Synthesis of Imidazoheterocycle-Hydrazine, -Carbamate, and Imidazocinnoline Derivatives

Article abstract of DOI:10.1055/s-0036-1588374

Iron-catalyzed amination of imidazoheterocycles with diethyl azodicarboxylate (DEAD) under mild conditions has been developed. This strategy tolerates a wide range of functional groups to afford diverse imidazoheterocycle-hydrazines in moderate to excelle

Full text of DOI:10.1055/s-0036-1588374

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
paper
A
J. Jiao et al.
Paper
Synthesis
Synthesis of Imidazoheterocycle-Hydrazine, -Carbamate, and
Imidazocinnoline Derivatives
Jing Jiaoa,b
N
Li Xua
R
Het
6 examples
up to 89% yield
N
Wenxu Zhenga
Ping Xionga
Mao-Lin Hu*b
Ri-Yuan Tang*a,b
N
NH
EtO
R
N
Het
N
DEAD
FeCl3
R
Het
O
N
N
NH
EtO
H
N
OEt
Het
3 examples
up to 81% yield
O
O
N
R = aryl, alkyl
a Department of Applied Chemistry, College of Materials and
Energy, South China Agricultural University, Guangzhou
510642, P. R. of China
24 examples
up to 95% yield
N
N
rytang@scau.edu.cn
b College of Chemistry and Materials Engineering, Wenzhou
University, Wenzhou 325035, P. R. of China
maolin@wzu.edu.cn
Received: 15.09.2016
Accepted after revision: 21.11.2016
Published online: 15.12.2016
cleavage of N–N bond of diethyl azodicarboxylate (DEAD).18
It is also reported that bipheylhydrazine-1,2-dicarboxylates
can undergo a cyclization to produce benzocinnoline.19 In-
spired by these works, we envisioned synthesizing imidazo-
heterocycle-carbamates and imidazocinnolines from imid-
azoheterocycle-hydrazines (Scheme 1, d). As well known,
carbamate is a significant structural unit, which is preva-
lent in medicinal and agricultural chemicals (such as ure-
thane, Metolcarb, Carbofuran and Pirimicarb) (Scheme 1,
b).20 As for cinnoline, it has been considered as a privileged
scaffold in medicinal chemistry due to its promising anti-
cancer activities (Scheme 1, c).21 Additionally, fused cinno-
lines have also been applied in organic nonlinear optic
(NLO) materials by utilizing a polarized heteroaromatic π-
system.22 Therefore, it is highly necessary to explore effi-
cient synthetic methods for imidazoheterocycle-hydra-
zines, -carbamates, and imidazocinnolines. Herein, we re-
port an iron-catalyzed method for the synthesis of imidazo-
heterocycle-hydrazines, which can be further transformed
to imidazoheterocycle-carbamates and imidazocinnolines
(Scheme 1, d).
The reaction between 6-phenylimidazo[2,1-b]thiazole
(1a) and DEAD (2a) was used as the reaction model, and the
results are summarized in Table 1. At the outset, we rea-
soned that the addition of Lewis acid may favor the amina-
tion addition of 1a with DEAD. Thus several Lewis acids
such as PdCl2, AlCl3, FeCl3, and ZnCl2 were evaluated in
DMSO at 80 °C for 12 hours (Table 1, entries 1–4). FeCl3, as
an ecofriendly reagent, was proved to be the most effective,
giving the target product 3 in 81% yield (entry 3). Next, var-
ious solvents, including NMP, DMA, MeCN, EtOH, DCE, tolu-
ene, and 1,4-dioxane, were investigated in the presence of
10 mol% of FeCl3 at 80 °C (entries 5–11). MeCN is a prefera-
ble solvent for the amination, giving product 3 in 93% yield
(entry 7). Encouraged by this result, we attempted lowering
DOI: 10.1055/s-0036-1588374; Art ID: ss-2016-h0637-op
Abstract Iron-catalyzed amination of imidazoheterocycles with dieth-
yl azodicarboxylate (DEAD) under mild conditions has been developed.
This strategy tolerates a wide range of functional groups to afford di-
verse imidazoheterocycle-hydrazines in moderate to excellent yields.
Significantly, imidazoheterocycle hydrazines can be converted into im-
idazoheterocycle carbamates and imidazocinnolines.
Key words iron, amination, imidazoheterocycle, carbamate, cinnoline
Imidazoheterocycles are a class of important drug skele-
ton with a broad range of biological activities.1 Many drugs
such as saripidem, nicopidem, alpidem, zolpidem, and
SIRT1 activator have been developed from imidazohetero-
cycles (Scheme 1, a).2 In recent years, increasing attention
has been paid to the diversity synthesis of imidazohetero-
cycles.3 Direct introduction of pharmacophores onto imid-
azoheterocycles is particularly interesting because it is an
effective way to engineer bioactive molecules for drug dis-
covery.4–16 These reaction techniques include thiolation,4
thiocyanation,5 dithiocarbamation,6 phosphonation,7 nitro-
sation,8 amination,9 carbonylation,10 trifluoromethylation,11
trifluoromethylthiolation,12 fluorination,13 heteroaryla-
tion,14 alkenylation,15 and alkylation.16 Although great prog-
ress has been achieved, there is still an intrinsic need to in-
troduce novel pharmacophores onto imidazoheterocycles
for drug development. Very recently, we have successfully
carried out the dithiocarbamation of imidazoheterocycles.6
However, the introduction of carbamate onto imidazohet-
erocycles has not yet been developed. In addition, although
some efforts have been devoted to the synthesis of several
heterocycle-fused imidazopyridines,17 the synthesis of cin-
noline-fused imidazoheterocycles is not yet reported. It is
reported that the carbamate motif can be derived from the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
J. Jiao et al.
Paper
Synthesis
Table 1 Screening of Optimal Conditionsa
a
N
N
N
R1
R1
N
N
R1
S
N
O
Ph
catalyst
solvent
S
N
O
N
N
OEt
N
+
EtO
N
Ph
R2
R2
N
NH
N
O
O
R2
EtO
H
OEt
O
Nicopidem, Saripidem
Alpidem, Zolpidem
O
2
1a
Entry
Cat. (mol %)
Solvent
Temp (°C)
Isolated yield (%)
N
N
N
1
2
PdCl2 (10)
AlCl3 (10)
FeCl3 (10)
ZnCl2 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (5)
–
DMSO
DMSO
DMSO
DMSO
NMP
80
80
80
80
80
80
80
80
80
80
80
80
80
60
r.t.
79
72
81
55
32
66
93
37
13
76
72
84
65
66
32
HN
HO
S
O
SIRT1 activator
3
b
4
N
H
O
O
5
O
N
O
N
N
O
O
H2N
O
6
DMA
O
N
O
HN
7
MeCN
EtOH
DCE
8
Urethane
Metolcarb
Pirimicarb
O
Carbofuran
9
c
10
11
12
13
14
15
1,4-dioxane
toluene
MeCN
H
N
N
OMe
N
N
O
O
OMe
N
N
N
N
N
MeCN
cinnoline (antibacterial)
anticancer
topoisomerase I inhibitor
FeCl3 (10)
FeCl3 (10)
MeCN
MeCN
d
This work
N
a Reaction conditions: 1a (0.2 mmol), 2 (0.3 mmol), solvent (2 mL), reaction
time 12 h.
N
R
Het
N
N
R
Het
R
N
OEt
HN
Het
N
OEt
N
H
O
+
HN
O
O
O
delight, the substrate with a hydroxyl group on the benzene
ring also performed well to give product 8 in 78% yield. By
comparison with 6-phenylimidazo[2,1-b]thiazole, 6-meth-
ylimidazo[2,1-b]thiazole was less reactive in the amination,
only a 67% yield of product 9 was obtained. It may result
from the conjugation effect between benzene ring and im-
idazole ring, which can stabilize the imidazole ring to favor
the reaction, whereas the methyl group has no conjugation
effect with the imidazole ring, leading to a lower yield. It
was pleasing to find that imidazo[2,1-b]benzothiazoles also
underwent the amination smoothly to give products 10–12
in good yields.
Next, the scope of imidazo[2,1-b]pyridines was also in-
vestigated (products 13–24). 2-Phenylimidazo[1,2-a]pyri-
dine appears to have excellent reactivity to give product 13
in 95% yield. Generally, the substrates with an electron-
donating group have better reactivity than those with an
electron-withdrawing group. For example, the substrate
with a methoxy group gave product 16 in 91% yield, where-
as the substrate with a fluoro group provided product 17 in
73% yield. The reaction of halo-substituted substrates (in-
cluding fluorine, chlorine, bromine, and ester) proceeded
well to give the corresponding products in moderate to
good yields (products 17–21). It is noteworthy that both
products 18 and 19 are synthetically useful for further
OEt
N
OEt
N
EtO
N
Het
O
N
N
N
Scheme 1 Biological molecules for imidazoheterocycles, carbamates,
and cinnolines
the loading of FeCl3 to obtain a desirable yield (entry 12). It
was shown that the amination still proceeded well with an
84% yield of product 3 in the presence of 5 mol% of FeCl3. On
the contrary, the yield of 3 was reduced to 65% when the
reaction was conducted in the absence of FeCl3 (entry 13).9
These results suggest that Lewis acid indeed accelerate the
amination. Further study shows that the reaction is highly
dependent on the temperature. The reaction at 60 °C gave
product 3 only in 66% yield in the presence of 10 mol% of
FeCl3 (entry 14), and the yield was sharply reduced to 32%
when the reaction was conducted at room temperature
(entry 15).
With the optimized reaction conditions in hand (Table
1, entry 7), the scope and generality of imidazoheterocycles
were investigated (Scheme 2). Imidazothiazole with a
methyl on the thiazole ring was tolerated well under the
standard conditions to give product 4 in 95% yield. To our
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
J. Jiao et al.
Paper
Synthesis
modification by coupling reaction at the halo group. The
substrate with an ester group also performed well to give
product 20 in 56% yield. The substrates with a biphenyl or a
naphthyl group were also tolerated well under the standard
conditions, giving products 22 and 23 in 80% and 84% yield,
respectively. Because of the poor reactivity, 2-methylimid-
azo[1,2-a]pyridine gave only product 24 in 54% yield. To our
delight, imidazopyrimidine is also a suitable substrate for
this transformation, providing the target product 25 in 77%
yield. By comparison with DEAD, diisopropyl diazene-1,2-
dicarboxylate showed poor reactivity in the reaction with
imidazothiazole 1a, only a 72% yield of product 26 was ob-
tained, which may result from the steric effect of isopropyl
group.
To date, direct introduction of carbamate onto heterocy-
cles is still a challenge, which results in a slow progress in
this field. We reasoned that whether imidazoheterocycle-
carbamates can be prepared from imidazoheterocycle-
hydrazines by the cleavage of the N–N bond in hydrazines.
Based on the previous work,18 we set out to investigate the
N
O
Het
R
NH
O
FeCl3 (10 mol%)
N
N
N
OEt
Het
+
R
EtO
N
N
MeCN, 80 °C, 12 h
N
O
EtO
OEt
H
O
2
3
1
S
N
S
N
S
N
S
N
S
N
O
Cl
N
N
N
N
N
N
N
N
NH
N
NH
NH
N
NH
EtO
EtO
EtO
EtO
NH
EtO
OEt
OEt
O
OEt
OEt
O
O
O
O
O
OEt
N
O
O
O
O
5, 72%
7, 89%
4, 95%
3, 93%
6, 61%
S
N
S
HO
N
S
S
N
S
N
N
N
N
EtO
N
N
EtO
N
O
N
EtO
NH
EtO
NH
N
N
NH
N
NH
EtO
NH
O
OEt
O
OEt
OEt
O
O
OEt
O
O
O
OEt
O
O
8, 78%
9, 67%
10, 91%
11, 88%
12, 90%
N
N
N
N
N
O
N
N
N
N
N
F
N
N
N
N
NH
N
NH
NH
NH
NH
EtO
EtO
EtO
EtO
EtO
OEt
OEt
OEt
OEt
OEt
O
O
O
O
O
O
O
O
O
O
13, 95%
14, 88%
15, 85%
16, 91%
17, 73%
EtO
O
N
Cl
Br
N
N
N
N
N
Ph
Br
N
N
N
N
N
NH
N
N
N
N
EtO
NH
NH
NH
NH
EtO
EtO
EtO
EtO
OEt
O
OEt
OEt
OEt
OEt
O
O
O
O
O
O
O
O
O
18, 83%
20, 56%
19, 80%
22, 80%
21, 66%
N
N
N
N
N
S
N
N
N
N
N
N
N
NH
N
NH
NH
EtO
EtO
NH
EtO
O
OEt
OEt
O
O
OEt
O
O
O
O
O
O
O
26, 72%
23, 84%
25, 77%
24, 54%
Scheme 2 The scope of amination. Reagents and conditions: 1 (0.2 mmol), 2 (0.3 mmol, 1.5 equiv), FeCl3 (10 mol%), and MeCN (2 mL) at 80 °C for 12 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
J. Jiao et al.
Paper
Synthesis
transformation of imidazoheterocycle-hydrazines to the
corresponding carbamates. It was shown that the cleavage
of the N–N bond in hydrazines proceeded smoothly in the
presence of ethyl bromoacetate and Cs2CO3 in MeCN at 80
°C, providing imidazoheterocycle-carbamates in moderate
to good yields (Scheme 3, products 27–32). It was demon-
strated that various imidazoheterocycles (including imida-
zothiazole, imidazopyridine, and imidazopyrimidine) have
good tolerance in the transformation.
Based on the amination results, a plausible mechanism
for the current transformation is outlined in Scheme 5. Ini-
tially, substrate 1a may have a resonance structure A, which
undergoes a nucleophilic addition with DEAD to afford in-
termediate B. In the absence of FeCl3, intermediate B can be
further transformed into product 3 through a four-mem-
bered-ring transition state (TS1) under heating conditions.
In the FeCl3-catalyzed reaction, intermediate B would che-
late with FeCl3 to form intermediate C, followed by TS2 to
produce intermediate D with release of HCl. Finally, inter-
mediate D reacts with HCl to give product 3.
N
N
Cs2CO3 (2 equiv)
Het
Ar
NH
O
Het
Ar
N
BrCH2CO2Et (1 equiv)
N
S
N
S
N
N
NH
MeCN, 80 °C, 3 h
EtO
EtO
Ph
Ph
A
OEt
N
N
O
O
1a
DEAD
N
S
N
S
N
S
N
S
N
S
N
N
Cl
O
S
N
Ph
H
N
N
iron-
free
Ph
H
N
N
Ph
FeCl3
Cl
Fe
N
NH
OEt
NH
OEt
NH
OEt
H
O
O
O
N
N
OEt
O
Cl
O
N
N
OEt
N
O
O
OEt
Cl
OEt
O
O
OEt
B
27, 79%
28, 72%
29, 61%
C
TS1
EtO
N
N
N
N
N
S
N
N
Cl
S
N
S
N
N
S
N
Ph
NH
NH
NH
OEt
30, 89%
Ph
Ph
Fe
O
O
O
N
Cl
N
N
H
Cl
HCl
OEt
OEt
N
Cl
OEt
N
NH
N
EtO
Fe
O
Cl
EtO
O
N
OEt
32, 41%
HCl
31, 77%
O
FeCl3
O
O
Cl
OEt
O
Scheme 3 Synthesis of imidazoheterocycle-carbamates. Reagents and
conditions: imidazoheterocycle-hydrazines (0.2 mmol), Cs2CO3 (2
equiv), BrCH2CO2Et (0.2 mmol, 1 equiv), in MeCN (2 mL) at 80 °C for 3
h.
TS2
D
3
EtO
Scheme 5 Proposed mechanism
To better understand the details for the FeCl3-catalyzed
amination of imidazoheterocycles with DEAD, DFT calcula-
tions were performed (Figure 1). For the hydrogen atom mi-
gration step, the noncatalyzed reaction via TS1 requires an
activation free energy of 32.57 kcal/mol. Interestingly,
when the nitrogen atom of amide is coordinated to FeCl3,
intermediate C is readily formed from intermediate B with
a remarkable drop of activation free energy (–12.90
kcal/mol). At the aid of FeCl3, the dehydrogenation occurs
via TS2 with a significantly reduced barrier of 6.05
kcal/mol, demonstrating that the dehydrogenation step is
efficiently catalyzed by FeCl3.
In summary, we have developed an iron-catalyzed strat-
egy for the convenient synthesis of imidazoheterocycle-
hydrazines from the amination of imidazoheterocycles with
DEAD under mild conditions. Importantly, imidazohetero-
cycle-hydrazines are allowed to be further transformed to
imidazoheterocycle-carbamates and imidazocinnolines.
These compounds are expected to have great potential ap-
plications in medicinal and material chemistry.
Subsequently, imidazocinnolines were prepared from
imidazoheterocycle-hydrazines. As shown in Scheme 4,
both imidazopyridine-hydrazine and imidazothiazole-
hydrazine are suitable for this oxidative cyclization, giving
target product in moderate to good yields (products 33–
35). These fused imidazocinnolines are of great interest in
the field of organic materials.
N
Het
R
NH
O
N
N
PhI(OAc)2 (2.5 equiv)
TFA, r.t., 12 h
Het
N
N
EtO
OEt
N
N
O
N
N
S
N
S
N
N
N
N
N
N
N
N
N
33, 81%
35, 54%
34, 68%
Scheme 4 Synthesis of imidazocinnolines. Reagents and conditions: 3
(0.2 mmol), PhI(OAc)2 (2.5 equiv), and TFA (2 mL) at r.t. for 12 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
J. Jiao et al.
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Synthesis
Hydrazination of Imidazoheterocycles with DEAD; Diethyl 1-(6-
Phenylimidazo[2,1-b]thiazol-5-yl)hydrazine-1,2-dicarboxylate
(3); Typical Procedure
S
N
Ph
H
N
O
N
N
O
A 15 mL tube with a Teflon cap, equipped with a magnetic stirring
bar, was charged with substrate 1a (40 mg, 0.20 mmol), DEAD (52 mg,
0.3 mmol, 1.5 equiv), and FeCl3 (3 mg, 10 mol%). After the addition of
MeCN (2 mL), the tube was capped and the contents were stirred at
80 °C for 12 h. After cooling to r.t., the crude mixture was diluted with
EtOAc, and the EtOAc layer was washed with brine (3 × 10 mL). The
combined organic phases were dried (anhyd Na2SO4), filtered through
a Celite pad, and washed with EtOAc. The filtrate was concentrated in
vacuo, and the resulting residue was purified by column chromatog-
raphy (hexane–EtOAc) to afford product 3 as a light yellow solid.
OEt
OEt
TS1
S
32.57
N
Ph
N
H
+
S
_
N
O
N
N
Ph
H
O
N
Cl
OEt
OEt
B
O
N
Fe
Cl
Cl
15.37
N
OEt
EtO
O
Yield: 69.6 mg (93%); white solid; mp 123.8–125.1 °C.
TS2
IR (ATR): 3226, 2974, 1746, 1501, 1239, 1093, 760, 679 cm–1
.
6.05
0.00
S
1H NMR (500 MHz, CDCl3): δ = 7.82 (s, 1 H), 7.64 (d, J = 7.5 Hz, 2 H),
7.35–7.30 (m, 3 H), 7.24–7.19 (m, 1 H), 6.73 (s, 1 H), 4.20–4.03 (m, 4
H), 1.31–1.07 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 156.8, 155.1, 148.1, 138.4, 133.1,
128.8, 127.9, 126.3, 125.3, 119.3, 112.1, 64.0, 62.6, 14.4, 14.3.
N
Ph
N
H
–12.90
N
+
S
O
Ph
EtO
N
N
Cl
N
H
LRMS (EI, 70 eV): m/z (%) = 374 (26), 301 (27), 214 (27), 207 (33), 187
(100).
HRMS (ESI): m/z calcd for C17H17N4O4S (M – H)–: 373.0965; found:
373.0969.
+
OEt
Fe
Cl
Cl
–18.60
O
N
N
O
S
N
O
OEt
Ph
EtO
N
H
C
O
N
N
O
OEt
OEt
Diethyl 1-(2-Methyl-6-phenylimidazo[2,1-b]thiazol-5-yl)hydra-
3
zine-1,2-dicarboxylate (4)
Figure 1 Free energy profile for pathways (unit: kcal/mol)
Yield: 73.7 mg (95%); white solid; mp 184.6–185.7 °C.
IR (ATR): 3299, 2968, 1746, 1504, 1242, 1076, 778 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.69 (s, 1 H), 7.61 (d, J = 7.5 Hz, 2 H),
7.51 (s, 1 H), 7.26 (d, J = 6.0 Hz, 2 H), 7.20–7.18 (m, 1 H), 4.10 (m, 4 H),
2.32 (s, 3 H), 1.12 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 156.9, 155.2, 147.5, 139.5, 133.2,
128.7, 127.6, 126.2, 119.7, 115.7, 111.5, 63.9, 62.5, 14.4, 14.3.
1H and 13C NMR spectra were measured on a Bruker Avance III 500
instrument (500 MHz for 1H, 125 MHz for 13C NMR spectroscopy) us-
ing CDCl3 or DMSO-d6 as the solvent, referenced to internal TMS (0.0
ppm) as the standard. Mass spectra were measured on a Shimadzu
GC-MS-QP2010 Plus spectrometer (EI). HRMS (ESI) analysis was mea-
sured on a Bruker micrOTOF-Q II instrument. IR analysis was mea-
sured on a Nicolet IS10 spectrometer (ATR).
HRMS (ESI): m/z calcd for C18H19N4O4S (M – H)–: 387.1121; found:
387.1148.
Diethyl 1-[6-(4-Methoxyphenyl)imidazo[2,1-b]thiazol-5-yl]hydra-
zine-1,2-dicarboxylate (5)
Analytical Data for Products 3–35
Note: The phenomenon of the rotational isomerization of amides can
be found in the 1H NMR spectra.
Yield: 58.2 mg (72%); yellow solid; mp 179.2–180.1 °C.
IR (ATR): 3228, 2914, 1755, 1504, 1245, 1056, 776, 698 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.65 (d, J = 8.0 Hz, 3 H),
6.90 (d, J = 8.0 Hz, 2 H), 6.77 (s, 1 H), 4.21–4.17 (m, 4 H), 3.81 (s, 3 H),
1.26–1.21 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 159.3, 156.9, 155.2, 148.0, 140.9,
127.6, 125.8, 119.4, 114.2, 111.7, 63.9, 62.5, 55.3, 14.4, 14.3.
Computational Details
The calculations were carried out using the Gaussian 09 programs,23
where the Density Functional Theory on Becke’s three-parameter
nonlocal exchange functional along with the Lee–Yang–Parr nonlocal
correlation functional (B3LYP)24,25 was employed. The 6-31G (d) basis
set was applied for all the atoms except the metal, S and Cl atoms, for
which LANL2DZ basis set including a double valence basis set with
the Hay and Wadt effective core potential (ECP) was used.26,27 Besides,
an additional d polarization shells were added for Cl with exponent of
0.514 and S with exponent of 0.421. The solvent effect of MeCN (ex-
perimentally used) was considered by the polarized continuum
(PCM) model combined with the addition of the MeOH molecule to
the calculated system.28–30 Frequency analysis was used to confirm
whether the structure is a minimum (with no imaginary frequency)
or a transition state (only with one imaginary frequency) and to pro-
vide free energies at 298.15 K.
HRMS (ESI): m/z calcd for C18H21N4O5S (M + H)+: 405.1227; found:
405.1233.
Diethyl 1-[6-(4-Chlorophenyl)imidazo[2,1-b]thiazol-5-yl]hydra-
zine-1,2-dicarboxylate (6)
Yield: 49.8 mg (61%); white solid; mp 175.6–177.0 °C.
IR (ATR): 3260, 2921, 1739, 1510, 1251, 1068, 769, 650 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.10 (s, 1 H), 7.84 (s, 1 H), 7.57 (d, J =
7.5 Hz, 2 H), 7.20 (d, J = 7.0 Hz, 2 H), 6.72 (s, 1 H), 4.21–4.08 (m, 4 H),
1.22–1.02 (m, 6 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
J. Jiao et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3): δ = 157.0, 155.1, 148.3, 139.8, 133.6,
HRMS (ESI): m/z calcd for C21H19N4O4S (M – H)–: 423.1121; found:
131.5, 128.8, 127.6, 120.2, 119.5, 112.4, 64.1, 62.6, 14.3.
423.1100.
HRMS (ESI): m/z calcd for C17H18N4O5S (M + H)+: 409.0732; found:
409.0732.
Diethyl 1-(7-Methyl-2-phenylbenzo[d]imidazo[2,1-b]thiazol-3-
yl)hydrazine-1,2-dicarboxylate (11)
Yield: 77.1 mg (88%); yellow solid; mp 193.9–195.1 °C.
Diethyl 1-[6-(p-Tolyl)imidazo[2,1-b]thiazol-5-yl]hydrazine-1,2-di-
IR (ATR): 3265, 2921, 1762, 1501, 1232, 1046, 809, 723 cm–1
.
carboxylate (7)
Yield: 69.1 mg (89%); yellow solid; mp 165.4–166.3 °C.
IR (ATR): 3283, 2916, 1728, 1454, 1245, 1058, 824, 761 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.88 (s, 1 H), 7.60 (d, J = 7.5 Hz, 2 H),
7.31–7.27 (m, 1 H), 7.21 (d, J = 7.5 Hz, 2 H), 6.79 (s, 1 H), 4.27–4.10 (m,
4 H), 2.37 (s, 3 H), 1.28–1.13 (m, 6 H).
1H NMR (500 MHz, CDCl3): δ = 8.10 (s, 1 H), 7.69 (d, J = 6.0 Hz, 2 H),
7.47–7.43 (m, 3 H), 7.34 (t, J = 7.5 Hz, 1 H), 7.27 (d, J = 9.0 Hz, 1 H),
7.18 (s, 1 H), 4.59–3.95 (m, 4 H), 2.45 (s, 3 H), 1.31–1.04 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 155.7, 155.4, 146.4, 140.0, 135.1,
133.0, 130.5, 130.0, 129.2 , 128.1, 127.2, 126.2, 123.7, 122.2, 114.9,
64.2, 62.5, 21.3, 14.5, 14.3.
.
13C NMR (125 MHz, CDCl3): δ = 156.8, 155.1, 148.1, 141.0, 137.8,
130.3, 129.5, 126.1, 119.4, 111.9, 64.0, 62.6, 21.3, 14.4, 14.3.
HRMS (ESI): m/z for C22H21N4O4S (M –
H)–: 437.1278; found:
437.1295.
HRMS (ESI): m/z calcd for C18H19N4O4S (M – H)–: 387.1121; found:
387.1145.
Diethyl 1-(6,7-Dimethyl-2-phenylbenzo[d]imidazo[2,1-b]thiazol-
3-yl)hydrazine-1,2-dicarboxylate (12)
Diethyl 1-[6-(2-Hydroxyphenyl)imidazo[2,1-b]thiazol-5-yl]hydra-
Yield: 81.4 mg (90%), yellow solid; mp 200.6–201.6 °C.
zine-1,2-dicarboxylate (8)
Yield: 60.8 mg (78%), yellow solid; mp 166.7–168.2 °C.
IR (ATR): 3283, 2963, 1757, 1507, 1236, 1061, 777 cm–1
.
IR (ATR): 3279, 2921, 1746, 1507, 1249, 1063, 753, 673 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.91 (s, 1 H), 7.61 (d, J = 7.5 Hz, 2 H),
7.35 (t, J = 7.5 Hz, 3 H), 7.24 (t, J = 7.0 Hz, 1 H), 7.18 (s, 1 H), 4.26–4.02
(m, 4 H), 2.31 (s, 3 H), 2.26 (s, 3 H), 1.20–1.05 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 154.6, 154.4, 145.7, 138.9, 134.1,
133.1, 132.0, 129.7, 128.3, 128.1, 127.0, 126.7 , 125.9, 125.2, 122.9,
121.0, 115.0, 63.1, 61.4, 19.3, 18.9, 13.5, 13.3.
1H NMR (500 MHz, CDCl3): δ = 11.93 (s, 1 H), 7.98 (s, 1 H), 7.49 (s, 1
H), 7.37 (d, J = 7.0 Hz, 1 H), 7.25–7.16 (m, 1 H), 7.06–6.99 (m, 1 H),
6.91–6.69 (m, 2 H), 4.19 (dd, J = 14.5, 7.0 Hz, 4 H), 1.29–1.13 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 157.0, 154.9, 146.0, 139.5, 129.6,
124.7, 119.5, 119.4, 119.2, 118.0, 116.1, 112.6, 64.2, 62.7, 62.3, 14.4,
14.3.
HRMS (ESI): m/z calcd for C23H23N4O4S (M – H)–: 451.1434; found:
451.1429.
HRMS (ESI): m/z calcd for C17H17N4O5S (M – H)–: 389.0914; found:
389.0930.
Diethyl 1-(2-Phenylimidazo[1,2-a]pyridin-3-yl)hydrazine-1,2-di-
carboxylate (13)
Diethyl 1-(6-Methylimidazo[2,1-b]thiazol-5-yl)hydrazine-1,2-di-
Yield: 69.9 mg (95%); yellow solid; mp 141.7–142.3 °C.
carboxylate (9)
Yield: 41.8 mg (67%); yellow solid; mp 67.8–69.2 °C.
IR (ATR): 3246, 1745, 1723, 1534, 1245, 1053, 738, 685 cm–1
.
IR (ATR): 3021, 2975, 1746, 1539, 1230, 1061, 613 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.78 (s, 1 H), 7.74 (s, 1 H), 6.76 (s, 1 H),
4.24–4.08 (m, 4 H), 2.22 (s, 3 H), 1.21–1.12 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 156.7, 154.8, 148.0, 139.3, 121.5,
.
1H NMR (500 MHz, CDCl3): δ = 8.71 (s, 1 H), 7.79 (d, J = 7.5 Hz, 2 H),
7.61 (d, J = 9.0 Hz, 2 H), 7.42 (t, J = 7.0 Hz, 2 H), 7.34 (t, J = 7.0 Hz, 1 H),
7.29–7.26 (m, 1 H), 6.89 (t, J = 6.5 Hz, 1 H), 4.36–4.06 (m, 4 H), 1.29–
1.06 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 156.9, 155.3, 143.1, 139.5, 132.9,
128.9, 128.4, 126.9, 125.9, 124.7, 118.5, 117.4, 112.5, 64.0, 62.6, 14.4,
14.3.
119.1, 112.9, 63.9, 62.6, 14.4, 12.6.
LRMS (EI, 70 eV): m/z (%) = 312 (39), 239 (25), 152 (34), 125 (100),
124 (21).
HRMS (ESI): m/z calcd for C12H15N4O4S (M – H)–: 311.0808; found:
311.0813.
LRMS (EI, 70 eV): m/z (%) = 368 (39), 295 (37), 207 (42), 181 (100), 78
(42).
HRMS (ESI): m/z calcd for C19H19N4O4 (M – H)–: 367.1401; found:
367.1400.
Diethyl 1-(2-Phenylbenzo[d]imidazo[2,1-b]thiazol-3-yl)hydra-
zine-1,2-dicarboxylate (10)
Diethyl 1-(6-Methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)hydra-
zine-1,2-dicarboxylate (14)
Yield: 77.0 mg (91%); white solid; mp 159.6–161.1 °C.
IR (ATR): 3312, 2988, 1726, 1514, 1232, 1050, 736 cm–1
.
Yield: 67.2 mg (88%); gray solid; mp 189.7–191.1 °C.
1H NMR (500 MHz, CDCl3): δ = 8.25 (s, 1 H), 7.69 (t, J = 7.5 Hz, 3 H),
7.50–7.44 (m, 3 H), 7.35 (t, J = 7.5 Hz, 2 H), 7.18 (s, 1 H), 4.47–4.04 (m,
4 H), 1.34–1.03 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 155.7, 155.4, 146.6, 140.3, 133.0,
132.5, 129.9, 129.4, 129.2, 128.2, 126.2, 125.0, 123.7, 122.3, 115.4,
64.3, 62.5, 14.5, 14.3.
IR (ATR): 3301, 2981, 1743, 1717, 1521, 1236, 1055, 777 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.46 (s, 1 H), 7.77 (d, J = 5.5 Hz, 2 H),
7.67 (s, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 7.39 (s, 2 H), 7.31 (s, 1 H), 7.11 (d,
J = 7.5 Hz, 1 H), 4.39–4.20 (m, 4 H), 2.37 (s, 3 H), 1.39–1.08 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 156.8, 155.4, 142.1, 139.3, 133.1,
128.9, 128.2, 126.8, 122.2, 118.2, 116.7, 63.9, 62.5, 18.3, 14.4, 14.3.
LRMS (EI, 70 eV): m/z (%) = 424 (37), 351 (32), 264 (31), 262 (20), 237
(100).
HRMS (ESI): m/z calcd for C20H21N4O4 (M – H)–: 381.1559; found:
381.1566.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
J. Jiao et al.
Paper
Synthesis
Diethyl 1-[2-(p-Tolyl)imidazo[1,2-a]pyridin-3-yl]hydrazine-1,2-di-
Diethyl 1-(8-Bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)hydra-
carboxylate (15)
zine-1,2-dicarboxylate (19)
Yield: 64.9 mg (85%); yellow solid; mp 117.8–119.0 °C.
Yield: 71.4 mg (80%); white solid; mp 177.4–178.7 °C.
IR (ATR): 3286, 2981, 1745, 1716, 1507, 1241, 1069, 826, 755 cm–1
.
IR (ATR): 3233, 2981, 1749, 1520, 1252, 1063, 728 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.69 (s, 1 H), 7.69–7.59 (m, 4 H), 7.27–
7.16 (m, 3 H), 6.86 (t, J = 6.5 Hz, 1 H), 4.27–4.07 (m, 4 H), 2.35 (s, 3 H),
1.23–1.07 (m, 6 H).
1H NMR (500 MHz, CDCl3): δ = 8.71 (s, 1 H), 7.79 (d, J = 7.0 Hz, 2 H),
7.66–7.43 (m, 2 H), 7.42–7.27 (m, 3 H), 6.76 (t, J = 6.5 Hz, 1 H), 4.34–
4.04 (m, 4 H), 1.35–1.03 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 156.8, 155.3, 143.0, 139.6, 138.2,
130.0, 129.6, 126.8, 125.7, 124.6, 118.1, 117.2, 112.3, 63.9, 62.5, 62.0,
21.2, 14.4, 14.3.
13C NMR (125 MHz, CDCl3): δ = 156.8, 155.0, 140.8, 140.4, 132.4,
128.8 128.9, 128.2, 124.1, 119.8, 112.5, 111.5, 64.1, 62.7, 14.4, 14.3.
LRMS (EI, 70 eV): m/z (%) = 446 (31), 286 (41), 261 (92), 259 (100),
156 (39).
HRMS (ESI): m/z calcd for C20H21N4O4 (M – H)–: 381.1559; found:
381.1567.
HRMS (ESI): m/z calcd for C19H18BrN4O4 (M – H)–: 445.0506; found:
445.0509.
Diethyl 1-[2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl]hydra-
zine-1,2-dicarboxylate (16)
Diethyl 1-[8-(Ethoxycarbonyl)-2-phenylimidazo[1,2-a]pyridin-3-
Yield: 72.4 mg (91%); yellow oil.
yl]hydrazine-1,2-dicarboxylate (20)
IR (ATR): 3258, 1733, 1540, 1257, 1053, 760 cm–1
.
Yield: 49.3 mg (56%); white solid; mp 179–181 °C.
1H NMR (500 MHz, CDCl3): δ = 8.61 (s, 1 H), 7.63 (s, 1 H), 7.53 (d, J =
9.0 Hz, 1 H), 7.32 (s, 1 H), 7.21–7.16 (m, 3 H), 6.81–6.79 (m, 2 H),
4.15–4.06 (m, 4 H), 3.73 (s, 3 H), 1.18–0.98 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 160.1, 156.9, 155.2, 143.0, 139.3,
134.2, 129.9, 125.9, 119.0, 117.3, 114.6, 112.5, 112.2, 77.3, 77.1, 76.8,
64.0, 62.5, 55.3, 14.3, 14.2.
IR (ATR): 2974, 1706, 1566, 1295, 1195, 1069, 864, 743, 698 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.86 (s, 1 H), 8.01 (d, J = 7.0 Hz, 1 H),
7.82–7.80 (m, 3 H), 7.36 (t, J = 7.4 Hz, 2 H), 7.31–7.25 (m, 1 H), 6.92 (t,
J = 7.0 Hz, 1 H), 4.57–4.54 (m, 2 H), 4.25–4.14 (m, 4 H), 1.51 (t, J = 7.0
Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 0.99 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 164.5, 156.9, 155.0, 140.5, 140.2,
132.3, 130.1, 128.7, 128.6, 126.9, 119.8, 118.9, 111.4, 64.0, 62.6, 61.6,
14.4, 14.2.
HRMS (ESI): m/z calcd for C20H21N4O5 (M – H)–: 397.1506; found:
397.1516.
HRMS (ESI): m/z calcd for C22H25N4O6 (M + H)+: 441.1769; found:
441.1783.
Diethyl 1-(6-Fluoro-2-phenylimidazo[1,2-a]pyridin-3-yl)hydra-
zine-1,2-dicarboxylate (17)
Yield: 56.4 mg (73%); white solid: mp 183.5–184.3 °C.
Diethyl 1-[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl]hydra-
IR (ATR): 3312, 3001, 1749, 1504, 1318, 1239, 1056, 778 cm–1
.
zine-1,2-dicarboxylate (21)
Yield: 58.9 mg (66%); yellow solid; mp 189.6–191.3 °C.
IR (ATR): 3243, 2986, 1749, 1530, 1242, 1061, 837, 756, 668 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.73 (s, 1 H), 7.77–7.70 (m, 3 H), 7.58
(dd, J = 9.0, 4.5 Hz, 1 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.33 (t, J = 7.0 Hz, 1 H),
7.18 (t, J = 8.0 Hz, 1 H), 4.27–4.11 (m, 4 H), 1.26–1.08 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 157.0, 155.0, 153.3 (d, JC,F = 236.3 Hz),
140.7, 140.9, 132.6, 128.9, 128.5, 126.8, 119.7, 117.8 (d, JC,F = 25.0 Hz),
111.7 (d, JC,F = 40.0 Hz), 64.1, 62.7, 62.1, 14.4, 14.3.
.
1H NMR (500 MHz, CDCl3): δ = 8.70 (s, 1 H), 7.90 (s, 1 H), 7.76–7.54
(m, 3 H), 7.50 (d, J = 6.5 Hz, 2 H), 7.28 (s, 1 H), 6.90 (s, 1 H), 4.35–4.19
(m, 4 H), 1.30–1.13 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 156.7, 155.1, 143.1, 138.4, 132.0,
131.8, 128.5, 126.1, 124.7, 122.5, 118.6, 117.3, 112.7, 64.1, 62.6, 14.4,
14.3.
LRMS (EI, 70 eV): m/z (%) = 386 (25), 253 (40), 224 (52), 199 (100), 96
(36).
HRMS (ESI): m/z calcd for C19H18FN4O4 (M – H)–: 385.1306; found:
HRMS (ESI): m/z calcd for C19H18BrN4O4 (M – H)–: 445.0506; found:
385.1309.
445.0518.
Diethyl 1-(8-Chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)hydra-
Diethyl 1-[2-([1,1′-Biphenyl]-4-yl)imidazo[1,2-a]pyridin-3-yl]hy-
zine-1,2-dicarboxylate (18)
drazine-1,2-dicarboxylate (22)
Yield: 69.7 mg (83%); white solid; mp 180.3–181.6 °C.
Yield: 71.0 mg (80%); yellow solid: mp 192.5–193.4 °C.
IR (ATR): 3027, 2969, 1749, 1536, 1230, 1061, 735 cm–1
.
IR (ATR): 3106, 2914, 1739, 1537, 1245, 1056, 740 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.67 (s, 1 H), 7.80 (d, J = 7.5 Hz, 2 H),
7.45–7.32 (m, 5 H), 6.82 (t, J = 6.5 Hz, 1 H), 4.22–4.17 (m, 4 H), 1.23 (t,
J = 7.1 Hz, 3 H), 1.07 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.7, 155.0, 140.3, 132.5, 132.4,
128.9, 128.6, 127.1, 124.7, 123.5, 123.1, 119.8, 112.0, 64.1, 62.7, 14.3.
1H NMR (500 MHz, CDCl3): δ = 8.71 (s, 1 H), 7.88 (d, J = 8.0 Hz, 2 H),
7.64 (dd, J = 17.5, 8.0 Hz, 6 H), 7.45 (t, J = 7.5 Hz, 2 H), 7.36 (t, J = 7.5
Hz, 1 H), 7.29 – 7.26 (m, 1 H), 6.89 (t, J = 6.5 Hz, 1 H), 4.27–4.11 (m, 4
H), 1.25–1.05 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 156.9, 155.3, 143.2, 141.0, 140.5,
139.1, 131.8, 128.8, 127.6, 127.5, 127.3, 127.0, 125.9, 124.7, 118.5,
117.4, 112.5, 64.0, 62.6, 14.4, 14.3.
LRMS (EI, 70 eV): m/z (%) = 402 (27), 269 (88), 242 (56), 240 (73), 215
(100).
HRMS (ESI): m/z calcd for C19H18ClN4O4 (M – H)–: 401.1011; found:
401.1035.
HRMS (ESI): m/z calcd for C25H23N4O4 (M – H)–: 443.1714; found:
443.1729.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
J. Jiao et al.
Paper
Synthesis
Diethyl 1-(2-(Naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)hydra-
Imidazoheterocycle-Carbamates; Ethyl (6-Phenylimidazo[2,1-
zine-1,2-dicarboxylate (23)
b]thiazol-5-yl)carbamate (27); Typical Procedure
Yield: 70.2 mg (84%); yellow solid; mp 71.2–72.5 °C.
IR (ATR): 3231, 2916, 1731, 1503, 1236, 1058, 755 cm–1
A 15 mL tube with a Teflon cap, equipped with a magnetic stirring
bar, was charged with substrate 3 (75 mg, 0.20 mmol) and Cs2CO3
(130 mg, 0.40 mmol, 2 equiv) in MeCN (2 mL). To this mixture was
added ethyl bromoacetate (33 mg, 0.20 mmol, 1 equiv), and the mix-
ture was heated at 80 °C until the starting material was consumed, as
indicated by TLC. The mixture was quenched with sat. aq NH4Cl and
extracted with EtOAc. The extracts were collected and washed with
brine, dried (anhyd Na2SO4) and concentrated in vacuo. The resulting
residue was purified by column chromatography to give product 27;
yield: 45.3 mg (79%), yellow solid; mp 145.7–146.6 °C.
.
1H NMR (500 MHz, CDCl3): δ = 8.73 (s, 1 H), 8.31 (s, 1 H), 7.88–7.82
(m, 5 H), 7.64 (d, J = 8.5 Hz, 1 H), 7.48 (d, J = 2.9 Hz, 2 H), 7.27 (s, 1 H),
6.88 (s, 1 H), 4.29–4.08 (m, 4 H), 1.28–1.03 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 156.9, 155.3, 143.2, 133.54, 133.1,
130.2, 128.5, 128.4, 127.6, 126.4, 126.3, 125.9, 124.6, 124.4, 118.8,
117.3, 112.5, 64.0, 62.5, 62.1, 14.3, 14.2.
HRMS (ESI): m/z calcd for C23H21N4O4 (M – H)–: 417.1557; found:
417.1573.
IR (ATR): 2978, 1564, 1461, 1239, 1093, 979, 860 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.79–7.64 (m, 3 H), 7.18–7.01 (m, 4 H),
6.59 (s, 1 H), 4.12 (s, 2 H), 1.20 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 155.2, 146.9, 139.6, 133.2, 128.4,
128.3, 127.3, 126.4, 116.3, 112.4, 62.2, 14.5.
HRMS (ESI): m/z calcd for C14H14N3O2S (M + H)+: 288.0801; found:
288.0807.
Diethyl 1-(2-Methylimidazo[1,2-a]pyridin-3-yl)hydrazine-1,2-di-
carboxylate (24)
Yield: 33.0 mg (54%); yellow oil.
IR (ATR): 3244, 2979, 1733, 1537, 1229, 1066, 760 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.40 (s, 1 H), 7.64 (s, 1 H), 7.43 (d, J =
8.0 Hz, 1 H), 7.14 (s, 1 H), 6.76 (s, 1 H), 4.26–4.09 (m, 4 H), 2.31 (s, 3
H), 1.23–1.15 (m, 6 H).
Ethyl [6-(4-Methoxyphenyl)imidazo[2,1-b]thiazol-5-yl]carbamate
(28)
13C NMR (125 MHz, CDCl3): δ = 141.8, 138.1, 127.7, 125.4, 124.1,
123.0, 118.3, 115.8, 111.1, 62.8, 61.5, 13.4, 11.9.
Yield: 45.6 mg (72%); white solid; mp 114.3–115.6 °C.
IR (ATR): 2971, 1703, 1539, 1452, 1256, 958, 887 cm–1
.
LRMS (EI, 70 eV): m/z (%) = 306 (48), 218 (49), 144 (46), 119 (100), 78
(51).
1H NMR (500 MHz, CDCl3): δ = 7.66 (s, 2 H), 7.12 (s, 1 H), 6.81–6.68 (s,
3 H), 4.22 (s, 2 H), 3.77 (s, 3 H), 1.30–1.12 (m, 3 H).
HRMS (ESI): m/z calcd for C14H17N4O4 (M – H)–: 305.1244; found:
305.1244.
13C NMR (125 MHz, CDCl3): δ = 158.9, 155.3, 146.7, 139.7, 127.7,
126.0, 117.3, 115.4, 113.8, 112.0, 77.4, 77.1, 76.9, 62.2, 55.2, 14.5.
HRMS (ESI): m/z calcd for C15H16N3O3S (M + H)+: 318.0907; found:
318.0912.
Diethyl 1-(2-Phenylimidazo[1,2-a]pyrimidin-3-yl)hydrazine-1,2-
dicarboxylate (25)
Yield: 56.8 mg (77%); yellow solid; mp 142.9–144.0 °C.
IR (ATR): 3223, 1748, 1506, 1458, 1233, 1056, 756 cm–1
.
Ethyl [6-(4-Chlorophenyl)imidazo[2,1-b]thiazol-5-yl]carbamate
1H NMR (500 MHz, CDCl3): δ = 9.06 (s, 1 H), 8.58 (s, 1 H), 7.89 (d, J =
7.0 Hz, 2 H), 7.82 (s, 1 H), 7.41 (d, J = 6.0 Hz, 2 H), 7.35 (d, J = 6.0 Hz, 1
H), 6.94 (s, 1 H), 4.19 (d, J = 7.5 Hz, 4 H), 1.28–1.03 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 157.1, 154.9, 151.0, 145.8, 141.0,
132.7, 132.2, 128.8, 127.2, 116.8, 108.8, 64.2, 62.7, 14.3.
(29)
Yield: 39.2 mg (61%); yellow solid; mp 179.8–180.5 °C.
IR (ATR): 2974, 1626, 1470, 1242, 965, 851 cm–1
1H NMR (500 MHz, CDCl3): δ = 7.69 (s, 1 H), 7.31–7.23 (m, 2 H), 7.23
(s, 1 H), 6.99 (s, 1 H), 6.81 (s, 1 H), 4.24 (s, 2 H), 1.26 (s, 3 H).
.
LRMS (EI, 70 eV): m/z (%) = 369 (22), 296 (30), 209 (16), 182 (100), 79
(26).
HRMS (ESI): m/z calcd for C18H18N5O4 (M – H)–: 368.1535; found:
368.1367.
13C NMR (125 MHz, CDCl3): δ = 154.9, 147.2, 138.9, 133.2, 131.8,
128.7, 127.6, 117.2, 116.0, 112.8, 62.5, 14.5.
HRMS (ESI): m/z calcd for C14H13ClN3O2S (M + H)+: 322.0412; found:
322.0417.
Diisopropyl 1-(6-Phenylimidazo[2,1-b]thiazol-5-yl)hydrazine-1,2-
dicarboxylate (26)
Ethyl (2-Phenylbenzo[d]imidazo[2,1-b]thiazol-3-yl)carbamate
(30)
Yield: 57.9 mg (72%); white solid; mp 168–170 °C.
Yield: 59.9 mg (89%); yellow solid; mp 151.6–152.8 °C.
IR (ATR): 2981, 1733, 1603, 1450, 1242, 973, 784, 716 cm–1
.
IR (ATR): 2973, 1533, 1414, 1382, 1245, 1053, 885, 738 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.86–7.78 (m, 1 H), 7.73–7.63 (m, 2 H),
7.41–7.34 (m, 2 H), 7.29–7.25 (m, 1 H), 7.11 (s, 1 H), 6.82–6.73 (m, 1
H), 5.06–4.93 (m, 2 H), 1.35–1.00 (m, 12 H).
13C NMR (125 MHz, CDCl3): δ = 156.5, 154.6, 148.1, 140.9, 133.2,
128.8, 127.8, 126.3, 120.4, 119.4, 112.0, 72.2, 70.6, 21.9.
1H NMR (500 MHz, CDCl3): δ = 7.81 (s, 2 H), 7.67 (s, 2 H), 7.39 (m, 4 H),
7.26 (s, 1 H), 4.34–4.09 (m, 2 H), 1.40–1.24 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 155.5, 145.7, 132.9, 132.4, 130.2,
129.1, 128.4, 127.5, 126.4, 126.1, 124.7, 124.0, 117.8, 112.9, 62.5, 14.6.
HRMS (ESI): m/z calcd for C18H16N3O2S (M + H)+: 338.0958; found:
338.0962.
LRMS (EI, 70 eV): m/z (%) = 401 (65), 314 (100), 187 (48), 229 (48),
273 (46).
HRMS (ESI): m/z calcd for C19H23N4O4S (M + H)+: 403.1435; found:
403.1451.
Ethyl [2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]carbamate
(31)
Yield: 48.7 mg (77%); yellow solid; mp 165.7–166.5 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
J. Jiao et al.
Paper
Synthesis
IR (ATR): 2973, 1633, 1513, 1334, 1235, 1053, 838, 758 cm–1
.
HRMS (ESI): m/z calcd for C15H9N4S (M + H)+: 277.0543; found:
252.0547.
1H NMR (500 MHz, CDCl3): δ = 7.85 (s, 1 H), 7.74–7.65 (m, 3 H), 7.49
(d, J = 7.5 Hz, 1 H), 7.16 (d, J = 6.5 Hz, 3 H), 6.77 (t, J = 6.0 Hz, 1 H), 4.23
(s, 2 H), 1.43–1.10 (m, 3 H).
Acknowledgment
13C NMR (125 MHz, CDCl3): δ = 155.2, 142.6, 138.0, 133.7, 131.3,
128.5, 128.2, 125.4, 122.5, 117.3, 114.5, 112.6, 62.3, 14.5.
HRMS (ESI): m/z calcd for C16H15ClN3O2 (M + H)+: 316.0847; found:
316.0848.
We gratefully acknowledge the NSFC (Nos. 21202121, 21371137 and
21571143) and Guangzhou Science Technology Program Project (No.
201607010142) for their financial support.
Ethyl (2-Phenylimidazo[1,2-a]pyrimidin-3-yl)carbamate (32)
Supporting Information
Yield: 23.1 mg (41%); yellow solid; mp 157.3–158.5 °C.
IR (ATR): 2983, 1718, 1556, 1453, 1239, 956, 869, 766 cm–1
1H NMR (500 MHz, CDCl3): δ = 8.43 (s, 1 H), 8.18 (s, 1 H), 7.92 (s, 2 H),
.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588374.
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p
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7.35–7.30 (m, 3 H), 6.82 (s, 1 H), 4.25 (s, 2 H), 1.33–1.26 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 154.9, 150.4, 145.3, 140.0, 132.0,
128.6, 128.5, 127.5, 113.0, 108.7, 62.5, 14.5.
References
HRMS (ESI): m/z calcd for C15H15N4O2 (M + H)+: 283.1190; found:
283.1199.
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Cinnoline Derivatives; Pyrido[2′,1′:2,3]imidazo[4,5-c]cinnoline
(33); Typical Procedure
To a stirred mixture of 13 (74 mg, 0.20 mmol) in trifluoroacetic acid
(1 mL) was added PhI(OAc)2 (161 mg, 0.5 mmol, 2.5 equiv) at r.t. The
reaction was brought to r.t. and then stirred for 12 h. The progress of
the reaction was monitored by TLC. After completion, the reaction
was quenched with ice cooled water, neutralized with sat. aq NaHCO3,
and then extracted with EtOAc. The organic layers were combined,
washed with brine, dried (anhyd Na2SO4), and concentrated in vacuo.
The resulting residue was purified by column chromatography to give
the product 33; yield: 35.6 mg (81%); white solid; mp 202.2–203.1 °C.
IR (ATR): 2928, 1617, 1523, 1234, 1245, 1053, 752 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.33 (d, J = 6.5 Hz, 1 H), 8.74–8.70 (m, 2
H), 7.93–7.92 (m, 3 H), 7.80–7.77 (m, 1 H), 7.24 (t, J = 7.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 149.4, 148.6, 141.8, 134.2, 133.2,
130.6, 130.2, 129.3, 125.2, 122.0, 120.1, 118.0, 113.2.
HRMS (ESI): m/z calcd for C13H9N4 (M + H)+: 221.0822; found:
221.0830.
9-Methylthiazolo[2′,3′:2,3]imidazo[4,5-c]cinnoline (34)
Yield: 32.6 mg (68%); white solid; mp 206.6–207.4 °C.
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IR (ATR): 2921, 1613, 1508, 1257, 993, 845, 761 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.65 (d, J = 7.5 Hz, 1 H), 8.55 (d, J = 7.5
Hz, 1 H), 8.06 (s, 1 H), 7.85 (s, 2 H), 2.61 (s, 3 H).
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241.0540.
Benzo[4′,5′]thiazolo[2′,3′:2,3]imidazo[4,5-c]cinnoline (35)
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IR (ATR): 2978, 1625, 1534, 1238, 1061, 905, 746 cm–1
.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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