Phenylphosphonic acid as efficient and recyclable catalyst in the synthesis of α-aminophosphonates under solvent-free conditions

Article abstract of DOI:10.1055/s-0033-1341069

Phenylphosphonic acid is an efficient, friendly and reusable heterogeneous catalyst for the synthesis of α-aminophosphonates through a 'one-pot' three-component reaction of amines, carbonyl compounds and dialkyl phosphites under solvent-free conditions. This methodology illustrates a very simple procedure, with wide applicability, extending the scope to aliphatic and aromatic amines, aliphatic and aromatic aldehydes and aliphatic ketones. It also enabled the synthesis of α-aminophosphonates in large scale, clean conversion, easy workup and purification. Excellent results were obtained in each case obtaining the desire compounds in moderate to good yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341069

LETTER
▌1145
letter
Phenylphosphonic Acid as Efficient and Recyclable Catalyst in the Synthesis
of α-Aminophosphonates under Solvent-Free Conditions
Phenylphosphonic Acid as Efficient and Recyclable Catalyst
Mercedes Bedolla-Medrano,a Eugenio Hernández-Fernández,b Mario Ordóñez*a
a
Centro de Investigaciones Químicas, Universidad Autónoma del Estado de Morelos, 62209 Cuernavaca, Morelos, México
Fax +52(777)3297997; E-mail: palacios@uaem.mx
b
Facultad de Ciencias Químicas, Universidad Autónoma de Nuevo León, Pedro de Alba S/N, Ciudad Universitaria, 66400 San Nicolás de los
Garza, Nuevo León, México
Received: 19.12.2013; Accepted after revision: 03.03.2014
ponent reaction between aldehydes or ketones, amines
Abstract: Phenylphosphonic acid is an efficient, friendly and reus-
and dialkyl or diaryl phosphites. For this reaction a wide
able heterogeneous catalyst for the synthesis of α-aminophospho-
spectrum of catalysts have been used including Brønsted
and Lewis acids, organocatalysts, transition-metal oxides,
nates through a ‘one-pot’ three-component reaction of amines,
carbonyl compounds and dialkyl phosphites under solvent-free con-
ditions. This methodology illustrates a very simple procedure, with heteropolyacids, polymer-supported catalysts, ionic liq-
uids, nanocatalysts, and many more.18 However, in spite
of the potential utility of this reaction, the catalytic pro-
wide applicability, extending the scope to aliphatic and aromatic
amines, aliphatic and aromatic aldehydes and aliphatic ketones. It
also enabled the synthesis of α-aminophosphonates in large scale,
cess suffers from one or more disadvantages such as the
clean conversion, easy workup and purification. Excellent results
were obtained in each case obtaining the desire compounds in mod-
use of expensive or less available and stoichiometric
amounts of catalyst, use of toxic catalysts, specialized
handling techniques and tedious workup are necessary,
long reaction times, vigorous reaction conditions, require-
ment of excess of reagents, use of flammable organic sol-
vents, unsatisfactory yield and lack of generality.
Furthermore, some of these catalysts can decompose or
deactivate with the water generated during the imine for-
mation. For these reasons, the introduction of an efficient,
environmentally friendly, water-resistant and recyclable
catalyst for the synthesis of α-aminophosphonates under
solvent-free conditions is still a challenge.
erate to good yields.
Key words: α-aminophosphonates, phenylphosphonic acid cata-
lyst, solvent-free conditions, heterogeneous catalysis
α-Aminophosphonates are probably the most important
substitutes for the corresponding protein and nonprotein
α-amino acids in biological systems, because these com-
pounds are considered as stable mimetics of tetrahedral
transition state of peptide hydrolysis,1 and have wide ap-
plications in medicinal, bioorganic, agricultural and or-
ganic synthesis.2–5 Many α-aminophosphonates as well as
their derivatives have applications as antibacterial,6 anti-
cancer,7 anti-HIV,8 antimalarial,9 and antifungal agents,10
and are also carriers of hydrophilic organic molecules
across phospholipid bilayer membranes.11 Some of them
show also pesticidal, insecticidal and herbicidal activity,12
and function as plant growth regulators.13 The inert nature
of the C–P bond in α-aminophosphonates as well as phys-
ical and structural similarity to the biologically important
phosphate ester and carboxylic acid functionalities con-
tribute a great deal to these activities. Additionally, the α-
aminophosphonates have been used as key synthetic inter-
mediates for the preparation of more complex compounds
and as organocatalyst.14,15
Therefore, in connection with our program on the devel-
opment of novel organic synthetic methodologies,19 here-
in we report our investigation on the synthesis of α-
aminophosphonates through a ‘one-pot’ three-component
reaction between aldehydes and ketones, benzylamine
and dimethyl phosphite in the presence of phosphorus ac-
ids as catalysts, which have also been used in the carbon-
ylation of nitrobenzene,20 three-component Ugi,21
Biginelli,22 and Pictet–Spengler reactions.23 The use of
these acidic catalysts displays several advantages such as
operational simplicity, nontoxicity, reusability, low cost
and easy isolation after completion of the reaction.
In order to optimize the reaction conditions for the synthe-
sis of α-aminophosphonates, different phosphorus com-
pounds such as diphenylphosphinic acid (1),
diphenylphosphate (2), phenylphosphinic acid (3), pro-
pylphosphonic acid (4), and phenylphosphonic acid (5)
were tested as catalysts. Firstly, we carried out the reac-
tion of benzaldehyde with benzylamine and dimethyl
phosphite at 50 °C in the presence of 10 mol% of catalyst
under solvent-free conditions (Table 1),24 and found that
all catalysts 1–5 promoted the reaction affording the α-
aminophosphonate 6a in good yield. The results in Table
1 show that the most efficient catalysts are the
phenylphosphinic acid 3 and phenylphosphonic acid 5,
which in only 30 minutes afforded the desired product
Due to the relevant properties exhibited by α-aminophos-
phonates and their derivatives, during the past decades nu-
merous useful synthetic approaches have been developed
for their preparation in both racemic and optically pure
forms,16 but certainly the Kabachnik–Fields reaction17 is
one of the most widely used methods for the synthesis of
these compounds, which involves a ‘one-pot’ three-com-
SYNLETT 2014, 25, 1145–1149
Advanced online publication: 07.04.2014
DOI: 10.1055/s-0033-1341069; Art ID: ST-2013-S1153-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1146
M. Bedolla-Medrano et al.
LETTER
with good yield (Table 1, entries 4 and 6), and the other In order to compare the efficiency of phenylphosphonic
catalysts could only equalize this performance with longer acid 5 as catalyst, benzaldehyde, (S)-α-methylbenzyl-
reaction times (Table 1, entries 2, 3 and 5). These results amine and dimethyl phosphite were allowed to react in the
are in agreement with the pKa values described in the lit- presence of 10 mol% of 5 at 50 °C, yielding the α-amino-
erature for these catalysts.25 However, the reaction under phosphonates 6b and 6c in 64% yield (Table 2, entry 1),
catalyst- and solvent-free conditions at 80 °C gave 6a in but when the reaction was performed at 80 °C, the mixture
only 37% yield after five hours (Table 1, entry 1). De- of (R,S)- and (S,S)-6b was obtained in excellent yield with
creasing the catalyst amount of 10 mol% to 5 mol% or 2.5 predominance of the R,S-diastereoisomer (Table 2, entry
mol% resulted in lower yields.
2). Similar results were obtained using diethyl phosphite,
giving α-aminophosphonates (R,S)- and (S,S)-6c (Table 2,
entry 3). The diastereoisomeric ratio was determined by
31P NMR spectroscopy at 202 MHz, and the configuration
was assigned by analogy with results reported in the liter-
ature.26,27 In the next screening, benzaldehyde was reacted
with aniline and dimethyl and diethyl phosphite at 50 °C
for one hour, affording the α-aminophosphonates 6d and
6e in excellent yield (Table 2, entries 4 and 5).
Table 1 Identification of the Most Efficient Catalyst for the ‘One-
Pot’ Three-Component Synthesis of α-Aminophosphonate 6a
H
N
O
O
BnNH2
O
P(OMe)2
catalyst
Bn
+
H
neat, 50 °C
H
P(OMe)2
6a
Table 2 Synthesis of α-Aminophosphonates 6b–e
Entry
1
Catalyst (10 mol%) pKa
Time (h) Yield (%)a
H
N
O
O
P(OR2)2
R1NH2
O
R1
5 (10 mol%)
–
–
5.0
1.0
37
76
H
+
O
P
neat, heat
Ph
Ph
OH
H
P(OR2)2
2
3
4
5
6
2.30
6b–e
1
O
P
Entry R1
R2
Conditions
Yield (%)a
PhO
PhO
OH
2.40
1.73
2.49
1.86
1.0
0.5
1.5
0.5
88
93
86
90
1
2
3
4
5
6b: (S)-CH(Me)Ph
6b: (S)-CH(Me)Ph
6c: (S)-CH(Me)Ph
6d: Ph
Me
Me
Et
50 °C, 2.0 h
80 °C, 1.5 h
80 °C, 3.0 h
50 °C, 1.0 h
50 °C, 1.0 h
64b
92b
98c
98
2
O
P
Ph
H
OH
3
Me
Et
O
6e: Ph
96
n-Pr
P
OH
HO
a Isolated yield after chromatographic purification.
4
b The R,S- and S,S-diastereoisomers were obtained with 76:24 dr.
c The R,S- and S,S-diastereoisomers were obtained with 80:20 dr.
O
Ph
P
OH
HO
Next, to ensure the efficiency and fidelity of this proce-
dure as a general methodology, we employed a series of
aldehydes and ketones, benzylamine and dimethyl phos-
phite to obtain the desired α-aminophosphonates under
the optimized conditions using 5 as catalyst. For this study
benzylamine was selected because the benzyl fragment
can be easily removed by hydrogenolysis to give the cor-
responding α-aminophosphonates which can be used as
key building blocks.
5
a Isolated yield after chromatographic purification.
With these results in hand and taking into account that
phenylphosphinic acid 3 is an homogeneous catalyst, and
considering that the phenylphosphonic acid (5) promotes
the reaction as an heterogeneous catalyst, we proposed 5
as the best catalyst for the synthesis of α-aminophospho-
nates through ‘one-pot’ three-component conditions.
The described methodology illustrates a very simple pro-
cedure, with wide applicability, extending the scope to al-
iphatic and aromatic aldehydes and aliphatic ketones.
Thus, the α-aminophosphonates 6f–k were obtained in ex-
cellent yields using aromatic aldehydes bearing electron-
donating groups (Table 3, entries 1–6), whereas aromatic
aldehydes with electron-withdrawing groups gave the α-
aminophosphonates 6l–n in moderate yields (Table 3, en-
tries 7–9). The electron-donating or electron-withdrawing
property of the aromatic aldehydes tested, showed to have
The ability to recycle and reuse 5 as well as its catalytic
activity was studied in this system. In this context, 5 can
be easily separated by filtration of the reaction mixture af-
ter dispersing in ethyl acetate. The recyclability of the het-
erogeneous catalytic system was also examined and can
be reused for more than five successive times in new ex-
periments without yield loss to generate 6a with purities
similar to those obtained in the first run.
Synlett 2014, 25, 1145–1149
© Georg Thieme Verlag Stuttgart · New York

LETTER
Phenylphosphonic Acid as Efficient and Recyclable Catalyst
1147
a dramatic influence on the reaction course, which can be Finally, the reaction of aliphatic ketones with benzyl-
explained by a simple consideration of the electronic ef- amine and dimethyl phosphite was tested, affording the
fect, whereas the heteroaromatic entities such as 3-indole- quaternary α-aminophosphonates 6w–y in good to excel-
carboxaldehyde, 2-pyrrolecarboxaldehyde and furfural lent yields (Table 3, entries 18–20). Additionally, the
were also tested under this protocol, obtaining the α-ami- compound 6w was obtained on a five-gram scale, demon-
nophosphonates 6o–q in good yield, thus demonstrating strating that phenylphosphonic acid (5) can be used as cat-
that the procedure is quite suitable with this kind of com- alyst in the large-scale synthesis of α-aminophosphonates.
pounds regardless of the unprotected heteroatoms (Table The formation of α-hydroxyphosphonates as a by-product
3, entries 10–12). On the other hand, the reaction of ali- was not observed in any of the reactions.
phatic aldehydes with benzylamine and dimethyl phos-
phite produced the α-aminophosphonates 6r–u in good
yields (Table 3, entries 13–16). Additionally, the reaction
of cinnamaldehyde gave the α-aminophosphonate 6v in
Based on the above results, we suggest a mechanism
wherein the in situ formation of the imine intermediate,
generated from condensation reaction of aldehyde or ke-
tone and benzylamine, is activated by protonation giving
86% yield (Table 3, entry 17).
a nine-membered transition state (Figure 1), wherein 5
could play two roles: (1) the phenylphosphonic acid hy-
drogen activates the imine as a Brønsted acid; and (2) the
phosphoryl oxygen activates the nucleophile by coordi-
Table 3 ‘One-Pot’ Three-Component Synthesis of α-Aminophos-
phonates 6f–z
H
N
O
nating with the hydrogen of the phosphite as a Brønsted
O
BnNH2
5 (10 mol%)
P(OMe)2
base, as has been proposed for chiral phosphonic acids.28
Bn
R1
R2
+
R1
O
R2
neat, 50 °C
H
P(OMe)2
6f–z
OMe
H
O
R
P
O
Ph
OMe
Entry R1
R2
Time
(min)
Yield
(%)a
Product
P
H
HO
O
H N
Bn
1
2
3-HOC6H4
H
H
50
50
25
70
60
55
85
60
70
30
60
60
60
70
20
35
100
20
20
40
79
79
98
82
88
65b
60b
63
47b
90
80
85
56
76
63
77
86
75
76
98
6f
Figure 1 Proposed mechanism for the synthesis of α-aminophos-
phonates catalyzed by phenylphosphonic acid
3,4-(HO)2C6H3
6g
6h
6i
3
3,4-(MeO)2C6H3
4-MeOC6H4
2-MeO C6H4
4-PhC6H4
4-MeO2CC6H4
4-ClC6H4
4-F3CC6H4
3-indole
2-pyrrole
2-furyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Et
In conclusion, we have developed an efficient and facile
method for the synthesis of tertiary and quaternary α-ami-
nophosphonates in moderated to excellent yields, through
the ‘one-pot’ three-component reaction of aldehydes and
ketones with benzylamine and dimethyl phosphite in the
presence of catalytic amount of phenylphosphonic acid
under solvent-free conditions. Utilization of mild reaction
conditions, large-scale synthesis, clean conversion, easy
workup, purification of reaction products and reusable
phenylphosphonic acid make this process extra attractive
for the synthesis of α-aminophosphonates.
4
5
6j
6
6k
6l
7
8
6m
6n
6o
6p
6q
6r
6s
9
10
11
12
13
14
15
16
17
18
19
20
Acknowledgment
We gratefully acknowledge CONACyT of Mexico for financial
support via project 181816. We thank Victoria Labastida-Galván
for the technical assistance in MS and José Luis Viveros-Ceballos
for the technical assistance in NMR. MBM also thanks CONACyT
for the Graduate Scholarship 248554.
n-Pr
i-Bu
i-Pr
6t
t-Bu
6u
6v
6w
6x
6y
References and Notes
(E)-PhHC=CH
Me
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1145–1149

1148
M. Bedolla-Medrano et al.
LETTER
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Compound 6g: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 3.48 [d, J = 10.5 Hz, 3 H, (MeO)2P], 3.52 (AB system, J
= 13.3 Hz, 1 H, Bn), 3.78 (AB system, J = 13.3 Hz, 1 H, Bn),
3.79 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.89 (d, J = 20.1 Hz, 1
H, CHP), 6.63 (ddd, J = 8.0, 2.0, 2.0 Hz, 1 H, HAr), 6.77 (d,
J = 8.0 Hz, 1 H, HAr), 7.11 (dd, J = 2.0, 2.0 Hz, 1 H, HAr),
7.20–7.31 (m, 5 H, HAr). 13C NMR (100 MHz, CDCl3): δ =
50.8 (d, J = 17.6 Hz, Bn), 53.8 [d, J = 7.1 Hz, (MeO)2P], 54.1
[d, J = 7.6 Hz, (MeO)2P], 58.2 (d, J = 157.8 Hz, CHP), 114.7
(d, J = 5.0 Hz), 115.1, 121.0 (d, J = 8.1 Hz), 126.0, 127.2,
128.4 (2 × C), 139.0, 145.0 (2 × C). 31P NMR (161.9 MHz,
CDCl3): δ = 26.62. HRMS (FAB+): m/z [M + H]+ calcd for
C16H21NO5P: 338.1157; found: 338.1159.
Compound 6k: white solid; mp 94–96 °C. 1H NMR (400
MHz, CDCl3): δ = 2.44 (br s, 1 H, NH), 3.58 (AB system,
J = 13.3 Hz, 1 H, Bn), 3.58 [d, J = 10.5 Hz, 3 H, (MeO)2P],
3.75 [d, JHP = 10.6 Hz, 3 H, (MeO)2P], 3.84 (AB system,
J = 13.3 Hz, 1 H, Bn), 4.10 (d, J = 20.2 Hz, 1 H, CHP), 7.22–
7.36 (m, 6 H, HAr), 7.40–7.52 (m, 4 H, HAr), 7.59–7.64 (m, 4
H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.3 (d, J = 17.4
Hz, Bn), 53.6 [d, J = 6.6 Hz, (MeO)2P], 53.9 [d, J = 6.6 Hz,
(MeO)2P], 59.1 (d, J = 154.3 Hz, CHP), 127.1, 127.3, 127.4,
127.5, 128.5 (d, J = 6.7 Hz), 128.9, 129.1 (d, J = 5.5 Hz),
134.6, 139.3, 140.7, 140.9, 141.0. 31P NMR (161.9 MHz,
CDCl3): δ = 23.05. HRMS (FAB+): m/z [M + H]+ calcd for
C22H25NO3P: 382.1572; found: 382.1588.
Compound 6l: colorless liquid. 1H NMR (400 MHz, CDCl3):
δ = 2.17 (br s, 1 H, NH), 3.52 (AB system, J = 13.3 Hz, 1 H,
Bn), 3.58 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.74 [d, J = 10.6
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Hz, 3 H, (MeO)2P], 3.80 (AB system, J = 13.3 Hz, 1 H, Bn),
Bn), 3.64 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.81 [d, J = 10.6
Hz, 3 H, (MeO)2P], 3.87 (AB system, J = 13.3 Hz, 1 H, Bn),
4.12 (d, J = 22.2 Hz, 1 H, CHP), 6.36–6.42 (m, 2 H, HAr),
7.22–7.35 (m, 5 H, HAr), 7.46 (ddd, J = 2.5, 1.8, 0.8 Hz, 1 H,
HAr). 13C NMR (100 MHz, CDCl3): δ = 51.3 (d, J = 16.4 Hz,
CH2Ph), 52.7 (d, J = 162.5 Hz, CHP), 53.4 [d, J = 6.9 Hz,
(MeO)2P], 53.9 [d, J = 6.8 Hz, (MeO)2P], 109.5 (d, J = 7.5
3.93 (s, 3 H, MeO), 4.13 (d, J = 20.7 Hz, 1 H, CHP), 7.21–
7.36 (m, 5 H, HAr), 7.52 (AA′BB′ system, J = 8.3, 2.2 Hz, 2
H, HAr), 8.06 (AA′BB′ system, J = 8.3 Hz, 2 H, HAr). 13
C
NMR (100 MHz, CDCl3): δ = 51.5 (d, J = 17.3 Hz, Bn), 52.3
(MeO2C), 53.7 [d, J = 6.9 Hz, (MeO)2P], 54.0 [d, J = 6.9 Hz,
(MeO)2P], 59.4 (d, J = 152.8 Hz, CHP), 127.5, 128.5, 128.7,
128.8 (d, J = 5.9 Hz), 130.0, 130.1, 138.9, 141.1, 166.9. 31
P
Hz), 110.6, 127.2, 128.4 (2 × C), 138.8, 142.7 (2 × C). 31
P
NMR (161.9 MHz, CDCl3): δ = 22.15. HRMS (FAB+): m/z
[M + H]+ calcd for C18H23NO5P: 364.1314; found: 364.1322.
Compound 6n: white solid; mp 59–62 °C. 1H NMR (400
MHz, CDCl3): δ = 2.35 (br s, 1 H, NH), 3.52 (AB system, J
= 13.2 Hz, 1 H, CH2Ph), 3.61 [d, J = 10.6 Hz, 3 H, (MeO)2P],
3.74 [d, J = 10.6 Hz, 3 H, (MeO)2P], 3.79 (AB system, J =
13.2 Hz, 1 H, CH2Ph), 4.12 (d, J = 20.6 Hz, 1 H, CHP), 7.21–
7.35 (m, 5 H, HAr), 7.55 (AA′BB′ system, J = 8.1, 1.4 Hz, 2
NMR (81 MHz, CDCl3): δ = 23.36. HRMS (FAB+): m/z [M
+ H]+ calcd for C14H19NO4P: 296.1052; found: 296.1039.
Compound 6r: colorless oil. 1H NMR (400 MHz, CDCl3): δ
= 0.88 (t, J = 7.3 Hz, 3 H, Me), 1.31–1.43 (m, 1 H, CH2),
1.49–1.64 (m, 3 H, NH, CH2), 1.68–1.81 (m, 1 H, CH2), 2.91
(ddd, J = 12.2, 8.5, 4.6 Hz, 1 H, CHP), 3.77 [d, J = 9.9 Hz, 3
H, (MeO)2P], 3.80 [d, J = 9.9 Hz, 3 H, (MeO)2P], 3.87 (AB
system, J = 13.1, 1.8 Hz, 1 H, Bn), 3.96 (AB system, J = 13.1
Hz, 1 H, Bn), 7.20–7.37 (m, 5 H, HAr). 13C NMR (100 MHz,
CDCl3): δ = 14.0 (Me), 19.4 (d, J = 10.9 Hz, CH2), 32.1
(CH2), 52.3 (d, J = 5.0 Hz, CH2Ph), 52.8 [d, J = 7.6 Hz,
(MeO)2P], 53.0 [d, J = 6.4 Hz, (MeO)2P], 53.7 (d, J = 149.4
Hz, CHP), 127.2, 128.5 (2 × C), 140.1. 31P NMR (161.9
MHz, CDCl3): δ = 28.35. HRMS (FAB+): m/z [M + H]+ calcd
for C13H23NO3P: 272.1416; found: 272.1415.
H, HAr), 7.64 (AA′BB′ system, J = 8.1 Hz, 2 H, HAr). 13
C
NMR (100 MHz, CDCl3): δ = 51.5 (d, J = 17.1 Hz, CH2Ph),
53.7 [d, J = 6.9 Hz, (MeO)2P], 54.0 [d, J = 7.0 Hz, (MeO)2P],
59.3 (d, J = 153.0 Hz, CHP), 124.3 (q, J = 275.0, CF3), 125.7
(dq, J = 3.6, 3.6 Hz), 127.6, 128.5, 128.7, 129.1 (d, J = 5.9
Hz), 130.4 (dq, J = 32.2, 2.9 Hz), 138.9, 140.1 (d, J = 3.5
Hz). 31P NMR (161.9 MHz, CDCl3): δ = 24.78 (q, J = 2.5
Hz). HRMS (FAB+): m/z [M + H]+ calcd for C17H20F3NO3P:
374.1133; found: 374.1035.
(25) (a) Failes, T. W.; Battle, A. R.; Chen, C.; Cullinane, C.;
Woods, R.; Elliott, R.; Deacon, G. B.; Hambley, T. W.
J. Inorg. Biochem. 2012, 115, 220. (b) Quin, L. D.; Dysart,
M. R. J. Org. Chem. 1962, 27, 1012. (c) Ohta, K. Bull.
Chem. Soc. Jpn. 1992, 65, 2543. (d) Nagarajan, K.; Shelly,
K. P.; Perkins, R. R.; Stewart, R. Can. J. Chem. 1987, 65,
1729.
(26) (a) Heydari, A.; Karimian, A.; Ipaktschi, J. Tetrahedron
Lett. 1998, 39, 6729. (b) Saidi, M. R.; Azizi, N. Synlett 2002,
1347.
(27) (a) Tibhe, G. D.; Labastida-Galván, V.; Ordóñez, M. Rapid
Commun. Mass Spectrom. 2011, 25, 951. (b) Tibhe, G. D.;
Lagunas-Rivera, S.; Vargas-Díaz, E.; García-Barradas, O.;
Ordoñez, M. Eur. J. Org. Chem. 2010, 6573.
(28) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe, K. Org. Lett.
2005, 7, 2583.
Compound 6p: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 2.56 (br s, 1 H, NH), 3.43 [d, J = 10.4 Hz, 3 H, (MeO)2P],
3.60 (AB system, J = 13.4 Hz, 1 H, CH2Ph), 3.74 [d, J = 10.5
Hz, 3 H, (MeO)2P], 3.82 (AB system, J= 13.4 Hz, 1 H, CH2Ph),
4.09 (d, J = 20.2 Hz, 1 H, CHP), 6.10–6.17 (m, 2 H, HAr),
6.78 (ddd, J = 4.3, 2.6, 1.8 Hz, 1 H, HAr), 7.18–7.35 (m, 5 H,
HAr), 9.71 (br s, 1 H, NH-pyrrole). 13C NMR (100 MHz,
CDCl3): δ = 51.2 (d, J = 16.9 Hz, CH2Ph), 52.5 (d, J = 160.4
Hz, CHP), 53.5 [d, J = 6.9 Hz, (MeO)2P], 53.9 [d, J = 7.0 Hz,
(MeO)2P], 108.1, 109.5 (d, J = 9.4 Hz), 119.0, 124.8 (d, J =
5.4 Hz), 127.2, 128.4, 128.5, 139.5. 31P NMR (161.9 MHz,
CDCl3): δ = 22.70. HRMS (FAB+): m/z [M + H]+ calcd for
C14H20N2O3P: 295.1212; found: 295.1224.
Compound 6q: yellow liquid. 1H NMR (200 MHz, CDCl3):
δ = 1.94 (br s, 1 H, NH), 3.60 (AB system, J = 13.3 Hz, 1 H,
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Synlett 2014, 25, 1145–1149

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