Copper(ii)-catalyzed cascade approach for the synthesis of pyrrolo[2,1-f][1,2,4]triazine-fused isoquinolines

Article abstract of DOI:10.1039/c3ra47324d

We report herein a one-pot copper(ii)-catalyzed coupling-cyclization leading to small molecules based on a novel structural motif, i.e. the pyrrolo[2,1-f][1,2,4]triazine moiety fused with an isoquinoline ring. The reaction is easy to perform in good to excellent yields with high atom economy and exhibits a broad substrate scope.

Full text of DOI:10.1039/c3ra47324d

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Copper(II)-catalyzed cascade approach for the
synthesis of pyrrolo[2,1-f][1,2,4]triazine-fused
isoquinolines†
Cite this: RSC Adv., 2014, 4, 11168
a
b
a
a
a
*
*
Jianyang Chen, Bo Liu, Yanhong Chen, Qian He and Chunhao Yang
Received 5th December 2013
Accepted 4th February 2014
We report herein a one-pot copper(II)-catalyzed coupling-cyclization leading to small molecules based
on a novel structural motif, i.e. the pyrrolo[2,1-f][1,2,4]triazine moiety fused with an isoquinoline ring. The
reaction is easy to perform in good to excellent yields with high atom economy and exhibits a broad
substrate scope.
DOI: 10.1039/c3ra47324d
www.rsc.org/advances
Introduction
The development of synthetic organic chemistry in pharma-
ceutical science provides new opportunities to synthesize new
bioactive chemical entities. The transition-metal-catalyzed
cascade cyclization reaction has been used as a major method to
construct heterocyclic scaffolds from readily accessible organic
compounds.1 In the past few years, Lewis acids (complexes of
Ag, Cu, Fe, Au, Pd etc.) have emerged as powerful catalysts for
the purpose. The feasibility of activating C-heteroatom bonds
like C–O, C–N, C–S bond by coordination to these catalysts has
led to the development of a variety of catalytic reactions
involving C-heteroatom bond formation with high atom
economy.2
Fig.
1 Examples of pyrrolo[2,1-f][1,2,4]triazine derivatives and
isoquinolines.
As a privileged fragment, pyrrolo[2,1-f ][1,2,4]triazine skel-
eton is an important moiety that has been found to be present
in several pharmaceutical candidates, exhibiting anticancer,3
anti-inammatory4 activities (Fig. 1). For example, EGFR tyro-
sine kinase inhibitors BMS690514,5 BMS599626 6 and IGF1R
inhibitor BMS754807 7 all contain a pyrrolo[2,1-f ][1,2,4]triazine
scaffold. Therefore, the design and synthesis of novel pyrrolo-
[2,1-f ][1,2,4]triazine scaffolds attract the attention of both
organic and medicinal chemists.8
Isoquinoline-fused polycyclic compounds are important
structural moieties that appear in both natural products and
therapeutic agents and have wide applications in pharmaceu-
tical research (Fig. 1).9 Considerable efforts have been made to
develop efficient methods for the synthesis of this class of
compounds. Using cascade addition of nucleophiles and cycli-
zation, many reports in the literature9b,10 have showed the
successful synthesis of fused 1,2-dihydroisoquinolines in the
presence or absence of Lewis acid catalysts like AgOTf,11 AuCl,12
or Yb(OTf)3 (ref. 13) (Scheme 1 eqn 1).
As a part of our interest in the construction of heterocyclic
scaffolds using substituted N-amino pyrroles as building blocks
to expand medicinal chemistry space,8a,14 in this paper we
aState Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, 555 Zu
Chong Zhi Road, Shanghai 201203, P.R. China. E-mail: chyang@simm.ac.cn; Fax:
+86-21-50806770
bGuangdong Provincial Academy of Chinese Medical Sciences, (The Second Affiliated
Hospital of Guangzhou University of Chinese Medicine), 5th Floor, Science Building,
55 Neihuanxi Road, Guangzhou Higher Education Mega Center, Guangzhou,
510006, P.R. China. E-mail: doctliu@263.net
† Electronic supplementary information (ESI) available. CCDC 909484. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra47324d
Scheme 1 A possible route for the construction of diverse 4bH-iso-
quino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one.
11168 | RSC Adv., 2014, 4, 11168–11175
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
hypothesized that the condensation reaction of 2-alky-
nylbenzaldehydes and N-amino pyrrole-2-carboxyamide would
provide the corresponding imine intermediate, which would
follows cascade addition of nucleophiles and cyclization to
afford fused isoquinolines in the presence of appropriate Lewis
acids (Scheme 1 eqn (2)).
Results and discussion
Scheme 2 Transformation of 4a to the target compound 3a.
In order to explore this proposal, methyl 1-amino-5-carbamoyl-
1H-pyrrole-3-carboxylate (1a) was treated with 1.2 equiv. of 2-((4-
chlorophenyl)ethynyl)benzaldehyde (2a) in the presence of a
variety of transition metal catalysts and solvents. The results
were summarized in Table 1. When the reaction was treated by
and only the imine 4a was obtained. We speculate the trans-
formation may proceed through the imine intermediate. So we
conducted an experiment using imine 4a and CuBr2 in DMF at
80–90 ꢀC to prove the proposition. Fortunately the imine can
transform to the target compound in 81% yield (shown in
Scheme 2). However, addition of base and ligand failed to give
the desired product 3a (Table 1, entries 10 and 11). Finally we
also investigated the effect of reaction time. The yield was
slightly lowered when monitored the progress in 2 hours, and
the yield did not change when extending reaction time to 7
hours (Table 1, entries 13 and 14). The compound 3a was
characterized by the 1H NMR, 13C NMR and DEPT spectra
analysis.
With the optimal conditions in hand, we examined the scope
of the copper(II)-catalyzed annulation strategy with the results
shown in Table 2. We rst investigated the electron effects of
substituents of 2-(phenylethynyl)benzaldehydes. When R was
phenyl, it was found that the electron-withdrawing groups (–Cl,
–F, –CO2CH3, –NO2) on the R afforded the target products in
good to excellent yields (60–85%, Table 2, entries 1, 4, 5, 8, 12,
13, and 16). And the electron-donating groups (–CH3, –OCH3)
˚
AuCl (0.1 equiv.) in the presence of 4 A MS in dichloroethane
(DCE) at room temperature, the expected product 3a was not
obtained, but imine 4a was isolated in 59% yield (Table 1,
entry 1). Elevating the temperature to 80–90 ꢀC gave the product
3a in 30% yield and the imine 4a in 20% yield (Table 1, entry 2).
When gold(I) chloride was replaced by more cheaper copper
catalyst Cu(OTf)2, the same yield was obtained (Table 1, entry 3
vs. entry 2). In order to improve the solubility of reactants,
dimethyl formamide (DMF) was employed as the solvent and
the product 3a was obtained in 65% yield (Table 1, entry 4).
Then other catalysts such as CuCl2$2H2O and CuBr2 were
screened. 3a was obtained in 72% and 83% yields, respectively
(Table 1, entries 5 and 6). Without the catalyst the target
product 3a was not afforded, with a result of imine 4a obtained
in 73% yield (Table 1, entry 12). However, CuCl,
Cu(NO3)2$3H2O, anhydrous FeCl3 did not make this trans-
formation proceed under the conditions (Table 1, entries 7–9),
Table 1 Selected optimization studiesa
Entry
Catalyst
Additive
Solvent
Temp./ꢀC
Yield of 3ab
4ac
˚
1
2
3
4
5
6
7
8
AuCl
AuCl
Cu(OTf)2
Cu(OTf)2
CuCl2$H2O
CuBr2
CuCl
FeCl3
Cu(NO3)2$3H2O
CuCl2$H2O
CuCl2$H2O
—
4 A MS
DCE
DCE
DCE
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
r.t.
0
30
31
65
72
83
59
20
15
0
0
0
30
40
46
28
24
73
Trace
0
—
—
—
—
—
—
—
—
80–90
80–90
80–90
80–90
80–90
80–90
80–90
80–90
80–90
80–90
80–90
80–90
80–90
n.d.
n.d.
n.d.
n.d.
n.d.
0
9
10d
11d
12
13
14
Phen
Phen + DBU
—
—
—
CuBr2
CuBr2
61e
83f
a
b
Reaction condition: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (0.02 mmol), solvent (3 ml), 4 h. Yield isolated by column chromatograph.
c
d
e
f
Yield isolated by column chromatograph. Phen (0.04 mmol), DBU (0.4 mmol) was added. Reaction time for 2 h. Reaction time for 7
h. r.t.: room temperature. Phen: 1,10-phenanthroline. DBU:1,8-diazabicyclo[5.4.0]undec-7-ene. n.d. ¼ not detected.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 11168–11175 | 11169

View Article Online
RSC Advances
Paper
Table 2 Synthesis of substituted 4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-6(5H)-one compoundsa
Entry
1
1
2
3
Yieldb (%)
Entry
13
1
2
3
Yieldb (%)
83
1b
2d
81
2
3
1a
1a
79
56
14
15
1b
1b
2b
2i
92
73
4
1a
75
16
1b
2h
2j
85
5
6
7
1a
1a
1a
64
78
17
18
19
1b
1b
1a
72
84
71
c
—
2l
8
1a
60
20
1b
64
9
1a
1a
1a
75
77
81
21
22
23
1b
1a
94
75
71
10
11
2n
2a
2c
67d
40e
12
a
b
c
Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), CuBr2 (0.02 mmol), DMF (3 ml), 80 ꢀC, 4 h. Isolated yield. An inseparable mixture of
d
e
unidentied products was obtained. An inseparable mixture of 3l and its brominated product in a ratio of 83 : 17 detected by LC-MS. The
pure compound 3l was obtained in the presence of Cu(OTf)2.
11170 | RSC Adv., 2014, 4, 11168–11175
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
process proposed in two approaches. In path I, intermediate B2,
formed by the attack of the nitrogen of the tautomer of amide at
the imine, would carry on regiospecic hydroamination reac-
tion, leading to the formation of D. In path II, copper-coordi-
nated isoquinolinium cation C1, formed by nucleophilic attack
of imine nitrogen atom at the alkynyl group, would be trapped
by the tautomer of pyrrolo-2-amide, with the result of formation
of D. Finally protonation might then occur to give compound 3t.
Furthermore, the structure of compound 3t was determined by
the X-ray crystallographic analysis (Fig. 2).
Conclusions
Scheme 3 A possible mechanism for the Cu(II)-catalysed cyclization
of 1b with 2m as an example.
In conclusion, we have developed a Cu(II)-catalyzed coupling–
cyclization reaction that allowed facile access to an impressive
variety of pyrrolo[2,1-f][1,2,4]triazine-fused isoquinolines in
good to excellent yields. The reaction proceeded with high
6-endo-dig regioselectivity, and the product was conrmed by
X-ray crystallographic study. This method appeared to be
compatible with different substituted starting materials that
have different electronic properties, increasing its applicability
to various functional groups. Furthermore this reaction is
easy to operate and atom-economical, which will make it
attractive for the construction of variety of bioactive
heterocyclic compounds. Currently biological evaluation of
these compounds is under investigation.
on the R could also give moderate to excellent yields (56–92%,
Table 2, entries 2, 3, 6, 9, 11, 14, and 15). The similar results
were also observed when R2 was electron-withdrawing group
uoride or electron-donating group methoxyl except 2g (Table 2,
entries 5, 6, 8, and 9). We proposed that the two electron-
donating groups of 2g reduced the electrophilicity at the remote
end of the alkyne, which thereby reduced the efficiency of the
desired transformation by a 6-endo-dig cyclization approach
(Table 2, entry 7). To our delight, the reaction went smoothly
when R was alkyl or substituted alkyl. For example, alkyne 2j
bearing a cyclopropyl group provided the target product 3j in
77% yield (Table 2, entry 10). Alkyne 2l and 2n, containing the
aliphatic chain with hydroxyl group, were also suitable
substrates for this reaction with excellent yields (71–94%,
Table 2, entries 18, 19, 21, 22). We also investigated the electron
effects of substituents on N-amino pyrrole-2-carboxyamide. The
results showed that the electron-withdrawing group (–CO2CH3)
gave much lower yields than that of un-substituted substrates
(Table 2, entry 2 vs. 14, 3 vs. 11, 4 vs. 13, 8 vs. 16, 18 vs. 19, and 21
vs. 22) and the electron-donating group (-isopropyl) was also
tolerated in this reaction (Table 2, entry 23).
Experimental section
Reagents (chemicals) were purchased from commercial sour-
ces, and used without further purication. Analytical thin layer
chromatography (TLC) used was HSGF 254 (0.15–0.2 mm
thickness, Yantai Jiangyou company, China). Nuclear magnetic
resonance spectra were recorded on Varian Mercury-300 and/or
Varian Mercury-500 spectrometers with TMS as internal stan-
dard. Chemical shi were reported in parts per million (ppm, d)
downeld from TMS. Low- and high-resolution mass spectra
(LRMS and HRMS) were recorded on a Finnigan/MAT-95 spec-
On the basis of all the above results, the mechanism
hypothesis, by taking the reaction of 1b and 2m as an example,
has been proposed and shown in Scheme 3. At rst, Conden-
sation between 1b and 2m would generate imine 4b. Imine 4b
can be converted to the nal product 3t through a cascade
¨
trometer. Melting points (m.p.) were measured by Buchi 510
melting point apparatus and were uncorrected.
General procedure for the synthesis of 2f, 2g and 2l
To a stirred solution of 2-bromobenzaldehyde (2 mmol) and
terminal aromatic alkynes (2.4 mmol) in Et3N (10 ml) was added
PdCl2(PPh3) (0.04 mmol) and CuI (0.02 mmol). The resulted
ꢀ
mixture was heated under a nitrogen atmosphere at 50 C for
4 h and then cooled to room temperature. Aer the separation
of ammonium salt by ltration and removing of solvent under
reduced pressure, the residue was puried by column
chromatography on silica gel to afford the corresponding
2-(arylethyl)benzaldehyde 2f, 2g and 2l.
4-Methoxyl-2-(phenylethynyl)benzaldehyde (2f). White solid.
Yield 75%. m.p. 65–68 ꢀC. 1H NMR (300 MHz, CD3Cl) d 10.51 (d,
J ¼ 0.8 Hz, 1H), 7.92 (d, J ¼ 8.8 Hz, 1H), 7.59–7.54 (m, 2H), 7.41–
7.36 (m, 3H), 7.09 (d, J ¼ 2.6 Hz, 1H), 6.97 (ddd, J ¼ 8.8, 2.6, 0.8
Hz, 1H), 3.91 (s, 3H). 13C NMR (125 MHz, CDCl3) d 190.4, 163.8,
Fig. 2 X-ray crystal structure of 3t.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 11168–11175 | 11171

View Article Online
RSC Advances
Paper
ꢀ
131.7, 129.6, 129.5, 129.2, 129.0, 128.6, 122.2, 117.0, 115.6, 96.1, 5 min. Then the system was vigorously stirred at 80–90 C for
84.9, 55.7. HRMS (ESI) calcd for C16H12O2 [M + H]+: 237.0916, 4 h. Aer completion of the reaction, the mixture was poured
found: 237.0918.
into water, and then extracted with ethyl acetate (10 ml ꢂ 3).
4,5-Dimethoxy-2-(phenylethynyl)benzaldehyde (2g). White The combined organic layer was washed by saturated brine, and
1
ꢀ
solid. Yield 86%. m.p. 90–94 C. H NMR (300 MHz, CD3Cl) d then concentrated in vacuo to afford the crude product. The
10.50 (s, 1H), 7.56 (dd, J ¼ 6.7, 3.1 Hz, 2H), 7.43 (s, 1H), 7.41– pure product was obtained aer purication of the residue by
7.34 (m, 3H), 7.06 (s, 1H), 4.00 (s, 3H), 3.96 (s, 3H). 13C NMR (125 silica gel column chromatography (eluted with petroleum
MHz, CDCl3) d 190.5, 153.7, 149.7, 131.6, 130.2, 128.9, 128.5, ether–ethyl acetate 3 : 1).
122.5, 121.6, 114.3, 108.2, 95.0, 84.8, 56.4, 56.2. HRMS (ESI)
calcd for C17H15O3 [M + H]+: 267.1021, found: 267.1024.
Methyl 12-(4-chlorophenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f ]-
[1,2,4]triazin-6(5H)-one-8-carboxylate (3a). White solid. m.p.
1
4-Fluoro-2-(3-hydroxyprop-1-yn-1-yl)benzaldehyde (2l). Yellow 283–287 ꢀC. H NMR (300 MHz, DMSO-d6) d 8.57 (s, 1H), 7.48–
1
ꢀ
solid. Yield 81%. m.p. 72–75 C. H NMR (300 MHz, CDCl3) d 7.45 (m, 1H), 7.41(d, J ¼ 7.0 Hz, 2H), 7.33–7.26 (m, 4H), 7.07 (d,
10.41 (d, J ¼ 0.8 Hz, 1H), 7.93 (dd, J ¼ 8.7, 5.8 Hz, 1H), 7.25–7.10 J ¼ 8.2 Hz, 2H), 6.92 (d, J ¼ 1.2 Hz, 1H), 6.36 (s, 1H), 6.05 (s, 1H),
(m, 2H), 4.57 (d, J ¼ 4.4 Hz, 2H), 2.13 (t, J ¼ 6.7 Hz, 1H, OH). 13
C
3.65 (s, 3H). 13C NMR (125 MHz, DMSO-d6) d 163.6, 157.8, 142.7,
NMR (151 MHz, CDCl3) d 190.0, 165.6 (d, 1JC,F ¼ 253 Hz), 132.8 134.2, 132.9, 130.9, 130.7, 130.4, 128.6, 128.1, 127.7, 127.7,
(d, 4JC,F ¼ 2.6 Hz), 130.3 (d, 3JC,F ¼ 10.2 Hz), 128.5 (d, 3JC,F ¼ 10.9 126.7, 125.6, 125.5, 112.8, 111.0, 108.79, 69.36, 51.73. IR (KBr): n
Hz), 120.0 (d, 2JC,F ¼ 23.4 Hz), 116.8 (d, 2JC,F ¼ 22.1 Hz), 95.5, 80.2 3137.62, 3058.55, 1725.98, 1654.62, 1560.13, 759.82 cmꢁ1
.
(d, 4JC,F ¼ 2.8 Hz), 51.5. HRMS (ESI) calcd for C10H8FO2 [M + H]+: LCMS (ESI): m/z 406.2 [M + H]+, 428.1 [M + Na]+. HRMS (ESI)
179.0508, found: 179.0509.
calcd for C22H17ClN3O3 [M + H]+ 406.0958, found 406.0965.
Methyl 12-(4-methoxylphenyl)-4bH-isoquino[2,1-a]pyrrolo-
[2,1-f ][1,2,4]triazin-6(5H)-one-8-carboxylate (3b). Green solid.
General procedure for the AuCl-catalyzed reaction for
synthesis of 4a and 4b
1
ꢀ
m.p. 245–250 C. H NMR (300 MHz, DMSO-d6) d 8.54 (s, 1H),
7.43–7.35 (m, 3H), 7.32–7.24 (m, 2H), 6.95–6.89 (m, 3H), 6.82–
6.76 (m, 2H), 6.34 (s, 1H), 5.97 (s, 1H), 3.69 (s, 3H), 3.63 (s, 3H).
13C NMR (125 MHz, DMSO-d6) d 163.6, 159.9, 157.9, 143.7,
131.3, 130.3, 130.0, 128.0, 127.7, 127.3, 126.5, 126.2, 125.6,
125.3, 113.9, 112.6, 110.8, 108.1, 69.4, 55.6, 51.6. IR (KBr): n
3399.89, 3139.54, 1718.26, 1664.27, 1560.13, 1508.06, 759.82
cmꢁ1. LCMS (ESI): m/z 402.2 [M + H]+, 424.2 [M + Na]+. HRMS
(ESI) calcd for C23H20N3O4 [M + H]+: 402.1454, found 402.1471.
Methyl 12-p-tolyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]tri-
azin-6(5H)-one-8-carboxylate (3c). White solid. m.p. > 300 ꢀC. 1H
NMR (300 MHz, DMSO-d6) d 8.55 (s, 1H), 7.44–7.36 (m, 3H),
7.32–7.25 (m, 2H), 7.05 (d, J ¼ 7.5 Hz, 2H), 6.92–6.87 (m, 3H),
6.34 (s, 1H), 5.97 (s, 1H), 3.63 (s, 3H), 2.23 (s, 3H). 13C NMR (125
MHz, DMSO-d6) d 163.7, 157.9, 143.9, 138.8, 131.2, 130.4, 129.0,
128.5, 128.0, 127.7, 127.4, 126.6, 125.6, 125.4, 112.6, 110.9,
108.2, 69.4, 51.7, 21.2. IR (KBr): n 3426.89, 3164.61, 2921.63,
1724.05, 1658.48, 759.82 cmꢁ1. LCMS (ESI): m/z 386.2 [M + H]+,
408.2 [M + Na]+. HRMS (ESI) calcd for C23H20N3O3 [M + H]+:
386.1505, found 386.1490.
To a DCE (3 ml) solution of 1a (0.2 mmol) and 2a (0.24 mmol) in
10 ml two-neck ask was added AuCl (10 mmol%) and some
molecular sieves under a nitrogen atmosphere. The mixture was
stirred at room temperature for 0.5–1 hour. The white precipi-
tate was collected by ltration, washed by water and ether, and
then dried in vacuo to obtain white solid 4a.
(E)-Methyl 5-carbamoyl-1-(2-((4-chlorophenyl)ethynyl) ben-
zylidene)amino-1H-pyrrole-3-carboxylate (4a). White solid. m.p.
1
265–270 ꢀC. H NMR (300 MHz, DMSO-d6) d 9.16 (s, 1H), 8.36–
8.34 (m, 1H), 8.08–8.04 (m, 1H), 7.86–7.81 (m, 1H), 7.78–7.73
(m, 1H), 7.70–7.55(m, 5H), 7.56–7.50 (m, 2H), 7.17–7.13 (m, 1H),
3.76 (s, 3H). 13C NMR (125 MHz, DMSO-d6) d 164.0, 160.7, 155.7,
134.5, 133.8, 133.7, 133.4, 132.5, 130.0, 129.4, 128.3, 127.6,
123.6, 122.2, 121.2, 115.0, 114.0, 94.7, 87.9, 51.8. IR (KBr): n
3409.53, 3139.54, 1708.62, 1679.69, 1490.70, 1238.08, 761.74,
516.83 cmꢁ1. LCMS (ESI): m/z 406.2 [M + H]+, 428.1 [M + Na]+.
HRMS (ESI) calcd for C22H17ClN3O3 [M + H]+ 406.0958, found
406.0965.
(E)-1-((2-(Phenylethynyl)benzylidene)amino)-1H-pyrrole-2-
carboxamide (4b). White solid. m.p. 190–194 ꢀC. 1H NMR
(300 MHz, DMSO-d6) d 9.10 (s, 1H), 8.05–8.00 (m, 1H), 7.83–7.80
(m, 1H), 7.79–7.76 (m, 1H), 7.74–7.70 (m, 1H), 7.66–7.61 (m,
2H), 7.60–7.54 (m, 2H), 7.47–7.41 (m, 4H), 6.83 (dd, J ¼ 4.0, 1.8
Hz, 1H), 6.29 (dd, J ¼ 4.0, 3.1 Hz, 1H). 13C NMR (125 MHz,
DMSO-d6) d 161.2, 150.7, 133.9, 133.509, 132.1, 131.9, 129.9,
129.8, 129.3, 127.3, 127.0, 123.6, 122.3, 117.1, 115.7, 109.0, 95.9,
86.7. IR (KBr): n 3401.82, 3160.76, 1658.48, 1641.13, 1454.06,
1255.43, 755.96 cmꢁ1. HRMS (ESI) calcd for C20H16N3O [M + H]+
314.1293, found 314.1306.
Methyl
12-(4-carboxylmethylphenyl)-4bH-isoquino[2,1-a]-
pyrrolo[2,1-f ][1,2,4]triazin-6(5H)-one-8-carboxylate (3d). Yellow
solid. m.p. 240–245 ꢀC. 1H NMR (300 MHz, CDCl3) d 7.88 (d, J ¼
8.2 Hz, 2H), 7.49–7.41 (m, 1H), 7.35–7.31 (m, 2H), 7.27–7.21 (m,
2H), 7.08 (d, J ¼ 8.0 Hz, 2H), 6.96–6.94 (m, 1H), 6.22–6.19 (s,
1H), 5.93 (s, 1H), 5.82 (s, 1H), 3.90 (s, 3H), 3.70 (s, 3H). 13C NMR
(125 MHz, CDCl3) d 166.4, 163.6, 157.8, 142.8, 137.7, 130.9,
130.8, 130.6, 129.5, 128.5, 127.9, 126.9, 126.6, 125.9, 125.7,
124.4, 114.0, 113.1, 108.6, 70.1, 52.3, 51.5. IR (KBr): n 3145.33,
1714.41, 1656.55, 1562.06, 759.82 cmꢁ1. LCMS (ESI): m/z 430.2
[M + H]+, 452.2 [M + Na]+. HRMS (ESI) calcd for C24H20N3O5 [M +
H]+: 430.1403, found 430.1399.
General procedure for the Cu(II)-catalyzed annulation reaction
Methyl 3-uoro-12-phenyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f ]-
In a 10 ml reaction tube, N-amino-1H-pyrrole-2-carboxyamide [1,2,4]triazin-6(5H)-one-8-carboxylate (3e). Yellow solid. m.p.
1
ꢀ
(0.2 mmol), 2-alkynylbenzaldehyde (0.24 mmol), CuBr2 270–274 C. H NMR (300 MHz, DMSO-d6) d 8.62 (s, 1H), 7.38–
(0.02 mmol) were mixed and stirred at room temperature for 7.20 (m, 7H), 7.02 (d, J ¼ 7.2 Hz, 2H), 6.88 (d, J ¼ 1.6 Hz, 1H),
11172 | RSC Adv., 2014, 4, 11168–11175
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
6.36 (s, 1H), 6.04 (s, 1H), 3.61 (s, 3H). 13C NMR (151 MHz, CDCl3) 1708.62, 1656.55, 1562.06, 763.67 cmꢁ1. LCMS (ESI): m/z 336.2
1
d 163.6, 161.5 (d, JC,F ¼ 245 Hz), 157.8, 143.2, 132.9, 129.6 (d, [M + H]+, 358.2 [M + Na]+. HRMS (ESI) calcd for C19H18N3O3 [M +
3
2JC,F ¼ 17.9 Hz), 129.3, 129.1 (d, JC,F ¼ 7.4 Hz), 128.8, 128.4, H]+ 336.1348, found 336.1364.
128.3, 127.6 (d, 3JC,F ¼ 7.4 Hz), 127.5, 127.4, 127.2, 124.3, 117.7
12-p-Tolyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-
(d, 2JC,F ¼ 22.2 Hz), 113.9 (d, 2JC,F ¼ 20.0 Hz), 113.0, 69.7 (d, 4JC,F 6(5H)-one (3k). White solid. m.p. 222–226 ꢀC. 1H NMR (400
¼ 1.4 Hz), 51.5. IR (KBr): n 3409.53, 3149.19, 1712.48, 1654.62, MHz, CDCl3) d 7.42 (ddd, J ¼ 8.6, 7.6, 4.0 Hz, 1H), 7.29 (dd, J ¼
1562.06, 757.89 cmꢁ1. LCMS (ESI): m/z 390.2 [M + H]+: 412.2 [M + 4.0, 0.9 Hz, 1H), 7.21 (d, J ¼ 7.5 Hz, 1H), 6.99 (d, J ¼ 7.7 Hz, 2H),
Na]+. HRMS (ESI) calcd for C22H17N3O3F [M + H]+: 390.1254, 6.90 (dd, J ¼ 4.3, 1.6 Hz, 1H), 6.87–6.81 (m, 2H), 6.35 (dd, J ¼ 2.8,
found 390.1236.
1.6 Hz, 1H), 6.23 (d, J ¼ 1.7 Hz, 1H), 5.86–5.81 (m, 2H), 5.70 (s,
Methyl 2-methoxy-12-phenyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f ]- 1H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3) d 158.7, 144.6,
[1,2,4]triazin-6(5H)-one-8-carboxylate (3f). White solid. m.p. 138.8, 131.4, 131.0, 130.4, 128.7, 128.3, 127.1, 126.5, 125.9,
1
302–305 ꢀC. H NMR (300 MHz, DMSO-d6) d 8.46 (s, 1H), 7.36– 125.4, 123.8, 123.5, 112.1, 107.2, 106.4, 70.2, 21.3. IR (KBr): n
7.17 (m, 5H), 7.04–6.96 (m, 2H), 6.89–6.84 (m, 3H), 6.29 (s, 1H), 3419.17, 3172.33, 1731.76, 1654.62, 763.67, 738.60 cmꢁ1. LCMS
5.96 (s, 1H), 3.77 (s, 3H), 3.62 (s, 3H). 13C NMR (125 MHz, (ESI): m/z 328.2, [M + H]+, 350.2, [M + Na]+. HRMS (ESI) calcd for
DMSO-d6) d 164.49, 161.70, 158.76, 145.14, 134.88, 133.30,
C
21H18N3O [M + H]+, 328.1450, found 328.1430.
130.27, 130.19, 129.56, 129.37, 128.52, 126.36, 120.12, 113.95,
12-(4-Nitrophenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]-
1
ꢀ
113.46, 111.65, 111.38, 109.15, 70.00, 56.64, 52.56. IR (KBr): n triazin-6(5H)-one (3l). Yellow solid. m.p. 302–306 C. H NMR
3399.89, 3139.54, 1718.26, 1664.27, 1560.13, 1508.06, (300 MHz, CDCl3) d 8.10–7.99 (m, 2H), 7.46 (ddd, J ¼ 7.6, 6.8, 2.1
759.82 cmꢁ1. LCMS (ESI): m/z 402.2 [M + H]+, 424.2 [M + Na]+. Hz, 1H), 7.40–7.22 (m, 2H), 7.15 (d, J ¼ 8.7 Hz, 2H), 6.91 (dd, J ¼
HRMS (ESI) calcd for C23H20N3O4 [M + H]+: 402.1454, found 4.3, 1.6 Hz, 1H), 6.35 (dd, J ¼ 2.8, 1.6 Hz, 1H), 6.24 (d, J ¼ 1.5 Hz,
402.1471.
1H), 5.93 (s, 1H), 5.86 (dd, J ¼ 4.3, 2.8 Hz, 1H), 5.67 (s, 1H). 13
C
Methyl 2-uoro-12-(4-nitrophenyl)-4bH-isoquino[2,1-a]pyr- NMR (125 MHz, DMSO-d6) d 158.5, 147.9, 142.6, 141.1, 130.7,
rolo[2,1-f ][1,2,4]triazin-6(5H)-one-8-carboxylate (3h). Yellow 130.3, 130.2, 128.1, 127.9, 127.1, 125.7, 124.3, 123.9, 123.4,
solid. m.p. > 300 ꢀC. 1H NMR (300 MHz, DMSO-d6) d 8.64 (s, 1H), 111.2, 109.1, 106.6, 69.6. IR (KBr): n 3397.96, 3178.11, 1666.20,
8.13 (d, J ¼ 8.8 Hz, 2H), 7.61 (d, J ¼ 1.7 Hz, 1H), 7.52–7.46 (m, 1348.00, 727.03 cmꢁ1. LCMS (ESI): m/z 359.2 [M + H]+, 381.2 [M
1H), 7.36 (d, J ¼ 8.7 Hz, 2H), 7.23–7.16 (m, 2H), 6.91 (d, J ¼ 1.7 + Na]+. HRMS (ESI) calcd for C20H14N4NaO3 [M + Na]+,381.0964,
Hz, 1H), 6.44 (s, 1H), 6.16 (s, 1H), 3.62 (s, 3H). 13C NMR (125 found 381.0981.
MHz, DMSO-d6) d 163.5, 163.4 (d, 1JC,F ¼ 244.8 Hz), 157.7, 148.1,
12-(4-Carboxylmethylphenyl)-4bH-isoquino[2,1-a]pyrrolo-
3
3
ꢀ
143.1, 140.2, 132.9 (d, JC,F ¼ 9.4 Hz), 130.5 (d, JC,F ¼ 9.2 Hz), [2,1-f][1,2,4]triazin-6(5H)-one (3m). White solid. m.p. >300 C.
4
130.4, 127.7, 125.4, 123.6, 123.1 (d, JC,F ¼ 3.2 Hz), 114.7 (d, 1H NMR (300 MHz, CDCl3) d 7.85 (d, J ¼ 8.1 Hz, 2H), 7.48–7.40
2
2JC,F ¼ 22.4 Hz), 113.1, 112.3 (d, JC,F ¼ 23.0 Hz), 111.4, 108.8, (m, 1H), 7.37–7.19 (m, 2H), 7.05 (d, J ¼ 8.0 Hz, 2H), 6.89 (dd, J ¼
68.8, 51.7. IR (KBr): n 3392.17, 3201.25, 1662.34, 1635.34, 4.2, 1.7 Hz, 1H), 6.32 (dd, J ¼ 2.8, 1.6 Hz, 1H), 6.23 (s, 1H), 5.90
1521.56, 1348.00, 750.17 cmꢁ1. LCMS (ESI): m/z 435.2 [M + H]+, (s, 1H), 5.82 (dd, J ¼ 4.3, 2.7 Hz, 1H), 5.62 (s, 1H), 3.89 (s, 3H).
457.1 [M + Na]+. HRMS (ESI) calcd for C22H15FN4O5Na [M + Na]+: 13C NMR (125 MHz, DMSO-d6) d 166.2, 158.5, 143.6, 139.2,
457.0924, found 457.0930.
130.9, 130.3, 130.1, 129.1, 128.1, 127.6, 127.0, 125.5, 124.3,
Methyl 3-uoro-12-(4-methoxylphenyl)-4bH-isoquino[2,1-a]- 123.9, 110.9, 108.3, 106.4, 69.5, 52.7. IR (KBr): n 3423.03,
pyrrolo[2,1-f ][1,2,4]triazin-6(5H)-one-8-carboxylate (3i). White 3174.26, 1720.19, 1652.70, 771.39, 738.60 cmꢁ1. LCMS (ESI): m/z
solid. m.p. 261–265 ꢀC. 1H NMR (300 MHz, DMSO-d6) d 8.59 (s, 372.2 [M + H]+, 394.2[M + Na]+. HRMS (ESI) calcd for
1H), 7.39 (s, 1H), 7.35–7.25 (m, 3H), 6.94–6.89 (m, 3H), 6.81–6.76
C
22H17N3O3Na [M + Na]+, 394.1168, found 394.1171.
12-(4-Methoxylphenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f ]-
(m, 2H), 6.34 (s, 1H), 5.98 (s, 1H), 3.69 (s, 3H), 3.64 (s, 3H). 13
C
1
NMR (125 MHz, DMSO-d6) d 163.6, 160.6 (d, JC,F ¼ 245 Hz), [1,2,4]triazin-6(5H)-one (3n). Yellow solid. m.p. 240–246 ꢀC.
159.9, 157.8, 143.1, 130.1 ꢂ 2, 128.4 (d, 3JC,F ¼ 8.3 Hz), 128.0 (d, 1H NMR (300 MHz, CDCl3) d 7.46–7.38 (m, 1H), 7.32–7.27
4JC,F ¼ 3.2 Hz), 127.8, 127.4 (d, 3JC,F ¼ 7.9 Hz), 126.1, 125.5, 117.2 (m, 2H), 7.20 (d, J ¼ 7.5 Hz, 1H), 6.93–6.84 (m, 3H), 6.73–6.64
(d, 2JC,F ¼ 20.9 Hz), 115.1 (d, 2JC,F ¼ 23.3 Hz), 113.9, 112.7, 111.0, (m, 2H), 6.36–6.33 (m, 1H), 6.22 (t, J ¼ 2.0 Hz, 1H), 5.88–5.83 (m,
107.2, 68.9, 55.6, 51.7. IR (KBr): n 3401.82, 3139.54, 1712.48, 2H), 5.55 (s, 1H), 3.76 (s, 3H). 13C NMR (100 MHz, CDCl3) d
1652.70, 1562.06, 1509.99, 833.10, 759.82 cmꢁ1. LCMS (ESI): m/z 159.9, 158.6, 144.2, 131.4, 130.4, 129.7, 127.0, 126.5, 126.2,
420.2 [M + H]+, 442.1 [M + Na]+. HRMS (ESI) calcd for 125.8, 125.4, 123.8, 123.4, 113.3, 112.1, 107.2, 106.4, 70.1, 55.2.
C
23H19FN3O3 [M + H]+: 420.1360, found 420.1345.
Methyl
12-cyclopropyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f ]- cmꢁ1. LCMS (ESI): m/z 344.2, [M + H]+, 366.2, [M + Na]+. HRMS
IR (KBr): n 3137.62, 3064.33, 1658.48, 1550.49, 1509.99, 736.67
[1,2,4]triazin-6(5H)-one-8-carboxylate (3j). White solid. m.p. (ESI) calcd for C21H18N3O2 [M + H]+, 344.1399, found 344.1411.
255–260 ꢀC. 1H NMR (300 MHz, CDCl3) d 7.63 (d, J ¼ 1.7 Hz, 1H),
3-Fluoro-12-(4-methoxylphenyl)-4bH-isoquino[2,1-a]pyrrolo-
7.42–7.33 (m, 2H), 7.25–7.21 (m, 2H), 7.13 (d, J ¼ 7.5 Hz, 1H), [2,1-f][1,2,4]triazin-6(5H)-one (3o). White solid. m.p. 240–
6.11 (d, J ¼ 1.3 Hz, 1H), 5.72 (d, J ¼ 1.2 Hz, 1H), 5.63 (s, 1H), 3.85 245 ꢀC. 1H NMR (400 MHz, CDCl3) d 7.25–7.16 (m, 1H), 7.12 (td,
(s, 3H), 1.02–0.92 (m, 1H), 0.79–0.59 (m, 2H), 0.55–0.38 (m, 2H). J ¼ 8.5, 2.6 Hz, 1H), 7.04 (dd, J ¼ 8.1, 2.6 Hz, 1H), 6.89 (dd, J ¼
13C NMR (125 MHz, CDCl3) d 164.1, 157.6, 145.4, 131.0, 130.6, 4.3, 1.6 Hz, 1H), 6.85 (d, J ¼ 8.3 Hz, 2H), 6.69 (d, J ¼ 8.8 Hz, 2H),
127.7, 127.0, 126.4, 125.5, 125.2, 124.5, 114.1, 112.7, 103.8, 70.1, 6.34 (dd, J ¼ 2.8, 1.6 Hz, 1H), 6.19 (s, 1H), 5.85 (dd, J ¼ 4.3, 2.8
51.6, 11.4, 6.7, 5.1. IR (KBr): n 3421.10, 3176.18, 3131.83, Hz, 1H), 5.83 (s, 1H), 5.62 (s, 1H), 3.76 (s, 3H). 13C NMR (125
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 11168–11175 | 11173

View Article Online
RSC Advances
Paper
MHz, DMSO-d6) d 160.5 (d, 1JC,F ¼ 243.2 Hz), 159.4, 158.1, 143.3,
129.4, 128.3 (d, 3JC,F ¼ 7.2 Hz), 127.8 (d, 4JC,F ¼ 2.5 Hz), 127.7 (d,
12-Phenyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f][1,2,4]triazin-
6(5H)-one (3t). White solid. m.p. 240–245 ꢀC. 1H NMR
(300 MHz, CDCl3) d 7.47–7.38 (m, 1H), 7.32–7.27 (m, 3H), 7.24–
7.14 (m, 3H), 7.01–6.96 (d, J ¼ 7.3 Hz, 2H), 6.89 (dd, J ¼ 4.3, 1.6
Hz, 1H), 6.35–6.30 (m, 1H), 6.23 (d, J ¼ 1.2 Hz, 1H), 5.88 (s, 1H),
5.81 (dd, J ¼ 4.3, 2.8 Hz, 1H), 5.60–5.52 (m, 1H). 13C NMR (125
MHz, CDCl3) d 158.7, 144.5, 133.8, 131.2, 130.5, 128.8, 128.5,
128.0, 127.2, 126.5, 125.9, 125.5, 123.7, 123.5, 112.2, 107.3,
2
3JC,F ¼ 6.4 Hz), 126.2, 123.8, 123.6, 116.5 (d, JC,F ¼ 21.8 Hz),
114.7 (d, 2JC,F ¼ 23.5 Hz), 113.3, 110.3, 106.1, 105.8, 68.69, 55.06.
IR (KBr): n 3423.03, 3176.18, 1735.62, 1658.48, 1511.92, 734.75
cmꢁ1. LCMS (ESI): m/z 362.2 [M + H]+, 384.2 [M + Na]+. HRMS
(ESI) calcd for C21H17FN3O2 [M + H]+ 362.1305, found 362.1311.
2-Fluoro-12-(4-nitrophenyl)-4bH-isoquino[2,1-a]pyrrolo[2,1-f ]-
1
106.4, 70.1. IR (KBr): n 3430.74, 3166.54, 1650.77, 736.67 cmꢁ1
.
ꢀ
[1,2,4]triazin-6(5H)-one (3p). Yellow solid. m.p. 296–300 C. H
NMR (300 MHz, DMSO-d6) d 8.33 (s, 1H), 8.08 (d, J ¼ 8.5 Hz, 2H),
7.52–7.45 (m, 1H), 7.26 (d, J ¼ 8.7 Hz, 2H), 7.20–7.16 (m, 2H),
HRMS (ESI) calcd for C20H16N3O [M + H]+ 314.1293, found
314.1306.
6.79 (s, 1H), 6.66–6.62 (m, 1H), 6.38 (s, 1H), 6.10 (s, 1H), 5.87–
3-Chloro-12-hydroxylethyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f ]-
1
5.81 (m, 1H). 13C NMR (125 MHz, DMSO-d6) d 163.4 (d, JC,F
¼
1
ꢀ
[1,2,4]triazin-6(5H)-one (3u). Yellow solid. m.p. 220–224 C. H
NMR (300 MHz, DMSO-d6) d 8.08 (s, 1H), 7.45–7.32 (m, 3H),
7.18 (d, J ¼ 8.2 Hz, 1H), 6.72 (d, J ¼ 4.0 Hz, 1H), 6.20–6.16 (m,
2H), 5.86 (s, 1H), 4.65–4.60 (m, 1H), 3.42–3.34 (m, 1H), 3.28–
3.20 (m, 1H), 2.16–2.09 (m, 1H), 1.95–1.82 (m, 1H). 13C NMR
(125 MHz, DMSO-d6) d 159.0, 144.1, 131.1, 130.9, 130.7, 128.9,
128.5, 127.0, 125.1, 124.8, 111.7, 107.6, 104.6, 69.6, 59.8, 34.2.
IR (KBr): n 3143.40, 2921.63, 1654.62, 1554.34, 1328.71, 728.96
cmꢁ1. LCMS (ESI): m/z 316.1 [M + H]+, 338.1 [M + Na]+. HRMS
(ESI) calcd for C16H14N3O2NaCl, [M + Na]+ 338.0672, found
338.0670.
3
244.6 Hz), 158.4, 148.0, 143.8, 140.7, 133.3 (d, JC,F ¼ 9.3 Hz),
130.5(d, 3JC,F ¼ 8.8 Hz), 130.1, 124.2, 124.0, 123.5, 123.3(d, 4JC,F
2
2
¼ 3.2 Hz), 114.4 (d, JC,F ¼ 22.4 Hz), 112.1(d, JC,F ¼ 22.7 Hz),
111.3, 108.2, 106.7, 68.9. IR (KBr): n 3396.03, 3201.25, 1664.27,
1635.34, 1521.56, 1348.00, 750.17 cmꢁ1. LCMS (ESI) m/z 377.2
[M + H]+, 399.2 [M + Na]+. HRMS: calcd for C20H14N4O3F [M +
H]+: 377.1050, found 377.1045.
12-Cyclopropyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f ][1,2,4]tri-
azin-6(5H)-one (3q). White solid. m.p. 196–201 ꢀC. 1H NMR (300
MHz, CDCl3) d 7.42–7.33 (m, 1H), 7.22 (d, J ¼ 4.0 Hz, 2H), 7.12
(d, J ¼ 7.7 Hz, 1H), 7.06 (dd, J ¼ 2.8, 1.6 Hz, 1H), 6.97 (dd, J ¼ 4.2,
1.6 Hz, 1H), 6.20 (dd, J ¼ 4.2, 2.8 Hz, 1H), 6.13 (d, J ¼ 1.5 Hz,
1H), 5.68 (d, J ¼ 1.3 Hz, 1H), 5.40 (s, 1H), 0.98–0.86 (m, 1H),
0.77–0.57 (m, 2H), 0.49 (m, 2H). 13C NMR (100 MHz, CDCl3) d
158.4, 146.5, 131.3, 130.3, 126.6, 126.3, 125.8, 125.0, 124.3,
123.4, 111.9, 106.6, 102.8, 70.2, 11.3, 7.1, 5.0. IR (KBr): n 3133.76,
2923.56, 1650.77, 757.89, 730.89 cmꢁ1. LCMS (ESI): m/z 278.2 [M
+ H]+, 300.2 [M + Na]+. HRMS (ESI) calcd for C17H15N3ONa [M +
Na]+, 300.1113, found 300.1131.
Methyl 3-chloro-12-hydroxylethyl-4bH-isoquino[2,1-a]pyrrolo-
[2,1-f ][1,2,4]triazin-6(5H)-one-8-carboxylate (3v). White solid.
1
ꢀ
m.p. 282–286 C. H NMR (300 MHz, DMSO-d6) d 8.40 (s, 1H),
8.07–8.05 (m, 1H), 7.45–7.37 (m, 2H), 7.21 (d, J ¼ 8.0 Hz, 1H),
7.02 (d, J ¼ 1.7 Hz, 1H), 6.24 (s, 1H), 5.91 (s, 1H), 4.66 (t, J ¼ 5.1
Hz, 1H), 3.76 (s, 3H), 3.42–3.22 (m, 2H), 2.28–2.14 (m, 1H), 1.94–
1.80 (m, 1H). 13C NMR (125 MHz, DMSO-d6) d 164.6, 158.2,
158.2, 143.2, 131.1, 130.9, 128.8, 128.6, 128.5, 127.2, 126.2,
114.1, 111.8, 105.0, 69.3, 59.6, 52.6, 34.0. IR (KBr): n 3382.53,
3259.11, 1695.12, 1666.20, 1301.72, 767.53 cmꢁ1. LCMS (ESI): m/
z 374.2 [M + H]+, 396.1, [M + Na]+. HRMS (ESI) calcd for
2-Fluoro-12-hydroxymethyl-4bH-isoquino[2,1-a]pyrrolo[2,1-f]
1
[1,2,4]triazin-6(5H)-one (3r). White solid. m.p. 256–260 ꢀC. H
C
18H16N3O4NaCl [M + Na]+ 396.0727, found 396.0740.
NMR (300 MHz, CDCl3) d 7.18 (dd, J ¼ 8.3, 5.3 Hz, 1H), 7.00 (dd, J
¼ 2.8, 1.5 Hz, 1H), 6.92–6.80 (m, 3H), 6.15 (dd, J ¼ 4.3, 2.8 Hz,
1H), 5.99 (d, J ¼ 6.2 Hz, 2H), 3.80 (d, J ¼ 14.8 Hz, 1H), 3.60 (d,
9-Isopropyl-12-(4-chlorophenyl)-4bH-isoquino[2,1-a]pyrrolo-
[2,1-f ][1,2,4]triazin-6(5H)-one (3w). White solid. m.p. 278–
J ¼ 14.9 Hz, 1H). 13C NMR (125 MHz, DMSO-d6) d 163.4 (d, 1JC,F
243.9 Hz), 158.1, 146.5, 133.6(d, 3JC,F ¼ 9.3 Hz), 130.1 (d, 3JC,F
¼
¼
¼
1
ꢀ
282 C. H NMR (300 MHz, CDCl3) d 7.49–7.38 (m, 1H), 7.37–
7.20 (m, 3H), 7.15 (d, J ¼ 8.2 Hz, 2H), 6.96 (d, J ¼ 4.4 Hz,
1H), 6.79 (d, J ¼ 8.3 Hz, 2H), 6.15 (s, 1H), 5.91 (s, 1H), 5.73
(d, J ¼ 4.4 Hz, 1H), 5.55 (s, 1H), 2.48–2.36 (m, 1H), 1.01 (d, J
¼ 6.8 Hz, 3H), 0.57 (d, J ¼ 7.0 Hz, 3H). 13C NMR (151 MHz,
CDCl3) d 158.92, 143.55, 143.28, 135.04, 132.66, 131.29,
130.45, 129.87, 128.40, 127.38, 126.50, 126.23, 125.56, 122.43,
112.66, 108.23, 102.89, 70.31, 25.07, 23.64, 19.87. IR (KBr) n
3237.62, 3058.55, 1725.98, 1654.62, 1560.13, 1382.15, 1368.40,
920.78, 758.82 cmꢁ1. LCMS (ESI): m/z 390.2 [M + H]+, 412.1
[M + Na]+. HRMS (ESI) calcd for C23H21ClN3O [M + H]+
390.1373, found 390.1384.
4
2
9.1 Hz), 124.1, 123.9, 123.1 (d, JC,F ¼ 3.2 Hz), 113.1 (d, JC,F
22.1 Hz), 111.3 (d, 2JC,F ¼ 22.7 Hz), 110.8, 106.6, 102.3, 68.9, 58.1.
IR (KBr): n 3351.68, 3183.90, 2919.70, 1643.05, 1619.91, 740.53
cmꢁ1. LCMS (ESI): m/z 286.2 [M + H]+, 308.1 [M + Na]+. HRMS
(ESI) calcd for C15H13N3O2F [M + H]+ 286.0992, found 286.1015.
Methyl 2-uoro-12-hydroxylmethyl-4bH-isoquino[2,1-a]pyr-
rolo[2,1-f ][1,2,4]triazin-6(5H)-one-8-carboxylate (3s). Yellow
solid. m.p. 300–304 ꢀC. 1H NMR (300 MHz, CD3Cl) d 7.69 (d, J ¼
1.7 Hz, 1H), 7.35–7.32 (m, 2H), 7.31–7.27 (m, 1H), 7.02–6.91 (m,
2H), 6.09 (m, 2H), 3.85 (m, 4H), 3.83–3.76 (m, 1H). 13C NMR (125
1
MHz, DMSO-d6) d 163.8, 163.4 (d, JC,F ¼ 244.3), 157.5, 145.1,
3
3
133.4 (d, JC,F ¼ 9.4 Hz), 130.2 (d, JC,F ¼ 9.2 Hz), 127.7, 125.3,
Acknowledgements
122.8 (d, 4JC,F ¼ 3.2 Hz), 113.5 (d, 2JC,F ¼ 22.4 Hz), 113.2, 111.5
2
(d, JC,F ¼ 22.8 Hz), 110.9, 103.5, 68.6, 58.5, 51.8. IR (KBr): n This work was nancially supported by the Chinese Academy of
3482.81, 3183.90, 2919.70, 1700.91, 1666.20, 1560.13, 763.67 Sciences (‘Interdisciplinary Cooperation Team’ Program for
cmꢁ1. LCMS (ESI): m/z 344.2 [M + H]+, 366.2 [M + Na]+. Science and Technology Innovation), the National Natural
HRMS (ESI) calcd for C17H15N3O4F [M + H]+ 344.1047, found Science Foundation of China (21072205, 81202398), and
344.1029.
SKLDR/SIMM (SIMM1105KF-02).
11174 | RSC Adv., 2014, 4, 11168–11175
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
J. S. Tokarski, C. Yu, S. Oppenheimer, H. Zhang,
P. Marathe, J. Fargnoli, F. Y. Lee, T. W. Wong and
G. D. Vite, J. Med. Chem., 2009, 52, 6527.
7 J. E. Dinchuk, C. Cao, F. Huang, K. A. Reeves, J. Wang,
F. Myers, G. H. Cantor, X. Zhou, R. M. Attar, M. Gottardis
and J. M. Carboni, Endocrinology, 2010, 151, 4123.
Notes and references
1 (a) I. P. Beletskaya and V. P. Ananikov, Chem. Rev., 2011, 111,
1596; (b) I. Nakamura and Y. Yamamoto, Chem. Rev., 2004,
104, 2127; (c) A. V. Gulevich, A. S. Dudnik, N. Chernyak
and V. Gevorgyan, Chem. Rev., 2013, 113, 3084; (d) I. Ojima,
M. Tzamarioudaki, Z. Li and R. J. Donovan, Chem. Rev.,
1996, 96, 635.
2 (a) E. M. Beccalli, G. Broggini, M. Martinelli and
S. Sottocornola, Chem. Rev., 2007, 107, 5318; (b)
J. Y. K. Seung hwan Cho, J. Kwak and S. Chang, Chem. Soc.
Rev., 2011, 40, 5068; (c) N. Kuhl, M. N. Hopkinson,
J. Wencel-Delord and F. Glorius, Angew. Chem., Int. Ed.,
2012, 51, 10236; (d) V. P. Mehta and B. Punji, RSC Adv.,
2013, 3, 11957; (e) J. Bariwal and E. Van der Eycken, Chem.
Soc. Rev., 2013, 42, 9283.
3 (a) G. Liu, S. Abraham, L. Tran, T. D. Vickers, S. Xu,
M. J. Hadd, S. Quiambao, M. W. Holladay, H. Hua,
J. M. Ford Pulido, R. N. Gunawardane, M. I. Davis,
S. R. Eichelberger, J. L. Apuy, D. Gitnick, M. F. Gardner,
J. James, M. A. Breider, B. Belli, R. C. Armstrong and
D. K. Treiber, J. Med. Chem., 2012, 55, 3250; (b) G. R. Ott,
G. J. Wells, T. V. Thieu, M. R. Quail, J. G. Lisko,
E. F. Mesaros, D. E. Gingrich, A. K. Ghose, W. Wan, L. Lu,
M. Cheng, M. S. Albom, T. S. Angeles, Z. Huang,
L. D. Aimone, M. A. Ator, B. A. Ruggeri and B. D. Dorsey,
J. Med. Chem., 2011, 54, 6328.
4 (a) C. Liu, J. Lin, S. T. Wrobleski, S. Lin, J. Hynes, H. Wu,
A. J. Dyckman, T. Li, J. Wityak, K. M. Gillooly, S. Pitt,
D. R. Shen, R. F. Zhang, K. W. McIntyre, L. Salter-Cid,
D. J. Shuster, H. Zhang, P. H. Marathe, A. M. Doweyko,
J. S. Sack, S. E. Kiefer, K. F. Kish, J. A. Newitt,
M. McKinnon, J. H. Dodd, J. C. Barrish, G. L. Schieven and
K. Leheris, J. Med. Chem., 2010, 53, 6629; (b) J. Hynes,
A. J. Dyckman, S. Lin, S. T. Wrobleski, H. Wu,
K. M. Gillooly, S. B. Kanner, H. Lonial, D. Loo,
K. W. McIntyre, S. Pitt, D. R. Shen, D. J. Shuster, X. Yang,
R. Zhang, K. Behnia, H. Zhang, P. H. Marathe,
A. M. Doweyko, J. S. Tokarski, J. S. Sack, M. Pokross,
S. E. Kiefer, J. A. Newitt, J. C. Barrish, J. Dodd,
G. L. Schieven and K. Leheris, J. Med. Chem., 2007, 51, 4.
5 T. W. Wong, F. Y. Lee, S. Emanuel, C. Fairchild, J. Fargnoli,
B. Fink, A. Gavai, A. Hammell, B. Henley, C. Hilt,
J. T. Hunt, B. Krishnan, D. Kukral, A. Lewin, H. Malone,
D. Norris, S. Oppenheimer, G. Vite and C. Yu, Clin. Cancer
Res., 2011, 17, 4031.
8 (a) Y. Chen, H. Xiang, C. Tan, Y. Xie and C. Yang,
Tetrahedron, 2013, 69, 2714; (b) S. A. Patil, B. A. Otter and
R. S. Klein, J. Heterocycl. Chem., 1994, 31, 781; (c) K. S. Kim,
S. Lu, L. A. Cornelius, L. J. Lombardo, R. M. Borzilleri,
G. M. Schroeder, C. Sheng, G. Rovnyak, D. Crews,
R. J. Schmidt, D. K. Williams, R. S. Bhide, S. C. Traeger,
P. A. McDonnell, L. Mueller, S. Sheriff, J. A. Newitt,
A. T. Pudzianowski, Z. Yang, R. Wild, F. Y. Lee,
R. Batorsky, J. S. Ryder, M. Ortega-Nanos, H. Shen,
M. Gottardis and D. L. Roussell, Bioorg. Med. Chem. Lett.,
2006, 16, 3937; (d) J. Wang, X. Wang, Y. Chen, S. Chen,
G. Chen, L. Tong, L. Meng, Y. Xie, J. Ding and C. Yang,
Bioorg. Med. Chem. Lett., 2012, 22, 339; (e) T. Saito,
T. Obitsu, H. Kohno, I. Sugimoto, T. Matsushita,
T. Nishiyama, T. Hirota, H. Takeda, N. Matsumura,
S. Ueno, A. Kishi, Y. Kagamiishi, H. Nakai and Y. Takaoka,
Bioorg. Med. Chem., 2012, 20, 1122; (f) T. Thieu,
J. A. Sclafani, D. V. Levy, A. McLean, H. J. Breslin, G. R. Ott,
R. P. Bakale and B. D. Dorsey, Org. Lett., 2011, 13, 4204.
´
9 (a) V. Sridharan, P. A. Suryavanshi and J. C. Menendez, Chem.
Rev., 2011, 111, 7157; (b) Q. Huang, J. A. Hunter and
R. C. Larock, Org. Lett., 2001, 3, 2973; (c) D. Pla,
A. Marchal, C. A. Olsen, A. Francesch, C. Cuevas,
´
F. Albericio and M. Alvarez, J. Med. Chem., 2006, 49, 3257;
(d) E.-J. Park, E. Kiselev, M. Conda-Sheridan, M. Cushman
and J. M. Pezzuto, J. Nat. Prod., 2011, 75, 378; (e)
M. A. Rashid, K. R. Gustafson and M. R. Boyd, J. Nat. Prod.,
2001, 64, 1249; (f) C. W. Wright, S. J. Marshall,
P. F. Russell, M. M. Anderson, J. D. Phillipson, G. C. Kirby,
D. C. Warhurst and P. L. Schiff, J. Nat. Prod., 2000, 63,
1638; (g) H. Sorek, A. Rudi, I. Goldberg, M. Aknin and
Y. Kashman, J. Nat. Prod., 2009, 72, 784; (h) D. S. Bhakuni
and S. Gupta, J. Nat. Prod., 1982, 45, 407.
10 (a) X. Yao and C.-J. Li, Org. Lett., 2006, 8, 1953; (b)
M. Chrzanowska and M. D. Rozwadowska, Chem. Rev.,
2004, 104, 3341.
11 H. Gao and J. Zhang, Adv. Synth. Catal., 2009, 351, 85.
12 N. T. Patil, A. K. Mutyala, P. G. V. V. Lakshmi, P. V. K. Raju
and B. Sridhar, Eur. J. Org. Chem., 2010, 1999.
13 P. M. k. K. Siva Kumar, M. Appi Reddy and Md. Ferozudlin,
Chem. Commun., 2011, 46, 10263.
14 (a) H. Xiang, Y. Chen, Q. He, Y. Xie and C. Yang, RSC Adv.,
2013, 3, 5807; (b) M. Wang, C. Tan, Q. He, Y. Xie and
C. Yang, Org. Biomol. Chem., 2013, 11, 2574.
6 A. V. Gavai, B. E. Fink, D. J. Fairfax, G. S. Martin,
L. M. Rossiter, C. L. Holst, S.-H. Kim, K. J. Leavitt,
H. Mastalerz, W.-C. Han, D. Norris, B. Goyal,
S. Swaminathan, B. Patel, A. Mathur, D. M. Vyas,
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 11168–11175 | 11175