A facile synthesis of ω-aminoalkyl ammonium hydrogen phosphates

Article abstract of DOI:10.1016/j.cclet.2012.06.010

A series of ω-aminoalkyl ammonium hydrogen phosphates were synthesized through a simple and efficient three-step method. The starting materials, ω-aminoalkyl alcohols (AC-n, with carbon number n = 3, 4, 5, 6), were amino-protected with 9-fluorenylmethyl chloroformate (Fmoc-Cl), followed by phosphorylation with POCl₃ and deprotection in piperidine/DMF. The structures of each intermediate and final product were confirmed by ¹H NMR, FTIR and mass spectrum. The yield of each step was about 77-92%, with a total yield higher than 56%. This new method was superior in low-cost raw materials, mild reaction temperatures (0-25°C) and easy purification methods.

Full text of DOI:10.1016/j.cclet.2012.06.010

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 923–926
www.elsevier.com/locate/cclet
A facile synthesis of v-aminoalkyl ammonium hydrogen phosphates
*
Wei Bo Kong, Xiao Yong Zhou, Yang Yang, Xing Yi Xie
Department of Polymeric Biomaterials and Artificial Organs, College of Polymer Science and Engineering,
Sichuan University, Chengdu 610065, China
Received 20 April 2012
Available online 4 July 2012
Abstract
A series of v-aminoalkyl ammonium hydrogen phosphates were synthesized through a simple and efficient three-step method.
The starting materials, v-aminoalkyl alcohols (AC-n, with carbon number n = 3, 4, 5, 6), were amino-protected with 9-
fluorenylmethyl chloroformate (Fmoc-Cl), followed by phosphorylation with POCl3 and deprotection in piperidine/DMF. The
structures of each intermediate and final product were confirmed by 1H NMR, FTIR and mass spectrum. The yield of each step was
about 77–92%, with a total yield higher than 56%. This new method was superior in low-cost raw materials, mild reaction
temperatures (0–25 8C) and easy purification methods.
# 2012 Xing Yi Xie. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Amino alcohol; Phosphorus oxychloride; Synthesis; Aminoalkyl ammonium hydrogen phosphate
1. Introduction
v-Aminoalkyl dihydrogen phosphates and their salts are safe and active cosmetic ingredients, promoting fibroblast
proliferation and collagen biosynthesis [1]. Their phosphate groups possess unique bonding ability to metals [2] and
ceramics [3], thereby functionalizing their surfaces with the amino groups for further modifications with bioactive
molecules. Due to their hetero-functionality, they often serve as linkers for various bioconjugates [4,5]. In addition,
they can be used as flame retardants for fibers [6] and fuel concentrates for autos [7].
Synthesis of v-aminoalkyl dihydrogen phosphates usually involves selective phosphorylation to the hydroxyl
group from corresponding a, v-amino alcohol, rather than the amino group. Strong phosphorylation agents like
phosphorus oxychloride (POCl3) are generally not suitable due to reaction with the amino group [8]. Only 3-
aminopropane phosphoric acid has been synthesized through that way where cyclophosphamide was formed initially,
followed by acid-catalyzed breakdown the P–N bond in its six-membered ring [1]. Some milder agents such as
orthophosphoric acid, pyrophosphoric acid, and polyphosphoric acid might be good choices in terms of selective
phosphorylation [9,10]. However, a high reaction temperature (140–250 8C) and a long reaction time (18–40 h) in
vacuum were utilized in these methods, hindering their industrialization due to high energy cost and low yield (<50%,
sometimes ꢀ20%). Another more effective agent, i.e., 2-(N,N-dimethylamino)-4-nitrophenyl phosphate, has been
developed to synthesize 2-aminoethyl dihydrogen phosphate in a mild condition (about 115 8C for 3 h) [8]. But the
* Corresponding author.
E-mail addresses: xiexingyi@263.net, xiexingyi@scu.edu.cn (X.Y. Xie).
1001-8417/$ – see front matter # 2012 Xing Yi Xie. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.010

[(Scheme_1)TD$FIG]
924
W.B. Kong et al. / Chinese Chemical Letters 23 (2012) 923–926
Scheme 1. Synthesis route of v-aminoalkyl ammonium hydrogen phosphates.
synthesis of the phosphorylation agent itself was very complicated, involving a purification process through ionic
exchange columns.
In this study, we explored a general procedure to synthesis v-aminoalkyl ammonium hydrogen phosphates, using
low-cost POCl3 as a phosphorylation agent, as shown in Scheme 1. Firstly, each a, v-amino alcohol (AC-n, with
carbon number n = 3, 4, 5, 6 hereafter) was reacted with 9-fluorenylmethyl chloroformate (Fmoc-Cl) to protect the
amino group. The resulting product (Fmoc-AC-n) was recrystallized from an ethyl acetate/petroleum ether mixture.
Secondly, each Fmoc-AC-n was phosphorylated with overdosed POCl3 to form a dichloride phosphate which was
further hydrolyzed in ice water, forming an amino-protected intermediate (Fmoc-AC-P-n). It was insoluble in water
due to the bulky hydrophobic Fmoc group, and was separated by simple filtration. Finally, the protecting Fmoc group
was removed in piperidine/DMF mixture, forming a precipitate (i.e., piperidine salt of aminoalkyl dihydrogen
phosphate) which was filtered and washed with ethyl acetate. The purified precipitate was dissolved in aqueous
ammonia to remove piperidine by chloroform extraction. The aqueous phase was concentrated and dried to form a
white salt of v-aminoalkyl ammonium hydrogen phosphate (AC-P-n). All the three synthesis steps were carried out at
0–5 8C or room temperature, using traditional organic reactions and simple purification methods. The yield of each
step ranged from 77% to 92%, with the total yield in 56–67% (Table 1).
The chemical structures of each intermediate and final product are confirmed by 1H NMR and FTIR. The H signals
at d 7.33, 7.41, 7.70, 7.89 (hydrogen A–D) and at d 4.2, 4.4 (hydrogen E and F) are characteristic for Fmoc group
(Fig. 1A), showing the success of amino protection in Fmoc-AC-n. Accordingly, their FTIR spectra displayed four
Table 1
The yield and mass spectrum results of each intermediate and final product.
Compound
Characterization
n = 3
n = 4
n = 5
n = 6
Fmoc-AC-n
Yield (%)
83
83
84
82
ESI MS
Calcd. M (Da)
Found [M+Na]+ (m/z)
297.14
311.15
325.17
339.18
320.10
334.09
348.11
362.11
Fmoc-AC-P-n
AC-P-n
Yield (%)
85
77
88
85
ESI MS
Calcd. M (Da)
Found [MÀH]À (m/z)
Yield (%)
377.10
391.12
405.13
419.15
À376.01
92
À390.04
88
À404.01
91
À418.06
92
ESI MS
Calcd. M (Da)
Found [MÀH]À (m/z)
155.03
169.05
183.07
197.08
À154.04
65
À168.03
56
À182.06
67
À196.02
64
Total yield (%)

[(Fig._1)TD$FIG]
W.B. Kong et al. / Chinese Chemical Letters 23 (2012) 923–926
925
Fig. 1. 1H NMR (A) and FTIR (B) spectra of each intermediate and final product.
absorptions (indicated by * in Fig. 1B) resulted from Fmoc protection, i.e., aromatic C–H stretching at 3066 cmÀ1
,
amide C O stretching at 1960 cmÀ1, C–N stretching at 1543 cmÀ1 and aromatic C–H bending at 737 cmÀ1. After
phosphorylation, the Fmoc hydrogen signals were retained, while a new broad peak appeared in d 4.5–5.5, indicated
the presence of P-OH in each Fmoc-AC-P-n (Fig. 1A). The FTIR spectra displayed prominent P O vibrations at
1020 cmÀ1 (Fig. 1B), further proving the formation of phosphoric acid groups. For the final products AC-P-n, the H
+
signals of Fmoc groups disappeared (Fig. 1A). Their FTIR spectra demonstrated a broad ammonium (NH4 ) N–H
stretching (2200–3600 cmÀ1) and a phosphate P O stretching at 1078 cmÀ1. The mass spectra data also confirmed the
structures of each intermediate and final product (Table 1).
In conclusion, we have successfully synthesized a series of v-aminoalkyl ammonium hydrogen phosphates using
amino-protection method in mild conditions, with total yields over 56%. If necessary, these products can easily be
acidized to obtain the corresponding phosphoric acids. This simple and effective method might promote the scientific
research about the properties and applications of v-aminoalkyl dihydrogen phosphates and their salts.
2. Experimental
All the chemicals were of analytical grades and used as received. The 1H NMR (400 MHz) and FTIR spectra were
reported in Fig. 1. The yields and mass spectrum (ESI mode) data are shown in Table 1.
Synthesis of Fmoc-AC-n: Each a, v-amino alcohol (0.025 mol) was dissolved in 25 mL THF and cooled to 0–5 8C
in an ice bath. Fmoc-Cl (2.587 g, 0.01 mol) in 20 mL THF was added dropwise in 2–2.5 h, under N2 atmosphere and
magnetic stirring. Following another 7-h stirring at room temperature, the pH was adjusted to 4, using 10% HCl. The
reaction mixture was extracted with 40 mL Â 3 saturated NaCl solution to remove the byproduct, a, v-amino alcohol
hydrochloride. The organic phase was dried by anhydrous NaSO4. The solvent was evaporated at 35 8C under reduced
pressure. The residue was recrystallized from an ethyl acetate/petroleum ether (7:1, v/v) mixture, and vacuum-dried at
35 8C for 10 h to obtain the product.
Synthesis of Fmoc-AC-P-n: Each Fmoc-AC-n (0.01 mol) was dissolved in 20 mL THF, and dropped into 15 mL
POCl3 (0.16 mol) in ꢀ1.5 h under reduced pressure. The reaction temperature was kept at ꢀ0 8C using an ice bath. The
reaction mixture was stirred for another 7 h. Thereafter it was poured into 400 mL ice water to hydrolyze the dichloride

926
W.B. Kong et al. / Chinese Chemical Letters 23 (2012) 923–926
phosphate intermediate for 3 h. The resulting precipitate was filtered, water-washed 3 times, freeze-dried for 9 h, and
finally air-dried at 35 8C for 2 h. Thus the designed product was obtained.
Synthesis of AC-P-n: Each Fmoc-AC-P-n (0.005 mol) was dissolved in 5 mL DMF, added to 20 mL piperidine/
DMF (1:4, v/v) [11], and the mixture was stirred for 30 min at 0–5 8C. The resulting white precipitate (i.e., piperidine
salt of v-aminoalkyl dihydrogen phosphates) was filtered, and washed with ethyl acetate. Thereafter it was dissolved
in 25 mL ammonia solution (25 wt.%) to remove piperidine by extraction with 25 mL Â 4 chloroform. The aqueous
phase was freeze-dried for 12 h, and then vacuum-dried at 35 8C for 10 h, to obtain the target product as a white
powder. 13C NMR (100 MHz, D2O): n = 3, d 63.94 (d, J = 4.2 Hz), 39.56, 29.78 (d, J = 6.4 Hz); n = 4, d 65.78
(d, J = 5.2 Hz), 41.35, 29.20 (d, J = 6.8 Hz), 25.83; n = 5, d 66.34 (d, J = 4.8 Hz), 41.55, 31.66 (d, J = 6.4 Hz), 28.61,
24.30; n = 6, d 66.70 (d, J = 4.7 Hz), 41.43, 31.92 (d, J = 6.7 Hz), 28.77, 27.36, 26.61. 31P NMR (162 MHz, 0.5 mL
D2O + 2 mL H3PO4): n = 3, d À0.07; n = 4, d À0.05; n = 5, d À0.28; n = 6, d À0.12. C/N molar ratio (elemental
analysis), found (calcd.): n = 3, 1.62 (1.5); n = 4, 2.29 (2.0); n = 5, 2.43 (2.5); n = 6, 2.73 (3.0).
Acknowledgments
This work was sponsored by the National Science Foundation of China (No. 50973069) and the Scientific Research
Foundation for the Returned Overseas Chinese Scholars, State Education Ministry (No. 20101561-3-3).
References
[1] O.S. Lee, Y.H. Byon, B.S. Lee, US Patent 5,723,645 (1998).
[2] S. Gengrinovitch, PCT Int. Appl. WO 2006056984 A2 (2006).
[3] A. Bouladjine, A. Al-Kattan, P. Dufour, Langmuir 25 (2009) 12256.
[4] R. Barker, K.W. Olsen, J.H. Sharper, J. Biol. Chem. 247 (1972) 7135.
[5] L. Halby, V.A. Ryabinin, A.N. Sinyakovb, Bioorg. Med. Chem. Lett. 15 (2005) 3720.
[6] A. Mizuguchi, K. Sato, A. Sakurai, JP 47002517 B4 (1972).
[7] E.R. Morrison, US Patent 3,402,030 A (1968).
[8] Y. Taguchi, Y. Mushika, J. Org. Chem. 40 (1975) 2310.
[9] E. Cherbuliez, J. Rabinowitz, Helv. Chim. Acta 41 (1958) 1168.
[10] L.D. Li, W. Tang, W.J. Liu, Chin. J. Org. Chem. 28 (2008) 489.
[11] C.M. Zhang, J.X. Guo, L. Wang, et al. Chin. Chem. Lett. 22 (2011) 631.