Highly efficient synthesis of α-aminophosphonates catalyzed by hafnium(IV) chloride

Article abstract of DOI:10.1016/j.tetlet.2016.03.033

A highly efficient one-pot method for the synthesis of a variety of α-aminophosphonates via the one-pot three-component reaction of aldehyde, amine, and phosphite has been developed using only 2 mol % HfCl₄ as the catalyst. The NMR evidence strongly indicated the catalytic roles of Hf(IV) on the activation of aldehyde, phosphite, and imine intermediate.

Full text of DOI:10.1016/j.tetlet.2016.03.033

Accepted Manuscript
Highly efficient synthesis of α-aminophosphonates catalyzed by hafnium(IV)
chloride
Xiao-Chuan Li, Shan-Shan Gong, De-Yun Zeng, Yue-Hai You, Qi Sun
PII:
S0040-4039(16)30255-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.033
TETL 47421
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 January 2016
8 March 2016
10 March 2016
Please cite this article as: Li, X-C., Gong, S-S., Zeng, D-Y., You, Y-H., Sun, Q., Highly efficient synthesis of α-
aminophosphonates catalyzed by hafnium(IV) chloride, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.03.033
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Tetrahedron Letters
Highly efficient synthesis of α-aminophosphonates catalyzed by hafnium(IV) chloride
Xiao-Chuan Li, Shan-Shan Gong*, De-Yun Zeng, Yue-Hai You, Qi Sun
Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science and Technology Normal University, 605 Fenglin Avenue, Nanchang, Jiangxi 330013, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly efficient one-pot method for the synthesis of a variety of α-aminophosphonates via the
one-pot three-component reaction of aldehyde, amine, and phosphite has been developed by
using only 2 mol% HfCl4 as the catalyst. The NMR evidence strongly indicated the catalytic
roles of Hf(IV) on the activation of aldehyde, phosphite, and imine intermediate.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Aminophosphonate
Hafnium chloride
Catalysis
Aldehyde
Phosphite
As structural mimics of natural amino acids, aminophosphonic
acids and their esters have been extensively investigated as
transition-state analog inhibitors of a huge variety of enzymes
with physiological and pathologcial importance, such as metallo-
proteases,1 aspartic proteases,2 phosphatases,3 ligases,4 and
Among the reported catalysts, ZrOCl2·8H2O15 attracted our
attention in our synthesis of alkyldiamine-based bis-α-
aminophosphates because of its catalytic activity and non-
toxicity. Meanwhile, we also noticed that HfCl4, a closely related
Group IV metal salt, exhibited even superior activities in various
metal-catalyzed reactions.16 Inspired by these reports, we tested
the possiblity to utilized HfCl4 to promote the Kabachnik-Fileds
reaction. In this paper, we report the employment of HfCl4 as a
highly efficient and robust catalyst for the synthesis of a diversity
of α-aminophosphonates via the one-pot three-component
reaction of aldehyde, amine, and phosphite. Compared to the
reactions promoted by Zr(IV) salts, HfCl4-catalyzed formation of
α-aminophosphates is not only faster and cleaner but also
glycotranferases.5 As
a
result, natural and synthetic
aminophosphonic acids have exhibited a broad range of
biological activities to bacterial/viral/fungal infection,
neurotransmission, cardiovascular misfunction, and plant/insect
growth.6 Recent research have further extended their applications
as anticancer7 and antituberculosis8 agents.
Among the available synthetic methods for α-
aminophosphates, the three-component reaction of aldehyde,
amine, and phosphite, also known as Kabachnik-Fields reaction,9
has gained much attention due to its one-pot manner and
convenience in parrallel synthesis of diverse structural analogs. It
has been well recognized that solvent-free conditions are
preferred due to the elimiation of water in the reaction. However,
clogging of α-aminophosphonate product in the absence of
solvent prohibited the completion of the reaction in many cases.
In the past decade, various Brønsted and Lewis acids catalysts,
such as CF3CO2H,10 InCl3,11 TaCl5,12 lanthanide triflates,13 and
Mg(ClO4)2,14 and microwave conditions have been employed to
improve the synthetic efficiency of the Kabachnik-Fileds reaction
in different organic solvents. However, the applications of these
catalysts are still not satisfactory due to their own limitations
such as high cost, toxcity, specificity to aryladehyde/arylamine,
and sensitivity to moisture. In addition, the detailed catalytic
mechanisms of these catalysts have not been thoroughly
1
requires less amount of catalyst (2 mol%) in ethanol. 31P and H
NMR data strongly indicated the effects of Hf(IV) on the
activation of both reactants and imine intermediate.
In the preliminary experiments, benzaldehyde, aniline, and
dimethylphosphite (1:1:1.05 equiv) were reacted in the presence
or absence of 10 mol% of various metal catalysts in ethanol
([aldehyde]=[amine]=1.0 M) at room temperature without inert
gas protection. The results listed in Table 1 clearly showed that
Mg(ClO4)2 exhibited almost no catalytic activity when compared
to the control reaction without catalyst (incomplete at 48 h). In
contast, all Zr(IV)-catalyzed reactions went to completion in 12–
14 h with ~90% isolated yields of α-aminophosphate 1.
Interestingly, HfCl4 significantly shortened the reaction time to
only 6 h and racemic 1 was isolated in 98% yield. It was also
observed that the reaction time of HfCl4-catalyzed reaction was
significantly prolonged at lower reaction concentrations. In
contrast, the HfCl4-catalyzed reaction under solvent-free
eludicated.
———
 Corresponding author. Tel.: +86-791-8380-5183; fax: +86-791-8382-6894; E-mail addresses: gongshanshan@jxstnu.edu.cn;
sunqi@jxstnu.edu.cn.

2
Tetrahedron
Table 1. The effect of catalyst on the synthesis of α-aminophosphonate 1
temperature (80 ºC), polar byproducts began to show up on TLC
plate. The solvent effect was also investigated at 60 ºC (Table 3,
entry 5–7). The HfCl4-catalyzed Kabachnik-Fields reaction
proceeded with high yield of 1 in dichloroethane (DCE), THF,
and CH3CN, except that longer reaction time was required.
Table 3. The effects of temperature and solvent on the synthesis of α-
aminophosphonate 1
Entry
Catalyst
--
Reaction time (h)
Isolated yield of 1 (%)
Entry
Temperature
(ºC)
Solvent
Reaction time
(h)
Isolated yield
of 1 (%)
1
2
3
4
5
6
48
48
12
14
12
6
58a
60a
91
1
2
3
4
5
6
7
20
40
60
80
60
60
60
EtOH
EtOH
EtOH
EtOH
DCE
6
2.5
0.5
0.17
2
98
98
98
90
97
95
98
Mg(ClO4)2
ZrOCl2·8H2O
ZrCl4
90
ZrCp2Cl2
HfCl4
92
98
aThe reaction was incomplete and quenched at 48 h.
THF
3.5
1
CH3CN
condition finished in only 2 h at room temperature. But the
solidification of the reaction system lowered the yield of 1 to
90%. Therefore, 1.0 M appeared to be a proper concentration for
the HfCl4-catalyzed reaction.
With the optimized reaction conditions, a diversity of α-
aminophosphonates were synthesized. As shown in Table 4, the
reactions with both arylaldehyde and arylamine afforded the
corresponding α-aminophosphonates 1–10 in excellent yields and
completed in 30 min. It is noteworthy that dialkylphosphite and
trialkylphosphite resulted in no significant difference in terms of
reaction time and yield. In comparison, when alkylaldehydes
and/or alkylamines were employed as reactants, longer reaction
time (1–2 h) was required and the yields of α-aminophosphonates
11–23 were marginally decreased. The application of HfCl4
catalyst for the synthesis of more complicated bis-functionalized
alkyldiamines afforded the desired bis-α-aminophosphonates 24–
27 in 82–87% yields.
Table 2. Effect of the amount of HfCl4 on the synthesis of α-aminophosphonate 1
Entry
Amount of HfCl4
(mol%)
Reaction time
(h)
Isolated yield of 1
(%)
1
2
3
4
10
5
6
8
98
98
2
6
98
1
48
82a
aThe reaction was incomplete and quenched at 48 h.
In the following step, we gradually reduced the amount of
HfCl4 catalyst from 10 mol% to 1 mol%. As shown in Table 2,
the reaction time was prolonged to 8 h without any effect on the
yield of 1, when 5 mol% HfCl4 was used. However, it was
surprising to observe that the reaction time was abnormally
restored to 6 h, when the amount of HfCl4 was reduced to 2
mol%. However, further decrease the amount of HfCl4 to 1 mol%
drastically affected the outcome of the reaction. 31P NMR tracing
of the reaction with 2 mol% HfCl4 confirmed the smooth and
almost quantitative transformation of dimethylphosphite (δ =
1
12.3 ppm, JP,H = 710 Hz) to α-aminophosphonate 1 (δ = 25.8
ppm) within 6 h.
Figure 1. The 31P NMR tracing experiment for the synthesis of 1 with 2 mol%
HfCl4 catalyst at room temperature.
Figure 2. The 31P NMR tracing experiment of the promoted H-D exchange
reaction of dimethylphosphite in MeOH-d4 by 2 mol% HfCl4 (A) and its rate
comparison with the control experiment without HfCl4 (B).
As expected, increasing reaction temperature remarkably
accelerated the reaction rate (Table 3, entry 1–4). When the
reaction with 2 mol% HfCl4 was performed at 60 ºC, the reaction
time was shorten to only 30 min without affecting the yield of 1.
Though the reaction finished in 10 min at further elevated

Table 4. HfCl4-catalyzed one-pot three-component synthesis of α-aminophosphonates (1–27)
a The reactions with dialkylphosphite and trialkylphosphite showed no difference in terms of yield and reaction time.
1
It has been proposed that the Kabachnik-Fields reaction
proceeded via sequential condensation of aldehyde and amine
followed by nucleophilic addition of phosphite to the imine
intermediate.9 However, it has also been proposed that the
reaction path may involve the formation of another plausible
intermediate, α-hydroxyphosphonate.17 Our 31P NMR tracing
experiment (Figure 1) clearly showed that no peak corresponding
to α-hydroxyphosphonate was observed during the entire reaction
process. In the control experiment with benzaldehyde,
dimethylphosphite, and 2 mol% HfCl4, no reaction was observed.
(triplet, δ = 11.8 ppm, JP,D = 109 Hz) in 2 h. In the control
experiment, it took 20 h for the proton-deuterium exchange
reaction to reach the same extent (Figure 2B). These results
suggested that Hf(IV) accelerated the tautomerization rate
between the inactive H-phosphonate and reactive phosphite
forms,19 thereby contributing to the overall promotion of the
Kabachnik-Fields reaction.
To clarify the catalytic roles of HfCl4 on the one-pot three-
1
component reaction, we utilized 31P and H NMR to examine the
interactions of HfCl4 with the individual reactants and imine
1
intermediate. H NMR data showed that addition of 2 mol%
HfCl4 promoted the conversion of benzaldehyde to the dimethyl
acetal within 3 min in MeOH-d4, indicating the strong effect of
Hf(IV) on the activation of aldehyde. Similarly, Hf(IV)-catalyzed
fast conversion of benzaldehyde to the corresponding imine in
the presence of aniline was observed within 3 min. In comparison,
complete formation of imine without HfCl4 catalyst required
about 15–20 min. In contrast, the shifts of aniline proton signals
upon addition of 2 mol% HfCl4 were negligible. The 31P NMR
peaks of dimethylphosphite alone in MeOH showed no
difference at all before and after the addition of 2 mol% of HfCl4.
Interestingly, when 2 mol% of HfCl4 was added to dimethyl-
phosphite in MeOH-d4, the proton-deuterium exchange reaction
was drastically promoted.18 As shown in Figure 2A, 99% of P–H
Figure 3. The triple activation roles of Hf(IV) on the formation of α-aminophos-
phonates in the one-pot three-component reaction.
In the following research, we treated the isolated imine with
dimethylphosphite in MeOHand monitored the reaction with 31P
NMR. The two-component reaction was as sluggish as the one-
pot three-component reaction (Table 1, entry 1). However,
addition of 2 mol% HfCl4 drastically accelerated the reaction rate,
suggesting that the nucleophilic addition of phosphite to the
imine is the rate-limiting step and Hf(IV) also plays an important
role on the activation of the imine intermediate. It is worth
mentioning that when the isolated imine alone was treated with
10 mol% HfCl4, about 15% of the imine was converted to
benzaldehyde dimethyl acetal in MeOH-d4 when equilibrium was
1
(doublet, δ = 12.3 ppm, JP,H = 710 Hz) was converted to P–D

4
Tetrahedron
15. (a) Yadav, J. S.; Reddy, B. V. S.; Raj, K. S.; Reddy, K. B.; Prasad, A. R.
reached. In contrast, 2 mol% HfCl4 caused no shift from the
Synthesis, 2001, 2277–2280; (b) Bhagat, S.; Chakraborti, A. K. J. Org.
Chem. 2008, 73, 6029–6032.
16. (a) Zhi, L.; Yamamoto, H. J. Am. Chem. Soc. 2010, 132, 7878–7880; (b)
Ishihara, K.; Nakayama, M.; Ohara, S.; Yamamoto, H. Tetrahedron,
2002, 58, 8179–8188; (c) Samyoung, A.; Young, S. S.; Bok, R. Y.; II, N.
J. Organometallics 2000, 19, 277–2780.
imine back to the acetyl. These results indicated that less amount
of HfCl4 catalyst favored the equilibrium of the imine
intermediate, which may compensate the for reaction rate loss
due to the lowered amount of catalyst. On the basis of the above
results, the mechanism of the HfCl4-catalyzed Kabachnik-Fields
reaction is proposed in Figure 3.
17. (a) Bunnal, S.; Hiromichi, E.; Tsutomu, K. J. Am. Chem. Soc. 2007, 129,
1978–1986; (b) Roman, G. Tetrahedron 1995, 51, 10627–10632; (c)
Babak, K. Tetrahedron Lett. 2003, 44, 1051–1053.
18. (a) McFarlane, W.; Rycroft, D. S. Mol. Phys. 1972, 24, 893–895; (b)
Peterson, A. C.; Levsen, S. M.; Cremer, S. E. Phosphorus, Sulfur
Silicon Relat. Elem. 1996, 115, 241–254.
In summary, we have developed a highly efficient protocol for
the HfCl4-catalyzed synthesis of
a variety of α-amino-
phosphonates via the one-pot three-component reaction of
aldehyde, amine, and phosphite in organic solvents. The
experimental data showed that the catalytic activity of HfCl4 is
superior to that of the reported Zr(IV) salts in terms of reaction
rate, product yield, and amount needed. In addition, the strong
NMR evidence elucidated the triple roles of Hf(IV) on the
activation of aldehyde, phosphite, and imine intermediate.
19. (a) Stawinski, J.; Kraszewski, A. Acc. Chem. Res. 2002, 35, 952–960; (b)
Kraszewski, A.; Stawinski, J. Pure Appl. Chem., 2007, 79, 2217–2227.
Supplementary Material
Supplementary
data
(experimental
procedures,
characterization data, and NMR spectra of new compounds)
associated with this article can be found at
Acknowledgments
We thank the National Natural Science Foundation of China
(21262014 and 21562021), Major Science and Technology
Project (20143ACB21014) and Fellowship for Young Scientists
(2015) of Jiangxi Province, Foundation for Returned Chinese
Scholars from MOHRSS (2015).
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Highly efficient synthesis of α-
aminophosphonates catalyzed by
hafnium(IV) chloride
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Xiao-Chuan Li, Shan-Shan Gong*, De-Yun Zeng, Yue-Hai You, Qi Sun*

3
Highlights：
 HfCl4-catalyzed efficient synthesis of α-aminophosphonates has been developed.
 The catalytic activity of HfCl4 is superior to that of the reported Zr(IV) salts.
 The triple catalytic roles of Hf(IV) were elucidated by strong NMR evidence.