An efficient synthesis of N,N-bis[2-(2-nitrophenylamino)ethyl]glycine glycosyl esters and antiviral activity

Article abstract of DOI:10.3184/030823408X338675

N,N-bis[2-(2-nitrophenylamino)ethyl]glycine glycosyl esters were synthesised in good yields at room temperature using DMAP/Et₃N. All of the new synthesised compounds were of β-configuration. The compounds show good antiviral activity against to

Full text of DOI:10.3184/030823408X338675

486 RESEARCH PAPER
AUGUST, 486–488
JOURNAL OF CHEMICAL RESEARCH 2008
An efficient synthesis of N,N-bis[2-(2-nitrophenylamino)ethyl]glycine
glycosyl esters and antiviral activity
Hong Chen, Si-Qing Huang* and Jian-Ying Xie
Department of Applied Chemistry, Guangdong Ocean University, Zhanjiang 524088, P.R. China
N,N-bis[2-(2-nitrophenylamino)ethyl]glycine glycosyl esters were synthesised in good yields at room temperature
using DMAP/Et3N. All of the new synthesised compounds were of E-configuration. The compounds show good
antiviral activity against tobacco mosaic virus(TMV).
Keywords: N,N-bis[2-(2-nitrophenylamino)ethyl]glycine, glycosyl esters, DMAP/Et3N
Saccharide ester compounds possess broad biological
activities.1 A number of authors have reported the bioactivity
of saccharide esters, and of the aryloxy carboxylic acids. They
are applied widely in agricultural and medicinal chemistry, as
well as plant virus inhibitors.
of the synthesised compounds are up to 65.3%. The anti-TMV
data given in Table 2 indicate that O-acetylglycosyls affect
anti-TMV activity of the compounds, the inhibition rate of
lactopyranosyl derivatives is higher than glucopyranosyl and
galactopyranosyl analogues. The inhibiting percentage against
TMV was expressed by calculating the withered spot number
in the tobacco leaf, with a dosage of 0.001% and NS-837
(its inhibiting percentage reaches 80%) as control.
DMAP (4-dimethylaminopyridine) has been applied
widely in organic synthesis.2,3ꢀ '0$3ꢀ FDQꢀ HI¿FLHQWO\ꢀ
FDWDO\VHꢀ HVWHUL¿FDWLRQꢀ UHDFWLRQVꢁꢀ EXWꢀ LWꢀ KDVꢀ EHHQꢀ UDUHO\ꢀ
reported as a catalyst for the synthesis of N,N-bis[2-
(2-nitrophenylamino)ethyl] glycine glycosyl esters by using
Į-O-acetylglycosyl bromide as the active group and N,N-bis
[2-(2-nitrophenylamino)ethyl]glycine as lead compounds.
,Qꢀ RUGHUꢀ WRꢀ ¿QGꢀ QHZꢀ SODQWꢀ YLUXFLGHVꢁꢀ ZHꢀ GHVLJQHGꢀ DQGꢀ
synthesised a series of O-acetylglycosyl saccharide esters,4,5
some of which displayed improved anti-TMV activity.
Tobacco mosaic virus (TMV) is a phytovirus, that can harm
plants. Considering the wide application of saccharide
ester compounds and their potential to serve as antiviral
agents, and in conjunction with our recent work on the
search for new phytoantiviral agents,4,5,6 we decided to
develop a simpler method for the synthesis substituted
saccharide ester compounds and designed novel N,N-
bis[2-(2-nitrophenylamino)ethyl] glycine glycosyl esters.
We selected DMAP as catalyst, Et3N (triethylamine) was
XVHGꢀ DVꢀ GHDFLGL¿FDWLRQꢀ UHDJHQWꢁꢀ IRXUꢀ QHZꢀ VDFFKDULGHꢀ HVWHUVꢀ
were synthesised in the system of DMAP/Et3N. Experimental
UHVXOWVꢀVKRZꢀWKDWꢀ'0$3ꢀLVꢀDQꢀHI¿FLHQWꢀFDWDO\VWꢀZLWKꢀ\LHOGVꢀRIꢀ
over 60%. The biological test results indicate that the antiviral
activities of the synthesised compounds against tobacco
mosaic virus (TMV) are up to 65.3%. The synthetic route is
as follows (Scheme 1).
7KHꢀ SURGXFWVꢀ ZHUHꢀ FRQ¿UPHGꢀ E\ꢀ ,5ꢁꢀ 1H NMR, MS and
elemental analysis. The compounds 1–4 are of ȕꢂFRQ¿JXUDWLRQꢀ
in the system of DMAP/Et3N. Their structure is same as
compared with a phase transfer catalytic method. In the IR
spectra of compounds 1–4, two strong and wide bi-shoulder
peaks of pyranose ring, appear at 1000–1100 cm-1 and 1200–
1300 cm-1, and the absorbance at 1720 cm-1 or so is attributed
to the carbonyl group. In the 1H NMR spectra, the assignments
of the hydrogen atoms in peaks are very obvious, the coupling
constant J1–2 between C1–H1 and C2–H2 is 7.20–7.92 Hz.
Generally, the structures of saccharide esters can be determined
according to chemical shift of C1–H1 NMR of pyranose and
coupling constant of H1–H2. Because the coupling constant
between C1–H1 and C2–H2 of ȕꢂFRQ¿JXUDWLRQꢀRIꢀVDFFKDULGHꢀ
ester is 7–10 Hz,8 therefore, the synthesised compounds 1–4
have ȕꢂFRQ¿JXUDWLRQꢀꢃ7DEOHꢀꢄꢅꢆ
$VꢀIDUꢀDVꢀZHꢀNQRZꢁꢀWKLVꢀZDVꢀWKHꢀ¿UVWꢀH[DPSOHꢀRIꢀN,N-bis[2-
(2-nitrophenylamino)ethyl] glycine glycosyl esters using
DMAP/Et3N method. The mechanism of the reaction is shown
in Scheme 2.
The molecular ions (M + H)+ peak were obtained by FAB
(fast atom bombardment) of the saccharide ester, whereas
by the EI (electron impact) method, no molecular ion
peaks were obtained except for a 331 (m/z) fragment peak,
We found that the reaction with DMAP/Et3N proceeded
quickly and smoothly at room temperature under mild
conditions and with a substantially increased yield and
decrease in the reaction time compared with the phase transfer
catalytic method (Table 2).
The preliminary biological tests showed that antiviral
activities of the products are moderate, the antiviral activities
which corresponding to
a O-tetra-acetylglucopyranosyl
fragment, or O-tetra-acetylgalactopyranosyl fragment,
and a 259 (m/z) fragment peak, which corresponding to a
O-acetylxylopyranosyl fragment and a 619 (m/z) fragment
peak, which corresponding to the O-octa-acetyllactosyl
fragment and some fragment peaks (242, 271, 229, 169, 109
NHCH2CH2
NO2
NCH2COOGL
NHCH2CH2 NCH2COOH
GL-Br
DMAP/Et3N
NO2
2
2
OAc
O
CH2OAc
O
OAc
OAc
OAc
O
O
AcO
O
OAc
OAc
GL
=
OAc
OAc
OAc
O
AcO
AcO
CH2OAc
OAc
OAc
OAc
OAc
Scheme 1
* Correspondent. E-mail: huangsq2005@sina.com;
huangsq2005@163.com

JOURNAL OF CHEMICAL RESEARCH 2008 487
Table 1 Structure of the compounds 1–4
Compound
GL–Br
Product
O
C
6
5
OAc
OAc
OAc
CH2N CH2CH2NH
O2N
O
O
O
4
1
OAc
1
OAc
Br
Br
AcO
AcO
2
AcO
2
OAc
3
OAc
O
C
6
5
OAc
AcO
O
CH2N
CH2CH2NH
O2N
O
O
2
4
OAc
1
OAc
2
2
3
OAc
OAc
6
OAc
2'
CH2OAc
CH2OAc
O
C
OAc
3'
5
O
O
O
1
CH2N CH2CH2NH
O2N
OAc
OAc
4'
OAc
OAc
1'
4
3
4
OAc
3
Br
O
O
O
O
2
OAc
5'
2
OAc
CH2OAc
CH2OAc
6'
OAc
O
C
O
5
CH2N
O
CH2CH2NH
O2N
O
2
OAc
4
1
OAc
Br
AcO
2
AcO
3
OAc
OAc
Table 2 Reaction time, yield and antiviral activity of the compounds 1–4
Compound
Reaction time/h
Yielda/%
Yieldb/%
Activity/%
Method a
Method b
1
2
3
4
2.0
2.0
1.5
1.5
5.5
5.5
4.5
4.5
86
84
73
61
82
80
54
43
57.8
58.2
65.3
53.5
Method a: DMAP/Et3N, reaction temperature 20–25°C. Method b: the phase transfer catalyst (Bu4NBr), reaction temperature
50–60°C. Yielda obtained using Method a. Yieldb obtained using Method b. Activity(%) is antiviral activity against tobacco
mosaic virus.
Varian Mercury-VX300 (300 MHz) NMR instrument, using TMS, as
internal standard. FAB mass spectra of the complexes were recorded
using a JEOL SX-120 instrument.
m/z) of pyranose ring were obtained. Moreover, some fragment
peak (184, 142, 77 m/z) of N,N-bis[2-(2-nitrophenylamino)
ethyl]glycine was obtained by both FAB and EI methods.
General procedure for the preparation of N,N-bis[2-(2-nitrophenyl-
amino)ethyl]glycine glycosyl esters (compounds 1–4)
Experimental
IR spectra were obtained using a Shimadzu IR-435 IR spectrometer.
The elemental analyses were recorded on an Immunomedia MT-3
elemental analyser. 1H NMR spectra were recorded in acetone-d6 on a
1.25 mmol N,N-bis[2-(2-nitrophenylamino)ethyl]glycine, 1.25 mmol
Į-O-acetylglycosyl bromide, 0.10 mmol DMAP, 40 ml DMF were
DGGHGꢀLQWRꢀDꢀIRXUꢂQHFNHGꢁꢀURXQGꢂERWWRPHGꢀÀDVNꢆꢀ7KHꢀWHPSHUDWXUHꢀZDVꢀ
CH2OAc
OAc
CH2OAc
OAc
Br-
+
O
CH3
CH3
CH3
CH3
O
OAc
OAc
+
N
N
Br
N
N
OAc
OAc
O
O
OAc
O
O
OAc
OAc
CH2OAc
CH2OAc
OAc
OAc
CH2OAc
OAc
O
Br-
O
CH3
CH3
O
O
+
RCO-H/Et3N
HN
OCR +
N
OAc
O
OAc
OAc
CH2OAc
CH3
CH3
Et3N,-HBr
N
N
NHCH2CH2
NO2
NCH2
R =
2
Scheme 2

488 JOURNAL OF CHEMICAL RESEARCH 2008
kept constant at 0°C, 0.25 ml triethylamine was slowly dropped into
reaction system under stirring, and the reaction kept at 20–25°C for
ꢄꢆꢇ±ꢈꢆꢉꢀKꢆꢀ$VꢀVRRQꢀDVꢀWKHꢀUHDFWLRQꢀ¿QLVKHGꢁꢀWKHꢀVROXWLRQꢀZDVꢀ¿OWUDWHGꢆꢀ
After separation, organic phase was washed to neutrality with water
and dried with anhydrous magnesium sulfate. The dense liquid was
obtained by the vapourisation of solvent under condition of vacuum
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ethyl acetate and separated through silica gel chromatography using
ethyl acetate as eluant, N,N-bis[2-(2-nitrophenylamino)ethyl]glycine
glycosyl esters were obtained by the evaporation of the solvent.
1: Light yellow dense liquid, 1+ꢀ105ꢀGDWDꢁꢀįH 7.98 (2 u t, 2H,
ArH), 7.44 (m, 2H, ArH), 6.95 (d, 2H, ArH), 6.60 (m, 2H, ArH), 5.92–
5.98 (d, Jꢀ ꢀꢊꢆꢋꢈꢀ+]ꢀꢄ+ꢅꢀꢃ&1-H1 of pyranose ring), 4.75–5.40 (m, 3H,
3.15 (m, 2H, N–H); 2.10 (m, 4H, N–CH2–C) 2.05 (m, 21H, CH3& 2ꢅꢀ
0.98 (t, 4H, –CH21ꢅꢍꢀȞꢎFP-1: 3400 (N–H), 2950 (CH2), 1745, 1670
ꢃ& 2ꢅꢁꢀ ꢄꢑꢄꢉꢁꢀ ꢄꢇꢄꢉꢀ ꢃ&6H6), 1570 (–NO2), 1030–1080, 1210–1250
(bi-shoulder peaks of pyranose ring); Found: C, 52.03; H, 5.60; N,
6.59; Required for C44H55N5O23: C, 51.71; H, 5.39; N, 6.86%; FAB-
MS (m/z,%), 1022 ([M + H]+, 3.5).
4: Yellow dense liquid, 1H NMR data, 7.98 (2 u t, 2H, ArH), 7.44
(m, 2H, ArH), 6.95 (d, 2H, ArH), 6.60 (m, 2H, ArH), 5.90–5.92 (d,
Jꢀ ꢀꢊꢆꢈꢉꢀ+]ꢀꢄ+ꢅꢀꢃ&1–H1 of pyranose ring), 3.51–3.21 (m, 5H, C2-
5–H2-5 of pyranose ring), 3.64 (s, 2H, –N–CH2& 2ꢅꢁꢀꢄꢆꢏꢉꢀꢃPꢁꢀꢏ+ꢁꢀ
N–CH2–C), 3.12 (m, 2H, –NH–), 2.05 (m, 9H, CH3& 2ꢅꢀꢉꢆꢋꢇꢀꢃWꢁꢀꢏ+ꢁꢀ
C–CH21±ꢅꢍꢀ ȞꢎFP-1: 3350 (N–H), 2900 (CH2ꢅꢁꢀ ꢄꢊꢑꢉꢁꢀ ꢄꢊꢈꢉꢀ ꢃ& 2ꢅꢁꢀ
1620, 1510 (C6H6), 1570 (–NO2), 1010–1070, 1200–1300 (bi-
shoulder peaks of pyranose ring); Found: C, 52.23; H, 5.12; N, 10.21;
Required for C29H35N5O13: C, 52.65; H, 5.30; N, 10.59%; FAB-MS
(m/z,%), 662 ([M + H]+, 4.3).
C
2-4–H2-4 of pyranose ring), 3.45 (m, 1H, C5–H5 of pyranose ring),
4.18 (m, 2H, C6–H6 of pyranose ring), 3.55 (s, 2H, –NCH2& 2ꢅꢁꢀꢌꢆꢄꢇꢀ
(m, 2H, N–H); 2.10 (m, 4H, N–CH2–C) 2.05 (m, 12H, CH3& 2ꢅꢀꢄꢆꢉꢇꢀ
(t, 4H, –CH21ꢅꢍꢀȞꢎFP-1: 3350 (N–H), 2925 (CH2ꢅꢁꢀꢄꢊꢏꢉꢁꢀꢄꢊꢉꢉꢃ& 2ꢅꢁꢀ
1610, 1510 (C6H6), 1570 (–NO2), 1020–1090, 1210–1290 (bi-
shoulder peaks of pyranose ring); Found: C, 52.19; H, 5.09; N, 9.73;
Required for C32H39N5O15: C, 52.39; H, 5.32; N, 9.54%; FAB-MS
(m/z,%),734 ([M + H]+, 5.6).
We thank the National Natural Science Foundation of China
and the Department of Education of Guangdong Province
1DWXUDOꢀ 6FLHQFHꢀ )RXQGDWLRQꢀ RIꢀ &KLQDꢀ IRUꢀ ¿QDQFLDOꢀ VXSSRUWꢆꢀ
Helpful discussion with Professor Xiaoling Huang is also
acknowledged.
2: Light yellow dense liquid, 1+ꢀ105ꢀGDWDꢁꢀįH 7.98 (2 u t, 2H,
ArH), 7.44 (m, 2H, ArH), 6.95 (d, 2H, ArH), 6.60 (m, 2H, ArH), 5.89–
5.93 (d, Jꢀ ꢀꢊꢆꢐꢊꢀ+]ꢀꢄ+ꢅꢀꢃ&1–H1 of pyranose ring), 5.20–5.48 (m, 3H,
C2-4–H2-4 of pyranose ring), 3.95 (m, 1H, C5–H5 of pyranose ring),
4.10 (m, 2H, C6–H6 of pyranose ring), 3.42 (s, 2H, –N–CH2& 2ꢅꢁꢀ
3.72 (m, 2H, N–H); 2.10 (m, 4H, N–CH2–C) 1.95 (m, 12H, CH3& 2ꢅꢀ
1.15 (t, 4H, –CH21ꢅꢍꢀȞꢎFP-1: 3350 (N–H), 2950 (CH2), 1740, 1710
ꢃ& 2ꢅꢁꢀ ꢄꢑꢄꢇꢁꢀ ꢄꢇꢄꢉꢀ ꢃ&6H6), 1570 (–NO2), 1020–1080, 1210–1280
(bi-shoulder peaks of pyranose ring); Found: C, 52.50; H, 5.06; N,
9.08; Required for C32H39N5O15: C, 52.39; H, 5.32; N, 9.54%; FAB-
MS (m/z,%),734 ([M + H]+, 6.2).
Received 1 June 2008; accepted 23 June 2008
Paper 08/5303 doi: 10.3184/030823408X338675
Published online: 21 August 2008
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3: Light yellow dense liquid; +ꢀ105ꢀGDWDꢁꢀįH 7.95 (2 u t, 2H,
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5.90–5.92 (d, Jꢀ ꢀꢊꢆꢈꢉꢀ+]ꢀꢄ+ꢅꢀꢃ&1–H1 of pyranose ring), 5.33–4.75
(m, 6H, C2',3',4'–H2',3',4', C2,3,4–H2,3,4 of pyranose ring), 3.72 (m, 1H,
C5–H5 of pyranose ring), 4.35 (m, 1H, C5'–H5' of pyranose ring), 4.15
(m, 4H, C6'–H6', C6–H6of pyranose ring), 3.40 (s, 2H, –N–CH2& 2ꢅꢁꢀ