Highly efficient one-pot four-component Kabachnik-Fields synthesis of novel α-amino phosphonates under solvent-free and catalyst-free conditions

Article abstract of DOI:10.1039/c5ra18311a

In the present study, a simple and highly efficient protocol for the preparation of novel α-amino phosphonates is achieved based on the one-pot reaction of ninhydrin, 1,2-phenylenediamines, aniline derivatives, and dialkyl or diaryl phosphites, without using any catalyst under solvent-free conditions. The main advantages of the reaction are short reaction time, high yields, simple workup, and no need for further purification.

Full text of DOI:10.1039/c5ra18311a

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: Z. Rashid, H.
Naeimi and R. ghahremanmzadeh, RSC Adv., 2015, DOI: 10.1039/C5RA18311A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 6
RSC Advances
Dynamic Article Links ►
View Article Online
DOI: 10.1039/C5RA18311A
RSC Advances
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
PAPER
Highly efficient oneꢀpot fourꢀcomponent KabachnikꢀFields synthesis of
novel αꢀamino phosphonates under solventꢀfree and catalystꢀfree
conditions
5
Zahra Rashid,a Hossein Naeimi,b* and Ramin Ghahremanzadeha**
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
In the present study, a simple and highly efficient protocol for preparation of novel αꢀamino phosphonates is achieved based on the oneꢀ
pot reaction of ninhydrin, 1,2ꢀphenylenediammines, aniline derivatives, and dialkyl or diaryl phosphites, without using any catalyst under
10 solventꢀfree conditions. The main advantages of the reaction are short reaction time, high yields, simple workup, and no need for further
purification.
bDepartment of Organic Chemistry, Faculty of Chemistry, University of
Kashan, Kashan, 87317, I.R. Iran. Fax: +98-03615511121; Tel: +98-
45 03615912388; E-mail: Naeimi@kashanu.ac.ir
Introduction
Electronic Supplementary Information (ESI) available: [details of any
During the past few years, much attention has been focused on
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
15 the development of new protocols in organic synthesis for
environmentally benign processes due to increasing green
chemistry concerns.1, 2 As a result, many reactions are designed to
proceed cleanly and efficiently such as catalystꢀ and solventꢀfree
synthesis and multicomponent reactions (MCRs).3ꢀ5 MCRs are
20 special type of synthetically useful organic reactions that have
emerged as a powerful tool to construct complex molecular
architecture in a single chemical step to produce a product that
incorporates substantial portions of all the reactants with high
atom efficiency.6 They are basically different from two
25 component stepwise reactions such as: the simplicity of oneꢀpot
procedure, possible structural variation, complicated synthesis,
and large number of accessible compounds.7 Multicomponent
reactions under solventꢀfree conditions have gained significant
interest due to several advantages over the conventional methods
30 including less chemical pollution, low cost, simplicity in process
and handling and, easier workup that these factors are vital
especially in industry. 8, 9
50 biological activities such as anticancer agents,11 antiviral agents,12
enzyme inhibitors,13 peptide mimics,14 antibiotic,15 antithrombotic
agent,16 antiꢀinflammatory agent,17 and etc. Due to that, in recent
years, significant efforts have been devoted for preparation of
these valuable compounds. One of the most common and
55 convenient methods for the synthesis of these compounds is
Kabachnik–Fields reaction.18 This reaction is a oneꢀpot, threeꢀ
component reaction of carbonyl compound, amines and
phosphites. A wide range of catalysts has been employed for the
Kabachnik–Fields reaction to obtain phosphorylated derivatives
60 such as; Lewis acids,19ꢀ22 Brønsted acids,23ꢀ25 nano catalysts,26, 27
and heterogeneous catalysts.28 But most of the reported
procedures suffer from several shortcomings such as; long
reaction times, the use of hazardous and expensive solvents and
catalysts, low yields of the products, harsh reaction conditions,
65 and tedious workup procedures that are harmful to environment,
and limit the use of these methods. Hence, the development of an
effective and simple method under green reaction conditions for
the synthesis of mentioned structures would extend the important
scope of the synthesis of these compounds.
The chemistry of organic phosphorus compounds has shown a
remarkable growth throughout the past
5
decades.10 αꢀ
35 Aminophosphonates are phosphorus analogs of αꢀamino acids,
constitute an important class of compounds in pharmaceutical
chemistry with wide range of useful pharmacological and
70
In continuation of our program that purposes to develop
environmentally friendly methods for the preparation of
heterocyclic compounds,29ꢀ31 the present work was aimed to
synthesize novel αꢀaminophosphonates in a simple and efficient
Notes and references
40 aNanobiotechnology Research Center, Avicenna Research Institute,
ACECR, Tehran, Iran. Fax+ 98-02122432021; Tel: +98-02122432020;
E-mail: r.ghahremanzadeh@avicenna.ac.ir
75 method from
a fourꢀcomponent condensation reaction of
ninhydrin, 1,2ꢀphenylenediammines, various anilines, and dialkyl
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

RSC Advances
Page 2 of 6
View Article Online
DOI: 10.1039/C5RA18311A
or diaryl phosphites without using catalyst under solventꢀfree 50 C, 73.80; H, 4.95; N, 7.38%;. Found C, 73.92; H, 4.89; N, 7.47%;
condition (Scheme 1).
MS: m/z 569.
Results and discussion
O
R1
In recent years, the green situation has become an outstanding
55 topic. The reactions under catalystꢀ and solventꢀfree conditions
are substantially safe, nontoxic, environmentally friendly, and
inexpensive. In this research, we have planned oneꢀpot and four
component condensation reaction in order to synthesis of novel
α–amino phosphonates under solvent free conditions without
60 using catalyst with the hope that new biological activities could
be developed. To attain this goal, at first an equimolar mixture of
ninhydrin (1) and oꢀphenylenediamine (2) was taken in a 5 ml
glass test tube. The reaction mixture was stirred at room
temperature for the synthesis of 11Hꢀindeno[1,2ꢀb]quinoxalinꢀ11ꢀ
65 one (3) as a yellow powder. Then pꢀmethyl aniline (4) was added
and temperature was slowly increased until 70 °C. After
completion of the reaction (as indicated by TLC and reaction
mixture color changed to red), diphenyl phosphites was added.
The reaction proceeded efficiently with completely conversion to
70 afford the corresponding 7a (90% yields) within short reaction
time (20 min) at 70 °C. The steps of synthesis are shown in
Scheme 2.
NH2
O
OR2
O
NH
P
OR2
N
1
O
R1
Solvent Free
Catalyst Free
4
R
R
NH2
R
N
HPO(OR2)2
7
NH2
R
6
2
5
Scheme 1 Oneꢀpot synthesis of novel αꢀaminophosphonates under
solventꢀfree and catalystꢀfree conditions.
Experimental
10
The chemicals used in this work were obtained from Fluka and
Merck and were used without purification. Melting points were
measured on an Electrothermal 9200 apparatus. IR spectra were
recorded as KBr pellets on a PerkinꢀElmer 781 spectrophotometer
1
15 and an Impact 400 Nicolet FTꢀIR spectrophotometer. H NMR
and 13C NMR spectra were recorded in DMSO–d6 solvents on a
Bruker DRXꢀ400 spectrometer with tetramethylsilane as internal
reference. The elemental analyses (C, H, N) were obtained from a
Carlo ERBA Model EA 1108 analyzer. The purity determination
20 of the substrates and reaction monitoring were accomplished by
TLC on silicaꢀgel polygram SILG/UV 254 plates (from Merck
Company).
NH2
Me
O
O
O
N
Solvent Free
Me
4a
1
N
O
Solvent Free
70 °C, 60 min
N
r.t. 10 min
NH2
N
3
5
N
NH2
2a
Me
Typical General procedure for synthesis of
aminophosphonates
α
O
P
NH
O
25 A mixture of ninhydrin 1 (1 mmol) and 1,2ꢀphenylenediamines 2
(1 mmol) was stirred by a magnet in a test tube under solvent free
conditions at room temperature for 10 min, followed by the
addition of aniline derivatives (1 mmol) temperature was slowly
increased until 70 °C. The reaction mixture was stirred for
30 appropriate time, after nearly complete conversion into an
intermediate presumed to be the corresponding internediate 5 (as
indicated by TLC), alkyl /aryl phosphite (1 mmol) was then
added to the reaction mixture which was heated at 70 °C. After
completion of the reaction (as assessed by TLC), the reaction
35 mixture was cooled to room temperature, and EtOH (5 mL) was
added to the crude products and stirred for a while. Then, the
mixture was filtered and the precipitate washed with EtOH to
afford the pure products. The spectroscopic and analytical data
for synthesized compounds are presented below.
O
N
N
7a
Scheme 2 Model reaction for the synthesis of αꢀaminophosphonates.
The structure of 7a was confirmed by fourier transform
infrared (FTꢀIR), HNMR, and 13 CNMR. The FTꢀIR spectra of
7a shows the presence of absorption band at 3293 cm region
corresponding to the stretching vibrations of the NH groups.
While the absorption bands at the 1381–1383 cm ꢀ1 region are due
80 to the symmetric stretching vibrations of the P=O group and
absorption bands within the 896–905 cm region are attributed
to the P–O–C groups. In the H NMR spectrum, the signal at δ=
75
1
ꢀ1
ꢀ1
1
1.88 ppm with three integral values indicate the presence of –CH3
protons of –CH3 group of aromatic ring. The dublet signal at δ=
85 6.94 ppm (J= 11.6 Hz) (D2O exchangeable) confirmed the
presence of –NH proton. The aromatic protons exhibited
multiplet in the region δ= 6.08–8.29 ppm with 22 integral values
40
Diphenyl 11ꢀ(pꢀtolylamino)ꢀ11Hꢀindeno[1,2ꢀb]quinoxalinꢀ11ꢀ
ylphosphonate (7a): Yellow powder (Yield: 90%). mp>300°C.
IR (KBr) (νmax/ cm–1): 3384, 1589, 1487, 1268, 1189, 930, 768.
1H NMR (DMSOꢀd6, 400 MHz): δppm: 1.85 (3H, s, CH3) 6.94
13
(supporting information). In the C NMR, the peak at δ= 20.28
ppm shows the presence of methyl carbon of aromatic ring. The
90 Carbon banded to the phosphorus resonated as doublet at δ=
67.85 ppm (J= 148 Hz). Also this spectra exhibit expected 26
peaks of substituted aromatic carbons at in the 116.34–153.78
ppm region. The results agree well with our expected product
(supporting information)
3
45 (1H, d, NH, j HP=11.6 Hz), 6.08ꢀ8.28 (22 H, m, ArH).13C NMR
1
(DMSOꢀd6, 100 MHz): δppm: 20.2, 67.9 (1C, d, CꢀP,
j CP=148
Hz), 116.3, 120.6, 120.9, 123.3, 126.1, 127.8, 129.5, 129.8,
130.1, 130.3, 130.5, 131.3, 132.5, 137.6, 141.2, 142.4, 142. 8,
143.0, 143.4, 150.2, 150.5, 153.8. Anal. Calcd for C35H28N3O3P:
2
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 3 of 6
RSC Advances
View Article Online
DOI: 10.1039/C5RA18311A
The multicomponent reaction proceeds through
cyclocondensation of ninhydrin (1) and oꢀphenylenediamine (2)
to give indenoquinoxlineꢀ11ꢀone (3), which further condensed
with aniline (4) to produce intermediate (9), then the dialkyl
phosphite is added on
intermediate (9) to furnish the αꢀaminophosphonate. A probable
mechanistic pathway has been proposed in scheme 3.
5
the C=N band of the
O
H2N
10
ꢀ H2O
ꢀ H2O
N
O
O
15
20
25
O
N
H2N
O
NH2
O
1
N
2
3
H2N
O
2
4
H
ꢀ
)
R
O
(
O
P
6
H
O
OR
N
NH
P
OR
N
N
N
N
5
30
7
Scheme 3 Probable mechanism for the synthesis of αꢀaminophosphonate.
35
Encouraged by this success, we extended the reaction of
ninhydrin and 1,2ꢀphenylenediammines, with a range of aromatic
and steric effect of electronꢀdonating substituents didn’t have
effect on time of the reaction and yields. While anilines bearing
amines, and dialkyl or diaryl phosphites under same conditions 50 electron withdrawing groups such as oꢀNO2, mꢀNO2, and pꢀNO2
40 for the synthesis of libraries of these compounds. The structure of
groups decreased the reactivity of anilines, and even after 24 h
the corresponding imines (5) were not formed and the reaction
was stopped at this stage.
prepared products is shown in scheme 4. All products were
obtained in high to excellent yields in short reaction times with
high purity. The influence of electronꢀwithdrawing and electronꢀ
donating substituents on the aromatic ring of aniline upon the
45 reaction yields and time of reaction was investigated. The results
showed that anilines with electronꢀdonating group on the
aromatic ring reacted successfully. Based on results, type, size,
55
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

RSC Advances
Page 4 of 6
Dynamic Article Links ►
View Article Online
DOI: 10.1039/C5RA18311A
RSC Advances
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
PAPER
Br
Me
Cl
Me
O
P
O
P
NH
NH
O
O
NH
O
O
P
O
NH
O
P
O
O
N
O
N
N
O
N
N
N
N
N
7a (90 %)
7b (89 %)
7c (93 %)
7d (84%)
Cl
MeO
Me
Me
O
P
O
NH
O
NH
O
P
O
O
P
P
NH
NH
O
O
O
O
N
N
O
O
N
N
N
N
7f (82 %)
Me
Me
Me
N
N
Me
O
Me
7e (86 %)
7g(89 %)
7h(85 %)
Cl
Me
Br
Me
Me
Me
P
Me
Et
Me
Me
Me
Me
Me
O
P
NH
O
P
O
O
O
NH
NH
NH
O
O
Me
Me
P
Et
O
O
O
O
N
N
N
N
Me
Me
N
Me
N
N
N
Me
7i (83 %)
7j (85 %)
7k (92 %)
7l (80 %)
Me
Br
Cl
Me
Me
Et
O
P
Et
NH
O
NH
Et
O
Et
O
P
O
O
NH
P
NH
O
Et
O
O
Et
P
O
N
Et
O
N
Et
O
N
N
N
Me
N
N
N
Me
7m (86 %)
7n (83 %)
7o (87 %)
7p (89%)
Br
MeO
Me
O
P
NH
O
Me
O
P
NH
Me
O
O
N
Me
O
N
N
Me
N
Me
7q (92%)
7r (92%)
5
Scheme 4 Structure of produced αꢀamino phosphonates and yields.
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 4

Page 5 of 6
RSC Advances
Dynamic Article Links ►
View Article Online
DOI: 10.1039/C5RA18311A
RSC Advances
Cite this: DOI: 10.1039/c0xx00000x
www.rsc.org/xxxxxx
PAPER
R. Cuberes, J. Frigola, S. GarcíaꢀGranda, Molecules, 2008, 13, 301ꢀ
318;(d) N. S. Zefirov, E. D. Matveeva, Arkivok, 2008, 1ꢀ17.
19. M. V. N. Reddy, S. D. Dindulkar, Y. T. Jeong, Tetrahedron Lett.
60 2011, 52, 4764ꢀ4767.
Conclusions
In the present research, an efficient and operationally simple
Kabachnik– Fields reaction for the synthesis of novel αꢀ
aminophosphonates under solventꢀfree and catalystꢀfree
conditions has been developed. Mild, nonꢀhazardous,
environment friendly reaction conditions and short reaction times
are significant advantages of this method. The work up is easy
and furnished the desired products in excellent yields.
20. Z. Rezaei, H. Firouzabadi, N. Iranpoor, A. Ghaderi, M. Reza Jafari, A.
A. Jafari, H. R. Zare, Eur. J. Med. Chem. 2009, 44, 4266ꢀ4275.
21. S. Bhagat, A. K. Chakraborti, J. Org. Chem.2007, 72, 1263ꢀ1270.
22. A. K. Bhattacharya, Y. Kaur, Synthtic lett. 2007, 5, 745ꢀ748.
65 23. T. Akiyama, Chem. Rev. 2007, 107, 5744ꢀ5758.
24. (a) S. M. Vahdat, R. Baharfar, M. Tajbakhsh, A. Heydari, S. M.
Baghbanian, S. Haksar, Tetrahedron Lett. 2008, 49, 6501ꢀ6504; (b) B.
Kaboudin, E. Jafari, J. Iran. Chem. Soc., 2008, 5, 97ꢀ102.
25. S. D. Mitragotri, D. M. Pore, U. V. Desai, P. P. Wadgaonkar, Catal.
70 Commun. 2008, 9, 1822ꢀ1826.
5
10 Acknowledgements
26. (a) D. Saberi, S. Cheragi, S. Mahdudi, J. Akbari, A. Heydari,
Tetrahedron Lett. 2013, 54, 6403–6406; (b) B. V. Subba Reddy, A. Siva
Krishna, A. V.Ganesh, G. G. K. S. Narayana Kumar, Tetrahedron Lett.
2011, 52, 1359ꢀ1362.
75 27. S. M. Agawane, J. M. Nagarkar, Tetrahedron Lett. 2011, 52, 3499ꢀ
3504.
We are thankful from University of Kashan for supporting this
work by grant number 159148/36, and also gratefully
acknowledge financial support from the Avicenna Research
Institute.
15
28. A. Heydari, H. Hamadi, M. Pourayoubi, Catal. Commun. 2007, 8,
1224–1226
29. R. Ghahremanzadeh, T. Amanpour, A. Bazgir, J. Heterocyclic Chem.
80 2009, 46, 1266ꢀ1270.
30. A. Bazgir, G. hosseini, R. Ghahremanzadeh, Acs Comb. Sci., 2013,
15, 530ꢀ534.
References
1. R. C. Cioc, E. Ruijter, R. V. A. Orru, Green Chem., 2014, 16, 2958ꢀ
2975.
2. N. Poomathi, S. Mayakrishnan, D. Muralidharan, R. Srinivasan, P. T.
20 Perumal, Green Chem., 2015,17, 3362ꢀ3372.
31. G. Imani Shakibaei, S. Samadi, R. Ghahremanzadeh, A. Bazgir, Acs
Comb. Sci. 2010, 12, 295ꢀ297.
3. S. Kumar, P. Sharma, K. K. Kapoor, M. S. Hundal, Tetrahedron, 2008,
64, 536ꢀ542.
4. P. M. Habib, V. Kavala, C. W. Kuo, M. J. Raihan, C. F. Yao,
Tetrahedron, 2010, 66, 7050ꢀ70565.
25 5. R. Ghahremanzadeh, G. Imani Shakibaei, S. Ahadi, A. Bazgir, J.
Comb. Chem.2010, 12, 191–194.
6. R. C. Cioc, E. Ruijter, R. V. A. Orru, Green Chem., 2014, 16, 2958ꢀ
2975.
7. G. Frapper, C. Bachmann, Y. Gu, R. C. De Sousa, F. Jérôme, Phys.
30 Chem. Chem. Phys., 2011, 13, 628ꢀ636; (b) J. P. Wan, Y. Liu, RSC Adv.,
2012, 2, 9763ꢀ9777.
8. E. T. Tigineh , Y. S. Wen , L. K. Liu, Tetrahedron, 2015, 71, 170ꢀ175.
9. M. Ghorbania, H. R. Shaterian, S. Noura, F. Khammar , K. Behbodi, B.
Reisi, M. Oftadeh, J. mol. liq., 2015, 204, 15–20.
35 10. F. H. Osman, F. A. ElꢀSamahy, Chem. Rev. 2002, 102, 629ꢀ677.
11. (a) L. Gu, C. Jin, Org. Biomol. Chem. 2012, 10, 7098ꢀ7102; (b) L. Jin,
B. Song, G. Zhang, R. Xu, S. Zhang, X.Gao, D. Hu, Y. Song, Bioorg.
Med. Chem. Lett. 2006, 16, 1537–1543;(c) P. Kafarski, B. Lejczak, Curr.
Med. Chem.: Anti-Cancer, 2001, 1, 301–312301
40 12. (a) N. Long, X. J. Cai, B. A. Song, S. Yang, Z. Chen, P. S. Bhaduri,
D.Y. Hu, L. H. Jin, W. J. Xue, Agric. Food. Chem. 2008, 56, 5242ꢀ
5246;(b) J. Zhou, B. A. Fan, L. H. Song, P. S. Jin, D. Y. Bhaduri, S. Hu,
H. T. Yang, Phosphorus Sulfur Silicon Relat. Elem. 2010, 186, 81–87.
13. S. D. Lombaert, L. Blanchard, J. Tan, Y. Sakane, C. Berry, R.D. Ghai,
45 Bioorg. Med. Chem. Lett. 1995, 5, 145ꢀ150.
14. B. Lejczak, P. Kafarski, H. Sztajer, P. Mastarlerz, J. Med. Chem.
1986, 29, 2212–2217.
15. H. V. Patel, K. V. Vyas, P. S. Fernandes, Indian J. Chem. 1990,
29(B), 836ꢀ842.
50 16. F. R. Atherton, C. H. Hassall, R. W. Lambert, J. Med. Chem. 1986,
29, 29ꢀ40.
17. R. D. Dillard, D. E. Pavey, D. N. Benslay, J. Med. Chem. 1973, 16,
251ꢀ253.
18. (a) P. S. Reddy, P. V. G. Reddy, S. M. Reddy, Tetrahedron Lett.
55 2014, 55, 3336ꢀ3339; (b) . K. Azizi, M. Karimi, A. Heydari, Tetrahedron
Lett., 2014, 55, 7236ꢀ7239; (c) E. Alcalde, N. Mesquida, C. AlvarezꢀRúa,
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 5

RSC Advances
Page 6 of 6
View Article Online
DOI: 10.1039/C5RA18311A
Graphical Abstract
O
R
1
NH
2
O
P
O
OR
2
NH
OR
2
O
R1
N
Solvent Free
2 Catalyst Free
HPO(OR2)
R
R
NH
2
R
N
NH
2
R
A simple and saf e one-pot four component synthesis of Kabachnik-Fields synthesis of
α
novel -amino phosphonates under solvent-free and catalyst-f ree conditions is reported