MoO2Cl2 as a novel catalyst for the synthesis of α-aminophosphonates

Article abstract of DOI:10.1016/j.catcom.2010.10.005

This work reports the use of MoO₂Cl₂ as a novel catalyst for the synthesis of α-aminophosphonates. The system HP(O)(OEt)₂/MoO₂Cl₂ (5 mol%) was applied in the synthesis of several α-aminophosphonates i

Full text of DOI:10.1016/j.catcom.2010.10.005

Catalysis Communications 12 (2011) 337–340
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Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
MoO2Cl2 as a novel catalyst for the synthesis of α-aminophosphonates
Rita G. de Noronha a, Carlos C. Romão a, Ana C. Fernandes b,
⁎
a
Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Av. da República - EAN, 2781-157 Oeiras, Portugal
Centro de Química Estrutural, Complexo I, Instituto Superior Técnico, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 January 2010
Received in revised form 29 September 2010
Accepted 5 October 2010
Available online 21 November 2010
This work reports the use of MoO2Cl2 as a novel catalyst for the synthesis of α-aminophosphonates. The
system HP(O)(OEt)2/MoO2Cl2 (5 mol%) was applied in the synthesis of several α-aminophosphonates in
excellent yields under solvent-free conditions.
© 2010 Elsevier B.V. All rights reserved.
Keywords:
α-Aminophosphonates
C–P bond formation
MoO2Cl2
HP(O)(OEt)2
1. Introduction
We have also demonstrated that MoO2Cl2 is a good catalyst for the
synthesis of aromatic ketones and sulfones and for the C–C and C–S
α-Aminophosphonates and α-aminophosphonic acids [1] are
structurally analogous to α-amino acids and constitute an important
class of compounds with diverse biological activities and potential to
be employed as enzyme inhibitors [2,3], antibiotics [4], and antitumor
agents [5,6]. They also have a wide range of antiviral [7] and antifungal
properties and are extensively used as insecticides and herbicides [8].
Among the various synthetic approaches for their preparation
[9–13], the nucleophilic addition of dialkylphosphites to imines
(Pudovik reaction) [10–13] is established as the most useful method.
Several metal complexes have been used as effective catalysts for this
reaction, including ytterbium [10], boron [11], aluminium [12], and
zirconium [13] complexes. However, due to the biological activities of
α-aminophosphonates, the search for new catalysts leading to an
efficient and practical methodology for the synthesis of these
compounds is highly desired.
Over the last years, we have demonstrated that high valent oxo-
complexes activate X–H (X=Si and B) bonds [14–16]. We also
described the efficient hydrosilylation of aldehydes and ketones
[14,15] and the reduction of several functional groups such as
aromatic nitro compounds [17], imines [18], amides [19], esters
[20], sulfoxides [16,21–23], pyridine N-oxides [21], and alkenes [24] to
the corresponding amines, alcohols, sulfides, pyridines, and alkanes
using the catalytic systems silane/oxo-complexes or borane/oxo-
complexes.
bond formation [25].
Very recently, we have reported the development of a novel
method for the preparation of α-hydroxyphosphonates using the
catalytic system HP(O)(OEt)2/MoO2Cl2 (5 mol%; see Scheme 1) [26].
This methodology proved to be highly efficient for the synthesis of
α-hydroxyphosphonates and for the C–P bond formation.
Our computational studies [26] indicated that this reaction
proceeds with low activation barriers, starting with the coordination
of the P=O bond of HP(O)(OEt)2 to molybdenum and hydrogen
transfer from P–H to the oxygen in Mo=O forming Mo–OH. The new
intermediate reacts with the aldehyde substrate in two steps. In the
first step, the aldehyde binds the metal through the carbonyl and the
P–C bond forms; in the second step, the hydrogen is transferred from
Mo–OH to the oxygen of the final product. These results opened a new
area of catalysis for these complexes as excellent catalysts for C–P
bond forming reactions.
In this work, we investigated the use of the high valent oxo-
molybdenum complex MoO2Cl2 as a novel catalyst for the hydropho-
sphonylation of imines.
2. Experimental
2.1. General
Solvents were purified by conventional methods and distilled
under nitrogen, prior to use. Diethylphosphonate and MoO2Cl2 were
obtained from Aldrich. Flash chromatography was performed on MN
Kieselgel 60 M 230–400 mesh. 1H NMR, and 13 C NMR spectra were
measured on a Bruker Avance III 400-MHz spectrometer. Chemical
⁎
Corresponding author. Tel.: +351 218419264; fax: +351 218464457.
E-mail address: anacristinafernandes@ist.utl.pt (A.C. Fernandes).
1566-7367/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.catcom.2010.10.005

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R.G. de Noronha et al. / Catalysis Communications 12 (2011) 337–340
Scheme 1. Hydrophosphonylation of aldehydes catalyzed by MoO2Cl2.
Table 1
Hydrophosphonylation of imines catalyzed by MoO2Cl2.a
Entry
1
Substrate
Product
Time (min)
5
Yield (%)b
95
2
5
89
5
90
3
4
60
85
5
15
80
6
15
87

R.G. de Noronha et al. / Catalysis Communications 12 (2011) 337–340
339
Table 1 (continued)
Entry
Substrate
Product
Time (min)
Yield (%)b
7
20
80
8
5
95
9
30
95
a
All reactions were carried out with 2.0 mmol of imine, 2.4 mmol of HP(O)(OEt2)2 and 5 mol % of MoO2Cl2.
Isolated yield.
b
shifts are reported in parts per million (ppm) downfield from an
internal standard.
thin layer chromatography and by 1H NMR. The analysis of the Table 1
results showed that the hydrophosphonylations were very fast,
producing the α-aminophosphonates in good to excellent yields.
The reactions of the aryl-N-aryl imines containing the trifluor-
omethyl-, cyano- and fluoro- groups required only 5 minutes to give
the corresponding α-aminophosphonates in excellent isolated yields
(Table 1, entries 1–3). Longer reaction times (30–60 min) were
needed for the reactions of aryl-N-alkyl imines (Table 1, entries 4
and 9).
The hydrophosphonylation of the imines, prepared from hydro-
cinnamaldehyde and cinnamaldehyde, also afforded the
corresponding α-aminophosphonates in good to excellent yields
within 5–30 minutes (Table 1, entries 8 and 9).
Excellent chemoselectivity was observed for substrates containing
various substituents such as CF3, F, CN, NO2, and OCH3 (Table 1, entries
1–5 and 7) and also having a double bond conjugated to the imino
group (entry 8). To the best of our knowledge, this is the first example
of the synthesis of α-aminophosphonates catalyzed by a high valent
oxo-molybdenum complex.
2.2. General procedure for the hydrophosphonylation of imines with the
system HP(O)(OEt)2/MoO2Cl2
In a typical experiment, to a mixture of imine (2 mmol) and MoO2Cl2
(5 mol%) wasadded HP(O)(OEt)2 (2.4 mmol). Thereaction mixture was
stirred at 80 °C under inert atmosphere and the progress of the reaction
was monitored by TLC and 1H NMR. When the reaction is complete,
water (3 mL) was added and the mixture was stirred at 80 °C. After
1 hour, the reaction mixture was cooled to ambient temperature and
extracted with ethyl acetate (2×10 mL). The combined organic layers
were dried over Na2SO4, filtered and the solvent removed under
reduced pressure. Whenever necessary the residue was purified by flash
chromatography with appropriate mixtures of n-hexane and ethyl
acetate to afford the α-aminophosphonates, which are well known
compounds.
3. Results and discussion
Unfortunately, it was not possible to characterize, by spectroscopic
methods, the species formed in the reaction between HP(O)(OEt)2
and MoO2Cl2, due to its instability. For this reason, we propose a
mechanism for this reaction (Scheme 2) based on the DFT studies
performed for the hydrophosphonylation of aldehydes with the
same catalytic system [26]. We suggest a similar initial activation of
In order to explore the scope and the limitations of this novel
method, we investigated the reaction of several imines with the
system HP(O)(OEt)2/MoO2Cl2 (5 mol%) at 80 °C under solvent-free
conditions (Table 1). The progress of the reactions was monitored by

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R.G. de Noronha et al. / Catalysis Communications 12 (2011) 337–340
The application of oxo-complexes to other C-X bond forming
reactions and to the asymmetric hydrophosphonylation of imines are
currently being investigated in our group.
Acknowledgments
This research was supported by FCT through Project PTDC/QUI/71741/
2006. RGN thanks FCT for a postdoctoral grant (SFRH/BPD/27215/2006).
The NMR spectrometers are part of the National NMR Network and were
purchased in the framework of the National Programme for Scientific Re-
equipment, Contract REDE/1517/RMN/2005, with funds from POCI 2010
(FEDER) and Fundação para a Ciência e a Tecnologia (FCT).
References
[1] V.P. Kukhar, H.R. Hudson (Eds.), Aminophosphinic and aminophosphonic acids
chemistry and biological activity, Jonh Wiley-Sons LTD, New York, 2000.
[2] E. Alonso, E. Alonso, A. Solis, C. del Pozo, Synlett (2000) 698–700.
[3] A. Peyman, W. Stahl, K. Wagner, D. Ruppert, K.-H. Budt, Bioorg. Med. Chem. Lett. 4
(1994) 2601–2604.
[4] F.R. Atherton, C.H. Hassall, R.W. Lambert, J. Med. Chem. 29 (1986) 29–40.
[5] X. Rao, Z. Song, L. He, Heteroatom. Chem. 19 (2008) 512–516.
[6] I. Kraicheva, A. Bogomilova, I. Tsacheva, G. Momekov, K. Troev, Eur. J. Med. Chem.
44 (2009) 3363–3367.
[7] J. Huang, R. Chen, Heteroatom. Chem. 11 (2000) 480–492.
[8] M.K. Mao, J.E. Franz, Synthesis (1991) 920–922.
[9] M. Ordóñez, H. Rojas-Cabrera, C. Cativiela, Tetrahedron 65 (2009) 17–49.
[10] P. Merino, E. Marqués-López, R.P. Herrera, Adv. Synth. Catal. 350 (2008) 1195–1208.
[11] I.L. Odinets, O.I. Artyushin, N. Shevchenko, P.V. Petrovskii, V.G. Nenajdenko, G.-V.
Röschenthaler, Synthesis (2009) 577–582.
Scheme 2. Proposed catalytic system for the hydrophosphonylation of imines with the
catalytic system HP(O)(OEt)2/MoO2Cl2.
[12] J.P. Abell, H. Yamamoto, J. Am. Chem. Soc. 130 (2008) 10521–10523.
[13] J.S. Yadav, B.V.S. Reddy, K.S. Raj, K.B. Reddy, A.R. Prasad, Synthesis (2001)
2277–2280.
[14] A.C. Fernandes, R. Fernandes, C.C. Romão, B. Royo, Chem. Commun. (2005) 213–214.
[15] P.J. Costa, C.C. Romão, A.C. Fernandes, B. Royo, P.M. Reis, M.J. Calhorda, Chem. Eur.
J. 13 (2007) 3934–3941.
HP(O)(OEt)2 by coordination of P=O bond to molybdenum and
hydrogen transfer from P–H to the oxygen in Mo=O, forming Mo–OH
(see Scheme 2) as reported before [26]. In the next step, the imine
binds to the molybdenum of the intermediate 2 through the nitrogen,
followed by the C–P bond formation. Finally, the hydrogen is
transferred from Mo–OH to the nitrogen of the final product.
In conclusion, we have demonstrated that MoO2Cl2 is a novel and
efficient catalyst for the synthesis of α-aminophosphonates by the
addition of HP(O)(OEt)2 to imines. This methodology has high yields,
good chemoselectivity, and short reaction times under mild and
solvent-free conditions.
[16] A.C. Fernandes, J.A. Fernandes, F.A. Almeida Paz, C.C. Romão, Dalton Trans. (2008)
6686–6688.
[17] R.G. Noronha, A.C. Fernandes, C.C. Romão, J. Org. Chem. 74 (2009) 6960–6964.
[18] A.C. Fernandes, C.C. Romão, Tetrahedron Lett. 46 (2005) 8881–8883.
[19] A.C. Fernandes, C.C. Romão, J. Mol, Catal A Chem. 272 (2007) 60–63.
[20] A.C. Fernandes, C.C. Romão, J. Mol, Catal A Chem. 253 (2006) 96–98.
[21] A.C. Fernandes, C.C. Romão, Tetrahedron 62 (2006) 9650–9654.
[22] A.C. Fernandes, C.C. Romão, Tetrahedron Lett. 48 (2007) 9176–9179.
[23] S.C.A. Sousa, A.C. Fernandes, Tetrahedron Lett. 50 (2009) 6872–6876.
[24] R.G. Noronha, A.C. Fernandes, C.C. Romão, Tetrahedron Lett. 51 (2010) 1048–1051.
[25] R.G. Noronha, A.C. Fernandes, C.C. Romão, Tetrahedron Lett. 50 (2009) 1407–1410.
[26] R.G. Noronha, P.J. Costa, C.C. Romão, M.J. Calhorda, A.C. Fernandes, Organome-
tallics 28 (2009) 6206–6212.
These results extend the use of the high valent oxo-molybdenum
complexes as excellent catalysts for C–P bond forming reactions. We
believe that this procedure will be a useful and attractive alternative
to the existing methods for the synthesis of α-aminophosphonates.