Microwave-assisted solvent-free and catalyst-free Kabachnik-Fields reactions for α-amino phosphonates

Article abstract of DOI:10.1016/j.tetlet.2005.12.027

A highly efficient solvent-free and catalyst-free method for the synthesis of α-amino phosphonates is developed by a microwave-assisted three-component Kabachnik-Fields reaction involving aldehyde, amine, and dimethyl phosphite.

Full text of DOI:10.1016/j.tetlet.2005.12.027

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1125–1127
Microwave-assisted solvent-free and catalyst-free
Kabachnik–Fields reactions for a-amino phosphonates
Xue-Jun Mu,a Mao-Yi Lei,a Jian-Ping Zoua,* and Wei Zhangb,*
aKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University,
1 Shizi St. Suzhou 215006, Jiangsu, China
bFluorous Technologies, Inc., University of Pittsburgh Applied Research Center, 970 William Pitt Way, Pittsburgh, PA 15238, USA
Received 4 October 2005; revised 3 December 2005; accepted 6 December 2005
Available online 27 December 2005
Abstract—A highly efficient solvent-free and catalyst-free method for the synthesis of a-amino phosphonates is developed by a
microwave-assisted three-component Kabachnik–Fields reaction involving aldehyde, amine, and dimethyl phosphite.
ꢀ 2005 Elsevier Ltd. All rights reserved.
a-Amino phosphonates are phosphorus analogs of
amino acids,1 which have been widely used as imaging
agents and as antitumor, antihypertensive, and antibac-
terial agents.2 Among the literature methods, the
Kabachnik–Fields reaction3 is one of the most conve-
nient approaches to a-amino phosphonates. It is a
one-pot, three-component reaction of carbonyl com-
pound, amine, and dialkyl phosphite. The reaction usu-
ally needs a Lewis acid catalyst such as indium(III)
chloride,4 rare earth triflates,5 and scandium tris(dodecyl
sulfate).6 Recently, SmI2,7 LiClO4,8 metal triflates
[M(OTf)n, M = Li, Mg, Al, Cu, Ce],9 TaCl5-SiO2,10
montmorillonite clay,11 Al2O3,12 CF3CO2H,13 scan-
dium(tris-dodecyl sulfate),6 BF3ÆEt2O,14 and tetra-tert-
butyl-substituted phthalocyanines Pht-1-Pht-315 have
also been reported as the catalysts. A broad range of
catalysts has been employed for the Kabachnik–Fields
reaction. However, many of these catalysts are expensive
and have to be used in stoichiometric amount. The cat-
alyst-free synthesis of a-amino phosphonates is rather
limited.16
O
no solvent
no catalyst
R1 P(OMe)2
R1CHO
R2NH2
HPO(OMe)2
+
+
MW (180W)
2 min
H
NHR2
1
Scheme 1.
A catalyst-free Kabachnik–Fields reaction of benzalde-
hyde, aniline, and dimethyl phosphite was first
attempted using ethanol as a solvent. After the reaction
mixture was stirred at room temperature for 2 h, no
desired product 1a was detected (Table 1, entry 1).
Similar results were obtained when the reactions were
carried out at different temperatures and in different
solvents such as toluene and CH2Cl2 (Table 1, entries
4–5).
Catalyst-free Kabachnik–Fields reactions under the sol-
vent-free conditions were then explored. The reaction of
benzaldehyde, aniline, and dimethyl phosphate at 50 ꢁC
for 2 h gave desired product 1a in 76% yield. A higher
yield (85%) was obtained after heating the reaction mix-
ture at 80 ꢁC for 2 h (Table 1, entry 8).19 Finally, micro-
wave heating was introduced to reduce the reaction
time. Indeed, after the reaction mixture was irradiated
in a multimood microwave reactor at 180 W for only
2 min, the reaction was completed and the yield of 1a
was increased to 98% (Table 1, entry 9).20
Microwave-promoted17 solvent-free18 heterogeneous
reactions have received much attention due to their high
efficiency, cost effective, and environmentally friend
characteristics. Described in this paper is a microwave-
assisted solvent-free and catalyst-free method for the
synthesis of a-amino phosphonates (Scheme 1).
*
Corresponding authors. Tel./fax: +86 512 65112371 (J.-P.Z.); tel.: +1
412 8263062; fax: +1 412 8263053 (W.Z.); e-mail addresses:
wuyanhong@pub.sz.jsinfo.net; w.zhang@fluorous.com
To evaluate the synthetic scope, reactions of different
aldehydes and amines with dimethyl phosphite were
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.027

1126
X.-J. Mu et al. / Tetrahedron Letters 47 (2006) 1125–1127
Table 1. Catalyst-free synthesis of a-aminophosphonate 1a
nates. The reaction process is highly efficient, economic,
and also environmentally friendly.
Entry
Solvent
Temp (ꢁC)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
Toluene
rt
50
reflux
Reflux
Reflux
rt
50
80
80, mwc
120
120
120
120
120
120
120
120
2
nrb
nr
nr
nr
nr
nr
76
85
98
Acknowledgements
CH2Cl2
We thank the Key Laboratory of Organic Synthesis of
Jiangsu Province and Suzhou Scientific Committee for
financial supports (JSK016 and SG 0219).
Solvent-free
Solvent-free
Solvent-free
Solvent-free
a Isolated yields.
Supplementary data
b nr = no reaction.
c mw = microwave heating.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2005.12.027.
conducted and the results are shown in Table 2. Reac-
tions involving benzaldehydes and anilines produced
products 1a–1e and 1i–1n in excellent yields.19 Reactions
of aliphatic amines, aliphatic aldehydes, and hetero-
cyclic aldehydes such as 2-furylaldehyde and 2-thiophene
aldehyde produced corresponding products 1f–1g, 1o–
1r, and 1s–1u in good to excellent yields. Steric hindered
tert-butyl aldehyde and 2,6-dimethyl aniline were also
evaluated. In the case of reaction involving benzalde-
hyde and 2,6-dimethylaniline, good yield of 1v (78%)
was produced. However, reactions involving tert-butyl
aldehyde, p-toluidine, or 2,6-dimethyl aniline afforded
1w and 1x in 53% and 40% yields, respectively, much
lower than reactions using other substrates listed in
Table 2.
References and notes
1. Sheridan, R. P. J. Chem. Inf. Comput. Sci. 2002, 42, 103.
2. (a) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon
Relat. Elem. 1991, 63, 1993; (b) Allen, M. C.; Fuhrer, W.;
Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989, 32,
1652; (c) Grembecka, J.; Mucha, A.; Cierpicki, T.;
Kafarski, P. J. Med. Chem. 2003, 46, 2641; (d) Moore, J.
D.; Sprott, K. T.; Fisher, A. J.; Tony, M. Biochemistry
2002, 67, 8123; (e) Liu, W.; Rogers, C. J.; Fisher, A. J.;
Toney, M. Biochemistry 2002, 41, 12320; (f) Kim, K. S.;
Hurh, E. Y.; Youn, J. N.; Park, J. I. J. Org. Chem. 1999,
64, 9272; (g) Osipov, S. N.; Artyushin, O. I.; Kolomeits, A.
F.; Bruneau, C.; Dixneuf, P. H. Synlett 2000, 1031;
(h) Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J.
Chem. Soc., Perkin Trans. 1 1984, 2845; (i) Atherton, F.
R.; Hassal, C. H.; Lambert, R. W. J. Med. Chem. 1986,
29, 29.
In summary, we have developed a novel microwave-
assisted, catalysts-free, and solvent-free Kabachnik–
Fields reaction for the synthesis of a-amino phospho-
3. (a) Kabachnik, M. I.; Medved, T. Y. Dokl. Akad. Nauk
SSSR. 1952, 689; Chem. Abstr. 1953, 47, 2724b; (b) Fields,
E. K. J. Am. Chem. Soc. 1952, 74, 1528; (c) For a review
on the Kabachnik–Fields reaction, see: Cherkasov, R. A.;
Galkin, V. I. Russ. Chem. Rev. 1998, 67, 857.
4. Ranu, B. C.; Hajra, A.; Jana, U. Org. Lett. 1999, 1, 1141.
5. (a) Qian, C. T. T.; Huang, S. J. Org. Chem. 1998, 63, 4125;
(b) Lee, S.; Park, J. H.; Kang, J.; Lee, J. K. Chem.
Commun. 2001, 1698.
6. Manabe, K.; Kobayashi, S. Chem. Commun. 2000, 669.
7. Xu, F.; Luo, Y. Q.; Deng, M. Y.; Shen, Q. Eur. J. Org.
Chem. 2003, 4728.
8. Saidi, M. R.; Azizi, N. Synlett 2002, 1347.
9. Firouzabadi, H.; Iranpoor, N.; Sobhani, S. Synthesis 2004,
16, 2692.
10. Chandrasekhar, S.; Prakash, S. J.; Jagadeshwar, V.;
Narsihmulu, C. Tetrahedron Lett. 2001, 42, 5561.
11. Yadav, J. S.; Reddy, B. V. S.; Madan, C. Synlett 2001,
1131.
12. Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42,
8211.
13. Akiyama, T.; Sanada, M.; Fuchibe, K. Synlett 2003, 1463.
14. Ha, H.-J.; Nam, G.-S. Synth. Commun. 1992, 22, 1143.
15. Matveeva, E. D.; Podrugina, T. A.; Tishkovskaya, E. V.;
Tomilova, L. G.; Zefirov, N. S. Synlett 2003, 15, 2321.
16. Ranu, B. C.; Hajra, A. Green Chem. 2002, 4, 551.
17. Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
18. For a general review on solvent-free reactions, see:
Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025.
19. General procedures for preparation of a-amino phospho-
nates under conventional heating: Benzaldehyde (1 mmol),
Table 2. Microwave-assisted synthesis of a-aminophosphonates
Producta
R1
R2
Time
(min)
Yield
(%)b
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
98
94
96
97
96
86
87
86
96
94
91
89
87
84
88
83
85
80
88
76
85
78
53
40
p-MeC6H4
p-ClC6H4
o-ClC6H4
m-BrC6H4
Naphthyl
Cyclohexyl
PhCH2
1g
1h
1i
p-MeOC6H4
p-MeOC6H4
p-MeOC6H4
p-NO2C6H4
p-NO2C6H4
p-NO2C6H4
i-Propyl
i-Propyl
i-Propyl
i-Propyl
2-Furyl
2-Furyl
2-Thiophene
Ph
Ph
1j
p-MeC6H4
p-ClC6H4
Ph
p-MeOC6H4
p-ClC6H4
Ph
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-MeC6H4
p-ClC6H4
p-NO2C6H4
2,6-diMeC6H3
p-MeC6H4
2,6-diMeC6H3
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
1u
1v
1w
1x
tert-Butyl
tert-Butyl
a Products were characterized by their NMR and MS spectra.
b After flash column chromatography.

X.-J. Mu et al. / Tetrahedron Letters 47 (2006) 1125–1127
1127
aniline (1 mmol), and dimethyl phosphite (2 mL) were
added into a 25 mL three-necked flask. The mixture was
stirred at 80 ꢁC for 2 h. The reaction mixture was then
diluted with water and extracted with CH2Cl2 (20 mL).
The organic layer was washed with H2O (3 · 10 mL), dried
over anhydrous Na2SO4, filtered, and concentrated. The
crude product was purified by silica gel flash column
chromatography eluted with 2:1 petroleum ether/acetone
to give pure a-amino phosphonate 1a in 85% yield.
multimood microwave oven. The reaction mixture was
diluted with water and extracted with CH2Cl2 (20 mL).
The organic layer was washed with H2O (3 · 10 mL), dried
over anhydrous Na2SO4, filtered, concentrated, and the
crude product was purified by silica gel flash column
chromatography eluted with 2:1 petroleum ether/acetone
to give pure a-amino phosphonate 1a in 98% yield, mp
90–91 ꢁC. 1H NMR (400 MHz) (CDCl3): d 7.48–6.59
(10H, m, 2C6H5), 4.81 (1H, d, 1JPH = 24.40 Hz, CH), 3.76
2
2
20. General procedures for preparation of a-amino phospho-
nates under microwave irradiation: Benzaldehyde
(1 mmol), aniline (1 mmol), and dimethyl phosphite
(2 mL) were added into a 25 mL three-necked flask. The
mixture was then heated at 80 ꢁC for 2 min at 180 W in a
(3H, d, JPH = 10.60 Hz, OCH3), 3.46 (3H, d, JPH =
10.60 Hz, OCH3); 13C NMR (100 MHz) (CDCl3): d
146.4, 135.9, 129.6, 129.2, 128.5, 128.2, 118.9, 114.2, 55.5
1
(d, JCP = 150.2 Hz, CH), 54.3, 54.2; HRMS calcd for
C15H18NO3P 291.1024, found 291.1022.