A novel preparation of pyridine-urea hybrids and elucidation of their structures

Article abstract of DOI:10.1002/hc.20560

A mechanistically unique and serendipitously discovered reaction providing a variety of pyridine-urea hybrids via the thiophenol-initiated uracil ring opening and pyridine ring-forming process was reported. The identification process of the hybrids and th

Full text of DOI:10.1002/hc.20560

Heteroatom Chemistry
Volume 20, Number 6, 2009
A Novel Preparation of Pyridine–Urea Hybrids
and Elucidation of Their Structures
Xuesen Fan, Dong Feng, Xia Wang, Yingying Qu, and Xinying Zhang
School of Chemistry and Environmental Sciences, Henan Key Laboratory for Environmental
Pollution Control, Henan Normal University, Xinxiang, Henan 453007, People’s Republic of China
Received 13 May 2009; revised 13 May 2009, 18 September 2009
found applications as amide bond surrogates [5], al-
ABSTRACT: A mechanistically unique and serendip-
lowing for a β-sheet-like display of functionality [6],
itously discovered reaction providing a variety of
and as fluorescence probe [7], intermediate for the
pyridine–urea hybrids via the thiophenol-initiated
synthesis of hydantocidin [8], and inhibitors of Met
uracil ring opening and pyridine ring-forming process
kinase [9]. Therefore, it is of great synthetic and bio-
was reported. The identification process of the hybrids
logical interests to develop novel and efficient meth-
and the pathway through which they were formed
ods to prepare hybrids combining both pyridine and
ꢀ
C
were also briefly described.
2009 Wiley Periodicals,
urea moiety in one molecule with potentially syner-
getic biological activities.
Inc. Heteroatom Chem 20:362–368, 2009; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20560
Recently, we have an on-going program to de-
sign and synthesize nucleoside–heterocycle hybrids
as potential antiviral agents that has already resulted
in several antiviral lead compounds [10]. As a con-
tinuation, we were interested in the preparation of
hybrids of pyrimidine nucleoside with 2-amino-6-
sulfanyl-3,5-dicyano pyridines because both pyrimi-
dine nucleoside [11] and 2-amino-4-aryl-6-sulfanyl-
3,5-dicyano pyridines [12] showed diverse biological
potency, especially with regard to antiviral activities.
The preparation is based on literature procedures
[12], involving a one-pot three-component conden-
sation of benzylidenemalononitrile, thiophenol, and
malononitrile (Scheme 1). Unexpectedly, during
the preparation of such a pyrimidine nucleoside-
substituted pyridine hybrid, a novel procedure lead-
ing to pyridine–urea hybrids was discovered.
INTRODUCTION
Azaheterocycles are prominent in natural products,
pharmaceutical, and functional materials. Of vari-
ous azaheterocycles, pyridine structural unit occurs
in many medicinally interesting natural products
and substituted pyridine derivatives have been re-
ported to show promising biological activities [1–3].
On the other hand, ureas are important compo-
nents of biologically active molecules, having greater
hydrogen-bonding potential than amides while be-
ing less acidic than sulfonamides [4]. Ureas have also
Correspondence to: Xuesen Fan; e-mail: xuesen.fan@henannu.
edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
RESULTS AND DISCUSSIONS
Contract grant number: 20772025.
In our preparation of the pyrimidine nucleoside–
Contract grant sponsor: Program for Science & Technology
Innovation Talents in Universities of Henan Province.
Contract grant number: 2008HASTIT006.
Contract grant sponsor: Natural Science Foundation of
Department of Education of Henan Province.
Contract grant number: 2008A150013.
2009 Wiley Periodicals, Inc.
pyridine
hybrid,
benzylidenemalononitrile
(Scheme 1) is replaced by 5-(2ꢁ,2ꢁ-dicyanovinyl)-
2ꢁ-deoxyuridine (1a; Scheme 2). Compound 1a was
prepared from the condensation of 3ꢁ,5ꢁ-diacetyl-
5-formyl-2ꢁ-deoxyuridine and malononitrile; 1b
c
ꢀ
362

A Novel Preparation of Pyridine–Urea Hybrids and Elucidation of Their Structures 363
NC
NC
SH
CN
S
NC
+
+
NCCH2CN
N
H2N
2-Amino-4-aryl-6-sulfanyl-3,5-dicyano pyridine
SCHEME 1
was prepared from 5-formyl-2ꢁ-deoxyuridine and
malononitrile; 7 was prepared in a similar manner
from 5-formyluracil and malononitrile. Thus, 1a,
thiophenol (2) and malononitrile (3) were mixed
together and treated with triethylamine (Et3N) in
refluxing ethanol. It was then found that the desired
hybrid (4a; Scheme 2) could be obtained but only
in low yield (22%). Upon checking the reaction
mixture, it turned out that the low yield of 4a was
partly due to the formation of a byproduct (5a).
Efforts were then made to elucidate the structure of
this unknown compound and the possible pathway
through which it was formed.
O
HN
CN
S
N
HN
O
AcO
O
OAc
5a
SCHEME 3
ophilic in nature and it underwent an intramolecu-
lar Michael addition on the sixth carbon of the uracil
moiety to give an intermediate B. The following ring-
opening process is initiated by loss of a proton at-
tached on the fifth carbon of the uracil ring due to
its relatively strong acidic nature (C). With the elec-
trons transformed to N1 from C5, the C6–N1 bond
broke and the disturbed pyrimidine ring opened (D).
At the same time, a more stable pyridine ring was
formed to give an acylurea derivative (5a), contain-
ing a five-membered sugar moiety and a pyridine
ring.
In the first place, it showed the molecular weight
(MW) of 5a is 498. Since that of 1a and thiophenol
(2) are 388 and 110, respectively, it is suggested that
5a is formed from the reaction between 1a and 2. To
confirm, a mixture of 1a and 2 in ethanol was treated
with Et3N. As expected, it gave 5a in high yield. With
further spectra analysis, including UV, 1H NMR, 13
C
NMR, Cosy, HMBC, and HMQC, it was identified as
a hybrid of pyridine and sugar-substituted urea as
shown in Scheme 3.
The intriguing mechanism of the reaction cas-
cade leading to 5a is illustrated in Scheme 4. The
reaction was initiated by nucleophilic attack of thio-
phenol on the cyano group in 1a to give an adduct
(A). Within the adduct, the NH group is nucle-
To the best of our knowledge, this is the first time
such a uracil ring-opening and pyridine ring-forming
cascade have ever been reported. For uracil ring
opening in the reaction of 5-formyl-2ꢁ-deoxyuridine
O
O
N
NC
HN
N
OAc
+
O
SH
NH
NC
O
O
+
+
NCCH2CN
AcO
5a
CN
S
NC
OAc
O
N
H2N
OAc
2
3
1a
4a
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

364 Fan et al.
O
O
O
HN
N
OAc
OAc
HN
N
O
OAc
Et3N
O
HN
N
O
O
NC
O
O
N
NH
C
OAc
OAc
OAc
S
S
HN
C
CN
CN
S
B
A
O
O
O
OAc
HN
N
OAc
OAc
O
HN
N
HN
O
N
H
O
O
Et3N+H
O
N
O
N
N
OAc
OAc
OAc
S
S
S
CN
CN
CN
5a
D
C
SCHEME 4
TABLE 1 Preparation of Pyridine–Urea Hybrids
with primary alkyl amines through a Michael ad-
dition on C6 of the pyrimidine ring, see [13]; and
it provides a simple and efficient alternative for
the preparation of biologically important pyridine–
urea hybrids. To explore the scope and generality
of this novel procedure and to get more hybrids for
SAR (structure and activity relationship) study, more
thiophenol substrates were tried (Scheme 5) and the
results were included in Table 1.
It is noted that unsubstituted thiophenol or
thiophenol with either an electron-withdrawing or
electron-donating group underwent this process ef-
ficiently. Its easy going nature, high efficiency, and
generality make this process a highly potential al-
ternative for the preparation of pyridine–acylurea
hybrids.
Reaction
Time (h)
Yield
(%)a
Entry
R
X
Product
1
2
3
4
5
6
7
8
9
Ac
H
Ac
H
Ac
H
Ac
H
H
H
5a
5b
5c
5d
5e
5f
5g
5h
5i
2
2
2
2
2
2
2
2
2
2
95
92
97
96
88
84
92
90
91
86
4-CH3
4-CH3
2-Br
2-Br
4-Cl
4-Cl
4-F
Ac
H
10
4-F
5j
aIsolated yields.
To further explore the scope of this novel se-
quence, uracil-5-yl-methylene malononitrile (6) was
prepared from 5-formyluracil and was treated with
thiophenol in ethanol-containing catalytic amounts
of Et3N. It successfully underwent a similar reaction
and gave a pyridine-substituted acylurea derivative
(7) with a yield of 89% (Scheme 6).
X-ray crystallography of 7 gave a solid confor-
mation of its structure (Scheme 7). Single crystals of
7 were obtained by slow evaporation of the solvent
O
O
NC
CN
SH
HN
NH
X
Et3N
NC
RO
N
S
+
O
N
O
HN
Ethanol
RO
O
O
X
OR
OR
5
2
1
SCHEME 5
Heteroatom Chemistry DOI 10.1002/hc

A Novel Preparation of Pyridine–Urea Hybrids and Elucidation of Their Structures 365
O
and high selectivity, this novel process has the poten-
tial to be developed as a simple and efficient way to
prepare novel pyridine–urea hybrids. The biological
activity screen of compound 4, 5, and 7 is currently
underway, and the results will be reported in due
course.
O
NC
NC
SH
CN
HN
NH
Et3N
+
N
Ethanol
S
N
H
6
O
O
H2N
7
2
SCHEME 6
EXPERIMENTAL
Melting points were measured by a Kofler mi-
cromelting point apparatus and were uncorrected.
1H NMR spectra were determined on a Bruker AC
400 spectrometer as DMSO-d6, CD3OD, or CDCl3
solutions. Chemical shifts (δ) were expressed in
ppm downfield from the internal standard tetram-
ethylsilane, and coupling constants J were given
in hertz. Mass spectra were recorded on a Bruker
Esquire 3000 mass spectrometer. The HRMS (high-
resolution mass spectra) were performed on a JEOL
HX 110A spectrometer.
from a water–methanol (1:2 v/v) solution. Crystal
data of 7: C14H10N4O2S, colorless, crystal dimensions
0.32 × 0.23 × 0.05 mm, Triclinic, space group P-1,
˚
˚
˚
a = 7.185 (9) A, b = 7.718 (9) A, c = 12.095 (14) A,
α = 99.548 (12)◦, β = 91.258 (14)◦, γ = 93.960 (14)◦,
3
˚
V = 659.4 (14) A , M = 298.32, Z = 2, Dx = 1.502 Mg
r
−3
α
−1
˚
m , λ(Mo K ) = 0.71073 A, μ = 0.26 mm , F(000)
=
308, 2.7◦ < θ < 25.5◦, R = 0.076, wR(F2) = 0.252,
int
S = 1.00, largest difference peak and hole: 0.56 and
−3
˚
−0.27e A . CCDC reference number 729807.
Finally, as a bonus of the above-mentioned ob-
servation, the reaction of 1a, 2, and 3 was run again
but with a different sequence of substrates addi-
tion. Thus, instead of mixing 1a, malononitrile and
thiophenol together at one time, 1a and malononi-
trile was treated with Et3N first in ethanol for about
10 min. Then thiophenol was added to the reaction
mixture (Scheme 8). To our delight, it resulted in
an improved reaction and gave 4a with a yield of
33%. Through similar procedure, 4b was obtained
with a yield of 35%, which was also better than the
yield (25%) obtained through the procedure shown
in Scheme 2. No further optimization was attempted
[12a].
Typical Procedure for the Preparation of 5a
To a suspension of 1a (0.5 mmol) and 2 (0.6 mmol)
in ethanol (2 mL), Et3N (10 μL) was added. The sus-
pension was refluxed for 2 h. Volatiles were evapo-
rated in vacuo, and the residue was purified on silica
gel (hexane/ethyl acetate, 3:1) to yield 5a as colorless
solid. Other pyridine–urea hybrids were obtained in
a similar manner.
5a: Colorless solid, mp 151–152◦C; 1H NMR
(400 MHz, CDCl3) δ: 2.13 (s, 6H, 2×CH3), 2.18–2.48
(m, 2H, CH2), 4.18–4.28 (m, 3H, CH, CH2), 5.19–
5.22 (m, 1H, CH), 6.05–6.11 (m, 1H, CH), 7.44–
7.58 (m, 5H, Ar-H), 8.74 (d, 1H, CH, J = 2.4 Hz),
8.99 (d, 1H, CH, J = 2.4 Hz), 9.29 (d, 1H, NH,
J = 9.6 Hz), 11.01 (br s, 1H, NH). 13C NMR (100
MHz, CDCl3) δ: 21.1, 21.3, 38.4, 64.6, 75.1, 81.6,
81.8, 106.3, 114.9, 123.6, 126.9, 129.8, 130.5, 135.8,
140.1, 153.3, 155.04, 165.4, 168.4, 170.9, 171.0. IR
(KBr): 3295, 2225, 1748, 1690, 1590, 1530 cm−1; ESI
LRMS m/z: 499 (MH+), 521 (MNa+). HRMS (FAB):
Calcd for C23H23N4O7S: 499.1288 (MH)+, found
499.1283.
In conclusion, a series of pyridine-attached acy-
lurea derivatives were obtained through a novel
uracil ring-opening and pyridine ring-forming se-
quence. With its high efficiency, simple procedure,
5b: Colorless solid, mp 171–172◦C; 1H NMR (400
MHz, DMSO-d6) δ: 1.90–2.03 (m, 2H, CH2), 3.36–
3.39 (m, 2H, CH2), 3.64–3.67 (m, 1H, OH), 4.12–
4.15 (m, 1H, CH), 4.77 (t, 1H, OH, J = 5.6 Hz),
5.03 (d, 1H, CH, J = 4.4 Hz), 5.71–5.76 (m, 1H,
CH), 7.47–7.61 (m, 5H, ArH), 8.70 (d, 1H, CH,
J = 2.4 Hz), 8.78 (d, 1H, NH, J = 9.6 Hz), 8.88
(d, 1H, J = 2.4 Hz), 10.94 (br s, 1H). 13C NMR
(100 MHz, DMSO-d6) δ: 41.0, 62.8, 71.8, 81.1, 87.4,
106.0, 115.6, 125.8, 127.3, 130.4, 130.9, 136.1, 142.3,
152.9, 153.1, 165.8, 166.1. IR (KBr): 3380, 3305,
SCHEME 7
Heteroatom Chemistry DOI 10.1002/hc

366 Fan et al.
O
O
O
N
NC
NC
OR
HN
N
O
HS
HN
N
OR
NH
O
O
Et3N
Ethanol
2
+
NCCH2CN
O
O
OR
CN
S
NC
RO
CN OR
3
NC
O
N
H2N
CN CN
OR
1
4
a: R = Ac; b: R = H
SCHEME 8
LRMS m/z: 577 (MH+), 599 (MNa+). HRMS (FAB):
Calcd for C23H22BrN4O7S: 577.0393 (MH+), found
577.0399.
2233, 1700, 1530 cm−1; ESI LRMS m/z: 415 (MH+),
437 (MNa+). HRMS (FAB): Calcd for C19H19N4O5S:
415.1077 (MH+), found 415.1093.
5f: Colorless solid, mp 113–115◦C; 1H NMR (400
MHz, DMSO-d6) δ:1.99–2.08 (m, 2H, CH2), 3.65–3.68
(m, 1H, OH), 4.05–4.09 (m, 3H, CH2, CH), 4.81 (m,
1H, OH), 5.12–5.14 (m, 1H, CH), 5.73–5.77 (m, 1H,
CH), 7.47–7.88 (m, 4H, ArH), 8.78 (d, 1H, CH, J =
2.4 Hz), 8.80 (d, 1H, NH, J = 9.2 Hz), 8.89 (d, 1H, CH,
J = 2.4 Hz), 11.00 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) δ: 40.8, 62.3, 71.7, 80.8, 87.1, 105.9, 115.2,
125.8, 129.4, 130.4, 132.9, 134.2, 138.5, 142.2, 152.6,
152.8, 164.6, 165.5. IR (KBr): 3376, 3310, 2225, 1700,
1588, 1534 cm−1; ESI LRMS m/z: 493 (MH+), 515
(MNa+). HRMS (FAB): Calcd for C19H18BrN4O5S:
493.0182 (MH+), found 493.0163.
5c: Colorless solid, mp 161–162◦C; 1H NMR
(400 MHz, DMSO-d6) δ: 2.05 (s, 3H, CH3), 2.08
(s, 3H, CH3), 2.26–2.28 (m, 2H, CH2), 2.38 (s, 3H,
CH3), 4.08–4.13 (m, 3H, CH2, CH), 5.12–5.14 (m,
1H, CH), 5.78–5.84 (m, 1H, CH), 7.33 (d, 2H, ArH,
J = 8.0 Hz,), 7.49 (d, 2H, ArH, J = 8.0 Hz), 8.72
(d, 1H, J = 2.0 Hz, CH), 8.89 (d, 1H, CH, J =
2.0 Hz), 8.93 (d, 1H, NH, J = 9.0 Hz), 11.08 (br
s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 21.0,
21.2, 21.3, 37.2, 64.6, 75.4, 81.0, 81.3, 105.5, 115.3,
123.3 125.3, 130.8, 135.9, 140.7, 142.0, 152.7, 153.1,
165.8, 166.4, 170.5, 170. IR (KBr): 3294, 2226, 1746,
1687, 1592, 1528 cm−1; ESI LRMS m/z: 513 (MH+),
535 (MNa+). HRMS (FAB): Calcd for C24H25N4O7S:
513.1445 (MH+), found 513.1456.
5g: Colorless solid, mp 143–144◦C; 1H NMR (400
MHz, DMSO-d6) δ: 2.04 (s, 3H, CH3), 2.05 (s, 3H,
CH3), 2.26–2.28 (m, 2H, CH2), 4.08–4.12 (m, 3H, CH,
CH2), 5.12–5.14 (m, 1H, CH), 5.80–5.82 (m, 1H, CH),
7.59–7.66 (m, 4H, ArH), 8.75 (d, 1H, CH, J = 2.4 Hz),
8.92 (d, 1H, CH, J = 2.4 Hz), 8.94 (d, 1H, NH, J =
9.2 Hz), 11.10 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) δ: 21.0, 21.2, 37.2, 64.6, 75.4, 81.0, 81.3,
105.8, 115.2, 125.6, 126.0, 130.2, 135.8, 137.7, 142.1,
152.7, 153.0, 165.5, 165.7, 170.5, 170.7. IR (KBr):
3280, 2225, 1748, 1690, 1533 cm−1; ESI LRMS m/z:
533 (MH+), 555 (MNa+). HRMS (FAB): Calcd for
C23H22ClN4O7S: 533.0898 (MH+), found 533.0899.
5h: Colorless solid, mp 177–179◦C. 1H NMR (400
MHz, DMSO-d6) δ: 1.98–2.08 (m, 2H, CH2), 3.36–3.41
(m, 2H, CH2), 3.67–3.69 (m, 1H, OH), 4.14–4.15 (m,
1H, CH), 4.81 (t, 1H, J = 5.2 Hz, OH), 5.06–5.08 (m,
1H, CH), 5.73–5.79 (m, 1H, CH), 7.60 (d, 2H, J =
8.0 Hz, ArH), 7.65 (d, 2H, J = 8.0 Hz, ArH), 8.74 (d,
1H, CH, J = 2.4 Hz), 8.80 (d, 1H, J = 9.2 Hz, NH),
8.91 (d, 1H, CH, J = 2.4 Hz,), 10.97 (s, 1H, NH).
13C NMR (100 MHz, DMSO-d6) δ: 62.5, 73.0, 80.8,
87.6, 105.5, 115.3, 123.3, 125.4, 130.8, 135.9, 140.7,
142.0, 152.6, 152.9, 165.5, 166.3. IR (KBr): 3377,
3318, 2229, 1702, 1588, 1534 cm−1; ESI LRMS m/z:
449 (MH+), 471 (MNa+). HRMS (FAB): Calcd for
C19H18ClN4O5S: 449.0687 (MH+), found 449.0673.
5d: Colorless solid, mp 163–165◦C; 1H NMR (400
MHz, DMSO-d6) δ: 1.97–2.05 (m, 2H, CH2), 2.38 (s,
3H, CH3), 3.36–3.41 (m, 2H, CH2), 3.66–3.69 (m,
1H, OH), 4.14–4.15 (m, 1H, CH), 4.81 (t, 1H, J =
5.2 Hz, OH), 5.06–5.08 (m, 1H, CH), 5.73–5.79 (m,
1H, CH), 7.33 (d, 2H, J = 8.0 Hz, ArH), 7.49 (d, 2H,
J = 8.0 Hz, ArH), 8.71 (d, 1H, CH, J = 2.4 Hz),
8.80 (d, 1H, NH, J = 9.2 Hz), 8.88 (d, 1H, CH, J =
2.4 Hz), 10.97 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) δ: 21.3, 40.8, 62.5, 71.6, 80.8, 87.1, 105.5,
115.3, 123.3, 125.4, 130.8, 135.9, 140.7, 142.0, 152.6,
152.9, 165.5, 166.3. IR (KBr): 3379, 3310, 2230,
1703, 1587, 1534 cm−1; ESI LRMS m/z: 429 (MH+),
551 (MNa+). HRMS (FAB): Calcd for C20H21N4O5S:
429.1233 (MH+), found 429.1238.
5e: Colorless solid, mp 111–112◦C; 1H NMR (400
MHz, DMSO-d6) δ: 2.05 (s, 3H, CH3), 2.08 (s, 3H,
CH3), 2.19–2.28 (m, 2H, CH2), 4.08–4.12 (m, 3H,
CH2, CH), 5.12–5.14 (m, 1H, CH), 5.80–5.84 (m, 1H,
CH), 7.14–7.86 (m, 4H, ArH), 8.77–8.92 (m, 3H, NH,
2 × CH), 11.09 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) δ: 23.3, 23.5, 66.8, 77.6, 83.3, 83.5, 108.1,
117.4, 127.9, 130.8, 131.6, 132.6, 135.1, 136.4, 140.7,
144.5, 155.0, 155.2, 166.9, 167.9, 172,7, 172.9. IR
(KBr): 3299, 2221, 1750, 1688, 1596, 1533 cm−1; ESI
Heteroatom Chemistry DOI 10.1002/hc

A Novel Preparation of Pyridine–Urea Hybrids and Elucidation of Their Structures 367
5i: Colorless solid, mp 143–144◦C; 1H NMR (400
4a: Colorless solid, mp 166–167◦C; 1H NMR
(400 MHz, DMSO-d6) δ: 1.99 (s, 3H, CH3), 2.07 (s,
3H, CH3), 2.43–2.49 (m, 2H, CH2), 4.22–4.25 (m,
3H, CH2, CH), 5.21–5.23 (m, 1H, CH), 6.23–6.26 (m,
1H, CH), 7.49–7.58 (m, 5H, ArH), 7.77 (br s, 2H,
NH2), 8.17 (s, 1H, CH), 12.00 (br s, 1H, NH). 13C
NMR (100 MHz, DMSO-d6) δ: 20.5, 20.6, 37.0, 37.0,
64.4, 74.8, 82.7, 85.6, 85.7, 89.3, 89.4, 95.4, 95.5,
109.5, 115.1, 115.3, 115.4, 115.7, 127.7, 129.8, 130.2,
135.7, 142.9, 142.9, 150.5, 151.6, 160.5, 166.9, 167.0,
170.6, 170.7. IR (KBr): 3434, 3332, 3223, 3069, 2217,
1745, 1690, 1550 cm−1; ESI LRMS m/z: 563 (MH+),
585 (MNa+). HRMS (FAB): Calcd for C26H23N6O7S:
563.1349 (MH+), found 563.1353.
MHz, DMSO-d6) δ: 2.05 (s, 3H, CH3), 2.08 (s, 3H,
CH3), 2.26–2.28 (m, 2H, CH2), 4.08–4.12 (m, 3H, CH,
CH2), 5.12–5.14 (m, 1H, CH), 5.78–5.84 (m, 1H, CH),
7.36–7.70 (m, 4H, ArH), 8.74–8.93 (m, 3H, NH, 2 ×
CH), 11.08 (s, 1H, NH). 13C NMR (100 MHz, DMSO-
d6) δ: 23.3, 23.5, 39.4, 66.8, 77.6, 83.2, 83.5, 107.8,
117.5, 119.5, 119.7, 124.8, 127.7, 140.7, 140.8, 144.3,
154.9, 155.2, 167.9, 168.1, 172.7, 172.9. IR (KBr):
3300, 2226, 1736, 1680, 1534 cm−1; ESI LRMS m/z:
517 (MH+), 539 (MNa+). HRMS (FAB): Calcd for
C23H22FN4O7S: 517.1194 (MH+), found 517.1199.
5j: colorless solid, mp 177–178◦C; 1H NMR (400
MHz, DMSO-d6) δ: 1.94–2.03 (m, 2H, CH2), 3.37–3.39
(m, 2H, CH2), 3.67–3.68 (m, 1H, OH), 4.15–4.16 (m,
1H, CH), 4.82 (t, 1H, J = 5.2 Hz, OH), 5.07–5.08 (m,
1H, CH), 5.73–5.78 (m, 1H, CH), 7.36–7.70 (m, 4H,
ArH), 8.73 (d, 1H, CH, J = 2.0 Hz), 8.81 (d, 1H, NH,
J = 9.2 Hz,), 8.90 (d, 1H, CH, J = 2.0 Hz), 10.98
(s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) δ: 62.5,
71.6, 80.8, 87.1, 105.6, 115.3, 117.2, 117.5, 122.6,
125.6, 138.5, 138.6, 142.0, 152.7, 152.8, 162.5, 165.0,
165.5, 165.8. IR (KBr): 3385, 3300, 2228, 1705, 1588,
1530 cm−1; ESI LRMS m/z: 433 (MH+), 455 (MNa+).
HRMS (FAB): Calcd for C19H18FN4O5S: 433.0983
(MH+), found 433.0996.
4b: Colorless solid, mp >250◦C; 1H NMR
(400 MHz, CD3OD) δ: 2.25–2.41 (m, 2H, CH2), 3.72–
3.84 (m, 2H, CH2), 3.95–3.96 (m, 1H, CH), 4.43–4.47
(m, 1H, CH), 6.32–6.36 (m, 1H, CH), 7.46–7.58 (m,
5H, ArH), 8.59 (s, 1H, CH). 13C NMR (100 MHz,
CD3OD) δ: 41.1, 61.3, 70.6, 70.6, 85.9, 88.1, 108.3,
108.4, 114.5, 114.7, 114.8, 115.0, 127.6, 129.3, 129.8,
135.6, 143.0, 143.1, 150.2, 150.9, 151.0, 160.2, 161.0,
167.8, 167.9. IR (KBr): 3455, 3195, 3047, 2216,
1711, 1683, 1554 cm−1; ESI LRMS m/z: 479 (MH+),
501 (MNa+). HRMS (FAB): Calcd for C22H19N6O5S:
479.1138 (MH+), found 479.1125.
Procedure for the Preparation of Compound 7
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To a suspension of 6 (0.5 mmol) and 2 (0.6 mmol)
in ethanol (2 mL), TEA (10 μL) was added. The sus-
pension was refluxed for 2 h. Volatiles were evapo-
rated in vacuo, and the residue was purified on silica
gel (hexane/ethyl acetate, 3:1) to yield 7 as colorless
solid.
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1
7: Colorless solid, H NMR (400 MHz, DMSO-
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