T3P-promoted Kabachnik-Fields reaction: An efficient synthesis of α-aminophosphonates

Article abstract of DOI:10.1016/j.tetlet.2013.07.145

A simple and efficient synthesis of α-aminophosphonates has been developed via the one-pot three-component reactions of aldehydes, amines, and trialkyl phosphites. The reactions occurred rapidly at room temperature in the presence of 1 equiv of propylphosphonic anhydride (T3P) as the condensing agent, and the α-aminophosphonate products were obtained in high yields.

Full text of DOI:10.1016/j.tetlet.2013.07.145

Accepted Manuscript
T3P® -promoted Kabachnik–Fields reaction: an efficient synthesis of α-amino‐
phosphonates
Mátyás Milen, Péter Ábrányi-Balogh, András Dancsó, Dávid Frigyes, László
Pongó, György Keglevich
PII:
S0040-4039(13)01313-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.145
TETL 43343
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 June 2013
5 July 2013
19 July 2013
Please cite this article as: Milen, M., Ábrányi-Balogh, P., Dancsó, A., Frigyes, D., Pongó, L., Keglevich, G., T3P
® -promoted Kabachnik–Fields reaction: an efficient synthesis of α-aminophosphonates, Tetrahedron Letters (2013),
doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.145
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an efficient synthesis of α-
aminophosphonates
Mátyás Milen*, Péter Ábrányi-Balogh, András Dancsó, Dávid Frigyes, László Pongó, György Keglevich*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
T3P®-promoted Kabachnik–Fields reaction: an efficient synthesis of α-
aminophosphonates
Mátyás Milena,b, Péter Ábrányi-Baloghb, András Dancsóa, Dávid Frigyesa, László Pongóa, György
Keglevichb,
aEgis Pharmaceuticals PLC., Chemical Research Division, 1475 Budapest, P.O.B. 100, Hungary
bDepartment of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient synthesis of α-aminophosphonates has been developed via the one-pot
three-component reactions of aldehydes, amines and trialkyl phosphites. The reactions occurred
rapidly at room temperature in the presence of one equivalent of propylphosphonic anhydride
(T3P®) as the condensing agent, and the α-aminophosphonate products were obtained in high
yields.
Available online
2013 Elsevier Ltd. All rights reserved.
Keywords:
α-aminophosphonates
T3P®
Kabachnik–Fields reaction
three-component condensation
mechanism
α-Aminophosphonic acids and their derivatives are considered
to be structural analogues of α-amino acids.1 Compounds bearing
an α-aminophosphonate moiety play an important role in
biochemical and medicinal chemistry as enzyme inhibitors,2
peptide mimics,3 antibiotics,4 herbicides,5 plant growth
regulators,6 and haptens of catalytic antibodies.7 Various
methodologies have been reported in the literature for the
preparation of α-aminophosphonates.8 Among these, the three-
component Kabachnik–Fields condensation of an aldehyde, an
amine, and a dialkyl or trialkyl phosphite is one of the most
important methods for the synthesis of α-aminophosphonates.9 In
general, this reaction is catalyzed by Brønsted or Lewis acids,
such as trifluoroacetic acid,10 lanthanum(III) triflate,11 tin(II)
triflate,12 samarium(II) iodide,13 indium(III) chloride14 and
tantalum(V) chloride on silica gel15 using dialkyl phosphites, or
by copper(II) triflate16 and scandium tris(dodecyl sulfate),17
where triethyl phosphite is the reagent. However, some of these
species are expensive and moisture sensitive, or the methods
applying them require long reaction times, heating, or special
apparatus, etc. When using other Lewis acids such as SnCl2,
SnCl4, ZnCl2, MgBr2 or BF3·Et2O, the reaction does not take
place in one step, because the water formed from condensation of
the amine and the carbonyl compound can decompose or
deactivate the catalysts.18 It is worth mentioning that a few green
protocols have been developed based on microwave (MW)
irradiation,19 ultrasound,20 and the use of ionic liquids.21 We have
suggested that under MW conditions there is no need to use any
In continuation of our efforts to develop efficient synthetic
methods in the field of α-hydroxyphosphonates and α-
aminophosphonates,23 we now describe a simple and highly
efficient procedure for the preparation of α-aminophosphonates
via a one-pot, three-component, T3P-catalyzed reaction of
aromatic aldehydes, aromatic primary amines and triethyl
phosphite.
T3P is a well known green coupling reagent and a powerful
water scavenger with several advantages including low toxicity
and low allergic potential, broad functional group tolerance, the
generation of products in high yields and purity, and easy work-
up procedures due to the formation of water-soluble by-
products.24 A number of applications have been developed using
this reagent, such as the one-pot conversion of carboxylic acids
into carbamates,25 Beckmann rearrangement of aldoximes and
ketoximes,26 synthesis of Nα-protected amino thioamides,27
acetylation and thioacetylation of aldehydes,28 reduction of
carboxylic acids to alcohols,29 and syntheses of Weinreb amide
derivatives.30 Furthermore, T3P has been investigated
extensively in the preparation of various heterocyclic
compounds.31
Initially, a mixture of benzaldehyde (1) and aniline (2a) was
treated with triethyl phosphite in the presence of equimolar T3P
in ethyl acetate at 26 °C. The reaction took place smoothly and
resulted in the formation of the corresponding α-
aminophosphonate 3a in a yield of 92% within a very short time
of 5 minutes (Table 1, entry 1). The reaction proved capricious
catalyst.22 Moreover, this procedure was solvent-free.
———
 Corresponding author. Tel.: +36 1 463 1111/5883; fax: +36 1 463 3648; E-mail address: gkeglevich@mail.bme.hu (G. Keglevich).

2
Tetrahedron Letters
without or with a small amount of T3P. Chandrasekhar at al.
All the α-aminophosphonates prepared (3a-p and 5a-i) were
1
have accomplished the solvent and catalyst-free reaction of
carbonyl compounds, amines and triethyl phosphite at room
temperature in variable reaction times (15 min–12 h). The
products were obtained in yields of 80–95%.32 However,
according to our observations, the three-component reaction of
benzaldehyde, aniline and triethyl phosphite under solvent-free
conditions without any catalyst gave the corresponding product
in a conversion of only 80% at 26 °C after 24 hours. When this
reaction was carried out under similar conditions, but using ethyl
acetate as the solvent, the conversion was only 50% after 24
hours. In contrast, our results with T3P, indicate the clear
advantage of using this reagent.
characterized by 31P, 13C and H NMR spectroscopy and mass
spectrometry. Products 3a,b,d-i,n and 5a-d,f have been described
and characterized previously,35–42 while compounds 3c,j-m,o,p
and 5e,g-i have not been characterized, or are new.
26 °C, 5 min
HNAr1
T3P
Ph CHO
+
Ar1 NH2
+
P(OEt)3
EtOAc
Ph
P(O)(OEt)2
2a-p
1
3a-p
Scheme 1. The condensation of benzaldehyde, aromatic amines and
triethyl phosphite.
As a possible extension, a series of aromatic aldehydes and
aromatic amines were used in the three-component synthesis of
α-aminophosphonates applying T3P (Schemes 1 and 2). The
results are summarized in Table 133 and Table 2.34 Independent of
the nature of the aromatic aldehyde or amine, products 3a-p and
5a-i were obtained in good to excellent yields (between 80% and
96%). On the other hand, this protocol was used successfully in
the presence of different functional groups, such as ester (3h),
methylsulfanyl (3k), keto (3l), benzyloxy (5g) and cyano (5h). In
all cases (except 5f), the reaction time was five minutes.
26 °C, 5 min
HNPh
T3P
Ar2 CHO Ph NH2
1a-i 2a
+
+
P(OEt)3
Ar2
P(O)(OEt)2
EtOAc
5a-i
Scheme 2. The condensation of substituted benzaldehydes, aniline
and triethyl phosphite.
Table 1
Results of the condensation of benzaldehyde, aromatic amines and triethyl phosphite
Lit
Entry
Ar1
Product
Yield (%)
δP (CDCl3)
23.2
23.3
23.0
23.0
22.8
22.8
21.7
22.4
23.3
23.3
22.6
21.2
23.0
22.6
22.6
23.1
δP
m.p. (°C)
90–91
m.p.Lit (°C)
1
2
3
4
5
6
7
8
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
92
86
81
94
89
82
90
92
91
89
94
91
88
87
96
80
23.335
-
89–9036
4-MeC6H4
4-PhC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-EtO2CC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
2-MeSC6H4
2-Ph(OC)C6H4
3-PhOC6H4
3-F3CC6H4
3-F3COC6H4
1-naphthyl
119–120
105–106
109–111
120–121
118–120
144–145
178–180
76–77
118–12037
-
-
23.238
111–11238
-
11939
23.240
12239
-
-
145–14737
179–18041
9
23.142
70–7342
10
11
12
13
14
15
16
-
-
-
-
-
-
-
-
-
49–51
-
121–122
103–104
69–70
3m
3n
3o
22.838
104–10538
-
-
-
-
3p
104–105
Table 2
Results of the condensation of substituted benzaldehydes, aniline and triethyl phosphite
Lit
Entry
Ar2
Product
Yield (%)
δP (CDCl3)
δP
m.p. (°C)
65–66
84–85
84.5–86
151–153
122–123
99–100
92–93
m.p.Lit (°C)
1
2
3
4
5
6
7
8
9
4-MeC6H4
4-FC6H4
5a
5b
5c
5d
5e
5f
5g
5h
90
89
90
94
89
95
87
94
84
23.4
22.8
22.5
21.3
22.1
23.4
23.4
21.5
23.535
66–6837
23.038
85–8638
4-ClC6H4
4-O2NC6H4
4-F3CC6H4
4-MeOC6H4
4-BnOC6H4
3-NCC6H4
1-naphthyl
-
83–8443
21.435
153–15443
-
-
23.535
102–10343
-
-
-
-
-
-
114–116
124–125
5i
23.4

3
O
HO P
Pr
O
P
O
+
Ph
H2N Ph
CHO
HO
O
O
P
O
Pr
Pr
(EtO)3P
Ph CH
"T3P  H2O"
P(OEt)3
(EtO)2P
O CH2CH3
Ph CH NH Ph
Ph CH
N
Ph
N Ph
-H2O
9
Ph CH NH Ph
6
7
10
11
T3P
O
O
P
O
 "T3P  EtOH"
12
-
HO P
O
O
P
OH
O
P
O
P
O
Pr
Pr
Pr
Pr
O
O
P
OH
(EtO)2P
O
9 (T3P  H2O)
O
Pr
Pr
Ph CH
Ph CH
NH Ph
NHPh
3a
8
Scheme 3. Mechanism for the T3P-catalyzed condensation reacion of benzaldehyde and aniline.
6. Emsley, J.; Hall, D. Chemistry of Phosphorus; Harper & Row:
London, 1976, pp 494.
Three α-aminophosphonates 3a, 3d and 3g were also prepared
using diethyl phosphite instead of triethyl phosphite.44 The
reaction time was twice as long (10 min) as that with triethyl
phosphite. The products 3a, 3d and 3g were obtained in yields of
92%, 94%, and 98%, respectively.
A possible mechanism for the T3P-promoted Kabachnik–
Fields reaction is suggested in Scheme 3. In the first stage of this
reaction an imine 7 is formed from the benzaldehyde and the
aniline via adduct 6. This condensation reaction may be
promoted by T3P to afford imine 7 along with P,P',P''-tripropyl
triphosphonic acid (―T3P·H2O‖) (9) as the by-product. The
dehydration may take place via adduct 8. In the next step, the
imine 7 reacts with triethyl phosphite in a nucleophilic addition,
and after protonation by T3P·H2O (9), the phosphonium salt 11
formed is stabilized by an Arbuzov fission to furnish α-
aminophosphonate 3a and T3P·EtOH (12) as the by-product.
7. (a) Hirschmann, R.; Smith III, A. B.; Taylor, C. M.; Benkovic, P.
A.; Taylor, S. D.; Yager, K. M.; Sprengler, P. A.; Venkovic, S. J.
Science 1994, 264, 234; (b) Smith III, A. B.; Taylor, C. M.;
Benkovic, S. J.; Hirschmann, R. Tetrahedron Lett. 1994, 35, 6853.
8. (a) Kukhar, V. P.; Solodenko, V. A. Russ. Chem. Rev. (Engl.
Transl.) 1987, 56, 859; (b) Laschat, S.; Kunz, H. Synthesis 1992,
90; (c) Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42, 8211.
(d) Matveeva, E. D.; Podrugina, T. A.; Tishkovskaya, E. V.;
Tomilova, L. G.; Zefirov, N. S. Synlett 2003, 2321. (e) Pavlov, V.
Ya.; Kabachinik, M. M.; Zobnina, E. V.; Ponomarev, G. V.;
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K.; Acke, D.; Stevens, C. V. ARKIVOC 2006, (i), 31-45 and refs.
therein.
9. (a) Kabachnik, M.I.; Medved, T.Y. Dokl. Akad. Nauk SSSr 1952,
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2012, 17, 12821; (d) Zefirov, N.S.; Matveeva, E.D. ARKIVOC
2008, (i), 1.
10. Akiyama, T.; Sanada, M.; Fuchibe, K. Synlett 2003, 1463.
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4728.
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15. Chandrasekhar, S.; Prakash, S. J.; Jagadeshwar, V.; Narsihmulu,
C. Tetrahedron Lett. 2001, 42, 5561.
In summary, a convenient and efficient method has been
developed for the synthesis of α-aminophosphonates via the
T3P-promoted Kabachnik–Fields reaction using triethyl
phosphite as the P-containing reagent. The advantages of this
method comprise mild reaction conditions, short reaction times,
and high yields.
16. Paraskar, A. S.; Sudalai, A. ARKIVOC 2006, (x), 183.
17. Manabe, K.; Kobayashi, S. Chem. Commun. 2000, 669.
18. (a) Zon, J. Pol. J. Chem. 1981, 55, 643; (b) Lashat, S.; Kunz, H.
Synthesis 1992, 90.
19. Yadav, J. S.; Reddy, B. V. S.; Madan, C. Synlett 2001, 1131; (b)
Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42, 8211; (c)
Kabachnik, M. M.; Zobnina, E. V.; Beletskaya, I. P. Synlett 2005,
1393.
Acknowledgment
This project was supported by the Hungarian Scientific and
Research Fund (OTKA K83118).
Supplementary data
20. Xia, M.; Lu, Y. D. Ultrason. Sonochem. 2007, 14, 235.
21. (a) Yadav, J. S.; Reddy, B. V. S.; Sreedhar, P. Green Chem. 2002,
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T. G.; Jayaram, R. V. Tetrahedron Lett. 2012, 53, 2277.
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Engl. 1986, 25, 277; (c) Schwarz, M. Synlett 2000, 1369; (d)
García, A. L. L. Synlett 2007, 1328.
25. Augustine, J. K.; Bombrun, A.; Mandal, A. B.; Alagarsamy, P.;
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Tetrahedron Lett. 2011, 52, 1074.
27. Madhu, C.; Basavaprabhu, Vishwanatha, T. M.; Sureshbabu, V.
V. Tetrahedron Lett. 2012, 53, 1406.
NMR spectral and HR-MS data for all compounds associated
with this article can be found in the online version, at
http://............
References and notes
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Aminophosphinic Acids: Chemistry and Biological Activity,
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4
Tetrahedron
28. Augustine, J. K.; Bombrun, A.; Sauer, W. H. B.; Vijaykumar, P.
and washed with 10% NaHCO3 solution (15 mL). The organic
phase was dried (Na2SO4), filtered and concentrated. The residue
was purified by flash chromatography on silica gel (Merck 107736
Silica gel 60 H, CH2Cl2–MeOH) to afford products 3a-p.
34. α-Aminophosphonates 5a-i were prepared in a similar manner
using aniline (0.18 mL, 2.0 mmol) and the aldehyde (2.0 mmol, 4-
methylbenzaldehyde 0.24 mL, 4-fluorobenzaldehyde 0.21 mL, 4-
chlorobenzaldehyde 0.28 g, 4-nitrobenzaldehyde 0.30 g, 4-
(trifluoromethyl)benzaldehyde 0.27 mL, 4-methoxybenzaldehyde
0.24 mL, 4-(benzyloxy)benzaldehyde 0.41 g, 3-formylbenzonitrile
0.26 g, 1-naphthaldehyde 0.27 mL). The work-up was carried out
as above to give products 5a-i.
Tetrahedron Lett. 2012, 53, 5030.
29. Nagendra, G.; Madhu, C.; Vishwanatha, T. M.; Sureshbabu, V. V.
Tetrahedron Lett. 2012, 53, 5059.
30. Sharnababi, K. M.; Nagendra, G.; Vishwanatha, T. M.;
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Tetrahedron Lett. 2011, 52, 4417; (b) Augustine, J. K.; Bombrun,
A.; Venkatachaliah, S. Tetrahedron Lett. 2011, 52, 6814; (c) Wen,
X.; Bakali, J. E.; Deprez-Poulain, R.; Deprez, B. Tetrahedron Lett.
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Naik, P. P.; Krishnamurthy, G. Tetrahedron Lett. 2012, 53, 4639;
(f) Kumar, K. S. S.; Swaroop, T. R.; Harsha, K. B.;
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Pudovik, A. N. Russ. J. Gen. Chem. 1994,
33. General procedure for synthesis of α-aminophosphonates (3a-
p): To the stirred mixture of benzaldehyde (0.20 mL, 2.0 mmol)
and amine (2.0 mmol, aniline: 0.18 mL, 4-toluidine: 0.21 g,
biphenyl-4-amine: 0.34 g, 4-fluoroaniline: 0.19 mL, 4-
chloroaniline: 0.26 g, 4-bromoaniline: 0.24 g, 4-nitroaniline: 0.28
g, ethyl 4-aminobenzoate: 0.33 g, 4-methoxyaniline: 0.25 g, 3,4-
dimethoxyaniline: 0.31 g, 2-(methylthio)aniline: 0.25 mL, 2-
aminobenzophenone: 0.39 g, 3-phenoxyaniline: 0.37 g, 3-
(trifluoromethyl)aniline: 0.25 mL, 3-(trifluoromethoxy)aniline:
0.27 mL, naphthalene-1-amine: 0.29 g) was added (1.2 mL, 2.0
mmol) of T3P (Aldrich 50% solution in EtOAc). If the mixture did
not become a solution, (in the cases of the examples covered by
entries 3 and 7 of Table 1) CH2Cl2 (2 mL) and EtOAc (2 mL) were
added. After 5 min, (0.35 mL, 2.0 mmol) of P(OEt)3 was added
and the mixture was stirred at 26 °C. After completion of the
reaction (5–10 min), the mixture was diluted with EtOAc (15 mL)
64, 833.
42. Goulioukina, N. S.; Bondarenko, G. N.; Lyubimov, S. E.;
Davankov, V. A.; Gavrilov, K. N.; Beletskaya, I. P. Adv. Synth.
Catal. 2008, 350, 482.
43. Mohamed, Z.; Abdelhakim, E.; Abdessamad, M.; Ahmed, R.;
Said, S. J. Chem. Res. 2005, 324.
44. α-Aminophosphonates 3a, 3d and 3g were prepared according to
the general method above, using diethyl phosphite (0.26 mL, 2.0
mmol) instead of triethyl phosphite. Benzaldehyde (0.2 mL, 2.0
mmol) and the corresponding amine (2.0 mmol, aniline: 0.18 mL,
4-fluoroaniline: 0.19 mL, 4-nitroaniline 0.28 g) were the other
reaction components. The reaction time was 10 min. Products 3a,
3d and 3g were obtained in yields of 92%, 94%, and 98%,
respectively.