Base-Promoted Intermolecular Cyclization of Substituted 3-Aryl(Heteroaryl)-3-chloroacrylaldehydes and Tetrahydroisoquinolines: An Approach to Access Pyrrolo[2,1-a]isoquinolines

Article abstract of DOI:10.1021/acs.joc.6b01781

We have developed a new base-promoted intermolecular cascade cyclization reaction of substituted 3-aryl(heteroaryl)-3-chloroacrylaldehydes and tetrahydroisoquinolines in one pot. The reaction provides a facile and practical synthesis of pyrrolo[2,1-a]isoquinolines. A number of pyrrolo[2,1-a]isoquinolines were synthesized in moderate to high yields (up to 97%).

Full text of DOI:10.1021/acs.joc.6b01781

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Note
Base-Promoted Intermolecular Cyclization of Substituted 3-
Aryl(Heteroaryl)-3-chloroacrylaldehydes and Tetrahydroisoquino-
lines: An Approach to Access Pyrrolo[2,1-a]isoquinolines
Ziqi Yang, Ning Lu, Zhonglin Wei, Jungang Cao, Dapeng Liang, Haifeng Duan, and Yingjie Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01781 • Publication Date (Web): 01 Nov 2016
Downloaded from http://pubs.acs.org on November 1, 2016
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The Journal of Organic Chemistry
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Base-Promoted Intermolecular Cyclization of Substituted 3-Aryl(Het-
eroaryl)-3-chloroacrylaldehydes and Tetrahydroisoquinolines: An
Approach to Access Pyrrolo[2,1-a]isoquinolines
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Ziqi Yang, Ning Lu, Zhonglin Wei, Jungang Cao, Dapeng Liang, Haifeng Duan*, Yingjie Lin*
Department of Organic Chemistry, College of chemistry, Jilin University, Changchun 130012, P.R. China.
ABSTRACT: We have developed a new base-promoted intermolecular cascade cyclization reaction of substituted 3-aryl(heteroaryl)-
3-chloroacrylaldehydes and tetrahydroisoquinolines in one-pot. The reaction provides a facile and practical synthesis of pyrrolo[2,1-
a]isoquinolines. A number of pyrrolo[2,1-a]isoquinolines were synthesized in moderate to high yields (up to 97%).
Scheme 1 Representative natural products.
quitous in various natural products and some biologically active
molecules. Representative compounds such as lamellarin D, la-
mellarin a 20-sulfate; and derivatives crispine A, trolline and
oleracein E are depicted in Scheme 1. Among them, lamellarin
D is a potent inhibitor of human topoisomerase I5, lamellarin a
20-sulfate is an inhibitor of HIV integrase6 and even other la-
mellarins have activities of anticancer7-9; in addition, crispine A
emerged as a target of great interest, due to potential biological
and pharmaceutical activities10, 11, the synthesis of pyrolo[2,1-
a]isoquinoline derivatives has been the focus of organic chem-
ists’ research for a long time12-18. Accordingly, a number of syn-
thetic methods which include metal and metal-free catalysis
have been reported. Sequential elegant works (Scheme 2) using
metal catalysis (e.g., Ir, Ru, Rh, Ag, Cu etc.) were accomplished
Scheme 2 Existing Strategies for the synthesis of pyr-
rolo[2,1-a]isoquinolines.
by several research groups19-27
.
Pyrrolo[2,1-a]isoquinoline1-4 (Scheme 1 a) framework is ubi-
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Table 1 Optimization of reaction conditionsa
DABCO (1,4-diazabicyclo[2.2.2]octane), DIPEA (N,N-diiso-
propylethylamine), DMAP (4-dimethylaminopyridine)
1
2
,
TMEDA (tetramethylethylenediamine) and TEA (trimethyla-
mine) were used instead of K2CO3. Obviously, among these ba-
ses, TEA gave the best yield (56%, entry 4), and remarkably,
DMAP gave us an extremely decrease (26%, entry 8), it might
due to DMAP is a weak nucleophile but strong base33. Thus we
used TEA as the optimal base for further optimization including
screening of solvents, reaction temperature, additives and the
loading of substrates. As results shown in Table 1, compared
with DMF, high polarity of solvents such as DMSO was also
beneficial to the reaction (48%, entry 10), however, compared
with DMF or DMSO, other solvents of relative low polarity,
such as, CH2Cl2, THF and CH3CN (entries 11, 12 and 13), gave
a trace amount of product 4a. The results showed that the reac-
tion temperature have apparent effect on the reaction, both
lower and higher temperature would depress the conversion of
substrates (entries 14 and 15). In addition, some additives such
as activated 4Å molecular sieves and silica or the oxidant MnO2
could not apparently improve the yields (separately 55%, 55%,
entries 16, 17 and 18); Gratifyingly, increasing the amount of
THIQ and TEA led to a high yield (93%, entry 19; more details
see SI Table 1); Further experiments exhibited that oxygen had
no impact on this reaction in which a radical pathway might not
be involved. Ultimately, the optimal reaction conditions identi-
fied were as follows: 2.5 equivalents of TEA, 4 equivalents of
THIQ, DMF used as solvents, and the reaction temperature of
120°C.
3
4
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9
Entry
T(°C)
Base
Addi-
tive
/
/
/
/
/
/
/
/
/
/
/
/
/
/
Solvent
Yieldb(%)
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2
3
4
5
6
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8
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10
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12
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15
16
17
18
19
20
90/120
120
120
120
120
120
120
120
120
t-BuOK
NaOH
K2CO3
TEA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DCE
N.Dc
34
42
56
31
45
50
26
47
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DBU
DABCO
DIPEA
DMAP
TMEDA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
TEA
120
48
reflux
reflux
reflux
100
150
120
120
120
120
120
Traced
Trace
Trace
38
THF
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
/
4Å
silica
MnO2
/
42
55e
55e
38e
93f
/
92g
aReaction conditions: 1a (1.20 mmol), 2a (1.80 mmol), 3a (1.80
b
mmol), solvent (3 mL), at 120°C 16 h, under Ar protect. Isolated
yield of 4a. cNo desired product, detected by HRMS. dDetected by
HRMs. eAdditive/1a (m/m=1:1). f1a (1.20 mmol), 2a (4.80 mmol),
3a (3.00 mmol). g1a (1.20 mmol), 2a (4.80 mmol), 3a (3.00 mmol),
without Ar protection.
With optimized conditions in hand (Table 1, entry 20), we
next explored the scope and limitations of this reaction by em-
ploying various (Z)-3-aryl(heteroaryl)-3-chloroacrylaldehydes
1 and THIQs 2 (Scheme 2). An assembly of 20 compounds was
synthesized using this protocol and gave the best yield up to
97%. The results indicated that compounds 1 with electron-
withdrawing (F, Cl, Br and NO2) or electron-donating groups
(Me and OMe) were well tolerated and provided the corre-
sponding products in moderate to high yields. As shown in Ta-
ble 2, when R1 is a meta- or para-substituted group on phenyl
ring, the corresponding product was obtained in a high yield (up
to 97%, entry 4e). However, ortho-substituents such as F and
Br due to their steric hindrance are no beneficial to the reaction
(34% 4g and 43% 4k); surprisingly the substrate which involve
ortho-substituent OMe gave a satisfying yield of 71% (4b).
Substrates with the substituent R2 such as Me and phenyl all
provided corresponding products in good to excellent yields re-
spectively (84% 4o and 61% 4q).
In recent years, metal-free catalysis has been of great inter-
ests in the construction of pyrrolo[2,1-a]isoquinoline frame-
work. These metal-free catalysis pathways involve stepwise
coupling of radicals, which were in situ formed in the presence
of t-BuOK/DMF28, or concerted reaction followed by oxidation
in I2/H2O229, KI/TBHP30 or TBAI/TBHP31 system, such as [3+2]
cycloaddition between 1,4-dicarbonyl-2-butenes and alkyl 2-
(3,4-dihydroisoquinolin-2(1H)-yl)acetates. Although afore-
mentioned successful synthetic methods have been developed,
new and facile approaches are still desirable in terms of great
structural diversity of pyrrolo[2,1-a]isoquinoline derivatives. In
this context, we developed a new and facile synthetic method
of pyrrolo[2,1-a]isoquinolines which include intermolecular
cascade cyclization of substituted 3-aryl(heteroaryl)-3-chloro-
acrylaldehydes and tetrahydroisoquinolines in one-pot reaction
promoted by Et3N/DMF.
Similarly, 1-chloro-3,4-dihydronaphthalene-2-carbaldehyde
also gave corresponding product 4p in 41% yield. Subsequently,
when condensed 3-aryl- and 3-heteroaryl-substituted 3-chloro-
acrylaldehydes including naphthalene and thiophene frame-
works were subjected to the optimized conditions, products 4r
and 4s were obtained in excellent isolated yields (89% and
95%). Finally, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in
place of THIQ reacted with 1a, this reaction also led to the cor-
responding product 4t in a satisfactory yield (77%). Unfortu-
nately, while N-methylbenzylamine and piperidine were used,
corresponding products were not detected.
Initially, the optimal reaction conditions in Yan’s work28
were also used to examine the reaction of (Z)-3-chloro-3-phe-
nylacrylaldehyde (1a) with THIQ (1,2,3,4-tetrahydroisoquino-
line, 2a). Unfortunately, 3-phenyl-5,6-dihydropyrrolo[2,1-
a]isoquinoline (4a) has not been detected and the substrate 1a
was transformed to complicated by-products (Table 1, entry 1).
Surprisingly, reducing basicity of inorganic bases is beneficial
to the reaction; for example, when NaOH or K2CO3 was used
as the base, the product 4a was obtained in 34% and 42% iso-
lated yields respectively (entries 2 and 3), and 4a was confirmed
by crystal structure (CCDC: 142117132; more details please see
SI ). Encouraged by these preliminary results, a variety of or-
ganic bases such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene),
To get insight on the reaction mechanism we performed some
additional experiments (Scheme 3). In experiment A, a mixture
Z and E isomers of 3-chloro-3-(2-fluorophenyl)acrylaldehyde
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The Journal of Organic Chemistry
(1gg, Z/E=1.5:1 detected by 1H NMR see SI) in place of 1g was
used to investigate the effect of E/Z configuration on the reac-
tion. Interestingly, product 4g was obtained in 34% yield (Sche-
Scheme 4 Suggested mechanism
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4
Table 2 Scope of tandem reactiona
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in a high yield (90%, Scheme 3, C).
Thus, based on these experiment results, a plausible mecha-
nism for this reaction is tentatively proposed in Scheme 4. Ini-
tially, intermediate A was first formed from compounds 1 and
2 via a Michael addition, then nucleophilic substitution between
A and THIQ gave an intermediate B under base circumstance.
B prompted by TEA was transformed to intermediate C in situ,
then D was generated by 6π-electrocyclization and subsequent
elimination of THIQ (Path a); or through path b, A firstly
prompted by TEA to give intermediate E, then F might be
formed through a nucleophilic addition. Final product 4 was
generated after the dehydration of F.
aReaction conditions: 1a (1.20 mmol), 2a (4.80 mmol), 3a (3.00
mmol), solvent (3 mL), at 120°C 16 h, without Ar protection.
me 3, A). The result is similar to the data of 4g which derived
from (Z)-3-chloro-3-(2-fluorophenyl)acrylaldehyde (1g) used
as the substrate in Table 2, and showed that geometric configu-
ration might have no effect on the reaction result. Compared
with (Z)-3-chloro-3-phenylacrylaldehyde (1a), (Z)-3-bromo-3-
phenylacrylaldehyde (1aa) also might undergo the same inter-
mediate in this protocol and give 4a in a similar high yield (92%,
Scheme 3, B). In Yan’s work28, intramolecular dehydrative cou-
pling of tertiary amines and ketones promoted by t-BuOK/DMF
through a radical process34, however, under the same conditions,
the reaction of (Z)-3-chloro-3-phenylacrylaldehyde (1a) with
tetrahydroisoquinoline could not afford corresponding product
4a (Table 1, entry 1). In addition, another investigation using
TEMPO to catch possible radical intermediate under argon at-
mosphere was not successful, and the product was still obtained
In conclusion, we have developed a new TEA-prompted in-
termolecular cascade cyclization reaction of substituted 3-
aryl(heteroaryl)-3-chloroacrylaldehydes and tetrahydroisoquin-
olines in one-pot. The reaction provides a facile and practical
synthesis of pyrrolo[2,1-a]isoquinolines. A number of pyr-
rolo[2,1-a]isoquinolines were synthesized in moderate to high
yields and the mechanism of the reaction was tentatively pro-
posed.
EXPERIMENTAL SECTION
General Information. Reactions were monitored using thin-layer
chromatography (TLC) on commercial silica gel plates (GF254).
Visualization of the developed plates was performed under UV
light (254 nm). Flash column chromatography was performed on
1
silica gel (200-300 mesh). H and 13C NMR were recorded at 400
Scheme 3 Mechanistic Studies
MHz and 101 MHz, respectively, chemical shifts were reported in
ppm referenced to the H2O (δ 3.33) in DMSO standard for 1H NMR.
Chemical shifts of 13C NMR are reported relative to CDCl3 (δ 77.0).
Coupling constants, J, were reported in hertz (Hz). High resolution
mass spectra (HRMS) were obtained on an ESI-Q-TOF mass spec-
trometer. And DMF was freshly distilled from CaH2 and TEA was
freshly distilled from KOH.
General Procedure for the Synthesis of Substrate 1. Phosphorus
oxychloride (5.10 g, 33.29 mmol) was added dropwise over 15 min,
to an ice-cooled stirred solution of dry N,N-Dimethylformamide
(10 mL). After 30 min, the appropriate acetophenone derivative
(8.32 mmol) dissolved in 5 mL N,N-Dimethylformamide was
added dropwise to the POCl3/DMF complex. The reaction mixture
was stirred for 1 h at 0°C then heated at 65°C for 8 h. Cooled at
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room temperature and finally poured in an ice-cold saturated
104.1 , 41.9 , 29.6 , 21.1 . HRMS (ESI) m/z calcd for C19H18N [M
+ H]+ 260.1434, found 260.1434.
1
2
3
4
5
6
7
8
NaOAc water solution (20 mL). The resulting mixture was ex-
tracted with ethyl acetate (3×15 mL). The organic phase was
washed with water (3×10 mL), brine (10 mL), dried over Na2SO4
and concentrated in vacuo. Thus obtained residue was subjected to
column chromatography purification on silica gel eluting with pe-
troleum ether/ethyl acetate (95:0.5) to give cis-products35.
3-(3,4-dimethoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquino-
line (4f). Yellow solid, mp 115-117°C; 4f (238mg, 65%); 1H NMR
(400 MHz, DMSO) δ 7.56 (d, J= 7.6 Hz, 1H), 7.23 (t, J= 7.9 Hz,
2H), 7.10 (t, J= 7.4 Hz, 1H), 7.02 (d, J= 8.2 Hz, 2H), 6.96 (dd, J=
8.2, 1.9 Hz, 1H), 6.61 (d, J= 3.7 Hz, 1H), 6.23 (d, J= 3.7 Hz, 1H),
4.11 (t, J= 6.5 Hz, 2H), 3.80 (d, J= 6.9 Hz, 6H), 2.99 (t, J= 6.5 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 148.7 , 148.2 , 134.0 , 130.5 ,
130.4 , 129.8 , 127.6 , 127.0 , 125.6 , 125.4 , 122.4 , 121.0 , 112.2 ,
111.1 , 108.7 , 103.9 , 55.8 , 55.8 , 41.8 , 29.5 . HRMS (ESI) m/z
calcd for C20H20NO2 [M + H]+ 306.1489, found 306.1486
General Procedures for the Synthesis of 4. To a suspension of β-
chlorovinyl aldehydes 1 (1.20 mmol) and THIQ 2 (4.80 mmol) in
DMF 3 mL added TEA (3.00 mmol) slowly. Then heated to 120°C
for 16 h. The residue was treated with water (30 mL) and then ex-
tracted with EA (3×15 mL), brine (10 mL), dried over Na2SO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel eluting with petroleum ether/ethyl ac-
etate (50:1) to afford the desired compound 4.
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3-(2-fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4g).
Yellow solid, mp 53-55°C; 4g (107 mg, 34%); 1H NMR (400 MHz,
DMSO) δ 7.60 (d, J= 7.5 Hz, 1H), 7.50 – 7.40 (m, 2H), 7.38 – 7.21
(m, 4H), 7.13 (t, J= 7.4 Hz, 1H), 6.68 (d, J= 3.7 Hz, 1H), 6.29 (d,
3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (4a). White
1
solid, mp 109-111°C; 4a (271 mg, 92%); H NMR (400 MHz,
J= 3.6 Hz,1H), 3.94 (t, J= 6.4 Hz, 2H), 2.99 (t, J= 6.5 Hz, 2H). 13
C
DMSO) δ 7.58 (d, J= 7.7 Hz, 1H), 7.49 – 7.41 (m, 4H), 7.38 – 7.29
(m, 1H), 7.25 (t, J= 7.8 Hz, 2H), 7.12 (t, J= 7.5, 1.1 Hz, 1H), 6.65
(d, J= 3.7 Hz, 1H), 6.30 (d, J= 3.7 Hz, 1H), 4.12 (t, J= 6.6 Hz, 2H),
3.00 (t, J= 6.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 134.2 ,
132.8 , 130.9 , 130.6 , 129.8 , 128.5 , 128.4 , 127.7 , 127.0 , 126.7 ,
125.5 , 122.5 , 109.4 , 104.2 , 42.0 , 29.5 . HRMS (ESI) m/z calcd
for C18H16N [M + H]+ 246.1277, found 246.1270.
NMR (101 MHz, CDCl3) δ 159.8 (d, J = 246.8 Hz), 131.7 (d, J =
3.0 Hz), 131.2 , 130.7 , 129.7 , 129.1 (d, J = 8.1 Hz), 127.8 , 127.7 ,
127.1 , 125.7 , 124.1 (d, J = 3.6 Hz), 122.5 , 120.8 (d, J = 15.1 Hz),
115.7 (d, J = 22.4 Hz), 110.7 , 104.2 , 42.2 (d, J = 4.7 Hz), 29.5 .
HRMS (ESI) m/z calcd for C18H15FN [M + H]+ 264.1183, found
264.1182.
3-(3-fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4h).
1
White solid, mp 102-104°C; 4h (288 mg, 91%); H NMR (400
3-(2-methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline
(4b). White solid, mp 108-110°C; 4b (235 mg, 71%); 1H NMR (400
MHz, DMSO) δ 7.55 (d, 1H), 7.38 (t, 1H), 7.30 – 7.19 (m, 3H),
7.09 (t, J= 12.5, 4.8 Hz, 2H), 7.02 (t, 1H), 6.59 (d, J= 3.7 Hz, 1H),
6.11 (d, J= 3.6 Hz, 1H), 3.87 – 3.71 (m, 5H), 2.94 (t, J= 6.5 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 157.1 , 131.9 , 130.8 , 130.7 ,
130.2 , 130.0 , 129.1 , 127.7 , 126.9 , 125.3 , 122.4 , 122.0 , 120.6 ,
110.8 , 109.6 , 103.7 , 55.3 , 42.2 , 29.5 . HRMS (ESI) m/z calcd
for C19H18NO [M + H]+ 276.1383, found 276.1372.
MHz, DMSO) δ 7.59 (d, J= 7.7 Hz, 1H), 7.52 – 7.43 (m, 1H), 7.34
– 7.21 (m, 4H), 7.19 – 7.10 (m, 2H), 6.66 (d, J= 3.8 Hz, 1H), 6.38
(d, J= 3.8 Hz, 1H), 4.15 (t, J= 6.6 Hz, 2H), 3.01 (t, J= 6.5 Hz, 2H).
13C NMR (101 MHz, CDCl3) δ 162.7 (d, J = 245.8 Hz), 134.9 (d,
J = 8.3 Hz), 132.9 (d, J = 2.3 Hz), 131.5 , 130.7 , 129.9 (d, J = 8.7
Hz), 129.6 , 127.7 , 127.1 , 125.8 , 124.0 (d, J = 2.8 Hz), 122.7 ,
115.1 (d, J = 22.0 Hz), 113.4 (d, J = 21.1 Hz), 110.0 , 104.4 , 42.1 ,
29.5 . HRMS (ESI) m/z calcd for C18H15FN [M + H]+ 264.1183,
found 264.1183.
3-(3-methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline
1
(4c). White solid, mp 81-83°C; 4c (301 mg, 91%); H NMR (400
3-(4-fluorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4i).
White solid, mp 106-108°C; 4i (259 mg, 82%); 1H NMR (400 MHz,
DMSO) δ 7.58 (d, J= 7.5 Hz, 1H), 7.50 (dd, J= 8.3, 5.7 Hz, 2H),
7.32 – 7.20 (m, 3H), 7.12 (t, J= 7.4 Hz, 1H), 6.64 (d, J= 3.6 Hz,
1H), 6.28 (d, J= 3.6 Hz, 1H), 6.28 (d, J= 3.6 Hz, 1H), 4.09 (t, J=
6.5 Hz, 2H), 3.00 (t, J= 6.4 Hz, 2H). 13C NMR (101 MHz, CDCl3)
δ 161.9 (d, J = 246.7 Hz), 133.1 , 130.9 , 130.6 , 130.2 (d, J = 8.0
Hz), 129.8 , 129.0 (d, J = 3.3 Hz), 127.7 , 127.1 , 125.6 , 122.5 ,
115.3 (d, J = 21.5 Hz), 109.3 , 104.2 , 41.9 , 29.5 . HRMS (ESI)
m/z calcd for C18H15FN [M + H]+ 264.1183, found 264.1178.
MHz, DMSO) δ 7.58 (d, J= 7.5 Hz, 1H), 7.36 (t, J= 7.9 Hz, 1H),
7.24 (t, J= 8.0 Hz, 2H), 7.12 (t, J= 11.1, 3.7 Hz, 1H), 7.01 (3, J=
15.6, 5.0 Hz, 2H), 6.91 (d, J= 8.2, 2.2 Hz, 1H), 6.64 (d, J= 3.7 Hz,
1H), 6.31 (d, J= 3.7 Hz, 1H), 4.14 (t, J= 6.5 Hz, 2H), 3.81 (s, 3H),
3.00 (t, J= 6.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 159.5 ,
134.0 , 133.9 , 130.9 , 130.6 , 129.7 , 129.3 , 127.6 , 127.0 , 125.5 ,
122.4 , 120.8 , 114.1 , 112.0 , 109.4 , 104.2 , 55.0 , 41.9 , 29.4 .
HRMS (ESI) m/z calcd for C19H18NO [M + H]+ 276.1383, found
276.1383.
3-(4-methoxyphenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline
(4d). White solid, mp 100-102°C; 4d (284 mg, 86%); 1H NMR (400
MHz, DMSO) δ 7.56 (d, J= 7.6 Hz, 1H), 7.38 (d, J= 8.7 Hz, 2H),
7.23 (t, J= 7.8 Hz, 2H), 7.10 (t, J= 7.4 Hz, 1H), 7.02 (d, J= 8.7 Hz,
2H), 6.61 (d, J= 3.7 Hz, 1H), 6.20 (d, J= 3.7 Hz, 1H), 4.07 (t, J=
6.5 Hz, 2H), 3.80 (s, 3H), 2.99 (t, J= 6.5 Hz, 2H). 13C NMR (101
MHz, CDCl3) δ 158.6 , 134.0 , 130.5 , 130.3 , 129.9 , 129.8 , 127.7 ,
127.0 , 125.4 , 125.4 , 122.4 , 113.8 , 108.7 , 104.0 , 55.2 , 41.8 ,
29.5 . HRMS (ESI) m/z calcd for C19H18NO [M + H]+ 276.1383,
found 276.1379.
3-(4-chlorophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4j).
1
Yellow solid, mp 100-102°C; 4j (319 mg, 95%); H NMR (400
MHz, DMSO) δ 7.59 (d, J= 7.6 Hz, 1H), 7.49 (s, 4H), 7.25 (t, J=
9.7, 7.5 Hz, 2H), 7.13 (t, J= 7.4, 1.0 Hz, 1H), 6.66 (d, J= 3.8 Hz,
1H), 6.33 (d, J= 3.8 Hz, 1H), 4.12 (t, J= 6.6 Hz, 2H), 3.00 (t, J=
6.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 132.9 , 132.6 , 131.3 ,
131.2 , 130.6 , 129.6 , 129.6 , 128.6 , 127.7 , 127.1 , 125.7 , 122.6 ,
109.7 , 104.4 , 42.0 , 29.5 . HRMS (ESI) m/z calcd for C18H15ClN
[M + H]+ 280.0888, found 280.0887.
3-(2-bromophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4k).
1
3-(p-tolyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4e). White
Yellow solid, mp 87-89°C; 4k (167 mg, 43%); H NMR (400 MHz,
1
solid, mp 103-105°C; 4e (302 mg, 97%); H NMR (400 MHz,
DMSO) δ 7.77 (b, 1H), 7.60 (b, 1H), 7.51 – 7.42 (m, 2H), 7.39 –
7.32 (m, 1H), 7.25 (t, J= 9.8, 4.1 Hz, 2H), 7.12 (t, J= 7.5, 1.1 Hz,
1H), 6.64 (d, J= 3.7 Hz, 1H), 6.19 (d, J= 3.7 Hz, 1H), 3.77 (t, J=
6.5 Hz, 2H), 3.00 (t, J= 6.5 Hz, 2H). 13C NMR (101 MHz, CDCl3)
δ 134.1 , 132.8 , 132.7 , 132.5 , 130.6 , 130.2 , 129.6 , 129.4 , 127.8 ,
127.1 , 127.0 , 125.6 , 125.2 , 122.5 , 109.9 , 103.5 , 42.1 , 29.3 .
DMSO) δ 7.57 (d, J= 7.7 Hz, 1H), 7.35 (d, J= 8.1 Hz, 2H), 7.28 –
7.19 (m, 4H), 7.11 (t, 1H), 6.63 (d, J= 3.7 Hz, 1H), 6.24 (d, J= 3.7
Hz, 1H), 4.09 (t, J= 6.6 Hz, 2H), 2.99 (t, J= 6.5 Hz, 2H), 2.34 (s,
3H). 13C NMR (101 MHz, CDCl3) δ 136.5 , 134.3 , 130.6 , 130.6 ,
130.0 , 129.9 , 129.1 , 128.5 , 127.7 , 127.0 , 125.4 , 122.5 , 109.0 ,
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HRMS (ESI) m/z calcd for C18H15BrN [M + H]+ 324.0382, found
324.0380.
126.1 , 125.5 , 125.3 , 124.5 , 124.0 , 120.3 , 119.0 , 44.6 , 30.1 .
HRMS (ESI) m/z calcd for C24H20N [M + H]+ 322.1590, found
322.1596.
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4
5
6
7
8
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3-(3-bromophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4l).
White solid, mp 128-130°C; 4l (362 mg, 93%); 1H NMR (400 MHz,
DMSO) δ 7.65 (s, 1H), 7.59 (d, J= 7.6 Hz, 1H), 7.50 (dd, J= 14.9,
7.8 Hz, 2H), 7.40 (t, J= 7.8 Hz, 1H), 7.25 (3, J= 9.5, 7.7 Hz, 2H),
7.14 (t, J= 7.3 Hz, 1H), 6.66 (d, J= 3.8 Hz, 1H), 6.38 (d, J= 3.8 Hz,
1H), 4.13 (t, J= 6.5 Hz, 2H), 3.01 (t, J= 6.5 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 134.8 , 132.5 , 131.5 , 131.1 , 130.6 , 129.9 ,
129.6 , 129.5 , 127.7 , 127.1 , 126.9 , 125.8 , 122.7 , 122.5 , 110.1 ,
104.4 , 42.0 , 29.5 . HRMS (ESI) m/z calcd for C18H15BrN [M +
H]+ 324.0382, found 324.0385.
3-(naphthalen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4r).
Yellow solid, mp 51-53°C; 4r (315 mg, 89%); 1H NMR (400 MHz,
DMSO) δ 8.00 (t, J= 13.1, 5.4 Hz, 2H), 7.84 – 7.76 (m, 1H), 7.67
– 7.47 (m, 5H), 7.32 – 7.21 (m, 2H), 7.12 (t, J= 7.4, 1.1 Hz, 1H),
6.76 (d, J= 3.6 Hz, 1H), 6.31 (d, J= 3.6 Hz, 1H), 3.74 (t, J= 6.1 Hz,
2H), 2.96 (t, J= 6.5 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 133.6 ,
132.9 , 131.9 , 130.6 , 130.5 , 130.4 , 129.8 , 128.5 , 128.2 , 128.2 ,
127.8 , 127.1 , 126.3 , 125.9 , 125.9 , 125.5 , 125.2 , 122.4 , 110.8 ,
103.9 , 42.0 , 29.4 . HRMS (ESI) m/z calcd for C22H18N [M + H]+
296.1434, found 296.1434.
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13
14
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18
19
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23
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26
27
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29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
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49
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51
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53
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58
59
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3-(4-bromophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline
(4m). White solid, mp 120-122°C; 4m (358 mg, 92%); H NMR
1
3-(thiophen-2-yl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4s).
Yellow solid, mp 72-74°C; 4s (287 mg, 95%) 1H NMR (400 MHz,
DMSO) δ 7.59 (d, J= 7.6 Hz, 1H), 7.53 (dd, J= 4.5, 1.8 Hz, 1H),
7.30 – 7.21 (m, 2H), 7.20 – 7.09 (m, 3H), 6.64 (d, J= 3.8 Hz, 1H),
6.35 (d, J= 3.8 Hz, 1H), 4.18 (t, J= 6.7 Hz, 2H), 3.04 (t, J= 6.6 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 134.5 , 131.2 , 130.4 , 129.4 ,
127.7 , 127.4 , 127.1 , 126.8 , 125.8 , 125.1 , 124.6 , 122.6 , 110.6 ,
104.3 , 41.5 , 29.3 . HRMS (ESI) m/z calcd for C16H14NS [M + H]+
252.0841, found 252.0841.
(400 MHz, DMSO) δ 7.67 – 7.54 (m, 3H), 7.46 – 7.37 (m, 2H),
7.28 – 7.20 (m, 2H), 7.16 – 7.09 (m, 1H), 6.66 (d, J= 3.8 Hz, 1H),
6.34 (d, J= 3.8 Hz, 1H), 4.12 (t, J= 6.6 Hz, 2H), 3.00 (t, J= 6.5 Hz,
2H). 13C NMR (101 MHz, CDCl3) δ 132.9 , 131.7 , 131.5 , 131.4 ,
130.6 , 129.9 , 129.6 , 127.7 , 127.1 , 125.8 , 122.6 , 120.7 , 109.7 ,
104.4 , 42.0 , 29.5 . HRMS (ESI) m/z calcd for C18H15BrN [M +
H]+ 324.0382, found 324.0379.
3-(4-nitrophenyl)-5,6-dihydropyrrolo[2,1-a]isoquinoline (4n).
1
Brown solid, mp 168-170°C; 4n (282 mg, 81%); H NMR (400
8,9-dimethoxy-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline
(4t). White solid, mp 173-175°C; 4t (282 mg, 77%); 1H NMR (400
MHz, DMSO) δ 7.48 – 7.39 (m, 4H), 7.36 – 7.26 (m, 1H), 7.15 (s,
1H), 6.89 (s, 1H), 6.57 (d, J= 3.6 Hz, 1H), 6.26 (d, J= 3.6 Hz, 1H),
4.08 (t, J= 6.4 Hz, 2H), 3.78 (d, J= 15.5 Hz, 6H), 2.93 (t, J= 6.4
Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 148.2 , 147.3 , 133.8 ,
132.9 , 131.0 , 128.4 , 128.3 , 126.6 , 123.2 , 122.7 , 111.1 , 109.1 ,
106.0 , 102.9 , 56.0 , 55.9 , 42.2 , 29.1 . HRMS (ESI) m/z calcd for
C20H20NO2 [M + H]+ 306.1489, found 306.1486.
MHz, DMSO) δ 8.27 (d, J= 8.4 Hz, 2H), 7.74 (d, J= 8.4 Hz, 2H),
7.64 (d, J= 7.4 Hz, 1H), 7.28 (t, J= 11.4, 7.4 Hz, 2H), 7.18 (t, J=
7.2 Hz, 1H), 6.75 (d, J= 3.2 Hz, 1H), 6.60 (d, J= 3.2 Hz, 1H), 4.23
(t, J= 6.1 Hz, 2H), 3.05 (t, J= 5.8 Hz, 2H). 13C NMR (101 MHz,
DMSO) δ 145.6 , 139.2 , 133.3 , 132.2 , 131.7 , 129.3 , 128.5 ,
128.4 , 127.6 , 126.8 , 124.4 , 123.2 , 112.8 , 106.0 , 42.6 , 29.1 .
HRMS (ESI) m/z calcd for C18H15N2O2 [M + H]+ 291.1128, found
291.1131.
2-methyl-3-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (4o).
Yellow oil; 4o(261 mg, 84%); 1H NMR (400 MHz, DMSO) δ 7.41
(t, J= 7.5 Hz, 2H), 7.29 (dd, J= 19.0, 7.3 Hz, 3H), 7.21 (d, J= 7.4
Hz, 1H), 6.98 (t, J= 6.8 Hz, 1H), 6.92 – 6.82 (m, 2H), 6.72 (s, 1H),
3.98 (t, J= 6.5 Hz, 2H), 3.00 (t, J= 6.4 Hz, 2H), 1.89 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 136.9 , 131.5 , 130.3 , 129.6 , 128.4 ,
127.8 , 126.5 , 126.2 , 125.2 , 125.1 , 123.6 , 121.9 , 118.7 , 118.4 ,
44.2 , 30.1 , 10.5 . HRMS (ESI) m/z calcd for C19H18N [M + H]+
260.1434, found 260.1436.
ASSOCIATED CONTENT
Supporting Information
Experimental details on the optimization of the reaction conditions
1
and x-ray data, along with copies of H and 13C NMR spectra of
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
The Supporting Information is available free of charge on the ACS
Publications website.
5,6,12,13-tetrahydrobenzo[6,7]indolo[2,1-a]isoquinoline (4p).
Yellow solid, mp 170-172°C; 4p (133 mg, 41%); 1H NMR (400
MHz, DMSO) δ 7.83 (d, J= 7.5 Hz, 1H), 7.69 (d, J= 7.6 Hz, 1H),
7.30 (d, J= 7.2 Hz, 1H), 7.27 – 7.09 (m, 4H), 7.05 (dd, J= 7.3, 6.5
Hz, 1H), 6.75 (s, 1H), 3.95 (t, J= 6.3 Hz, 2H), 3.00 (t, J= 6.3 Hz,
2H), 2.81 – 2.70 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 136.9 ,
132.9 , 132.3 , 130.1 , 128.3 , 127.9 , 126.7 , 126.1 , 125.8 , 125.0 ,
124.5 , 124.0 , 123.9 , 122.6 , 117.4 , 115.9 , 44.4 , 31.5 , 30.4 ,
21.2 . HRMS (ESI) m/z calcd for C20H18N [M + H]+ 272.1434,
found 272.1434.
AUTHOR INFORMATION
Corresponding Author
* Email: linyj@jlu.edu.cn.
* Email: duanhf@jlu.edu.cn.
Notes
The authors declare no competing financial interest.
Author Contributions
Ziqi Yang, Ning Lu, Zhonglin Wei, Jungang Cao, Dapeng Liang,
Haifeng Duan*, Yingjie Lin*
2,3-diphenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (4q). Yel-
1
low solid, mp 64-66°C; 4q (235 mg, 61%); H NMR (400 MHz,
DMSO) δ 7.41 – 7.33 (m, 3H), 7.24 (t, J= 6.3 Hz, 3H), 7.19 (s, 1H),
7.17 – 7.11 (m, 2H), 7.04 (dt, J= 15.9, 5.7 Hz, 4H), 6.89 (t, J= 7.6
Hz, 1H), 6.75 (d, J= 7.8 Hz, 1H), 4.13 (t, J= 6.4 Hz, 2H), 3.07 (t,
J= 6.2 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 136.5 , 135.5 ,
131.8 , 130.9 , 129.5 , 128.5 , 128.0 , 128.0 , 127.9 , 126.6 , 126.5 ,
ACKNOWLEDGMENT
We thank the financial support from the National Natural Science
Foundation of China (No. 51373067).
2.
M. V. R. Reddy, M. R. Rao, D. Rhodes, M. S. Hansen,
K. Rubins, F. D. Bushman, Y. Venkateswarlu and D. J.
Faulkner, Journal of medicinal chemistry, 1999, 42,
1901-1907.
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