An extremely efficient three-component reaction of aldehydes/ketones, amines, and phosphites (Kabachnik-Fields reaction) for the synthesis of α-aminophosphonates catalyzed by magnesium perchlorate

Article abstract of DOI:10.1021/jo062140i

(Chemical Equation Presented) Commercially available magnesium perchlorate is reported as an extremely efficient catalyst for the synthesis of α-aminophosphonates. A three-component reaction (3-CR) of an amine, an aldehyde or a ketone, and a di-/trialkyl phosphite (Kabachnik-Fields reaction) took place in one pot under solvent-free conditions to afford the corresponding α-aminophosphonates in high yields and short times. The use of solvent retards the rate of the reaction and requires a much longer reaction time than that for neat conditions. The reactions involving an aldehyde, an aromatic amine without any electron-withdrawing substituent, and a phosphite are carried out at rt. The reactions involving cyclic ketones, aromatic amines with an electron-withdrawing substituent, and aryl alkyl ketone (e.g., acetophenone) require longer reaction times at rt or heating. Magnesium perchlorate was found to be superior to other metal perchlorates and metal triflates during the reaction of 4-methoxybenzaldehyde, 2,4-dinitroaniline, and dimethyl phosphite. The catalytic activity of various magnesium compounds was influenced by the counteranion, and magnesium perchlorate was found to be the most effective. The reaction was found to be general with di-/trialkyl phosphites and diaryl phosphite. The Mg(ClO₄)₂-catalyzed α- aminophosphonate synthesis in the present study perhaps represents a true three-component reaction as no intermediate formation of either an imine or α-hydroxy phosphonate was observed that indicated the simultaneous involvement of the carbonyl compound, the amine, and the phosphite in the transition state.

Full text of DOI:10.1021/jo062140i

An Extremely Efficient Three-Component Reaction of Aldehydes/
Ketones, Amines, and Phosphites (Kabachnik-Fields Reaction) for
the Synthesis of r-Aminophosphonates Catalyzed by Magnesium
Perchlorate
Srikant Bhagat and Asit K. Chakraborti*
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research
(NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India
akchakraborti@niper.ac.in
ReceiVed October 16, 2006
Commercially available magnesium perchlorate is reported as an extremely efficient catalyst for the
synthesis of R-aminophosphonates. A three-component reaction (3-CR) of an amine, an aldehyde or a
ketone, and a di-/trialkyl phosphite (Kabachnik-Fields reaction) took place in one pot under solvent-
free conditions to afford the corresponding R-aminophosphonates in high yields and short times. The use
of solvent retards the rate of the reaction and requires a much longer reaction time than that for neat
conditions. The reactions involving an aldehyde, an aromatic amine without any electron-withdrawing
substituent, and a phosphite are carried out at rt. The reactions involving cyclic ketones, aromatic amines
with an electron-withdrawing substituent, and aryl alkyl ketone (e.g., acetophenone) require longer reaction
times at rt or heating. Magnesium perchlorate was found to be superior to other metal perchlorates and
metal triflates during the reaction of 4-methoxybenzaldehyde, 2,4-dinitroaniline, and dimethyl phosphite.
The catalytic activity of various magnesium compounds was influenced by the counteranion, and
magnesium perchlorate was found to be the most effective. The reaction was found to be general with
di-/trialkyl phosphites and diaryl phosphite. The Mg(ClO4)2-catalyzed R-aminophosphonate synthesis in
the present study perhaps represents a true three-component reaction as no intermediate formation of
either an imine or R-hydroxy phosphonate was observed that indicated the simultaneous involvement of
the carbonyl compound, the amine, and the phosphite in the transition state.
Introduction
ditional reagents, heating, long time, costly and moisture
sensitive catalysts, special apparatus, etc., and the reported
methodologies do not work well with electron-deficient amines
such as nitro anilines.
The R-aminophosphonate moiety is a versatile and novel
pharmacophore due to the broad spectrum of biological activity
exhibited by compounds bearing this structural unit.1 Thus, the
development of new synthetic methodologies for R-aminophos-
phonates2 has attracted the attention of medicinal/organic
chemists. Recently, various methodologies have been developed
for the synthesis of R-aminophosphonates.3 However, still there
remains a need to develop a more efficient method, particularly
keeping in view the disadvantages associated with some of the
reported procedures such as the requirement of solvent, ad-
While designing a new catalyst, we thought that the use of a
more effective electrophilic activation agent should accelerate
the overall reaction rate, and a metal salt derived from a strong
protic acid should be an ideal contender. The large negative H0
value of -14.1 of TfOH4 makes TfOH the strongest protic acid,
and thus, metal triflates drew attention as catalysts.3f,g,k,q
However, TfOH is liberated from metal triflates and may be
the actual catalytic agent.5 The in situ generation of TfOH might
be the reason for the potential side reactions (e.g., dehydration,
rearrangement, etc.) with acid-sensitive substrates or deactivation
* To whom correspondence should be addressed. Fax: 91-(0)-172 2214692;
Tel: 91-(0)-172 2214683.
10.1021/jo062140i CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/25/2007
J. Org. Chem. 2007, 72, 1263-1270
1263

Bhagat and Chakraborti
SCHEME 1. Mg(ClO4)2-Catalyzed 3-CR of an Aldehyde/
Ketone, an Amine, and Di-/Trialkyl Phosphite Leading to
the Formation of r-Aminophosphonate
TABLE 1. Mg(ClO4)2-Catalyzed Synthesis of r-Aminophosphonate
during the Reaction of 1, 2, and DMP under Various Conditionsa
entry
catalyst
solvent T (°C) time (h) yieldb,c (%)
1
2
3
4
5
6
7
8
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
neat
neat
DCM
MeCN
THF
80
rt
rt
rt
rt
rt
80
rt
0.5
6
24
24
24
10
6
85
85
81
81
80
Mg(ClO4)2‚6H2O neat
40d
60d
nild
Mg(ClO4)2‚6H2O neat
Mg(ClO4)2
H2O
24
of the amine substrates due to salt formation. Thus, metal triflate-
catalyzed reactions are often carried out in the presence of
stoichiometric amounts of additional reagents such as molecular
sieves, MgSO4, etc. This brings the attention to triflimides6 as
HNTf2 is a weaker Brønsted acid than TfOH7 and ligand
exchange is not common with triflimides.8 However, metal
triflimides are costly, very few are available commercially, and
they require additional efforts and costly reagents to prepare.9
Hence, we focused our attention on catalysts derived from
HClO4 as it is weaker than TfOH. Recently, we reported metal
perchlorates as efficient electrophilic activation catalysts for
acylation, imine formation, thia-Michael addition, and acylal
formation reactions.10
a 1 (2.5 mmol) was treated with 2 (2.5 mmol) and DMP (2.5 mmol) in
the presence of the catalyst (5 mol %) under solvent-free conditions (except
for entries 3-5 and 8). b Yield of the isolated and purified 3. c The product
was characterized by the IR, H and 13C NMR, and MS. d The unreacted
1
starting materials remained unchanged (TLC).
order of mixing the substrates did not influence the product
yield. The use of organic solvents required longer reaction times
(entries 3-5, Table 1), but no significant amount of 3 was
formed in carrying out the reaction in water (entry 8, Table 1).
However, the use of magnesium perchlorate hydrate [Mg-
(ClO4)2‚6H2O] was less effective (entries 6 and 7, Table 1). A
similar decrease in the catalytic property of Mg(ClO4)2‚6H2O
compared to that of Mg(ClO4)2 has been observed in the
acylation reactions.10a,11
Results and Discussion
We planned to evaluate the catalytic property of Mg(ClO4)2
with other metal perchlorates during the three-component reac-
tion of 1, 2, and DMP (Table 2). The best results were obtained
with Mg(ClO4)2 either at rt for 6 h or at 80 °C for 30 min. In all
Herein, we report that Mg(ClO4)2 is an extremely efficient
catalyst for the formation of R-aminophosphonate by a one-
pot, three-component reaction of an aldehyde/ketone, an amine,
and a di-/trialkyl phosphite under solvent-free conditions
(Scheme 1).
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H.; Iranpoor, N.; Sobhani, S. Synthesis 2004, 2692. (h) Thiourea dvt.: Joly,
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(j) Ionic liquid: Yadav, J. S.; Reddy, B. V. S.; Sreedhar, P. Green Chem.
2002, 4, 436-438. (k) Ln(OTf)3 in ionic liquid: Lee, S.; Park, J. H.; Kang,
J.; Lee, J. K. Chem. Commun. 2001, 1698. (l) Al2O3 under microwave
heating: Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42, 8211. (m)
Montmorillonite KSF under microwave heating: Yadav, J. S.; Reddy, B.
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To determine the best experimental conditions, the reaction
of 4-methoxybenzaldehyde (1) as a representative less electro-
philic aldehyde, 2,4-dinitroaniline (2) as an electron-deficient
and sterically hindered amine, and dimethyl phosphite (DMP)
was considered as the model (Table 1). The best results were
obtained in the presence of Mg(ClO4)2 at rt affording the desired
R-aminophosphonate dimethyl [(2,4-dinitrophenylamino)-(4-
methoxyphenyl)methyl]phosphonate (3) in 85% yield after 6 h
at rt and after 30 min at 80 °C (entries 1 and 2, Table 1). The
(1) Enzyme inhibitory: (a) LAP: Giannousis, P. P.; Bartlett, P. A. J.
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W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med. Chem. 1989, 32, 1652.(c)
Class C â-lactamase: Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassall, C.
H.; Holmes, S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S. Nature
1978, 272, 56. Pratt, R. F. Science 1989, 246, 917. (d) Human collagenase:
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Markwell, R. E.; Miles-Williams, A. J.; Rahman, S. S.; Ward, R. S. J. Med.
Chem. 1994, 37, 158. (e) Phosphatase: Beers, S. A.; Schwender, C. F.;
Loughney, D. A.; Malloy, E.; Demarest, K.; Jordan, J. Bioorg. Med. Chem.
1996, 4, 1693. (f) S-Adenosyl-L-homocysteine hydrolase: Steere, J. A.;
Sampson, P. B.; Honek, J. F. Bioorg. Med. Chem. Lett. 2002, 12, 457. (g)
R(2-6)Sialyltransferase transition-state analogue: Skropeta, D.; Schwo¨rer,
R.; Schmidt, R. R. Bioorg. Med. Chem. Lett. 2003, 13, 3351. Antifungal:
(h) Maier, L.; Diel, P. J. Phosphorous, Sulfur, Silicon 1991, 57, 57.
Antioxidants: (i) Bonarska, D.; Kleszczyska, H.; Sarapuk, J. Cell. Mol.
Biol. Lett. 2002, 7, 929. Herbicidal: (j) NÄ ska, H.; Bonarska, D.; Bielecki,
K.; Sarapuk, J. Cell. Mol. Biol. Lett. 2002, 7, 929.
(2) (a) Kabachnik, M. I.; Medve, T. Y. Dokl. Akad. Nauk SSSR 1952,
83, 689; Chem. Abstr. 1953, 47, 2724b. (b) Fields, E. K. J. Am. Chem.
Soc. 1952, 74, 1528. (c) Pudovik, A. N. Dokl. Akad. Nauk SSSR 1952, 83,
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Erokhina, T. S. Usp. Khim. 1974, 43, 2045; Chem. Abstr. 1975, 82, 43486.
(e) Redmore, D. Topics in Phosphorous Chemistry; Grifith, E. J., Grayson,
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Cherkasov, R. A.; Galkin, V. I. Russ. Chem. ReV. 1998, 67, 857. (g) Fields,
S. C. Tetrahedron 1999, 55, 12237. (h) Moonen, K.; Laureyn, I.; Stevens,
C. V. Chem. ReV. 2004, 104, 6177.
(11) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi,
M.; Rinaldi, S.; Sambri, L. Synlett 2003, 39.
1264 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of R-Aminophosphonates Catalyzed by Magnesium Perchlorate
TABLE 2. Various Metal Perchlorate Catalyzed Synthesis of 3
TABLE 3. Comparison of the Catalytic Efficiency of Mg(ClO4)2
with Various Catalysts for the Synthesis of 3 during the Reaction of
1, 2, and DMPa
during the Reaction of 1, 2, and DMP under Various Conditionsa
entry
catalyst
Mg(ClO4)2
Mg(ClO4)2
LiClO4
LiClO4
LPDE
NH4ClO4
NH4ClO4
Zn(ClO4)2‚6H2O
Zn(ClO4)2‚6H2O
Fe(ClO4)2‚xH2O
Fe(ClO4)2‚xH2O
Fe(ClO4)3‚xH2O
Fe(ClO4)3‚xH2O
Co(ClO4)2‚6H2O
Co(ClO4)2‚6H2O
Cu(ClO4)2‚6H2O
Cu(ClO4)2‚6H2O
ZrO(ClO4)2‚6H2O
ZrO(ClO4)2‚6H2O
BiO(ClO4)2‚xH2O
BiO(ClO4)2‚6H2O
In(ClO4)3‚xH2O
In(ClO4)3‚6H2O
Yb(ClO4)3
T (°C)
time (h)
yieldb,c (%)
entry
catalyst
Mg(ClO4)2
Mg(ClO4)2
LiOTf
Mg(OTf)2
Al(OTf)3
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3-MgSO4 DCM
In(OTf)3-MgSO4 THF
InCl3
ZrCl4
Cu(BF4)2
[bmIm]BF4
solvent
neat
neat
neat
neat
neat
neat
neat
T (°C) time (h) yieldb,c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
80
rt
rt
80
rt
80
rt
80
rt
80
rt
80
rt
80
rt
80
rt
80
rt
80
rt
80
rt
0.5
6
10
6
24
1
10
1
10
1
10
1
10
1
10
1
10
1
10
1
10
1
10
1
85
85
1
2
3
4
5
6
7
8
9
10
11
12
13
80
rt
0.5
6
6
6
6
6
6
48
48
24
24
24
24
85
traced
40d
20d,e
25d
5d
85
80
80
80
80
80
rt
20d
50d
20d
40d
60d
30d
40d
12d
40d
15d
40d
20d
60d
5d
50e
tracef
10g
80
rt
THF
MeCN
neat
traceh
tracei
30
rt
80
rt
[bmIm]BF4
25j,k
a 1 (2.5 mmol) was treated with 2 (2.5 mmol) and DMP (2.5 mmol) in
the presence of the catalyst (5 mol % except for entry 13) under solvent-
free conditions (except for entries 8-11 and 13). b Yield of the isolated
and purified 3. c The product was characterized by the IR, 1H and 13C NMR,
and MS. d Compare with ref 3g. e Compare with ref 3k. f Compare with
ref 3q. g Compare with ref 3f. h Compare with 3p. i Compare with ref 20.
j Compare with ref 3j. k The catalyst (ionic liquid) itself was used as solvent.
50d
20d
70d
30d
60d
20d
30d,f
nild,f
80
rt
Yb(ClO4)3
10
TABLE 4. Comparison of the Catalytic Efficiency of Various
Magnesium Salts for the Synthesis of 3 during the Reaction of 1, 2,
and DMPa
a 1 (2.5 mmol) was treated with 2 (2.5 mmol) and DMP (2.5 mmol) in
the presence of the catalyst (5 mol % except for entry 5) under solvent-
free conditions (except for entries 5, 23, and 24). b Yield of the isolated
and purified 3. c The product was characterized by the IR, 1H and 13C NMR,
and MS. d The unreacted starting materials remained unchanged (TLC).e 3
equiv of LiClO4 (as a 5 M solution in Et2O) was used. f A 40% (wt/vol)
aqueous solution was used.
entry
catalyst
solvent
T (°C)
time (h)
yieldb,c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Mg(ClO4)2
Mg(ClO4)2
MgSO4
MgSO4
MgSO4
MgSO4
MgSO4
MgCl2
MgCl2
MgBr2
MgBr2
MgI2
neat
neat
neat
neat
DCM
DCE
THF
neat
neat
neat
neat
neat
neat
neat
80
rt
80
rt
0.5
6
1
24
24
4
4
1
24
1
24
1
85
85
20d
5d
rt
nild
30d
nild
5
reflux
reflux
80
rt
80
rt
80
rt
80
cases where the desired aminophosphonate 3 was formed in poor
yield, the unreacted starting materials remained unchanged (TLC).
nil
10
nil
10
nil
50e
The present method is far more superior to the use of
LiClO4,12 which required 2-10 equiv of LiClO4, additional
reagent (e.g., TMSCl), and solvent. The superiority of Mg-
(ClO4)2 over LiClO4 was due to the better electrophilic activation
ability of Mg+2 ion compared to that of Li+ as the former cation
has a higher charge to size ratio (the Z2/r values of Mg+2 and
Li+ are 5.56 and 1.35 e2 m-10, respectively).13 The inferior
catalytic property of Fe(ClO4)2‚6H2O, Zn(ClO4)2‚6H2O, Co-
(ClO4)2‚6H2O, and Cu(ClO4)2‚6H2O was due to the lower Z2/r
values of 5.19, 5.33, 5.40, and 5.48 e2 m-10, respectively, of
the Fe+2, Zn+2, Co+2, and Cu+2 ions.12 However, although the
Z2/r values of 8.82, 11.39, 13.85, and 22.22 e2 m-10, respec-
tively, of the Bi+3, In+3, Fe+3, and Zr+4 ions are higher than
MgI2
Mg(OTf)2
24
6
a 1 (2.5 mmol) was treated with 2 (2.5 mmol) and DMP (2.5 mmol) in
the presence of the catalyst (5 mol %) under solvent-free conditions (except
for entries 5-7). b Yield of the isolated and purified 3. c The product was
characterized by the IR, 1H and 13C NMR, and MS. d Compare with ref
3f,q. e Compare with ref 3g.
the result obtained with the Mg(ClO4)2-catalyzed reaction with
that of other reported catalysts/systems (Table 3).
that of the Mg+2 ion the lower hydrolysis constants (pKa )
To find out the influence of the counteranion on the catalytic
property, various magnesium salts were used as the promoter
during the reaction of 1, 2, and DMP (Table 4). The far more
superior catalytic activity of Mg(ClO4)2 over the other magne-
sium salts correlates well with the acidic strength of the
corresponding protic acids (except for TfOH).15
To establish the generality, various aldehydes/ketones, amines,
and DMP or diethyl phosphite (DEP) were subjected to a one-
pot reaction (3-CR) catalyzed by Mg(ClO4)2 (Table 5).
Excellent results were obtained during the reaction of aryl/
heteroaryl/alkyl/aryl alkyl aldehydes/ketones with aryl/het-
eroaryl/alryl alkyl amines and dimethyl/ethyl phosphite. The
reaction was compatible with various functional groups such
as Cl, OMe, NO2, OH, NMe2, CN, and CO2Me that do not
interfere by competitive complex formation with the catalyst.
Excellent chemoselectivity was observed for substrates contain-
h
values13 of 1.58, 3.70, 2.19, and 0.22 of these ions compared
to a value of 11.42 of Mg+2 make these metal hydrates less
effective as the associated water molecules decreased the
electrophilicity of the central metal ions. Thus, the lack of
appreciable catalytic activity of Mg(ClO4)2‚6H2O was due to
the decrease of the electrophilic property of the Mg+2 ion by
the water molecules in the hydrate.
The superiority of the present methodology over some of the
recently reported procedures was established by comparison of
(12) (a) Azizi, N.; Rajabi, F.; Saidi, M. R. Tetrahedron Lett. 2004, 45,
9233. (b) Azizi, N.; Saidi, M. R. Tetrahedron 2003, 59, 5329. (c) Saidi, M.
R.; Azizi, N. Synlett 2002, 1347. (d) Heydari, A; Karimian, A.; Ipaktschi,
J. Tetrahedron Lett. 1998, 39, 6729.
(13) Huheey, J. E. Inorganic Chemistry: Principles of Structure and
ReactiVity, 3rd ed.; Harper & Row: Singapore, 1983.
J. Org. Chem, Vol. 72, No. 4, 2007 1265

Bhagat and Chakraborti
TABLE 5. Synthesis of r-Aminophosphonate during the Reaction of Various Aldehydes/Ketones, Amines, and DMP/DEP in the Presence of
a
Anhydrous Mg(ClO4)2
1266 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of R-Aminophosphonates Catalyzed by Magnesium Perchlorate
Table 5 (Continued)
J. Org. Chem, Vol. 72, No. 4, 2007 1267

Bhagat and Chakraborti
Table 5 (Continued)
a The aldehyde/ketone (2.5 mmol) was treated with the amine (2.5 mmol) and DMP/DEP (2.5 mmol) in the presence of Mg(ClO4)2 (5 mol %) at rt (except
for entries 10, 11, 21, 22, 24, 27, and 53) under solvent-free conditions. b Yield of the purified R-aminophosphonate, characterized by IR, 1H and 13C NMR,
and MS. c The reaction was carried out at 80 °C. d The reaction carried out at rt took 6 h to give 85% yield. e The reaction was carried out with 1.5 equiv
of the phosphite. f A 90% yield was obtained when the reaction was carried out at 80 °C for 45 min. g The product was formed in 80 and 85% yields at rt
after 20 h under neat conditions and under reflux in DCE after 4 h, respectively. h The product was formed in 90% yield in DCE under reflux after 2 h.
1268 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of R-Aminophosphonates Catalyzed by Magnesium Perchlorate
TABLE 6. Synthesis of r-Aminophosphonate during the Reaction
SCHEME 2. Role of Mg(ClO4)2 for r-Aminophosphonate
Formation during the 3-CR Involving an Aldehyde, an
Amine, and Di-/Trialkyl Phosphite
a
of 1, Aniline, and Various Phosphites in the Presence of Mg(ClO4)2
entry
phosphite
time (min)
yieldb,c (%)
1
2
3
4
5
6
7
HP(O)(OMe)2
HP(O)(OEt)2
P(OEt)3
2
5
96
95
90
91
83
80
98
10
10
20
25
5
HP(O)(OBun)2
P(OBun)3
P(OPri)3
HP(O)(OPh)2
a 1 (2.5 mmol) was treated with aniline (2.5 mmol) and the phosphite
(2.5 mmol) in the presence of Mg(ClO4)2 (5 mol %) at rt under solvent-
free conditions. b Yield of the isolated and purified R-aminophosphonate.
1
c The product was characterized by IR, H and 13C NMR, and MS.
of Mg(ClO4)2 (5 mol %) at 80 °C for 6 h. The alternative path-
way involving an intermediate formation of R-aminophospho-
nate by nucleophilic addition of the phosphite to the carbonyl
carbon followed by nucleophilic displacement of the hydroxyl
group by the amine21 also appears unlikely as the treatment of
4-methoxybenzaldehyde with dimethyl phosphite in the presence
of Mg(ClO4)2 (5 mol %) at 80 °C for 6 h did not produce any
significant amount of the corresponding R-hydroxyphosphonate
(IR, NMR, MS). Thus, in the absence of intermediate formation
of the imine and the hydroxyphosphonate, this represents a truly
3-CR in which all three reactants/components are simultaneously
involved in the product formation. We, therefore, propose that
coordination of the Mg+2 ion with the carbonyl oxygen atom,
the hydroxyl/alkoxyl group of the di-/trialkyl phosphite, and
the nitrogen atom of the amine followed by the electrostatic
attraction between the electrophilic carbonyl carbon atom with
the lone pair of electrons of the phosphorus forms the TS-I,
which undergoes rearrangement toform the TS-II. The intramo-
lecular nucleophilic displacement of the hydroxyl/alkoxyl group,
complexed with the Mg(ClO4)2 in the TS-II, by the nitrogen
atom of the amine complexed with the Mg(ClO4)2 affords the
R-aminophosphonate and liberates the Mg(ClO4)2.
We have described herein commercially available anhydrous
Mg(ClO4)2 as a new and extremely efficient catalyst for
synthesis of R-aminophosphonate by a three-component, one-
pot reaction. With the increasing concern for need of green
synthetic procedures, the advantages such as the (i) solvent-
free reaction,22 (ii) high yields, (iii) excellent chemoselectivity,
and (iv) ease of product isolation/purification fulfill the triple
bottom line philosophy of green chemistry23 and make the
present methodology environmentally benign.
ing a halogen atom (entries 14-16, Table 5) and having a double
bond conjugated to a carbonyl group (entry 35, Table 5) that
did not experience any competitive aromatic nucleophilic
substitution of the halogen atom and conjugate addition to the
R,â-unsaturated carbonyl group, respectively. No competitive
nucleophilic methyl ether cleavage was observed for substrates
having an aryl O-Me group (entries 3-13, 21-28, and 43-50,
Table 5), although phosphites possess good nucleophilic prop-
erty.16 The reaction with dimethyl acetal of aminoacetaldehyde
(entry 49, Table 5) further exemplified the case of chemose-
lectivity and mildness of the reaction as no competitive
nucleophilic substitution of the methoxy group or cleavage of
the acetal moiety took place.
To evaluate the efficiency of this catalyst system as a general
methodology with respect to the phosphite, 4-methoxybenzal-
dehyde and aniline were treated with various di-/trialkyl phos-
phites under the catalytic influence of Mg(ClO4)2 (Table 6).
The role of Mg(ClO4)2 is depicted in Scheme 2. It has been
anticipated that the formation of R-aminophosphonate from the
reaction of an aldehyde, an amine, and a phosphite involves a
two-step process:17 (i) the nucleophilic addition of the amine to
the carbonyl group forming an imine followed by (ii) the nucleo-
philic addition of the phosphite to the imine.18-20 However, no
imine formation was observed (IR, NMR, MS) when 4-methoxy-
benzaldehyde was treated with 2,4-dinitroaniline in the presence
Experimental Section
Typical Procedures for R-Aminophosphonate Synthesis.
Reactions with Dialkyl/Aryl Phosphites. Dimethyl [(2,4-Dini-
trophenylamino)(4-methoxyphenyl)methyl]phosphonate (Table
(17) Gancarz, R. Tetrahedron 1995, 51, 10627.
(18) Mastalerz, P. In Handbook of Organophosphorous Chemistry; Engel,
R., Ed.; Marcel Dekker: New York, 1992; Chapter 7.
(19) Szabo´, A.; Ja´szay, Z. M.; Hergeds, L.; Tke, L.; Petneha´zy, I.
Tetrahedron Lett. 2003, 44, 4603.
(20) Yadav, J. S.; Reddy, B. V. S.; Raj, K. S.; Reddy, K. B.; Prasad, A.
R. Synthesis 2001, 2277.
(21) Kaboudin, B. Tetrahedron Lett. 2003, 44, 1051.
(22) Garrett, R. L. In Designing Safer Chemicals; Garrett, R. L., De Vito,
S. C., Eds.; American Chemical Society Symposium Series 640; American
Chemical Society: Washington, DC, 1996; Chapter 1.
(23) Tundo, P.; Anastas, P.; Black, D. S.; Breen, J.; Collins, T.; Memoli,
S.; Miyamoto, J.; Polyakoff, M.; Tumas, W. Pure Appl. Chem. 2000, 72,
1207.
(14) (a) Yatsimirksii, K. B.; Vasil’ev V. P. Instability Constants of
Complex Compounds; Pergamon, Elmsford, NY, 1960. (b) Bjerrum, Schwar-
zenbach, G., Sillen, L. G., Eds. Stability Constants of Metal-Ion Com-
plexes: PartII. Inorganic Ligands; The Chemical Society, London,
1958.
(15) The pKa values of aqueous HClO4, H2SO4, HI, HBr, and HCl are
-10, -9, -9, -8, and -6.1, respectively. Anslyn, E. V.; Dougherty, D.
A. Modern Physical Organic Chemistry; University Science Books: Mill
Valley, CA, 1960.
(16) Variot, G.; Collect, A. Acros Org. Acta 1995, 1, 40.
J. Org. Chem, Vol. 72, No. 4, 2007 1269

Bhagat and Chakraborti
5, Entry 11). The mixture of 4-methoxybenzaldehyde (1) (0.68 g,
5 mmol) and Mg(ClO4)2 (56 mg, 5 mol %) was stirred magnetically
for 10-15 min, after which time 2,4-dinitroaniline (2) (0.91 g, 5
mmol) and DMP (0.55 g, 5 mmol) were added and the reaction
mixture was stirred at rt for 6 h. The reaction mixture was extracted
with EtOAc (3 × 10 mL). The combined EtOAc extracts were dried
(Na2SO4) and concentrated under reduced pressure to afford a
yellow solid (1.8 g) which on passing through a column of silica
gel and elution with EtOAc-hexane (80:20) afforded dimethyl
[(2,4-dinitrophenylamino)(4-methoxyphenyl)methyl]phosphonate (3)
(1.75 g, 85%): mp 101 °C; IR (KBr) ν 1516, 1618, 2955, 3315
Dimethyl [(Adamantan-1-ylamino)-(4-methoxyphenyl)meth-
yl]phosphonate (Table 5, Entry 50). The treatment of 1 (0.34 g,
2.5 mmol) with 1-adamantylamine (0.37 g, 2.5 mmol) and DMP
(0.27 g, 2.5 mmol) in the presence of Mg(ClO4)2 (28 mg, 5 mol
%) under magnetic stirring at rt for 15 min followed by usual
workup and chromatographic purification [silica gel: EtOAc-
hexane (95:5) as eluent] afforded the dimethyl [(adamantan-1-
ylamino)(4-methoxyphenyl)methyl]phosphonate (0.85 g, 90%) as
1
white solid: mp 101 °C; H NMR (CDCl3, 300 MHz) δ 1.43-
1.60 (m, 12 H), 1.87 (s, 1 H), 1.97 (s, 2 H), 3.46 (d, 3 H, J )
10.30 Hz), 3.77-3.81 (2s, 9 H), 4.21-4.29 (1JP-H ) 24.4 Hz),
6.84 (d, 2 H, J ) 8.2 Hz), 7.33 (d, 2 H, J ) 7.1 Hz); 13C NMR
(CDCl3, 75 MHz) δ 30.1, 37, 44.2, 52.1, 52.8, 53, 53.6, 54.3, 55.0,
55.7, 114.2, 129.6, 129.7, 132.3, 159.4; MS (APCI) m/z 379 (M)+,
270 [(M - P(O)(OMe)2]+. Anal. Calcd for C20H30NO4P: C, 63.31;
H, 7.97; N, 3.69. Found: C, 63.18; H, 7.95; N, 3.68.
1
cm-1; H NMR (CDCl3, 300 MHz): δ 3.62 (d, 3 H, J ) 10.68
Hz), 3.73 (d, 3 H, J ) 10.68 Hz), 3.80 (s, 3 H), 4.90-4.99 (dd, 1
1
H, JP-H ) 7.02 Hz, J ) 22.51 Hz). 6.78 (d, 1 H, J ) 9.4 Hz),
6.92 (d, 2 H, J ) 8.6 Hz), 7.36-7.30 (dd, 2 H, J ) 2.2, 8.7 Hz),
8.14-8.18 (dd, 1 H, J ) 2.5, 9.4 Hz), 9.13 (d, 1 H, J ) 2.3 Hz),
9.36 (m, 1 H); 13C NMR (CDCl3, 75 MHz): δ 54.3 (d, CHP ,1JP-C
) 154.62 Hz), 54.7, 55.9, 115.3, 124.5, 125.1, 129.2, 130.7, 132.2,
137.6, 147.7, 147.9, 160.6; 31P (CDCl3; 121 MHz) δ 27.4 (m); MS
(APCI) m/z ) 411 (M)+, 302 [(M - P(O)(OMe)2; 100]+. Anal.
Calcd for C16H18N3O8P: C, 46.72; H, 4.41; N, 10.22. Found: C,
46.69; H, 4.39; N, 10.20. Using this procedure, repeating the
reaction of 1 (2.72 g, 20 mmol), 2 (3.64 g, 20 mmol), and DMP
(2.2 g, 20 mmol) in the presence of Mg(ClO4)2 (0.22 g, 5 mol %)
afforded 3 (7.2 g, 87%) after the usual workup and purification.
The remaining reactions were carried out following this general
procedure. On each occasion, the spectral data (IR, NMR, and MS)
of prepared known compounds were found to be identical with those
reported in the literature. The following are a few representative
examples using heteroaryl amine, aryl alkyl ketone, and sterically
hindered aliphatic amine, respectively.
Reactions with Trialkyl Phosphites. Di-n-butyl [(4-Methoxy-
phenyl)phenylaminomethyl]phosphonate (Table 6, Entry 5). The
treatment of 1 (0.34 g, 2.5 mmol) with aniline (0.23 g, 2.5 mmol)
and tri-n-butyl phosphite (0.62 g, 5 mmol) in the presence of Mg-
(ClO4)2 (28 mg, 5 mol %) under magnetic stirring at rt for 20 min
followed by usual workup and chromatographic purification [silica
gel: EtOAc-hexane (25:75) as eluent] afforded the di-n-butyl [(4-
methoxyphenyl)phenylaminomethyl]phosphonate (0.84 g, 83%) as
a greenish black solid: mp 60 °C; IR (KBr) ν 1605, 2959, 3308
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.81-0.91 (m, 6 H), 1.2-
1
1.6 (m, 8 H), 3.59-4.05 (m, 7 H), 4.74 (d, 1 H, JP-H ) 22.1),
6.56-7.38 (m, 9 H); 13C NMR (CDCl3, 75 MHz) δ 13.5, 18.5,
18.6, 32.3, 32.5, 54.2, 55.2, 56.3, 66.8, 113.8, 118.2, 127.7, 128.8,
146.4, 159.3; 31P (CDCl3; 121 MHz) δ 29.19 (d, J ) 11.78 Hz);
MS (MALDI TOF TOF) m/z 405 (M)+, 212 [(M - P(O)(OnBu)2]+.
Anal. Calcd for C22H32NO4P: C, 65.17; H, 7.95; N, 3.45. Found:
C, 65.14; H, 7.93; N, 3.43.
Dimethyl [(Benzothiazol-2-ylamino)(4-methoxyphenyl)meth-
yl]phosphonate (Table 5, Entry 27). The treatment of 1 (0.34 g,
2.5 mmol) with 2-aminobenzothiazole (0.37 g, 2.5 mmol) and DMP
(0.27 g, 2.5 mmol) in the presence of Mg(ClO4)2 (28 mg, 5 mol
%) under magnetic stirring at 80 °C for 30 min followed by usual
workup and chromatographic purification [silica gel: EtOAc-
hexane (60:40) as eluent] afforded the dimethyl [(benzothiazol-2-
ylamino)(4-methoxyphenyl)methyl]phosphonate (0.75 g, 80%) as
a brownish yellow solid: mp 170 °C; 1H NMR (CDCl3, 300 MHz)
δ 3.54 (d, 3 H, J ) 10.6 Hz), 3.75 (s, 3 H), 3.80 (d, 3 H, J ) 10.7
Diisopropyl [(4-Methoxyphenyl)phenylaminomethyl]phospho-
nate (Table 6, Entry 6). Treatment of 1 (0.34 g, 2.5 mmol) with
aniline (0.23 g, 2.5 mmol) and triisopropyl phosphite (0.52 g, 2.5
mmol) in the presence of Mg(ClO4)2 (28 mg, 5 mol %) under
magnetic stirring at rt for 25 min followed by usual workup and
chromatographic purification [silica gel: EtOAc-hexane (35:65)
as eluent] afforded the diisopropyl [(4-methoxyphenyl)phenylami-
nomethyl]phosphonate (0.75 g, 80%) as a faded white solid: mp
103 °C; IR (KBr) ν 1602, 2929, 2979, 3307 cm-1; 1H NMR (CDCl3,
300 MHz) δ 0.95 (d, 3 H, J ) 6.17 Hz), 1.21-1.32 (m, 9 H), 3.76
(s, 3 H), 4.41-4.73 (m, 3 H), 6.56-7.39 (m, 9 H); 13C NMR
(CDCl3, 75 MHz) δ 23.3, 23.7, 54.8, 55.2, 56.8, 71.8, 113.8, 118.1,
128.1, 129.1, 146.5, 146.7, 159.1; 31P (CDCl3; 121 MHz) δ 27.30
(d, J ) 13.58 Hz); MS (APCI) m/z 377 (M)+, 212 [(M+ - P(O)
(OiPr)2]+. Anal. Calcd for C20H28NO4P: C, 63.65; H, 7.48; N, 3.71.
Found: C, 63.62; H, 7.46; N, 3.69.
Hz), 5.54-90 (d, 1 H,1JP-H ) 21.63 Hz), 6.86-7.54 (m, 8 H); 13
C
NMR (CDCl3, 75 MHz) δ 54.2, 54.5, 55.7, 56.2, 114.9, 119.8,
121.2, 122.3, 126.3, 127.3, 129.9, 131.6, 152.4, 160.2, 166.4; MS
(APCI) m/z 378 (M)+, 269 [(M - P(O)(OMe)2]+. Anal. Calcd for
C17H19N2O4PS: C, 53.96; H, 5.06; N, 7.40; S, 8.47. Found: C,
53.94; H,5.04.; N, 7.38; S, 8.45.
Dimethyl (1-Phenyl-1-phenylaminoethyl)phosphonate (Table
5, Entry 40). The treatment of acetophenone (0.30 g, 2.5 mmol)
with aniline (0.23 g, 2.5 mmol) and DMP (0.27 g, 2.5 mmol) in
the presence of Mg(ClO4)2 (28 mg, 5 mol %) under magnetic
stirring at 80 °C for 6 h followed by usual workup and chromato-
graphic purification [silica gel: EtOAc-hexane (50:50) as eluent]
afforded the dimethyl (1-phenyl-1-phenylaminoethyl)phosphonate
Acknowledgment. Financial support from the Organisation
for the Prohibition of Chemical Weapons (OPCW), The Hague,
The Netherlands, is gratefully acknowledged.
1
(0.61 g, 80%) as brownish yellow solid: mp 128 °C; H NMR
Supporting Information Available: General experimental
details, scanned spectra, and spectral data of all compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(CDCl3, 300 MHz) δ 1.97 (d, 3 H, J ) 16.5 Hz), 3.53-3.66 (m,
6 H), 6.38-7.81 (m, 10 H); 13C NMR (CDCl3, 75 MHz) δ 20.8,
54.7, 117.3, 119.0, 128.0, 128.6, 129.2; MS (APCI) m/z 305 (M)+,
196 [(M - P(O)(OMe)2]+. Anal. Calcd for C16H20NO3P : C, 62.9;
H, 6.6; N, 4.5. Found: C, 62.89; H, 6.5; N, 4.49.
JO062140I
1270 J. Org. Chem., Vol. 72, No. 4, 2007