Solvent-and catalyst-free reaction of (aminomethyl)phosphonates with epoxides: Synthesis of novel {[(2-hydroxyethyl)amino]methyl}phosphonates

Article abstract of DOI:10.1002/hc.20615

Uncatalyzed reaction of epoxides with (aminomethyl)phosphonates for the synthesis of novel {[(2-hydroxyethyl)amino]methyl}phosphonates is described. Treatment of (aminomethyl)phosphonates with epoxides without any catalyst and under solvent-free condition

Full text of DOI:10.1002/hc.20615

Heteroatom Chemistry
Volume 21, Number 5, 2010
Solvent-and Catalyst-Free Reaction of
(Aminomethyl)phosphonates with Epoxides:
Synthesis of Novel {[(2-Hydroxyethyl)
amino]methyl}phosphonates
Babak Kaboudin and Mina Sorbiun
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang,
Zanjan 45137-66731, Iran
Received 28 February 2010; revised 5 May 2010, 13 May 2010
rheumatoid arthritis, among others [1–7]. The pep-
ABSTRACT: Uncatalyzed reaction of epoxides with
tide bond cleavage by proteases makes them impor-
(aminomethyl)phosphonates for the synthesis of
tant targets for the development of novel inhibitors
novel {[(2-hydroxyethyl)amino]methyl}phosphonates
that serve as new agents against many diseases. This
is described. Treatment of (aminomethyl)phos-
cleavage occurred by nucleophilic attack from water
phonates with epoxides without any catalyst and
to carbonyl group on the peptide via the formation
under solvent-free conditions gives novel {[(2-
of a tetrahedral transition state [8,9]. Hydroxyethy-
hydroxyethyl)amino]methyl}phosphonates.
Using
lamine peptide isosteres are reported as proteases
inhibitors that can mimic this transition state owing
to their tetrahedral geometry (Scheme 1) [10–12].
Phosphonic acids are of growing importance in
understanding and modulating biological processes
[13,14]. The synthesis of α-substituted phosphoryl
derivatives (phosphonic and phosphinic acids) has
attracted significant attention because of their bi-
ological activities, with broad application as en-
zyme inhibitors, antimetabolites, and antibiotics
[15]. Among α-functionalized phosphonic acids,
(aminomethyl)phosphonic acids have biological ac-
tivities such as antibacterial, herbicidal, and fungi-
cidal [16–18]. (Aminomethyl)phosphonic acids, the
phosphonic acid analogues of 1-amino carboxylic
acids, are an important class of compounds that ex-
hibit a variety of interesting and useful properties.
We were interested in the synthesis of
novel (2-hydroxyethyl)amines containing the
(aminomethyl)phosphonate moiety (Scheme 2).
Recently, we reported a convenient and sim-
ple method for the synthesis of (aminomethyl)-
phosphonic acid ester 2 from aromatic aldehydes
(Scheme 3) [18].
this method, a series of {[(2-hydroxyethyl)amino]-
methyl}phosphonates was synthesized in good
ꢀ
C
yields. 2010 Wiley Periodicals, Inc. Heteroatom Chem
21:284–289, 2010; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20615
INTRODUCTION
Proteases are protolytic enzymes that control protein
synthesis via peptide bond cleavage. The pro-
teases are involved in various physiological pro-
cesses, namely, blood coagulation, digestion, im-
mune defense, and reproduction. Their activity is
also associated with many pathological disorders
and consequently with various human diseases, in-
cluding AIDS, stroke, hypertension, cancer, malaria,
Correspondence to: Babak Kaboudin; e-mail: kaboudin@
iasbs.ac.ir.
Contract grant sponsor: Institute for Advanced Studies in Basic
Sciences (IASBS) Research Council.
Contract grant number: G2009IASBS120.
2010 Wiley Periodicals, Inc.
c
ꢀ
284

Solvent- and Catalyst-Free Reaction of (Aminomethyl)phosphonates with Epoxides 285
O
OH
O
OH
O
O
H
H
H
H
70°C
15 h
+
C
P(OEt)2
PhO
N
P(OEt)2
N
N
NH2
R1
R2
OPh
2a
3a
SCHEME 1 Hydroxyethylamine peptide isosteres.
4a
SCHEME 4
Ring opening of 2,3-epoxypropyl phenyl
OH
O
ether (3a) in the presence of diethyl [amino(phenyl)methyl]-
phosphonate (2a).
H
N
P(OEt)2
R1
R2
31P NMR spectrum of 4a exhibits two peaks
at δ 23.97 and 24.08 ppm as a result of two
diastereoisomers. 13C NMR spectrum of 4a ex-
hibits two doublets at δ 60.4 and 61.3 ppm in-
dicative of the coupling C P (JCP = 154.7 Hz)
moiety in the molecule. As expected, similar nu-
cleophilic substitution reaction, the ring open-
ing of epoxides with (aminomethyl)phosphonates,
occurred at the sterically less hindered position
on the epoxide. For the study of the scope
and limitation of the reaction, treatment of vari-
ous (aminomethyl)phosphonates with epoxides un-
der solvent-free condition at 70–90◦C is sum-
marized in Table 1 and Scheme 5. A series
of {[(2-hydroxyethyl)amino]methyl}phosphonates
(Scheme 5 and Table 1) was synthesized from the re-
actions of (aminomethyl)phosphonates 2a–2e with
epoxides 3a–3c.
Whenever styrene oxide 3c and [amino-
(phenyl)methyl]phosphonate 2a were used, the
reaction gave two compounds 4i and 5 in approx-
imately 9:1 ratio, respectively, which was deter-
mined from the ratio of integrals from 31P NMR
(entry 9, Table 1). Ring opening of styrene oxide
with (aminomethyl)phosphonates took place at both
sterically less and more hindered positions on the
epoxide ring. The 31P NMR spectrum of reaction
mixture exhibits four peaks as a result of two di-
astereoisomers of compounds 4i and 5. A reasonable
SCHEME
2
{[(2-Hydroxyethyl)amino]methyl}phospho-
nates.
A straightforward synthetic approach to (2-
hydroxyethyl)amine isosteres is the ring opening
of epoxides with the protected amino acids, using
LiClO4 and Ca(OTf)2 as Lewis acid catalyst [19–21].
As part of our effort to synthesize novel organophos-
phorus compounds [22–34], herein, we report un-
catalyzed synthesis of {[(2-hydroxyethyl)amino]-
methyl}phosphonates via ring opening of epoxides
with (aminomethyl)phosphonates under solvent-
free conditions.
RESULTS AND DISCUSSION
The ring opening of 2,3-epoxypropyl phenyl ether
3a, chosen as a model compound, was stud-
ied in the presence of diethyl [amino(phenyl)-
methyl]phosphonate (2a). The progress of the
reaction was monitored by thin layer chromatog-
raphy (TLC) (Scheme 4). As described in the fol-
lowing text, treatment of 2a with 2,3-epoxypropyl
phenyl ether failed to give corresponding {[(2-
hydroxyethyl)amino]methyl}phosphonates 4a after
48 h at ambient temperature. We found that an in-
crease in the reaction temperature led to the accel-
eration of the reaction rate and an increase in the
yield of 4a. We obtained 4a in 70% isolated yield
after 15 h at 70◦C.
OH
O
H
N
P(OEt)2
Ph
O
O
H
C
Ar
O
70–90°C
Solvent-free
15–24 h
1) NH4OH (aq)/reflux/5 h
O
+
Ar
P(OEt)2
+
4
2) Diethyl phosphite/70°C/2–5 h
H
C
NH2
Ph
OH
ArCHO
Ar
P(OEt)2
H
N
.
3) p-TsOH H2O/THF/0°C/2 h
4) NH4OH
P(OEt)2
2
NH2
3c
Ph
Ar
1
2
5
SCHEME 3 Convenient and simple method for the syn-
thesis of [(amino(aryl)methyl]phosphonates 2 from aromatic
aldehydes.
SCHEME
5
Ring opening of styrene oxide with
[amino(aryl)methyl]phosphonates 2.
Heteroatom Chemistry DOI 10.1002/hc

286 Kaboudin and Sorbiun
TABLE
1
Ring Opining Epoxides with [Amino(aryl)methyl]phosphonates
2
for the Synthesis of Novel
{[(Hydroxyethyl)amino](aryl)methyl}phosphonates 4 and 5 Under Solvent- and Catalyst-Free Conditions at 70◦C for
15 h
Entry
Ar
R
Product(s)
Yield (%)a
Ratiob of 4:5
1
2
3
4
5
6
7
8
9
C H5-
PhOCH2-
PhOCH2-
PhOCH2-
PhOCH2-
4a
4b
4c
70
73
45
45
56
75
75
70
67
–
–
–
–
–
–
–
–
9:1
o-6CH C H5-
3
6
m-CH C H5-
p-CH3C6H5-
p-CH3O6C H5-
4d
PhOCH2-
4e
3
6
C H5-
(CH3)2CHOCH2-
(CH3)2CHOCH2-
(CH3)2CHOCH2-
Ph-
4fc
o-6CH C H5-
4gc
4hc
4i + 5
3
6
m-CH C6H5-
C H5-3
6
aYield refers to isolated yield by column chromatography.
bRatio of products was determined from the ratio of integrals from 31P NMR.
cReaction carried out at 90◦C for 24 h.
explanation for this observation is that electronic
factors influenced nucleophilic ring opening of
styrene oxide with (aminomethyl)phosphonates un-
der the reaction conditions (Scheme 6).
obtained on a 250 Brucker Avance instrument, with
the chemical shifts being reported as δ ppm and cou-
plings expressed in hertz. The chemical shift data for
each signal on 1H NMR are given in units of δ relative
to CHCl3 (δ = 7.26) for CDCl3 solution. For 13C NMR
spectra, the chemical shifts in CDCl3 were recorded
relative to the CDCl3 resonance (δ = 77.0). Silica gel
column chromatography was performed with Silica
gel 100 (Merck No. 10184). Merck Silica-gel 60 F254
plates (No. 5744) were used for TLC.
In summary, we present ring opening of epox-
ides with (aminomethyl)phosphonates for the syn-
thesis of novel {[(2-hydroxyethyl)amino]methyl}-
phosphonates, important building blocks for
the synthesis of transition-state analogue en-
zyme inhibitors. A series of {[(2-hydroxyethyl)-
amino]methyl}phosphonates
was
synthesized
from the reactions (aminomethyl)phosphonates
with epoxides. Similar to nucleophilic substi-
tution reaction, the ring opening of epoxides
with (aminomethyl)phosphonates occurred at
the sterically less hindered position on the
epoxide. Ring opening of styrene oxide with
(aminomethyl)phosphonates took place at both
sterically less and more hindered positions on the
epoxide ring. Some of the major advantages of
this protocol are simple procedure, easy work-up,
good yields, and solvent- and catalyst-free reaction
conditions.
General Procedure for the Preparation of
(Aminomethyl)phosphonates (2)
The aldehyde (15 mmol) was added to ammonium
hydroxide (30%, 15 mL) and the solution was stirred
for 5 h at reflux. During this time, a white precip-
itate was formed. The precipitate was removed by
filtration and dried. Diethyl phosphite (6 mmol) was
added to this solid and the resulting solution was
stirred for 2–5 h at 70◦C. p-Toluenesulfonic acid
(6 mmol) in 50 mL of THF was added to the reac-
tion mixture, which was stirred for 2 h at 0◦ C. The
precipitate was removed by filtration and washed
with THF (20 mL). The precipitate was added to
15 mL of ammonium hydroxide (10%) and stirred
for 30 min at room temperature. Extraction with
ether (3 × 50 mL), evaporation of the solvent, and
EXPERIMENTAL
All chemicals were commercial products and dis-
tilled or recrystallized before use. NMR spectra were
OH
O
OH
O
O
H
N
H
C
O
H
70–90°C
Solvent-free
15–24 h
P(OEt)2
N
P(OEt)2
+
Ar
P(OEt)2
+
R
NH2
R
R
Ar
Ar
4
2
5
3
SCHEME 6 Ring opening of epoxides with [amino(aryl)methyl]phosphonates 2.
Heteroatom Chemistry DOI 10.1002/hc

Solvent- and Catalyst-Free Reaction of (Aminomethyl)phosphonates with Epoxides 287
chromatography on silica gel with EtOAc/n-hexane
br, NH2), 3.71 (3H, s), 3.60–4.05 (4H, m), 4.53 (1H,
d, JHP = 17.5), 6.80 (2H, d, J = 8.25 Hz), 7.30 (2H, d,
J = 8.5 Hz). 31P NMR (101.2 MHz, CDCl3/H3PO4):
25.73 ppm. 13C NMR (62.90 MHz, CDCl3): 16.3 (m,
CH3), 53.1 (d, JPC = 150.3 Hz, CH), 55.1 (CH3), 62.54
(d, JPC = 6.9 Hz, CH2), 62.7 (d, JPC = 6.9 Hz, CH2),
113.8 (d, JPC = 2.5 Hz), 128.8 (d, JPC = 6.3 Hz), 129.5
(d, JPC = 2.6 Hz), 159.2 (d, JPC = 6.8 Hz).
(9:1) gave the pure products as oil. All products gave
satisfactory spectral data in accordance with the as-
signed structures and literature reports [18].
Diethyl [Amino(phenyl)methyl]phosphonate (2a)
[18]. 1H NMR (250 MHz, CDCl3): δ 1.02 (3H,
t, J = 7.11 Hz), 1.10 (3H, t, J = 7.07 Hz),
1.93 (2H, br, NH2), 3.6–3.8 (2H, m), 3.8–3.9
(2H, m), 4.08 (1H, d, JHP = 17 Hz), 7.11–7.30
(5H, m). 31P NMR (101.2 MHz, CDCl3/H3PO4): δ
25.26 ppm. 13C NMR (62.90 MHz, CDCl3): δ 16.2
(d, 3 JPC = 7.5 Hz, CH3), 16.3 (d, 3 JPC = 5.66 Hz, CH3),
53.6 (d, 1 JPC = 149.7 Hz, CH), 62.6 (pt, 2 JPC = 7.54 Hz,
CH2), 127.5 (d, JPC = 4.4 Hz), 128.19 (d, JPC = 1.9 Hz),
137.5 (d, JPC = 3.14 Hz).
General Procedure for the Ring Opening of
Epoxides with (Aminomethyl)phosphonates for
the Preparation of {[(2-Hydroxyethyl)amino]-
methyl}phosphonates (4 and 5)
(Aminomethyl)phosphonate 2 (5 mmol) was added
to the epoxide (5 mmol) and the reaction mixture
was stirred for 15–24 h at 70–90◦C. The mixture
was subjected to column chromatography on silica
gel with EtOAc/n-hexane (8:2) and evaporation of
the solvent under reduced pressure to give the pure
products in 45–75% yields. All products gave satis-
factory spectral data in accordance with the assigned
structures.
Diethyl [Amino(o-tolyl)methyl]phosphonate (2b)
[18]. 1H NMR (250 MHz, CDCl3): 0.92 (3H, t,
J = 7.07 Hz), 1.11 (3H, t, J = 7.11 Hz), 2.03 (2H, br,
NH2), 2.20 (3H, s), 3.60–4.05 (m, 4H), 4.31 (1H,
d, JHP = 17.3 Hz), 6.95–7.14 (3H, m), 7.30–7.50 (1H,
m). 31P NMR (101.2 MHz, CDCl3/H3PO4): 26.34 ppm.
13C NMR (62.90 MHz, CDCl3): 16.1 (d, 3 JPC = 5.7 Hz,
3
CH3), 16.3 (d, JPC = 5.7 Hz, CH3), 19.5 (CH3), 49.3
Diethyl {[(2 - Hydroxy - 3 - (4 - phenoxy)propyl) -
amino](phenyl)methyl}phosphonate 4a (Mixture of
Two Diastereoisomers). Colorless oil; 1H NMR
(250 MHz, CDCl3): 1.06 (3H, t, J = 7 Hz), 1.15–
1.35 (3H, m), 2.35–2.85 (4H, m, including OH and
NH), 3.65–4.20 (8H, m), 6.75–7.05 (3H, m), 7.15–7.55
(7H, m). 31P NMR (101.2 MHz, CDCl3/H3PO4): 23.97,
24.08 ppm. 13C NMR (62.90 MHz, CDCl3): 16.2 (d,
JPC = 5.7 Hz, CH3), 16.4 (d, JPC = 6.3 Hz, CH3), 50.1
(d, 3 JPC = 16.3 Hz, CH2), 50.6 (d, 3 JPC = 16.3 HZ, CH2),
60.4 (d, JPC = 154.7 Hz, CH), 61.3 (d, JPC = 152.85 Hz,
CH), 62.9–63.2 (m, CH2), 68.1 (CH) 68.9 (CH), 70.01
(CH2), 114.5, 120.8, 128.01 (d, JPC = 2.5 Hz), 128.3–
1
2
(d, JPC = 149.7 Hz, CH), 62.4 (d, JPC = 7.6 Hz,
2
CH2), 62.6 (d, JPC = 6.92 Hz, CH2), 126.1 (d,
JPC = 2.5 Hz, CH), 126.9 (d, JPC = 4.4 Hz, CH), 127.4
(d, JPC = 2.5 Hz, CH), 130.1 (d, JPC = 4.4 Hz, CH).
Diethyl [Amino(m-tolyl)methyl]phosphonate (2c)
[18]. 1H NMR (250 MHz, CDCl3): 1.0–1.28 (6H,
m), 1.65–2.0 (2H, br, NH2), 2.31 (3H, s), 3.59–4.10
(42H, m), 4.15 (1H, d, JHP = 17 Hz), 7.04–7.30 (4H,
m). 31P NMR (101.2 MHz, CDCl3/H3PO4): 25.62 ppm.
13C NMR (62.90 MHz, CDCl3): 16.2–16.4 (m, CH3),
1
21.4 (CH3), 53.8 (d, JPC = 137.8 Hz, CH), 62.4–62.8
2
(m, CH2), 124.7 (d, JPC = 6.3 Hz, CH), 128.3–128.8
(Ar), 137.47, 137.95 (d, JPC = 3.2 Hz).
128.6 (m), 129.4, 135.5 (d, JPC = 3.5 Hz), 135.7 (d,
JPC = 3.8 Hz), 158.6. Anal. Calcd for C20H28NO5P. C,
61.04; H, 7.18; N, 3.56%. Found: C, 61.12; H, 7.35;
N, 3.52%.
Diethyl [Amino(p-tolyl)methyl]phosphonate (2d)
[18]. 1H NMR (250 MHz, CDCl3): 1.0–1.28 (6H,
m), 1.8–2.0 (2H, br, NH2), 2.28 (3H, S), 3.73–
4.08 (4H, m), 4.16 (1H, d, JHP = 17.5 Hz), 7.10
(2H, d, J = 8.0 Hz), 7.3 (2H, d, J = 8.0 Hz). 31P
NMR (101.2 MHz, CDCl3/H3PO4): 25.69 ppm. 13C
NMR (62.90 MHz, CDCl3): 16.2–16.3 (m, CH3),
Diethyl {[(2 - Hydroxy - 3 - (4 - phenoxy)propyl) -
amino](o-tolyl)methyl}phosphonate 4b (Mixture of
Two Diastereoisomers). Colorless oil; 1H NMR
(250 MHz, CDCl3): 1.04–1.10 (3H, m), 1.22–1.30 (3H,
m), 2.36 (3H, s), 2.40–2.85 (3H, m, including NH),
3.69–3.78 (1H, m), 3.80–4.20 (7H, m, including OH),
4.35 (1H, d, JHP = 20.7 Hz), 6.84–6.95 (3H, m), 7.16–
7.27 (5H, m), 7.54 (1H, br).
1
21.1 (CH3), 53.50 (d, JPC = 150.3 Hz, CH), 62.6 (d,
2 JPC = 6.9 Hz, CH2), 62.7 (d, 2 JPC = 6.9 Hz, CH2), 127.5
(d, JPC = 6.3 Hz), 129.1 (d, JPC = 1.9 Hz), 134.4 (d,
JPC = 3.8 Hz), 137.5 (d,JPC = 3.1).
31P NMR (101.2 MHz, CDCl3/H3PO4): 24.57,
24.64 ppm. 13C NMR (62.90 MHz, CDCl3): 16.2
(d, JPC = 5.7 Hz), 16.4 (d, JPC = 5.7 Hz), 19.8,
49.3 (d, JPC = 16.3 Hz), 50.5 (d, JPC = 16.3 Hz),
55.6 (d, JPC = 152.8 Hz), 56.6 (d, JPC = 154.7 Hz),
Diethyl [Amino(p-methoxyphenyl)methyl]phos-
phonate (2e) [18]. 1H NMR (250 MHz, CDCl3): 1.11
(3H, t, J = 7.1 Hz), 1.20 (3H, t, J = 7 Hz), 1.19 (2H,
Heteroatom Chemistry DOI 10.1002/hc

288 Kaboudin and Sorbiun
62.7–63.3 (m), 68.1, 69.0, 70.0 (d, JPC = 6.50 Hz),
114.5, 120.9, 126.4, 127.3, 127.7, 129.4, 130.4, 134.0
(d, JPC = 3.5 Hz), 137.1 (d, JPC = 2.5 Hz), 158.5. Anal.
Calcd for C21H30NO5P. C, 61.89; H, 7.42; N, 3.44%.
Found: C, 61.75; H, 7.35; N, 3.52%.
(d, JPC = 157.2 Hz), 62.7–63.3 (m), 68.0, 68.9, 70.1,
113.9, 114.5, 120.9, 127.3 (d, JPC = 2.2 Hz), 127.6 (d,
JPC = 2.5 Hz), 129.4, 129.6 (d, JPC = 6.3 Hz), 158.6,
159.4 (d, JPC = 2.5 Hz). Anal. Calcd for C21H30NO6P.
C, 59.55; H, 7.14; N, 3.31%. Found: C, 59.45; H, 7.25;
N, 3.42%.
Diethyl {[(2 - Hydroxy - 3 - (4 - phenoxy)propyl) -
amino](m-tolyl)methyl}phosphonate 4c (Mixture of
Two Diastereoisomers). Colorless oil; 1H NMR
(250 MHz, CDCl3): 1.0–1.15 (3H, m), 1.20–1.40
(3H, m), 2.34 (3H, s), 2.55–2.85 (3H, m, including
NH), 3.69–3.84 (1H, m), 3.90–4.20 (8H, m, includ-
ing OH), 6.85–6.96 (3H, m), 7.11 (1H, br), 7.16–
7.35 (5H, m). 31P NMR (101.2 MHz, CDCl3/H3PO4):
23.98, 24.06 ppm. 13C NMR (62.90 MHz, CDCl3):
16.2 (d, JPC = 5.7 Hz), 16.4 (d, JPC = 5.7 HZ), 21.4,
49.3 (d, JPC = 16.3 Hz), 60.2 (d, JPC = 16.3 Hz), 61.3
(d, JPC = 152.8 Hz), 56.6 (d, JPC = 154.7 Hz), 62.7–
63.3 (m), 67.9, 69.0, 70.0, 114.5, 120.9, 125.5 (d,
JPC = 6.3 Hz), 128.43 (d, JPC = 2.52 Hz), 128.9 (d,
JPC = 2.6 Hz), 129.1 (d, JPC = 6.3 H), 129.2, 135.3 (d,
JPC = 3.5 Hz), 135.4 (d, JPC = 3.78 Hz), 138.1, 158.6.
Anal. Calcd for C21H30NO5P. C, 61.89; H, 7.42; N,
3.44%. Found: C, 61.66; H, 7.45; N, 3.32%.
Diethyl {[(2 - Hydroxy - 3 - (isopropoxy)propyl) -
amino](phenyl)methyl}phosphonate 4f (Mixture of
Two Diastereoisomers). Colorless oil; 1H NMR
(250 MHz, CDCl3): 1.02–1.18 (9H, m), 1.22–1.34
(3H, m), 2.34–2.75 (m, 3H, including NH), 3.25–
3.65 (4H, m, including OH), 3.65–4.15 (6H, m), 7.21–
7.40 (m, 5H). 31P NMR (101.2 MHz, CDCl3/H3PO4):
23.95 ppm. 13C NMR (62.90 MHz, CDCl3): 16.2
(d, JPC = 5.7 Hz), 16.4 (d, JPC = 5.7 Hz), 21.9, 50.5
3
(d, JPC = 16.3 Hz), 50.8 (d, JPC = 16.3 Hz), 60.3 (d,
JPC = 154.1 Hz), 61.3 (d, JPC = 152.8 Hz), 62.6–63.0
(m), 68.5, 69.7, 70.5, 72.1, 127.9 (d, JPC = 2.5 Hz),
128.4, 128.5 (d, JPC = 2.5 Hz), 135.6 (d, JPC = 3.14).
Anal. Calcd for C17H30NO5P. C, 56.79; H, 8.42; N,
3.90%. Found: C, 56.70; H, 8.35; N, 3.78%.
Diethyl {[(2 - Hydroxy - 3 - (isopropoxy)propyl) -
amino](o-tolyl)methyl}phosphonate 4g (Mixture of
Two Diastereoisomers). Colorless oil; 1H NMR
(250 MHz, CDCl3): 0.90–1.05 (9H, m), 1.12–1.22 (3H,
m), 2.23 (s, 3H), 2.30–2.75 (m, 3H, including NH),
Diethyl {[(2 - Hydroxy - 3 - (4 - phenoxy)propyl) -
amino](p-tolyl)methyl}phosphonate 4d (Mixture of
Two Diastereoisomers). Colorless oil; 1H NMR
(250 MHz, CDCl3): 1.13 (3H, t, J = 7 Hz), 1.21–1.35
(3H, m), 2.34 (4H, broad singlet, including NH),
2.65–2.85 (2H, m), 3.69–3.84 (1H, m), 3.90–4.20 (8H,
m, including OH), 6.86 (2H, d, J = 7.8), 6.94 (1H, t,
3.25–4.10 (8H, m, including OH), 4.21 (1H, d, JP H
=
20.7), 6.98–7.20 (m, 3H), 7.40–7.60 (m, 1H). 31P NMR
(101.2 MHz, CDCl3/H3PO4): 23.95 ppm; 31P NMR
(101.2 MHz, DMSO/H3PO4): 24.67, 24.70 ppm. 13C
NMR (62.90 MHz, CDCl3): 16.0 (d, JPC = 5.7 Hz), 16.2
(d, JPC = 5.7 Hz), 19.6, 21.9, 50.1 (d, JPC = 16.3 Hz),
50.7 (d, JPC = 16.3 Hz), 55.6 (d, JPC = 155.4 Hz), 56.2
(d, JPC = 153.4 Hz), 62.6–63.0 (m), 68.7, 69.4, 70.5
(d, JPC = 2.5 Hz), 71.9, 126.1–126.3 (m), 127.2–127.6
(m), 130.2 (d, JPC = 2.5 Hz), 134.0 (d, JPC = 2.5 Hz),
134.1 (d, JPC = 3.1 Hz), 136.9 (d, JPC = 3.8 Hz), 137.0
(d, JPC = 3.8 Hz). Anal. Calcd for C18H32NO5P. C,
57.88; H, 8.64; N, 3.75%. Found: C, 57.68; H, 8.45;
N, 3.60%.
J = 7.5), 7.15 (2H, d, J = 7.75), 7.18–7.35 (4H, m). 31
P
NMR (101.2 MHz, CDCl3/H3PO4): 24.12, 24.20 ppm.
13C NMR (62.90 MHz, CDCl3): 16.3 (d, JPC = 5.7 Hz),
3
16.4 (d, JPC = 5.7 Hz), 21.1, 50.0 (d, JPC = 16.3 Hz),
3
50.1 (d, JPC = 16.3 Hz), 60.4 (d, JPC = 154.7 Hz),
61.3 (d, JPC = 152.8 Hz), 62.6–63.4 (m), 67.9, 69.0,
70.0, 114.5, 121.0, 128.3 (d, JPC = 6.3 Hz), 129.3
(d, JPC = 8.8 Hz), 132.4 (d, JPC = 2.5 Hz), 133.8 (d,
2 JPC = 2.5 Hz), 158.5. Anal. Calcd for C21H30NO5P. C,
61.89; H, 7.42; N, 3.44%. Found: C, 61.80; H, 7.30;
N, 3.48%.
Diethyl {[(2 - Hydroxy - 3 - (isopropoxy)propyl) -
amino](m-tolyl)methyl}phosphonate 4h (Mixture of
Two Diastereoisomers). Colorless oil; 1H NMR
(250 MHz, CDCl3): 1.0–1.20 (9H, m), 1.22–1.35
(3H, m), 2.34 (s, 3H), 2.40–2.75 (m, 3H, in-
cluding NH), 3.25–3.65 (4H, m, including OH),
3.65–4.25 (6H, m), 7.0–7.30 (m, 4H). 31P NMR
(101.2 MHz, CDCl3/H3PO4): 23.95 ppm. 13C NMR
(62.90 MHz, CDCl3): 16.0 (d, JPC = 5.7 Hz), 16.2
(d, JPC = 5.7 Hz), 21.4, 22.0, 50.1 (d, JPC = 16.3 Hz),
50.7 (d, JPC = 16.3 Hz), 60.1 (d, JPC = 154.1 Hz), 61.2
(d, JPC = 152.8 Hz), 62.8–63.0 (m), 68.5, 69.6, 70.5
Diethyl {[(2 - Hydroxy - 3 - (4 - phenoxy)propyl) -
amino](p-methoxyphenyl)methyl}phosphonate
4e
(Mixture of Two Diastereoisomers). Colorless oil;
1H NMR (250 MHz, CDCl3): 1.12 (3H, t, J = 6.7 Hz),
1.18–1.32 (3H, m), 2.53–3.35 (4H, m, including
OH and NH), 3.77 (3H, s), 3.75–4.20 (8H, m),
6.80–6.95 (5H, m), 7.15–7.35 (4H, m). 31P NMR
(101.2 MHz, CDCl3/H3PO4): 24.17, 24.27 ppm. 13C
NMR (62.90 MHz, CDCl3): 16.3 (d, JPC = 5.7 Hz),
16.4 (d, JPC = 6.3 Hz), 49.8 (d, JPC = 16.3 Hz), 50.3 (d,
JPC = 16.35 Hz), 55.2, 59.6 (d, JPC = 157.2 Hz), 60.6
Heteroatom Chemistry DOI 10.1002/hc

Solvent- and Catalyst-Free Reaction of (Aminomethyl)phosphonates with Epoxides 289
[8] Powers, J. C.; Harper, J. W. In Proteinase In-
(d, JPC = 2.5 Hz), 72.1, 125.5 (d, JPC = 2.5 Hz), 128.3–
hibitors; Barrett, A. J., Salvesen, G. (Eds.); Elsevier:
Amsterdam, 1986.
[9] Mucha, A.; Kafarski, P. Tetrahedron 2002, 58, 5855–
5863.
[10] Kick, E. K.; Ellman, J. A. J Med Chem 1995, 38, 1427–
1430.
128.4 (m), 128.6–128.8 (m), 129.1 (d, JPC = 2.5 Hz),
135.5 (d, JPC = 2.5 Hz), 135.61 (d, JPC = 3.1 Hz),
138.0–138.1 (m). Anal. Calcd for C18H32NO5P. C,
57.88; H, 8.64; N, 3.75%. Found: C, 57.73; H, 8.56;
N, 3.65%.
[11] Monrue, J. A.; Homback, W. J.; Campbell, J. B.;
Ouellette, M. A.; Hatch, S. D.; Muesing, M. A.;
Wiskerchen, M. A.; Baxter, A. J.; Su, K.; Campanale,
K. Bioorg Med Chem Lett 1995, 5, 2885–
2890.
[12] Ghosh, A. K.; Bilcer, G.; Harwood, C.; Kawahama, R.;
Shin, D.; Hussain, K. A.; Hong, L.; Loy, J. A.; Nguyen,
C.; Koelsch, G.; Ermolieff, J.; Tang, J. J Med Chem
2001, 44, 2865–2868.
[13] Engel, R. Chem Rev 1977, 77, 349–367.
[14] Moonen, K.; Laureyn, I.; Stevens, C. V. Chem Rev
2004, 104, 6177–6215.
[15] Collinsova, M.; Jiracek, J. Curr Med Chem 2000, 7,
629–647.
[16] Kafarski, P.; Lejczak, B.; Tyka, R.; Koba, L.; Pliszczak,
E.; Wieczorek, P. J Plant Growth Regul 1995, 14, 199–
203.
[17] (a) Ishiguri, Y.; Yamada, Y.; Kato, T.; Sasaki,
M.; Mukai, K. Eur Pat Appl EP 82-301905, 1982;
(b) Chem Abstr 1983, 98, 102686.
[18] Kaboudin, B.; Moradi, K. Tetrahedron Lett 2005, 46,
2689.
[19] Sova, M.; Babicˇ, A.; Pecˇar, S.; Gobec, S. Tetrahedron
2007, 63, 141–147.
Diethyl {[(2 - Hydroxy - 2 - (phenyl)ethyl)amino] -
(phenyl)methyl}phosphonate 4i (Mixture of Two Di-
1
astereoisomers). Colorless oil; H NMR (250 MHz,
CDCl3): 1.0–1.80 (3H, m), 1.22–1.40 (3H, m), 2.53–
2.95 (3H, m, including NH), 3.55–4.30 (6H, m, in-
cluding OH), 4.65 (0.5 H, dd, J = 8.5 and 3.2 Hz),
4.74 (0.5 H, dd, J = 8.5 and 3.2 Hz), 7.20–7.38 (10H,
m). 31P NMR (101.2 MHz, CDCl3/H3PO4): 23.77,
23.89 ppm and a little amount of 5 detected by 31P
NMR 23.25 and 23.30 ppm. 13C NMR (62.90 MHz,
CDCl3): 16.2 (d, JPC = 5.0 Hz), 16.4 (d, JPC = 5.7 Hz),
54.8 (d, JPC = 16.3 Hz), 55.8 (d, JPC = 17.6 Hz), 59.8
(d, JPC = 154.7 Hz), 61.2 (d, JPC = 153.5 Hz), 62.6–
63.2 (m), 71.3, 72.5, 125.8, 127.4 (d, JPC = 2.2 Hz),
127.8, 128.0–128.7 (m), 128.29 (2CH), 135.3 (d,
JPC = 3.4 Hz), 135.7 (d, JPC = 3.4 Hz), 142.1, 142.2.
Anal. Calcd for C19H26NO4P. C, 62.78; H, 7.21; N,
3.86%. Found: C, 62.67; H, 7.25; N, 3.74%.
[20] Babicˇ, A.; Sova, M.; Gobec, S.; Pecˇar, S. Tetrahedron
Lett 2006, 47, 1733–1735.
[21] Higashibayashi, S.; Tomonori, M.; Shinko, K.;
Hashimoto, K.; Nakata, M. Heterocycles 2002, 57,
111–122.
[22] Kaboudin, B.; Haghighat, H.; Yokomatsu, T. J Org
Chem 2006, 71, 6604.
REFERENCES
[1] Goeschke, R.; Cohen, N. C.; Wood, J. M.; Maibaum,
J. Bioorg Med Chem Lett 1997, 7, 2735–2740.
[2] Guthrie, R. Am J Cardiol 1993, 72, 22–24.
[3] Abbenante, G.; Fairlie, D. P. Med Chem 2005, 1, 71–
104.
[4] Freskos, J. N.; Fobian, Y. M.; Benson, T. E.; Moon, J.
B.; Bienkowski, M. J.; Brown, D. L.; Emmons, T. L.;
Heintz, R.; Laborde, A.; McDonald, J. J.; Mischke, B.
V.; Molyneaux, J. M.; Mullins, P. B.; Prince, D. B.;
Paddock, D. J.; Tomassellia, A. G.; Winterrowd, G.
Bioorg Med Chem Lett 2007, 17, 78–81.
[5] Leung, D.; Abbenante, G.; Fairlie, D. P. J Med Chem
2000, 43, 305–341.
[6] Naka, H.; Teruya, K.; Bang, J. K.; Aimoto, S.;
Tatsumi, T.; Konno, H.; Nosakab, K.; Akaji, K. Bioorg
Med Chem Lett 2006, 16, 3761–3764.
[7] Freskos, J. N.; Fobian, Y. M.; Benson, T. E.;
Bienkowski, M. J.; Brown, D. L.; Emmons, T. L.;
Heintz, R.; Laborde, A.; McDonald, J. J.; Mischke,
B. V.; Molyneaux, J. M.; Moon, J. B.; Mullins, P. B.;
Prince, D. B.; Paddock, D. J.; Tomassellia, A. G.;
Winterrowd, G. Bioorg Med Chem Lett 2007, 17,
73–77.
[23] Kaboudin, B.; Zahedi, H. Chem Lett 2008, 37, 540.
[24] Kaboudin, B.; Haruki, T.; Yamaghishi, T.;
Yokomatsu, T. Tetrahedron 2007, 63, 8199.
[25] Kaboudin, B.; Haruki, T.; Yamagishi, T.; Yokomatsu,
T. Synthesis 2007, 3226.
[26] Kaboudin, B.; Jafari, E. Synthesis 2006, 3063.
[27] Kaboudin, B.; Elhamifar, D. Synthesis 2006, 224.
[28] Kaboudin, B.; Sorbiun, M. Tetrahedron Lett 2007,
48, 9015.
[29] Kaboudin, B.; Jafari, E. Synthesis 2007, 1823.
[30] Kaboudin, B.; Haghighat, H.; Yokomatsu, T.
Tetrahedron: Asymmetry 2008, 19, 862.
[31] Kaboudin, B.; Jafari, E. Synlett 2008, 1837.
[32] Kaboudin, B.; Jafari, E. Synthesis 2008, 2683.
[33] Kaboudin, B.; Saadati, F. Tetrahedron Lett 2009, 50,
1450–1452.
[34] Kaboudin, B.; Zahedi, H. Heteroatom Chem 2009, 20,
250–253.
Heteroatom Chemistry DOI 10.1002/hc