Synthesis of novel N-alkyl/aryl-N′-(4-arylthiazol-2-yl)-N″- xylosyl guanidines

Article abstract of DOI:10.1002/hc.20379

The reaction of 2,3,4-tri-O-acetyl-β-D-xylopyranosyl isothiocyanate (1) and 2-amino-4-arylthiazoles (2) gave xylosylthioureas 3. These thiourea derivatives reacted with alkyl/aryl amine in the presence of HgCl₂ to give a new series of N-alkyl/a

Full text of DOI:10.1002/hc.20379

Heteroatom Chemistry
Volume 18, Number 6, 2007
ꢀ
Synthesis of Novel N-Alkyl/Aryl-N -(4-
Gen Li,1 Peng Wu,1 and Ling Hua Cao1,2
ꢀꢀ
arylthiazol-2-yl)-N -xylosyl Guanidines
1College of Chemistry and Chemical Engineering, Xinjiang University, Urumqi,
830046, People’s Republic of China
2State Key Laboratory of Elemento-organic Chemistry, Nankai University,
Tianjin, 300071, People’s Republic of China
Received 21 April 2006; revised 18 August 2006
exhibit remarkable antibacterial [7], bactericidal
ABSTRACT: The reaction of 2,3,4-tri-O-acetyl-β-
D-xylopyranosyl isothiocyanate (1) and 2-amino-
4-arylthiazoles (2) gave xylosylthioureas 3. These
thiourea derivatives reacted with alkyl/aryl amine
[8], antiuder [9], and antagonism of MRP1 [10]
activities. In addition, their syntheses have gener-
ated continued research interest in recent years,
resulting in many new efficient synthetic methods
and guanidinylation reagents for different classes of
guanidine compounds [11–14]. We are interested in
the preparation of N,Nꢀ,Nꢀꢀ-substituted guanidines
that contain sugar and thiazole moieties with
the objective of obtaining new biologically active
compounds using common reagent HgCl2 that can
be conveniently obtained everywhere.
in the presence of HgCl2 to give
a new se-
ries of N-alkyl/aryl-Nꢀꢀ-(4-arylthiazol-2-yl)-Nꢀꢀ-xylosyl
guanidines 4. Some of the synthesized guani-
dines were screened for their biological activity.
ꢁ
C
2007 Wiley Periodicals, Inc. Heteroatom Chem 18:688–
694, 2007; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20379
INTRODUCTION
RESULTS AND DISCUSSION
Guanidine-containing
sugars
and
sugar-like
The easily accessible xylosyl isothiocyanate 1 [15]
reacted with 2-amino-4-arylthiazoles 2 [16] in ben-
zene to give xylosylthioureas 3 (Scheme 1). N,Nꢀ-
Substituted xylosyl thioureas reacted smoothly with
amine in the presence of HgCl2. The incoming amine
may be either alkyl or aryl. Thus, this process pro-
vides a very efficient route to N,Nꢀ,Nꢀꢀ-substituted
xylosylguanidines. It compares very favorably with
the existing methods for the preparation of glyco-
sylguanidines in that the present methods are both
effective and convenient.
Thus, in the course of guanylation, a less po-
lar intermediate was obtained, which then converted
to the desired guanidine product. The intermediates
were presumed to be carbodiimides. These observa-
tions are consistent with the reaction mechanism
molecules have wide range of biologically
a
important applications such as inhibition of in-
appropriate mitogenic signaling [1], therapy for
bacterial infections [2], treatment of non–insulin-
dependent diabetes [3], and inhibition of enzymes
including thrombin [4], glycosidases [5], and nitric
oxide synthases [6]. A number of compounds
containing thiazole moiety have been reported to
Correspondence to: Ling Hua Cao; e-mail: clhxj@xju.edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant numbers: 29962002 and 20462006.
Contract grant sponsor: State Key Laboratory of Elemento-
organic Chemistry of Nankai University.
c
ꢀ
2007 Wiley Periodicals, Inc.
688

Synthesis of Novel N-Alkyl/Aryl-Nꢀ-(4-arylthiazol-2-yl)-Nꢀꢀ-xylosyl Guanidines 689
SCHEME 1 Reagents and Conditions: (i) benzene, reflux: (ii) Et3N, alkyl/aryl amine, HgCl2, DMF.
proposed for guanylation of bisbutyloxycarbonyl
thioureas [17]: HgCl2 promotes a formal elimina-
tion of H2S from thiourea starting material to pro-
duce carbodiimide intermediates; amines then add
to the carbodiimides to yield guanidine products. It
appears that HgCl2 causes the first step to proceed ef-
ficiently regardless of the nature of the substituents.
The guanylation reactions were performed with the
selected thiourea substrate in the presence of less
than 1 equivalent of the incoming amine.
In the IR spectra of compounds 4a–4t, there
are characteristic absorption bands of guanidyl at
1620 cm−1, while the absorption bands of NHCSNH
in compounds 3a–3e at 1510 cm−1 disappeared in
compounds 4a–4t. Otherwise, the spectra display a
broad band at 3410 cm−1 (NH) and at about 1750
cm−1 (CO in sugar ring) in all products.
In the ESI-MS, the molecular ion peaks of com-
pounds 4 were obtained as base peaks, which indi-
cate that all products of 4 are stable.
BIOLOGICAL ACTIVITY
The HIV-1 protease inhibitory activity of synthe-
sized compounds 4a, 4b, 4e, 4f, and 4g were tested.
Reference drug indinavir was provided by Glaxo
Co. Substrate was supplied by MP Co. The HIV-1
protease enzyme was synthesized in the laboratory
and stored at −85◦C. Potential inhibitors were first
solubilized in DMSO or distilled water just before
the biological activity assay, and the following final
drug concentrations were routinely used for eval-
uation: 250, 50, 10, 2.0, and 0.40 µg/mL. The di-
luted solution was mixed with buffer containing
fluorescence-labeled HIV-1 substrate and then with
gene-engineered HIV-1 protease. The mixture was
incubated under optimal conditions and the fluores-
cent intensity was determined by FLUO Star Galaxy
fluorometry. The HIV-1 protease inhibitory activ-
ity was analyzed and expressed as 50% inhibitory
concentration (IC50). The results are summarized in
Table 1. The results showed that compounds 4b and
4e exhibited moderate HIV-1 protease inhibitory ac-
tivity. Meanwhile, compounds 4a, 4b, 4e, 4f, and 4g
were tested against angiotensin-converting enzyme
(ACE), and 4g showed activity against ACE.
1H NMR spectra show two signals of NH in com-
pounds 3a–3e that appeared at about δ 10.00–11.50,
whereas one of NH signals shifted to δ 5.30–5.70 in
compounds 4a–4t. It is possible that the deshield-
ing effect of CS is stronger than that of CN and
the anisotropic effect of the aromatic ring, namely,
this NH proton, which is at the syn-position of the
imino group, must shift upfield. Therefore, in com-
pounds 3a–3e, the sugar ring C1 H displayed signals
at about δ 5.80; it appeared at higher field in com-
pounds 4a–4t at about δ 5.40. The sugar ring C1
H
reveals a triplet due to its coupling with C2 H and
N H. The signal for NH proton in compounds 4c,
4d, 4g, 4h, 4k, 4l, 4o, 4p, 4s, and 4t appeared at δ
11.00–11.60, whereas in the remaining compounds
of 4, it appeared at δ 9.90–10.50. This result is not
surprising as the aryl moiety shifts these signals to a
lower field region.
EXPERIMENTAL
Melting points were taken on a Yanaco MP-S3 micro
melting point apparatus. IRspectra were recorded in
Heteroatom Chemistry DOI 10.1002/hc

690 Li, Wu, and Cao
TABLE 1 Anti-HIV-1 Protease Inhibitory Results of Tested Compounds
Concentration (µg/mL)
Compound
250
50
10
2.0
0.40
IC50
4a
4b
4e
4f
23.6
42.8
66.76
12.48
39.75
3.88
2.82
2.44
1.45
−17.56
−2.38
−1.41
−2.30
−1.59
−6.88
−10.94
−7.12
7.79
−5.24
−15.34
−5.34
−8.29
4.03
–
118.29
23.50
–
−2.27
4g
11.47
–
KBr pellets on a Brucker Equinox 55 FT-IR appara-
tus. 1H NMR spectra were recorded on an Inova-400
(using TMS as internal standard, chemical shifts ex-
pressed in δ ppm). Mass spectra were obtained on HP
1100-MS mass spectrometry workstation via ESI+.
TLC was performed on silica gel GF254 (Qindao of
China), with ethyl acetate and light petroleum (frac-
tion boiling in the range of 60◦C–90◦C) and detection
by UV light or iodine. Column chromatography was
performed on 200–300 mesh silica gel.
(br, 1H, NH). MS: m/z (%) 527 (100), 529 (33). Anal.
calcd. for C21H22ClN3O7S2 (527.99): C, 47.77%; H,
4.20%; N, 7.96%. Found: C, 47.61%; H, 4.21%; N,
7.97%.
N-[4-(p-Bromophenyl)thiazol-2-yl]-Nꢀ-(2,3,4-
tri-O-acetyl-β-D-xylopyranosyl)thiourea (3c). Yield,
76%; mp 208◦C–210◦C; IR: ν = 3403 (NH), 1746
(C O), 1579 (aryl), 1501 (N C S), 1045 (C O C),
1
909 cm−1 (sugar ring C1 H); H NMR (CDCl3): δ =
1.95 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.07 (s, 3H,
CH3), 3.86–5.30 (m, 5H, sugar ring-H), 5.76 (t, 1H,
sugar ring C1 H, J = 9.6 Hz), 6.65 (s, 1H, thiazole
C4 H), 7.23–7.82 (m, 4H, Ar H), 10.23 (br, 1H,
NH), 11.26 (br, 1H, NH). MS: m/z (%) 571 (100), 573
(97). Anal. calcd. for C21H22BrN3O7S2 (571.45): C,
44.06%; H, 3.87%; N, 7.34%. Found: C, 44.18%; H,
3.85%; N, 7.36%.
Preparation of Thiourea Derivatives 3a–3e
An equimolecular mixture of 2 (23 mmol) and xylo-
syl isothiocyanate (25 mmol) in 30 mL of dry ben-
zene were refluxed in a water bath for more than
10 h. After cooling, the solid product was filtered
and washed with ether and water, then finally crys-
tallized from ethanol to give thiourea derivatives
3a–3e.
N-[4-(p-Methylphenyl)thiazol-2-yl]-Nꢀ-(2,3,4-tri-
O-acetyl-β-D-xylopyranosyl)thiourea
(3d). Yield,
N-(4-Phenylthiazol-2-yl)-Nꢀ-(2,3,4-tri-O-acetyl-β-
D-xylopyranosyl)thiourea (3a). Yield, 62%; mp
194◦C–196◦C; IR: ν = 3425 (NH), 1748 (C O), 1566
(aryl), 1510 (N C S), 1040 (C O C), 908 cm−1
(sugar ring C1 H); 1H NMR (CDCl3): δ = 2.02
(s, 3H, CH3), 2.10 (s, 3H, CH3), 2.18 (s, H, CH3),
3.90–5.37 (m, 5H, sugar ring-H), 5.83 (t, 1H, sugar
ring C1 H, J = 9.4 Hz), 6.78 (s, 1H, thiazole C4 H),
7.20–7.83 (m, 5H, Ar H), 10.12 (br, 1H, NH), 11.04
(br, 1H, NH). MS: m/z(%) 493 (100) Anal. calcd.
for C21H23N3O7S2 (493.55): C, 51.11%; H, 4.70%; N,
8.51%. Found: C, 51.26%; H, 4.71%; N, 8.48%.
73%; mp 200◦C–202◦C; IR: ν = 3400 (NH), 1752
(C O), 1579 (aryl), 1510 (N C S), 1041 (C O C),
1
907 cm−1 (sugar ring C1 H); H NMR (CDCl3): δ =
1.97 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.12 (s, 3H,
CH3), 2.35 (s, 3H, CH3), 3.74–5.40 (m, 5H, sugar
ring-H), 5.77 (t, 1H, sugar ring C1 H, J = 9.2 Hz),
6.78 (s, 1H, thiazole C4 H), 7.01–7.75 (m, 4H,
Ar H), 10.26 (br, 1H, NH), 11.28 (br, 1H, NH). MS:
m/z (%) 507 (100). Anal. calcd. for C22H25N3O7S2
(507.58): C, 52.06%; H, 4.96%; N, 8.28%. Found: C,
51.90%; H, 4.93%; N, 8.30%.
N-[4-(p-Methoxylphenyl)thiazol-2-yl]-Nꢀ-(2,3,4-tri-
N-[4-(p-Chlorophenyl)thiazol-2-yl]-Nꢀ-(2,3,4-tri-O-
acetyl-β-D-xylopyranosyl)thiourea (3b). Yield, 66%;
mp 210◦C–203◦C; IR: ν = 3400 (NH), 1742 (C O),
1579 (aryl), 1506 (N C S), 1036 (C O C), 909
O-acetyl-β-D-xylopyranosyl)thiourea
(3e). Yield,
67%; mp 190◦C–192◦C; IR: ν = 3387 (NH), 1755
(C O), 1564 (aryl), 1509 (N C S), 1034 (C O C),
910 cm−1 (sugar ring C1 H); 1H NMR (CDCl3):
δ = 2.01 (s, 3H, CH3), 2.04 (s, 3H, CH3), 2.08 (s,
3H, CH3), 3.80 (s, 3H, CH3O), 3.88–5.40 (m, 5H,
sugar ring-H), 5.86 (t, 1H, sugar ring C1 H, J =
9.6 Hz), 6.89 (s, 1H, thiazole C4 H), 7.05–7.80 (m,
4H, Ar H), 10.32 (br, 1H, NH), 11.34 (br, 1H, NH).
1
cm−1 (sugar ring C1 H); H NMR (CDCl3): δ = 1.97
(s, 3H, CH3), 2.06 (s, 3H, CH3), 2.11 (s, 3H, CH3),
3.88–5.33 (m, 5H, sugar ring-H), 5.79 (t, 1H, sugar
ring C1 H, J = 9.6 Hz), 6.69 (s, 1H, thiazole C4 H),
7.16–7.87 (m, 4H, Ar H), 10.21 (br, 1H, NH), 11.24
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Novel N-Alkyl/Aryl-Nꢀ-(4-arylthiazol-2-yl)-Nꢀꢀ-xylosyl Guanidines 691
MS: m/z (%) 523 (100). Anal. calcd. for C22H25N3O8S2
(523.58): C, 50.47%; H, 4.81%; N, 8.03%. Found: C,
50.62%; H, 4.79%; N, 8.00%.
(C O), 1626 (guanidine), 1590 (aryl), 1039 (C O C),
1
910 cm−1 (sugar ring C1 H); H NMR (CDCl3): δ =
2.10 (s, 3H, CH3), 2.14 (s, 3H, CH3), 2.18 (s, 3H,
CH3), 3.82–5.32 (m, 5H, sugar ring-H), 5.43 (t, 1H,
sugar ring C1 H, J = 9.2 Hz), 5.57 (br, 1H, NH),
6.64 (s, 1H, thiazole C4 H), 6.98–7.66 (m, 10H,
Ar H), 11.20 (br, 1H, NH). MS: m/z (%) 553 (100).
Anal. calcd. for C27H28N4O7S (552.60): C, 58.69%; H,
5.11%; N, 10.14%. Found: C, 58.86%; H, 5.12%; N,
10.11%.
Preparation of Guanidine Derivatives 4a–4t
The starting thiourea, amine (1.1 mmol), and tri-
ethylamine (2.2 mmol) were dissolved in dimethyl-
formamide (5 mL/mmol substrate) at room temper-
ature. The mixture was cooled in an ice bath. Then
HgCl2 (1.1 mmol) was added and the mixture was
stirred for 20 min, before it was warmed to room
temperature. When the reaction was completed
(TLC, in the solvent system of EtOAc/petroleum
ether 2:1, v/v), the reaction mixture was diluted with
ethyl acetate and filtered through celite, washing the
celite cake with additional ethyl acetate. The filtrate
was washed with water, then with brine, and finally
the organic phase was dried with MgSO4. The crude
product thus obtained was purified by flash chro-
matography on a silica column (in the solvent sys-
tem of EtOAc/petroleum ether 1:1, v/v) to give com-
pounds 4a–4t.
N-(p-Methoxylphenyl)-Nꢀ -(4-phenylthiazol-2-yl)-
Nꢀꢀ-(2,3,4-tri-O-acetyl-β-D-xylopyranosyl) guanidine
(4d). Yield, 70%; mp 190◦C–192◦C; IR: ν = 3380
(NH), 1738 (C O), 1619 (guanidine), 1558 (aryl),
1040 (C O C), 906 cm−1 (sugar ring C1 H); 1H
NMR (CDCl3): δ = 2.01 (s, 3H, CH3), 2.09 (s,
3H, CH3), 2.13 (s, 3H, CH3), 3.81 (s, 3H, CH3O),
3.90–5.24 (m, 5H, sugar ring-H), 5.36 (t, 1H, sugar
ring C1 H, J = 9.6 Hz), 5.50 (br, 1H, NH), 6.88 (s,
1H, thiazole C4 H), 7.10–7.82 (m, 9H, Ar H), 11.49
(br, 1H, NH). MS: m/z (%) 583 (100). Anal. calcd.
for C28H30N4O8S (582.63): C, 57.72%; H, 5.19%; N,
9.62%. Found; C, 57.54%; H, 5.21%; N, 9.65%.
N-Isopropyl-Nꢀ -(4-phenylthiazol-2-yl)-Nꢀꢀ-(2,3,4-
tri-O-acetyl-β-D-xylopyranosyl)guanidine (4a). Yield,
80%; mp 135◦C–137◦C; IR: ν = 3349 (NH), 1738
(C O), 1626 (guanidine), 1575 (aryl), 1038 (C O C),
907 cm−1 (C1 H); 1H NMR (CDCl3): δ = 1.35 (d,
6H, isopropyl-2CH3, J = 6.1 Hz), 1.99 (s, 3H, CH3),
2.05 (s, 3H, CH3), 2.11 (s, 3H, CH3), 3.90–5.29 (m,
6H, sugar ring-H, isopropyl-CH), 5.37 (t, 1H, sugar
ring C1 H, J= 9.6 Hz), 5.50 (br, 1H, NH), 6.89 (s,
1H, thiazole C4 H), 7.06–7.87 (m, 5H, Ar H), 10.11
(br, 1H, NH). MS: m/z (%) 519 (100). Anal. calcd.
for C24H30N4O7S (518.58): C, 55.59%; H, 5.83%; N,
10.80%. Found: C, 55.42%; H, 5.85%; N, 10.77%.
N-Isopropyl-Nꢀ -[4-(p-chlorophenyl)thiazol-2-yl]-
Nꢀꢀ -(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)guanidine
(4e). Yield, 82%; mp 140◦C–142◦C; IR: ν = 3353
(NH), 1739 (C O), 1620 (guanidine), 1590 (aryl),
1032 (C O C), 912 cm−1 (sugar ring C1 H); 1H
NMR (CDCl3): δ = 1.30 (d, 6H, isopropyl-2CH3,J
= 5.9 Hz), 1.99 (s, 3H, CH3), 2.07 (s, 3H, CH3),
2.11 (s, 3H, CH3), 3.93–5.31 (m, 6H, sugar ring-H,
isopropyl-CH), 5.35 (t, 1H, sugar ring C1 H, J =
9.7Hz), 5.52 (br, 1H, NH), 6.83 (s, 1H, thiazole
C4 H), 6.92–7.89 (m, 4H, Ar H), 10.25 (br, 1H,
NH). MS: m/z (%) 553 (100), 555 (35). Anal. calcd.
for C24H29ClN4O7S (552.03): C, 52.12%; H, 5.29%;
N, 10.13%. Found: C, 51.96%; H, 5.30%; N, 10.10%.
N-Benzyl-Nꢀ -(4-phenylthiazol-2-yl)-Nꢀꢀ-(2,3,4-tri-
O-acetyl-β-D-xylopyranosyl) guanidine (4b). Yield,
85%; mp 140◦C–142◦C; IR: ν = 3410 (NH), 1740
(C O), 1621 (guanidine), 1585 (aryl), 1036 (C O C),
1
907 cm−1 (sugar ring C1 H); H NMR (CDCl3): δ =
N-Benzyl-Nꢀ-[4-(p-chlorophenyl)thiazol-2-yl]-Nꢀꢀ-
(2,3,4-tri-O-acetyl-β-D-xylopyranosyl) guanidine (4f).
Yield, 83%; mp 153◦C–155◦C; IR: ν = 3407 (NH),
1746 (C O), 1627 (guanidine), 1583 (aryl), 1037
(C O C), 908 cm−1 (sugar ring C1 H); 1H NMR
(CDCl3): δ = 2.03 (s, 3H, CH3), 2.06 (s, 3H, CH3),
2.12 (s, 3H, CH3), 3.70–5.26 (m, 7H, sugar ring-H,
benzyl-CH2), 5.35 (t, 1H, sugar ring C1 H, J =
9.2 Hz), 5.46 (br, 1H, NH), 6.84 (s, 1H, thiazole
C4 H), 7.05–7.80 (m, 9H, Ar H), 10.60 (br, 1H,
NH). MS: m/z (%) 601 (100), 603 (33). Anal. calcd.
for C28H29ClN4O7S (600.14): C, 55.95%; H, 4.86%;
N, 9.32%. Found; C, 56.13%; H, 4.84%; N, 9.35%.
2.02 (s, 3H, CH3), 2.06 (s, 3H, CH3), 2.11 (s, 3H,
CH3), 3.71–5.25 (m, 7H, sugar ring-H, benzyl-CH2),
5.36 (t, 1H, sugar ring C1 H, J = 9.2 Hz), 5.48 (br,
1H, NH), 6.85 (s, 1H, thiazole C4 H), 7.12–7.81
(m, 10H, Ar H), 10.58 (br, 1H, NH). MS: m/z (%)
567 (100). Anal. calcd. for C28H30N4O7S (566.63): C,
59.35%; H, 5.34%; N, 9.89%. Found: C, 59.50%; H,
5.30%; N, 9.86%.
N-Phenyl-Nꢀ -(4-phenylthiazol-2-yl)-Nꢀꢀ-(2,3,4-tri-
O-acetyl-β-D-xylopyranosyl) guanidine (4c). Yield,
70%; mp 182◦C–184◦C; IR: ν = 3362 (NH), 1746
Heteroatom Chemistry DOI 10.1002/hc

692 Li, Wu, and Cao
N-Phenyl-Nꢀ-[4-(p-chlorophenyl)thiazol-2-yl]-Nꢀꢀ-
(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)guanidine (4g).
Yield, 68%; mp 178◦C–180◦C; IR: ν = 3368 (NH),
1739 (C O), 1621 (guanidine), 1598 (aryl), 1032
(C O C), 913 cm−1 (sugar ring C1 H); 1H NMR
(CDCl3): δ = 2.10 (s, 3H, CH3), 2.12 (s, 3H, CH3),
2.15 (s, 3H, CH3), 3.81–5.20 (m, 5H, sugar ring-H),
5.39 (t, 1H, sugar ring C1 H, J = 9.2 Hz), 5.58 (br,
1H, NH), 6.85 (s, 1H, thiazole C4 H), 6.96–7.52
(m, 9H, Ar H), 11.27 (br, 1H, NH). MS: m/z (%)
587 (100), 589 (32). Anal. calcd. for C27H27ClN4O7S
(586.12): C, 55.24%; H, 4.64%; N, 9.54%. Found: C,
55.06%; H, 4.62%; N, 9.57%.
for C28H29BrN4O7S (644.09): C, 52.10%; H, 4.53%;
N, 8.68%. Found: C, 52.25%; H, 4.52%; N, 8.65%.
N-Phenyl-Nꢀ-[4-(p-bromophenyl)thiazol-2-yl]-Nꢀꢀ-
(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)guanidine (4k).
Yield, 71%; mp 179◦C–181◦C; IR: ν = 3365 (NH),
1740 (C O), 1627 (guanidine), 1592 (aryl), 1038
(C O C), 908 cm−1 (sugar ring C1 H); 1H NMR
(CDCl3): δ = 2.02 (s, 3H, CH3), 2.06 (s, 3H, CH3),
2.13 (s, 3H, CH3), 3.82–5.23 (m, 5H, sugar ring-H),
5.41 (t, 1H, sugar ring C1 H, J = 9.2 Hz), 5.58 (br,
1H, NH), 6.64 (s, 1H, thiazole C4 H), 6.96–7.64
(m, 9H, Ar H), 11.29 (br, 1H, NH). MS: m/z (%)
631 (100), 633 (97). Anal. calcd. for C27H27BrN4O7S
(630.07): C, 51.35%; H, 4.31%; N, 8.87%. Found: C,
51.52%; H, 4.30%; N, 8.85%.
N-(p-Methoxylphenyl)-Nꢀ-[4-(p-chlorophenyl)thia-
zol-2-yl]-Nꢀꢀ-(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)gua-
nidine (4h). Yield, 65%; mp 169◦C–171◦C; IR: ν
= 3382 (NH), 1746 (C O), 1618 (guanidine), 1587
(aryl), 1038 (C O C), 912 cm−1 (sugar ring C1 H);
1H NMR (CDCl3): δ = 2.12 (s, 3H, CH3), 2.16 (s,
3H, CH3), 2.20 (s, 3H, CH3), 3.69 (s, 3H, CH3O),
3.86–5.21 (m, 5H, sugar ring-H), 5.42 (t, 1H, sugar
ring C1 H, J = 9.6 Hz), 5.56 (br, 1H, NH), 6.76 (s,
1H, thiazole C4 H), 6.98–7.82 (m, 8H, Ar H), 11.38
(br, 1H, NH). MS: m/z (%) 617 (100), 619 (33). Anal.
calcd. for C28H29ClN4O8S (616.13): C, 54.50%; H,
4.74%; N, 9.08%. Found: C, 54.60%; H, 4.72%; N,
9.06%.
N-(p-Methoxylphenyl)-Nꢀ-[4-(p-bromophenyl)thi-
azol-2-yl]-Nꢀꢀ -(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)-
guanidine (4l). Yield, 68%; mp 166◦C–168◦C; IR: ν
= 3362 (NH), 1743 (C O), 1619 (guanidine), 1592
(aryl), 1030 (C O C), 920 cm−1 (sugar ring C1 H);
1H NMR (CDCl3): δ = 2.12 (s, 3H, CH3), 2.18 (s,
3H, CH3), 2.25 (s, 3H, CH3), 3.58 (s, 3H, CH3O),
3.87–5.23 (m, 5H, sugar ring-H), 5.39 (t, 1H, sugar
ring C1 H, J = 9.6 Hz), 5.56 (br, 1H, NH), 6.68 (s,
1H, thiazole C4 H), 6.98–7.81 (m, 9H, Ar H), 11.34
(br, 1H, NH). MS: m/z (%) 661 (100), 663 (98). Anal.
calcd. for C28H29BrN4O8S (660.09): C, 50.84%; H,
4.42%; N, 8.47%. Found: C, 50.99%; H, 4.40%; N,
8.49%.
N-Isopropyl-Nꢀ -[4-(p-bromophenyl)thiazol-2-yl]-
Nꢀꢀ-(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)guanidine (4i).
Yield, 82%; mp 141◦C–143◦C; IR: ν = 3355 (NH),
1737 (C O), 1621 (guanidine), 1594 (aryl), 1031
(C O C), 910 cm−1 (sugar ring C1 H); 1H NMR
(CDCl3): δ = 1.33 (d, 6H, isopropyl-2CH3, J = 6.0
Hz), 2.10 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.21 (s, 3H,
CH3), 3.92–5.33 (m, 6H, sugar ring-H, isopropyl-
CH), 5.36 (t, 1H, sugar ring C1 H, J = 9.6 Hz), 5.56
(br, 1H, NH), 6.88 (s, 1H, thiazole C4 H), 7.02–7.89
(m, 4H, Ar H), 10.23 (br, 1H, NH). MS: m/z (%)
597 (100), 599 (97). Anal. calcd. for C24H29BrN4O7S
(596.09): C, 48.25%; H, 4.89%; N, 9.38%. Found; C,
48.12%; H, 4.90%; N, 9.40%.
N-Isopropyl-Nꢀ-[4-(p-methylphenyl)thiazol-2-yl]-
Nꢀꢀ -(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)guanidine
(4m). Yield, 80%; mp 133◦C–135◦C; IR: ν = 3345
(NH), 1750 (C O), 1622 (guanidine), 1590 (aryl),
1040 (C O C), 907 cm−1 (sugar ring C1 H); 1H
NMR (CDCl3): δ = 1.34 (d, 6H, isopropyl-2CH3, J =
5.9 Hz), 1.98 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.10
(s, 3H, CH3), 2.73 (s, 3H, CH3), 3.90–5.30 (m, 6H,
sugar ring-H, isopropyl-CH), 5.17 (t, 1H, sugar ring
C1 H, J= 9.4Hz), 5.49 (br, 1H, NH), 6.78 (s, 1H,
thiazole C4 H), 7.18–7.63 (m, 4H, Ar H), 10.25
(br, 1H, NH). MS: m/z (%) 533 (100). Anal. calcd.
for C25H32N4O7S (532.61): C, 56.38%; H, 6.06%; N,
10.52%. Found: C, 56.21%; H, 6.08%; N, 10.55%.
N-Benzyl-Nꢀ -[4-(p-bromopheny)lthiazol-2-yl]-Nꢀꢀ-
(2,3,4-tri-O-acetyl-β-D-xylopyranosyl) guanidine (4j).
Yield, 80%; mp 156◦C–158◦C; IR: ν = 3410 (NH),
1748 (C O), 1622 (guanidine), 1588 (aryl), 1032
(C O C), 912 cm−1 (sugar ring C1 H); 1H NMR
(CDCl3): δ = 2.11 (s, 3H, CH3), 2.15 (s, 3H, CH3),
2.23 (s, 3H, CH3), 3.73–5.32 (m, 7H, sugar ring-H,
beneyl-CH2), 5.43 (t, 1H, sugar ring C1 H, J =
9.2 Hz), 5.56 (br, 1H, NH), 6.75 (s, 1H, thiazole
C4 H), 6.98–7.80 (m, 9H, Ar H), 10.60 (br, 1H,
NH). MS: m/z (%) 645 (100), 647 (96). Anal. calcd.
N-Benzyl-Nꢀ-[4-(p-methylpheny)lthiazol-2-yl]-Nꢀꢀ-
(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)guanidine (4n).
Yield, 74%; mp 125◦C–127◦C; IR: ν = 3350 (NH),
1758 (C O), 1620 (guanidine), 1580 (aryl), 1032
(C O C), 909 cm−1 (sugar ring C1 H); 1H NMR
(CDCl3): δ = 2.01 (s, 3H, CH3), 2.06 (s, 3H, CH3),
2.10 (s, 3H, CH3), 2.41 (s, 3H, CH3), 3.70–5.30 (m,
7H, sugar ring-H, beneyl-CH2), 5.35 (t, 1H, sugar
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Novel N-Alkyl/Aryl-Nꢀ-(4-arylthiazol-2-yl)-Nꢀꢀ-xylosyl Guanidines 693
ring C1 H, J = 9.4 Hz), 5.45 (br, 1H, NH), 6.69 (s,
NMR (CDCl3): δ = 1.99 (s, 3H, CH3), 2.05 (s,
3H, CH3), 2.08 (s, 3H, CH3), 3.72 (s, 3H, CH3O),
3.91–5.33 (m, 7H, sugar ring-H, beneyl-CH2), 5.37
(t, 1H, sugar ring C1 H, J = 9.4 Hz), 5.52 (br, 1H,
NH), 6.80 (s, 1H, thiazole C4 H), 7.10–7.78 (m, 9H,
Ar H), 10.52 (br, 1H, NH). MS: m/z (%) 597 (100).
Anal. calcd. for C29H32N4O8S (596.66): C, 58.38%; H,
5.41%; N, 9.39%. Found: C, 58.20%; H, 5.42%; N,
9.41%.
1H, thiazole C4 H), 6.99–7.84 (m, 9H, Ar H), 10.55
(br, 1H, NH). MS: m/z (%) 581 (100). Anal. calcd.
for C29H32N4O7S (580.66): C, 59.99%; H, 5.55%; N,
9.65%. Found: C, 59.86%; H, 5.57%; N, 9.63%.
N-Phenyl-Nꢀ-[4-(p-methylphenyl)thiazol-2-yl]-Nꢀꢀ-
(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)guanidine (4o).
Yield, 70%; mp 110◦C–112◦C; IR: ν = 3410 (NH),
1755 (C O), 1622 (guanidine), 1587 (aryl), 1030
(C O C), 911 cm−1 (sugar ring C1 H); 1H NMR
(CDCl3): δ = 2.02 (s, 3H, CH3), 2.07 (s, 3H, CH3), 2.11
(s, 3H, CH3), 2.40 (s, 3H, CH3), 3.88–5.06 (m, 5H,
sugar ring-H), 5.24 (t, 1H, sugar ring C1 H, J = 9.2
Hz), 5.43 (br, 1H, NH), 6.75 (s, 1H, thiazole C4 H),
7.01–7.64 (m, 9H, Ar H), 11.21 (br, 1H, NH). MS:
m/z (%) 567 (100). Anal. calcd. for C28H30N4O7S
(566.63): C, 59.35%; H, 5.34%; N, 9.89%. Found; C,
59.47%; H, 5.36%; N, 9.87%.
N-Phenyl-Nꢀ -[4-(p-methoxylphenyl)thiazol-2-yl]-
Nꢀꢀ -(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)guanidine
(4s). Yield, 55%; mp 104◦C–106◦C; IR: ν = 3389
(N H), 1754 (C O), 1617 (guanidine), 1579 (aryl),
1041 (C O C), 910 cm−1 (sugar ring C1 H);1H NMR
(CDCl3): δ = 1.98 (s, 3H, CH3), 2.10 (s, 3H, CH3), 2.16
(s, 3H, CH3), 3.80 (s, 3H, CH3O), 3.88–5.16 (m, 5H,
sugar ring-H), 5.35 (t, 1H, sugar ring C1 H, J = 9.4
Hz), 5.51 (br, 1H, NH), 6.79 (s, 1H, thiazole C4 H),
6.95–7.72 (m, 9H, Ar H), 11.25 (br, 1H, NH). MS:
m/z (%) 583 (100). Anal. calcd. for C28H30N4O8S
(582.63): C, 57.72%; H, 5.19%; N, 9.62%. Found: C,
57.89%; H, 5.20%; N, 9.59%.
N-(p-Methoxylphenyl)-Nꢀ-[4-(p-methylphenyl)thia-
zol-2-yl]-Nꢀꢀ -(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)-
guanidine (4p). Yield, 60%; mp 110◦C–111◦C; IR:
ν = 3380 (NH), 1753 (C O), 1621 (guanidine), 1585
(aryl), 1029 (C O C), 920 cm−1 (sugar ring C1 H);
1H NMR (CDCl3): δ = 2.02 (s, 3H, CH3), 2.10 (s, 3H,
CH3), 2.14 (s, 3H, CH3), 2.35 (s, 3H, CH3), 3.80 (s,
3H, CH3O), 3.86–5.26 (m, 5H, sugar ring-H), 5.36
(t, 1H, sugar ring C1 H, J = 9.2 Hz), 5.48 (br, 1H,
NH), 6.77 (s, 1H, thiazole C4 H), 6.98–7.88 (m, 9H,
Ar H), 11.47 (br, 1H, NH). MS: m/z (%) 597 (100).
Anal. calcd. for C29H32N4O8S (596.66): C, 58.38%; H,
5.41%; N, 9.39%. Found; C, 58.21%; H, 5.39%; N,
9.42%.
N-Methoxylphenyl-Nꢀ-[4-(p-methoxylphenyl)thia-
zol-2-yl]-Nꢀꢀ -(2,3,4-tri-O-acetyl-β-D-xylopyranosyl)-
guanidine (4t). Yield, 70%; mp 185◦C–186◦C; IR:
ν = 3340 (NH), 1751 (C O), 1620 (guanidine), 1581
(aryl), 1037 (C O C), 908 cm−1 (sugar ring C1 H);
1H NMR (CDCl3): δ = 1.97 (s, 3H, CH3), 2.11 (s, 3H,
CH3), 2.20 (s, 3H, CH3), 3.77 (s, 3H, CH3O), 3.80 (s,
3H, CH3O), 3.78–5.20 (m, 5H, sugar ring-H), 5.41
(t, 1H, sugar ring C1 H, J = 9.6 Hz), 5.51 (br, 1H,
NH), 6.84 (s, 1H, thiazole C4 H), 7.02–7.76 (m, 8H,
Ar H), 11.24 (br, 1H, NH). MS: m/z (%) 613 (100).
Anal. calcd. for C29H32N4O9S (612.65): C, 56.85%; H,
5.26%; N, 9.14%. Found: C, 56.43%; H, 5.28%; N,
9.11%.
N-Isopropyl-Nꢀ -[4-(p-methoxylphenyl)thiazol-2-
yl]-Nꢀꢀ -(2,3,4-tri-O-acetyl-β-D-xylpyranosyl)guanidine
(4q). Yield, 83%; mp 159◦C–160◦C; IR: ν = 3365
(NH), 1756 (C O), 1618 (guanidine), 1578 (aryl),
1038 (C O C), 913 cm−1 (sugar ring C1 H); 1H
NMR (CDCl3): δ = 1.36 (d, 6H, isopropyl-2CH3, J =
6.0 Hz), 2.02 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.23
(s, 3H, CH3), 3.85 (s, 3H, CH3O), 3.90–5.23 (m, 6H,
sugar ring-H, isopropyl-CH), 5.41 (t, 1H, sugar ring
C1 H, J = 9.6 Hz), 5.51 (br, 1H, NH), 6.68 (s, 1H,
thiazole C4 H), 7.03–7.79 (m, 4H, Ar H), 10.35
(br, 1H, NH). MS: m/z (%) 549 (100). Anal. calcd.
for C25H32N4O8S (548.61): C, 54.37%; H, 5.88%; N,
10.21%. Found: C, 54.55%; H, 5.86%; N, 10.19%.
ACKNOWLEDGMENT
The authors are grateful to the National Center of
China for Drug Screening for the anti-ACE and HIV
protease inhibitory test.
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