A new one-pot synthesis of α-amino phosphonates catalyzed by butyldimethyl(1-phenylethyl)ammonium bromide

Article abstract of DOI:10.1246/cl.2005.444

Butyldimethyl(1-phenylethyl)ammonium bromide is found to be an efficient catalyst for the three-component reaction of an aldehyde, aromatic amine, and trimethylphosphite in refluxing CH₂Cl₂ to afford corresponding α-amino phosphonate in high yield. Copyright

Full text of DOI:10.1246/cl.2005.444

444
Chemistry Letters Vol.34, No.3 (2005)
A New One-pot Synthesis of ꢀ-Amino Phosphonates Catalyzed
by Butyldimethyl(1-phenylethyl)ammonium Bromide
K. Rosi Reddy, K. Srinivasa Reddy, Ch. Venkateshwar Reddy, M. Mahesh,
P. V. K. Raju, and V. V. Narayana Reddyꢀ
Organic Chemistry Division II, Indian Institute of Chemical Technology, Hyderabad – 500 007, India
(Received December 10, 2004; CL-041514)
Butyldimethyl(1-phenylethyl)ammonium bromide is found
to afford the ꢀ-amino phosphonates (4a–4o) in high yields
(>81%) and in shorter reaction time (2.5–3.5 h).20 The results
obtained are summarized in Table 1. The generality of this reac-
tion is further extended to ketones and secondary amines. Ke-
tones such as methy lisobutyl ketone and cyclohexanone reacted
with aniline to afford dimethyl (1-anilino-1,3-dimethylbutyl)-
phosphonate and dimethyl (1-anilinocyclohexyl)phosphonate
in 75 and 88% yield, respectively. Benzaldehyde reacted with
secondary amines such as piperidine and pyrrolidine to afford di-
methyl phenyl(piperidino)methylphosphonate and dimethyl
phenyl(pyrrolidin-1-yl)methylphosphonate in 76 and 77% yield,
respectively. These results indicate the scope and versatility of
the reaction of various aldehydes or ketones with aromatic as
well as secondary amines. Catalysts like tetrabutylammonium
bromide (TBAB, 0.65 mol %) gave lower yield of product 4a
(48%) in comparison to I under similar reaction conditions
(Table 1).
The compounds 4j, 4k, 4l, 4m are synthesized for the first
time and their structures have been unequivocally assigned by
IR, 1H NMR, 13C NMR, and mass spectroscopic data. It is inter-
esting to note that a doublet at ꢁ 4.68–4.88 ppm in all these com-
pounds with a coupling constant of 25 Hz due to 2JH,P coupling is
assignable to proton ꢀ to phosphonate moiety and it is diagnostic
for ꢀ-amino phosphonates.
to be an efficient catalyst for the three-component reaction of
an aldehyde, aromatic amine, and trimethylphosphite in reflux-
ing CH2Cl2 to afford corresponding ꢀ-amino phosphonate in
high yield.
ꢀ-Amino phosphonates have acquired great attention in syn-
thetic organic chemistry due to their structural analogy to ꢀ-
amino acids and their varied utility as herbicides,1 peptidemi-
mics,2 potent antibiotics,3 enzyme inhibitors,4 haptens of catalyt-
ic antibodies,5 and pharmacological agents.6 In view of their ver-
satile biological activity, a variety of synthetic methodologies
have been developed.7 Pudovik,8 the pioneer of this chemistry,
used imines under catalytic conditions of NaOMe for this trans-
formation and notable are some of the recent methods in which
Lewis acids such as SnCl4,9 ZrCl4,10 InCl3,11 ZnCl2/MgBr2,12
AlCl3,13 lithium perchlorate in diethyl ether (LPDE),14 lantha-
nide triflates,15 scandium tris(dodecylsulfate),16 and polysty-
rene-supported sulphonic acid (PS-SO3H)17 are used to give bet-
ter yields of ꢀ-amino phosphonates. However, many of these
methods lack simplicity of one-pot, one-step synthesis, and use
dialkylphosphite along with a desiccant and in some cases the
Lewis acids are used in stoichiometric amounts. In view of this
there is still a need to develop new catalytic procedures for the
synthesis of ꢀ-amino phosphonates. Therefore we envisaged
use of butyldimethyl(1-phenylethyl)ammonium bromide (I) as
catalyst in one-pot, one step, three component reaction. The cat-
alyst I is a stable quaternary ammonium salt which can be pre-
pared easily in the laboratory. We have explored its utility as
an efficient catalyst for oxidation, esterification, alkylation reac-
tions,18 and Biginelli’s cyclocondensation reaction.19
The reaction is presumed to proceed through the hydrolysis
of trimethyl phosphite by water generated during imine forma-
tion to yield dimethyl phosphite, which in turn react with imines
to form ꢀ-amino phoshonates.
Table 1. Butyldimethyl(1-phenylethyl)ammonium bromide (I)
catalyzed formation of ꢀ-amino phosphonates
Producta
R
R0
Time/h Yield/%b
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
C6H5
4-ClC6H4
4-CH3C6H4
4-HOC6H4
4-O2NC6H4
2-ClC6H4
2-HOC6H4
3-BrC6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2.5
2.5
3.0
2.5
2.5
2.5
3.0
3.5
89
91
92
87
90
85
87
85
85
87
87
86
89
82
81
CH3
-
Br
+
N
CH3
CH3
H3C
I
In the present paper, we wish to report the use of I as a cat-
alyst for the synthesis of ꢀ-amino phosphonates (Scheme 1).
The three-component reaction is performed under relatively sim-
ple reaction conditions by heating together an aldehyde (1), ar-
omatic amine (2), trimethylphosphite (3) in the ratio of 1.2:1:1
and the catalyst (0.35–0.5 mol %) in refluxing dichloromethane
4-CH3OC6H4 3.0
C6H5
C6H5
3-HO,4-CH3OC6H4
C6H5
2-HOC6H4
4-FC6H4
C6H5
3-O2NC6H4
C6H5
C6H5
3.5
3.0
3.0
3.0
3.5
3.5
O
H
C
OCH3
P
OCH3
OCH3
Catalyst(0.3 0.5 mol%)
R1NH2
P
+
CH3-(CH2)4
CH3-(CH2)8
RCHO+
R
DCM/Reflux, 2.5 3.5 h.
OCH3
H3CO
NHR1
1
2
3
4 a
o
aAll products were characterized by IR, 1H NMR, 13C NMR, and
mass spectroscopy, Isolated and unoptimised yields.
b
Scheme 1.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.3 (2005)
445
Table 2. Effect of solvents on the synthesis of 4a
11 B. C. Ranu, A. Hajar, and J. Jana, Org. Lett., 1, 1141 (1991).
12 J. Zon, J. Polym. Chem., 53, 643 (1981).
13 A. Manjula, B. Vittal Rao, and N. Parvathi, Synth. Commun.,
33, 2963 (2003).
14 a) A. Heydari, M. Zarei, R. Alijanianzadeh, and H. Tavakol,
Tetrahedron Lett., 42, 3629 (2001). b) M. R. Saidi and N.
Azizi, Synlett, 2002, 1347. c) N. Azizi and M. R. Saidi,
Eur. J. Org. Chem., 2003, 4630.
15 a) C. Qian and T. Huang, J. Org. Chem., 63, 4125 (1998). b)
S. Lee, J. H. Park, J. Kang, and J. K. Lee, Chem. Commun.,
2001, 1698.
Entry
Solventa
Catalyst/mol %
Yield/%
1
2
3
4
5
Toluene
THF
Acetonitrile
Dichloromethane
Dichloromethaneb
0.35
0.35
0.35
0.35
none
37
74
68
89
trace
aReflux temperature for 3.5 h.; bReflux for 10 h.
The effect of solvent on the synthesis 4a is studied in differ-
ent organic solvents and the results are summarized in Table 2.
Dichloromethane was found to be the solvent of choice for car-
rying out the three-component reaction.
16 K. Manabe and S. Kobayashi, Chem. Commun., 2000, 669.
17 S. Iimura, D. Nobutou, K. Manabe, and S. Kobayashi, Chem.
Commun., 2003, 1644.
In summary the results reveal that the catalyst is effective in
catalytic amount to synthesize ꢀ-amino phosphonates in high
yield without using any desiccant. Moreover, the catalyst can
be prepared in the laboratory and insensitive to moisture unlike
the conventional Lewis acid catalysts.
18 Ch. Venkateshwar Reddy, M. Mahesh, P. V. K. Raju, and
V. V. Narayana Reddy, Synth. Commun., 32, 2797 (2002).
19 K. Rosi Reddy, Ch. Venkateshwar Reddy, M. Mahesh,
P. V. K. Raju, and V. V. Narayana Reddy, Tetrahedron Lett.,
44, 8173 (2003).
20 General procedure for the synthesis of ꢀ-amino phospho-
nates 4: A mixture containing an aldehyde (12 mmol), amine
(10 mmol), trimethyl phosphite (10 mmole) and quaternary
ammonium bromide salt (0.35 mol %) in dichloromethane
(15 mL) was refluxed for appropriate time as mentioned in
Table 1. After completion of the reaction, as indicated by
TLC, the reaction mixture was washed with water (2 ꢁ 15
mL), dried over Na2SO4, concentrated under vacuum and
the crude mixture was purified by column chromatography
on silica gel (Hexane: EtOAc 8:2) to afford pure product.
Spectroscopic data: Dimethyl [(2-hydoxyphenyl)amino]-
(phenyl)methylphosponate (4j): mp. 120 ꢂC; 1H NMR
(CDCl3, 400 MHz) ꢁ 3.43 (d, J ¼ 10:57 Hz, 3H, –OCH3),
3.90 (d, J ¼ 10:48 Hz, 3H, –OCH3), 4.89 (d, J ¼ 25:8 Hz,
1H, –CH), 5.7 (brs, 1H, –NH, D2O exchangeable), 6.49–
6.52 (m, 2H, Ar), 6.60 (t, J ¼ 7:5 Hz, 1H, Ar), 6.75 (d,
J ¼ 8:8 Hz, 1H, Ar), 7.09–7.1 (m, 3H, Ar), 7.39 (d,
J ¼ 7:8 Hz, 2H, Ar), 9.2 (brs, 1H, –OH, D2O exchangeable).
13C NMR (CDCl3, 100 MHz) ꢁ 53.97, 54.53, 56.68, 111.91,
114.36, 118.36, 119.88, 127.89, 127.96, 128.57, 134.59,
134.80, 135.34, 145.11. FABMS: m=z (%) 307 (18) (Mþ),
198 (100), 154 (8), 77 (10). IR (KBr) ꢂ ¼ 3275, 2985,
2140, 1275, 1210, 1040 cmꢃ1. Dimethyl [(4-Fluorophenyl)-
amino](phenyl)methylphosponate (4k): mp. 82 ꢂC; 1H NMR
(CDCl3, 400 MHz) ꢁ 3.41 (d, J ¼ 10:58 Hz, 3H, –OCH3),
3.78 (d, J ¼ 10:54 Hz, 3H, –OCH3), 4.68 (d, J ¼ 24:31 Hz,
1H, –CH), 5.26 (brs, 1H, NH, D2O exchangeable), 6.49–
6.52 (m, 2H, Ar), 6.76 (t, J ¼ 7:8 Hz, 2H, Ar), 7.24–7.36
(m, 3H, Ar), 7.44 (d, J ¼ 7:5 Hz, 2H, Ar); 13C NMR (CDCl3,
100 MHz): ꢁ 54.01, 58.58, 56.73, 114.62, 115.01, 115.36,
115.44, 115.55, 127.72, 127.95, 128.57, 135.22, 142.23,
155.27, 157.15; FAB MS: m=z (%) : 309 (20), (Mþ), 200
(100), 77 (4), 57 (3); IR (KBr) ꢂ ¼ 3320, 2980, 1520,
K. R. R and K. S. R are thankful to the Director IICT,
for financial support. M. M. and Ch. V. R. thank the CSIR,
New Delhi, for the award of fellowships.
References and Notes
1
a) A. Barder, Aldrichimica Acta, 21, 15 (1988). b) J. Emsley
and E. D. Hall, ‘‘The Chemistry of Phosphorus,’’ Harper and
Row, London (1976).
2
3
4
P. Kafarski and B. Lejczak, Phosphorus, Sulfur Silicon
Relat. Elem., 63, 1993 (1991).
F. R. Atherton, C. H. Hassell, and R. W. Lambert, J. Med.
Chem., 29, 29 (1986).
a) M. C. Allen, W. Fuhrer, B. Tuck, R. Wade, and
J. M. Wood, J. Med. Chem., 32, 1652 (1989). b) T. R. Burke,
J. J. Barchi, C. George, G. Wolf, S. E. Shoelson, and X. Yan,
J. Med. Chem., 38, 1386 (1995).
5
a) R. Hirtchmann, A. B. Smith, III, C. M. Taylor, P. A.
Benkovic, S. D. Taylor, K. M. Yager, P. A. Sprengler, and
S. J. Venkovic, Science, 265, 234 (1994). b) A. B. Smith,
III, C. M. Taylor, J. Benkovic, and R. Hirtchmann,
Tetrahedron Lett., 37, 6853 (1994).
6
7
E. K. Baylis, C. D. Campbell, and J. G. Dingwall, J. Chem.
Soc., Perkin Trans. 1, 1984, 2845.
a) T. Yokomatsu, Y. Yoshida, and S. Shibuya, J.
Org. Chem., 59, 7930 (1994). b) V. P. Kukhar and V. A.
Solodenko, Russ. Chem. Rev., 56, 859 (1987). c) S.
Chandrasekhar, Ch. Narsihmulu, S. Shameem Sultana, B.
Saritha, and S. Jaya Prakash, Synlett, 2003, 505.
A. N. Pudovik, Dokl. Akad. Nauk SSSR, 83, 865 (1987);
Chem. Abstr., 47, 4300g (1953).
8
9
S. Laschat and H. Kunz, Synthesis, 1992, 90.
10 J. S. Yadav, B. V. S. Reddy, R. K. Sarita, B. K. Reddy, and
A. R. Prasad, Synthesis, 2001, 2277.
1480, 1230, 1020, 825 cmꢃ1
.
Published on the web (Advance View) February 23, 2005; DOI 10.1246/cl.2005.444