions were carried out with 2.0 mmol of 4-(methylthio)benzaldehyde, 2.0 mmol of aniline and
2.0 mmol of HP(O)(OEt)2.
b Isolated yields
Aminophosphonylation of 4-(methylthio)benzaldehyde with aniline catalyzed by
[CpRu(PPh3)2Cl] (0.5 mol%) was investigated with the H-phosphonates HP(O)(OEt)2,
HP(O)(OMe)2, HP(O)(OBu)2 and HP(O)(OPh)2 under solvent-free conditions at 80 ºC
in air atmosphere (Table 2). Although all H-phosphonates afforded the α-
aminophosphates in excellent yields, the reaction with HP(O)(OEt)2 was much faster,
requiring only 15 minutes (Table 2, entry 1). In contrast, the reaction performed with
HP(O)(OPh)2 needed 24 h to be completed (Table 2, entry 4).
3

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Table 2
Direct aminophosphonylation of 4-(methylthio)benzaldehyde with aniline catalyzed by
a
[CpRu(PPh3)2Cl] using different HP(O)(OR)2
b
Entry
1
HP(O)(OR)2
HP(O)(OEt)2
Product
Time
Yield (%)
95
15 min
2
3
4
HP(O)(OMe)2
HP(O)(OBu)2
HP(O)(OPh)2
25 min
94
94
94
1 h
24 h
a The reactions were carried out with 2.0 mmol of 4-(methylthio)benzaldehyde, 2.0 mmol
aniline and 2.0 mmol of HP(O)(OR)2.
b Isolated yields.
To evaluate the efficiency of the system HP(O)(OEt)2/[CpRu(PPh3)2Cl] (0.5
mol%), it was tested in the direct aminophosphonylation of a large variety of aldehydes
with aniline under solvent-free conditions at 80 ºC in air atmosphere (Table 3). In
general, the reactions were very fast, affording the corresponding α-aminophosphonates
in good to excellent yields, with high chemoselectivity, tolerating several functional
groups such as -OCH3, -SCH3, -F, -Br, -CF3, -OH, -CO2R, and heterocyclic or Cp rings.
4

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Table 3
Direct
aminophosphonylation
of
aldehydes
with
the
system
HP(O)(OEt)2/[CpRu(PPh3)2Cl]a
b
Entry
1
Aldehyde
Product
Time
Yield (%)
97
20 min
2
3
15 min
35 min
95
95
4
30 min
95
5
6
30 min
20 min
94
92
7
O
20 min
91
H
5

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8
40 min
80
9
2 h
75
98
10
1.5 h
a The reactions were carried out with 2.0 mmol of aldehyde, 2.0 mmol aniline and 2.0 mmol
of HP(O)(OEt)2.
b Isolated yields.
Direct aminophosphonylation of 4-(methylthio)benzaldehyde was also explored
using different anilines containing electron-donating and electron-withdrawing groups
with the system HP(O)(OEt)2/[CpRu(PPh3)2Cl] (0.5 mol%) producing the
corresponding α-aminophosphonates in excellent yields (Table 4).
Table 4
Direct aminophosphonylation of 4-(methylthio)benzaldehyde with different anilines
using the system HP(O)(OEt)2/[CpRu(PPh3)2Cl]a
R
HN
O
NH2
[CpRu(PPh3)2Cl] (0.5 mol%), HP(O)(OEt)2
solvent free conditions, 80 ºC
P(OEt)2
O
H
+
R
H3CS
H3CS
b
Entry
Aniline
Product
Time
Yield (%)
99
1
2
10 min
15 min
95
6

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3
4
15 min
95
75
30 min
1h 30 min
85
5
a The reactions were carried out with 2.0 mmol of 4-(methylthio)benzaldehyde, 2.0 mmol
aniline and 2.0 mmol of HP(O)(OEt)2.
b Isolated yields.
Finally, the direct aminophosphonylation of different aldehydes using methyl-N-
aniline with the system HP(O)(OEt)2/[CpRu(PPh3)2Cl] (0.5 mol%) was studied,
obtaining the corresponding tertiary α-aminophosphonates in good to excellent yields.
Table 5
Direct aminophosphonylation of aldehydes with methyl-N-aniline using the system
HP(O)(OEt)2/[CpRu(PPh3)2Cl]a
b
Entry
1
Aldehyde
Product
Time (h)
2
Yield (%)
94
2
2
79
7

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3
4
2.5
70
73
3
5
3
70
a The reactions were carried out with 2.0 mmol of aldehyde, 2.0 mmol methyl-N-aniline and 2.0 mmol of
HP(O)(OEt)2.
b Isolated yields.
To study the possible use of the complex [CpRu(PPh3)2Cl] (0.5 mol%) as
catalyst in multiple cycles, successive reactions were carried out by sequential addition
of fresh substrate 4-(methylthio)benzaldehyde, aniline and HP(O)(OEt)2 to the reaction
mixture. The results showed that [CpRu(PPh3)2Cl] can be used for at least 12 catalytic
cycles with excellent yields (Figure 2).
O
HN
[CpRu(PPh3)2Cl] (0.5 mol%), HP(O)(OEt)2
solvent free conditions, 80 ºC, 15 min
NH2
H
P(OEt)2
+
H3CS
O
H3CS
100
80
60
40
20
0
88
89
86
95
91
96
93
90
85
96
92
86
1
2
3
4
5
6
7
8
9
10 11 12
Catalytic cycle
Fig 2. Use of the complex [CpRu(PPh3)2Cl] as catalyst in multiple cycles. The reactions were carried out
by successive addition of 4-(methylthio)benzaldehyde (1 mmol), aniline (1 mmol) and HP(O)(OEt)2 (2
mmol). Yields were determined by 1H NMR spectroscopy, using mesitylene as an internal standard.
8

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Aminophosphonylation of aldehydes catalyzed by cyclopentadienyl ruthenium
complexes should start with the formation of the imine by reaction between the
aldehyde and aniline. Then, the activation of the H-phosphonate by the catalyst
[CpRu(PPh3)2Cl] should occur, producing the species [CpRu(PPh3)Cl(PO)(OEt)2]-,
detected by mass spectrometry. Finally, the reaction between this species and the imine
lead to the formation of α-aminophosphonate.
3.Conclusions
In this work it has been demonstrated that the system HP(O)(OEt)2/[CpRu(PPh3)2Cl]
(0.5 mol%) is very efficient for the aminophosphonylation of a large variety of
aldehydes with different anilines under solvent-free conditions. This is the first example
of aminophosphonylation of aldehydes catalyzed by a ruthenium complex. This method
is highly chemoselective, tolerating a large range of functional groups including -SCH3,
-OCH3, -F, -Br, -CF3, -OH, CO2CH3, and heterocyclic or Cp rings.
The reactions were performed with a small amount of catalyst (0.5 mol%), with high
yields and short reaction times, and the complex [CpRu(PPh3)2Cl] can be used for at
least 12 cycles with excellent activity. This work extends the use of CpRu(II)
complexes as efficient catalysts for C-P bond forming reactions.
4 . Experimental Section
4.1 General information
Aldehydes, anilines and H-phosphonates were obtained from commercial suppliers and
were used without further purification. The catalysts [CpRu(PPh3)2Cl],35
[CpRu(PPh3)(2,2′-bipy)][PF6],36
[CpRu(dppe)Cl],35
[CpRu(PPh3)(phen)][PF6]37
[CpRu(PPh3)2(NCXylAc)][PF6],38 and [CpRu(PPh3)2(Fru)][PF6]39 were prepared
according to literature procedures. Flash chromatography was performed on MN
Kieselgel 60M 230-400 mesh. 1H NMR, 13C NMR and 31P NMR spectra were measured
on a Bruker Avance II+ 400 MHz and 300 MHz spectrometers. Chemical shifts are
reported in parts per million (ppm) downfield from an internal standard. Microanalyses
were performed at Laboratório de Análises do Instituto Superior Técnico, using a Fisons
Instruments EA1108 system and data acquisition, integration and handling were
performed using the software package Eager-200 (Carlo Erba Instruments).
9

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4.2. General Procedure for Direct Aminophosphonylation of Aldehydes with
HP(O)(OEt)2/[CpRu(PPh3)2Cl]
The mixture of aldehyde (2 mmol), aniline (2 mmol) and [CpRu(PPh3)2Cl] (0.5 mol%,
0.073 g) was stirred during 5 minutes at room temperature. To this mixture was added
HP(O)(OEt)2 (2.0 mmol, 0.26 mL) and the reaction mixture was stirred at 80 °C under
air atmosphere (the reaction times are indicated in Tables 3-5). The progress of the
1
reaction was monitored by TLC and H NMR spectroscopy. When the reaction is
complete, water (3.0 mL) was added and the mixture was stirred at 80 °C. After 1 hour,
the reaction mixture was cooled to ambient temperature and extracted with ethyl acetate
(2×10.0 mL). The combined organic layers were dried over Na2SO4, filtered and the
solvent removed under reduced pressure. The residue was purified by flash
chromatography with n-hexane:ethyl acetate (3:1) to afford the α-aminophosphonates,
which are known compounds.20,22,27
4.3. NMR characterization of products
1
Table 2, entry 1: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.38 (d, J = 8.0 Hz, 2H,
H-arom), 7.20 (d, J = 8.0 Hz, 2H, H-arom), 7.09 (t, J = 8.0 Hz, 2H, H-arom), 6.68 (t,
J = 8.0 Hz, 1H, H-arom), 6.58 (d, J = 8.0 Hz, 2H, H-arom), 4.98 (s, 1H, NH), 4.75 (d,
J = 24.0 Hz, 1H, CH), 4.17-4.06 (m, 2H, OCH2CH3), 3.99-3.93 (m, 1H, OCH2CH3),
3.77-3.71 (m, 1H, OCH2CH3), 2.43 (s, 3H, SCH3), 1.27 (t, J = 4.0, 8.0 Hz, 3H,
13
OCH2CH3), 1.14 (t, J = 8.0 Hz, 3H, OCH2CH3) ppm. C NMR (101 MHz, CDCl3) δ
146.29 (d, J = 15.15 Hz, Cq), 138.26 (d, J = 4.04 Hz, Cq), 132.65 (d, J = 3.03 Hz, Cq),
129.21 (s, CH-arom), 128.34 (d, J = 6.06 Hz, CH-arom), 126.61 (d, J = 3.03 Hz,
CH-arom), 118.52 (s, CH-arom), 113.94 (s, CH-arom), 63.43 (t, J = 6.06, 7.07 Hz,
OCH2CH3), 55.66 (d, J = 152.51 Hz, CH), 16.47 (d, J = 6.06 Hz, OCH2CH3), 16.28 (d,
31
J = 6.06 Hz, OCH2CH3), 15.67 (s, SCH3) ppm. P NMR (162 MHz, CDCl3) δ 22.77
ppm. Anal. Calcd. for C18H24NO3PS: C, 59.16; H, 6.62; N, 3.83. Found: C, 59.07; H,
6.50; N, 3.69.
1
Table 2, entry 2: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.41 (d, J = 8.0 Hz, 2H,
H-arom), 7.24 (d, J = 8.0 Hz, 2H, H-arom), 7.14 (t, J = 8.0 Hz, 2H, H-arom), 6.74 (t,
J = 4.0, 8.0 Hz, 1H, H-arom), 6.61 (d, J = 8.0 Hz, 2H, H-arom), 4.79 (d, J = 20.0 Hz,
2H, NH, CH), 3.80 (d, J = 12.0 Hz, 3H, OCH3), 3.55 (d, J = 8.0 Hz, 3H, OCH3), 2.48 (s,
3H, SCH3) ppm. 13C NMR (101 MHz, CDCl3) δ 146.9 (d, J = 15.15 Hz, Cq), 138.55 (d,
J = 4.04 Hz, Cq), 132.39 (d, J = 3.03 Hz, Cq), 129.32 (s, CH-arom), 128.32 (d, J = 5.05
10

ACCEPTED MANUSCRIPT
Hz, CH-arom), 126,72 (d, J = 2.02 Hz, CH-arom), 118.77 (s, CH-arom), 114.01 (s,
CH-arom), 55.36 (d, J = 152.51 Hz, CH), 53.99 (d, J = 4.04 Hz, OCH3), 53.92 (d,
31
J = 4.04 Hz, OCH3), 15.67 (s, SCH3) ppm. P NMR (162 MHz, CDCl3) δ 25.22 ppm.
Anal. Calcd. for C16H20NO3PS: C, 56.96; H, 5.98; N, 4.15. Found: C, 56.79; H, 5.83; N,
4.01.
1
Table 2, entry 3: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.38 (d, J = 8.0 Hz, 2H,
H-arom), 7.20 (d, J = 8.0 Hz, 2H, H-arom), 7.10 (t, J = 8.0 Hz, 2H, H-arom), 6.69 (t,
J = 8.0 Hz, 1H, H-arom), 6.57 (d, J = 8.0 Hz, 2H, H-arom), 4.78-4.67 (m, 2H, CH+NH),
4.10-3.98 (m, 2H, OCH2CH2CH2CH3), 3.94-3.87 (m, 1H, OCH2CH2CH2CH3), 3.71-
3.63 (m, 1H, OCH2CH2CH2CH3), 2.44 (s, 3H, SCH3), 1.62-1.58 (m, 2H,
OCH2CH2CH2CH3), 1.48-1.44 (m, 2H, OCH2CH2CH2CH3), 1.38-1.32 (m, 2H,
OCH2CH2CH2CH3), 1.27-1.21 (m, 2H, OCH2CH2CH2CH3), 0.89 (t, J = 8.0 Hz, 3H,
13
OCH2CH2CH2CH3), 0.84 (t, J = 8.0 Hz, 3H, OCH2CH2CH2CH3) ppm. C NMR (101
MHz, CDCl3) δ 146.35 (d, J = 15.15 Hz, Cq), 138.21 (d, J = 4.04 Hz, Cq), 132.89 (d,
J = 3.03 Hz, Cq), 129.27 (s, CH-arom), 128.37 (d, J = 5.05 Hz, CH-arom), 126.70 (d,
J = 3.03 Hz, CH-arom), 118.54 (s, CH-arom), 113.94 (s, CH-arom), 67.09 (d, J = 7.07
Hz, OCH2CH2CH2CH3), 66.08 (d, J = 8.08 Hz, OCH2CH2CH2CH3), 55.70 (d,
J = 151.50 Hz, CH), 32.64 (d, J = 5.05 Hz, OCH2CH2CH2CH3), 32.47 (d, J = 5.05 Hz,
OCH2CH2CH2CH3), 18.71 (d, J = 10.10 Hz, OCH2CH2CH2CH3), 15.80 (s, SCH3),
13.66 (d, J = 5.05 Hz, OCH2CH2CH2CH3) ppm. 31P NMR (162 MHz, CDCl3) δ 22.76
ppm. Anal. Calcd. for C22H32NO3PS: C, 62.68; H, 7.65; N, 3.32. Found: C, 62.55; H,
7.57; N, 43.29.
Table 2, entry 4: Beige solid. 1H NMR (CDCl3, 400 MHz) δ 7.45 (dd, J = 4.0, 8.0 Hz,
2H, H-arom), 7.26-7.19 (m, 6H, H-arom), 7.17-7.07 (m, 6H, H-arom), 6.90 (d, J = 8.0
Hz, 2H, H-arom), 6.74 (t, J = 4.0, 8.0 Hz, 1H, H-arom), 6.62 (d, J = 8.0 Hz, 2H,
H-arom), 5.10 (dd, J = 8.0, 16.0 Hz, 1H, CH), 4.92 (t, J = 8.0 Hz, 1H, NH), 2.43 (s, 3H,
13
SCH3) ppm. C NMR (101 MHz, CDCl3) δ 150.47 (d, J = 10.10 Hz, Cq), 150.29 (d,
J = 10.10 Hz, Cq), 145.88 (d, J = 5.05 Hz, Cq), 138.99 (d, J = 3.03 Hz, Cq), 129.83 (d,
J = 8.08 Hz, Cq), 129.40 (s, CH-arom), 128.67 (s, CH-arom), 126.87 (d, J = 3.03 Hz,
CH-arom), 120.77 (d, J = 4.04 Hz, CH-arom), 120.43 (s, CH-arom), 114.18 (s,
31
CH-arom), 55.87 (d, J = 144.54 Hz, CH), 15.76 (s, SCH3) ppm. P NMR (162 MHz,
CDCl3) δ 15.43 ppm. Anal. Calcd. for C26H24NO3PS: C, 67.66; H, 5.24; N, 3.03. Found:
C, 67.50; H, 5.19; N, 2.93.
11

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Table 3, entry 122: Beige solid. 1H NMR (CDCl3, 400 MHz) δ 7.38 (d, J = 8.0 Hz, 2H,
H-arom), 7.09 (t, J = 8.0 Hz, 2H, H-arom), 6.85 (d, J = 8.0 Hz, 2H, H-arom), 6.67 (t,
J = 4.0, 8.0 Hz, 1H, H-arom), 6.59 (d, J = 8.0 Hz, 2H, H-arom), 4.81 (brs, 1H, NH),
4.70 (d, J = 24.0 Hz, 1H, CH), 4.15-4.07 (m, 2H, OCH2CH3), 3.99-3.89 (m, 1H,
OCH2CH3), 3.75-3.66 (m, 4H, OCH2CH3+OCH3), 1.27 (t, J = 4.0, 8.0 Hz, 3H,
OCH2CH3), 1.13 (t, J = 4.0, 8.0 Hz, 3H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3)
δ 159.39 (d, J = 3.03 Hz, Cq), 146,46 (d, J = 15.15 Hz, Cq), 129.22 (s, CH-arom),
129.04 (d, J = 6.06 Hz, CH-arom), 127.78 (d, J = 3.03 Hz, Cq), 118.42 (s, CH-arom),
114.14 (d, J = 3.03 Hz, CH-arom),113.97 (s, CH-arom), 63.32 (d, J = 4.04 Hz,
OCH2CH3), 63.25 (d, J = 4.04 Hz, OCH2CH3), 55.45 (d, J = 153.52 Hz, CH), 55.30 (s,
31
OCH3), 16.53 (d, J = 6.06 Hz, OCH2CH3), 16.35 (d, J = 6.06 Hz, OCH2CH3) ppm. P
NMR (162 MHz, CDCl3) δ 23.29 ppm. Anal. Calcd. for C18H24NO4P: C, 61.88; H, 6.92;
N, 4.01. Found: C, 61.02; H, 6.89; N, 3.94.
1
Table 3, entry 321: Beige solid. H NMR (CDCl3, 400 MHz) δ: 7.45 (dd, J = 4.0 Hz,
J = 8.0 Hz, 2H, H-arom), 7.11 (t, J = 8.0 Hz, 2H, H-arom), 7.02 (t, J = 8.0 Hz, 2H,
H-arom), 6.70 (d, J = 4.0, 8.0 Hz, 1H, H-arom), 6.57 (d, J = 8.0 Hz, 2H, H-arom), 4.74
(d, J = 24.0 Hz, 1H, CH), 4.47 (brs, 1H, NH), 4.14-4.08 (m, 4H, OCH2CH3), 3.98-3.94
(m, 1H, OCH2CH3), 3.78-3.72 (m, 1H, OCH2CH3), 1.28 (t, J = 8.0 Hz, 3H, OCH2CH3),
1.14 (t, J = 4.0, 8.0 Hz, 3H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3) δ 163.74 (d,
J = 4.04 Hz, Cq), 161.32 (t, J = 8.08, 4.04 Hz, Cq), 146.20 (d, J = 15.15 Hz, Cq),
131.75 (t, J = 3.03 Hz, Cq), 129.53 (t, J = 3.03, 6.06 Hz, CH-arom), 129.37 (d,
J = 15.15 Hz, CH-arom), 118.67 (s, CH-arom), 115.77 (d, J = 3.03 Hz, CH-arom),
115.55 (d, J = 2.02 Hz, CH-arom), 113.93 (s, CH-arom), 63.46 (d, J = 7.07 Hz,
OCH2CH3), 63.34 (s, OCH2CH3), 55.46 (d, J = 152.51 Hz, CH), 16.52 (d, J = 5.05 Hz,
OCH2CH3), 16.32 (d, J = 6.06 Hz, OCH2CH3) ppm. 31P NMR (162 MHz, CDCl3)
δ 22.93 ppm. Anal. Calcd. for C17H21FNO3P: C, 60.53; H, 6.27; N, 4.15. Found: C,
59.98; H, 6.11; N, 4.03.
1
Table 3, entry 4: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.24 (t, J = 8.0 Hz, 2H,
H-arom), 6.83-6.78 (m, 3H, H-arom), 4.50 (d, J = 16.0 Hz, 1H, CH), 4.30 (s, 2H, Cp),
13
4.30-3.90 (m, 11H, Cp, OCH2CH3) 1.21-1.14 (m, 6H, OCH2CH3) ppm. C NMR (101
MHz, CDCl3) δ 147.23 (d, J = 6.06 Hz, Cq), 129.30 (s, CH-arom), 118.30 (s,
CH-arom), 113.55 (s, CH-arom), 85.33 (d, J = 7.07 Hz, Cq), 68.69 (s, CH, Cp), 68.03
(s, CH, Cp), 67.67 (s, CH, Cp), 65.93 (d, J = 2.02 Hz, CH, Cp), 63.13 (d, J = 7.07 Hz,
OCH2CH3), 62.55 (d, J = 7.07 Hz, OCH2CH3), 51.77 (d, J = 162.61 Hz, CH), 16.45 (d,
12

ACCEPTED MANUSCRIPT
31
J = 5.05 Hz, OCH2CH3), 16.35 (d, J = 5.05 Hz, OCH2CH3) ppm. P NMR (162 MHz,
CDCl3) δ 21.91 ppm. Anal. Calcd. for C23H32FeNO3P: C, 60.40; H, 7.05; N, 3.06.
Found: C, 59.99; H, 6.90; N, 2.94.
1
Table 3, entry 5: Beige solid. H NMR (CDCl3, 400 MHz) δ 8.01 (d, J = 8.0 Hz, 2H,
H-arom), 7.56 (d, J = 8.0 Hz, 2H, H-arom), 7.09 (t, J = 8.0, 4.0 Hz, 2H, H-arom), 6.70
(t, J = 8.0 Hz, 1H, H-arom), 6.57 (d, J = 8.0 Hz, 2H, H-arom), 5.35 (brs, 1H, NH), 4.82
(d, J = 24.0 Hz, 1H, CH), 4.17-4.07 (m, 2H, OCH2CH3), 4.00-3.94 (m, 1H, OCH2CH3),
3.89 (s, 3H, OCH3), 3.78-3.70 (m, 1H, OCH2CH3), 1.28 (t, J = 8.0, 4.0 Hz, 3H,
OCH2CH3), 1.14 (t, J = 4.0, 8.0 Hz, 3H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3)
δ 166.87 (s, C=O), 146.10 (d, J = 15.15 Hz, Cq), 141.57 (d, J = 3.03 Hz, Cq), 129.95 (d,
J = 3.03 Hz, CH-arom), 129.86 (d, J = 3.03 Hz, CH-arom), 129.33 (s, CH-arom),
127.97 (d, J = 5.05 Hz, Cq), 118.79 (s, CH-arom), 113.92 (s, CH-arom), 63.64 (d,
J = 7.07 Hz, OCH2CH3), 63.54 (d, J = 7.07 Hz, OCH2CH3), 56.20 (d, J = 149.48 Hz,
CH), 52.23 (s, OCH3), 16.51 (d, J = 8.08 Hz, OCH2CH3), 16.32 (d, J = 8.08 Hz,
OCH2CH3) ppm. 31P NMR (162 MHz, CDCl3) δ 21.69 ppm.Anal. Calcd. for
C19H24NO5P: C, 60.47; H, 6.41; N, 3.71. Found: C, 59.23; H, 6.02; N, 3.59.
Table 3, entry 640: Beige solid. 1H NMR (CDCl3, 400 MHz) δ 7.07 (t, J = 8.0, 4.0 Hz,
2H, H-arom), 7.00 (s, 1H, H-arom), 6.91 (d, J = 8.0 Hz, 1H, H-arom), 6.84 (d, J = 8.0
Hz, 1H, H-arom), 6.66 (t, J = 8.0, 4.0 Hz, 1H, H-arom), 6.61 (d, J = 8.0 Hz, 2H,
H-arom), 4.89 (brs, 1H, NH), 4.70 (d, J = 24.0 Hz, 1H, CH), 4.16-4.05 (m, 2H,
OCH2CH3), 3.97-3.91 (m, 1H, OCH2CH3), 3.74-3.66 (m, 4H, OCH2CH3+OCH3), 1.25
(t, J = 4.0, 8.0 Hz, 3H, OCH2CH3), 1.11 (t, J = 4.0, 8.0 Hz, 3H, OCH2CH3) ppm.
13C NMR (101 MHz, CDCl3) 147.19 (d, J = 3.03 Hz, Cq), 146.29 (d, J = 4.04 Hz, Cq),
145.75 (d, J = 3.03 Hz, Cq), 128.96 (s, CH-arom), 127.00 (d, J = 2.02 Hz, Cq), 120.78
(d, J = 8.08 Hz, CH-arom), 118.21 (s, CH-arom), 114.72 (d, J = 2.02 Hz, CH-arom),
113.77 (s, CH-arom), 110.53 (d, J = 5.05 Hz, CH-arom), 63.21 (t, J = 7.07 Hz,
OCH2CH3), 55.62 (d, J = 153.52 Hz, CH), 55,71 (s, OCH3), 16.25 (d, J = 5.05 Hz,
OCH2CH3), 16.09 (d, J = 5.05 Hz, OCH2CH3) ppm. 31P NMR (162 MHz, CDCl3) δ
22.86 ppm. Anal. Calcd. for C18H24NO5P: C, 59.17; H, 6.62; N, 3.83. Found: C, 58.24;
H, 5.97; N, 3.69.
Table 3, entry 722: Beige solid. 1H NMR (CDCl3, 400 MHz) δ 7.47 (d, J = 8.0 Hz, 2H,
H-arom), 7.32 (t, J = 8.0 Hz, 2H, H-arom), 7.25 (t, J = 8.0 Hz, 1H, H-arom), 7.09 (t,
J = 8.0 Hz, 2H, H-arom), 6.68 (t, J = 4.0, 8.0 Hz, 1H, H-arom), 6.60 (d, J = 12.0 Hz,
2H, H-arom), 4.88 (brs, 1H, NH), 4.76 (d, J = 24.0 Hz, 1H, CH), 4.14-4.08 (m, 2H,
13

ACCEPTED MANUSCRIPT
OCH2CH3), 3.94-3.90 (m, 1H, OCH2CH3), 3.70-3.64 (m, 1H, OCH2CH3), 1.28 (t,
J = 4.0, 3H, 8.0 Hz, OCH2CH3), 1.10 (t, J = 4.0, 3H, 8.0 Hz, OCH2CH3) ppm. 13C NMR
(101 MHz, CDCl3) δ 146.43 (d, J = 15.15 Hz, Cq), 136.01 (s, Cq), 128.67 (d,
J = 2.02 Hz, CH-arom), 128.00 (d, J = 2.02 Hz, CH-arom), 127.92 (s, CH-arom),
118.47 (s, CH-arom), 113.95 (s, CH-arom), 63.41 (d, J = 1.01 Hz, OCH2CH3), 63.34 (d,
J = 2.02 Hz, OCH2CH3), 56.16 (d, J = 151.5 Hz, CH), 16.51 (d, J = 6.06 Hz,
OCH2CH3), 16.27 (d, J = 6.06 Hz, OCH2CH3) ppm. 31P NMR (162 MHz, CDCl3) δ
23.02 ppm. Anal. Calcd. for C17H22NO3P: C, 63.94; H, 6.94; N, 4.39. Found: C, 63.80;
H, 6.77; N, 4.28.
Table 3, entry 8: Beige solid. 1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 4H, H-arom), 7.12
(t, J = 8.0 Hz, 2H, H-arom), 6.73 (t, J = 4.0, 8.0 Hz, 1H, H-arom), 6.56 (d, J = 8.0 Hz,
2H, H-arom), 4.83 (d, J = 20.0 Hz, 2H, NH+CH), 4.16-4.10 (m, 2H, OCH2CH3), 4.04-
3.98 (m, 1H, OCH2CH3), 3.85-3.79 (m, 1H, OCH2CH3), 1.29 (t, J = 4.0, 8.0 Hz, 3H,
OCH2CH3), 1.16 (t, J = 8.0 Hz, 3H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3)
δ 146.02 (d, J = 15.15 Hz, Cq), 140.51 (s, Cq), 130.09 (s, Cq), 129.42 (s, CH-arom),
128,26 (d, J = 5.05 Hz, CH-arom), 125.65 (s, CH-arom), 118.95 (s, CH-arom), 113.92
(s, CH-arom), 63.69 (d, J = 7.07 Hz, OCH2CH3), 64.00 (d, J = 7.07 Hz, OCH2CH3),
56.04 (d, J = 150.49 Hz, CH), 16.53 (d, J = 6.06 Hz, OCH2CH3), 16.31 (d, J = 6.06 Hz,
OCH2CH3) ppm. 31P NMR (162 MHz, CDCl3) δ 21.91 ppm. Anal. Calcd. for
C18H21F3NO3P: C, 55.82; H, 5.46; N, 3.62. Found: C, 55.70; H, 5.31; N, 3.53.
Table 3, entry 927: Beige solid. 1H NMR (CDCl3, 400 MHz) δ 7.46 (d, J = 8.0 Hz, 2H,
H-arom), 7.36 (t, J = 4.0, 8.0 Hz, 2H, H-arom), 7.11 (t, J =8.0, 12.0 Hz, 2H, H-arom),
6.71 (t, J = 12.0, 8.0 Hz, 1H, H-arom), 6.56 (d, J = 12.0 Hz, 2H, H-arom), 4.76-4.66 (m,
2H, NH, CH), 4.18-3.92 (m, 3H, OCH2CH3), 3.85-3.72 (m, 1H, OCH2CH3), 1.29 (t,
13
J = 8.0, 12.0 Hz, 3H, OCH2CH3), 1.14 (t, J = 8.0, 12.0 Hz, 3H, OCH2CH3) ppm. C
NMR (101 MHz, CDCl3) δ 146.15 (d, J = 19.19 Hz, Cq), 135.32 (d, J = 4.04 Hz, Cq),
131.86 (d, J = 4.04 Hz, CH-arom), 129.63 (d, J = 7.07 Hz, CH-arom), 129.37 (s,
CH-arom), 121.98 (d, J = 6.06 Hz, Cq), 118.82 (s, CH-arom), 113.98 (s, CH-arom),
63.55 (d, J = 9.09 Hz, OCH2CH3), 63.42 (s, OCH2CH3), 55.77 (d, J = 200.99 Hz, CH),
31
16.57 (d, J = 8.08 Hz, OCH2CH3), 16.39 (d, J = 8.08 Hz, OCH2CH3) ppm. P NMR
(162 MHz, CDCl3) δ 22.10 ppm. Anal. Calcd. for C17H21BrNO3P: C, 51.27; H, 5.32; N,
3.52. Found: C, 51.04; H, 5.19; N, 3.38.
Table 3, entry 1020: Brown solid. 1H NMR (CDCl3, 400 MHz) δ 7.40 (s, 1H, H-arom),
7.17 (t, J = 8.0 Hz, 2H, H-arom), 6.76 (t, J = 8.0, 4.0 Hz, 1H, H-arom), 6.69 (d,
14

ACCEPTED MANUSCRIPT
J = 8.0 Hz, 2H, H-arom), 6.41 (t, J = 4.0 Hz, 1H, H-arom), 6.34 (s, 1H, H-arom), 4.93
(d, J = 24.0 Hz, 1H, CH), 4.44 (brs, 1H, NH), 4.25-4.15 (m, 2H, OCH2CH3), 4.13-4.04
(m, 1H, OCH2CH3), 3.95-3.85 (m, 1H, OCH2CH3), 1.32 (t, J = 4.0, 8.0 Hz, 3H,
OCH2CH3), 1.22 (t, J = 8.0, 4.0 Hz, 3H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3)
δ 149.13 (s, Cq), 145.96 (d, J = 45.45 Hz, Cq), 142.50 (s, CH-arom), 129.20 (s,
CH-arom), 118.20 (s, CH-arom), 113.95 (s, CH-arom), 110.79 (s, CH-arom), 108.80 (d,
J = 7.07 Hz, CH-arom), 63.36 (s, OCH2CH3), 50.23 (d, J = 160.59 Hz, CH), 16.45 (d,
31
J = 6.06 Hz, OCH2CH3), 16.30 (d, J = 6.06 Hz, OCH2CH3) ppm. P NMR (162 MHz,
CDCl3) δ 20.61 ppm. Anal. Calcd. for C15H20NO4P: C, 58.25; H, 6.52; N, 4.53. Found:
C, 57.96; H, 6.41; N, 4.38.
1
Table 4, entry 1: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.37 (d, J = 8.0 Hz, 2H,
H-arom), 7.20 (d, J = 8.0 Hz, 2H, H-arom), 6.69 (d, J = 8.0 Hz, 2H, H-arom), 6.56 (d,
J = 12.0 Hz, 2H, H-arom), 5.42 (brs, 1H, NH), 4.66 (d, J = 24.0 Hz, 1H, CH), 4.18-4.07
(m, 2H, OCH2CH3), 4.00-3.94 (m, 1H, OCH2CH3), 3.79-3.71 (m, 1H, OCH2CH3), 3.68
(s, 3H, OCH3), 2.48 (s, 3H, SCH3), 1.29 (t, J = 8.0 Hz, 3H, OCH2CH3), 1.15 (t, J = 8.0
Hz, 3H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3) δ 152.92 (s, Cq), 140.11 (d,
J = 16.16 Hz, Cq), 138.29 (d, J = 4.04 Hz, Cq), 132.65 (d, J = 3.03 Hz, Cq), 128.46 (d,
J = 6.06 Hz, CH-arom), 126.60 (d, J = 3.03 Hz, CH-arom), 115.55 (s, CH-arom),
114.83 (s,
CH-arom), 63.58 (d, J = 7.07 Hz, OCH2CH3), 63.46 (d, J = 7.07 Hz,
OCH2CH3), 56.70 (d, J = 152.51 Hz, CH), 55.74 (s, OCH3), 16.54 (d, J = 6.06 Hz,
31
OCH2CH3), 16.35 (d, J = 6.06 Hz, OCH2CH3), 15.71 (s, SCH3) ppm. P NMR (162
MHz, CDCl3) δ 22.75 ppm. Anal. Calcd. for C19H26NO4PS: C, 57.71; H, 6.63; N, 3.54.
Found: C, 57.62; H, 6.54; N, 3.40.
1
Table 4, entry 3: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.36 (d, J = 4.0 Hz, 2H,
H-arom), 7.21 (d, J = 8.0 Hz, 2H, H-arom), 6.81 (t. J = 8.0 Hz, 2H, H-arom), 6.52-6.49
(m, 2H, H-arom), 6.64 (d, J = 24,0 Hz, 1H, CH), 4.14-4.09 (m, 2H, OCH2CH3), 3.99-
3.93 (m, 1H, OCH2CH3), 3.77-3.71 (m, 1H, OCH2CH3), 2.81 (brs, 1H, NH), 2.46 (s,
3H, SCH3), 1.30 (t, J = 4.0, 8.0 Hz, 3H, OCH2CH3), 1.15 (t, J = 8.0 Hz, 3H, OCH2CH3)
ppm. 13C NMR (101 MHz, CDCl3) δ 157.52 (s, Cq), 155.18 (s, Cq), 142.66 (d, J = 2.02
Hz, Cq), 138.46 (d, J = 3.03 Hz, Cq), 132.37 (d, J = 3.03 Hz, Cq), 128.35 (d, J = 5.05
Hz, CH-arom), 126.59 (d, J = 3.03 Hz, CH-arom), 115.58 (s, CH-arom), 114.96 (d,
J = 7.07 Hz, CH-arom), 63.49 (d, J = 7.07 Hz, OCH2CH3), 56.32 (d, J = 152.51 Hz,
CH), 16.47 (d, J = 5.05 Hz, OCH2CH3), 16.28 (d, J = 6.06 Hz, OCH2CH3), 15.62 (s,
15

ACCEPTED MANUSCRIPT
SCH3) ppm. 31P NMR (162 MHz, CDCl3) δ 22.62 ppm. Anal. Calcd. for
C18H23FNO3PS: C, 56.39; H, 6.05; N, 3.65. Found: C, 56.22; H, 5.93; N, 3.55.
1
Table 4, entry 4: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.35 (t, J = 4.0 Hz, 2H,
H-arom), 7.22-7.16 (m, 4H, H-arom), 6.45 (d, J = 8.0 Hz, 2H, H-arom), 4.84 (brs, 1H,
NH), 4.66 (d, J = 24.0 Hz, 1H, CH), 4.19-4.08 (m, 2H, OCH2CH3), 3.97-3.92 (m, 1H,
OCH2CH3), 3.76-3.72 (m, 1H, OCH2CH3), 2.45 (s, 3H, SCH3), 1.29 (t, J = 8.0 Hz, 3H,
OCH2CH3), 1.14 (t, J = 4.0, 8.0 Hz, 3H, OCH2CH3) ppm. 13C NMR (CDCl3, 101 MHz)
δ 145.39 (d, J = 15.2 Hz, Cq), 138.64 (s, Cq), 132.21 (s, Cq), 132.03 (s, CH-arom),
128.32 (d, J = 5.05 Hz, CH-arom), 126.70 (d, J = 3.03 Hz, CH-arom), 115.61 (s,
CH-arom), 110.39 (s, Cq), 63.56 (d, J = 7.07 Hz, OCH2CH3), 63.47 (d, J = 7.07 Hz,
OCH2CH3), 55.78 (d, J = 152.51 Hz, CH), 16.55 (d, J = 6.06 Hz, OCH2CH3), 16.37 (d,
31
J = 5.05 Hz, OCH2CH3), 15.72 (s, SCH3) ppm. P NMR (162 MHz, CDCl3) δ 22.38
ppm. Anal. Calcd. for C18H23BrNO3PS: C, 48.66; H, 5.22; N, 3.15. Found: C, 48.51; H,
5.08; N, 3.03.
1
Table 4, entry 5: Beige solid. H NMR (CDCl3, 400 MHz) δ: 7.32 (d, J = 8.0 Hz, 2H,
H-arom), 6.97 (d, J = 8.0 Hz, 2H, H-arom), 6.77 (d, J = 4.0 Hz, 1H, H-arom), 6.62 (d,
J = 8.0 Hz, 1H, H-arom), 6.54 (d, J = 8.0 Hz, 1H, H-arom), 6.48 (d, J = 8. 0 Hz, 1H,
H-arom), 4.86 (d, J = 24.0 Hz, 1H, CH), 4.29-4.21 (m, 2H, OCH2CH3), 4.00-3.90 (m,
1H, OCH2CH3), 3.74-3.65 (m, 1H, OCH2CH3), 2.32 (s, 3H, SCH3), 1.29 (t, J = 8.0 Hz,
3H, OCH2CH3), 1.13 (t, J = 8.0 Hz, 3H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3)
δ 145.25 (s, Cq), 138.17 (d, J = 3.03 Hz, Cq), 134.84 (d, J = 17.2 Hz, Cq), 132.30 (d,
J = 1.01 Hz, Cq), 128.55 (d, J = 6.06 Hz, CH-arom), 126.35 (d, J = 2.02 Hz, CH-arom),
119.93 (s, CH-arom), 118.44 (s, CH-arom), 114.56 (s, CH-arom), 112.07 (s, CH-arom),
64.32 (d, J = 7.07 Hz, OCH2CH3), 63.77 (d, J = 8.08 Hz, OCH2CH3), 55.52 (d,
J = 155.54 Hz, CH), 16.47 (d, J = 5.05 Hz, OCH2CH3), 16.22 (d, J = 6.06 Hz,
OCH2CH3), 15.47 (s, SCH3) ppm. 31P NMR (162 MHz, CDCl3) δ: 24.08 ppm. Anal.
Calcd. for C18H24NO4PS: C, 56.68; H, 6.34; N, 3.67. Found: C, 56.60; H, 6.27; N, 3.59.
1
Table 5, entry 1: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.41 (d, J = 8.0 Hz, 2H,
H-arom), 7.19 (t, J = 8.0 Hz, 2H, H-arom), 7.14 (d, J = 8.0 Hz, 2H, H-arom), 6.85 (d,
J = 12.0 Hz, 2H, H-arom), 6.74 (t, J = 4.0, 12.0 Hz, 1H, H-arom), 5.28 (d, J = 24.0 Hz,
1H, CH), 4.18-3.95 (m, 4H, OCH2CH3), 2.91 (s, 3H, CH3), 2.34 (s, 3H, SCH3),
1.19-1.14 (m, 6H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3) δ 149.62 (d, J = 7.07
Hz, Cq), 138.00 (s, Cq), 130.44 (d, J = 8.08 Hz, Cq), 128.91 (s, CH-arom), 128.76 (d,
J = 9.09 Hz, CH-arom), 125.68 (s, CH-arom), 117.67 (s, CH-arom), 113.47 (s,
16

ACCEPTED MANUSCRIPT
CH-arom), 62.57 (d, J = 7.07 Hz, OCH2CH3), 61,62 (d, J = 7.07 Hz, OCH2CH3), 60.82
(d, J = 154.53 Hz, CH), 34.12 (s, CH3), 16.02 (d, J = 5.05 Hz, OCH2CH3), 15.85 (d,
31
J = 5.05 Hz, OCH2CH3), 14.81 (s, SCH3) ppm. P NMR (162 MHz, CDCl3) δ 22.13
ppm. Anal. Calcd. for C19H26NO3PS: C, 60.14; H, 6.91; N, 3.69. Found: C, 59.97; H,
6.85; N, 3.54.
Table 5, entry 2: Beige solid. 1H NMR (CDCl3, 400 MHz) δ 5.49 (dd, J = 4.0, 8.0 Hz,
2H, H-arom), 7.23 (t, J = 8.0 Hz, 2H, H-arom), 6.98 (t, J = 8.0 Hz, 2H, H-arom), 6.87
(d, J = 8.0 Hz, 2H, H-arom), 6.78 (t, J = 4.0, 8.0 Hz, 1H, H-arom), 5.30 (d, J = 24.0 Hz,
1H, CH), 4.21-4.00 (m, 4H, 2OCH2CH3), 2.93 (s, 3H, CH3), 1.22-1.17 (m, 6H,
2OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3) δ 163.45 (s, Cq), 160.99 (s, Cq),
149.91 (d, J = 8.08 Hz, Cq), 130.58 (s, CH-arom), 129.08 (s, CH-arom), 118.16 (s,
CH-arom), 115.32 (s, CH-arom), 113.85 (s, CH-arom), 63.04 (d, J = 7.07 Hz,
OCH2CH3), 62.03 (d, J = 7.07 Hz, OCH2CH3), 61.01 (d, J = 161.60 Hz, CH), 34.39 (s,
31
CH3), 16.30 (d, J = 5.05 Hz, OCH2CH3), 16.11 (d, J = 6.06 Hz, OCH2CH3) ppm. P
NMR (162 MHz, CDCl3) δ 22.05 ppm. Anal. Calcd. for C18H23FNO3P: C, 61.53; H,
6.60; N, 3.99. Found: C, 60.38; H, 6.49; N, 3.84.
1
Table 5, entry 3: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.41 (q, J = 8.0 Hz, 4H,
H-arom), 7.23 (t, J = 8.0 Hz, 2H, H-arom), 6.85 (d, J = 8.0 Hz, 2H, H-arom), 6.78 (t,
J = 8.0 Hz, 1H, H-arom), 5.26 (d, J = 24.0 Hz, 1H, CH), 4.20-4.00 (m, 4H, OCH2CH3),
13
2.92 (s, 3H, CH3), 1.22-1.18 (m, 6H, OCH2CH3) ppm. C NMR (101 MHz, CDCl3) δ
149.87 (d, J = 7.07 Hz, Cq), 133.46 (d, J = 7.07 Hz, Cq), 131.51 (s, CH-arom), 130.40
(d, J = 9.09 Hz, CH-arom), 129.14 (s, CH-arom), 121.93 (s, Cq), 118.27 (s, CH-arom),
113.88 (s, CH-arom), 63.12 (d, J = 7.07 Hz, OCH2CH3), 62.11 (d, J = 7.07 Hz,
OCH2CH3), 61.22 (d, J = 160.59 Hz, CH), 34.57 (s, CH3), 16.39 (d, J = 6.1 Hz,
OCH2CH3), 16.22 (d, J = 5.1 Hz, OCH2CH3) ppm. 31P NMR (162 MHz, CDCl3) δ 21.66
ppm. Anal. Calcd. for C18H23BrNO3P: C, 52.44; H, 5.62; N, 3.40. Found: C, 52.33; H,
5.47; N, 3.29.
1
Table 5, entry 4: Beige solid. H NMR (CDCl3, 400 MHz) δ 7.30 (d, J = 8.0 Hz, 2H,
H-arom), 7.06 (s, 1H, H-arom), 6.92 (d, J = 2.0 Hz, 2H, H-arom), 6.80 (d, J = 8.0 Hz,
1H, H-arom), 6.53 (d, J = 8.0 Hz, 2H, H-arom), 4.25 (d, J = 24.0 Hz, 1H, CH),
3.99-3.94 (m, 2H, OCH2CH3), 3.84-3.80 (m, 5H, OCH2CH3+OCH3), 2.75 (s, 3H, CH3),
1.14-1.11 (t, J = 4.0, 8.0 Hz, 6H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3) δ
148.38 (s, Cq), 146.77 (s, Cq), 144.95 (Cq), 130.04 (d, J = 8.08 Hz, CH-arom), 128.93
(s, CH-arom), 125.19 (d, J = 5.05 Hz, Cq), 122.14 (d, J = 9.09 Hz, CH-arom), 114.64 (s,
17

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CH-arom), 112.47 (s, CH-arom) 112.27 (d, J = 7.07 Hz, CH-arom), 62.68 (d, J = 7.07
Hz, OCH2CH3), 62.54 (d, J = 7.07 Hz, OCH2CH3), 55.83 (s, OCH3), 49.72 (d,
J = 139.38 Hz, CH), 30.64 (s, CH3), 16.31 (s, OCH2CH3), 16.25 (s, OCH2CH3) ppm. 31P
NMR (162 MHz, CDCl3) δ 26.36 ppm. Anal. Calcd. for C19H26NO5P: C, 60.15; H,
6.91; N, 3.69. Found: C, 59.01; H, 6.79; N, 3.53.
1
Table 5, entry 5: Beige solid. H NMR (CDCl3, 400 MHz) δ 8.00 (d, J = 8.0 Hz, 2H,
H-arom), 7.60 (d, J = 8.0 Hz, 2H, H-arom), 7.25 (t, J = 8.0 Hz, 2H, H-arom), 6.87 (d,
J = 8.0 Hz, 2H, H-arom), 6.80 (t, J = 8.0 Hz, 1H, H-arom), 5.37 (d, J = 24.0 Hz, 1H,
CH), 4.20-4.03 (m, 4H, OCH2CH3), 3.89 (s, 3H, OCH3), 2.98 (s, 3H, CH3), 1.24-1.19
13
(m, 6H, OCH2CH3) ppm. C NMR (101 MHz, CDCl3) δ 166.70 (s, C=O), 149.95 (s,
Cq), 139.92 (s, Cq), 129.71 (s, CH-arom), 129.23 (s, CH-arom), 128.70 (s, Cq), 118.15
(s, CH-arom), 113.87 (s, CH-arom), 63.22 (d, J = 8.08 Hz, OCH2CH3), 62.28 (d,
J = 7.07 Hz, OCH2CH3), 61.68 (d, J = 159.58 Hz, CH), 52.04 (s, OCH3), 34.87 (s, CH3),
16.43 (d, J = 6.1 Hz, OCH2CH3), 16.26 (d, J = 5.1 Hz, OCH2CH3) ppm. 31P NMR
(162 MHz, CDCl3) δ 21.57 ppm. Anal. Calcd. for C20H26NO5P: C, 61.37; H, 6.70; N,
3.58. Found: C, 60.19; H, 6.58; N, 3.40.
4.4. Use of the catalyst [CpRu(PPh3)2Cl] in several catalytic cycles
To a mixture of 4-(methylthio)benzaldehyde (1.0 mmol), aniline (1.0 mmol) and
[CpRu(PPh3)2Cl] (0.5 mol %) was added HP(O)(OEt)2 (2.0 mmol). The reaction
mixture was stirred at 80 ºC under an air atmosphere during 15 min. The reaction
1
mixture was cooled and the yield was determined by H NMR spectroscopy using
mesitylene (1.0 mmol) as internal standard. In the next catalytic cycles,
4-(methylthio)benzaldehyde (1.0 mmol), aniline (1.0 mmol), HP(O)(OEt)2 (2.0 mmol)
and mesitylene (1.0 mmol) was added to the reaction mixture and stirred at 80 ºC. The
yields were determined by 1H NMR spectroscopy.
Acknowledgements
This research was supported by Fundação para a Ciência e Tecnologia through project
UID/QUI/00100/2013. Ivânia Cabrita (SFRH/BD/74280/2010), Sara Sousa and Pedro
Florindo thank FCT for grants. Ana Fernandes (IF/00849/2012) acknowledges FCT for
the “Investigador FCT” Program. Authors also thank the Portuguese NMR Network
(IST-UTL Center) for providing access to the NMR facilities.
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References
1 Kukhar, V. P.; Hudson, H. R. Aminophosphinic and aminophosphonic acids
chemistry and biological activity, Jonh Wiley-Sons LTD, New York, 2000.
2 Alonso, E.; Alonso, E.; Solis, A.; del Pozo, C. Synlett 2000, 698-700.
3 Peyman, A.; Stahl, W.; Wagner, K.; Ruppert, D.; Budt, K.-H. Bioorg. Med. Chem.
Lett. 1994, 4, 2601-2604.
4 Atherton, F. R.; Hassall, C. H.; Lambert, R. W. J. Med. Chem. 1986, 29, 29-40.
5 Rao, X.; Song, Z.; He, L. Heteroatom. Chem. 2008, 19, 512-516.
6 Kraicheva, I.; Bogomilova, A.; Tsacheva, I.; Momekov, G.; Troev, K. Eur. J. Med.
Chem. 2009, 44, 3363-3367.
7 Huang, J.; Chen, R. Heteroatom. Chem. 2000, 11, 480-492.
8 Mao, M. K.; Franz, J. E. Synthesis 1991, 920-922.
9 Joly, G. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004,126, 4102-4103.
10 Pettersen, D.; Marcolini, M.; Bernardi, L.; Fini, F.; Herrera, R. P.; Sgarzani, V.;
Ricci, A. J. Org. Chem. 2006, 71, 6269-6272.
11 Saito, B.; Egami, H.; Katsuki, T. J. Am. Chem. Soc. 2007, 129, 1978-1986.
12 Abell, J. P.; Hisashi Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 10521-10523.
13 Xu, W.; Zhang, S.; Yang, S.; Jin, L.-H.; Bhadury, P. S.; Hu, D.-Y.; Zhang, Y.
Molecules 2010,15, 5782-5796.
14 Ohara, M.; Nakamura, S.; Shibata, N. Adv. Synth. Catal. 2011, 353, 3285-3289.
15 Yan, Z.; Wu, B.; Xiang Gao, X.; Chen, M.-W.; Zhou, Y.-G. Org. Lett. 2016, 18,
692-695.
16 Keglevich, G.; Erika Bálint, E. Molecules 2012, 17, 12821-12835.
17 Kafarski, P.; Gorny vel Gorniak, M.; Andrasiak, I. Curr Green Chem. 2015, 2, 218-
222.
18 Sudhapriya, N.; Balachandran, C.; Awale, S.; Perumal, P. T. New J. Chem. 2017, 41,
5582-5594.
19 Sivala, M. R.; Devinenib, S. R.; Gollac, M.; Medarametlab, V.; Pothuru, G. K.;
Chamarthic, N. R. J. Chem. Sci. 2016, 128, 1303-1313.
20 Li, X.-C.; Gong, S.-S.; Zeng, D.-Y.; You, Y.-H.; Sun, Q. Tetrahedron Lett. 2016, 57,
1782-1785.
21 Lee, S.-G.; Park, J. H.; Kang, J.; Lee, J. K. Chem. Commun. 2001, 1698-1699.
19

ACCEPTED MANUSCRIPT
22 Tang, J.; Wang, L.; Wang, W.; Zhang, L.; Wu, S.; Mao, D. J. Fluorine Chem. 2011,
132, 102-106.
23 Xu, F.; Luo, Y.; Deng, M.; Shen, Q. Eur. J. Org. Chem. 2003, 4728-4730.
24 Chandrasekhar, S.; Prakash, S. J.; Jagadeshwar, V.; Narsihmulu, C. Tetrahedron
Lett. 2001, 42, 5561-5563.
25 Dindulkar, S. D.; Reddy, M. V.; Jeong, Y. T. Catal. Commun. 2012, 17, 114-117
26 Zhan, Z. P.; Li, J. P. Synth. Commun. 2005, 35, 2501-2504.
27 Azizi, N.; Saidi, M. R. Eur. J. Org. Chem. 2003, 4630-4633.
28 Rezaei, Z.; Firouzabadi, H.; Iranpoor, N.; Ghaderi, A.; Jafari, M. R.; Jafari, A. A.;
Zare, wH. R. Eur. J. Med. Chem. 2009, 44, 4266-4275.
29 Noronha, R. G.; Romão, C. C.;. Fernandes, A. C. Catal. Commun. 2011, 12, 337-
340.
30 Mu, X.-J.; Lei, M.-Y.; Zou, J.-P.; Zhang, W. Tetrahedron Lett. 2006, 47, 1125-
1127.
31 Keglevich, G.; Szekrenyi, A. Lett. Org. Chem. 2008, 5, 616-622.
32 Bálint, E.; Takács, J.; Drahos, L.; Juranovič, A.; Kočevar, M.; Keglevich, G.
Heteroatom Chem. 2013, 24, 221-225.
33 Tajti, Á.; Bálint, E.; Keglevich, G. Curr. Org. Synth. 2016, 13, 638-645.
34 Bálint, E.; Tajti, Á.; Kalocsai, D.; Mátravölgyi, B.; Karaghiosoff, K.; Czugler, M.;
Keglevich, G. Tetrahedron 2017, 73, 5659-5667.
35 Ashby, G. S.; Bruce, M. I.; Tomkins, I. B.; Walli, R. C. Aust. J. Chem. 1979, 32,
1003-1016.
36 Moreno, V.; Font-Bardia, M.; Calvet, T. T.; Lorenzo, J.; Avilés, F. X.; Garcia, M.
H.; Morais, T. S.; Valente, A.; Robalo, M. P. J. Inorg. Biochem. 2011, 105, 241-249.
37 Florindo, P. R.; Pereira, D. M.; Borralho, P. M.; Costa, P. J.; Piedade, M. F. M.;
Rodrigues, C. M. P.; Fernandes, A. C. Dalton Trans. 2016, 45, 11926-11930.
38 Florindo, P. R.; Pereira, D. M.; Borralho, P. M.; Rodrigues, C. M. P.;
Piedade, M. F. M.; Fernandes, A. C. J. Med. Chem. 2015, 58, 4339-4347.
39 Florindo, P. R.; Marques, I. J.; Nunes, C. D.; Fernandes, A. C. J. Organomet.
Chem. 2014, 760, 240-247.
40 Rezaei, Z.; Khabnadideh, S.; Zomorodian, K.; Pakshir, K.; Nadali, S.; Mohtashami,
N.; Mirzaei, E. F. Int J Med Chem 2011, 26; 678101.
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Highlights
[CpRu(PPh3)2Cl] is a very efficient catalyst for the direct aminophosphonylation of
aldehydes
The catalyst [CpRu(PPh3)2Cl] can be use in 12 catalytic cycles with excellent activity
The reactions can be performed under solvent free conditions