Facile synthesis of α-amino phosphonates in water by Kabachnik-Fields reaction using magnesium dodecyl sulfate

Article abstract of DOI:10.1002/hc.20689

The three-component reaction of aldehydes, amines and triethyl or diphenyl phosphite was efficiently catalyzed by magnesium dodecyl sulfate at room temperature in water to give various α-amino phosphonates in high yields. The catalyst is easily available from inexpensive sodium dodecyl sulfate and magnesium bromide.

Full text of DOI:10.1002/hc.20689

Heteroatom Chemistry
Volume 22, Number 3/4, 2011
Facile Synthesis of α-Amino Phosphonates
in Water by Kabachnik–Fields Reaction Using
Magnesium Dodecyl Sulfate
Kaori Ando and Tomoe Egami
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193,
Japan
Received 29 September 2010; revised 29 October 2010
Especially, use of aqueous media as a reaction sol-
ABSTRACT: The three-component reaction of alde-
vent has attracted much attention. Kobayashi et al.
hydes, amines and triethyl or diphenyl phosphite was
reported that the three-component reaction of alde-
efficiently catalyzed by magnesium dodecyl sulfate at
hydes, amines, and triethyl phosphite was effectively
room temperature in water to give various α-amino
catalyzed by scandium tris(dedecyl sulfate) to give
phosphonates in high yields. The catalyst is easily
various α-amino phosphonates in high yields in wa-
available from inexpensive sodium dodecyl sulfate
ter [6]. However, scandium(III) salts are expensive
ꢀ
C
and magnesium bromide. 2011 Wiley Periodicals, Inc.
and 4 equiv of P(OEt)3 was needed in order to get
high yields. Therefore, we decided to study the effect
of other metal dodecyl sulfates and the analogues
Heteroatom Chem 22:358–362, 2011; View this article on-
line at wileyonlinelibrary.com. DOI 10.1002/hc.20689
for the one-pot Kabachnik–Fields reaction to find a
more efficient and less expensive catalyst. Here, we
would like to report our results.
INTRODUCTION
The synthesis of α-amino phosphonates has
attracted much attention due to their significant
biological activities such as antibacterial and anti-
HIV, structural analogy to α-amino acids, and tran-
sition state mimics of peptide hydrolysis [1,2]. Nu-
cleophilic addition reaction of phosphites to imines
is one of the most preferred methods [3]. A one-pot
reaction of aldehydes (or ketones), amines, and di-
alkyl, or diaryl phosphites via the Kabachnik–Fields
reaction [4] is one of the most attractive alternates.
Recently, various catalysts have been developed for
this reaction [5]. However, still there remains a need
to develop a more efficient method, particularly from
the viewpoint of today’s environmental concerns.
R'
Sc(O3SOC12H25 3
)
NH
P(OEt)2
(0.1 eq)
RCHO + R'NH2 + P(OEt)3
(1 eq) (1 eq) (4 eq)
R
H2O, 30 °C
O
First, the reaction of benzaldehyde, aniline, and
P(OEt)3 3a was tested as a model reaction in the
presence of various catalysts in water (Table 1).
The catalysts 1 were prepared from MgBr2, CaCl2,
and AlCl3 with sodium dodecyl sulfate by following
Kobayashi’s procedure [7]. The catalyst 2a was pre-
pared from Mg(OH)2 with dodecylbenzensulfonic
acid, and 2b was prepared from CaCl2 with sodium
dodecylbenzensulfonate. When 0.1 equiv of 1a was
used as a catalyst, the reaction proceeded smoothly
to give α-amino phosphonate 4a in 99% yield in
1 h (entry 1). Reduction of the quantity of 3a to
2.0 and 1.2 equiv reduced the yield only slightly
Dedicated to Professor Kin-ya Akiba on the occasion of his 75th
birthday.
Correspondence to: K. Ando; e-mail: ando@gifu-u.ac.jp.
2011 Wiley Periodicals, Inc.
c
ꢀ
358

Facile Synthesis of α-Amino Phosphonates by Kabachnik–Fields Reaction 359
TABLE 1 Three-Component Synthesis of α-Amino Phosp-
nonate 4a in Water
TABLE 2 Three-Component Synthesis of 4 Catalyzed by 1a
Ph
1a
NH
P(OEt)2
Ph
Ph
(0.1 eq)
catalyst
(0.1 eq)
NH
P(OEt)2
PhCHO + PhNH2 + 3
1.0 eq 1.0 eq
Ph
PhCHO + PhNH2 + P(OEt)3
H2O
O
4a
H2O
3a
1.0 eq
1.0 eq
O
4a
Entry 3,equivs Solvent (mol/L) Time (h) Yield (%)
3a (Equiv)
Catalyst
Time (h)
Yield (%)
1
2
3a, 1.2
3a, 1.2
3a, 1.2
3a, 1.2
3a, 1.2
3a, 1.2
3b, 2.0
3b, 2.0
3b, 1.2
3c, 2.0
H2O, 0.17
H2O, 1
1
1
1
1
6
6
1
6
24
2
89
91
87
81
1
2
3
4
5
6
7
8
4.0
2.0
1.2
4.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1a
1
1
1
99
92
89
93
82
78
70
47
84
80
84
84
1a
3
H2O, 1.7
H2O, 0.17
THF, 0.17
CH2Cl2, 0.17
H2O, 0.17
H2O, 0.17
neatd
1a
4a
5
1b
72
1b
1
1.5
1
2.5
2
5
6
7
8
9
73
1c
1d
82b
92c
55
MgSO4
MgSO4–1d
MgSO4-THFa
2a
9
10
H2O, 0.17
97e
10
11
12
1
1
a1d and MgCl2 was used instead of 1a.
2b
bAfter work-up, the concentrated crude mixture was left overnight.
cAfter work-up, the concentrated crude mixture was left for 28 h.
dWithout 1a.
The reaction was performed in 0.17 mol/L water.
a5 equiv.
eThe corresponding diphenyl phosphonate.
(entries 2 and 3). The yield of the reaction using 1.2
equiv of 3a was 89% and higher than that of the
literature yield using 4 equiv of 3a and expensive
Sc(O3SOC12H25)3 (88% yield) [6]. Thus, the quantity
of 3a was set to 1.2 equiv. The use of the calcium
catalyst 1b and the alminum catalyst 1c gave slightly
reduced 82% and 78% yields (entries 5 and 6). Al-
though Kobayashi reported that sodium dodecyl
sulfate 1d (0.3 equiv) gave α-amino phosphonate
in a very low yield, the reaction using 1d gave 4a
in 70% yield (entry 7). Recently, the use of 1d as
a catalyst in water at 50◦C was reported to give α-
amino phosphonate [8]. In the presence of 0.1 equiv
of MgSO4, the reaction proceeded to give 4a in 47%
yield after 2.5 h (entry 8). From the comparison of
the structure with 1a, MgSO4 lacks long alkyl chains,
which are needed to dissolve the organic substrates
in water. Adding 1d (0.1 equiv) or THF (5 equiv) to
to give 4a in slightly reduced 84% yield after 1 h
(entries 11 and 12). Thus, the magnesium salt 1a
is the most effective catalyst. Since our method re-
quires neither expensive reagents nor heating, the
superiority of the Mg(O3SOC12H25)2 1a to both the
corresponding Sc and Na salts is clear.
To determine the best experimental conditions,
the reaction of benzaldehyde and aniline was stud-
ied using the catalyst 1a (Table 2). First, the effect
of the concentration of the reaction was studied.
The yields obtained from the reactions with 3a per-
formed in 0.17, 1.0, and 1.7 mol/L aqueous solution
were 89%, 91%, and 87% yields, respectively (entries
1–3). Thus, the concentration did not have a big in-
fluence on the product’s yields. When the catalyst 1a
was prepared in situ, that is, 0.1 equiv of 1d and
0.1 equiv of MgCl2 were used instead of 1a, 4a
was obtained in 81% yield after 1 h (entry 4).
Thus, the catalyst prepared in situ was slightly
less effective than 1a. The use of organic solvents
(THF and CH2Cl2) required longer reaction time,
and moderate 72% and 73% yields were obtained
after 6 h, respectively (entries 5 and 6). When di-
ethyl phosphite 3b was used instead of 3a, the
product 4a was not detected by TLC during the
reaction. However, 4a was isolated by column chro-
matography in 82% yield (entry 7). Careful moni-
toring of the reaction by TLC showed that the re-
action did not proceed in water even after 6 h.
The main product right after the work-up is the
corresponding imine. Since the reaction mixture
was left as a concentrated state for a while, we
P(OEt)3
(EtO)2P(O)H
(PhO)2P(O)H
3a
3b
3c
M(OSOC12H25 n
)
SO3
M
C12H25
1a 1b
: M=Mg, : M=Ca
2
1c 1d
: M=Al, : M=Na
2a: M=Mg, 2b: M=Ca
the reaction mixture, the yield of 4a increased from
47% to 84% and 80%, respectively (entries 9 and
10). Thus, MgSO4 also works as an effective cata-
lyst if a catalytic amount of dissolving reagents is
present. Recently, the use of Mg(ClO4)2 as a catalyst
for the Kabachnik–Fields reaction was also reported
[9]. Both magnesium and calcium dedecylbensen-
sulfonate, 2a and 2b, can also catalyze the reaction
Heteroatom Chemistry DOI 10.1002/hc

360 Ando and Egami
speculated that the reaction between the imine and
3b occurred in the solvent-free condition. In fact, the
yield of 4a was increased to 92% by leaving the reac-
tion mixture as a concentrated state for 28 h after the
work-up (entry 8). Furthermore, 4a was obtained in
55% yield when benzaldehyde, aniline, and diethyl
phosphite 3b was stirred for 24 h without catalyst
and without solvent (entry 9). The improvement of
the yield was obtained when diphenyl phosphite 3c
was used instead of 3b. The reaction of the imine
with 3c occurred smoothly in water and the α-amino
phosphonate was obtained in 97% yield after 2 h.
To establish the generality, various aldehydes
and amines were subjected to the one-pot three-
component reaction using the catalyst 1a in water.
The results are summarized in Table 3. Excellent
results were obtained from the reaction of benzalde-
hyde and triethyl phosphite 3a with aromatic amines
(entries 1–3). The reaction with o-anisidine gave
α-amino phosphonate 4b in 78% yield along with
the corresponding imine (5%). When 1.0 equiv of 3a
was added to the reaction mixture, and 0.5 equiv of
3a was added again 1 h later, the yield was improved
to 84%. Since the reactivity of the intermediate
imine having o-anisidine group (electron-donating
o-methoxy-substituted phenyl group) is supposed to
be lower than that of the N-phenylimine, decompo-
sition of 3a in water may compete with the reac-
tion. Therefore, excess amount of 3a improved the
yield. The reaction with 4-chloroaniline proceeded
smoothly to give the product 4c in 81% yield. In
this case, there is no intermediate imine left but
5% of benzaldehyde was detected after the work-up.
Since the nucleophilicity of 4-chloroaniline is lower
than that of aniline, the imine formation is slower
than that from aniline. The reactions of benzalde-
hyde and aliphatic amines were next studied. The
reaction with i-propylamine gave only trace amount
of α-amino phosphonate and the main product
was the intermediate imine from benzaldehyde and
TABLE 3 Synthesis of α-Aminophosphonate from Various Aldehydes, Amines, and Phosphites
R'
Catalyst
(0.1 eq)
NH
P(OR'')2
P(OEt)3
3a
3c
RCHO + R'NH2
1.0 eq
+
(PhO) P(O)H
R
2
1.0 eq
H2O
O
4
Entry
RCHO
R’NH2
o-MeOC6H4NH2
P(OEt)3 (Eq)
Catalyst
Time (h) Product Yield (%) Ratioa
1
2
3
4
5
6
7
8
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
PhCHO
3a, 1.2
1a
1a
1a
1a
1a
5
2
2
3
2
2
6
4
6
5
5
2
3
2
2
2
2
4
3
3
4b
4b
4c
-
4d
4d
4e
4f
4g
4h
4h
4h
4h
4i
78
84
81
o-MeOC6H4NH2 3a, 1.0 + 0.5
p-ClC6H4NH2
i-PrNH2
3a, 1.2
3a, 1.2
3c, 2.0
3c, 2.0
3a, 1.2
3c, 1.5
3a, 1.2
3c, 2.0
3c, 2.0
3c, 1.5
3c, 1.5
3a, 1.2
3a, 1.2
3a, 1.2
3a, 1.0 + 0.5
3c, 1.5
3c, 1.5
3c, 1.5
b
-
i-PrNH2
i-PrNH2
PhCH2NH2
PhCH2NH2
(58)c
(74)c
29b
77
1a, Et3N
1a
1a
1a
1a
9
(S)-PhMeCHNH2
(S)-PhMeCHNH2
(S)-PhMeCHNH2
(S)-PhMeCHNH2
(R)-PhMeCHNH2
PhNH2
77
53
77
87
80
77
81
70
78
74
52
58
76:24
76:24
76:25
76:24
76:24
10
11
12
13
14
15
16
17
18
19
20
1a, Et3N
1a, sparteine
1a, Pr3N
1a
p-ClC6H4CHO
p-ClC6H4CHOd
p-MeOC6H4CHO
p-MeOC6H4CHO
n-Octanal
n-Octanal
c-HexCHO
PhNH2
PhNH2
PhNH2
1a
1a
1a
4i
4j
4j
4k
4l
(S)-PhMeCHNH2
PhCH2NH2
(S)-PhMeCHNH2
1a, Et3N
1a, Et3N
1a, Et3N
76:25
76:24
4m
aDiastereomer ratio.
bThe corresponding imine was obtained mainly.
cAfter the aqueous work-up, the concentrated crude mixture was analyzed in the presence of methyl benzoate as a reference.
d2.5 mol/L THF solution was used instead of solid p-ClC6H4CHO.
Heteroatom Chemistry DOI 10.1002/hc

Facile Synthesis of α-Amino Phosphonates by Kabachnik–Fields Reaction 361
i-propylamine. It seems that the nucleophilicity of
des or aliphatic amines more effectively proceeded
with diphenyl phosphite in the presence of magne-
sium dodecyl sulfate (0.1 equiv) and triethylamine
(0.1 equiv). The catalyst is easily available from inex-
pensive sodium dodecyl sulfate and magnesium bro-
mide, and the reaction can be performed in water at
room temperature. These features make the present
methodology an environment friendly chemical
process.
3a is not enough for the imine having the electron-
donating alkyl substituent. When 3c was used in-
stead of 3a, α-amino phosphonate 4d was isolated
in 25% yield after column chromatography. Since
the NMR spectrum of the crude mixture showed the
yield of 4d was much higher than that, the puri-
fied 4d was submitted to column chromatography
again. As a result, 80% of 4d was recovered and 20%
of 4d decomposed. Owing to the instability of 4d,
the yield was measured by the comparison with the
peak of methyl benzoate (0.2 mmol) added after the
aqueous work-up. This showed that the yield of 4d
was 58% (entry 5). Furthermore, the yield was im-
proved to 74% when the reaction was performed in
the presence of 0.1 equiv of triethylamine. The reac-
tion with benzaldehyde, benzylamine, and P(OEt)3
3a gave only 29% yield of the α-amino phosphonate
4e along with 70% of the corresponding imine (en-
try 7). The product 4f was obtained in 77% yield
by using diphenyl phosphite 3c and 0.1 equiv of tri-
ethylamine. Interestingly, more lipophilic phenethy-
lamine reacts faster with benzaldehyde and 3a in
the presence of the catalyst 1a to give 4g in 77%
yield after 6 h. The reaction with 3c was also im-
proved using 0.1 equiv of amines, triethylamine,
sparteine, and tripropylamine (entries 10–13). The
yield of 4h was higher by using more lipophilic
sparteine (87% yield). The diastereoselectivity was
76:24 and did not much influenced by the reaction
conditions. The reaction of p-chlorobenzaldehyde
with aniline and 3a gave 4i in 77% yield (entry 14).
Since p-chlorobenzaldehyde is solid at room tem-
perature and was not soluble well in the reaction
media, the yield of 4i was improved to 81% by using
2.5 mol/L THF solution of p-chlorobenzaldehyde in-
stead of solid p-chlorobenzaldehyde (entry 15). For
the reaction of p-methoxybenzaldehyde with aniline
and 3a, 4j was obtained in 78% yield when 1.0 and
0.5 equiv of 3a were added separately (entry 17).
For the aliphatic aldehydes, the reaction with amines
and 3a hardly occurred. However, the use of 3c in
the presence of 0.1 equiv of 1a and 0.1 equiv of tri-
ethylamine promoted the reaction efficiently (entries
18–20).
EXPERIMENTAL
Instrumentation and Chemicals
Melting points were uncorrected. The 1H NMR spec-
tra were recorded on a JEOL α-400 (400 MHz)
in CDCl3 using tetramethylsilane as an internal
1
standard (δ = 0 ppm). H NMR data are reported
as follows: chemical shift, integration, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet,
br = broad, m = multiplet), coupling constants (Hz).
The mass spectra (MS) were taken on a JEOL JNM
700 mass spectrometer. The column chromatogra-
phy was carried out using silica gel 60N of Kanto
Chemical Co., Ltd. Commercially available reagents
were used without purification. The α-amino phos-
phonates 4a, [8] 4b, [10a] 4c, [8] 4e, [8] 4h, [10b] 4i,
1
[8] and 4j [5a] are known compounds and their H
NMR spectra are identical to the reported values.
Magnesium dodecyl sulfate (1a): To a solution of
sodium dodecyl sulfate (3.036 g, 10 mmol) in H2O
(15 mL) was added MgBr2·6H2O (1.411 g, 5 mmol)
at room temperature. Viscous white precipitates ap-
peared immediately, and the mixture was stirred for
2 h. The white lustrous solid was filtrated and dried
(1 mmHg/15 h at room temperature).
Typical experimental procedure (Table 1, entry
3): To a suspension of 1a (0.028 g, 0.05 mmol)
in H2O (3.0 mL), aniline (0.046 mL, 0.5 mmol),
benzaldehyde (0.052 mL, 0.50 mmol), and P(OEt)3
(0.105 mL, 0.6 mmol) were added successively at
room temperature. The mixture was stirred for 1 h.
1 mol/L NaOH (10 mL × 2) was added, and the aque-
ous layer was extracted with ethyl acetate (10 mL).
The combined organic extracts were washed with
brine, dried (MgSO4), and concentrated under re-
duced pressure. The residue was purified by flash
chromatography (silica gel/hexane-AcOEt (2:3)) to
give pure 4a (0.1427 g, y. 89%) [8].
In conclusion, the three-component reaction of
aldehydes, amines, and triethyl or diphenyl phos-
phite in water was effectively catalyzed by mag-
nesium dodecyl sulfate (0.1 equiv) to give various
α-amino phosphonates in high yields. Probably,
magnesium dodecyl sulfate forms stable dispersion
systems with organic substrates in water and the
magnesium cation combines aldehydes and amines
to form the corresponding imines, which reacts with
phosphites. The reactions for either aliphatic aldehy-
Diphenyl phenyl-(i-propylamino)methylphospho-
1
nate 4d: Colorless oil. H NMR δ 1.01 (3H, d, J =
6.2 Hz), 1.05 (3H, d, J = 6.2 Hz), 1.96 (1H, brs), 2.79
(1H, septet, J = 6.2 Hz), 4.48 (1H, d, J = 22.0 Hz),
6.85–6.90 (2H, m), 7.05–7.40 (11H, m), 7.46–7.51
(2H, m); MS m/e 382 (M + 1+).
Heteroatom Chemistry DOI 10.1002/hc

362 Ando and Egami
Diphenyl (benzylamino)(phenyl)methylphospho-
(1H, dq, J = 4.2, 6.6 Hz), 7.03–7.385 (15H, m); minor
isomer: 1.10, 2.10 (11H, m), 1.35 (3H, d, J = 6.4 Hz),
3.17 (1H, dd, J = 3.2, 18.3 Hz), 3.91 (1H, brs), 4.22
(1H, dq, J = 1, 6.4 Hz), 7.03–7.385 (15H, m); MS m/e
216 (M + 1+-HP(O)(OPh)2).
nate 4f: Colorless solid recrystalized from CH2Cl2-
1
hexanes, mp 110–111◦C. H NMR δ 2.42 (1H, brs),
3.64 (1H, d, J = 13.3 Hz), 3.90 (1H, d, J = 13.3 Hz),
4.37 (1H, d, J = 20.3 Hz), 6.86–7.53 (20H, m); MS
m/e 430 (M + 1+).
Diethyl (α-phenylethylamino)(phenyl)methylphos-
1
phonate 4g: Colorless oil. H NMR major isomer: δ
ACKNOWLEDGMENTS
1.10 (3H, t, J = 7.1 Hz), 1.25–1.38 (6H, m), 2.25 (1H,
brs), 3.55–4.20 (6H, m), 7.21–7.33 (10H, m); minor
isomer: δ 1.05 (3H, t, J = 7.1 Hz), 1.25–1.38 (6H, m),
2.25 (1H, brs), 3.55–4.20 (6H, m), 7.21–7.33 (10H,
m); MS m/e 348 (M + 1+), 210 (M + 1+-HP(O)(OEt)2).
Diphenyl (α-phenylethylamino)(phenyl)methyl-
phosphonate 4h: Colorless oil. 1H NMR major
isomer: δ 1.32 (3H, d, J = 6.6 Hz), 2.36 (1H, bs),
3.97 (1H, q, J = 6.6 Hz), 4.44 (1H, d, J = 20.0 Hz),
6.85–7.43 (20H, m); minor isomer (S, S): [10b] δ 1.34
(3H, d, J = 6.6 Hz m), 2.36 (1H, bs), 3.66 (1H, dq, J
= 1.5, 6.8 Hz), 4.11 (1H, d, J = 22.7 Hz), 6.85–7.43
(20H, m); MS m/e 444 (M + 1+).
This work was partially supported by the Novartis
Foundation (Japan) for the Promotion of Science.
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t, J = 7.1 Hz), 1.33 (3H, d, J = 6.4 Hz), 1.01–1.38
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1
orless oil. H NMR δ 0.88 (3H, t, J = 6.8 Hz), 1.17–
1.35 (8H, m), 1.36–1.50 (1H, m), 1.56–1.68 (1H, m),
1.70–1.78 (1H, m), 1.94–2.07 (1H, m), 3.27 (1H, dd,
J = 4.2, 9.2, 10.6 Hz), 3.99 (1H, dd, J = 2.2, 13.2 Hz),
4.08(1H, dd, J = 1.0, 13.2 Hz), 7.12–7.35 (15H, m);
MS m/e 452 (M + 1+), 218 (M + 1+-HP(O)(OPh)2).
Diphenyl (α-phenylethylamino)cyclohexylmethyl-
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1
phosphonate 4m: Colorless oil. H NMR major iso-
mer: δ 1.10–2.10 (11H, m), 1.34 (3H, d, J = 6.6 Hz),
2.99 (1H, dd, J = 2.9, 12.2 Hz), 3.91 (1H, brs), 4.30
Heteroatom Chemistry DOI 10.1002/hc