New synthetic methodology leading to a series of novel heterocyclic α-aminophosphonates: A very attractive expansion of Kabachnik-Fields reaction

Article abstract of DOI:10.1016/j.tet.2012.02.059

A convenient one-pot three-component approach leading to synthesis of a series of novel heterocyclic α-aminophosphonates starting either from 2-hydroxyacetophenones or 2-hydroxybenzaldehyes was developed. Crown Copyright

Full text of DOI:10.1016/j.tet.2012.02.059

Tetrahedron 68 (2012) 3156e3159
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Tetrahedron
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New synthetic methodology leading to a series of novel heterocyclic a-
aminophosphonates: a very attractive expansion of KabachnikeFields reaction
,
b
a
c
a,
Zhibo Qu a, Xiaolan Chen a , Jinwei Yuan , Yunliang Bai , Tong Chen , Lingbo Qu b, Fujun Wang a, Xu Li a,
*
,d,
Yufen Zhao a
*
a Department of Chemistry, Zhengzhou University, Key Laboratory of Chemistry Biology and Organic Chemistry, Zhengzhou 450052, China
b School of Chemistry & Chemical Engineering, Henan University of Technology, Zhengzhou 450001, China
c High and New Technology Research Center of Henan Academy of Sciences, Zhengzhou 45001, China
d Department of Chemistry, Xiamen University, Xiamen 361005, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient one-pot three-component approach leading to synthesis of a series of novel heterocyclic a-
Received 17 January 2012
Received in revised form 20 February 2012
Accepted 24 February 2012
Available online 3 March 2012
aminophosphonates starting either from 2-hydroxyacetophenones or 2-hydroxybenzaldehyes was
developed.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
One-pot
Intramolecular cyclization
Mechanism
Heterocyclic a-Aminophosphonates
KabachnikeFields reaction
1. Introduction
numerous synthetic methodologies of a
-aminophosphonate,6e9 the
most noteworthy and remarkable one is KabachnikeFields re-
action,10 generally using amines, dialkyl phosphites and carbonyl
compounds as the reactants. Even though quite a lot research works,
which focused on the synthesis and biological tests of a-amino-
phosphonates have been reported, but surprisingly 3-amino-2-
hydroxy-2,3-dihydrobenzo[d][1,2]oxaphosphole 2-oxides, a kind
of heterocyclic a-aminophosphonates (Fig. 1b), to the best of our
knowledge, have not been described in the literature. The method-
ology towards synthesis of these 3-amino-2-hydroxy-2,3-
dihydrobenzo[d][1,2]oxaphosphole 2-oxides, a new kind of organ-
ophosphorus heterocycles, was accidentally found by our research
The chemistry of organophosphorus heterocycles has received
considerable attention owing to their unique structural features and
diverse potential biological properties. A large number of related
compounds were synthesized in the past two decades.1 1,2-Oxa-
phosphol-3-enes (Fig. 1a), which were examined as potential pre-
cursors of stabilized C-centred radicals,2 displayed diverse potential
biological properties, such as antiviral activity,3 cytotoxicity and
genotoxicity,4 antimicrobial activity.5 It is well known that
a-ami-
nophosphonates, to a great extent, have received much attention
because of their antifungal,6 antitumoral,7 and anti-Giardia.8 Among
group in the process of an intentional synthesis of
a-amino-
phosphonate through KabachnikeFields reaction through a one-
pot, three-component procedure using carbonyl compound, amine
and dialkyl phosphite. Herein, we disclose a facile methodology to
prepare these novel organophosphorus heterocycles.
7
3
2
R
R
4
R
4
NHR
O
O
R
R
6
(a)
(b)
R
P
P
1
O
OH
5
O
R
Fig. 1. The structures of 1,2-oxaphosphole 2-oxides derivatives.
2. Results and discussion
Instead of
KabachnikeFields reaction, a cyclic
shown in Scheme 1, namely 3-amino-2-hydroxy-6-methoxy-3-
propyl-2,3-dihydrobenzo[d][1,2]-oxaphosphole 2-oxide, was
a
-aminophosphonate 4a0, a regular product of
-aminophosphonate 4a as
a
* Corresponding authors. Tel./fax: þ86 371 67767051; e-mail address: chenxl@
zzu.edu.cn (X. Chen).
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.059

Z. Qu et al. / Tetrahedron 68 (2012) 3156e3159
3157
NH
O
no reaction
P
O
O
O
OH
O
O
4a'
CH3
Toluene
O
P
H
+
NH2
+
O
O
OH
Reflux
2 h
1
2
3
NH
3
4
8
9
feasible pathway
5
OH
2
1 equiv
1.2 equiv
P
6
O
O
1
4a
O
7
Scheme 1. Preparation of 2-hydroxy-6-methoxy-3-propylamino-2,3-dihydrobenzo[d][1,2]-oxaphosphole 2-oxide (compound 4a).
accidentally obtained using 4-methyloxyl-2-hydroxyacetophenone
1, propylamine 2 and diisopropyl phosphite 3 as reactants under
reflux in toluene.
by using diisopropyl phosphite as a phosphorus reactant under the
same reaction conditions. Using compounds 1, 2 and diisopropyl
phosphite 3 as the reactants, several solvent systems together with
a solvent-free system were further employed, respectively, to ex-
plore the optimal reaction condition for the preparation of cyclic
compound 4a. The reaction solutions were refluxed for 3 h at
a temperature close to each boiling point of the used solvents, and
maintained temperature at approximate 155 ꢀC in the case of the
solvent-free reaction system involved, respectively (Table 1, entries
10e15). The results show that the largest yield (yield: 77%) was
obtained by refluxing the reactants in toluene.
The scope of the reactants was then enlarged to cover various 2-
hydroxyacetophenones and amines as shown in Table 2. All the re-
actions were performed in toluene under reflux for 3 h using only
diisopropyl phosphite as the phosphorus reagent. It is worth illus-
trating here that only the corresponding cyclic products, namely 3-
amino-2-hydroxy-2,3-dihydrobenzo[d][1,2]-oxaphosphole 2-oxides
(4aeg) were afforded in relatively good yields as shown in Table 2.
Moreover, the fact that all the corresponding final cyclic products
automatically precipitated from toluene solution as they were
formed, significantly simplified the purification process. The final
Using compounds 1, 2 and diisopropyl phosphite as the reactants,
the influence of the reaction temperature on the reaction was sub-
sequently investigated in toluene solution at different temperatures
20, 30, 50, 80,110 ꢀC for 3 h (Table 1, entries 1e5). It can be seen that
the yield was zero when the reaction temperature was below 30 ꢀC,
however increased slightly over the temperature range of 30e50 ꢀC,
and increased quickly over the temperature range of 50e110 ꢀC,
from 3% to 77%. It was especially worth mentioning that the reaction
temperature was not increased further after the reactants began to
reflux at approximate 110 ꢀC, a boiling point of toluene. A relatively
optimal condition towards synthesis of 4a was further explored by
using reactants 1, 2 to react with any of the four other H-phospho-
nates besides diisopropyl phosphite 3 in toluene under reflux con-
ditions for 3 h, respectively, as shown in Table 1 (entries 6e9). The
results show that only cyclic product 4a was obtained in each ex-
perimental case. It can be seen that even though 4a could be syn-
thesized by using any of the four given H-phosphonates, no yield
obtained by using any of them was higher than 77%, a yield achieved
Table 1
Optimization of conditions
O
O
H3C
NH
OH
R
CH3
+
Solvent
P
+
O
+
2 ROH
NH2
H
P
temperature
O
OH
O R
O
O
O
1
2
3
4a
Entry
Temperature (ꢀC)
H-Phosphonates
Solvent
Yieldd (%)
1
2
3
4
5
6
7
8
20
30
50
Diisopropyl phosphite
Diisopropyl phosphite
Diisopropyl phosphite
Diisopropyl phosphite
Diisopropyl phosphite
Dimethyl phosphite
Diethyl phosphite
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH3CN
0a
0a
3a
80
38a
77a
40b
56b
61b
49b
0c
110
110
110
110
110
81
Dibenzyl phosphite
9
Diphenyl phosphite
Diisopropyl phosphite
Diisopropyl phosphite
Diisopropyl phosphite
Diisopropyl phosphite
Diisopropyl phosphite
Diisopropyl phosphite
10
11
12
13
14
15
66
THF
6c
101
117
152
155
Dioxane
n-C4H9OH
DMF
3c
0c
34c
41c
No solvent
a
Reaction conditions: using 4-methyloxyl-2-hydroxyacetophenone 1 (1 mmol), propylamine 2 (1 mmol) and diisopropyl phosphate 3 (1.2 mmol) in toluene (3 mL) at
different temperature for 3 h.
b
Reaction conditions: using 4-methyloxyl-2-hydroxyacetophenone 1 (1 mmol), propylamine 2 (1 mmol) to react with 5 different H-phosphonates 3 (1.2 mmol) in toluene
(3 mL) under reflux for 3 h.
c
Reaction conditions: using 4-methyloxyl-2-hydroxyacetophenone 1 (1 mmol), propylamine 2 (1 mmol) and diisopropyl phosphite 3 (1.2 mmol) as reactants, using dif-
ferent solvents (3 mL) under reflux conditions or at 155 ꢀC when non-solvent system employed for 3 h, respectively.
d
Isolated yields.

3158
Z. Qu et al. / Tetrahedron 68 (2012) 3156e3159
Table 2
Table 3
Various 2-hydroxyacetophenones and amines were investigated to be reacted with
Ratio of products (A/B). o-Hydroxybenzaldehyde and its derivatives (1 mmol), di-
verse amines (1 mmol), different H-phosphonates (1.2 mmol) in toluene (3 mL)
under reflux for 3 h
diisopropyl phosphitea
O
NHR2
H3C
NHR1
O
P
O
NHR1
OH
P
R2NH2
OH
O
Toluene
CH3
+
+
O
P
O
toluene
H
O
P
R1-NH2
H
reflux, 3h
O
O
+
R1
+
OH
O
4 a-g
H
OR2
R1
+
P
OR2
reflux, 3 h
OR2
OH
1
O
OH
2
3
OH
A
B
Entry
R1
R2
Yieldb (%)
4a
4b
4c
4d
4e
4f
6-OCH3
6-OCH3
6-OCH3
6-OCH3
6-OCH3
H
n-Pr
CH3
C2H5
H
n-Bu
n-Pr
n-Bu
77
65
70
75
68
70
69
Entry
R1, R2
Ratio of products (A/B)
1
2
3
4
5
6
7
8
9
R1¼n-Pr, R2¼i-Pr
R1¼n-Pr, R2¼Et
R1¼n-Pr, R2¼Me
R1¼n-Pr, R2¼n-Bu
R1¼n-Pr, R2¼i-Bu
R1¼n-Pr, R2¼Ph
R1¼n-Pr, R2¼PhCH2
R1¼Et, R2¼Ph
100:0
60:40
5:95
100:0
100:0
0:100
0:100
0:100
100:0
4g
H
a
Condition: o-hydroxyacetophenone and its derivatives 1 (1 mmol), diverse
amines 2 (1 mmol), were reacted with diisopropyl phosphite 3 (1.2 mmol) in tolu-
ene (3 mL) under reflux for 3 h.
R1¼Et, R2¼PhCH2
b
Isolated yields.
purification was accomplished by subsequent filtration followed by
washing with methanol and drying in vacuum. It is also worth no-
ticing that the methodology shown here exclude using aromatic
amines as the reactants. It is proved that even though aromatic
amines, such as aniline, 4-chloroaniline, p-methoxyaniline, 4-
methylaniline, 3-methylaniline, 4-nitroaniline, could effectively re-
act with 2-hydroxyacetophenones to afford the corresponding im-
ines, the imines could not undergo the addition reaction further with
H-phosphonates under the reaction condition, and let alone the
subsequent intramolecular ester exchange reaction leading to het-
reaction activity of diphenyl phosphate in the related reactions. It may
attribute to the better leaving group ability of the phenoxide anion
relative to that of an alkoxide anion or more positive of phosphorus
atom in case of diphenyl phosphite than dialkyl phosphite. The ortho-
hydroxyl most possibly attack the positive phosphorus via the intra-
molecular ester exchange reaction to form the corresponding het-
erocyclic a-aminophosphonates in the case when diphenyl phosphite
was employed. It is known that aldehydes are usually more reactive
towards nucleophilic additions than ketones because of both steric
and electronic effects. That’s why 2-hydroxybenzaldehyes and 2-
hydroxyacetophenones usually display varying results when com-
bined with amines and dialkyl phosphates under the reaction condi-
tions. It is also concluded from the results shown in Tables 2 and 4 that
the yields of the corresponding heterocyclic products are not influ-
enced obviously by various substituted groups attached to the
erocyclic a-aminophosphonates via a nucleophilic attack of ortho-
hydroxyl group to the partially positive phosphorus atom of phos-
phoryl group.
It strongly suggests from the above experimental results that the
heterocyclic
ing the relatively high steric hindrance of 2-hydroxyacetophenones.
It is conceivable that even if the acyclic -aminophosphonates pos-
a-aminophosphonates can be forced to form when us-
Table 4
a
Various o-hydroxybenzaldehydes and amines were investigated to be reacted with
sibly were formed via the reaction of 2-hydroxyacetophenones and
the amines, they were to a great extent prone to undergo an intra-
molecular ester exchange reaction to reduce their relatively high
steric hindrance.
diphenyl phosphitea
It is known that aldehydes are usually more reactive towards nu-
cleophilic additions than ketones because of both steric and electronic
effects. Aldehydes and ketones usually display varying results when
combined with chemical reagents. The reaction, using 2-
hydroxybenzaldehye, instead of 2-hydroxyacetophenone, along with
diisopropylphosphiteandpropylamineasthereactants, wastherefore
performed intentionally under reflux operating conditions in toluene
for 3 h as shown inTable 3. Itis canbeseenthatinstead ofaffordingthe
cyclic product B, the reaction of 2-hydroxybenzaldehye with isopropyl
Entry
R1
R2
Yieldb (%)
I-4a
I-4b
I-4c
I-4d
I-4e
I-4f
I-4g
I-4h
I-4i
H
H
H
H
Et
n-Pr
n-Bu
n-Hex
n-Oct
Et
76
80
75
70
90
65
85
81
76
79
83
65
74
68
70
75
69
67
66
65
H
5-NO2
5-NO2
5-NO2
5-NO2
3-NO2
3-NO2
3-NO2
3-NO2
5-Br
3,5-Br
3,5-I
3,5-I
5-I
phosphite and propylamine completely led to an a-amino mono-
n-Pr
phosphonate A, a normal product of KabachnikeFields reaction (Table
3, entry1). Syntheticmethodspossiblyleading2-hydroxybenzaldehye
to the formation of the heterocyclic product B were subsequently in-
vestigated. The reactions using different amines and H-phosphonates
along with 2-hydroxybenzaldehye as the reactants were investigated
as shown in Table 3. The molar ratios of compounds A and B were
determined from 31PNMRintegrationof twophosphorusatomsignals
n-Bu
n-Hex
Et
I-4j
I-4k
I-4l
n-Pr
n-Bu
n-Hex
n-Pr
n-Pr
n-Pr
n-Bu
n-Pr
n-Bu
CH2CH2NH2
I-4m
I-4n
I-4o
I-4p
I-4q
I-4r
I-4s
I-4t
of the products A (about
d 22 ppm) and B (about d 17 ppm) and the
related results are repeatable. It is especially worth emphasizing that
cyclic product B favoured reactions were practically realized by
employing diphenyl phosphite as a phosphoryl reagent in both cases:
propylamine and ethylamine being employed (Table 3, entries 6
and 8). It is concluded that in the case of o-hydroxybenzaldehydes,
5-I
H
a
Condition: o-hydroxybenzaldehyde and its derivatives I-1 (1 mmol), various
primary amines I-2 (1 mmol) were reacted with diphenyl phosphite (1.2 mmol) in
toluene (3 mL) under reflux for 3 h.
diphenyl phosphite can be used for heterocyclic
a-aminophos
b
Isolated yields.
phonates. The results may better be explained by the relatively high

Z. Qu et al. / Tetrahedron 68 (2012) 3156e3159
3159
benzene ring, no matter electron withdrawing groups such as eNO2,
eX, or electron donating group such as eOCH3. It may besupported by
the deduction that the reactivity of the carbonyl group, formaldehyde
group for 2-hydroxybenzaldehyes and formyl group for 2-
hydroxyacetophenones, are mainly affected by the hydroxyl group,
a relatively strong activating electron releasing group at the ortho
position.
Synthesis, using diphenyl phosphite, along with a variety of 2-
hydroxybenzaldehyes and primary amines as the reactants, was
further investigated by performing the reactions under reflux
conditions in toluene for 3 h, respectively, as shown in Table 4. As
expected, diphenyl phosphite unexceptionally brought about only
the cyclic products in any given case. Twenty 2-hydroxy-3-
heterocyclic a-aminophosphonates could be synthesized in relatively
high yields. In the case of using 2-hydroxybenzaldehye as the starting
reactant, the chemical reactions, towards only in the cyclic product
favoured direction, observably could be conducted by employing
diphenyl phosphite as the phosphoryl reagent under the circum-
stances. The approaches described here obviously have significant
advantages in terms of experimental simplicity, mild reaction condi-
tions and easy work-up, and would surely represent a convenient tool
for the synthesis of a variety of this novel type of organophosphorus
heterocycles.
Acknowledgements
alkylamino-2,3-dihydrobenzo[d][1,2]oxaphosphole
4aet) were obtained in relatively good yields.
Obviously, this reaction should be, in reality, a multistep pro-
cedure having quite a complex mechanism involved. Here the re-
lated mechanism is reasonably proposed as shown in Scheme 2.
2-oxides(I-
We are grateful to the National Natural Science Foundation of
China (No. 20972130, 21072178), Innovation Specialist Projects of
Henan Province (114200510023) and Technological Leading Pro-
jects of Local Government of Zhengzhou (112PLJRC359) for their
financial supports of this research.
O
O
I-2
HO
H
H P OPh
OPh I-3
H
H2N
N
N
H
OH
OH
OH
H2O
I-1
7
6
NH
OH
HN
O
P
HN
H2O
O
O
O
O
P
P
O
O
OH
O
I-4a
OH
9
OH
8
Scheme 2. A proposed reaction mechanism for compound I-4a.
The first step is the formation of the corresponding imine 7. Because
its formation is a reversible process, the application of any means,
permitting the elimination of the water formed is helpful for the
whole process. In the second step the compound diphenyl phos-
phite I-3 having PeH bond adds to the C]N bond of the transient
imine 7 to give the corresponding phosphonate 8. In the third step,
a novel five-membered ring intermediate 9 is formed by an intra-
molecular ester exchange reaction via a nucleophilic attack of or-
tho-hydroxyl group at the partially positive phosphorus atom of
phosphoryl group. It is reasonable to assume that the ester ex-
change reaction would be favoured by forming a relatively stable
intermediate 9 with a five-membered ring containing phosphorus
atom. The final product I-4a is finally obtained followed by a sub-
sequent hydrolysis of intermediate 9.
Supplementary data
Supplementary data related to this article can be found in the
online version, at doi:10.1016/j.tet.2012.02.059.
References and notes
1. Yu, F.; Lian, X.; Zhao, J.; Yu, Y.; Ma, S. J. Org. Chem. 2009, 74, 1130.
2. Julia, P.; Raquel, E. G.; Pascual, O. B.; Maria, C.; Miguel, A.; Fernando, L. Org. Lett.
2005, 7, 3869.
3. Belakhov, V. V.; Shneider, M. A.; Komarov, E. V.; Ionin, B. I.; Shtilbans, E. B.;
Rachkovskaya, L. A. Khim.-Farm. Zh. 1988, 22, 719.
4. Vanya, K.; Asya, D.; Karamfil, K.; Dobromir, E. Genetika 2009, 41, 179.
5. (a) Syam, P. G.; Hari, B. B.; Naga, R. C.; Reddy, C. D.; Reddy, S. Synth. Commun.
2009, 39, 1310; (b) Haranath, P.; Anasuyamma, U.; Raju, C. N.; Reddy, C. D.;
Reddy, C. S. J. Heterocycl. Chem. 2005, 42, 775.
6. Pan, L.; Liu, X. H.; Shi, Y. X.; Wang, B. L.; Wang, S. H.; Li, B. J.; Li, Z. M. Chem. Res.
Chin. Univers. 2010, 26, 389.
7. Hu, D. Y.; Wan, D. D.; Yang, S.; Song, B. A.; Bhadury, P. S.; Jin, L. H.; Yan, K.; Liu, F.;
Chen, Z.; Xue, W. J. Agric. Food Chem. 2008, 56, 998.
3. Conclusion
8. Michael, S.; Jay, C.; Ding, Z.; Aaron, S.; Atasi, D. C.; Siddhartha, D.; Stenen, E. P.
Org. Lett. 2010, 12, 4596.
Herein, we developed a convenient one-pot three-component
approach to the synthesis of a series of novel heterocyclic
a-amino-
phosphonates starting either from 2-hydroxyacetophenones or 2-
hydroxybenzaldehyes. Using diisopropyl phosphite along with 2-
hydroxyacetophenone or any of the substituted 2-hydroxyaceto
phenones and primary amines, a wide range of the corresponding
9. (a) Ibrahim, E. S.; Salah, M. E. K.; Mohamed, F. A. M.; Mohamed, A. H.; Ahmed,
A. A. E. G.; Mostafa, M. A. E. J. Am. Sci. 2011, 7, 604; (b) Bai, S.; Song, B. A.;
Bhadury, P. S.; Yang, S.; Hu, D. Y.; Xue, W. Chin. J. Chem. 2011, 29, 109.
10. (a) Kabachnik, M. I.; Medved, T. Y. Akad. Nauk SSSR 1952, 83, 689; (b) Kabachnik,
M. I.; Medved, T. Y. Akad. Nauk SSSR 1953, 1126; (c) Fields, E. J. Am. Chem. Soc.
1952, 74, 1528; (d) Cherkasov, R. A.; Galkin, V. I. Russ. Chem. Rev. 1998, 67, 847.