Coupling of aldehydes, amines, and trimethyl phosphite promoted by amberlyst-15: Highly efficient synthesis of α-aminophosphonates

Article abstract of DOI:10.1055/s-2008-1032034

A three-component reaction promoted by Amberlyst-15 of an amine, an aldehyde, and trimethyl phosphite (Kabachnik-Fields reaction) in one pot under mild conditions affords the corresponding α-aminophosphonate in high yield after a short reaction time at ambient temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032034

352
SHORT PAPER
Coupling of Aldehydes, Amines, and Trimethyl Phosphite Promoted by
Amberlyst-15: Highly Efficient Synthesis of a-Aminophosphonates
a
-Aminophosphonate
s
a
by
A
mberl
h
yst-15 Prom
m
C
oupling ood Tajbakhsh,*a Akbar Heydari,b Heshmatollah Alinezhad,a Mercedeh Ghanei,a Samad Khaksarb
b
Received 14 September 2007; revised 30 October 2007
temperatures, result in low yields, and require catalysts
that are difficult to prepare. Hence, a convenient, environ-
mentally benign, and practicably feasible method for the
synthesis of a-aminophosphonates is desirable.
Abstract: A three-component reaction promoted by Amberlyst-15
of an amine, an aldehyde, and trimethyl phosphite (Kabachnik–
Fields reaction) in one pot under mild conditions affords the corre-
sponding a-aminophosphonate in high yield after a short reaction
time at ambient temperature.
In recent years, the use of solid acidic catalysts has attract-
ed considerable attention.8 In this regard, Amberlyst-15
possesses unique properties such as environmental com-
patibility, nontoxicity, reusability, noncorrosiveness, se-
lectivity, and chemical and physical stability. Owing to
the numerous advantages associated with this inexpensive
and nonhazardous catalyst, Amberlyst-15 has been ex-
plored as a powerful catalyst for various organic reac-
tions.9
Key words: amines, phosphonates, Amberlyst-15 catalysis, nu-
cleophilic additions, multicomponent reactions
Due to their structural analogy to a-amino acids, a-amino-
phosphonic acids and their derivatives a-aminophospho-
nates continue to attract increased interest as synthetic
targets. These molecules have found a wide range of ap-
plications in the areas of industrial, biological, and medic-
inal chemistry, as inhibitors of synthase,1a HIV protease,1b
antibiotics,1c enzyme inhibitors,1d anti-thrombotic
agents,1e herbicides, fungicides, insecticides,1f,g plant
growth regulators,1h and as substrates in the synthesis of
phosphonopeptides.2 As a result, various synthetic ap-
proaches have been developed for the synthesis of a-ami-
nophosphonates. Nucleophilic addition reactions of
phosphates with imines is one of the most convenient of
these methods, and are usually promoted by base,3 protic,4
or Lewis acids such as tin(IV) chloride,5a zirconium(IV)
chloride,5b zinc(II) chloride,5c magnesium bromide,5c and
boron trifluoride–diethyl ether complex.5d However, these
methods do have some limitations; for example, many
imines are hygroscopic and not sufficiently stable to be
isolated. In addition, these reactions cannot be carried out
in one step with a carbonyl compound, an amine, and a tri-
alkyl phosphite, because the amine and water present dur-
ing imine formation can decompose or deactivate the
Lewis acid.6 This drawback has been overcome by some
recent methods using H3PW12O40,7a magnesium perchlor-
ate,7b trimethylanilinium chloride,7c bismuth nitrate pen-
tahydrate,7d scandium tris(dodecyl sulfate),7e,f indium(III)
chloride,7g samarium(II) iodide,7h metal triflates
[M(OTf)n, M = La, Li, Mg, Al, Cu, Ce],7i lithium perchlo-
rate,7j,k tantalum(V) chloride–silicon dioxide,7l alumina,7m
trifluoroacetic acid,7n montmorillonite KSF,7o and (bro-
modimethyl)sulfonium bromide.7p However, many of
these methods involve stoichiometric amounts of cata-
lysts, expensive reagents, long reaction times, and high
Amberlyst-15 with a sulfonic acid functionality is strong-
ly acidic and can be handled easily and removed from the
reaction mixtures by simple filtration. The ability to be re-
covered from reaction mixtures and to be reused, the ex-
perimental convenience, and being environmentally
benign are important advantages of Amberlyst-15 over
other conventional catalysts and solid acids. To investi-
gate its recyclability, the Amberlyst-15 catalyst was col-
lected by filtration, washed with acetone, and dried under
ambient conditions for one hour after each experiment.
The recovered catalyst was reused consecutively several
times with only a minimal variation in the yields of the
products. In the present work, Amberlyst-15 exhibits rel-
atively good stability, could be regenerated easily, and
showed high turnover numbers.
To find the optimum conditions for the three-component
reaction (Scheme 1), we stirred a solution of benzalde-
hyde (1, R1 = Ph) and aniline (2, R2 = Ph) in acetonitrile
for five minutes before adding Amberlyst-15 and trimeth-
yl phosphite (3) at ambient temperature. The reaction was
complete in 25 minutes and afforded dimethyl [anili-
no(phenyl)methyl]phosphonate (4a) in 92% yield
(Table 1, entry 1).
O
R1
H
MeO
OMe
R2
R1
H
P
N
P
Amberlyst-15
MeCN, r.t
1
O
+
OMe
OMe
H
N
OMe
3
R2
H
4
2
SYNTHESIS 2008, No. 3, pp 0352–0354
x
x
.
x
x
.2
0
0
8
Advanced online publication: 10.01.2008
DOI: 10.1055/s-2008-1032034; Art ID: Z21207SS
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
a-Aminophosphonates by Amberlyst-15 Promoted Coupling
353
Table 1 Synthesis of a-Aminophosphonates 4 from Various Alde-
reaction conditions give the corresponding a-aminophos-
phonates in low yield only. The present method does not
require any additives or promoters to facilitate the reac-
tion.
hydes and Amines
Entry R1
R2
Time
(min)
Product Yielda
4
(%)
92
94
87
89
86
96
87
83
96
83
89
91
87
89
84
84
87
84
87
In summary, we have successfully demonstrated the use
of Amberlyst-15 as an efficient catalyst for the three-com-
ponent synthesis of a-aminophosphonates at room tem-
perature. This procedure is attractive owing to its
operational simplicity and generally high yields of prod-
ucts.
1
2
Ph
Ph
25
35
40
30
35
20
35
35
25
45
30
35
35
90
90
60
60
60
60
4a
4b
4c
4d
4e
4f
3-ClC6H4
4-ClC6H4
tolyl
Ph
3
Ph
4
Ph
5
4-O2NC6H4
4-Me2NC6H4
4-HOC6H4
PMP
Ph
1
The H (500 MHz) and 13C (125 MHz) NMR data reported below
6
Ph
for selected products were determined on a Bruker Avance DRX
500 spectrometer. The spectroscopic and physical data for all com-
pounds corresponded to those given in the literature: 4a,7a–c,11 4b,10
4c,7a–c 4d,7p 4e,7c 4f,7b 4g,7b 4h,7l 4i,7b 4j,11 4k,7l 4l,7b 4m,7c 4n,7b 4o,7l
4p,7c 4q,7c 4r,7b and 4s.7b
7
Ph
4g
4h
4i
8
Ph
9
2-furyl
Ph
Ph
a-Aminophosphonates 4; General Procedure
10
11
12
13
14
15
16
17
18
19
4-ClC6H4
PMP
PMP
4-HOC6H4
Ph
4j
The amine 2 (2.2 mmol) and aldehyde 1 (2 mmol) were stirred for
a few minutes at r.t. in MeCN (4 mL) before the P(OMe)3 (3; 2.2
mmol) and Amberlyst-15 (0.2 g) were added and the mixture was
stirred for the appropriate time (see Table 1). After completion of
the reaction (followed by TLC), the catalyst was separated by filtra-
tion. The solvent was evaporated and the reaction mixture was di-
luted with CH2Cl2 (10 mL) and H2O (15 mL). The organic phase
was separated, dried (Na2SO4), and concentrated under vacuum,
and the crude mixture was purified by column chromatography
(hexane–EtOAc, 8:2); this afforded the pure dimethyl phosphonate
4.
Ph
4k
4l
PMP
Ph
4m
4n
4o
4p
4q
4r
4s
cinnamyl
prop-1-enyl
n-Pr
Ph
Ph
Dimethyl [Anilino(phenyl)methyl]phosphonate (4a)7a–c,11
1H NMR (500 MHz, CDCl3): d = 3.50 (d, J = 10.5 Hz, 3 H), 3.80 (d,
J = 10.6 Hz, 3 H), 4.82 (d, J = 24 Hz, 1 H), 4.84 (br s, 1 H), 6.60–
7.50 (m, 10 H).
n-pentyl
(CH2)2Ph
i-Pr
Ph
Ph
Ph
2
13C NMR (125 MHz, CDCl3): d = 54.1 (d, JP–C = 7.0 Hz, OCH3),
a Yield of isolated product.
54.2 (2JP–C = 6.8 Hz, OCH3), 56.2 (d, 1JP–C = 150 Hz, CH), 128.4 (d,
3JP–C = 3.1 Hz, CH), 129.1 (CH), 131.2 (CH), 136.0 (C), 146.6 (d,
2JP–C = 14.5 Hz, C).
This method was applied to a variety of substrates, and in
all cases the reaction proceeded smoothly at ambient tem-
perature to give the desired products in high yields.10 The
results are summarized in Table 1. Both electron-deficient
and electron-releasing benzaldehydes react efficiently
with aniline to give the corresponding a-aminophospho-
nates (Table 1, entries 2–8). 2-Furaldehyde also gave the
corresponding a-aminophosphonate in high yield
(Table 1, entry 9). Similarly substituted anilines reacted
with trimethyl phosphite and benzaldehyde or 4-meth-
oxybenzaldehyde to afford the corresponding a-amino-
phosphonates in high yields (Table 1, entries 10–13).
When a,b-unsaturated aldehydes reacted with aniline and
trimethyl phosphite in acetonitrile in the presence of Am-
berlyst-15 a longer reaction time was required for the
reaction to be completed and to give the 1,2-addition
products in high yields (Table 1, entries 14 and 15).
Dimethyl [Anilino(4-chlorophenyl)methyl]phosphonate (4c)7a,c
1H NMR (500 MHz, CDCl3): d = 3.50 (m, 1 H), 3.80 (d, J = 11.8
Hz, 3 H), 3.83 (d, J = 10.1 Hz, 3 H), 5.20 (d, J = 24 Hz, 1 H), 7.30–
8.20 (m, 9 H).
13C NMR (22.5 MHz, CDCl3): d = 56.1 (d, 2JP–C = 7.0 Hz, OCH3),
56.2 (d, 2JP–C = 6.8 Hz, OCH3), 57.2 (d, 1JP–C = 150 Hz, CH), 114.3
3
(CH), 120.0 (CH), 128.2 (d, JP–C = 5.8 Hz, CH), 128.4 (d,
3JP–C = 3.1 Hz, CH), 130.1 (CH), 131.2 (CH), 140.0 (C), 146.6 (d,
2JP–C = 14.5 Hz, C).
Dimethyl [Anilino(4-nitrophenyl)methyl]phosphonate (4e)7c
1H NMR (500 MHz, CDCl3): d = 3.70 (d, J = 10.1 Hz, 3 H), 3.74 (br
s, 1 H), 3.74 (d, J = 10.3 Hz, 3 H), 5.00 (d, J = 10.7 Hz, 1 H), 7.30–
8.40 (m, 9 H).
2
13C NMR (125 MHz, CDCl3): d = 58.1 (d, JP–C = 7.0 Hz, OCH3),
1
58.2 (2JP–C = 6.8 Hz, OCH3), 58.3 (d, JP–C = 150 Hz, CH), 115.3
3
(CH), 119.0 (CH) 129.2 (d, JP–C = 5.8 Hz, CH), 129.4 (d,
3JP–C = 3.1 Hz, CH), 130.1 (CH), 131.2 (CH), 136.0 (C), 147.6 (d,
2JP–C = 4.5 Hz, C).
In addition, this method is even effective with aliphatic al-
dehydes, which normally produce low yields due to their
intrinsic lower reactivity (Table 1, entries 16–19). How-
ever, it is interesting that the reactions of ketones and aro-
matic amines with trimethyl phosphite under similar
Dimethyl [Anilino(2-furyl)methyl]phosphonate (4i)7b
1H NMR (500 MHz, CDCl3): d = 3.60 (d, J = 10.6 Hz, 3 H), 3.80 (d,
J = 10.6 Hz, 3 H), 4.50 (br s, 1 H), 5.00 (d, J = 23.8 Hz, 1 H), 6.37–
7.40 (m, 8 H).
Synthesis 2008, No. 3, 352–354 © Thieme Stuttgart · New York

354
M. Tajbakhsh et al.
SHORT PAPER
1
13C NMR (125 MHz, CDCl3): d = 50.0 (d, JP–C = 159.6 Hz, CH),
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2
2
54.1 (d, JP–C = 5.8 Hz, OCH3), 54.4 (d, JP–C = 6.9 Hz, OCH3),
3
109.4 (d, JP–C = 6.8 Hz, CH), 111.2 (CH), 114.4 (d, CH), 119.5
(CH), 129.9 (d, CH), 143.1 (CH), 146.3 (d, JP–C = 13.3 Hz, C),
2
149.4 (C).
Dimethyl [4-Hydroxyanilino(phenyl)methyl]phosphonate
(4m)7c
1H NMR (90 MHz, CDCl3): d = 3.7 (dd, JP–C = 10.5 Hz, 6 H), 4.8
(d, JP-H = 27 Hz, 1 H), 7.1–8.0 (m, 10 H).
13C NMR (22.5 MHz, CDCl3): d = 51.9 (CH), 54.0 (OMe), 54.3
(OMe), 114.0 (CH), 121.9 (CH), 125.7 (CH), 129.3 (CH), 130.1
(CH), 131.2 (CH), 135.0 (C), 149.2 (C).
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1143.
Dimethyl (1-Anilinohexyl)phosphonate (4q)7c
1H NMR (90 MHz, CDCl3): d = 0.7 (t, J = 7.5 Hz, 3 H), 1.2–1.8 (m,
8 H), 3.6 (br s, NH), 3.7 (d, J = 9.9 Hz, 3 H), 3.8 (d, J = 9.9 Hz, 3
H), 3.9 (m, 1 H), 6.5–7.5 (m, 5 H).
(6) Yokomatsu, T.; Yoshida, Y.; Shibuya, S. J. Org. Chem.
13C NMR (22.5 MHz, CDCl3): d = 13.5 (CH3), 21.9 (CH2), 25.3 (d,
1994, 59, 7930.
3JP–C = 12.4 Hz, CH2), 30.3 (d, JP–C = 3.3 Hz, CH2), 31.1 (CH2),
3
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Chem. 1998, 63, 4125. (g) Ranu, B. C.; Hajra, A.; Jana, J.
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Shen, Q. Eur. J. Org. Chem. 2003, 4728. (i) Firouzabadi,
H.; Iranpoor, N.; Sobhani, S. Synthesis 2004, 2692.
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(k) Heydari, A.; Karimian, A.; Ipaktschi, J. Tetrahedron
Lett. 1998, 39, 6729. (l) Chandrasekhar, S.; Prakash, S. J.;
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2
2
52.2 (d, JP–C = 7.42 Hz, OCH3), 53.2 (d, JP–C = 7.4 Hz, OCH3),
53.7 (d, 1JP–C = 135 Hz, CH), 113.2 (CH), 118.0 (CH), 129.4 (CH),
149.0 (C).
Dimethyl (1-Anilino-3-phenylpropyl)phosphonate (4r)7b
1H NMR (90 MHz, CDCl3): d = 1.2–1.5 (m, 2 H), 2.1–2.4 (m, 2 H),
2.9 (br s, NH, 1 H), 3.5 (m, CH, 1 H), 3.8–3.9 (dd, J = 8.9, 9.0 Hz,
6 H), 6.5–7.5 (m, Ar, 10 H).
13C NMR (22.5 MHz, CDCl3): d = 31.8 (CH2), 36.6 (CH2), 52.1
(OCH3), 58.9 (CH3), 69.1 (CH), 112.8 (CH), 115.1 (CH), 118.4
(CH), 126.0 (CH), 128.5 (CH), 129.3 (CH), 140.9 (C), 146.6 (C).
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Synthesis 2008, No. 3, 352–354 © Thieme Stuttgart · New York