Synthesis of Benzoindolizines through 1,5-Electrocyclization/Oxidation Cascades

Article abstract of DOI:10.1021/acs.joc.8b02065

This study presents a convenient synthesis of pyrrolo[1,2-a]quinolines and pyrrolo[2,1-a]isoquinolines with simple quinolines or isoquinolines and Morita-Baylis-Hillman carbonates in the presence of copper acetate. A range of functionalized benzoindolizines could be assembled through an S_N2′/deprotonation/1,5-electrocyclization/oxidation cascade pathway in a one-step process.

Full text of DOI:10.1021/acs.joc.8b02065

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Article
Synthesis of Benzoindolizines Through 1,5-
Electrocyclization/Oxidation Cascades
Si-Wei Liu, Ying-Juan Gao, Yin Shi, Lin Zhou, Xue Tang, and Hai-Lei Cui
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02065 • Publication Date (Web): 29 Oct 2018
Downloaded from http://pubs.acs.org on October 29, 2018
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Synthesis of Benzoindolizines Through 1,5-Electrocyclization/Oxidation
Cascades
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Si-Wei Liu,† Ying-Juan Gao,† Yin Shi,† Lin Zhou, † Xue Tang †,‡ and Hai-Lei Cui*†
† Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave.,
Yongchuan, Chongqing, 402160, China;
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E-mail: cuihailei616@163.com
‡State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese
Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu
611137, China
Cu(OAc)2
OBoc
NMP, air
+
EWG
R1
R1
R1
N
N
N
R2
 In air
EWG
EWG
 Gram-scale possible
 Undistilled solvent
 Easy transformations
 Inexpensive catalyst
32 examples
up to 90% yields
6 examples
Abstract This study presents
a
convenient synthesis of pyrrolo[1,2-a]quinolines and
pyrrolo[2,1-a]isoquinolines with simple quinolines or isoquinolines and Morita–Baylis–Hillman
carbonates in the presence of copper acetate. A range of functionalized benzoindolizines could be
assembled through SN2’/deprotonation/1,5-electrocyclization/oxidation cascade pathway in a one-step
process.
Keywords: Pyrroloquinoline, Pyrroloisoquinoline, Electrocyclization, Quinoline, Isoquinoline
INTRODUCTION
Benzoindolizine is an important framework possessing wide occurrence in biologically active compounds
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(Fig 1).1 Furthermore, related benzoindolizine derivatives can also be used as useful building blocks and
functional materials.2 The great importance of potential applications have created a significant need for the
development of convenient synthetic methods as well as structurally diversified benzoindolizines.
Accordingly, a large number of attractive methodologies, including multicomponent reactions3, 1,3-dipolar
cycloadditions4, intramolecular cyclizations5, coupling/cyclization cascades6, C-H activation7,
condensation/cyclization cascades8, Michael addition/cyclization cascades9, substitution/cyclization
cascades10, amination/C-H activation cascades11, have been well established in past decades for the
construction of benzoindolizine derivatives. From the standpoint of green and sustainable chemistry, the
preparation of complex molecules bearing this privileged framework from readily available material is an
interesting and longstanding topic in synthetic chemistry. Therefore, considering the great significance of
structurally diversified pyrrolo[1,2-a]quinolines and pyrrolo[2,1-a]isoquinolines, the facile construction of
these molecules in a straightforward fashion from simple and easily accessible material is extremely
desirable.
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Ph
O
MeO
CF3
5
6
7
8
N
R
R
N
N
N
O
CF3
R
R
R
Ph
anticancer
NK1 receptor ligand
9
antibacterial
antifungal
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HO
MeO
HO
MeO
HO
MeO
O
O
O
O
N
N
N
MeO
MeO
HO
MeO
O
O
MeO
HO
OH
OSO3Na
OH
MeO
MeO
MeO
Lamellarin  20-sulfate
Lamellarin N
protein kinases inhibitor
Lamellarin D
anti-HIV-1 agent
topoisomerase I inhibitor
Figure 1. Representative Examples of Bioactive Pyrrolo[1,2-a]quinolines and
Pyrrolo[2,1-a]isoquinolines
Cyclizations based on the formation of 1,n-dipoles (n>3) and conjugated 1,3-dipoles have been
enabling the facile synthesis of highly functionalized and diversified azacycles in recent years.12-14 Fruitful
achievements in the construction of interesting nitrogen-containing molecules have been realized through
this strategy. In our previous work, we have developed a catalyst-free [2+2+2] cyclization of
dihydro-β-carboline and ynone allowing access to novel complex dimeric β-carboline derivatives in a
single step.15-16 The in situ generated 1,6-dipole was proposed as the key intermediate in this process. Based
on the same 1,n-dipole cyclization strategy, we have subsequently disclosed the formal [3+2] cyclizations
of dihydroisoquinoline with Morita–Baylis–Hillman (MBH) carbonates.17-18 Electrocyclizations of in situ
formed conjugated azomethine ylides successfully provided
a
range of interesting
tetrahydropyrrolo[2,1-a]isoquinolines and tetrahydroisoquinoline fused spirooxindoles. To prepare more
interesting heterocycles possessing privileged scaffold from simple material, we then tried to explore
further application of 1,n-dipole cyclization strategy on the synthesis of functionalized benzoindolizines.
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Inspired by the reported achievements and on the basis of retrosynthetic analysis, we envisioned that the
synthesis of pyrrolo[1,2-a]quinoline and pyrrolo[2,1-a]isoquinolines could be achieved by electrocyclic
closure of conjugated azomethine ylides and subsequent oxidation (Scheme 1). This retrosynthetic analysis
points to commercially available quinolines, isoquinolines and simple MBH carbonates as logical
precursors for synthesis. Here, we report our development of a formal [3+2] cyclization of (iso)quinolines
and MBH carbonates.
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R
N
EWG
OBoc
[O]
EWG
+
R
R
N
N
EWG
R
N
EWG
Scheme 1. Retrosynthetic Analysis.
RESULTS AND DISCUSSION
Initially, a catalyst-free reaction between quinoline 1a and MBH carbonate 2a in DMF was performed at
o
120 C (Table 1, entry 1). We were pleased to find that the desired pyrrolo[1,2-a]quinoline 3a could be
detected in an encouraging 48% yield under aerobic oxidation of dioxygen in air. However, the reaction
failed to run completely under the current conditions even after prolonged reaction time. As copper is an
inexpensive and environment-friendly metal catalyst used extensively in aromatization by oxidation, we
guessed that the employment of catalytic amount of copper salts would be helpful for the completion of
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reaction. Thus, a series of copper catalysts as well as palladium salt were screened in order to improve the
yield (entries 2-9). The screening of copper sources identified Cu(OAc)2 as the optimal catalyst which gave
a dramatically increased yield (76%). Examination of temperature and solvent led to a 98% NMR yield and
88% isolated yield of 3a (entries 10-15). As a control experiment, a 49% isolated yield was obtained in the
absence of Cu(OAc)2 indicating that the use of copper salts as oxidation catalyst is critical for this process
(entry 16). The role of Cu(OAc)2 as oxidant was further supported by the reaction performed under Ar
atmosphere, which provided 59% yield (entry 17). The use of undistilled solvent may also have influence
on reaction yield. The reaction under O2 atmosphere gave only 33% yield and more complicated
byproducts could be observed compared with other cases, although reaction could be completed in a much
shorter reaction time (entry 18). The reason for unexpected reaction yields obtained in these two reactions
(entries 17 and 18) has not been fully understood yet.
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Table 1 Optimization of Reaction Conditions for Synthesis of 3a.a,b
OBoc
COOMe
Me
+
N
N
Me
COOMe
1a
2a
3a
Yield
Entry
Catalyst
Solvent
T (oC)
t (h)
[%]b
48
69
25
56
64
76
14
65
18
68c
38c
30
<5
1
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
120
120
120
120
120
120
120
120
120
140
100
50
28
9
2
CuBr2
CuCl2
CuCl
CuBr
3
12
7
4
5
7
.
6
Cu(OAc)2 H2O
Cu(NO3)2
CuI
9.5
11.5
11.5
11.5
3
7
8
9
Pd(OAc)2
.
10
11
12
13
Cu(OAc)2 H2O
.
Cu(OAc)2 H2O
20
45
88
.
Cu(OAc)2 H2O
.
Cu(OAc)2 H2O
rt
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.
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Cu(OAc)2 H2O
DMSO
NMP
NMP
NMP
NMP
120
120
120
120
120
53
35
35
35
12
56
98 (88)c
.
Cu(OAc)2 H2O
-
49
.
Cu(OAc)2 H2O
59c,d
33c,e
.
Cu(OAc)2 H2O
a 1a (3 equiv, 0.6 mmol), 2a (1 equiv, 0.2 mmol), catalyst (20 mol%), solvent (0.2 mL), in air. b Determined by 1H NMR using CH2Br2
as internal standard. c Isolated yield. d Under Ar atmosphere. e Under O2 atmosphere.
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Next we turned our attention to the examination of substrate scope. As summarized in Table 2,
aromatic MBH carbonates bearing electron-donating groups can be successfully applied in this process
(3a-3d, 77-88%).19 The applicability of our process was demonstrated by gram-scale reaction of quinoline
1a and MBH carbonate 2d (methyl 2-(((tert-butoxycarbonyl)oxy)(phenyl)methyl)acrylate), affording 3d in
71% yield. However, regarding MBH carbonates with electron-withdrawing groups, steric and electronic
effects played an important role in the formation of final product. Bromo substituent at the 2-position of
phenyl ring (MBH carbonate 2e) led to 16% yield likely due to steric reason (3e). While reactions of MBH
carbonates with chloro substituents (MBH carbonates 2f and 2g) proceeded readily affording 3f and 3g in
65% and 80% yield respectively. Furfuryl group could be incorporated into benzoindolizine delivering
target molecule 3h in 30% yield by using MBH carbonate 2h. In the case of aliphatic aldehyde-derived
MBH carbonate 2i, no reaction was observed (3i). We reasoned that the formation of conjugated
azomethine ylides was difficult when lacking the stabilization effect of aromatic ring.20 MBH carbonates
bearing the groups of COOEt, COOBn and CN could be tolerated in this system giving 3j, 3k and 3l in
58-62% yield. A range of quinolines was then submitted to this process. Electronic nature of substituted
groups on the quinoline ring (Me, BocNH, MOMO, MeO and Br) has a limited effect on reaction yield,
while the position of substituents significantly influenced the reaction yield. For example, quinoline with a
substituent at C8 position gave no product at all. We reasoned that 8-methylquinoline is too sterically
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hindered to act as nucleophile in this cascade sequence. The failure of preparation of compound 3m is due
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to side reactions that involve the C4-methyl group of the quinoline precursor.21
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Table 2 Examination of substrate scope.a,b
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
Cu(OAc)2 H2O
R1
NMP, 120 oC, air
OBoc
R2
R1
+
N
EWG
R2
N
EWG
1
3
2
7
8
9
OMe
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R
N
N
OMe
COOMe
COOMe
3c, 37 h, 78%
3a, R = Me, 35 h, 88%
3b, R = MeO, 19 h, 88%
Cl
Br
Cl
N
N
N
COOMe
COOMe
COOMe
3d, 35 h, 77%
3e, 42 h, 16%
3f, 76 h, 65%
Gram-scale: 27 h, 71%
O
Cl
N
N
N
COOMe
COOMe
COOMe
3h, 29 h, 30%
3g, 29 h, 80%
3i, 65 h, 0%
Me
R
OMe
Me
N
N
N
EWG
COOMe
OMe
COOMe
3m, 120 h, trace
3j, EWG = COOEt, 42 h, 62%
3k, EWG = COOBn, 42 h, 60%
3l, EWG = CN, 25 h, 58%
3n, R = BocNH, 26 h, 74%
3o, R = OBn, 37 h, 87%
3p, R = Me, 45 h, 70%
OMe
MeO
Me
Me
N
MOMO
N
N
Me
OMe
COOMe
COOMe
COOMe
3s, 41 h, 0%
3q, 31 h, 63%
3r, 20 h, 58%
Br
OMe
Br
OMe
N
N
OMe
OMe
COOMe
3t, 53 h, 62%
COOMe
3u, 41 h, 66%
a 1a (3 equiv, 0.6 mmol), 2a (1 equiv, 0.2 mmol), Cu(OAc)2 H2O (20 mol%), NMP (0.2 mL), in air. b Isolated yield.
.
Then we focused on the synthesis of pyrrolo[2,1-a]isoquinolines using isoquinolines. MBH carbonates
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bearing electron-donating groups and electron-withdrawing groups could be tolerant in this process,
providing corresponding pyrroloisoquinolines in moderate to good yields (51-81%, Table 3, compounds
5a-5h). It’s worthy of note that the gram-scale reaction of isoquinoline 2a with MBH carbonate 2l
(tert-butyl (2-cyano-1-phenylallyl) carbonate) was successful providing compound 5f in 63% yield. Furan
moiety can also be successfully incorporated into pyrroloisoquinoline in 82% yield. Substituted
isoquinolines reacted with MBH carbonates smoothly giving the desired products in 59-81% yield (5j, 5k
and 5l).
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Table 3 Examination of substrate scope.a,b
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
Cu(OAc)2 H2O
R1
NMP, 120 oC, air
OBoc
EWG
N
R1
+
R2
N
R2
EWG
7
8
4
2
5
9
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N
N
N
COOMe
COOMe
MeO
COOMe
Me
MeO
5b, 31 h, 70%
OMe
5a, 41 h, 51%
5c, 32 h, 81%
N
N
N
COOMe
COOMe
EWG
Cl
Cl
Cl
5d, EWG = COOMe, 26 h, 79%
5e, EWG = COOEt, 22 h, 67%
5f, EWG = CN, 17 h, 63% (Gram-scale)
5h, 31 h, 75%
5g, 28 h, 61%
Br
Br
N
N
N
COOMe
COOMe
O
R
MeO
COOMe
R
OMe
5i, 31 h, 82%
5j, R = H, 44 h, 59%
5k, R = MeO, 45 h, 63%
5l, 35 h, 81%
a 1a (3 equiv, 0.6 mmol), 2a (1 equiv, 0.2 mmol), Cu(OAc)2 H2O (20 mol%), NMP (0.2 mL), in air. b Isolated yield.
.
We tried to further extend this methodology to other MBH adducts and nitrogen-containing aromatic
ring. As shown in Scheme 2, the reaction of MBH acetate 2p proceeded smoothly affording 3d in 61%
yield. Phenanthridine
6 is also a suitable candidate for this process, giving corresponding
pyrrolo[1,2-f]phenanthridine 7 in excellent yield (90%). 2-Phenylpyridine and 2,3-dimethylpyrazine failed
to deliver the desired azacycles 9 and 11, probably due to side reactions.
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OAc

Cu(OAc)2 H2O
NMP, 120 oC, air
COOMe
+
N
N
COOMe
7
2p
1a
8
3d, 36.5 h, 61%
9
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OBoc

Cu(OAc)2 H2O
N
MeO
COOMe
NMP, 120 oC, air
+
N
COOMe
MeO
OMe
6
2c
OMe
7, 46 h, 90%
OBoc

Cu(OAc)2 H2O
NMP, 120 oC, air
COOMe
Me
+
N
N
Me
2a
8
COOMe
9, 50 h, 0%

OBoc
Cu(OAc)2 H2O
NMP, 120 oC, air
Me
Me
N
N
Me
Me
N
COOMe
Me
+
N
Me
2a
10
COOMe
11, 99 h, 0%
Scheme 2. Attempts of further extension of substrate scope.
The synthetic application of the obtained pyrrolo[1,2-a]quinolines 3 was successfully demonstrated by
easy transformation to highly functionalized molecules 12-17 (Scheme 3). Mannich reaction of 3a at room
temperature gave tertiary amine 12 in 78% yield, while Vilsmeier-Haack reaction led to the formation of
compound 13 in 77% yield. Bromination of pyrrolo[1,2-a]quinolines 3d and 3f with NBS proceeded
readily providing compound 14 and 15 (66% and 81% yields respectively). The subsequent Suzuki
coupling of 15 afforded highly fused heterocycles 16 and 17 respectively in excellent yields.
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Morpholine
HCHO, AcOH
MeCN, rt
Cl
Cl
R
POCl3
DMF, rt
Cl
Cl
R
N
N
N
R = Cl
R = Cl
OHC
COOMe
COOMe
COOMe
N
13, 77%
3
10
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O
NBS, DCE, rt
12, 78%
Pd(PPh3)4
Na2CO3
Pd(PPh3)4
Na2CO3
R
H2O, DMF
120 oC
H2O, DMF
120 oC
R
N
N
N
COOMe
Br
COOMe
COOMe
O
O
O
B
14, R = Cl, 66%
15, R = H, 81%
N
B
O
O2N
16, quant
17, quant
N
NO2
Scheme 3. Transformations of pyrrolo[1,2-a]quinoline 3
Based on these results and previous reports4c-4f,12,14,17,18, we proposed a possible mechanism (Scheme
4). MBH carbonate 2a can be attacked by quinoline 1a giving intermediate A. The subsequent
deprotonation by the in situ generated tert-butoxide anion17,22 affords intermediates B and C.
Electrocyclization of conjugated azomethine ylide and a final oxidation of intermediate D23 provide
pyrrolo[1,2-a]quinolone 3a. Both copper acetate and oxygen in air play an important role in the final
oxidative aromatization of intermediate D.24 The possible intermolecular allylic alkylation reaction of
intermediate A may be the reason for the low yield observed in the case of 3m.17 While the lack of aromatic
ring resulted poor stability of intermediate B and C should be responsible for the failure of compound 3i.
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O
CO2
6
O
O
COOMe
7
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N
+
tBuO
+
COOMe
N
H
Me
1a
2a
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A
Me
N
B
N
COOMe
MeOOC
C
Me
Me
H
Me
[O]
Me
N
N
H
COOMe
COOMe
D 3aa
3a
Scheme 4. Proposed mechanism
CONCLUSION
In summary, we have established a convenient method for the construction of pyrrolo[1,2-a]quinolines and
pyrrolo[2,1-a]isoquinolines with simple quinolines or isoquinolines and MBH carbonates as starting
material in the presence of copper acetate in air. A variety of benzoindolizines could be accessed in
moderate to good yields (up to 90% yield) through a SN2’/deprotonation/electrocyclization/oxidation
pathway. The utility of this synthetic methodology has been demonstrated by easy transformations to
highly functionalized azacycles.
EXPERIMENTAL SECTION
General methods H NMR and 13C NMR spectra were recorded at Bruker Avance 400. Chemical shifts
1
1
are reported in ppm downfield from CDCl3 (δ = 7.26 ppm) for H NMR and relative to the central CDCl3
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resonance (δ = 77.0 ppm) for 13C NMR spectroscopy. Coupling constants are given in Hz. ESI-MS analysis
was performed using a LTQ Orbitrap mass spectrometer.
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All reagents and solvents were obtained from commercial sources and used without further
purification. Substituted quinolines 1 and MBH carbonates 2 were prepared according to reported
procedure. 22.25
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General procedure for the synthesis of compounds 3, 5 and 7
.
A mixture of quinoline 1 (or 4, 6) (0.6 mmol), MBH carbonate 2 (0.2 mmol), Cu(OAc)2 H2O (0.04 mmol)
and NMP (0.2 mL) was stirred at 120 oC in air. Upon the consumption of MBH carbonate 2 (monitored by
TLC), the mixture was concentrated and the residue was purified by a silica gel flash chromatography
(PE/EtOAc) to afford 3 (or 5, 7).
Methyl 3-(p-tolyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3a). Purified by flash column chromatography
(PE/EA = 200:3); 56.0 mg, 88% yield, yellow solid; m.p. 108-111℃. 1H NMR (400 MHz, CDCl3) δ 8.46 (s,
1H), 7.94 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 0.8, 7.6 Hz, 1H), 7.56-7.51 (m, 1H), 7.41-7.36 (m, 3H),
7.27-7.25 (m, 3H), 6.98 (d, J = 9.6 Hz, 1H), 3.81 (s, 3H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
165.2, 136.5, 132.8, 130.7, 130.5, 129.5, 128.74, 128.65, 128.2, 125.0, 124.7, 120.3, 119.2, 118.2, 116.65,
116.61, 114.4, 51.2, 21.3; IR (CH2Cl2, cm-1) υ 1697, 1607, 1561, 1539, 1518, 1503, 1463, 1452, 1436,
1235, 1140, 793, 735; ESI-HRMS: calcd. for C21H18NO2+ (M+H)+ 316.1332, found 316.1337.
Methyl 3-(4-methoxyphenyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3b). Purified by flash column
chromatography (PE/EA = 50:1); 58.4 mg, 88% yield, yellow solid; m.p. 166-170℃. 1H NMR (400 MHz,
CDCl3) δ 8.46 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.56-7.52 (m, 1H), 7.43-7.36 (m,
3H), 7.26-7.24 (m, 1H), 7.01-6.97 (m, 3H), 3.87 (s, 3H), 3.81 (s, 3H), 13C{1H} NMR (100 MHz, CDCl3) δ
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165.1, 159.2, 135.1, 132.8, 129.6, 128.8, 128.3, 125.0 124.7, 123.3, 120.5, 118.9, 118.2, 116.8, 116.7,
116.4, 114.4, 112.5, 55.3, 51.2; IR (CH2Cl2, cm-1) υ 1714, 1606, 1548, 1515, 1498, 1482, 1450, 1217, 1175,
792, 756; ESI-HRMS: calcd. for C21H18NO3+ (M+H)+ 332.1281, found 332.1285.
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Methyl 3-(3,5-dimethoxyphenyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3c). Purified by flash column
chromatography (PE/EA = 100:3); 56.7 mg, 78% yield, yellow solid; m.p. 140-144℃. 1H NMR (400 MHz,
CDCl3) δ 8.46 (s, 1H), 7.95-7.92 (m, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.57-7.53 (m, 1H), 7.39 (t, J = 7.6 Hz,
1H), 7.32 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 9.6 Hz, 1H), 6.66 (d, J = 2.4 Hz, 2H), 6.49 (t, J = 2.0 Hz, 1H),
3.85 (s, 6H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.1, 160.2, 135.7, 132.8, 129.6, 128.8,
128.3, 125.0, 124.7, 120.6, 118.9, 118.2, 116.8, 116.7, 114.4, 109.0, 107.3, 99.3, 55.4, 51.3; IR (CH2Cl2,
+
cm-1) υ 1715, 1594, 1456, 1427, 1401, 1205, 1153, 840; ESI-HRMS: calcd. for C22H20NO4 (M+H)+
362.1387, found 362.1390.
Methyl 3-phenylpyrrolo[1,2-a]quinoline-2-carboxylate (3d). Purified by flash column chromatography
(PE/EA = 80:1); 46.6 mg, 77% yield, yellow solid; m.p. 138-141℃. 1H NMR (400 MHz, CDCl3) δ 8.35 (s,
1H), 7.81 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.43-7.39 (m, 3H), 7.37-7.33 (m, 2H), 7.26 (t, J =
7.2 Hz, 2H), 7.16-713 (m, 1H), 6.87 (d, J = 9.6 Hz, 1H), 3.71 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
165.2, 133.8, 132.8, 130.7, 129.6, 128.8, 128.3, 127.9, 126.8, 125.0, 124.7, 120.5, 119.2, 118.1, 116.7,
116.7, 114.4, 51.2; IR (CH2Cl2, cm-1) υ 1700, 1645, 1599, 1562, 1539, 1506, 1479, 1453, 1434, 1209, 727;
+
ESI-HRMS: calcd. for C20H16NO2 (M+H)+ 302.1176, found 302.1178.
Methyl 3-(2-bromophenyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3e). Purified by flash column
chromatography (PE/EA = 90:1); 12.5 mg, 16% yield, yellow solid; m.p. 157-158℃. 1H NMR (400 MHz,
CDCl3) δ 8.49 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.65 (dd, J = 0.8, 7.6 Hz, 1H),
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7.59-7.54 (m, 1H), 7.42-7.36 (m, 3H), 7.27-7.23 (m, 1H), 7.03 (d, J = 9.6 Hz, 1H), 6.99 (d, J = 9.2 Hz, 1H),
3.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.9, 134.3, 131.8, 131.53, 131.51, 128.6, 127.85,
127.77, 127.4, 125.8, 124.8, 124.0, 123.5, 119.7, 116.9, 116.7, 116.6, 115.0, 113.4, 50.3; IR (CH2Cl2, cm-1)
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+
υ 1699, 1607, 1561, 1514, 1468, 1435, 1208, 1147, 747; ESI-HRMS: calcd. for C20H15BrNO2 (M+H)+
380.0281, found 380.0284.
Methyl 3-(3,4-dichlorophenyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3f). Purified by flash column
chromatography (PE/EA = 120:1); 48.3 mg, 65% yield, yellow solid; m.p. 173-175℃. 1H NMR (400 MHz,
CDCl3) δ 8.47 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.59-7.55 (m, 2H), 7.50 (d, J =
8.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.35-7.33 (m, 1H), 7.21 (d, J = 9.2 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H),
3.82 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.9, 133.9, 132.7, 132.3, 131.8, 130.9, 130.3, 129.8,
129.7, 128.9, 128.6, 125.3, 124.6, 121.5, 117.3, 117.0, 116.6, 116.4, 114.5, 51.4; IR (CH2Cl2, cm-1) υ 1716,
+
1613, 1595, 1566, 1537, 1502, 1471, 1453, 1439, 1209, 1143, 744; ESI-HRMS: calcd. for C20H14Cl2NO2
(M+H)+ 370.0396, found 370.0398.
Methyl 3-(4-chlorophenyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3g). Purified by flash column
chromatography (PE/EA = 100:1); 53.8 mg, 80% yield, yellow solid; m.p. 178-179℃. 1H NMR (400 MHz,
CDCl3) δ 8.48 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.58-7.54 (m, 1H), 7.44-7.39 (m,
5H), 7.22 (d, J = 9.6 Hz, 1H), 7.03 (d, J = 9.2 Hz, 1H), 3.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
165.0, 132.8, 132.3, 132.0, 129.6, 128.8, 128.4, 128.1, 125.1, 124.6, 120.9, 117.8, 117.7, 116.8, 116.6,
114.4, 51.3; IR (CH2Cl2, cm-1) υ 1721, 1561, 1540, 1500, 1478, 1451, 1440, 1407, 1397, 1210, 1139, 740;
ESI-HRMS: calcd. for C20H15ClNO2+ (M+H)+ 336.0786, found 336.0788.
Methyl 3-(furan-2-yl)pyrrolo[1,2-a]quinoline-2-carboxylate (3h). Purified by flash column
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chromatography (PE/EA = 130:1); 17.3 mg, 30% yield, yellow solid; m.p. 91-92℃. H NMR (400 MHz,
CDCl3) δ 8.45 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 5.6 Hz, 1H), 7.66 (d, J = 5.6 Hz, 1H),
7.57-7.53 (m, 2H), 7.40 (t, J = 5.6 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 3.2 Hz, 1H), 6.55-6.54 (m,
1H), 3.90 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.8, 148.6, 141.2, 132.6, 129.8, 128.7, 128.4,
125.2, 124.6, 121.1, 119.4, 117.6, 115.6, 114.4, 111.2, 109.5, 108.3, 51.5; IR (CH2Cl2, cm-1) υ 1714, 1590,
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1561, 1502, 1471, 1434, 1407, 1260, 1206, 1127, 763; ESI-HRMS: calcd. for C18H14NO3 (M+H)+
+
292.0968, found 292.0972.
Ethyl 3-phenylpyrrolo[1,2-a]quinoline-2-carboxylate (3j). Purified by flash column chromatography
(PE/EA = 100:1); 38.8 mg, 62% yield, yellow solid; m.p. 93-94℃. 1H NMR (400 MHz, CDCl3) δ 8.47 (s,
1H), 7.94 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.55-7.48 (m, 3H), 7.43 (t, J = 7.6 Hz, 2H),
7.39-7.33 (m, 2H), 7.26-7.24 (m, 1H), 6.98 (d, J = 9.6 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.8, 133.9, 132.8, 130.8, 129.6, 128.7, 128.3, 127.8, 126.8,
124.9, 124.7, 120.4, 119.2, 118.1, 117.2, 116.6, 114.4, 60.0, 14.2; IR (CH2Cl2, cm-1) υ 1696, 1597, 1558,
1538, 1503, 1477, 1451, 1442, 1235, 758; ESI-HRMS: calcd. for C21H18NO2 (M+H)+ 316.1332, found
+
316.1337.
Benzyl 3-phenylpyrrolo[1,2-a]quinoline-2-carboxylate (3k). The mixture was passed through a pad of
silica gel eluted with PE/EA (80/1). The eluate was concentrated and the residue was recrystallized with
1
PE/EA affording 3k as yellow solid, 45.5 mg, 60% yield; m.p. 144-147℃. H NMR (400 MHz, CDCl3) δ
8.43 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.48-7.42 (m, 3H), 7.36 (t, J = 7.2 Hz, 2H),
7.33-7.25 (m, 5H), 7.22-7.17 (m, 3H), 6.92 (d, J = 9.6 Hz, 1H), 5.22 (s, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.6, 136.3, 133.8, 132.8, 130.8, 129.7, 128.8, 128.4, 128.3, 128.1, 127.9, 126.8, 125.0, 124.7,
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7
+
1477, 1452, 1232, 1154, 750; ESI-HRMS: calcd. for C26H20NO2 (M+H)+ 378.1489, found 378.1489.
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3-Phenylpyrrolo[1,2-a]quinoline-2-carbonitrile (3l). Purified by flash column chromatography (PE/EA
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= 120:1); 31.1 mg, 58% yield, white solid; m.p. 147-150℃. H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H),
7.89 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.64-7.62 (m, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.53-7.49
(m, 2H), 7.47-7.37 (m, 3H), 7.14 (d, J = 9.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 132.4, 132.3,
129.0, 128.9, 128.8, 128.1, 127.5, 125.6, 124.5, 122.0, 120.4, 118.0, 117.4, 116.1, 114.4, 96.7; IR (CH2Cl2,
cm-1) υ 2219, 1739, 1645, 1599, 1560, 1542, 1500, 1476, 1452, 1443, 1402, 1195, 743; ESI-HRMS: calcd.
for C19H13N2+ (M+H)+ 269.1073, found 269.1075.
Methyl
7-((tert-butoxycarbonyl)amino)-3-(p-tolyl)pyrrolo[1,2-a]quinoline-2-carboxylate
(3n).
Performed at 0.05 mmol scale; Purified by flash column chromatography (PE/EA = 25:1); 16.0 mg, 74%
yield, yellow solid; m.p. 154-158℃. 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H),
7.75 (s, 1H), 7.45 (dd, J = 2.4, 9.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.26-7.23 (m, 3H), 6.93 (d, J = 9.6 Hz,
1H), 6.63 (s, 1H), 3.80 (s, 3H), 2.41 (s, 3H), 1.55 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.2, 152.8,
136.4, 135.4, 130.7, 130.5, 129.3, 128.7, 128.6, 125.4, 120.2, 119.5, 119.3, 119.2, 119.2, 118.8, 116.4,
115.0, 51.2, 28.4, 21.3, 14.1; IR (CH2Cl2, cm-1) υ 1700, 1570, 1548, 1532, 1506, 1444, 1418, 1397, 1213,
1154, 1137, 812; ESI-HRMS: calcd. for C26H27N2O4 (M+H)+ 431.1965, found 431.1967.
+
Methyl 7-(benzyloxy)-3-(p-tolyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3o). The mixture was passed
through a pad of silica gel eluted with Hexane/EA (40/1). The eluate was concentrated and the residue was
1
recrystallized with PE/EA affording 3o as yellow solid, 73.2 mg, 87% yield; m.p. 155-157℃. H NMR
(400 MHz, CDCl3) δ 8.38 (s, 1H), 7.85 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H), 7.43-7.33 (m, 5H),
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7.26-7.24 (m, 3H), 7.20 (dd, J = 2.8, 9.2 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 9.6 Hz, 1H), 5.15 (s,
2H), 3.80 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.2, 155.9, 136.6, 136.4, 130.8,
130.5, 129.2, 128.7, 128.6, 128.2, 127.5, 125.8, 120.0, 119.3, 118.8, 117.1, 116.3, 116.2, 115.7, 111.9,
100.0, 70.5, 51.2, 21.3; IR (CH2Cl2, cm-1) υ 1695, 1614, 1564, 1518, 1492, 1466, 1434, 1402, 1206, 1138,
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1023, 729; ESI-HRMS: calcd. for C28H24NO3 (M+H)+ 422.1751, found 422.1752.
Methyl 7-methyl-3-(p-tolyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3p). Purified by flash column
chromatography (PE/EA = 80:1); 45.4 mg, 70% yield, yellow solid; m.p. 184-185℃. 1H NMR (400 MHz,
CDCl3) δ 8.40 (s, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.40-7.38 (m, 3H), 7.33-7.31 (m, 1H), 7.26-7.21 (m, 3H),
6.90 (d, J = 9.2 Hz, 1H), 3.80 (s, 3H), 2.45 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.2,
136.3, 134.6, 130.9, 130.8, 130.5, 129.5, 129.4, 128.6, 128.6, 127.4, 120.2, 119.1, 118.2, 116.4, 116.4,
114.2, 51.1, 21.3, 21.0; IR (CH2Cl2, cm-1) υ 1705, 1642, 1563, 1492, 1434, 1233, 1209, 767; ESI-HRMS:
+
calcd. for C22H20NO2 (M+H)+ 330.1489, found 330.1490.
Methyl 3-(3,5-dimethoxyphenyl)-7-methoxypyrrolo[1,2-a]quinoline-2-carboxylate (3q). Purified by flash
column chromatography (PE/EA = 10:1); 49.2 mg, 63% yield, yellow solid; m.p. 150-155℃. 1H NMR (400
MHz, CDCl3) δ 8.38 (s, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.31 (d, J = 9.6 Hz, 1H), 7.14 (dd, J = 2.4, 9.2 Hz,
1H), 7.07 (d, J = 2.8 Hz, 1H), 6.95 (d, J = 9.6 Hz, 1H), 6.66 (s, 1H), 6.65 (s, 1H), 6.48 (m, 1H), 3.90 (s,
3H), 3.83 (s, 6H), 3.81 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.1, 160.2, 156.8, 135.8, 129.3,
127.2, 125.8, 120.4, 118.8, 118.7, 116.6, 116.4, 116.3, 115.7, 110.6, 108.9, 99.2, 55.7, 55.4, 51.3; IR
(CH2Cl2, cm-1) υ 1700, 1586, 1566, 1456, 1425, 1292, 1153, 1134, 809; ESI-HRMS: calcd. for
C23H22NO5+ (M+H)+ 392.1493, found 392.1494.
Methyl 8-(methoxymethoxy)-3-(p-tolyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3r). Performed at 0.045
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mmol scale; Purified by flash column chromatography (PE/EA = 10:1); 9.8 mg, 58% yield, yellow solid;
m.p. 150-151℃. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.54 (d, J = 8.8 Hz,
1H), 7.38 (d, J = 8.0 Hz, 2H), 7.26-7.24 (m, 2H), 7.16 (d, J = 9.6 Hz, 1H), 7.08 (dd, J = 2.0, 8.8 Hz, 1H),
6.94 (d, J = 9.6 Hz, 1H), 5.32 (s, 2H), 3.81 (s, 3H), 3.55 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 165.2, 157.5, 136.4, 133.8, 130.8, 130.5, 129.9, 129.7, 128.6, 120.0, 119.3, 118.8, 116.8, 116.4,
116.0, 114.5, 101.3, 94.7, 56.2, 51.2, 21.3; IR (CH2Cl2, cm-1) υ 1721, 1624, 1607, 1552, 1492, 1440, 1142,
817; ESI-HRMS: calcd. for C23H22NO4+ (M+H)+ 376.1543, found 376.1545.
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Methyl 4-bromo-3-(3,5-dimethoxyphenyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3t). Performed at 0.26
mmol scale; Purified by flash column chromatography (PE/EA = 10:1); 71.0 mg, 62% yield, yellow solid;
m.p. 132-133℃. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.58-7.55 (m, 2H),
7.41-7.37 (m, 1H), 7.30 (s, 1H), 6.55 (d, J = 2.4 Hz, 2H), 6.51 (t, J = 2.0 Hz, 1H), 3.81 (s, 6H), 3.74 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.4, 159.3, 136.4, 131.9, 128.7, 127.9, 125.7, 125.4, 124.6,
124.1, 121.7, 118.5, 116.8, 114.4, 112.1, 110.5, 105.5, 99.7, 55.3, 51.4; IR (CH2Cl2, cm-1) υ 1693, 1588,
1509, 1496, 1455, 1434, 1410, 1204, 1136, 745; ESI-HRMS: calcd. for C22H19BrNO4+ (M+H)+ 440.0492,
found 440.0498.
Methyl 6-bromo-3-(3,5-dimethoxyphenyl)pyrrolo[1,2-a]quinoline-2-carboxylate (3u). The mixture was
passed through a pad of silica gel eluted with PE/EA/DCM (200/3/2). The eluate was concentrated and the
residue was recrystallized with PE/EA affording 3u as yellow solid, 57.7 mg, 66% yield; m.p. 139-141℃.
1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.37 (t, J =
7.6 Hz, 3H), 6.65 (s, 1H), 6.64 (s, 1H), 6.50 (t, J = 2.0 Hz, 1H), 3.81 (s, 6H), 3.78 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 164.9, 160.3, 135.2, 133.8, 129.4, 129.2, 128.6, 124.1, 123.5, 119.7, 119.4, 119.2,
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117.5, 117.2, 113.9, 108.9, 99.4, 55.4, 51.4; IR (CH2Cl2, cm-1) υ 1729, 1593, 1537, 1502, 1464, 1446, 1433,
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1422, 1402, 1113, 1134, 1154, 757; ESI-HRMS: calcd. for C22H19BrNO4 (M+H)+ 440.0492, found
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440.0498.
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Methyl 1-(3,5-dimethoxyphenyl)pyrrolo[2,1-a]isoquinoline-2-carboxylate (5a). Purified by flash column
chromatography (PE/EA = 80:1); 36.8 mg, 51% yield, yellow solid; m.p. 144-146℃. 1H NMR (400 MHz,
CDCl3) δ 7.84 (s, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H),
7.31-7.27 (m, 1H), 7.18 (t, J = 8.0 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.60-6.57 (m, 3H), 3.80 (s, 6H), 3.72
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.8, 160.8, 138.2, 127.7, 127.5, 127.1, 126.8, 126.2, 126.2,
124.0, 123.3, 119.6, 118.9, 117.2, 113.7, 108.4, 100.0, 55.4, 51.2; IR (CH2Cl2, cm-1) υ 1715, 1592, 1520,
1453, 1422, 1398, 1146, 776; ESI-HRMS: calcd. for C22H20NO4+ (M+H)+ 362.1387, found 362.1389.
Methyl 1-(4-methoxyphenyl)pyrrolo[2,1-a]isoquinoline-2-carboxylate (5b). Purified by flash column
chromatography (PE/EA = 200:3); 46.2 mg, 70% yield, yellow solid; m.p. 182-185℃. 1H NMR (400 MHz,
CDCl3) δ 7.84 (s,1 H), 7.67 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.35 (d,
J = 8.4 Hz, 2H), 7.29-7.26 (m, 1H), 7.17-7.13 (m, 1H), 7.04 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 7.2 Hz, 1H),
3.91 (s, 3H), 3.72 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.0, 158.9, 131.6, 128.2, 127.6, 127.5,
127.1, 127.0, 126.5, 126.1, 124.1, 122.9, 119.6, 118.9, 117.3, 114.0, 113.6, 55.2, 51.1; IR (CH2Cl2, cm-1) υ
+
1711, 1646, 1598, 1508, 1462, 1436, 1398, 1177, 1028, 765; HRMS (ESI) m/z calcd for C21H18NO3
(M+H)+ 332.1281, found 332.1284.
Methyl 1-(p-tolyl)pyrrolo[2,1-a]isoquinoline-2-carboxylate (5c). Purified by flash column
chromatography (PE/EA = 110:1); 51.1 mg, 81% yield, yellow solid; m.p. 100-103℃. 1H NMR (400 MHz,
CDCl3) δ 7.76 (s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.36-7.34 (m, 1H), 7.26-7.18 (m,
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5H), 7.09-7.05 (m, 1H), 6.71 (d, J = 7.2 Hz, 1H), 3.64 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.9, 136.9, 133.0, 130.4, 129.3, 127.6, 127.5, 127.1, 127.0, 126.1, 124.1, 123.0, 120.0, 118.9,
117.2, 113.6, 51.1, 21.5; IR (CH2Cl2, cm-1) υ 1716, 1644, 1604, 1496, 1460, 1438, 1399, 1022, 950, 826;
HRMS (ESI) m/z calcd for C21H18NO2+ (M+H)+ 316.1332, found 316.1334.
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Methyl 1-phenylpyrrolo[2,1-a]isoquinoline-2-carboxylate (5d). Purified by flash column
chromatography (PE/EA = 120:1); 47.4 mg, 79% yield, yellow solid; m.p. 177-179℃. 1H NMR (400 MHz,
CDCl3) δ 7.86 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.51-7.43 (m, 6H), 7.35 (d, J = 8.4 Hz, 1H), 7.29-7.26 (m,
1H), 7.15-7.11 (m, 1H), 6.80 (d, J = 7.2 Hz, 1H), 3.70 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.9,
136.2, 130.6, 128.5, 127.6, 127.5, 127.4, 127.1, 126.9, 126.3, 126.1, 124.1, 122.9, 119.9, 119.0, 117.2,
113.7, 51.1; IR (CH2Cl2, cm-1) υ 1706, 1604, 1512, 1496, 1459, 1439, 1398, 1096, 772; HRMS (ESI) m/z
calcd for C20H16NO2+ (M+H)+ 302.1176, found 302.1179.
Ethyl 1-phenylpyrrolo[2,1-a]isoquinoline-2-carboxylate (5e). Purified by flash column chromatography
(PE/EA = 60:1); 42.1 mg, 67% yield, yellow solid; m.p. 105-107℃. 1H NMR (400 MHz, CDCl3) δ 7.87 (s,
1H), 7.68 (d, J = 7.6 Hz, 1H), 7.50-7.42 (m, 6H), 7.36 (d, J = 8.0 Hz, 1H), 7.29-7.25 (m, 1H), 7.14-7.10 (m,
1H), 6.79 (d, J = 7.2 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ 164.7, 136.5, 130.6, 128.4, 127.6, 127.5, 127.3, 127.1, 127.0, 126.2, 126.1, 124.1, 122.9, 119.8,
119.0, 117.8, 113.6, 59.8, 14.0; IR (CH2Cl2, cm-1) υ 1702, 1645, 1604, 1513, 1459, 1434, 1208, 779;
HRMS (ESI) m/z calcd for C21H18NO2+ (M+H)+ 316.1332, found 316.1335.
Methyl 1-(4-chlorophenyl)pyrrolo[2,1-a]isoquinoline-2-carboxylate (5g). Purified by flash column
chromatography (PE/EA = 120:1); 40.7 mg, 61% yield, yellow solid; m.p. 130-134℃. 1H NMR (400 MHz,
CDCl3) δ 7.85 (s, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.48-7.46 (m, 2H), 7.39-7.35 (m,
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3H), 7.32-7.29 (m, 1H), 7.20-7.15 (m, 1H), 6.81 (d, J = 7.2 Hz, 1H), 3.72 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 164.8, 134.8, 133.3, 132.1, 128.7, 127.7, 127.6, 127.3, 126.7, 126.3, 124.0, 122.8, 119.2,
118.4, 117.2, 113.8, 100.0, 51.1; IR (CH2Cl2, cm-1) υ 1712, 1603, 1545, 1515, 1490, 1472, 1460, 1439,
1185, 770; HRMS (ESI) m/z calcd for C20H15ClNO2+ (M+H)+ 336.0786, found 336.0789.
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Methyl 1-(3,4-dichlorophenyl)pyrrolo[2,1-a]isoquinoline-2-carboxylate (5h). Purified by flash column
chromatography (PE/EA = 50:1); 55.7 mg, 75% yield, yellow solid; m.p. 134-138℃. 1H NMR (400 MHz,
CDCl3) δ 7.76 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.49-7.43 (m, 3H), 7.29-7.20 (m, 3H), 7.17-7.11 (m, 1H),
6.74 (d, J = 7.6 Hz, 1H), 3.64 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.6, 136.5, 132.7, 132.4,
131.5, 130.41, 130.37, 127.9 127.7, 127.4, 126.6, 126.5, 126.4, 124.0, 122.8, 119.3, 117.1, 116.9, 113.9,
51.2; IR (CH2Cl2, cm-1) υ 1713, 1605, 1518, 1486, 1466, 1458, 1438, 1186, 773; HRMS (ESI) m/z calcd
for C20H14Cl2NO2+ (M+H)+ 370.0396, found 370.0399.
Methyl 1-(furan-2-yl)pyrrolo[2,1-a]isoquinoline-2-carboxylate (5i). The mixture was passed through a
pad of silica gel eluted with PE/EA (200:3). The eluate was concentrated and the residue was recrystallized
with PE/EA affording 5i as yellow solid, 48.0 mg, 82% yield; m.p. 145-148℃. 1H NMR (400 MHz, CDCl3)
δ 7.85 (s, 1H), 7.69-7.66 (m, 2H), 7.54 (d, J = 7.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.38-7.35 (m, 1H),
7.33-7.29 (m, 1H), 6.85 (d, J = 7.2 Hz, 1H), 6.64-6.63 (m, 1H), 6.53 (d, J = 2.8 Hz, 1H), 3.78 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 164.5, 147.4, 142.2, 129.3, 128.1, 127.8, 127.2, 126.8, 126.1, 123.9,
123.2, 119.4, 118.5, 114.1, 111.3, 110.5, 107.4, 51.4; IR (CH2Cl2, cm-1) υ 1704, 1625, 1517, 1495, 1458,
1439, 1183, 1126, 748; HRMS (ESI) m/z calcd for C18H14NO3+ (M+H)+ 292.0968, found 292.0969.
Methyl 7-bromo-1-phenylpyrrolo[2,1-a]isoquinoline-2-carboxylate (5j). The mixture was passed through
a pad of silica gel eluted with PE/EA (120:1). The eluate was concentrated and the residue was
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recrystallized with PE/EA affording 5j as yellow solid, 44.5 mg, 59% yield; m.p. 142-145℃. 1H NMR (400
MHz, CDCl3) δ 7.88 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.53-7.45 (m, 4H), 7.41-7.39 (m, 2H), 7.32 (d, J =
8.0 Hz, 1H), 7.28-7.26 (m, 1H), 6.94 (t, J = 8.0 Hz, 1H), 3.70 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
164.7, 135.9, 130.4, 130.1, 128.6, 128.6, 128.2, 127.6, 126.6, 125.5, 125.3, 122.3, 122.1, 120.6, 119.1,
117.9, 112.1, 51.2; IR (CH2Cl2, cm-1) υ 1710, 1592, 1510, 1469, 1441, 1108, 783; HRMS (ESI) m/z calcd
for C20H15BrNO2+ (M+H)+ 380.0281, found 380.0286.
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Methyl 7-bromo-1-(3,5-dimethoxyphenyl)pyrrolo[2,1-a]isoquinoline-2-carboxylate (5k). The mixture
was passed through a pad of silica gel eluted with PE/EA (120:1). The eluate was concentrated and the
residue was recrystallized with PE/EA affording 5k as yellow solid, 55.4 mg, 63% yield; m.p. 168-170℃.
1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.45 (d, J =
7.6 Hz, 1H), 7.31-7.26 (m, 1H), 7.03 (t, J = 8.0 Hz, 1H), 6.59-6.56 (m, 3H), 3.83 (s, 6H), 3.75 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 164.5, 160.9, 137.8, 130.1, 128.5, 128.4, 126.6, 125.4, 125.3, 122.6,
122.0, 120.4, 119.0, 117.9, 112.1, 108.3, 100.0, 55.4, 51.3; IR (CH2Cl2, cm-1) υ 1702, 1587, 1509, 1453,
+
1434, 1224, 1152, 780; HRMS (ESI) m/z calcd for C22H19BrNO4 (M+H)+ 440.0492, found 440.0498.
Methyl 8-bromo-1-(3,5-dimethoxyphenyl)pyrrolo[2,1-a]isoquinoline-2-carboxylate (5l). Purified by
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flash column chromatography (PE/EA = 50:1); 71.0 mg, 81% yield, yellow solid; m.p. 148-150 ℃ . H
NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.63 (d, J = 7.2 Hz, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.24-7.21 (m,
2H), 6.66 (d, J = 7.2 Hz, 1H), 6.51 (s, 3H), 3.75 (s, 6H), 3.67 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
164.6, 160.9, 137.8, 130.7, 129.3, 129.2, 125.7, 125.5, 125.1, 124.8, 120.0, 119.8, 119.2, 117.6, 112.5,
108.3, 100.0, 55.4, 51.2; IR (CH2Cl2, cm-1) υ 1716, 1611, 1582, 1538, 1512, 1461, 1428, 1202, 1162, 763;
HRMS (ESI) m/z calcd for C22H19BrNO4+ (M+H)+ 440.0492, found 440.0500.
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Methyl 1-(3,5-dimethoxyphenyl)pyrrolo[1,2-f]phenanthridine-2-carboxylate (7). The mixture was passed
through a pad of silica gel eluted with PE/EA/DCM (200:3:2). The eluate was concentrated and the residue
was recrystallized with PE/EA affording 7 as yellow solid, 73.9 mg, 90% yield; m.p. 206-208℃. 1H NMR
(400 MHz, CDCl3) δ 8.44 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz,
1H), 7.56 (t, J = 7.2 Hz, 1H), 7.49-7.43 (m, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 6.60-6.58
(m, 3H), 3.81 (s, 6H), 3.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.7, 160.9, 138.3, 132.3, 128.9,
128.1, 126.5, 126.3, 125.7, 125.2, 124.2, 124.0, 122.4, 121.3, 117.8, 117.3, 115.2, 108.3, 100.0, 55.4, 51.2;
IR (CH2Cl2, cm-1) υ 1710, 1609, 1584, 1516, 1504, 1492, 1473, 1453, 1427, 1404, 1201, 1021, 716; HRMS
(ESI) m/z calcd for C26H22NO4+ (M+H)+ 412.1543, found 412.1547.
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Gram-scale reaction of quinoline 1a and MBH carbonate 2d (Synthesis of compound 3d)
A mixture of quinoline 1a (3 eq, 10.2 mmol, 1.2 mL), MBH carbonate 2d (1 eq, 3.4 mmol, 1.0 g),
Cu(OAc)2·H2O (0.2 eq, 0.68 mmol, 0.136 g) and NMP (3.4 mL) was stirred at 120 oC in air. Upon the
consumption of 2d (monitored by TLC), the mixture was passed through a pad of silica gel eluted with
PE/EtOAc (25/1). The eluate was concentrated and the residue was recrystallized with PE/EtOAc affording
3d as yellow solid (0.727 g, 71% yield).
Gram-scale reaction of isoquinoline 4a and MBH carbonate 2l (Synthesis of compound 5f)
A mixture of isoquinoline 1a (3 eq, 12.0 mmol, 1.55g), MBH carbonate 2l (1 eq, 4.0 mmol, 1.04 g),
o
Cu(OAc)2·H2O (0.2 eq, 0.8 mmol, 0.160 g) and NMP (4.0 mL) was stirred at 120 C in air. Upon the
consumption of 2l (monitored by TLC), the mixture was passed through a pad of silica gel eluted with
PE/EtOAc (6/1). The eluate was concentrated and the residue was recrystallized with EtOH affording 5f as
yellow solid (0.453 g). The mother liquid was concentrated and the residue was purified by flash
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chromatography to give 0.227 g of 5f as yellow solid (63% yield totally).14e
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Synthesis of compound 12
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To a solution of 3f in acetonitrile (0.5 mL) was added a mixture of morpholine (0.12 mmol, 1.2 eq, 10.5
μL), paraformaldehyde (4.5 eq, 0.45 mmol, 13.4 mg) and acetic acid (87.6 μL). After the mixture was
stirred at rt for 39 h (monitored by TLC), it was diluted with DCM and washed with sat aq K2CO3 and
brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was
purified by a silica gel flash chromatography (PE/DCM/EtOAc = 50:20:3) to give compound 12 (Methyl
3-(3,4-dichlorophenyl)-1-(morpholinomethyl)pyrrolo [1,2-a]quinoline-2-carboxylate, 36.7 mg, 78% yield,
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yellow solid, m.p. 75-76℃); H NMR (400 MHz, CDCl3) δ 9.04 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 6.8 Hz,
1H), 7.56-7.52 (m, 1H), 7.50-7.48 (m, 2H), 7.42 (t, J = 7.6 Hz, 1H), 7.21-7.17 (m, 2H), 7.07 (d, J = 9.6 Hz,
1H), 4.32 (s, 2H), 3.75-3.72 (m, 7H), 2.72 (t, J = 4.4 Hz, 4H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.3,
135.0, 134.8, 132.04, 131.97, 130.7, 130.4, 129.9, 129.8, 128.7, 128.3, 127.9, 126.1, 124.9, 122.0, 120.3,
119.2, 117.2, 115.6, 77.2, 67.2, 52.5, 51.4; IR (CH2Cl2, cm-1) υ 1707, 1591, 1557, 1510, 1468, 1436, 1369,
1246, 1113, 751; ESI-HRMS: calcd. for C25H23Cl2N2O3+ (M+H)+ 469.1080, found 469.1085
Synthesis of compound 13
POCl3 (0.3 mmol, 3 eq, 27.5 μL) was added to 1 mL of DMF and the mixture was stirred at rt for 10 min
before a solution of compound 3f (0.1 mmol, 1 eq, 37.0 mg) in DMF (1 mL) was added. The resulting
mixture was stirred at rt until the reaction was complete (monitored by TLC). The reaction was then
quenched by addition of water and extracted with DCM. The organic phase was washed with water and
brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by a silica gel
flash
chromatography
(PE/DCM/EtOAc
=
4:3:1)
to
give
compound
13
(Methyl
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3-(3,4-dichlorophenyl)-1-formylpyrrolo[1,2-a]quinoline-2-carboxylate, 30.5 mg, 77% yield, yellow solid;
m.p. 155-156℃); 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.84 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.0 Hz,
1H), 7.70-7.86 ( m, 1H), 7.58-7.52 (m, 4H), 7.34 (d, J = 9.6 Hz, 1H), 7.29-7.26 (m, 1H), 3.83 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 178.4, 164.8, 136.2, 133.8, 132.7, 132.6, 132.0, 131.9, 130.6, 130.4,
129.6, 128.8, 128.6, 128.1, 128.0, 126.4, 125.9, 121.2, 118.4, 116.0, 52.5; IR (CH2Cl2, cm-1) υ 1704, 1646,
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+
1553, 1476, 1465, 1447, 1436, 1242, 1131, 808, 732; ESI-HRMS: calcd. for C21H14Cl2NO3 (M+H)+
398.0345, found 398.0349.
Synthesis of compound 14 or 15
A mixture of compound 3 (1 eq, 0.1 mmol), NBS (1.2 eq, 0.12 mmol, 21.4 mg), in DCE (0.1M, 1.0 mL)
was stirred at rt. Upon the consumption of 3 (monitored by TLC), the mixture was purified directly by a
silica gel flash chromatography (PE/ EtOAc) to afford compound 14 or 15.
Methyl 1-bromo-3-phenylpyrrolo[1,2-a]quinoline-2-carboxylate (14). Purified by flash column
chromatography (PE/EA = 120:1); 29.6 mg, 66% yield, yellow solid; m.p. 174-176℃. 1H NMR (400 MHz,
CDCl3) δ 9.53 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 0.8, 7.6 Hz, 1H), 7.55 (td, J = 1.2, 7.2 Hz, 1H), 7.51-7.48
(m, 2H), 7.46-7.42 (m, 1H), 7.21 (dd, J = 2.0, 8.4 Hz, 1H), 7.14 (d, J = 9.2 Hz, 1H), 7.07 (d, J = 9.6 Hz,
1H), 3.76 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.5, 133.5, 132.9, 131.1, 131.0, 130.4, 130.2,
129.0, 128.8, 127.8, 126.2, 125.2, 124.5, 121.2, 118.5, 116.4, 116.0, 115.9, 98.9, 50.7; IR (CH2Cl2, cm-1) υ
1706, 1659, 1632, 1594, 1557, 1536, 1493, 1467, 1442, 1246, 1190, 748; ESI-HRMS: calcd. for
+
C20H15BrNO2 (M+H)+ 380.0281, found 380.0284.
Methyl 1-bromo-3-(3,4-dichlorophenyl)pyrrolo[1,2-a]quinoline-2-carboxylate (15). Purified by flash
1
column chromatography (PE/EA = 100:3); 30.6 mg, 81% yield, yellow solid; m.p. 187-189℃. H NMR
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(400 MHz, CDCl3) δ 8.46 (s, 1H), 8.05 (dd, J = 1.2, 8.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.63-7.58 (m,
2H), 7.49-7.44 (m, 5H), 7.42-7.36 (m, 1H), 3.80 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.8, 133.1,
133.0, 130.6, 129.5, 129.3, 128.9, 128.0, 127.2, 125.6, 123.3, 121.5, 119.4, 117.13, 117.05, 114.8, 114.5,
51.4; IR (CH2Cl2, cm-1) υ 1696, 1597, 1559, 1532, 1497, 1475, 1436, 1235, 1144, 750; ESI-HRMS: calcd.
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+
for C20H13BrCl2NO2 (M+H)+ 447.9501 found 447.9508.
Synthesis of compound 16
A
mixture of compound 15 (1 eq, 0.1 mmol, 38.0 mg), 3-(4,4,5,5-tetramethyl
-1,3,2-dioxaborolan-2-yl)pyridine (2 eq, 0.2 mmol, 21.2 mg), Pd(PPh3)4 (0.1 eq, 0.01 mmol, 11.6 mg) and
o
Na2CO3 (2 eq, 0.2 mmol, 21.2 mg) in DMF (0.8 mL) and H2O (0.2 mL) was stirred at 120 C. Upon the
consumption of 15 (monitored by TLC), the reaction mixture was then cooled to rt, diluted with EtOAc,
washed with sat Na2CO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue
was purified by a silica gel flash chromatography (PE/EtOAc = 9:1) to give compound 16 (Methyl
1-(4-nitrophenyl)-3-phenylpyrrolo[1,2-a]quinoline-2-carboxylate, 42.6 mg, quant, yellow solid; m.p.
150-151℃); 1H NMR (400 MHz, CDCl3) δ 8.70-8.65 (m, 2H), 8.54 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H),
7.77-7.75 (m, 1H), 7.63-7.33 (m, 9H), 7.21 (s, 1H), 3.82 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
165.0, 150.3, 148.9, 137.1, 134.8, 133.4, 132.9, 130.6, 129.0, 128.9, 128.8, 128.0, 127.0, 127.0, 125.1,
123.8, 123.3, 120.2, 118.9, 117.2, 116.9, 114.9, 51.4; IR (CH2Cl2, cm-1) υ 1695, 1601, 1560, 1536, 1508,
+
1496, 1479, 1455, 1445, 1433, 1244, 1235, 1194, 752; ESI-HRMS: calcd. for C25H19N2O2 (M+H)+
379.1441, found 379.1445.
Synthesis of compound 17
A mixture of compound 15 (1 eq, 0.1 mmol, 38.0 mg), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)
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-1,3,2-dioxaborolane (2 eq, 0.1 mmol, 49.8 mg), Pd(PPh3)4 (0.1 eq, 0.01 mmol, 11.6 mg) and Na2CO3 (2
eq, 0.2 mmol, 21.2 mg) in DMF (0.8 mL) and H2O (0.2 mL) was stirred at 120 oC. Upon the consumption
of 15 (monitored by TLC), the reaction mixture was cooled to rt, diluted with DCM, washed with sat
Na2CO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated. The mixture was passed
through a pad of silica gel and eluted with PE/EtOAc (25/2). The eluate was concentrated and recrystallized
from PE/EtOAc affording 17 (Methyl 3-phenyl-1-(pyridin-3-yl)pyrrolo[1,2-a]quinoline-2-carboxylate, 42.4
mg, quant, red solid; m.p. 209-211℃); 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.32 (d, J = 8.4 Hz, 2H),
8.06 (d, J = 8.4 Hz, 1H), 7.64-7.57 (m, 4H), 7.51-7.49 (m, 2H), 7.44 (t, J = 7.2 Hz, 2H), 7.39-7.34 (m, 2H),
7.22 (s, 1H), 3.82 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.9, 147.3, 145.9, 133.3, 132.9, 130.63,
130.55, 130.4, 129.0, 128.7, 128.0, 127.1, 126.9, 125.2, 123.8, 123.3, 120.8, 118.9, 117.4, 117.1, 115.0,
51.4; IR (CH2Cl2, cm-1) υ 1693, 1646, 1592, 1510, 1494, 1469, 1435, 1409, 1342, 1087, 759; ESI-HRMS:
calcd. for C26H19N2O4+ (M+H)+ 423.1339, found 423.1336
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Conflict of interest The authors declare that they have no conflict of interest.
1
Supporting Information Available: H NMR and 13C NMR spectra for all new compounds, X-ray
crystallography data of compound 3c and CIF data for 3c (CIF). This material is available free of charge
via the Internet at http://pubs.acs.org.
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