Direct Synthesis of Dihydropyrrolo[2,1-a]Isoquinolines through FeCl3 Promoted Oxidative Aromatization

Article abstract of DOI:10.1002/adsc.201900756

We have developed a straightforward FeCl₃ promoted synthesis of dihydropyrrolo[2,1-a]isoquinolines through formal (3+2) cycloaddition/oxidative aromatization cascade of dihydroisoquinoline with Morita-Baylis-Hillman carbonates (up to 96% yield)

Full text of DOI:10.1002/adsc.201900756

Title: Direct Synthesis of Dihydropyrrolo[2,1-a]isoquinolines through
FeCl3 Promoted Oxidative Aromatization
Authors: Hai-Lei Cui, Lu Jiang, Hao Tan, and Si Liu
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900756
Link to VoR: http://dx.doi.org/10.1002/adsc.201900756

10.1002/adsc.201900756
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Direct Synthesis of Dihydropyrrolo[2,1-a]isoquinolines through
FeCl3 Promoted Oxidative Aromatization
Hai-Lei Cui,a* Lu Jiang,a Hao Tana and Si Liu a
a
Laboratory of Asymmetric Synthesis, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan,
Chongqing, 402160, China
E-mail: cuihailei616@163.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. We have developed a straightforward FeCl3
promoted synthesis of dihydropyrrolo[2,1-a]isoquinolines
through formal (3 + 2) cycloaddition/oxidative aromatization
cascade of dihydroisoquinoline with Morita–Baylis–Hillman
carbonates (up to 96% yield). Further modifications of the
obtained products were successful through simple chemical
transformations providing a diverse range of natural product-
like molecules (12 examples).
Keywords: Pyrroloisoquinoline; Oxidative aromatization;
Morita–Baylis–Hillman carbonates; Dihydroisoquinoline;
Iron Chloride
metal-free methods of Gao[3a] and Ito[3e], the
presences of H2O2 and O2 were required respectively
in the oxidative aromatization step. In addition, the
use of expensive and toxic metal catalysts may also
be necessary in many reports. To avoid the use of
expensive, toxic catalyst and reduce waste generated
from multistep manipulations, the development of
direct and catalytic way accessing structurally
diversified molecules of significant importance using
inexpensive and nontoxic catalysts is in great demand.
Introduction
Pyrroloisoquinoline as a privileged framework can be
found in a large number of biologically active
molecules and functional materials (Figure 1).[1] For
example, the lamellarin family has shown a wide
range of biological activities such as cytotoxicity and
antitumor activity. Accordingly, the efficient
construction of pyrroloisoquinoline deriveatives has
attracted much attention. Various elegant strategies
and methodologies have been established for the
assembly of this important scaffold, such as multistep
OMe
HO
MeO
MeO
HO
HO
MeO
O
N
O
O
N
synthesis[2],
1,3-dipolar
cyclization[3],
N
MeO
HO
MeO
MeO
O
O
O
multicomponent reaction[4], photocatalytic reaction[5],
electrocyclization[6] and other approches[7]. Inspired
by previous reports, we have recently developed
electrocyclization-based synthesis of nitrogen-
containing heterocycles.[8] By the formation of 1,n-
dipolars as key intermediates, a range of structurally
diversified novel pyrroloisoquinoline and other
isoquinoline-containing derivatives have been
synthesized from easily accessible materials.[9]
MeO
MeO
OH
MeO
Lamellarin D
OH
MeO
Lamellarin N
OH
MeO
Lamellarin I
(MDR reversal agent)
(topoisomerase I inhibitor)
(protein kinases inhibitor)
MeO
HO
HO
O
N
MeO
MeO
N
N
O
O
MeO
H
HO
MeO
(-)-trolline
(antiviral activity)
Crispine A
(anti-cancer agent)
OSO3Na
MeO
Lamellarin a 20-sulfate
(anti-HIV-1 agent)
Previous
successful
constructions
of
pyrroloisoquinolines always undergo the oxidative
aromatization step and thus require additional
stoichiometric amount of oxidants. For instance,
Xiao[5a], Rueping[3d] and Zhao[5b] have independently
reported excellent photocatalytic dipolar cyclization
and they utilized NBS as additional oxidant in their
studies; Wang[3c], Basavaiah[6a] and Shankaraiah[3f]
have also achieved impressive [3 + 2] cycloadditions
and they employed THBP as oxidant respectively for
the oxidation step. Additionally, in the attractive
Figure 1. Representative Pyrroloisoquinoline Deriveatives.
Iron salts are suitable catalysts for organic
synthesis, since they are abundant, inexpensive and
nontoxic.[10] Thus Iron salts have been applied
recently in a wide range of organic reactions, such as
oxidative coupling reactions[11]
,
Lewis acid
catalysis[12], aerobic oxidations,[13] photocatalysis[14]
1
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10.1002/adsc.201900756
Advanced Synthesis & Catalysis
and other reactions[15], for the construction of
structurally complex heterocycles. However,
compared with the wide utilization of other metal
catalysts, iron salts were used in a relatively narrow
scope in organic synthesis. As our ongoing efforts on
the synthesis of heterocycles from simple starting
material, we are interested in employing iron salts as
promotor in preparing nitrogen-containing molecules
through cascade reactions. Here, we report our
development of FeCl3 promoted synthesis of
dihydropyrrolo[2,1-a]isoquinolines through formal (3
easily
incorporated
into
dihydropyrrolo[2,1-
a]isoquinoline by using corresponding MBH
carbonates (3s and 3t, 60% and 56% yields). In the
case of compound 3m, the yield decreased to 77%
when performing at 1 mmol scale. Treatment of
cinnamyl aldehyde derived MBH carbonate in this
process led to 17% yield of desired product bearing
styryl group. The use of alkylated MBH carbonate
gave trace amount of product, likely due to the
instability of the generated intermediate. By changing
MBH carbonate, cyano group can be successfully
installed into dihydropyrroloisoquinoline in good
yield (3w, 82%). The employment of cyclopropen-1-
one derived MBH carbonate failed to deliver
compound 3x. While MBH bearing amide moiety
successfully afforded compound 3y in 37% yield.
Relative configuration of compound 3p was
confirmed by X-ray analysis and others were
assigned by analogy (See ESI).[17]
+
2) cycloadditions/oxidative aromatization of
dihydroisoquinoline with Morita–Baylis–Hillman
(MBH) carbonates.[16]
Results and Discussion
Initially, the reaction of dihydroisoquinoline 1a and
MBH carbonate 2a was selected as the model
o
Table 1. Optimization of reaction conditions.
reaction to test the efficiency of catalysts at 130 C.
As shown in Table 1, a range of metal catalysts
including iron, palladium and copper salts have been
screened (entries 1-7). Only iron chloride was found
to give a promising yield (45% yield). Further
screening of solvents identified DMSO as the best
solvent (entries 8-12). Complicated byproducts can
MeO
Catalyst
OBoc
N
MeO
MeO
Solvent, 130 o
C
MeO
COOMe
+
N
COOMe
MeO
1a
2a
MeO
3a
1
be detected by TLC and H NMR, indicating iron
mol
%
50
Yield
[%]
45
salts catalyzed oxidative cross-coupling reactions or
further oxidations may likely be involved in this
process. Thus we tested the reactions at lower
reaction temperature (entries 13 and 14). However,
the yields were dramatically decreased to 16% and
less than 10% respectively. It suggests that the
reaction temperature plays an important role in this
process. A lower catalyst loading gave an improved
yield (entry 15, 83%). Higher concentration resulted
in slightly improvement on reaction yield (entry 16,
91% NMR yield and 88% isolated yield). Lower
catalyst loading gave decreased yields with prolonged
reaction time (entries 17 and 18, 67% and 65% yields
respectively). Other iron salts, such as Fe2(SO4)3,
FePO4, Fe(OTf)3, Fe(OTf)2 and FeCl2 were not as
effective as FeCl3, giving relatively lower yields
(entries 19-23, 11-46%).
Entry Cat
Solvent
t (h)
1
2
3
4
5
6
7
8
FeCl3
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMF
PhCl
m-xylene
Glycol
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
3
3
3
3
3
3
3
3
3
3
3
3
6
24
3
4
6
6
3
3
3
3
3
Pd(OAc)2 50
CuCl2 50
Cu(OTf)2 50
Cu(OAc)2 50
<10
<10
<10
<10
<10
<10
41
17
16
13
72
16
<10
83
91 (88)g
67
65
25
18
11
CuI
50
Cu(OTf)2 50
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
50
50
50
50
50
50
50
25
25
5
9
10
11
12
13c
14d
15e
16f
17
18
19
20
21
22
23
Next, the reaction substrate scope and limitations
were investigated as shown in Scheme 1. MBH
carbonates derived from aromatic aldehydes bearing
electron-donating
groups
gave
desired
10
dihydropyrrolo[2,1-a]isoquinolines in good yields
(3a-3d, 67-88%). The change of ester group was
successful as compounds 3e-3g could be readily
prepared under the current catalytic system (58-90%
yields). Then various MBH carbonates possessing
electron-deficient groups were submitted to this
system, affording corresponding dihydropyrrolo[2,1-
a]isoquinolines in acceptable to excellent yields (36-
96% yields). Generally, MBH carbonates bearing
substituents at o-position provided lower reaction
yields than that with substituents at m- and p-position,
suggesting that steric effect has significant impact on
reaction yield. Naphthyl and thienyl moieties can be
Fe2(SO4)3 50
FePO4 50
Fe(OTf)3 50
Fe(OTf)2 50
25
46
FeCl2
50
[a]
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol),
o
[b]
catalyst and solvent (0.2 M) at 130 C.
The yield was
determined by 1H NMR using CH2Br2 as internal standard.
[c]
o
[d]
o
[e]
At 100 C. At 50 C. Performed at 0.2 mmol scale
[f]
[g]
with 25 mol% of catalyst (0.2 M).
yield.
0.4 M.
Isolated
2
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10.1002/adsc.201900756
Advanced Synthesis & Catalysis
[a]
We then turned our attention to the substrate scope
Scheme 1. Substrate Scope of MBH Carbonates.[a-d]
examination of imines (Scheme 2). Pleasingly, the
reaction of dihydroisoquinoline bearing free phenolic
hydroxy group proceeded smoothly affording the
desired azacycles in moderate yields regardless of the
nature of substituents on MBH carbonate (3z and
3aa). The use of 3,4-dihydroisoquinoline delivered
compounds 3ba, 3ca and 3da in moderate to good
yields (42-64%). As inseparable over-oxidized
product were detected in the cases of 3ca and 3da,
excess amount of imines (1.5 equiv) were used
instead in the cases of 3ba, 3ca and 3da. Generally,
significant improvements were observed in these
cases. Both 6-bromo-3,4-dihydroisoquinoline and 7-
Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), FeCl3
[b]
(25 mol%) and DMSO (0.5 mL) at 130 oC in air.
[c]
[d]
Isolated yield. Performed at 1 mmol scale for 8 h. At
130 oC for 3 h.
To our delight, the gram-scale reaction was
successful, albeit with decreased yield and prolonged
reaction time compared with 0.2 mmol scale reaction.
As shown in Scheme 3, 1.7 g of compound 3m could
be obtained in 71% yield using 1.2 equivalent of
MBH carbonate 2m.
bromo-3,4-dihydroisoquinoline
were
suitable
FeCl3, DMSO
130 oC, air, 4h
Ar
OBoc
candidates for this reaction, yielding compounds 3ea
and 3fa in good yields.[18] Interestingly, in the case of
7-nitro-3,4-dihydroisoquinoline, beside of the desired
product 3ga, over-oxidized product 3ha was isolated
in 56% yield. It indicates that the electronic nature of
the dihydroisoquinoline ring plays an important role
on the further aromatization of dihydroisoquinoline
N
+
EWG
Ar
R
N
R
EWG
2
1
3
MeO
HO
Br
N
N
N
N
Br
COOMe
COOMe
R
COOMe
COOMe
R
R
3ba, R = MeO, 42% (81%)c
3ca, R = Me, 59% (79%)c
3fa, 60%
ring.
Unfortunately,
the
employment
of
3ea, 73%
3z, R = H, 44%
3aa, R = Cl, 49%
dihydrocarboline imine failed to give compound 3ia.
In this case, complicated mixture containing formal
(3 + 2) cycloaddition product without further
aromatization was observed.
3da, R = H,
64% (83%)c
N
N
N
O2N
O2N
COOMe
N
Bn
COOMe
COOMe
Cl
3ia, 0%
3ha, 56%
3ga, 40%
FeCl3, DMSO
130 oC, air, 4h
Ar
OBoc
N
+
EWG
Ar
R
N
R
[a]
Scheme 2. Substrate Scope of Imines.[a-c]
Reaction
EWG
2
1
3
conditions: 1 (0.2 mmol, 1.0 equiv), 2 (0.3 mmol, 1.5
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
o
equiv), FeCl3 (0.25 equiv) and DMSO (0.5 mL) at 130 C
N
N
N
N
[b]
[c]
in air.
Isolated yield.
Reaction conditions: 1 (0.3
COOR
COOR
COOMe
COOMe MeO
mmol, 1.5 equiv), 2 (0.2 mmol, 1.0 equiv), FeCl3 (0.25
Me
equiv) and DMSO (0.5 mL) at 130 oC in air.
MeO
3e, R = Me, 75%
3f, R = Et, 90%
3g, R = tBu, 58%
OMe
3b, 67%
3c, R = Me, 79%
3d, R = Et, 68%
3a, 88%
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
To show the utilization of the obtained products,
further transformations and modifications have been
conducted as shown in Scheme 4. A variety of highly
functionalized dihydropyrroloisoquinolines could be
prepared through simple chemical transformations.
Treatment of compound 3p with NBS at room
temperature afforded compound 4a in 70% yield.
Suzuki coupling of compound 4a yielded compound
4b and 4c in 52% and 63% yields respectively.
Hydrolysis of compound 3m in a mixed solvent of
water and DMSO at 130 oC provided acid 4d
successfully in 86% yield. Further amidation of
compound 4d delivered highly functionalized amides
4e, 4f and 4g in moderate to good yields (50-85%).
Sulfonylation of compound 3z afforded compound 4h
in 50% yield. Vilsmeier–Haack reaction of compound
3p produced aldehyde 4i in 71% yield. A further
oxidative coupling reaction in the presence of iron
chloride (3 equivalent) led to the formation of
dimeric dihydropyrroloisoquinoline 4j in 82% yield.
Suzuki reaction and oxidative Heck coupling reaction
of compound 3da with 3-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)pyridine yielded highly substituted
heterocycle 4k in 61% yield. Mannich reaction of
COOtBu
COOEt
Cl
Br
COOEt
COOMe
Cl
Br
3j, 84%
3k, 52%
3h, 36%
3i, 59%
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
O2N
N
N
N
N
COOR
COOMe
COOtBu
COOEt
NC
Cl
Br
3n, 69%
3o, R = Me, 82%
3p, R = Et, 80%
3l, 86%
3m, 96% (77%)c
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
COOEt
COOMe
Cl
Cl
COOEt
S
COOEt
O2N
3q, 71%
3t, 56%
3r, 91%
3s, 60%
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
N
N
N
N
COOMe
COOEt
CN
O
3v, trace
3u, 17%
3w, 82%
3x, 0%
MeO
MeO
N
N
H
O
3y, 37%d
3
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10.1002/adsc.201900756
Advanced Synthesis & Catalysis
compound 3r generated multifunctionalized tertiary
amine 4l in 71% yield.
Scheme 4. Transformations of Dihydropyrrolo-
[a]
[b]
isoquinolines.[a-l]
NBS (1.1 equiv), DCM, rt.
mol%), 4,4,5,5-tetramethyl-2-(4-
nitrophenyl)-1,3,2-dioxaborolane (2.0 equiv), Na2CO3 (2.0
Pd(PPh3)4
(10
MeO
FeCl3 (25 mol%)
OBoc
[c]
equiv), H2O/DMF, 130 oC.
Pd(PPh3)4 (10 mol%),
DMSO (6 mL)
N
COOMe
130 oC, air, 32h
MeO
MeO
MeO
+
Benzyl acrylate (5.0 equiv), DIPEA (2.0 equiv), DMF, 130
N
Cl
COOMe
oC. [d] LiOH (10 equiv), H2O/DMSO, 130 oC. [e] EDCI (2.0
2m
7.2 mmol, 2.35 g
1a
6 mmol, 1.15 g
Cl
[f]
equiv), morpholine (1.2 equiv), DCM, rt.
EDCI (2.0
3m
1.7 g, 71%
[g]
o
equiv), tryptamine (1.2 equiv), DMAP, DCE, 50 C.
EDCI (2.0 equiv), N-(3-Aminopropyl)morpholine (1.2
Scheme 3. Gram-scale reaction.
equiv), DCM, rt. [h] PhSO2Cl (1.2 equiv), Et3N (1.5 equiv),
[i]
[j]
DCM, rt.
POCl3 (3.0 equiv), DMF, rt.
FeCl3 (3.0
[l]
equiv), DCM, rt.
Pd(PPh3)4 (10 mol%), 3-(4,4,5,5-
To get more evidence for mechanism study,
control experiments have been conducted (Scheme 5).
When the reaction was performed in air in the
absence of FeCl3, the desired product 3a could be
detected in 10% NMR yield, while the intermediate
3a’ could be detected in 66% NMR yield. When
conducted in the presence of FeCl3 and under Ar
atmosphere, formal (3 + 2) cycloaddition 3a’ can be
observed in 31% yield and oxidation product 3a was
observed in 5% yield. No oxidation product 3a can be
detected when the reaction was carried out without
catalyst under Ar. It indicates that both FeCl3 and air
are essential for the formation of final product. In the
presence of FeCl3, the intermediate 3p’ can be readily
tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.0 equiv),
Na2CO3 (2.0 equiv), H2O/DMF, 130 oC. [l] Morpholine (1.2
equiv), paraformaldehyde (5 equiv), AcOH, MeCN, 50 C.
DIPEA: N,N-Diisopropylethylamine. EDCI: 1-Ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride.
o
MeO
MeO
MeO
MeO
DMSO
130 oC, 4h
OBoc
N
N
MeO
MeO
COOMe
+
+
N
COOMe
COOMe
MeO
1a
2a
MeO
MeO
3a'
3a
0 mol% FeCl3, air: 3a' 66% yield (NMR)
25 mol% FeCl3, Ar: 3a' 31% yield (NMR)
0 mol% FeCl3, Ar: 3a' 35% yield (NMR)
3a 10% yield (NMR)
3a 5% yield (NMR)
3a 0% yield (NMR)
MeO
MeO
MeO
DMSO
130 oC, air, 4h
OBoc
N
N
o
MeO
MeO
MeO
COOEt
oxidized to final product 3p at 130 C in good yield
+
+
N
(83%). Trace product was observed at 50oC even with
prolonged reaction time, suggesting the reaction
temperature plays an important role in the oxidative
aromatization step. While the intermediates 3p’ and
3aa’ could be easily prepared in the absence of iron
chloride following a modified procedure according to
our previous report (See ESI). It demonstrates that
FeCl3 has no significant influence on the formal (3 +
2) cycloaddition.
COOEt
COOEt
NC
1a
2p
NC
NC
3p'
3p
without FeCl3 3p' 43% yield (NMR)
3p 22% yield (NMR)
MeO
MeO
MeO
MeO
N
FeCl3 (25 mol%)
DMSO, air
N
COOEt
COOEt
NC
NC
3p
3p'
130 oC, 4h, 83%
50 oC, 15h, trace
MeO
HO
MeO
HO
Cl
Cl
N
FeCl3 (25 mol%)
DMSO, air, 4h
N
COOMe
COOMe
Cl
Cl
MeO
NO2
N
3z'
3z, 41%
MeO
COOEt
Scheme 5. Control Experiments.
NC
4b, 52%
OMe
b
MeOOC
N
MeO
MeO
MeO
MeO
MeO
MeO
COOBn
OMe
OMe
N
N
On the basis of our results and previous reports, a
plausible mechanism was proposed as shown in
Scheme 6. Firstly, nucleophilic attack of imine 1 to
MBH carbonate 2 generates intermediate A. The
following deprotonation yields zwitterion B which
would be in equilibrium with intermediate C. 1,5-
Electrocyclization of intermediate C leads to the
formation of compound 3’. Finally, FeCl3 promoted
oxidative aromatization as key step for this process,
affords the final product 3. Further oxidative
aromatization would be possible and it depends on
the electronic nature of the dihydroisoquinoline
moiety.
N
c
Br
COOEt
4a, 70%
COOMe
COOEt
MeO
NC
4c, 63%
4j, 82%
NC
j
a
O
MeO
MeO
MeO
MeO
Cl
Cl
N
N
CHO
COOEt
N
Ar
i
l
N
COOMe
R
EWG
NC
4i, 71%
3
k
h
4l, 71%
d
MeO
N
PhO2
S
N
MeO
MeO
O
N
N
N
COOMe
Cl
COOMe
OH
Cl
O
4h, 50%
g
4k, 61%
e
Cl
4d, 86%
MeO
MeO
MeO
MeO
f
MeO
MeO
H
N
N
N
N
N
O
NH
N
O
O
O
NH
Cl
O
Cl
4g, 50%
4e, 85%
Cl
4f, 80%
4
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10.1002/adsc.201900756
Advanced Synthesis & Catalysis
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-CO2
-tBuOH
+
EWG
Ar
Ar
Ar
+
tBuO
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N
R
N
N
R
1
EWG
EWG
2
A
B
FeX2
FeX2
air
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FeX3
FeX3
Ar
Ar
Ar
Ar
N
N
N
R
N
EWG
R
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R
R
EWG
EWG
EWG
3'
3''
3
C
Scheme 6. Plausible Mechanism.
Conclusion
In conclusion, we have developed a straightforward
FeCl3 promoted synthesis of dihydropyrrolo[2,1-
a]isoquinolines through formal (3
+
2)
cycloaddition/oxidative aromatization cascade of
dihydroisoquinoline with MBH carbonates. Various
dihydropyrrolo[2,1-a]isoquinolines can be prepared
from easily accessible material (up to 96% yield).
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Further
modification
of
the
obtained
dihydropyrrolo[2,1-a]isoquinolines were successful
through simple chemical transformations providing a
diverse range of natural product-like molecules.
Notably, the gram-scale reaction can be performed
successfully in good yield.
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Experimental Section
General procedure for the synthesis of compounds 3:
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A mixture of dihydroisoquinoline imine 1 (0.2 mmol, 1.0
equiv), MBH carbonate 2 (0.3 mmol, 1.5 equiv) and FeCl3
(0.05 mmol, 0.25 equiv) in DMSO (0.5 mL) was stirred at
o
130 C for 4 h under air atmosphere. The mixture was
cooled to room temperature and diluted with DCM (3 mL).
The resulting solution was washed with water (1.0 mL x 3)
and dried with Na2SO4, then purified directly by a silica
gel flash chromatography (hexane/EtOAc) to afford
compound 3.
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Acknowledgements
We are grateful for the support provided for this study by the
National Science Foundation of China (21871035, 21502013).
We thank Prof. Yan-Kai Liu of Ocean University of China for
helpful suggestions on manuscript writing.
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dihydroisoquinoline ring could also be detected by
HRMS (ESI-HRMS: calcd. for C20H15BrNO2+ (M+H)+
380.0281, found 380.0289).
6
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10.1002/adsc.201900756
Advanced Synthesis & Catalysis
FULL PAPER
Direct Synthesis of Dihydropyrrolo[2,1-
a]isoquinolines through FeCl3 Promoted Oxidative
Aromatization
FeCl3 (25 mol%)
DMSO
OBoc
R1
R1
N
R1
EWG
N
R4
+
R2
R3
N
air, 130 oC, 4h
R2
12 examples
Adv. Synth. Catal. Year, Volume, Page – Page
R2
31 examples, up to 96% yield
· Abundant, inexpensive and nontoxic catalyst · Gram-scale possible
· Direct synthesis · Readily accessible material · Easy transformations
R5
EWG
Hai-Lei Cui,* Lu Jiang, Hao Tan and Si Liu
7
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