An efficient one-pot synthesis of heterocycle-fused 1,2,3-triazole derivatives as anti-cancer agents

Article abstract of DOI:10.1016/j.bmcl.2010.06.141

A series of heterocycle-fused 1,2,3-triazoles were easily prepared by the 1,3-dipolar cycloaddition of heterocyclic ketene aminals or N,O-acetals with sodium azide and polyhalo isophthalonitriles in a one-pot reaction at room temperature without a catalyst and evaluated in vitro against a panel of human tumour cell lines. 1,3-Oxazoheterocycle fused 1,2,3-triazoles were more potent against the tumour cell lines Skov-3, HL-60, A431, A549 and HepG-2 than 1,3-diazoheterocycle fused 1,2,3-triazoles. 4-Methoxyphenyl substituted 1,3-oxazoheterocycle fused 1,2,3-triazole 6j was found to be the most potent derivative with IC₅₀ values lower than 1.9 μg/mL against A431 and K562 human tumour cell lines.

Full text of DOI:10.1016/j.bmcl.2010.06.141

Bioorganic & Medicinal Chemistry Letters 20 (2010) 5225–5228
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
An efficient one-pot synthesis of heterocycle-fused 1,2,3-triazole derivatives
as anti-cancer agents
*
Sheng-Jiao Yan , Yong-Jiang Liu , Yu-Lan Chen, Lin Liu, Jun Lin
Key Laboratory of Medicinal Chemistry for Natural Resources (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming 650091, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of heterocycle-fused 1,2,3-triazoles were easily prepared by the 1,3-dipolar cycloaddition of
heterocyclic ketene aminals or N,O-acetals with sodium azide and polyhalo isophthalonitriles in a one-
pot reaction at room temperature without a catalyst and evaluated in vitro against a panel of human
tumour cell lines. 1,3-Oxazoheterocycle fused 1,2,3-triazoles were more potent against the tumour cell
lines Skov-3, HL-60, A431, A549 and HepG-2 than 1,3-diazoheterocycle fused 1,2,3-triazoles. 4-Methoxy-
phenyl substituted 1,3-oxazoheterocycle fused 1,2,3-triazole 6j was found to be the most potent deriva-
Received 28 April 2010
Revised 12 June 2010
Accepted 30 June 2010
Available online 23 July 2010
Keywords:
One-pot synthesis
1,2,3-Triazole
tive with IC50 values lower than 1.9
lg/mL against A431 and K562 human tumour cell lines.
Ó 2010 Elsevier Ltd. All rights reserved.
Anti-cancer agents
1,2,3-Triazole derivatives possess substantial biological activi-
ties, including anti-tumour,1 anti-HIV,2 antiallergic,3 antifungal,3b
and antimicrobial4,5 properties. 1,2,3-Triazoles have also been used
as building blocks for the synthesis of important bio-conjugations.6
Due to their broad range of biological activities and their value as
synthetic precursors for pharmaceutical compounds, 1,2,3-triazole
derivatives have received increasing attention. Many methods for
the synthesis of 1,2,3-triazoles have been reported in literature,
including 1,3-dipolar cycloaddition or cycloaddition of azides to
alkynes,7 nitroethenes,8 and sodium phenylacetylide.9 Among
them, the most common method is the azide-alkyne cycloaddi-
tion7h–j catalyzed by copper. The azides normally used in this reac-
tion are the tosyl azides,10 trimethylsilyl azide,8,11 azidobenzene,12
and sodium azide.13
However, these methods usually present limitations, such as the
need to employ multistep reactions15a–c to obtain the dangerous or-
ganic azides and the need to heat the reaction mixture,15c–e which
contain organic azides or 1,2,3-triazoles that are explosive when
heated.16 Among these procedures, only tosyl azides can be used
to effectively obtain heterocycle-fused 1,2,3-triazole 6 (Fig. 1). This
may be due to the strong electron-withdrawing properties of the
tosyl group. It is inferred that increasing the electron-withdrawing
ability of substituted azidobenzene can improve its reaction with
HKAs to form the heterocycle-fused 1,2,3-triazoles, just as in the
case of tosyl azides.
Polyhalo isophthalonitriles have been widely used as synthetic
materials in organic synthesis.17 We envisage the synthesis of
Heterocyclic ketene aminals (HKAs) are versatile intermediates
for the synthesis of a wide variety of heterocyclic compounds,14
especially 1,2,3-triazole derivatives15 (Fig. 1). For instance, HKAs
and glycosyl azide have been used to prepare N-glycosyl 1,2,3-tria-
zoles 315a and 4.15b HKAs have been reacted with 1-azido-4-nitro-
benzene at room temperature to synthesize N-aryl 1,2,3-triazole
5,15c while other azid-obenzes such as 1-azido-4-chlorobenzene,
1-azido-4-methylbenzene, and 1-azido-4-methoxy benzene, can
give both N-aryl 1,2,3-triazole 5 as the major product and thehetero-
cycle-fused 1,2,3-triazole 6 as the minor product.15c Tosyl azides
have been refluxed with HKAs in acetonitrile15d or dioxane15e to
obtain fused 1,2,3-triazole 6 in moderate yields.
OAc
OAc
OBz
OBz
R
O
O
NH
N
R
NH
N
n
OAc
OAc
Ref. 15a
N
n
OBz
N
N N
N N
3
4
Ref. 15b
O
NH
R
NH O
Ref.
15c
NH
Ref.
15d-e
R
n
N
n
n
N
N Ar
N N
R
N
N
N
1
H
6
5
Ref. 15c
Y
R
O
NH
N
NH
N
n
N
R
n
N N
5 yield = 8-76%
N
N
yield = 6-31%
6
* Corresponding author. Tel./fax: +86 871 5033215.
E-mail address: linjun@ynu.edu.cn (J. Lin).
These authors contributed equally to this paper.
Figure 1. 1,2,3-Triazoles derived from heterocyclic ketene aminals 1.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.06.141

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S.-J. Yan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5225–5228
4-azido-2,5,6-trihalobenz-ene-1,3-dinitriles from
a substitution
F
Z
O
NC
F
CN
F
reaction between polyhalo isophthalonitriles and sodium azide
in situ. This compound could have considerable reactivity and good
electronic properties due to the electron-withdrawing halo and
cyano groups. Based on these motivations, we attempted to obtain
a series of novel and temporary organic azides.
Furthermore, one-pot reaction at room temperature under
catalyst-free conditions, which have become a powerful tool to
rapidly construct diverse libraries of organic compounds since
the products are formed in a single step and diversity can be
achieved by simply varying each component, is highly desirable.
Thus, exploring a concise, efficient and safe method for the synthe-
sis of heterocycle-fused 1,2,3-triazole derivatives based on one-pot
reactions is very important and necessary.
DMF, rt
n
NaN3
N
R
Catalyst-free
One-pot
H
8
F
7a
1: Z=NH
2: Z=O
F
Z
O
NC
F
CN
NH2
n
N
N N
R
6
F
n=1,2; Z=NH, O
R=Me, p-MeOPh,
9a
p-MePh, Ph, p-ClPh
Scheme 2. Synthesis of heterocycle-fused 1,2,3-triazole derivatives 6.
In this Letter, we report a novel one-pot, three-component
synthesis of heterocycle-fused 1,2,3-triazole derivatives using a
room temperature reaction of sodium azide with polyhalo isopht-
halonitriles and HKAs or N,O-acetals. The heterocycle-fused 1,2,3-
triazoles 6 (Schemes 1 and 2) were obtained in excellent yields
(86–93%).
Initially, the reactions of HKAs 1a with polyhalo isophthalonitr-
iles 7a were chosen as models to test this protocol (Scheme 1). As
shown in Table 1, different solvents such as acetonitrile, 1,4-diox-
ane, toluene, and DMF were tested at room temperature (entries
1–6). It demonstrated that DMF was the optimum solvent (entry
6) to afford product 6a, while toluene was the poorest solvent (entry
1). This is because 1a and sodium azide are hardly soluble in toluene,
which presumably reduced the efficiency of the reaction. The HKAs
1a reacted with 7a in DMF at room temperature and proceeded
smoothly to form the target product 6a with 90% yield.
Table 1
Optimization of reaction conditionsa
Entry
HKAs
Substrate
Solvent
6 Yieldb (%)
9 Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1a
1b
1a
1b
7a
7a
7a
7a
7a
7a
7a
7b
7b
7c
7c
Toluene
DCM
THF
CH3CN
Dioxane
DMF
DMF
DMF
DMF
DMF
56
60
67
81
84
90
88
89
86
87
83
54
59
65
80
84
89
88
87
85
86
80
10
11
DMF
a
All reactions were done for 10 h at rt.
Isolated yields based on HKAs 1.
b
In order to study other organic azides in situ, 7b and 7c were
used as substrates to react with sodium azide and HKAs 1a and
1b under the same conditions. The HKAs 1b and the polyhalo
isophthalonitrile 7a were reacted in DMF to form the target prod-
uct 6b in good yield at room temperature. The results listed in Ta-
ble 1 demonstrate that polyhalo isophthalonitriles with various
substituents 7a–c were all good substrates for the reaction. The
procedure was straightforward and gave very good overall yields
(Table 1, entries 6–11). It is also worth mentioning that the struc-
ture of the polyhalo isophthalonitrile 7 had a noticeable influence
on the reaction.
The reactivity of 7 varied with the electron-withdrawing prop-
erties of groups X and Y, and the reactivities of the polyhalo isopht-
halonitriles under typical conditions were ranked in the following
order: 7a > 7b > 7c (Table 1, entries 6–11).
2,4,5,6-Tetrafluorobenzene-1,3-dinitrile 7a was found to be the
optimum substrate to react with different types of HKAs 1a–i
(Table 2, entries 1–9).18 The results demonstrated that HKAs with
various substituents and different ring-sizes were all good sub-
strates for the 1,3-dipolar cycloaddition reactions (entries 1–9).
Table 2
Synthesis of heterocycle-fused 1,2,3-triazole 6
Entry 1/2
6
9
n
Z
R
6 Yielda (%) 9a Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
6a
6b
6c
6d
6e
6f
6g
6h
6i
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
9a
1
1
1
1
1
2
2
2
2
1
1
1
1
NH p-MeOPh 90
NH p-MePh
NH Ph
NH p-ClPh
NH Me
NH p-MeOPh 92
NH p-MePh
NH Ph
NH p-ClPh
O
O
O
O
89
88
90
88
87
90
89
86
89
91
85
87
87
88
91
89
89
90
88
91
6j
6k
6l
p-MeOPh 93
p-MePh
Ph
86
87
89
6m 9a
p-ClPh
a
Isolated yields based on HKAs.
The reactions took 10 h at room temperature in DMF, and the
yields were generally good. The substituents of the HKAs rings only
slightly influenced the reactivity (e.g., entries 1 vs 6, 2 vs 7, 3 vs 8).
In order to expand the scope of the dipolar cycloaddition reac-
tion, HKAs 1a–i were replaced by N,O-acetals 2a–d (entries 1–5 vs
10–13) and subjected to the reaction conditions described above.
The reactions provided products in good yields.18
X
NC
X
CN
X
NH O
Solvent, rt
10h
NaN3
8
N
R
H
Y
1a: R=p-MeOPh
7a: X=F, Y=F
7b: X=F, Y=Cl
7c: X=Cl, Y=Cl
According to the observed and reported15c findings, the step-
wise mechanism employed in this case involved the initial forma-
tion of a 4-azido-2,5,6-trihalobenzene-1,3-dinitrile 10 from the
reaction of polyhalo isophthalonitrile 7 with sodium azide 8. Sub-
sequently, the temporary intermediate 10 reacted with HKAs 1 or
N,O-acetals 2 via an intermolecular 1,3-dipolar cycloaddition to
form 11, before the C–N bond was broken to give 12, which under-
went two competitive reaction pathways. In route A, intermediate
12 afforded 13 through an imine–enamine tautomerization,
1b: R=p-MePh
X
O
NH
N
NC
CN
R
N
X
NH2
9a: X=F, Y=F
9b: X=F, Y=Cl
9c: X=Cl, Y=Cl
N
Y
6a: R=p-MeOPh
6b: R=p-MePh
Scheme 1. Synthesis of heterocycle-fused 1,2,3-triazole derivatives.

S.-J. Yan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5225–5228
5227
Y
X
X
Z
O
R
X
Y
H
X
X
X
r
n
o
N N
HN
u
N N
t
e
R
N
NC
X
CN
N3
R
O
NC
X
CN
X
A
CN
NaN3
H
N
CN
CN
Y
X
X
1 or 2
8
O
N
Z
N
N
NC
12
Z
N
R
O
-NaX
NC
CN
CN
N
H
H
[3+2]
CN
Y
10
Y
7
n
n
11
CN
13
Z
N
n
X
X
X
H
R
Y
N
X
X
X
NH
N
N
NC
-H2O
N
NC
Z
N
O
NC
X
N
n
R
N
CN
H
N
n
n
N
R
Y
N
X
Y
R
N N
NH2
9
HO
Z
N N
6
NC
O
Z
N
n
Y
5
15
14
Scheme 3. Proposed mechanism for the formation of 1,2,3-triazoles.
Table 3
Cytotoxic activity of heterocycle-fused 1,2,3-triazoles in vitroa (IC50
O
O
,
l
g/mLb)
HepG-2
Z
O
N
n
N
No.
Compound
K562
Skov-3
HL60
A431
A549
N
N
6j
OCH3
R
N N
1
2
3
4
5
6
7
8
9
10
11
12
13
14
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
2.8
9.4
92
16.1
>200
3.4
1.5
28.6
3.2
159
>200
>200
>200
>200
190
124
>200
>200
9.6
>200
>200
>200
>200
>200
>200
>200
>200
>200
21.1
13.7
17.2
6.5
>200
>200
>200
57.6
>200
64.4
>200
>200
>200
1.9
>200
>200
>200
>200
>200
>200
>200
>200
>200
58
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
198
Best potent compound
n =2 > n =1;
R=p-MeOPh>p-MePh>Ph>p-ClPh
aganist K562 cells: Z=NH>Z=O
aganist Skov-3, HL-60, A431 and
A549 cell lines: Z=O>Z=NH
Scheme 4. Structure–activity relationship of heterocycle-fused 1,2,3-triazole
derivatives.
1.0
127
>200
>200
2.2
8.5
66.1
8.6
12.7
10.8
3.8
79
78
42
5.1
>200
>200
8.2
6m
Cisplatin (DDP)
0.5
1.4
0.6
by the electron-rich properties of the R group (Table 3, entries
1–4). The activity of the six-membered 1,3-diazoheterocycle
fused 1,2,3-triazole 6 against K562 cells followed the same pattern
(Table 3, entries 5–9). On the whole, the activity of six-membered
1,3-diazoheterocycle fused 1,2,3-triazoles against K562 cells more
active than that of five-member 1,3-diazoheterocycle fused 1,2,3-
triazoles (Table 3, entries 1–4 vs 6–9). As a result, 6g more active
than cisplatin against K562 cells (Table 3, entry 7). On the other
hand, 6a–i have lower activity to Skov-3, HL-60, A431, A549 and
Hep-2 cell lines (Table 3, entries 1–9).
However, the 1,3-oxazoheterocycle fused 1,2,3-triazoles 6j–m
exhibited lower cytotoxic activity against K562 cells (except 6j),
comparing with DDP (entries 10–13 vs 14). These four compounds
exhibited moderate cytotoxic activity against Skov-3, HL-60, A431
and A549 tumour cell lines (entries 10–13). 6j–m almost not
exhibited any cytotoxic activity against HepG-2 cells. These results
suggest that the isostere of N and O (Z = NH, O) play a vital role in
the modulation of cytotoxic activity to different tumour cell lines
(Table 3, entries 1–9 vs 10–13).
All in all, compounds 6a–m were more potent against the K562,
Skov-3 and A431 tumour cells. Of these, compound 6j, bearing
4-methoxy-phenyl substituents, was the most potent derivative
with IC50 values lower than 1.9 lg/mL against A431 and K562
human tumour cells (entry 10 and Scheme 4).
In conclusion, we have developed a simple one-pot synthesis of
biologically significant heterocycle-fused 1,2,3-triazole derivatives
in good yields at room temperature under catalyst-free conditions.
The protocol is applicable to a wide range of HKAs and polyhalo
isophthalonitrile compounds and allows the assembly of a diverse
set of heterocycle-fused 1,2,3-triazole derivatives. Compounds
6j–m proved to have moderate to good cellular cytotoxicity. The
electron-rich properties of the R group and 1,3-oxazohetero-cycle
played a vital role in the modulation of the cytotoxic activity,
and 6j proved to be the most promising lead for further structural
modifications guided by the valuable information provided by the
detailed SARs described here.
a
The cytotoxicity (as IC50 for each cell line) is the concentration of compound
that reduced the optical density of treated cells by 50% with respect to untreated
cells using the MTT assay.
b
Data represent the mean values of three independent determinations.
followed by the loss of 4-amino-2,5,6-trihalobenzene-1,3-dinitrile
9 and cyclo-condensation to obtain the target product 6. In route
B, the nitrogen atom of intermediate 12 attacked the carbonyl
group to form 15. After aromatization to eliminate water, N-aryl
1,2,3-triazole 5 was produced (Scheme 3). The strongly electron-
withdrawing ability of cyano groups and halogen atoms and the
larger steric-effects of the highly functionalized aryl ring decreased
the nucleophilicity of the nitrogen atom of intermediate 12. There-
fore, the reaction rate in route A was faster than that in route B. As
a result, we cannot obtain the N-aryl 1,2,3-triazole 5.
The synthesized heterocycle-fused 1,2,3-triazoles 6 were evalu-
ated for in vitro anti-cancer activity against human cells according
to procedures described in the literature.19 The tumour cells in-
cluded myeloid leukaemia (K562 and HL-60), ovarian carcinoma
(Skov-3), epidermoid carcinoma (A431), lung adenocarcinoma
(A549) and laryngeal carcinoma (Hep-2) cells. Cisplatin (DDP)
was used as the reference drug. The results of the cytotoxicity
studies are summarized in Table 3 (IC50 value, defined as the con-
centration corresponding to 50% growth inhibition). As shown in
Table 3, some of the compounds showed good activity against
the cells.
The data indicate that 1,3-diazoheterocycle fused 1,2,3-triazoles
6a–i have good activity towards K562 tumour cell line (Table 3, en-
tries 1–9 vs 14). The structures of the 1,3-diazoheterocycle fused
1,2,3-triazoles 6 have an obvious influence on the cytotoxicity
against K562 cells. The different substituents and same ring-sizes
(n = 1 or n = 2) of 1,2,3-triazoles all contribute to their bioactivity.
For example, the activity of five-membered 1,3-diazoheterocycle
fused 1,2,3-triazoles 6 against human K562 cells was increased

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S.-J. Yan et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5225–5228
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Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.06.141.
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18. General procedure for the 1,3-dipolar cycloaddition reaction: a 25 mL round-
bottom flask was charged with polyhalo isophthalonitrile 7 (2 mmol), DMF
(10 mL), and sodium azide (156 mg, 2.4 mmol). Then, HKAs 1 or N,O-acetals 2
(2 mmol) were added. The mixture was stirred for 10 h at room temperature
until 1 or 2 was completely consumed. The reaction was quenched with
subsequent additions of water (30 mL) and EtOAc (30 mL). The organic phase
was washed with water (10 mL Â 2), dried over Na2SO4, concentrated, and
purified by flash column chromatography to acquire the heterocycle-fused
1,2,3-triazole 6 in 86–93% yield and compound 9 in 85–91% yield. Compound
6e: light yellow solid, mp = 169–169.5 °C. IR (KBr): 3266, 2955, 1637,
2. (a) Alvarez, R.; Velazquez, S.; San, F.; Aquaro, S.; De, C.; Perno, C. F.; Karlsson, A.;
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Passamani, F.; Rodrigues, C. R.; Ferreira, V. F. Eur. J. Med. Chem. 2009, 44, 373.
3. (a) Buckle, D. R.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. J. Med. Chem. 1986, 29,
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Tetrahedron 2005, 61, 9118.
5. (a) Shen, J.; Woodward, R.; Kedenburg, J. P.; Liu, X.-W.; Chen, M.; Fang, L.-Y.;
Sun, D.-X.; Wang, P.-G. J. Med. Chem. 2009, 51, 7417; (b) Hou, D.-R.; Alam, S.;
Kuan, T. C.; Ramanathan, M.; Lin, T.-P.; Huang, M.-S. Bioorg. Med. Chem. Lett.
2009, 19, 1022; (c) Jordã, A. K.; Ferreira, V. F.; Lima, E. S.; de Souza, M. C. B. V.;
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Cunha, A. C. Bioorg. Med. Chem. 2009, 17, 3713; (d) Thompson, A. M.; Blaser, A.;
Anderson, R. F.; Shinde, S. S.; Franzblau, S. G.; Ma, Z.-K.; Denny, W. A.; Palmer, B.
D. J. Med. Chem. 2009, 52, 637.
1584 cmÀ1 1H NMR (500 MHz, DMSO-d6): d 2.41 (s, 3H, CH3), 4.21 (t, J = 8.5,
.
2H, NCH2), 4.41 (t, J = 8.2 Hz, 2H, NCH2), 7.26 (br, 1H, NH). 13C NMR (125 MHz,
DMSO-d6): d 26.2, 44.6, 52.8, 126.0, 152.9, 190.3. HRMS (TOF ES+): m/z calcd for
C6H8N4NaO [(M+Na)+], 175.0590; found, 175.0597. Compound 6j: white solid,
mp = 148.5–149 °C. IR (KBr): 3265, 2966, 2924, 2846, 1590, 1506, 1428, 1253,
1169 cmÀ1 1H NMR (500 MHz, DMSO-d6):
. d 3.85 (s, 3H, CH3O), 4.66 (t,
J = 8.3 Hz, 2H, NCH2), 5.53 (t, J = 8.3 Hz, 2H, OCH2), 7.08 (d, J = 8.8 Hz, 2H, ArH),
8.29 (d, J = 8.8 Hz, 2H, ArH). 13C NMR (125 MHz, DMSO-d6): d 44.6, 55.8, 82.6,
114.0, 123.2, 129.6, 132.4, 160.8, 163.4, 182.0. HRMS (TOF ES+): m/z calcd for
C
12H11N3NaO3 [(M+Na)+], 268.0693; found, 268.0697. Compound 6k: white
solid, mp = 142–143.5 °C. IR (KBr): 3432, 2920, 1637, 1570, 1164 cmÀ1 1H
.
NMR (500 MHz, DMSO-d6): d 1.94 (s, 3H, CH3), 4.20 (t, J = 8.3 Hz, 2H, NCH2),
5.07 (t, J = 8.4 Hz, 2H, OCH2), 6.91 (d, J = 7.9 Hz, 2H, ArH), 7.69 (d, J = 8.0 Hz, 2H,
ArH). 13C NMR (125 MHz, DMSO-d6): d 21.1, 44.2, 82.3, 122.6, 128.9, 129.7,
133.9, 143.2, 160.4, 182.8. HRMS (TOF ES+): m/z calcd for C12H11N3NaO2
[(M+Na)+], 252.0743; found, 252.0748. Compound 6l: white solid, mp = 135–
6. Bourne, Y.; Kolb, H. C.; Radic, Z.; Sharpless, K. B.; Taylor, P.; Marchot, P. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 1449.
7. (a) Balducci, E.; Bellucci, L.; Petricci, E.; Taddei, M.; Tafi, A. J. Org. Chem. 2009,
74, 1314; (b) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004; (c) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem.
2006, 51; (d) Gil, M. V.; Arévalo, M. J.; López, O. Synthesis 2007, 1589; (e) Zhang,
F.-Z.; Moses, J. E. Org. Lett. 2009, 11, 1587; (f) Wu, L.-Y.; Xie, Y.-X.; Chen, Z.-S.;
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Das, B.; Achari, B. J. Org. Chem. 2009, 74, 3612; For review, see: (h) Lutz, J. F.;
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2009, 109, 4207.
137 °C. IR (KBr): 3436, 3072, 2985, 1542, 1572, 1168 cmÀ1 1H NMR (500 MHz,
.
DMSO-d6): d 4.67 (t, J = 8.3 Hz, 2H, NCH2), 5.54 (t, J = 8.3 Hz, 2H, OCH2), 7.49–
7.57 (m, 2H, PhH), 7.63–7.66 (m, 2H, PhH), 8.20–8.27 (m, 1H, PhH). 13C NMR
(125 MHz, DMSO-d6): d 44.6, 82.9, 123.0, 128.7, 129.9, 133.2, 137.0, 161.0,
183.7. HRMS (TOF ES+): m/z calcd for C11H9N3NaO2 [(M+Na)+], 238.0587;
found, 238.0590. Compound 6m: white solid; mp = 145–147 °C. IR (KBr): 3433,
2971, 1641, 1583, 1162, 1088 cmÀ1 1H NMR (500 MHz, DMSO-d6): d 4.67 (t,
.
J = 8.5 Hz, 2H, NCH2), 5.55 (t, J = 8.4 Hz, 2H, OCH2), 7.65 (d, J = 8.5 Hz, 2H, Ph),
8.26 (d, J = 8.3 Hz, 2H, Ph). 13C NMR (125 MHz, DMSO-d6): d 44.7, 83.0, 129.0,
131.9, 135.5, 138.3, 161.1, 182.3. HRMS (TOF ES+): m/z calcd for C11H8ClN3NaO2
[(M+Na)+], 272.0197; found, 272.0204.
8. (a) Yang, D.; Fu, N.; Liu, Z.-L.; Li, Y.; Chen, B.-H. Synlett 2007, 278; (b) David, A.;
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