Phenylboronic acid as efficient and eco-friendly catalyst for the one-pot, three-component synthesis of α-aminophosphonates under solvent-free conditions

Article abstract of DOI:10.1055/s-0032-1316558

A simple, mild, and efficient one-pot, three-component synthetic method has been developed for the preparation of α-aminophosphonates using phenylboronic acid as catalyst under solvent-free conditions at 50°C. The process involves the reaction of carbonyl compounds (aldehydes or ketones) with benzylamine and dimethyl phosphite. A wide range of carbonyl compounds are compatible with this reaction, producing tertiary and quaternary α-aminophosphonates in moderated to excellent yields in short time. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316558

LETTER
▌1931
letter
Phenylboronic Acid as Efficient and Eco-Friendly Catalyst for the One-Pot,
Three-Component Synthesis of α-Aminophosphonates under Solvent-Free
Conditions
Catalyst for the Synthesis of α-Aminophosphonates
Gaurao D. Tibhe,a Mercedes Bedolla-Medrano,a Carlos Cativiela,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@ciq.uaem.mx
b
Departamento de Química Orgánica, ISQCH, Universidad de Zaragoza–CSIC, 50009 Zaragoza, Spain
Received: 11.04.2012; Accepted after revision: 24.05.2012
dures typically suffer from one or more disadvantages
Abstract: A simple, mild, and efficient one-pot, three-component
such as the use of expensive and stoichiometric amount of
synthetic method has been developed for the preparation of α-ami-
catalyst, specialized handling techniques and tedious
workup are necessary, long reaction time, vigorous reac-
nophosphonates using phenylboronic acid as catalyst under solvent-
free conditions at 50 °C. The process involves the reaction of car-
bonyl compounds (aldehydes or ketones) with benzylamine and di- tion conditions, requirement of excess of reagents, use of
methyl phosphite. A wide range of carbonyl compounds are
compatible with this reaction, producing tertiary and quaternary α-
aminophosphonates in moderated to excellent yields in short time.
solvent, unsatisfactory yield, and lack of generality. Fur-
thermore, some of these catalysts can decompose or deac-
tivate with the water generated during imine formation,
therefore the introduction of a new and efficient water-re-
Key words: α-aminophosphonates, one-pot three-component reac-
tion, phenylboronic acid, solvent-free conditions
sistant catalyst for the synthesis of α-aminophosphonates
is desirable to develop a more efficient, simple, and mild-
er protocol.
Multicomponent reactions (MCR) play an important role
On the other hand, phenylboronic acid [PhB(OH)2] has
in synthetic and combinatorial chemistry because of its fa-
been used as catalyst in the Biginelli reaction,28 but to the
cility to synthesize small druglike molecules with several
best of our knowledge it has not yet been used in one-pot,
degrees of structural diversity. Multicomponent reactions
three-component reaction for the synthesis of α-amino-
generally involve three or more different starting materi-
phosphonates. PhB(OH)2 has a wide spectra of advantages
als to form a product, which contains all essential parts of
as catalyst as it is commercially available, nontoxic, inex-
them.1 Strecker,2 Passerini,3,4 and the Kabachnik–Fields5
pensive, and can be regarded as a green compound be-
reactions are some examples of MCR involving three re-
cause of its ultimate degradation into the environmentally
agents. The latter is one of the most important methods for
friendly boric acid. Additionally, it is a water-tolerant en-
the synthesis of α-aminophosphonic acids and α-amino-
tity that can act as Brønsted or Lewis acid in the presence
phosphonates.
of water.29 Therefore, in connection with our program
concerning to the synthesis of α-aminophosphonates,20–33
we now report for the first time an operationally simple,
expeditious solvent-free synthesis of several tertiary and
quaternary α-aminophosphonates using commercially
available PhB(OH)2 as catalyst at 50 °C (Scheme 1). The
versatility of this catalyst was exploited by us obtaining
the α-aminophosphonates with moderated to excellent
yields in very short reaction times.
Because of its structural analogy with α-amino acids, the
α-aminophosphonic acids are considered as an important
class of compounds with interesting biological activities
and applications,6–8 such as peptide mimics,9 antibiot-
ics,10,11 enzyme inhibitors,12–15 antiparasitical or antitu-
moral agents, and many more.16,17 Due to their low
toxicity towards human beings, these compounds are at-
tractive for use in agriculture and medicinal chemistry.6,9
For this reason, the synthesis of α-aminophosphonates has
received considerable attention, and significant progress
has been made to develop more efficient methods for the
preparation of these compounds.18–20 In this context, the
one-pot, three-component reaction between an aldehyde,
an amine, and di- or trialkyl phosphite catalyzed by differ-
ent Lewis or Brønsted acids,21–27 is one of the most useful
methods for the synthesis of α-aminophosphonates due to
its versatility and high yields. In recent years, several cat-
alysts have been designed and employed for this reaction;
however, in spite of their potential utility, these proce-
Initially, for the reaction standardization, we carried out
the reaction of benzaldehyde with benzylamine and di-
methyl phosphite at 50 °C in the presence of 10 mol% of
PhB(OH)2 under solvent-free conditions.34 The PhB(OH)2
was found to promote the reaction efficiently, affording
the corresponding α-aminophosphonate 1a in 86% yield
in only 30 minutes (Table 1, entry 1). No base or other ad-
ditives were required in this process. When 2.5, 5.0, and
7.5 mol% of PhB(OH)2 were used the yields were slightly
lower. Additionally, the reaction of benzaldehyde with
benzylamine and dimethyl phosphite at 80 °C under cata-
lyst- and solvent-free conditions gave 1a in no more than
37% yield after five hours.
SYNLETT 2012, 23, 1931–1936
Advanced online publication: 26.07.2012
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DOI: 10.1055/s-0032-1316558; Art ID: ST-2012-S0318-L
© Georg Thieme Verlag Stuttgart · New York

1932
G. D. Tibhe et al.
LETTER
Table 1 Three-Component Synthesis of Tertiary α-Aminophospho-
nates 1a–k under Solvent-Free Conditionsa (continued)
O
PhB(OH)2
(10 mol%)
O
R
P(OMe)2
NHBn
O
+
BnNH3
+
R
H
P(OMe)2
H
50 °C
Entry Aldehyde
Time Product 1
Yield
(%)b
(min)
1a–k
O
Scheme
1
Three-component, one-pot reaction catalyzed by
P(OMe)2
NHBn
PhB(OH)2
CHO
5
30
85
After the optimization of the reaction conditions, the
scope and limitations of this protocol were investigated by
treating a diverse range of aromatic and aliphatic alde-
hydes with benzylamine and dimethyl phosphite in the
presence of 10 mol% of PhB(OH)2. The results are sum-
marized in Table 1. Regardless of the nature of the func-
tional groups attached to the aromatic aldehydes, all the
reactions proceeded smoothly, generating the correspond-
ing α-aminophosphonates in good yields (Table 1, entries
1–6). Even the one-pot, three-component reaction of un-
protected aldehydes such as the indole-3-carboxaldehyde
gave the α-aminophosphonate 1g with 92% yield in only
15 minutes (Table 1, entry 7). The reaction was also suc-
cessful with aliphatic aldehydes (Table 1, entries 8–10),
but for these aldehydes the addition of benzylamine was
carried out at 0 °C. However, the one-pot, three-compo-
nent reaction of cinnamaldehyde afforded the α-amino-
phosphonate 1g in only 62% yield (Table 1, entry 11). The
formation of α-hydroxyphosphonate as a byproduct was
not observed in any of the reactions.
HO
HO
1e
O
P(OMe)2
NHBn
Cl
Cl
CHO
6
30
73
92
1f
O
CHO
P(OMe)2
NHBn
7
15
HN
N
H
1g
O
P(OMe)2
NHBn
CHO
8
30
45
30
30
74
69
79
62
1h
1i
O
P(OMe)2
9
NHBn
CHO
Table 1 Three-Component Synthesis of Tertiary α-Aminophospho-
nates 1a–k under Solvent-Free Conditionsa
O
Entry Aldehyde
Time Product 1
(min)
Yield
(%)b
P(OMe)2
NHBn
CHO
10
11
O
1j
P(OMe)2
NHBn
O
1
30
86
93
CHO
P(OMe)2
NHBn
1a
CHO
O
1k
P(OMe)2
a At 50 °C using 10 mol% of PhB(OH)2 as catalyst.
b Isolated yield after chromatographic purification.
MeO
MeO
CHO
CHO
2
60
NHBn
1b
We continued our research testing the reactivity of ke-
tones under similar conditions. The results are summa-
rized in Table 1. The one-pot, three-component reaction
with aryl ketones was sluggish to afford the corresponding
α-aminophosphonates 2a–f (Table 2, entries 1–6). The re-
action was monitored by TLC, but the prolongation of re-
action time did not show an improvement in the yield.
However, aliphatic ketones were found to be more reac-
tive and produced the corresponding α-aminophospho-
O
P(OMe)2
NHBn
MeO
MeO
3
20
91
83
MeO
MeO
1c
O
P(OMe)2
NHBn
CHO
OMe
4
45
OMe
1d
Synlett 2012, 23, 1931–1936
© Georg Thieme Verlag Stuttgart · New York

LETTER
Catalyst for the Synthesis of α-Aminophosphonates
1933
Table 2 Three-Component Synthesis of Quaternary α-Aminophos-
phonates 2a–k under Solvent-Free Conditionsa
nates 2g–k in good to excellent yields in only 30 minutes
(Table 2, entries 7–11).
Entry
10
Ketone
Time Product 2
(h)
Yield
(%)b
Table 2 Three-Component Synthesis of Quaternary α-Aminophos-
phonates 2a–k under Solvent-Free Conditionsa
O
Entry
Ketone
Time Product 2
(h)
Yield
(%)b
Me
Me
P(OMe)2
Me
0.5
73
68
O
Me
O
NHBn
P(OMe)2
2j
1
4.0
37
28
O
O
Me
NHBn
P(OMe)2
Me
2a
O
11
0.5
O
NHBn
P(OMe)2
2k
2
3
8.0
O
Me
NHBn
a At 50 °C using 10 mol% of PhB(OH)2 as catalyst.
b Isolated yield after chromatographic purification.
Me
2b
O
Based on the above results, we suggest a mechanism
wherein the in situ formation of the imine intermediate A,
generated from condensation reaction of aldehyde or ke-
tone and benzylamine, is activated either by protonation
giving B or by coordination with the boron atom to give
C, both induced by the phenylboronic acid which acts as
a Lewis or Brønsted acid.26 In the next step, the nucleo-
philic attack of dimethyl phosphite to B or C afforded the
corresponding α-aminophosphonates (Scheme 2).
P(OMe)2
O
4.0
-
NHBn
2c
O
P(OMe)2
O
4
4.0
31
NHBn
Bn
R2
OH
B
+
N
Bn
R2
O
H
N
HO
Ph
BnNH2
R2
– H2O
PhB(OH)2
Bn
R2
or
R1
2d
N
R1
R1
R1
O
A
B
C
P(OMe)2
O
5
6
7
8.0
50
53
93
H P(OMe)2
O
NHBn
H
O
2e
P(OMe)2
N
O
Bn
R1
R2
P(OMe)2
O
8.0
Scheme 2 Proposed mechanism for the one-pot, three-component
NHBn
reaction catalyzed by PhB(OH)2
2f
O
In conclusion, we have developed a mild and efficient
method for the synthesis of tertiary and quaternary α-ami-
nophosphonates through a convenient one-pot, three-
component reaction of aliphatic or aromatic aldehydes or
ketones with benzylamine and dimethyl phosphite cata-
lyzed by PhB(OH)2 under solvent-free conditions. Some
notable advantages of this method are: (a) operationally
simple procedure and use of catalytic amount of
PhB(OH)2, (b) ability of catalyst as water-tolerant entity,
(c) general applicability to aliphatic and aromatic alde-
hydes and ketones, (d) reaction conditions tolerant to a va-
riety of sensitive functionalities, (e) short reaction time,
and (f) excellent reaction efficiency. This method could
be useful in the large-scale synthesis of α-aminophospho-
P(OMe)2
O
0.5
NHBn
2g
O
Me
Me
P(OMe)2
O
8
9
0.5
0.5
85
76
Me
NHBn
Me
2h
O
Me
P(OMe)2
Me
O
Me
NHBn
Me
2i
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1931–1936

1934
G. D. Tibhe et al.
LETTER
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nates, for example, conpounds 1i, 2g,h,j have been ob-
tained on a five-gram scale.
Acknowledgment
The authors thank CONACYT-MEXICO (Project 62271), Ministe-
rio de Ciencia e Innovación-FEDER (projects CTQ2007-62245
and CTQ2010-17436), Gobierno de Aragón (group E40), and
CONACYT-CSIC (project 2008MX0044) for their financial sup-
port. We thank to Victoria Labastida-Galván and Selene Lagunas-
Rivera for their technical assistance. Two of us, G.D.T. and M.B.M.
also thank the CONACYT for the Graduate Scholarships.
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iotSrat
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t
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References and Notes
(34) In a typical experiment, to a mixture of aldehyde or ketone
(2.5 mmol) and benzylamine (2.5 mmol) was added
PhB(OH)2 (10 mol%). The reaction mixture was stirred at
r.t. for 15 min. After this time, dimethyl phosphite (2.6
mmol) was added, and the reaction mixture was stirred at
50 °C for a specific period of time (see Tables 1 and 2), and
the progress of the reaction was monitored by TLC. The
crude was purified by flash chromatography with EtOAc–
hexane (70:30), obtaining the pure α-aminophosphonates.
1H NMR, 13C NMR, 31P NMR, and HRMS data for some
newly obtained α-aminophosphonates are as follows.
Compound 1c: white solid; mp 55–57 °C. 1H NMR (400
MHz, CDCl3): δ = 2.20 (br s, 1 H, NH), 3.55 [d, JHP = 10.8
Hz, 3 H, (CH3O)2P]. 3.74 [d, JHP = 10.4 Hz, 3 H, (CH3O)2P],
3.80 (AB system, J = 13.2 Hz, 2 H, CH2Ph), 3.89 (s, 3 H,
CH3O), 3.90 (s, 3 H, CH3O), 3.98 (d, JHP = 19.6 Hz, 1 H,
CHP), 6.86–7.00 (m, 3 H, HAr), 7.23–7.33 (m, 5 H, HAr).
13C NMR (100 MHz, CDCl3): δ = 51.3 (d, JCP = 16.7 Hz,
CH2Ph), 53.5 [d, JCP = 6.1 Hz (CH3O)2P], 53.8 [d, JCP = 7.5
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Hz (CH3O)2P], 56.1 (CH3O), 56.2 (CH3O), 59.1 (d, JCP
=
154.7 Hz, CHP), 111.5, 111.9, 121.4 (d, JCP = 7.6 Hz), 127.3,
128.0, 128.5, 128.6, 139.5, 149.2, 149.5. 31P NMR (80 MHz,
CDCl3): δ = 27.03. HRMS (FAB+): m/z calcd for
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C18H25NO5P: 366.1470; found: 366.1467.
Compound 1d: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 2.20 (br s, 1 H, NH), 3.51 [d, JHP = 10.4 Hz, 3 H,
(CH3O)2P], 3.56 (AB system, J = 13.2 Hz, 1 H, CH2Ph), 3.74
(AB system, J = 13.2 Hz, 1 H, CH2Ph), 3.78 [d, JHP = 10.8
Hz, 3 H, (CH3O)2P], 3.80 (s, 3 H, OCH3), 4.68 (d, JHP = 21.1
Hz, 1 H, CHP), 6.90 (d, JHH = 8.4 Hz, 1 H, HAr), 7.01 (t, JHH
= 7.2 Hz, 1 H, HAr), 7.20–7.31 (m, 6 H, HAr), 7.53–7.56 (m,
1 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.6 (d, J =
16.8 Hz, CH2Ph), 51.7 (d, JCP = 156.6 Hz, CHP), 53.4 [d, JCP
= 6.5 Hz (CH3O)2P], 53.9 [d, JCP = 6.6 Hz (CH3O)2P], 55.8
(CH3O), 111.0 (d, JCP = 2.2 Hz), 121.2 (d, JCP = 3.0 Hz),
124.4, 127.2, 128.4, 128.6, 129.0 (d, JCP = 5.6 Hz), 129.1 (d,
J
CP = 3.0 Hz), 139.8, 158.0 (d, JCP = 7.3 Hz). 31P NMR (80
MHz, CDCl3): δ = 27.66. HRMS (FAB+): m/z calcd for
C17H23NO4P: 336.1365; found: 336.1378.
Compound 1e: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 3.47 [d, JHP = 10.4 Hz, 3 H, (CH3O)2P], 3.53 (AB system,
J = 13.2 Hz, 1 H, CH2Ph), 3.78 (AB system, J = 12.8 Hz, 1
H, CH2Ph), 3.79 [d, JHP = 10.4 Hz, 3H, (CH3O)2P], 3.96 (d,
JHP = 20.8 Hz, 1 H, CHP), 6.75–6.86 (m, 2 H, HAr), 7.16–
7.25 (m, 3 H, HAr), 7.26–7.33 (m, 4 H, HAr). 13C NMR (100
MHz, CDCl3): δ = 51.0 (d, JCP = 18.0 Hz, CH2Ph), 53.7 [d,
JCP = 6.7 Hz, (CH3O)2P], 54.1 [d, JCP = 6.9 Hz (CH3O)2P],
58.8 (d, JCP = 155.0 Hz, CHP), 114.9 (d, JCP = 5.1 Hz), 115.8
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Synlett 2012, 23, 1931–1936
© Georg Thieme Verlag Stuttgart · New York

LETTER
(d, JCP = 2.9 Hz), 120.4 (d, JCP = 7.9 Hz), 127.1, 128.3, 128.4,
Catalyst for the Synthesis of α-Aminophosphonates
1935
(FAB+): m/z calcd for C18H23NO3P: 332.1416; found:
129.6 (d, JCP = 1.8 Hz), 136.3 (d, JCP = 2.8 Hz), 139.1, 157.6
(d, JCP = 2.8 Hz). 31P NMR (80 MHz, CDCl3): δ = 27.19.
HRMS (FAB+): m/z calcd for C16H21NO4P: 322.1208;
found: 322.1219.
332.1420.
Compound 2b: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 1.02 (t, JHH = 7.2 Hz, 3 H, CH3), 2.07–2.21 (m, 2 H,
CH2CH3 and NH), 2.40–2.50 (m, 1 H, CH2CH3), 3.51 [d,
JHP = 10.0 Hz, 3 H, (CH3O)2P], 3.70 (AB system, J = 13.2
Hz, 1 H, CH2Ph), 3.72 [d, JHP = 10.4 Hz, 3 H, (CH3O)2P],
3.76 (AB system, J = 12.8 Hz, 1 H, CH2Ph), 7.24–7.45 (m,
8 H, HAr), 7.70–7.73 (m, 2 H, HAr). 13C NMR (100 MHz,
CDCl3): δ = 7.9 (d, JCP = 6.1 Hz, CH3), 27.3 (CH2), 46.7 (d,
JCP = 9.1 Hz, CH2Ph), 53.2 [d, JCP = 7.6 Hz, (CH3O)2P], 53.5
[d, JCP = 6.0 Hz, (CH3O)2P], 64.4 (d, JCP = 142.6 Hz, CHP),
127.1, 127.3 (d, JCP = 3.1 Hz), 128.1, 128.2, 128.3, 128.5,
139.0, 140.8. 31P NMR (80 MHz, CDCl3): δ = 29.92. HRMS
(FAB+): m/z calcd for C18H25NO3P: 334.1572; found:
334.1581.
Compound 1f: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 2.30 (br s, 1 H, NH), 3.52 (AB system, J = 13.6 Hz, 1 H,
CH2Ph), 3.59 [d, JHP = 10.8 Hz, 3 H, (CH3O)2P], 3.73 [d,
JHP = 10.4 Hz, 3 H, (CH3O)2P], 3.79 (AB system, J = 13.6
Hz, 1 H, CH2Ph), 4.03 (d, JHP = 20.0 Hz, 1 H, CHP), 7.22–
7.38 (m, 9 H, HAr). 13C NMR (100 MHz, CDCl3): δ = 51.3
(d, J = 16.7 Hz, CH2Ph), 53.7 [d, JCP = 7.6 Hz, (CH3O)2P],
54.0 [d, JCP = 6.0 Hz, (CH3O)2P], 58.7 (d, JCP = 154.7 Hz,
CHP), 127.5, 128.5, 128.7, 129.0, 130.1 (d, JCP = 6.1 Hz),
134.0 (d, JCP = 4.5 Hz), 134.2 (d, JCP = 4.5 Hz), 139.0. 31
NMR (80 MHz, CDCl3): δ = 26.20. HRMS (FAB+): m/z
calcd for C16H20ClNO3P: 340.0869; found: 340.0872.
P
Compound 2d: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 1.80–1.87 (m, 1 H, CH2), 2.09–2.25 (m, 2 H, CH2), 2.32–
2.43 (m, 1 H, CH2), 2.78–2.85 (m, 2 H, CH2), 3.45 [d, JHP
Compound 1g: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 2.06 (br s, 1 H, NH), 3.51 [d, JHP = 10.4 Hz, 3 H,
=
(CH3O)2P], 3.66 (AB system, J = 13.2 Hz, 1 H, CH2Ph), 3.78
[d, JHP = 10.4 Hz, 3 H, (CH3O)2P], 3.86 (AB system, J = 13.2
Hz, 1 H, CH2Ph), 4.40 (d, JHP = 18.4 Hz, 1 H, CHP), 7.09–
7.38 (m, 9 H, HAr), 7.66 (d, JHH = 2.0 Hz 1 H, HAr), 9.10 (br
s, NH). 13C NMR (100 MHz, CDCl3): δ = 51.5 (d, JCP = 16.7
10.0 Hz, 3 H, (CH3O)2P], 3.51 (AB system, J = 12.0 Hz, 1
H, CH2Ph), 3.70 (AB system, J = 12.4 Hz, 1 H, CH2Ph), 3.75
[d, JHH = 10.8 Hz, 3H, (CH3O)2P], 7.13–7.33 (m, 8 H, HAr),
7.76–7.80 (m, 1 H, HAr). 13C NMR (100 MHz, CDCl3): δ =
20.3 (d, JCP = 3.1 Hz, CH2), 30.2 (CH2), 30.4 (CH2), 47.0 (d,
JCP = 12.1 Hz, CH2Ph), 53.7 [d, JCP = 7.6 Hz, (CH3O)2P],
54.1 [d, JCP = 7.6 Hz, (CH3O)2P], 60.2 (d, JCP = 148.7 Hz,
CHP), 126.2 (d, JCP = 3.0 Hz), 127.1, 127.7 (d, JCP = 3.0 Hz),
128.4, 128.5, 128.8 (d, JCP = 4.6 Hz), 128.9, 129.6, 139.8 (d,
JCP = 6.1 Hz), 140.6. 31P NMR (80 MHz, CDCl3): δ = 30.52.
HRMS (FAB+): m/z calcd for C19H25NO3P: 346.1572;
found: 346.1568.
Hz, CH2Ph), 51.6 (d, JCP = 162.3 Hz, CHP), 53.6 [d, JCP
=
7.6 Hz, (CH3O)2P], 53.9 [d, JCP = 7.6 Hz, (CH3O)2P], 109.7,
111.7, 119.5, 119.9, 122.3, 124.7 (d, JCP = 7.6 Hz), 127.0,
127.3, 128.5, 128.6, 136.5, 139.7. 31P NMR (80 MHz,
CDCl3): δ = 27.89. HRMS (FAB+): m/z calcd for
C18H22N2O3P: 345.1368; found: 345.1369.
Compound 1i: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 0.76 (d, JHH = 6.4 Hz, 3 H, CH3), 0.91 (d, JHH = 7.2 Hz,
3 H, CH3), 1.48–1.55 (m, 2 H, CH2), 1.60 (br s, 1 H, NH),
1.84–1.88 (m, 1 H, CH), 2.93–2.99 (m, 1 H, CHP), 3.79 [d,
JHP = 10.8 Hz, 3 H, (CH3O)2P], 3.80 [d, JHP = 10.0 Hz, 3 H,
(CH3O)2P], 3.86 (AB system, J = 13.2 Hz, 1 H, CH2Ph), 4.00
(AB system, J = 13.2 Hz, 1 H, CH2Ph), 7.23–7.35 (m, 5 H,
HAr). 13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 23.6
(CH3), 24.6 (d, JCP = 11.7 Hz, CH), 39.4 (d, JCP = 2.2 Hz,
CH2), 52.1 (d, JCP = 147.9 Hz, CHP), 52.5 (d, JCP = 3.7 Hz,
CH2Ph), 52.9 [d, JCP = 6.5 Hz, (CH3O)2P], 53.0 [d, JCP = 7.3
Hz, (CH3O)2P], 127.3, 128.5, 128.6, 140.3. 31P NMR (80
MHz, CDCl3): δ = 32.58. HRMS (FAB+): m/z calcd for
C14H25NO3P: 286.1572 found: 286.1570.
Compound 2e: dark brown oil. 1H NMR (400 MHz, CDCl3):
δ = 2.17 (br s, 1 H, NH), 2.30–2.43 (m, 1 H, CH2), 2.59–2.70
(m, 1 H, CH2), 3.00–3.05 (m, 2 H, CH2), 3.52 (AB system,
J = 12.8 Hz, 1 H, CH2Ph), 3.60 [d, JHP = 10.4 Hz, 3 H,
(CH3O)2P], 3.70 (AB system, J = 12.4 Hz, 1 H, CH2Ph), 3.72
[d, JHP = 10.4 Hz, 3 H, (CH3O)2P], 7.20–7.33 (m, 8 H, HAr),
7.49–7.52 (m, 1 H, HAr). 13C NMR (100 MHz, CDCl3): δ =
30.6 (d, JCP = 3.0 Hz, CH2), 32.2 (CH2), 46.9 (d, JCP = 12.1
Hz, CH2Ph), 53.6 [d, JCP = 7.6 Hz, (CH3O)2P], 54.3 [d, JCP
6.0 Hz, (CH3O)2P], 69.7 (d, JCP = 154.7 Hz, CHP), 125.1,
125.7 (d, JCP = 3.0 Hz), 126.7, 127.1, 128.3, 128.5, 128.7,
140.2, 140.5, 145.0 (d, JCP = 7.6 Hz). 31P NMR (80 MHz,
CDCl3): δ = 29.41. HRMS (FAB+): m/z calcd for
=
Compound 1j: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 1.06 [s, 9 H, (CH3)3C], 1.7 (br s, 1 H, NH), 2.57 (d,
JHP = 15.6 Hz, 1 H, CHP), 3.76 [d, JHP = 10.4 Hz, 3 H,
(CH3O)2P], 3.78 (AB system, J = 12.4 Hz, 1 H, CH2Ph), 3.79
[d, JHP = 10.8 Hz, 3H, (CH3O)2P], 4.05 (AB system, J = 12.4
Hz, 1 H, CH2Ph), 7.23–7.38 (m, 5 H, HAr). 13C NMR (100
MHz, CDCl3): δ = 27.7 [d, JCP = 6.5 Hz, (CH3)3C], 35.4 [d,
C18H23NO3P: 332.1416; found: 332.1431.
Compound 2f: brown solid; mp 85–87 °C. 1H NMR (400
MHz, CDCl3): δ = 1.80 (br s, 1 H, NH), 3.12 (dd, J = 16.4,
7.2 Hz, 2 H, CH2), 3.53 (dd, J = 16.4, 13.2 Hz, 2 H, CH2),
3.77 [d, JHP = 10.4 Hz, 3 H, (CH3O)2P], 3.78 [d, JHP = 10.4
Hz, 3H, (CH3O)2P], 3.84 (s, 2 H, CH2Ph), 7.16–7.25 (m, 9
H, HAr). 13C NMR (100 MHz, CDCl3): δ = 41.0 (d, JCP = 6.1
Hz, CH2), 48.4 (d, JCP = 6.1 Hz, CH2Ph), 53.4 [d, JCP = 6.0
Hz, (CH3O)2P], 64.3 (d, JCP = 156.3 Hz, CHP), 124.6, 127.0,
128.2, 128.4, 140.5, 140.6, 140.8. 31P NMR (80 MHz,
CDCl3): δ = 32.42. HRMS (FAB+): m/z calcd for
J
CP = 7.3 Hz, C(CH3)3], 52.1 [d, JCP = 6.6 Hz, (CH3O)2P],
52.8 [d, JCP = 7.3 Hz, (CH3O)2P], 55.4 (d, JCP = 2.2 Hz,
CH2Ph), 64.5 (d, JCP = 138.5 Hz, CHP), 127.3, 128.5, 128.6,
140.4. 31P NMR (80 MHz, CDCl3): δ = 31.99. HRMS
(FAB+): m/z calcd for C14H25NO5P: 286.1572; found:
286.1565.
C18H23NO3P: 332.1416; found: 332.1431.
Compound 2i: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 0.99 (t, JHH = 7.2 Hz, 3 H, CH3CH2), 1.31, (d, JHP = 16.0
Hz, 3 H, CH3), 1.65–1.78 (m, 2 H, CH2CH3 and NH),
1.81–1.91 (m, 1 H, CH2CH3), 3.80 [d, JHP = 10.4 Hz, 3 H,
(CH3O)2P], 3.82 [d, JHP = 10.4 Hz, 3H, (CH3O)2P], 3.83 (AB
system, J = 12.4 Hz, 1 H, CH2Ph), 3.90 (AB system, J = 12.4
Hz, 1 H, CH2Ph), 7.21–7.38 (m, 5 H, HAr). 13C NMR (100
MHz, CDCl3): δ = 7.2 (d, JCP = 7.6 Hz, CH3), 20.6 (CH3),
27.4 (CH2), 47.6 (CH2Ph), 52.9 [d, JCP = 7.6 Hz, (CH3O)2P],
53.2 [d, JCP = 7.6 Hz, (CH3O)2P], 57.1 (d, JCP = 141.1 Hz,
CP), 127.1, 128.4, 128.6, 141.2. 31P NMR (80 MHz, CDCl3):
Compound 1k: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 1.88 (br s, 1 H, NH), 3.67–3.82 [m, 8 H, (CH3O)2P, CHP,
and CH2Ph], 3.97 (AB system, J = 13.4 Hz, 1 H, CH2Ph),
6.12–6.17 (m, 1 H, CH), 6.62 (d, JHH = 16.0 Hz, 1 H, CH),
7.26–7.41 (m, 10 H, HAr). 13C NMR (100 MHz, CDCl3):
δ = 51.5 (d, JCP = 16.1 Hz, CH2Ph), 53.7 [d, JCP = 6.6 Hz,
(CH3O)2P], 53.9 [d, JCP = 7.3 Hz, (CH3O)2P], 57.7 (d, JCP
=
155.1 Hz, CHP), 124.1 (d, JCP = 6.6 Hz, CH), 126.8, 127.4,
128.2, 128.5, 128.7, 128.8, 134.9 (d, JCP = 14.0 Hz, CH),
136.5, 139.5. 31P NMR (80 MHz, CDCl3): δ = 27.06. HRMS
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1931–1936

1936
G. D. Tibhe et al.
LETTER
δ = 34.32. HRMS (FAB+): m/z calcd for C13H23NO3P:
272.1416; found: 272.1417.
(100 MHz, CDCl3): δ = 7.7 (d, JCP = 6.1 Hz, CH3), 25.8 (d,
J
CP = 4.5 Hz, CH2), 47.3 [d, JCP = 3.0 Hz, (CH3O)2P], 52.7
Compound 2j: yellow liquid. 1H NMR (400 MHz, CDCl3):
δ = 0.99 (t, JHH = 8.0 Hz, 6 H, CH3CH2), 1.71–1.85 (m, 5 H,
CH2CH3 and NH), 3.80 [d, JHP = 10.8 Hz, 6 H, (CH3O)2P],
3.85 (s, 2 H, CH2Ph), 7.22–7.38 (m, 5 H, HAr). 13C NMR
(d, JCP = 9.1 Hz, CH2Ph), 60.6 (d, JCP = 136.5 Hz, CHP),
127.0, 128.3, 128.5, 141.2. 31P NMR (80 MHz, CDCl3): δ =
30.61. HRMS (FAB+): m/z calcd for C14H25NO3P: 286.1572;
found: 286.1575.
Synlett 2012, 23, 1931–1936
© Georg Thieme Verlag Stuttgart · New York

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