A tandem copper (II)-promoted synthesis of 2-substituted pyrrolo[2,1-f][1,2,4] triazin-4(3H)-ones

Article abstract of DOI:10.1016/j.tet.2013.02.004

An efficient tandem method for the annulation of 1-amino-1H-pyrrole-2- amides with various substituted benzaldehydes, heteroaryl aldehydes, alkyl aldehydes or even acetals, promoted by cupric chloride, to synthesize 2-substituted pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones is reported. This approach provides a useful method for constructing the privileged structure in medicinal chemistry. Electron-donating groups on both partners could accelerate the reaction.

Full text of DOI:10.1016/j.tet.2013.02.004

Tetrahedron 69 (2013) 2714e2719
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Tetrahedron
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A tandem copper (II)-promoted synthesis of 2-substituted pyrrolo
[2,1-f][1,2,4] triazin-4(3H)-ones
*
Yanhong Chen, Haoyue Xiang, Cun Tan, Yuyuan Xie, Chunhao Yang
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai
201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient tandem method for the annulation of 1-amino-1H-pyrrole-2-amides with various
substituted benzaldehydes, heteroaryl aldehydes, alkyl aldehydes or even acetals, promoted by cupric
chloride, to synthesize 2-substituted pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones is reported. This approach
provides a useful method for constructing the privileged structure in medicinal chemistry. Electron-
donating groups on both partners could accelerate the reaction.
Received 12 November 2012
Received in revised form 18 January 2013
Accepted 1 February 2013
Available online 8 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Tandem annulation
Cupric chloride
1-Amino-1H-pyrrole-2-amides
Privileged structure
Pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones
1. Introduction
Pyrrolo[2,1-f][1,2,4]triazine is intriguing nitrogen-containing
heterocyclic skeleton, which has great potential in anti-cancer
agents inducing mitotic arrest,1 CRF,2 JAK,3 EGFR,4 IGF1R5 and
other kinases inhibitors.6 Several compounds containing the core
structure have entered clinical study such as BMS-582664,6f BMS-
599626,7 BMS-690518 and BMS-754807 (Fig. 1).5b
Pyrrolo[2,1-f][1,2,4]triazin-4(3H)-ones are the key intermediates
for the synthesis of pyrrolo[2,1-f][1,2,4]triazines. In the past few
years, several synthetic methods have been designed for the prep-
aration of this skeleton with 1-amino-1H-pyrrole-2-carboxylate or
1-amino-1H-pyrrole-2-carboxamide as the starting material.5a,6a,9
Most of the processes involved multi-step reactions, and suffered
from harsh conditions and low yields. To our knowledge, only few
literature involved the synthesis of pyrrolo[2,1-f][1,2,4]triazin-
4(3H)-ones with aryl ring at position 2.9c,9d,9fꢀ9h Benzoyl chloride9c
or benzimidate9h was employed in these previously reported
methods. Considering these reagents are sensitive to air and mois-
ture, and generally prepared in situ from acids or nitriles, com-
mercial available benzaldehydes would be a more practical and
convenient alternative. Most recently, Saito et al. reported a simple
O2/Darco-KB system to construct the core structure, but it needed
Fig. 1. Pyrrolo[2,1-f][1,2,4]triazines in clinical trials.
harsh conditions (130 ꢁC) and only provided moderate yields
(around 60%).9e Additionally, those methods failed to give the de-
sired product in our project. This promoted us to develop a novel
approach to construct the privileged scaffold, and herein we de-
veloped a general and convenient tandem Lewis acid promoted
reaction to synthesis of 2-substitued pyrrolo[2,1-f][1,2,4]triazin-
4(3H)-ones.
* Corresponding author. Tel./fax: þ86 21 50806770; e-mail addresses: chyang@
mail.shcnc.ac.cn, chyang@simm.ac.cn (C. Yang).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.004

Y. Chen et al. / Tetrahedron 69 (2013) 2714e2719
2715
2. Result and discussion
position were tolerated well in this reaction, and desired products
were isolated in yields ranging from 51% to 91% (Table 2, entries
1e13). Substrates with EWG reacted more slowly than those with
EDG under the same conditions (Table 2, entry 2 vs entry 4, entry
7 vs entry 8, entry 10 vs entry 11). The reason might be that the
EWG decreased the electric density of oxygen in carbonyl group,
which was adverse for its binding to Cu (II). Therefore, tempera-
ture was elevated to 130 ꢁC to accelerate the reaction when EWG
existed (Table 2, entries 5, 6 and 12). The different reaction time of
various substituents revealed that both steric and electronic ef-
fects could be dominant. For EWG, subtle change of electron
density had significant influence on the reaction (Table 2, entry 6
vs 9; Table 1, entry 7 vs Table 2, entry 8). When weak EWG bro-
mine was at the ortho-position, the steric hindrance became the
dominant factor (Table 2, entry 11). For electron-donating group,
electronic effect was dominant over steric effects, and almost the
same results were obtained regardless the position of EDG (Table
2, entries 2, 7and 10). The dominant role of electronic effects for
EDG was also proved by the case of 2l with two bulky methoxy
groups (Table 2, entry 13). When heteroaryl aldehydes 2me2o
were employed, the conditions appeared complex, and the yields
decreased greatly, especially for 2m (Table 2, entries 14e16). It is
The reaction of methyl 1-amino-5-carbamoyl-1H-pyrrole-3-
carboxylate (1a) and 4-bromobenzaldehyde (2a) was used as
a model reaction to optimize the reaction conditions. Initially, the
effect of additives was examined. The desired product could be
obtained promoted by Cu (I) or Cu (II). When the reaction occurred
in the presence of 1 equiv of Cu(OAc)2$H2O in DMSO at 100 ꢁC, the
product was isolated with 48% yield (Table 1, entry 1). A similar
result was observed when Cu(OAc)2$H2O was changed to CuBr2
(51%, Table 1, entry 2) and CuBr (54%, Table 1, entry 5). CuSO4$5H2O,
Cu(OTf)2$2H2O and CuO made the yields lower than 15% (Table 1,
entries 3, 4 and 6). To our delight, the yield could be increased to
77% when CuCl2$2H2O was employed (Table 1, entry 7). The yield
was also good when CuCl2$2H2O was replaced by CuCl (Table 1,
entry 8). It should be noted that when the reaction took place in the
presence of CuO, DDQ or without any additive, the major product
was methyl 2-(4-bromophenyl)-4-oxo-1,2,3,4-tetrahydropyrrolo
[2,1-f][1,2,4]triazine-6-carboxylate (Table 1, entries 6, 9, 10). In-
creasing the amount of CuCl2$2H2O to 2 equiv did not improve the
yield of the reaction (Table 1, entry 11), but decreasing it to
0.5 equiv prolonged the reaction time to 12 h (Table 1, entry 12).
Table 1
Optimization of the reaction conditionsa
Entry
Additive (equiv)
Solvent
Temperature (ꢁC)
Time (h)
Conversion (%)
Yield (%)b
1
2
3
4
5
6
7
8
Cu(OAc)2$H2O (1)
CuBr2 (1)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
100
100
100
100
100
100
100
90
24
6
100
100
83
87
100
79
100
100
100
100
100
100
100
100
100
100
48
51
13
5
54
9
77
67
0
CuSO4$5H2O (1)
Cu(OTf)2$2H2O (1)
CuBrd (1)
24
24
24
24
7
12
6
36
7
12
12
4
2
24
CuOc (1)
CuCl2$2H2O (1)
CuCld (1)
9
DDQc (1)
10
11
12
13
14
15
16
Nonec
0
CuCl2$2H2O (2)
CuCl2$2H2O (0.5)
CuCl2$2H2O (1)
CuCl2$2H2O (1)
CuCl2$2H2O (1)
CuCl2$2H2O (1)
76
73
77
74
72
62
115
130
100
a
Reaction conditions: 1a (0.3 mmol), 2a (0.3 mmol), additive in solvent (5 mL) at the indicated temperature.
Isolated yield.
The major product was methyl 2-(4-bromophenyl)-4-oxo-1,2,3,4-tetrahydropyrrolo[2,1-f][1,2,4]triazine-6-carboxylate.
The reactions proceeded under inert gas.
b
c
d
Screening of reaction temperature indicated that the reaction
speculated that coordination occurs between N/O/S of the sub-
strate and the additive copper (II), respectively. When the reaction
temperature of 1a and 2o was raised to 130 ꢁC (Table 2, entry 16),
the reaction time was shortened to 8 h while the yield of product
worked best at 100 ꢁC. Lowering the temperature to 90 ꢁC also
prolonged the reaction time (Table 1, entry 13). With elevated
temperature, the reaction time was shortened, but the reaction was
accompanied with some hardly removable side products (Table 1,
entries 14 and 15 vs entry 7). When the solvent was changed to
DMF, the reaction time was prolonged to 24 h and the yield was
only 62% (Table 1, entry 16).
3o was only 40%. a,b-Unsaturated aldehyde 2p and alkyl aldehydes
2qe2s could react smoothly with compound 1a in moderate yields
ranging from 41% to 62% (Table 2, entries 17e20). When the re-
action of 1a and 2r was performed at 130 ꢁC (Table 2, entry 19),
by-product was observed. Reactions of various aldehydes with 1b
were also explored. Compound 1b reacted faster than 1a under
the same conditions, and substrates with EWG gave higher yields
(Table 2, entries 21e23).
Under the optimized reaction conditions (1 equiv CuCl2$2H2O,
DMSO, 100 ꢁC), we investigated the scope and the limitations of
the reaction employing a variety of aldehydes with 1-amino-1H-
pyrrole-2-amides (1). The results were summarized in Table 2.
Benzaldehydes with various electron-donating (EDG) and
electron-withdrawing groups (EWG) at the para-, meso-, or ortho-
Then, we expanded the scope of compound 2 to acetals, the
results were summarized in Table 3. To our delight, 1a could also

2716
Y. Chen et al. / Tetrahedron 69 (2013) 2714e2719
Table 2
The annulation reaction of 1-amino-1H-pyrrole-2-carboxamide and various
aldehydes
Entry
R1
R2
Time (h)
Producta
1
2
3
4
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1a)
(1b)
(1b)
(1b)
Ph (2b)
7
5
6
24
3
9
(3b), 87%
(3c), 84%
(3d), 91%
(3e), 78%
(3e), 73%
(3f), 72%
(3g), 86%
(3h), 78%
(3i), 51%
(3j), 85%
(3k), 81%
(3k), 72%
(3l), 59%
(3m), 32%
(3n), 68%
(3o), 60%
(3p), 41%
(3q), 62%
(3r), 51%
(3s), 41%
(3t), 51%
(3u), 74%
(3v), 84%
4-MeOPh (2c)
4-AcNHPh (2d)
4-MeO2CPh (2e)
4-MeO2CPh (2e)
4-O2NPh (2f)
3-MeOPh (2g)
3-BrPh (2h)
3-O2NPh (2i)
2-MeOPh (2j)
2-BrPh (2k)
5b
6b
7
Scheme 1. Control experiments.
7
8
18
12
7
40
6
15
2
8
30
10
6
48
24
3
9b
10
11
12b
13
14
15
16
17
18
19
20
21
22
23
step with copper (II) as oxidant. However, the reaction worked well
with 1 equiv of copper (I) or 0.2 equiv of copper (II) in a quantitative
conversion (Table 1, entry 8 and Scheme 1b). The results indicate
that it is impossible to oxidize the intermediates 5 to the product
completely with only 1 equiv of copper (I) or 0.2 equiv of copper (II).
In view of these results, we would like to believe that a copper-
catalyzed dehydrogenation procedure occurred rather than a cop-
per-catalyzed aerobic oxidative dehydrogenation procedure or
a directly oxidative dehydrogenation procedure by copper (I)/(II) in
the last dehydrogenation step of 5a to 3a, especially under the inert
atmosphere condition. In some cases, DMSO has been reported as
an oxidative reagent.10 One more control experiment was designed
to investigate the effect of solvent. DMSO in the last step of this
reaction (Scheme 1c). Initially, we started this reaction in dioxane
using 1a and 2a as starting material under an inert atmosphere.
Nevertheless, the major product was the Schiff base 4a(monitored
by TLC). For this reason, we started the experiment from the in-
termediate 5a, and desired product 3a was obtained in almost 95%
conversion by 1H NMR analysis, together with only 5% of 5a residue.
These results illustrated that DMSO should not be the oxidant here,
but a suitable solvent for this reaction.
2-BrPh (2k)
2,6-Dimethoxyphenyl (2l)
2-Pyridinyl (2m)
2-Furanyl (2n)
2-Thiophenyl (2o)
2-Styryl (2p)
Ethyl (2q)
Isobutyl (2r)
Heptyl (2s)
4-MeOPh (2c)
4-BrPh (2a)
4-MeO2CPh (2e)
4
5
a
Isolated yield.
b
The temperature was 130 ꢁC.
Table 3
The annulation reaction of 1-amino-1H-pyrrole-2-carboxamide and acetals
In accordance with the results, a possible mechanism for the
formation of 2-substitued pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one
derivatives 3 was depicted in Scheme 2. Reaction of 1-amino-1H-
pyrrole-2-amides 1 with aldehydes 2 results in Schiff bases 4, and
then intramolecular cyclisation of 4 affords intermediates 5 pro-
moted by copper as the Lewis acid, and subsequently undergo
a dehydrogenation process in the presence of copper to afford the
products 3.
Entry
R2
R3
Time (h)
Producta
1
2
Ph
Et
Me
Et
12
6
(3b), 52%
(3q), 56%
a
Isolated yield.
react with benzaldehydedimethylacetal and propionaldehyde
diethyl acetal, but yields decreased by 35% and 6%, respectively.
Furthermore, longer reaction time was needed for benzaldehyde-
dimethylacetal compared to benzaldehyde (Table 3, entry 1 vs Table
2, entry 1).
To gain insight into the mechanism, the intermediates Schiff
base 4a and cyclized compound 5a were isolated and determined
by LC-MS and 1H NMR, respectively in the early stage of the re-
actions. In addition, control experiments were also performed to
elucidate the mechanism for the last dehydrogenation step of 5a to
3a (Scheme 1). Either under air or nitrogen atmosphere, both the
reaction of 1a and 2a performed very well to give the product in
same yield in the presence of 1 equiv of copper (II) (Table 1, entry 7
and Scheme 1a). It was suggested that the molecular oxygen was
not indispensable for this reaction, and therefore we wondered if
the reaction underwent a directly oxidative procedure at the last
Scheme 2. Proposed mechanism.
3. Conclusion
In summary, a tandem copper (II) -promoted procedure was
discovered to synthesize 2-substituted pyrrolo[2,1-f][1,2,4] triazin-

Y. Chen et al. / Tetrahedron 69 (2013) 2714e2719
2717
4(3H)-ones, which could provide a convenient approach to attrac-
tive privileged scaffold, with 1-amino-1H-pyrrole-2-amides (1) and
substituted benzaldehydes, heteroaryl aldehydes, alkyl aldehydes
or even acetals (2) as the starting materials under the condition of
1 equiv CuCl2$2H2O/DMSO/100 ꢁC. Electron-donating groups on
both partners could accelerate the reaction.
>300 ꢁC; 1H NMR (300 MHz, DMSO-d6):
d
12.38 (s, 1H), 8.18 (d,
J¼1.3 Hz, 1H), 8.09 (s, 4H), 7.24 (d, J¼1.3 Hz, 1H), 3.89 (s, 3H), 3.80 (s,
3H); 13C NMR (100 MHz, DMSO-d6):
d
171.9, 169.5, 161.3, 149.0,
135.6, 134.8, 132.8, 129.1, 120.3, 119.7, 114.5, 55.2, 54.8; HRMS (EI):
m/z calcd for C16H13N3O5: 327.0855; found 327.0848.
4.2.6. Methyl 2-(4-nitrophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]
4. Experiment section
4.1. General
triazine-6-carboxylate (3f). White solid; mp >300 ꢁC; 1H NMR
(300 MHz, DMSO-d6):
J¼8.5 Hz, 2H), 8.19 (d, J¼1.7 Hz, 1H), 7.24 (d, J¼1.7 Hz, 1H), 3.80 (s,
3H); 13C NMR (100 MHz, DMSO-d6):
163.3,154.8, 149.0,147.2,136.0,
d
12.51 (s, 1H), 8.37 (d, J¼8.5 Hz, 2H), 8.20 (d,
d
1-Amino-1H-pyrrole-2-amides (1) were synthesized in our lab
according to the literature.3b Other chemical reagents were
commercial products and used without purification in all cases.
1H and 13C NMR spectra were recorded on Varian Mercury-300
and Varian Mercury-400 spectrometers. MS and HRMS spectra
were recorded on a MAT-95 spectrometer. Melting points were
129.0, 124.3, 123.8, 119.8, 116.5, 108.2, 51.7; HRMS (EI): m/z calcd for
C14H10N4O5: 314.0651; found 314.0659.
4.2.7. Methyl 2-(3-methoxylphenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f]
[1,2,4]triazine-6-carboxylate (3g). White solid; mp >300 ꢁC; 1H
NMR (300 MHz, DMSO-d6):
d 12.23 (s, 1H), 8.16 (s, 1H), 7.55 (d,
€
measured by Buchi 510 melting point apparatus and were
uncorrected.
J¼7.9 Hz, 1H), 7.53 (s, 1H), 7.45 (t, J¼7.9 Hz, 1H), 7.23 (s, 1H), 7.15 (d,
J¼7.9 Hz, 1H), 3.84 (s, 3H), 3.80 (s, 3H); 13C NMR (100 MHz,
CF3COOD):
d 169.5, 161.3, 150.2, 133.1, 131.9, 128.8, 122.8, 121.7,
4.2. General procedure for the synthesis of pyrrolo[2,1-f]
[1,2,4]triazin-4(3H)-ones
120.2, 119.8, 114.4, 114.1, 57.8, 54.8; HRMS (EI): m/z calcd for
C15H13N3O4: 299.0906; found 299.0906.
A
mixture of 1-amino-1H-pyrrole-2-amides (0.3 mmol),
4.2.8. Methyl 2-(3-bromophenyl)-4-oxo-3,4-dihydro pyrrolo[2,1-f]
CuCl2$2H2O (0.3 mmol) and aldehydes or acetals (0.3 mmol) in
5 mL of DMSO was heated at indicated temperature in air until
completion. After cooling, the reaction solution was poured into
20 mL of water. The solid was precipitated, filtered to give the crude
product, which was purified by column chromatography on silica
gel, with CH2Cl2/MeOH as eluent to give the pure product.
[1,2,4]triazine-6-carboxylate (3h). White solid; mp 292e294 ꢁC; 1H
NMR (300 MHz, DMSO-d6):
d
12.29 (s, 1H), 8.16 (d, J¼1.8 Hz, 1H),
8.15 (d, J¼1.7 Hz, 1H), 7.96 (d, J¼8.0 Hz, 1H), 7.80 (d, J¼8.0 Hz, 1H),
7.51 (t, J¼8.0 Hz, 1H), 7.23 (d, J¼1.8 Hz, 1H), 3.80 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d 163.4, 154.8, 147.4, 134.2, 132.2, 130.8, 130.1,
126.5, 124.1, 121.8, 119.8, 116.3, 108.0, 51.6; HRMS (EI): m/z calcd for
C14H10BrN3O3: 346.9906; found 346.9908.
4.2.1. Methyl 2-(4-bromophenyl)-4-oxo-3,4-dihydro pyrrolo[2,1-f]
[1,2,4]triazine-6-carboxylate (3a). White solid; mp>300 ꢁC; 1H
4.2.9. Methyl 2-(3-nitrophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]
NMR (300 MHz, DMSO-d6):
d
12.29 (s, 1H), 8.14 (s, 1H), 7.89 (d,
triazine-6-carboxylate (3i). Light yellow solid; mp >300 ꢁC; 1H
J¼8.5 Hz, 2H), 7.75 (d, J¼8.5 Hz, 2H), 7.22 (s, 1H), 3.79 (s, 3H); 13C
NMR (300 MHz, DMSO-d6):
8.44 (dd, J¼8.0, 2.0 Hz, 1H), 8.39 (dd, J¼8.0, 2.0 Hz, 1H), 8.25 (d,
J¼1.7 Hz, 1H), 7.86 (t, J¼8.0 Hz, 1H), 7.26 (d, J¼1.7 Hz, 1H), 3.81 (s,
d
12.56 (s, 1H), 8.81 (t, J¼2.0 Hz, 1H),
NMR (100 MHz, DMSO-d6):
d
163.3, 154.8, 147.8, 131.7, 129.4, 129.2,
125.2, 123.9, 119.7, 116.2, 108.0, 51.5; HRMS (EI): m/z calcd for
C14H10BrN3O3: 346.9906; found 346.9901.
3H); 13C NMR (100 MHz, DMSO-d6):
d 163.4, 154.9, 147.8, 147.1,
133.8, 131.7, 130.5, 126.0, 124.2, 122.4, 119.8, 116.4, 108.2, 51.6;
4.2.2. Methyl
azine-6-carboxylate (3b). White solid; mp 286e288 ꢁC; 1H NMR
(300 MHz, DMSO-d6):
12.25 (s, 1H), 8.16 (d, J¼1.8 Hz, 1H),
7.97e7.95 (m, 2H), 7.63e7.51 (m, 3H), 7.23 (d, J¼1.8 Hz, 1H), 3.80 (s,
3H); 13C NMR (100 MHz, DMSO-d6):
163.4, 155.0, 148.7, 131.5,
4-oxo-2-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]tri-
HRMS (EI): m/z calcd for C14H10N4O5: 314.0651; found 314.0648.
d
4.2.10. Methyl 2-(2-methoxylphenyl)-4-oxo-3,4-dihydropyrrolo[2,1-
f][1,2,4]triazine-6-carboxylate (3j). White solid; mp 204e206 ꢁC;
d
1H NMR (300 MHz, DMSO-d6):
d
11.99 (s, 1H), 8.14 (d, J¼1.7 Hz,
130.0, 128.7, 127.4, 123.9, 119.7, 116.1, 108.0, 51.6; HRMS (EI): m/z
calcd for C14H11N3O3: 269.0800; found 269.0795.
1H), 7.55 (t, J¼8.3 Hz, 1H), 7.53 (d, J¼8.3 Hz, 1H), 7.22 (d, J¼1.7 Hz,
1H), 7.19 (d, J¼8.3 Hz, 1H), 7.07 (t, J¼8.3 Hz, 1H), 3.83 (s, 3H), 3.80
(s, 3H); 13C NMR (100 MHz, CF3COOD):
d 163.5, 157.3, 154.3,
4.2.3. Methyl 2-(4-methoxylphenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f]
148.4, 132.5, 130.3, 123.9, 120.3, 119.8, 119.7, 116.0, 111.8, 107.8,
55.7, 51.5; HRMS (EI): m/z calcd for C15H13N3O4: 299.0906; found
299.0915.
[1,2,4]triazine-6-carboxylate (3c). White solid; mp 298e300 ꢁC; 1H
NMR (300 MHz, DMSO-d6):
7.95 (d, J¼8.9 Hz, 2H), 7.21 (d, J¼1.8 Hz, 1H), 7.09 (d, J¼8.9 Hz, 2H),
3.84 (s, 3H), 3.80 (s, 3H); 13C NMR (100 MHz, CF3COOD):
169.6,
d
12.13 (s, 1H), 8.12 (d, J¼1.8 Hz, 1H),
d
4.2.11. Methyl 2-(2-bromophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-f]
164.6, 161.3, 150.4, 130.8, 128.5, 123.5, 120.0, 119.6, 117.2, 114.3, 57.3,
54.8; HRMS (EI): m/z calcd for C15H13N3O4: 299.0906; found
299.0905.
[1,2,4]triazine-6-carboxylate (3k). White solid; mp 226e228 ꢁC; 1H
NMR (300 MHz, DMSO-d6):
d
12.35 (s, 1H), 8.19 (d, J¼1.8 Hz, 1H),
7.82e7.77 (m, 1H), 7.73e7.68 (m, 1H), 7.57e7.50 (m, 2H), 7.27 (d,
J¼1.8 Hz, 1H), 3.80 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d 163.4,
4.2.4. Methyl 2-(4-acetamidophenyl)-4-oxo-3,4-dihydropyrrolo[2,1-
154.4, 149.1, 132.7, 132.4, 131.3, 127.8, 124.1, 121.6, 119.9, 116.2, 108.1,
51.6; HRMS (EI): m/z calcd for C14H10BrN3O3: 346.9906; found
346.9922.
f][1,2,4]triazine-6-carboxylate (3d). White solid; mp >300 ꢁC; 1H
NMR (300 MHz, DMSO-d6):
7.92 (d, J¼8.6 Hz, 2H), 7.72 (d, J¼8.6 Hz, 2H), 7.21 (s,1H), 3.80 (s, 3H),
2.08 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
168.8, 163.4, 155.0,
d 12.13 (s, 1H), 10.24 (s, 1H), 8.11 (s, 1H),
d
4.2.12. Methyl 2-(2,6-dimethoxylphenyl)-4-oxo-3,4-dihydropyrrolo
148.2, 142.2, 128.1, 124.0, 123.7, 119.7, 118.4, 116.0, 107.9, 51.5, 24.1;
HRMS (EI): m/z calcd for C16H14N4O4: 326.1015; found 326.1006.
[2,1-f][1,2,4]triazine-6-carboxylate
(3l). White
solid;
mp
254e256 ꢁC; 1H NMR (300 MHz, CDCl3):
d
9.80 (s, 1H), 7.92 (d,
J¼1.7 Hz, 1H), 7.42 (t, J¼8.5 Hz, 1H), 7.39 (d, J¼1.7 Hz, 1H), 6.63 (d,
4.2.5. Methyl 2-[4-(methoxycarbonyl)phenyl]-4-oxo-3,4-dihydro-
pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (3e). White solid; mp
J¼8.5 Hz, 2H), 3.86 (s, 3H), 3.77 (s, 6H); 13C NMR (100 MHz, CDCl3):
d 164.2, 158.5, 155.8, 144.1, 132.8, 124.5, 119.5, 116.8, 109.6, 108.4,

2718
Y. Chen et al. / Tetrahedron 69 (2013) 2714e2719
103.9, 56.0, 51.7; HRMS (EI): m/z calcd for C16H15N3O5: 329.1012;
1H), 3. 83 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
d 161.5, 155.0,
found 329.1010.
146.3, 128.7, 122.4, 121.4, 118.2, 114.1, 110.4, 107.3, 55.4; HRMS (EI):
m/z calcd for C13H11N3O2: 241.0851; found 241.0843.
4.2.13. Methyl 4-oxo-2-(pyridin-2-yl)-3,4-dihydropyrrolo[2,1-f][1,2,4]
triazine-6-carboxylate (3m). White solid; mp 236e238 ꢁC; 1H NMR
4.2.21. 2-(4-Bromophenyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one
(300 MHz, DMSO-d6):
d
11.71 (s, 1H), 8.75 (d, J¼5.2 Hz, 1H),
(3u). White solid; mp >300 ꢁC; 1H NMR (300 MHz, DMSO-d6):
8.24e8.15 (m, 2H), 8.06 (td, J¼7.5, 1.1 Hz, 1H), 7.66 (ddd, J¼7.5, 5.2,
d
12.05 (s, 1H), 7.91 (d, J¼8.6 Hz, 2H), 7.75 (d, J¼8.6 Hz, 2H), 7.68 (dd,
J¼2.6, 1.6 Hz, 1H), 6.95 (dd, J¼4.2, 1.6 Hz, 1H), 6.60 (dd, J¼4.2, 2.6 Hz,
1H); 13C NMR (100 MHz, DMSO-d6):
154.9, 145.9, 131.7, 129.7,
1.1 Hz, 1H), 7.26 (d, J¼1.8 Hz, 1H), 3.81 (s, 3H); 13C NMR (100 MHz,
CDCl3):
d
164.0, 153.7, 145.9, 145.0, 137.6, 126.5, 124.7, 120.3, 117.6,
d
110.4, 51.7; HRMS (EI): m/z calcd for C13H10N4O3: 270.0753; found
129.2, 124.8, 121.6, 118.3, 110.7, 107.6; HRMS (EI): m/z calcd for
270.0758.
C12H8BrN3O: 288.9851; found 288.9853.
4.2.14. Methyl 2-(furan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]
4.2.22. 2-[4-(Methoxycarbonyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-
triazine-6-carboxylate (3n). White solid; mp >300 ꢁC; 1H NMR
4(3H)-one (3v). White solid; mp >300 ꢁC; 1H NMR (300 MHz,
(300 MHz, DMSO-d6):
d
12.26 (s, 1H), 8.12 (d, J¼1.7 Hz, 1H), 7.98 (d,
DMSO-d6):
d
12.14 (s, 1H), 8.12 (d, J¼8.8 Hz, 2H), 8.08 (d, J¼8.8 Hz,
J¼1.6 Hz, 1H), 7.55 (d, J¼3.5 Hz, 1H), 7.20 (d, J¼1.7 Hz, 1H), 6.74 (dd,
2H), 7.71 (dd, J¼2.8, 1.8 Hz, 1H), 6.97 (dd, J¼4.2, 1.8 Hz, 1H), 6.62 (dd,
J¼3.5, 1.6 Hz, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CF3COOD):
J¼4.2, 2.8 Hz, 1H), 3.90 (s, 3H); 13C NMR (100 MHz, CF3COOD):
d
169.4, 160.5, 149.3, 143.6, 142.7, 128.5, 120.1, 120.0, 117.6, 115.0,
d 171.9, 161.2, 147.1, 135.9, 134.5, 132.8, 129.1, 126.9, 116.0, 115.8,
114.8, 55.8; HRMS (EI): m/z calcd for C12H9N3O4: 259.0593; found
114.0, 55.2; HRMS (EI): m/z calcd for C14H11N3O3: 269.0800; found
259.0584.
269.0794.
4.2.15. Methyl 4-oxo-2-(thiophen-2-yl)-3,4-dihydropyrrolo[2,1-f]
Acknowledgements
[1,2,4]triazine-6-carboxylate (3o). White solid; mp >300 ꢁC; 1H
NMR (300 MHz, DMSO-d6):
8.11 (d, J¼1.0 Hz, 1H), 7.86 (dd, J¼5.0, 1.0 Hz, 1H), 7.24e7.21 (m,
2H), 3.79 (s, 3H); 13C NMR (100 MHz, DMSO-d6):
163.3, 154.7,
144.4, 132.6, 131.4, 130.1, 128.2, 123.8, 119.7, 116.1, 108.4, 51.6;
HRMS (EI): m/z calcd for C12H9SN3O3: 275.0365; found 275.0364.
d
12.36 (s, 1H), 8.12 (d, J¼1.7 Hz, 1H),
This work was financially supported by the Ministry of Science
and Technology of China (National Science & Technology Major
Project ‘Key New Drug Creation and Manufacturing Program’
2012ZX09301001-001), the Chinese Academy of Sciences (‘In-
terdisciplinary Cooperation Team’ Program for Science and Tech-
nology Innovation), the National Natural Science Foundation of
China (20772138 and 90713034), and SKLDR/SIMM (SIMM1105KF-
02).
d
4.2.16. (E)-Methyl 4-oxo-2-styryl-3,4-dihydropyrrolo[2,1-f][1,2,4]tri-
azine-6-carboxylate (3p). White solid; mp >300 ꢁC; 1H NMR
(300 MHz, DMSO-d6):
d
12.04 (s, 1H), 8.09 (d, J¼1.6 Hz, 1H), 7.79 (d,
J¼16.6 Hz, 1H), 7.64 (d, J¼6.6 Hz, 2H), 7.54e7.30 (m, 3H), 7.21 (d,
References and notes
J¼1.6 Hz, 1H), 6.86 (d, J¼16.6 Hz, 1H), 3.80 (s, 3H); 13C NMR
1. Lombardo, L. J.; Bhide, R. S.; Kim, K. S.; Lu, S. WO2003099286-A1, 2003.
2. Saito, T.; Obitsu, T.; Kagamiishi, Y. US20100137318-A1, 2010.
(100 MHz, CF3COOD): d 170.1, 161.6, 150.8, 144.3, 136.6, 133.9, 131.8,
130.6, 128.9, 120.9, 120.6, 117.0, 115.4, 55.5; HRMS (EI): m/z calcd for
C16H13N3O3: 295.0957; found 295.0964.
3. (a) Harikrishnan, L. S.; Kamau, M. G.; Wan, H.; Inghrim, J. A.; Zimmermann, K.;
Sang, X.; Mastalerz, H. A.; Johnson, W. L.; Zhang, G.; Lombardo, L. J.; Poss, M. A.;
Trainor, G. L.; Tokarski, J. S.; Lorenzi, M. V.; You, D.; Gottardis, M. M.; Baldwin,
K. F.; Lippy, J.; Nirschl, D. S.; Qiu, R.; Miller, A. V.; Khan, J.; Sack, J. S.; Purandare,
A. V. Bioorg. Med. Chem. Lett. 2011, 21, 1425; (b) Abraham, S.; Chao, Q.; Hadd
Michael, J.; Holladay, M. W.; Liu, G.; Nambu, M. D.; Setti, E. WO2010002472-A1,
2010.
4. Hunt, J. T.; Mitt, T.; Borzilleri, R.; Gullo-Brown, J.; Fargnoli, J.; Fink, B.; Han, W.-C.;
Mortillo, S.; Vite, G.; Wautlet, B.; Wong, T.; Yu, C.; Zheng, X.; Bhide, R. J. Med. Chem.
2004, 47, 4054.
4.2.17. Methyl 2-ethyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-
6-carboxylate (3q). White solid; mp 246e247 ꢁC; 1H NMR
(300 MHz, DMSO-d6):
J¼1.8 Hz, 1H), 3.78 (s, 3H), 2.52 (q, J¼7.5 Hz, 2H), 1.20 (t, J¼7.5 Hz,
3H); 13C NMR (100 MHz, DMSO-d6):
163.5, 154.6, 153.1, 123.3,
d
11.86 (s, 1H), 8.02 (d, J¼1.8 Hz, 1H), 7.14 (d,
d
5. (a) Sampognaro, A. J.; Wittman, M. D.; Carboni, J. M.; Chang, C.; Greer, A. F.;
Hurlburt, W. W.; Sack, J. S.; Vyas, D. M. Bioorg. Med. Chem. Lett. 2010, 20, 5027;
(b) Wittman, M. D.; Carboni, J. M.; Yang, Z.; Lee, F. Y.; Antman, M.; Attar, R.;
Balimane, P.; Chang, C.; Chen, C.; Discenza, L.; Frennesson, D.; Gottardis, M. M.;
Greer, A.; Hurlburt, W.; Johnson, W.; Langley, D. R.; Li, A.; Li, J.; Liu, P.; Mastalerz,
H.; Mathur, A.; Menard, K.; Patel, K.; Sack, J.; Sang, X.; Saulnier, M.; Smith, D.;
Stefanski, K.; Trainor, G.; Velaparthi, U.; Zhang, G.; Zimmermann, K.; Vyas, D. M.
J. Med. Chem. 2009, 52, 7360.
6. (a) Kim, K. S.; Lu, S.; Cornelius, L. A.; Lombardo, L. J.; Borzilleri, R. M.; Schroeder,
G. M.; Sheng, C.; Rovnyak, G.; Crews, D.; Schmidt, R. J.; Williams, D. K.; Bhide, R.
S.; Traeger, S. C.; McDonnell, P. A.; Mueller, L.; Sheriff, S.; Newitt, J. A.;
Pudzianowski, A. T.; Yang, Z.; Wild, R.; Lee, F. Y.; Batorsky, R.; Ryder, J. S.;
Ortega-Nanos, M.; Shen, H.; Gottardis, M.; Roussell, D. L. Bioorg. Med. Chem. Lett.
2006, 16, 3937; (b) Hunt, J. T.; Bhide, R. S.; Borzilleri, R. M.; Qian, L.
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WO2009117157-A1, 2009. (d) Leftheris, K.; Rarrish, J.; Hynes, J. WO2002040486-
A2, 2002. (e) Sampognaro, A. J.; Wittman, M. D. WO2008131050-A1, 2008. (f)
Cai, Z.; Zhang, Y.; Borzilleri, R. M.; Qian, L.; Barbosa, S.; Wei, D.; Zheng, X.; Wu, L.;
Fan, J.; Shi, Z.; Wautlet, B. S.; Mortillo, S.; Jeyaseelan, R.; Kukral, D. W.; Kamath,
A.; Marathe, P.; D’Arienzo, C.; Derbin, G.; Barrish, J. C.; Robl, J. A.; Hunt, J. T.;
Lombardo, L. J.; Fargnoli, J.; Bhide, R. S. J. Med. Chem. 2008, 51, 1976.
7. Gavai, A. V.; Fink, B. E.; Fairfax, D. J.; Martin, G. S.; Rossiter, L. M.; Holst, C. L.;
Kim, S.-H.; Leavitt, K. J.; Mastalerz, H.; Han, W.-C.; Norris, D.; Goyal, B.;
Swaminathan, S.; Patel, B.; Mathur, A.; Vyas, D. M.; Tokarski, J. S.; Yu, C.;
Oppenheimer, S.; Zhang, H.; Marathe, P.; Fargnoli, J.; Lee, F. Y.; Wong, T. W.;
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119.8, 115.5, 107.6, 51.5, 25.3, 10.9; HRMS (EI): m/z calcd for
C10H11N3O3: 221.0800; found 221.0800.
4.2.18. Methyl 2-isobutyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]tri-
azine-6-carboxylate (3r). White solid; mp 258e259 ꢁC; 1H NMR
(300 MHz, DMSO-d6):
d
11.85 (s, 1H), 8.03 (d, J¼1.8 Hz, 1H), 7.14 (d,
J¼1.8 Hz, 1H), 3.78 (s, 3H), 2.36 (d, J¼7.3 Hz, 2H), 2.16e2.02 (m, 1H),
0.92 (d, J¼6.6 Hz, 6H); 13C NMR (100 MHz, DMSO-d6):
d 163.5, 154.7,
151.4, 123.3, 119.7, 115.6, 107.6, 51.5, 40.5, 26.5, 22.0; HRMS (EI): m/z
calcd for C12H15N3O3: 249.1113; found 249.1113.
4.2.19. Methyl 2-heptyl-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazine-
6-carboxylate (3s). White solid; mp 188e191 ꢁC; 1H NMR (300 MHz,
CDCl3):
d
10.81 (s, 1H), 7.87 (d, J¼1.8 Hz, 1H), 7.45 (d, J¼1.8 Hz, 1H),
3.87 (s, 3H), 2.65e2.60 (m, 2H),1.84e1.74 (m, 2H),1.42e1.30 (m, 8H),
0.88 (d, J¼6.3 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 164.1, 157.1, 151.1,
124.2, 118.8, 116.9, 109.9, 51.7, 32.7, 31.6, 28.9, 28.8, 26.6, 22.6, 14.0;
HRMS (EI): m/z calcd for C15H21N3O3: 291.1583; found 291.1588.
4.2.20. 2-(4-Methoxyphenyl)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one
(3t). White solid; mp 278e280 ꢁC; 1H NMR (300 MHz, DMSO-d6):
8. Loriot, Y.; Mordant, P.; Dorvault, N.; Rouge, T. D.; Bourhis, J.; Soria, J. C.; Deutsch,
E. Br. J. Cancer 2010, 103, 347.
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G. M.; Sheng, C.; Rovnyak, G.; Crews, D.; Schmidt, R. J.; Williams, D. K.; Bhide, R.
d
11.86 (s,1H), 7.94 (d, J¼8.9 Hz, 2H), 7.64 (dd, J¼2.6,1.6 Hz,1H), 7.07
(d, J¼8.9 Hz, 2H), 6.92 (dd, J¼4.3, 1.6 Hz, 1H), 6.57 (dd, J¼4.3, 2.6 Hz,

Y. Chen et al. / Tetrahedron 69 (2013) 2714e2719
2719
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Pudzianowski, A. T.; Yang, Z.; Wild, R.; Lee, F. Y.; Batorsky, R.; Ryder, J. S.;
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Aerssens, J. M. M.; Dlavari, M.; Filip, S.; Lowerson, K. A.; Davidenko, P. V.;
Reynov, M. V. WO2008092861-A1, 2008. (d) Saito, T.; Obitsu, T.; Kagamiishi, Y.;
Saitoh, T.; Techeuo, O. WO2008136377-A1, 2008. (e) Thieu, T.; Sclafani, J. A.;
Levy, D. V.; McLean, A.; Breslin, H. J.; Ott, G. R.; Bakale, R. P.; Dorsey, B. D. Org.
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Z.; Kiau, S.; Lobben, P.; Hynes, J.; Wu, J.; Parlanti, L.; Discordia, R.; Doubleday,
W. W.; Leftheris, K.; Dyckman, A. J.; Wrobleski, S. T.; Dambalas, K.; Tummala, S.;
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