One-pot synthesis of macrocyclic chiral phosphoramidates

Article abstract of DOI:10.1081/SCC-100105897

Nine new macrocyclic chiral phosphoramidates containing (S)-α-methylbenzyl-amine, L-amino acid methyl ester and 2,5-diaryl-1,3,4-oxadiazole units were synthesized by a convenient one-pot procedure.

Full text of DOI:10.1081/SCC-100105897

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ONE-POT SYNTHESIS OF MACROCYCLIC CHIRAL
PHOSPHORAMIDATES
Da-Ming Du a & Wen-Ting Hua a
a College of Chemistry and Molecular Engineering, Peking University , Beijing, 100871, P.
R. China
Published online: 16 Aug 2006.
To cite this article: Da-Ming Du & Wen-Ting Hua (2001) ONE-POT SYNTHESIS OF MACROCYCLIC CHIRAL
PHOSPHORAMIDATES, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:20, 3197-3203, DOI: 10.1081/SCC-100105897
To link to this article: http://dx.doi.org/10.1081/SCC-100105897
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SYNTHETIC COMMUNICATIONS, 31(20), 3197–3203 (2001)
ONE-POT SYNTHESIS OF MACROCYCLIC
CHIRAL PHOSPHORAMIDATES
Da-Ming Du* and Wen-Ting Hua
College of Chemistry and Molecular Engineering,
Peking University, Beijing 100871, P. R. China
ABSTRACT
Nine new macrocyclic chiral phosphoramidates containing
(S)-a-methylbenzyl-amine, L-amino acid methyl ester and
2,5-diaryl-1,3,4-oxadiazole units were synthesized by a conve-
nient one-pot procedure.
INTRODUCTION
The design and synthesis of new functionalized chiral macrocycles for
selective recognition of other species is of great interest to chemists.1 Over
the past 30 years, much attention has focused on the studies of crown ether
and azacrown ether macrocycles due to their application in catalysis, separa-
tion of metal cations, molecular recognition and biological applications.2–5
Macrocycles containing phosphorus may also have special application
in biological systems and recognition for neutral molecules. Friedrichsen
reported the synthesis and complexation behavior of phosphine oxide
bifunctional macrocyles.6 Cram has investigated the binding properties of
*Corresponding author.
3197
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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3198DU AND HUA
macrocyclic ether containing phosphoryl and N-oxide groups with alkali
metal salts.7 In this paper, we report the convenient synthesis of a
new type of chiral macrocyclic phosphoramidate receptor 1–3 containing
(S)-a-methylbenzylamine, L-amino acid methyl ester and 2,5-diaryl-1,3,4-
oxadiazole units.
RESULTS AND DISCUSSION
Chiral macrocyclic phosphoramidate receptors 1–3 were prepared
from 2,5-di(o-hydroxyphenyl)-1,3,4-oxadiazole or 2,5-di(m-hydroxyphe-
nyl)-1,3,4-oxadiazole (Scheme 1 and 2). 2,5-di(o-hydroxyphenyl)-1,3,4-oxa-
diazole reacted with phosphorus oxychloride in dilute dichloromethane
solution at room temperature to form dichloride, which was treated in
situ with (S)-a-methylbenzylamine or L-amino acid methyl ester hydrochlor-
ide to afford the corresponding [2 þ 2] cyclocondensation macrocyclic chiral
phosphoramidates 1–2 in 8–15% yield.
Products 1 and 2 are stereoisomers. The less polar compounds 1a–1d
may be the trans-isomer, and the more polar compounds 2a–2d are cis-
isomer based on the X-ray single crystal diffraction analysis of compound
2b. The two L-alanine substituents are in cis conformation in cis-isomer 2b.8
In previous paper, we have identified relative stereochemistry of two iso-
meric macrocyclic phosphoramidates containing glycine ethyl ester and 2,5-
diaryl-1,3,4-oxadiazole by x-ray crystal structure, the less polar isomer has
the trans configuration and polar isomer has cis configuration.9 The relative
stereochemistry of the two isomeric macrocyclic bis(phosphine oxides)
was also established on the basis of their molecular dipole moments,
the less polar isomer has the trans stereochemistry.10 We found a more
convenient method to get 2,5-di(m-hydroxyphenyl)-1,3,4-oxadiazole by
Scheme 1.

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3199
Scheme 2.
demethylation of 2,5-di(m-methoxyphenyl)-1,3,4-oxadiazole with anhy-
drous aluminum chloride in toluene at 80ꢀC for 5 h and 83% yield was
obtained. 2,5-di(m-hydroxyphenyl)-1,3,4-oxadiazole reacted with phos-
phorus oxychloride and (S)-a-methylbenzylamine under the same condition
to afford the corresponding macrocyclic chiral phosphoramidates 3 in 3%
yield. It may be a cis isomer, since cis isomers are always easier to obtain
than trans isomers in this series of macrocycles. The low yield of compound
3 may be ascribed to the metha-position of hydroxyl which is not suitable for
[2 þ 2] cyclocondensation reaction but preferable for intermolecular poly-
merization. The low solubility of 2,5-di(m-hydroxyphenyl)-1,3,4-oxadizole
in dichloromethane may be another reason for the low yield of product.
No [2 þ 2] cyclocondensation products were obtained in the reaction of
2,5-di(m-hydroxyphenyl)-1,3,4-oxadiazole with L-amino acid methyl ester
hydrochloride or the yields of corresponding products are too low that
products cannot be obtained.
The structures of these new chiral macrocycles were confirmed by
1H NMR, 31P-NMR, MS, IR spectra and elemental analysis. The above
one-pot synthesis of chiral macrocyclic phosphoramidate receptors is very
convenient though it has low yield. Further modification of substituents
and the oxadiazole ring can afford different chiral receptors for different
purposes. Further studies along this line are currently in progress.
EXPERIMENTAL
Melting points were measured on an XT-4 melting point apparatus
1
and uncorrected. H NMR spectra were recorded on a Varian 200 MHz

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DU AND HUA
spectrometer, tetramethylsilane (TMS) serving as internal standard, and
31P NMR spectra were recorded using 85% H3PO4 as external standard.
Infrared spectra were obtained on a Bruker Vector 22 spectrometer. Mass
spectra were obtained on a VG-ZAB-HS mass spectrometer. Optical rota-
tions were measured on a Perkin-Elmer 241 MC spectrometer. Elemental
analyses were carried out on an Elementar Vario EL instrument. 2,5-di(o-
hydroxyphenyl)-1,3,4-oxadizole was synthesized according to literature
procedure.11
2,5-Di(m-hydroxyphenyl)-1,3,4-oxadizole: 2,5-di(m-methoxyphenyl)-
1,3,4-oxadizole12 (2.8 g, 10 mmol) and anhydrous aluminum chloride
(6.6 g, 50 mmol) in toluene (100 mL) was stirred at 80ꢀC for 5 hr. After
removal of solvent under reduced pressure, ice-water (50 mL) was added
to the residue cooled in an ice-bath. The precipitate was filtered and
washed with water. The crude solid product was dissolved in sodium hydro-
xide solution. The aqueous solution was extracted with ethyl acetate
(3 Â 50 mL). The aqueous solution was acidified with 6N HCl to pH ¼ 2,
the white precipitate was filtered, washed with water and dried to afford 2,5-
di(m-hydroxyphenyl)-1,3,4-oxadizole 2.1 g (83%), m.p. 275–277ꢀC.
1H NMR (DMSO): d 6.94–7.04 (m, 2H, ArH), 7.37–7.54 (m, 6H, ArH),
10.01 (s, 2H, OH). IR (KBr): n 3389, 3031, 2939, 1593, 1549, 1462, 1292,
1203, 888, 736 cmꢁ1, EIMS: m/z 254 (Mþ, 62), 197(30), 181 (18), 121 (100),
93 (38).
General procedure for synthesis of macrocyclic chiral phosphoramidates:
2,5-di(hydroxyphenyl)-1,3,4-oxadiazole (1.0 g, 3.9 mmol) was dissolved in
120 mL of dichloromethane, and phosphorus oxychloride (0.7g, 4.4 mmol)
was added under N2, followed by the slow addition with stirring of triethy-
lamine (0.8 g, 8.0 mmol). After 1 h of additional stirring, a solution of amino
compound (4.2 mmol) and triethylamine (0.5 g, 4.8 mmol) in dichloro-
methane (10 mL) was added dropwise with constant stirring into the
above crude acid chloride solution. After the addition, the mixture was
stirred at room temperature for 24 h. The reaction mixture was washed
with brine, dried with anhydrous magnesium sulfate. After removal of sol-
vent under reduced pressure, the crude product was purified by column
chromatography on silica gel (elution with ethyl acetate-chloroform 2:1
v/v), products 1–3 were obtained.
1a: Yield 8%. m.p. 200–202ꢀC. [a]D25 ¼ þ 36.0ꢀ (c ¼ 0.4, CHCl3).
1H NMR (CDCl3): d 1.35 (d, J ¼ 6.8 Hz, 6H, CH3), 4.71–4.85 (m, 2H,
CH), 5.16 (t, J ¼ 8.9 Hz, 2H, NH), 7.03–8.00 (m, 26H, ArH). 31P NMR
(CDCl3): d 0.63. IR (KBr): n 3449, 3193, 1607, 1589, 1542, 1493, 1244,
1216, 926 cmꢁ1. FABMS: m/z 839 (Mþ, 5), 718 (12), 614 (22). Anal. for
C44H36N6O8P2 ꢂ 0:5H2O, Calcd.: C, 62.34; H, 4.40; N, 9.91. Found: C,
62.15; H, 4.36; N, 9.76.

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3201
2a: Yield 12%. m.p. 264–266ꢀC. [a]D20 ¼ þ 52.5ꢀ (c ¼ 0.4, CHCl3).
1H NMR (CDCl3): d 1.34 (d, J ¼ 6.8 Hz, 6H, CH3), 4.63–4.75 (m, 2H,
CH), 5.54–5.63 (dd, J ¼ 7.1, 9.5 Hz, 2H, NH), 7.03–7.85 (m, 26H, ArH).
31P NMR (CDCl3): d 1.00. IR (KBr): n 3253, 3174, 1608, 1584, 1548,
1493, 1439, 1257, 1205, 928 cmꢁ1. EIMS: m/z 838 (Mþ), 718, 614. Anal.
for C44H36N6O8P2 ꢂ 1H2O, Calcd.: C, 61.68; H, 4.47; N, 9.81. Found: C,
61.85; H, 4.29; N, 9.94.
1b: Yield 9%. m.p. 248–250ꢀC. [a]D20 ¼ þ9.3ꢀ (c ¼ 0.4, CHCl3).
1H NMR (CHCl3): d 1.26 (d, J ¼ 7.2 Hz, 6H, CH3), 3.35 (s, 6H, OCH3),
4.28–4.45 (m, 2H, CH), 5.34 (t, J ¼ 8.2, 9.6 Hz, 2H, NH), 7.30–7.39 (m,
4H, ArH). 7.49–7.58 (m, 4H, ArH), 7.74–7.80 (m, 4H, ArH), 7.96–8.00
(m, 2H, ArH), 8.11–8.15 (m, 2H, ArH). 31P NMR (CDCl3): d ꢁ0.17. IR
(KBr): n 3412, 3215, 1741, 1611, 1494, 1210, 1147, 924 cmꢁ1. FABMS: m/z
803 (M þ 1), 700, 599. Anal. for C36H32N6O12P2, Calcd.: C, 53.87; H, 4.02;
N, 10.47. Found: C, 53.80; H, 4.04; N, 10.41.
2b: Yield 10%. m.p. 234–236ꢀC. [a]D20 ¼ ꢁ37.5ꢀ (c ¼ 0.4, CHCl3).
1H NMR (CHCl3): d 1.28 (d, J ¼ 7.2 Hz, 6H, CH3), 3.48 (s, 6H, OCH3),
4.24–4.38 (m, 2H, CH), 5.47(t, J ¼ 9.3 Hz, 2H, NH), 7.21–7.32 (m, 4H,
ArH). 7.43–7.56 (m, 4H, ArH), 7.67–7.90 (m, 8H, ArH). 31P NMR
(CDCl3): d 0.51. IR (KBr): n 3450, 3210.8, 1750, 1610, 1494, 1439, 1206,
1147, 920 cmꢁ1
.
FABMS: m/z 803 (M þ 1), 700, 599. Anal. for
C36H32N6O12P2, Calcd.: C, 53.87; H, 4.02; N, 10.47. Found: C, 53.80; H,
4.02; N, 10.38.
1c: Yield 8%. m.p. 244–246ꢀC. [a]D20 ¼ þ78.8ꢀ (c ¼ 0.4, CHCl3).
1H NMR (CHCL3): d 3.57(s, 6H, CH 3), 5.59 (t, J ¼ 9.6 Hz, 2H, CH),
5.94 (t, J ¼ 9.0 Hz, 2H, NH), 6.99–8.08 (m, 26H, ArH). 31P NMR
(CDCl3): d ꢁ0.67. IR (KBr): n 3417, 3250, 1746, 1611, 1494, 1211,
935 cmꢁ1. FABMS: m/z 927(M þ 1), 762, 599. Anal. for C46H36N6O12P2,
Calcd.: C, 59.62; H, 3.92; N, 9.07. Found: C, 59.60; H, 3.92; N, 8.93.
2c: Yield 11%. m.p. 238–240ꢀC. [a]D20 ¼ þ14ꢀ (c ¼ 0.4, CHCl3).
1H NMR (CHCL3): d 3.49 (s, 6H, CH3), 5.38 (t, J ¼ 9.8 Hz, 2H, CH),
6.32 (t, J ¼ 9.0 Hz, 2H, NH), 7.07–7.86 (m, 26H, ArH). 13C NMR
(CHCl3): d 52.47, 58.37, 58.45, 116.37, 116.49, 116.74, 116.87, 122.31,
122.36, 122.58, 122.63, 125.10, 125.27, 126.82, 127.75, 128.45, 129.46,
129.53, 132.59, 137.88, 137.95, 148.44, 148.48, 148.56, 148.60, 161.11,
161.16, 171.38, 171.58. 31P NMR (CDCl3): d 0.06, 0.19. IR (KBr): n 3433,
3174, 1747, 1611, 1494, 1254, 1209, 933 cmꢁ1. FABMS: m/z 927(M þ 1),
762, 599. Anal. for C46H36N6O12P2, Calcd.: C, 59.62; H, 3.92; N, 9.07.
Found: C, 59.37; H, 3.99; N, 8.95.
1d: Yield 10.5%. m.p. 160–162ꢀC. [a]D20 ¼ ꢁ52ꢀ (c ¼ 0.4, CHCl3).
1H NMR (CHCl3): d 2.97(d, J ¼ 6.4 Hz, 4H, CH2), 3.56 (s, 6H, CH3),
4.64 (m, 2H, CH), 5.09 (t, J ¼ 9.2 Hz, 2H, NH), 6.90–7.84 (m, 24H, ArH),

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DU AND HUA
8.23 (d, J ¼ 7.4 Hz, 2H, ArH). 31P NMR (CDCl3): d ꢁ0.40, ꢁ0.26. IR (KBr):
n 3469, 3219, 1746, 1611, 1494, 1210, 1118, 933 cmꢁ1. FABMS: m/z 955
(M þ 1), 766, 599. Anal. for C48H40N6O12P2, Calcd.: C, 60.38; H, 4.22; N,
8.80. Found: C, 60.33; H, 4.20; N, 8.70.
2d: Yield 14.7%. m.p. 180–181ꢀC. [a]D20 ¼ ꢁ2.8ꢀ (c ¼ 0.4, CHCl3).
1H NMR (CHCl3): d 2.97(d, J ¼ 5.8 Hz, 4H, CH2), 3.45 (s, 6H, CH3),
4.60 (s, br, 2H, CH), 5.37 (s, br, 2H, NH), 6.97–7.89 (m, 26H, ArH). 31P
NMR (CDCl3): d 0.37. IR (KBr): n 3433, 3243, 1753, 1733, 1610, 1494,
1254, 1215, 1138, 913 cmꢁ1. FABMS: m/z 955 (M þ 1), 766, 599. Anal. for
C48H40N6O12P2, Calcd.: C, 60.38; H, 4.22; N, 8.80. Found: C, 60.29; H,
4.18; N, 8.75.
3: Yield 3%. m.p. 280–282ꢀC. [a]D20 ¼ ꢁ22.5ꢀ (c ¼ 0.2, 1:1 CHCl3-
1
MeOH). H NMR (DMSO): d 1.22 (d, J ¼ 6.6 Hz, 6H, CH3), 4.62 (m, 2H,
CH), 6.67–8.06 (m, 26H, ArH). 31P NMR (CDCl3): d 1.50. IR (KBr): n
3417, 3200, 1591, 1555, 1490, 1251, 1198, 937 cmꢁ1. FABMS: m/z 839
(M þ 1), 631. Anal. for C44H36N6O8P2, Calcd.: C, 63.01; H, 4.33; N,
10.02. Found: C, 62.85; H, 4.44; N, 9.91.
ACKNOWLEDGMENT
We are gratefully thank the financial support by the National Natural
Science Foundation of China (Grant No. 29872023) and China
Postdoctoral Science Foundation (1999).
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Received in the UK September 12, 2000

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