A highly efficient and useful synthetic protocol for the synthesis of bis[aryl(diethoxyphosphoryl)methyl]amines from aromatic aldehydes using acetyl chloride as an efficient catalyst

Article abstract of DOI:10.1055/s-2007-983720

A highly efficient and useful method for the synthesis of bis[aryl(diethoxyphosphoryl)methyl]amines has been developed. The treatment of aromatic aldehydes with ammonia followed by reaction with diethyl phosphite in the presence of acetyl chloride as cata

Full text of DOI:10.1055/s-2007-983720

PAPER
1823
A Highly Efficient and Useful Synthetic Protocol for the Synthesis of
Bis[aryl(diethoxyphosphoryl)methyl]amines from Aromatic Aldehydes
Using Acetyl Chloride as an Efficient Catalyst
Novel Synthesis
a
b
diethoxypho
a
sphoryl)me
k
thyl]amines Kaboudin,* Ehsan Jafari
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45195-1159, Iran
Fax +98(241)4249023; E-mail: kaboudin@iasbs.ac.ir
Received 6 March 2007; revised 26 April 2007
chlorophosphites was reported.16 However, these methods
have drawbacks, including harsh reaction conditions, long
reaction times, and side reactions. On the other hand, pro-
longed heating of chloromethylphosphonic acids in alka-
Abstract: A highly efficient and useful method for the synthesis of
bis[aryl(diethoxyphosphoryl)methyl]amines has been developed.
The treatment of aromatic aldehydes with ammonia followed by re-
action with diethyl phosphite in the presence of acetyl chloride as
catalyst gives bis[aryl(diethoxyphosphoryl)methyl]amines. This line solution also leads to the competitive hydrolysis
method is easy, rapid, and a high yielding method for the synthesis
product of the Cl–C bond to give hydroxymethylphospho-
nic acid.14 As part of our efforts to introduce novel meth-
of bis[aryl(diethoxyphosphoryl)methyl]amines with good diastereo-
selection from simple starting materials.
ods for the synthesis of organophosphorus compounds,17
herein we report a new method for the synthesis of bis[ar-
yl(diethoxyphosphoryl)methyl]amines.
Key words: acetyl chloride, diethyl phosphite, aldehyde, bis[ar-
yl(diethoxyphosphoryl)methyl]amine, addition reaction
Using acetyl chloride as a catalyst in organic synthesis has
attracted growing attention because it is inexpensive and,
Phosphorus–carbon bond formation has attracted growing
most probably, has greater industrial application than oth-
attention because of the novel application of the products
er acid catalysts.18 Recently, we have reported that the re-
in organic synthesis and bioorganic chemistry. a-Func-
action of diethyl [(arylmethylene)amino](phenyl)methyl-
tionalized phosphonic acids are valuable intermediates for
phosphonate and diimines with diethyl phosphite in the
the preparation of medicinal compounds and synthetic in-
presence of chlorotrimethylsilane gives bis[1-(diethoxy-
termediates.1–4 Among a-functionalized phosphonic ac-
phosphoryl)alkyl]amines as the sole product.19 Herein, a
ids, a-aminophosphonic acids are an important class of
new method for the synthesis of bis[aryl(diethoxyphos-
compounds that exhibit a variety of interesting and useful
phoryl)methyl]amines using aldehydes as simple starting
properties. a-Aminophosphonic acids are important sub-
material is described. The reaction of benzaldehyde, as a
stitutes for the corresponding a-amino acids in biological
model compound, with ammonia followed by reaction
systems.5 Indeed a number of potent antibiotics,6 enzyme
with diethyl phosphite in the presence of acetyl chloride
inhibitors,7 and pharmacological agents8 are a-amino-
(0.3 equiv) gave bis[(diethoxyphosphoryl)(phenyl)meth-
phosphonic acids or peptide analogues. Aminophosphon-
yl]amine (2a) as the sole product (Scheme 1).
ic acids are also found as constituents of natural
products.5f In contrast to the widely studied a-aminophos-
O
H
N
O
phonic acids derivatives,9–12 relatively few papers have
reported on the chemistry of bis[1-(diethoxyphosphor-
yl)alkyl]amines as an important class of a-aminophos-
phonic acid derivatives. Bis[1-(dialkoxyphosphoryl)alk-
yl]amines have been used as chelating agents for polyva-
lent, particularly for alkaline earth, metal ions.13 Many ef-
fective methods for the preparation of a-amino-
phosphonic acids have been developed, but, to the best of
our knowledge, few synthetic routes to bis[1-(diethoxy-
phosphoryl)alkyl] amines have been reported. The report-
ed methods involve prolonged heating of primary amines
with chloromethylphosphonic acids in alkaline solution14
or the Mannich-type reaction of an amine, formaldehyde,
and phosphorous acid.15 Recently, a new route for the
preparation of bis[1-(diethoxyphosphoryl)alkyl]amines
by the reaction of a-iminocarboxylate salts with dialkyl
(EtO)2P
P(OEt)2
aq NH4OH, reflux, 5 h
Ph
Ph
PhCHO
HP(O)(OEt)2, AcCl (0.3
equiv), CH2Cl2, 3 h, r.t.
(R*,S*)-2a
O
H
N
O
(EtO)2P
P(OEt)2
Ph
Ph
43% yield
80% de
(S*,S*)-2a
Scheme 1
The 31P NMR spectrum of 2a exhibited two peaks at d =
23.36 and d = 23.68 due to diastereomers; good diastereo-
selection can be obtained in this reaction (80%).
Using other acyl chlorides such as benzoyl chloride and 4-
nitrobenzoyl chloride also gave the same results but with
lower yields. It was suggested that in situ generation of
HCl catalyzed this reaction.
SYNTHESIS 2007, No. 12, pp 1823–1826
x
x.
x
x
.
2
0
0
7
Advanced online publication: 08.06.2007
DOI: 10.1055/s-2007-983720; Art ID: Z05607SS
© Georg Thieme Verlag Stuttgart · New York

1824
B. Kaboudin, E. Jafari
PAPER
O
H
N
O
O
H
N
O
aq NH4OH, reflux, 5 h
(EtO)2P
(EtO)2P
P(OEt)2
P(OEt)2
ArCHO
+
HP(O)(OEt)2, AcCl (0.3 equiv),
CH2Cl2, 3–6 h, r.t.
Ar
Ar
Ar
Ar
1
(R*,S*)-2
(S*,S*)-2
Scheme 2
Table 1 Reaction of Aldehydes 1 with Ammonia Solution followed Reaction with Diethyl Phosphite Using Acetyl Chloride as Catalyst
Entry
Ar
Time (h)
Product
Yielda (%)
deb (%)
31P NMR (d)
(S*,S*)
(R*,S*)
23.68
24.00
22.90
22.67
23.97
22.17
21.58
23.60
1
2
3
4
5
6
7
8
Ph
4
3
6
3
3
4
5
3
2a
2b
2c
2d
2e
2f
43
45
51
42
39
36
45
37
80
66
62
56
64
34
56
54
23.36
23.78
22.53
22.30
23.69
21.71
21.04
23.27
4-MeOC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
3-FC6H4
3-O2NC6H4
2-naphthyl
2g
2h
a Yield (over two steps, based on diethyl phosphite) refers to the total isolated yield by column chromatography.
b Diastereoselection was calculated from the 31P NMR spectrum.
Bis[aryl(diethoxyphosphoryl)methyl]amines 2: General Proce-
dure
Due to the presence of two stereogenic carbons bonded to
the nitrogen atom, this compound exists in two diastereo-
meric forms: one meso-isomer (R*,S*) and one racemic
pair (S*,S*). Recently the stereochemical assignment of
diastereomers of 2a was reported in the literature.16 Ac-
cording to this report, the (R*,S*)-diastereomer of 2a has
a signal at lower field (d = 23.68) in the 31P NMR spectra.
The aldehyde (18 mmol) was added to 30% NH4OH soln (15 mL)
and the soln was stirred at reflux for 5 h; during this time, a precip-
itate formed. The precipitate was removed by filtration and dried.
The solid was added to a mixture of diethyl phosphite (12 mmol) in
CH2Cl2 (20 mL). AcCl (4 mmol) was added dropwise to the mixture
and it was stirred at r.t. for 3 h. Evaporation of solvent and chroma-
tography on a plug of silica gel (EtOAc–MeOH, 9:1) followed by
removal of the solvent under reduced pressure gave the pure prod-
ucts as colorless oils in 36–51% yield. All products are known and
gave satisfactory spectral data in accord with the assigned structures
and literature reports.19
This process was successfully applied to other aromatic
aldehydes 1 (Scheme 2, Table 1). As shown in Table 1,
aromatic aldehydes react with ammonia followed by reac-
tion with diethyl phosphite in the presence of acetyl chlo-
ride to afford the desired products 2b–h in good yields.
Bis[(diethylphosphoryl)(phenyl)methyl]amine (2a)
Colorless oil; yield: 43%.
In summary, fast reaction rates, mild reaction conditions,
good yields, simple workup, and relatively clean reactions
with no tar formation make this method an attractive and
useful contribution. Indeed, a wide range of aromatic al-
dehydes 1 were converted into the corresponding bis[ar-
1H NMR (250 MHz, CDCl3): d = 1.10 (t, J = 7.1 Hz, 6 H), 1.26 (t,
J = 7.1 Hz, 6 H), 2.93 (br, 1 H, NH), 3.65–4.35 (m, 10 H), 7.29 (s,
10 H).
13C NMR (62.9 MHz, CDCl3): d = 134.3, 128.8, 128.2, 128.1, 62.6–
62.9 (c), 57.4 (dd, JPC = 155.1, 17.9 Hz), 16.1–16.3 (c).
yl(diethoxyphosphoryl)methyl]amines
2
using this
method. Further investigations on this reaction are now in
progress.
31P NMR (CDCl3): d = 23.36, 23.68.
Bis[(diethylphosphoryl)(4-methoxyphenyl)methyl]amine (2b)
Colorless oil; yield: 45%.
All chemicals were commercial products and distilled or recrystal-
lized before use. NMR spectra were taken with a 250 Bruker
Avance instrument; for 1H NMR the reference was residual CHCl3
(d = 7.26) for CDCl3 solns, for 13C NMR spectra the reference in
CDCl3 and DMSO solns was CDCl3 (d = 77.0). The chemical shifts
of 31P were recorded relative to external 85% H3PO4 (d = 0) with
broadband 1H decoupling. For 13C NMR spectroscopy, the designa-
tion ‘c’ refers to complex peak. Silica gel column chromatography
was carried out with silica gel 100 (Merck No. 10184). Merck silica
gel 60 F254 plates (No. 5744) were used for preparative TLC.
1H NMR (250 MHz, CDCl3): d = 1.14 (t, J = 7.1 Hz, 6 H), 1.29 (t,
J = 7.1 Hz, 6 H), 1.69 (br, 1 H, NH), 3.68–4.35 (m, 16 H), 6.87 (d,
J = 8.5 Hz, 4 H), 7.22 (d, J = 8.5 Hz, 4 H).
13C NMR (62.9 MHz, CDCl3): d = 159.4, 129.9, 125.9, 113.8, 62.4–
62.8 (c), 56.4 (dd, JPC = 156.7, 17.9 Hz), 55.1, 16.1–16.3 (c).
31P NMR (CDCl3): d = 23.78, 24.00.
Synthesis 2007, No. 12, 1823–1826 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of Bis[aryl(diethoxyphosphoryl)methyl]amines
1825
Bis[(4-chlorophenyl)(diethylphosphoryl)methyl]amine (2c)
Colorless oil; yield: 51%.
Acknowledgment
The Institute for Advanced Studies in Basic Sciences (IASBS) is
thanked for supporting this work.
1H NMR (250 MHz, CDCl3): d = 1.15 (t, J = 7.1 Hz, 6 H), 1.29 (t,
J = 7.1 Hz, 6 H), 2.19 (br, 1 H, NH), 3.65–4.35 (m, 10 H), 7.23 (d,
J = 8.25 Hz, 4 H), 7.33 (d, J = 8.25 Hz, 4 H).
13C NMR (62.9 MHz, CDCl3): d = 134.1, 132.9, 130.1, 128.9, 62.9–
63.2 (c), 56.9 (dd, JPC = 155.4, 17.6 Hz), 16.3–16.4 (c).
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31P NMR (CDCl3): d = 22.53, 22.90.
Bis[(diethylphosphoryl)(4-fluorophenyl)methyl]amine (2d)
Colorless oil; yield: 42%.
1H NMR (250 MHz, CDCl3): d = 1.04 (t, J = 7.0 Hz, 6 H), 1.18 (t,
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115.7, 115.3, 62.6–63.0 (c), 56.6 (dd, JPC = 156.6, 17.6 Hz), 16.1–
16.3 (c).
31P NMR (CDCl3): d = 22.30, 22.67.
Bis[(diethylphosphoryl)(4-methylphenyl)methyl]amine (2e)
Colorless oil; yield: 39%.
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J = 7.1 Hz, 6 H), 2.24 (s, 6 H), 2.85 (br, 1 H, NH), 3.60–4.25 (m, 10
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62.9 (c), 57.0 (dd, JPC = 156.0, 18.2 Hz), 21.1, 16.1–16.3 (c).
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J = 7.0 Hz, 6 H), 2.92 (br, 1 H, NH), 3.65–4.25 (m, 10 H), 6.85–7.09
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130.1, 124.5, 115.7, 115.3, 62.9–63.2 (c), 57.2 (dd, JPC = 155.1,
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31P NMR (CDCl3): d = 21.71, 22.17.
Bis[(diethylphosphoryl)(3-nitrophenyl)methyl]amine (2g)
Colorless oil; yield: 45%.
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(m, 10 H), 7.40–7.70 (m, 4 H), 8.05–8.41 (m, 4 H).
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123.4, 123.3, 62.8–63.7 (c), 57.3 (dd, JPC = 154.5, 16.6 Hz), 55.1,
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31P NMR (CDCl3): d = 23.27, 23.60.
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1826
B. Kaboudin, E. Jafari
PAPER
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Synthesis 2007, No. 12, 1823–1826 © Thieme Stuttgart · New York