One-pot Synthesis of Isoquinoline-Fused Isoquinolines via Intramolecular Hydroamination/Aza-Claisen Type Rearrangement Cascade

Article abstract of DOI:10.1002/adsc.202001576

A one-pot, two-step synthesis of isoquinoline-fused isoquinolines from α-amino acid esters and 2-alkynyl benzaldehydes are reported. The strategy comprises an unconventional Pictet-Spengler reaction between α-amino acid esters and 2-alkynyl benzaldehydes to give isoquinoline intermediates. Subsequent gold-catalyzed intramolecular hydroamination furnishes isoquinoline-fused isoquinolines. The scope of this strategy is further extended to prepare multisubstituted isoquinoline-fused isoquinolines via subjecting the N-allylated isoquinoline intermediates to gold-catalyzed intramolecular hydroamination followed by aza-Claisen type rearrangement. (Figure presented.).

Full text of DOI:10.1002/adsc.202001576

FULL PAPER
DOI: 10.1002/adsc.202001576
One-pot Synthesis of Isoquinoline-Fused Isoquinolines via
Intramolecular Hydroamination/Aza-Claisen Type
Rearrangement Cascade
Wei-Jung Chiu,+a Jin-Yu Chen,+a Shih-I Liu,a Indrajeet J. Barve,a, c
Wan-Wen Huang,a and Chung-Ming Suna, b,*
a
Department of Applied Chemistry,
National Chiao-Tung University,
1001 Ta-Hsueh Road, Hsinchu 300-10, Taiwan
E-mail: cmsun@nctu.edu.tw
Department of Medicinal and Applied Chemistry,
b
Kaohsiung Medical University,
100, Shih-Chuan 1st Road, Kaohsiung 807-08, Taiwan
Department of Chemistry,
c
MES Abasaheb Garware College,
Pune, India
+
Both authors contributed equally to this work.
Manuscript received: December 19, 2020; Revised manuscript received: March 27, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202001576
Abstract: A one-pot, two-step synthesis of isoquinoline-fused isoquinolines from α-amino acid esters and 2-
alkynyl benzaldehydes are reported. The strategy comprises an unconventional Pictet-Spengler reaction
between α-amino acid esters and 2-alkynyl benzaldehydes to give isoquinoline intermediates. Subsequent
gold-catalyzed intramolecular hydroamination furnishes isoquinoline-fused isoquinolines. The scope of this
strategy is further extended to prepare multisubstituted isoquinoline-fused isoquinolines via subjecting the N-
allylated isoquinoline intermediates to gold-catalyzed intramolecular hydroamination followed by aza-Claisen
type rearrangement.
Keywords: aza claisen-type rearrangement; hydroaminati-on; isoquinoline-fused isoquinolines
Introduction
molecular hydroamination reactions of alkynes. Sev-
eral groups have reported a gold-catalyzed transforma-
The past decade has witnessed a paradigm shift in the tion for the synthesis of 1,2-dihydroquinolines,[4]
drug design process. The inadequacy of the traditional indole-1-carboxamides,[5] azepines,[6] isoindolines and
single-target drug approach to treat modern complex isoquinolines,[7]
indoles,[8]
pyrrolidines.[9]
and
diseases led to the development of multi-target drugs.[1] tetrahydroisoquinolines.[10]
This feat could be achieved by coalescing two different
Tetrahydroisoquinoline and 1,2-dihydroisoquinoline
privileged chimeric cores into a single scaffold.[2] In are privileged scaffolds frequently found in various
view of that, various combinations of fused-hetero- alkaloids and pharmaceutical agents with a broad
cyclic frameworks are under development.[3]
spectrum of bioactivities.[11–14] Besides that a molecular
The intramolecular hydroamination reaction is an framework that combines isoquinoline moiety with
efficient synthetic method for the synthesis of interest- other pharmacophores units shows interesting pharma-
ing heterocycles whereby the addition of nucleophilic cological and material properties. For example, Berber-
À NH group to CÀ C triple bond is carried out. Gold- ine is an alkaloid found in Coptis chinensis plant and is
based catalysts as the carbophilic π-acid are proved to used for the treatment of diabetes (Figure 1).[15]
be promising and effective in carrying out intra-
Adv. Synth. Catal. 2021, 363, 1–10
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
methyl (8S)-6-phenyl-9,12,13,15b-tetrahydro-8H-[1,4]
dioxino[2,3-g]isoquinolino[1,2-a]isoquinoline-8-car-
boxylate 4a (Scheme 1).
In view of that, we aimed at the recognization of
the suitable metal catalysts which could assist a
difficult Pictet-Spengler reaction and subsequent intra-
molecular hydroamination consecutively. Accordingly,
when 1a and 2a was reacted in the presence of various
silver catalysts such as AgNO2, Ag2O, AgOTf and
AgSbF6, no desired product was obtained and the less
reactive L-3,4-dihydroxyphenylalanine methyl ester
Figure 1. Biologically active 1,2,3,4-tetrahydro isoquinoline-
fused heterocycles.
Pyrrolo-fused isoquinoline alkaloid, (+)-Crispine A was recovered. Also, gold catalysts such as AuCl
is obtained from Clathrus crispus and exhibits (10 mol%) and AuCl3 (10 mol%)[26] were ineffective to
cytotoxic activity against HeLa human cancer cells.[16] catalyze this reaction and afforded either gold-alkyne
Whereas, benzoindolizine is a π-conjugated isoquino- complex or Pictet-Spengler product 3a in poor yield.
line-fused pyrrole that displays fluorescence and is When TFA (20 equiv.) was used as a single catalyst,
effectively used for biological imaging.[17] Recently, only Pictet-Spengler product 3a was yielded in 83%
Cheng and co-workers reported the preparation of yield. As the sole catalysts failed to initiate the one-pot
isoquinoline-fused triazines through iodine- and base- cascade reaction, a dual catalytic system was tested.
mediated [3+3] cycloaddition by hydrazide and α- For that reason, one equivalent of TFA in combination
halohydroxamate.[18] Larock et al. synthesized isoqui- with AuCl (10 mol%) was employed in the reaction,
noline-fused indolines and pyrroles via copper-cata- and no any product was observed. No desired product
lyzed tandem reaction between o-haloarylalkynes and was observed despite increasing the TFA to 10
indoles/pyrroles.[19] Lately, synthesis of isoquinoline- equivalents in the same reaction. Next, the combina-
fused benzimidazoles from 2-alkynylbenzaldehydes tion of BF3.OEt2 (1 equiv.) with AuCl (10 mol%)
and o-phenylenediamines /aliphatic amines was re- afforded Pictet-Spengler product 3a in 68% yield.
ported by Mishra.[19] Similarly, Ouyang also developed When the same reaction was carried out at 55 C in the
°
the synthesis of isoquinoline-fused benzimidazoles presence of BF3.OEt2 only, the yield of 3a was
using copper-catalyzed electrophilic cyclization of 2- increased to 73% (3a-cis : 3a-trans=10:1). Conse-
ethynylbenzaldehydes with o-benzenediamines.[20] In quently, neither a single catalyst nor a combination of
2016, Ausekle reported a one-pot synthesis of iso- catalysts proved to be useful in promoting this trans-
quinoline-fused indoles/pyrroles from 1-bromo-2-(2,2- formation. Nonetheless, it was found that the Pictet-
difluorovinyl)benzenes and indoles/pyrroles through Spengler reaction between 1a and 2a could be
intramolecular Pd-catalyzed CÀ H arylation.[21] Kumar smoothly carried out with one equivalent of BF3.OEt2
°
et al. prepared isoquinoline-fused pyridines via Knoe- at 55 C for 16 h in 1,2-dichloroethane (DCE). We next
venagel/Michael/cyclization reactions.[22] Wang and co- explored optimization for the intramolecular hydro-
workers synthesized isoquinoline-fused triazepines amination of 3a-cis, a major product of Pictet-Spengler
using [4+3] annulation of cyclic azomethine imines reaction. Accordingly, the use of silver catalysts such
with propargylic carbamates.[23] To the best of our as AgNO3 and AgOTf yielded the desired product in
knowledge, there is no report on the synthesis of only a trace amount with the recovery of starting
isoquinoline-fused isoquinoline scaffold. Inspired by materials. When the silver catalyst was replaced by the
the worthiness of isoquinoline-fused heterocycles in gold catalyst like AuCl3, the desired product methyl
terms of their usefulness in various fields, we herein (6S)-2,3-dimethoxy-8-phenyl-5,13b-dihydro-6H-iso-
report a one-pot/two-step synthesis of isoquinoline- quinolino[1,2-a]isoquinoline-6-carboxylate 4a-cis was
fused isoquinolines through an unconventional Pictet- obtained in 27% yield. Proton NMR of 4a-cis showed
Spengler reaction followed by an intramolecular characteristic singlet peaks corresponding to Ha proton
hydroamination/aza-Claisen-type reaction cascade.
Results and Discussion
Initially, various 2-alkynyl benzaldehydes 2 were
prepared from 2-bromobenzaldehydes and alkynes by
Sonogashira conditions.[24] We commenced current
studies with methyl (S)-2-amino-3-(3,4-dimeth-
oxyphenyl)propanoate 1a and 2-(phenylethynyl)
benzaldehyde 2a as a model substrate to explore the
possible reaction for the one-pot, two-step synthesis of
Scheme 1. One-pot synthesis of isoquinolino[1,2-a] isoquino-
line 4a.
Adv. Synth. Catal. 2021, 363, 1–10
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
at 5.14 ppm and Hb proton at 6.68 ppm respectively. cis) on the aryl ring (R3) did not have much influence
The 4a-cis was further confirmed by X-crystallo- on the product formation.
graphic study (Figure 2).[27]
The scope of the current strategy is then further
When AuCl was used under the same conditions, extended for the synthesis of multi-substituted isoqui-
the yield of 4a-cis was increased to 85%. Finally, noline-fused isoquinolines. Accordingly, 3a-cis was
°
lowering the reaction temperature to 25 C drastically alkylated with allyl bromide in the presence of K2CO3
increased the yield of the desired product 4a-cis to to obtain 5a-cis. At the outset of our study of the aza-
93%. It is worth noting that when 3a-trans was Claisen-type rearrangement reaction, we screened
subjected to identical reaction condition, the rate of the various metal catalysts, additives and solvents and the
reaction was slower than its cis isomer and the 4a- results are summarized in Table 2. Initially, the use of
trans was obtained in 16 h. Mechanistically, AuCl metal catalysts such as InCl3, AgSbF6, AgOTf, AuCl3
activates the CÀ C triple bond of 3a by coordination and AuCl did not afford the desired product 6a-cis and
and 6-endo-dig nucleophilic attack of the nitrogen the starting material was recovered (Table 2, entries 1–
atom is performed and subsequent removal of the 7). The use of 1,2-bis(diphenylphosphino)benzene
catalyst gives cyclized product 4.
(dppBz) as a ligand in the same reaction was
We next attempted the whole reaction sequences in ineffective (Table 2, entries 8–9). The screening of
a two-step one-pot way. Therefore, 1a and 2a were various solvents for the AuCl catalyzed reaction failed
reacted in the presence of BF3.OEt2 (1 equiv.) in DCE to yield the cyclized product (Table 2, entries 10–14).
°
at 55 C for 16 h. After the generation of Pictet- Switching the use of gold salt to gold complex (PPh3)
Spengler products in situ, AuCl (10 mol%) was added AuCl (10 mol%) in the reaction was futile (Table 2,
and the reaction mixture was stirred at room temper- entry 15). Pleasingly, when the reaction was carried
ature for 8 h to obtain 4a-cis/4a-trans (10:1) in 73% out in the presence of (PPh3)AuCl (100 mol%) in 1,2-
°
yield.
dichloroethane at 70 C for 16 h, a new product was
Next, the substrate scope of this two-step, one-pot obtained in 37% yield with unreacted starting material
cascade reaction for the synthesis of isoquinolino[1,2- 3a-cis (Table 2, entry 16).
a]isoquinolines 4 was investigated (Table 1). Various
The use of (PPh3)AuCl (10 mol%)/Ag2CO3 combi-
2-alkynyl benzaldehydes 2 were successfully partici- nation did not yield the 6a-cis product (Table 2,
pated in the reaction and all the products were obtained entry 17). Next, (PPh3)AuCl was tested with a combi-
in good yield. Under the standard reaction conditions, nation of silver salts AgOCOCF3/AgNTf2, and we
heterocyclic 2-alkynyl benzaldehydes also worked well observed only slight increase in the yield (40%)
to yield major products (4b-cis, 4e-cis, 4f-cis, 4h-cis, (Table 2, entries 18–19). We then tested the same
4k-cis and 4n-cis) in good yield. However, the 3t-cis reaction in different solvents; however, the yield was
and 3u-cis prepared from 2- (phenylethynyl)furan-3- improved to merely 45% in CH3CN (Table 2, en-
carbaldehyde and 2-(phenylethynyl)thiophene-3-car- tries 20–23). Switching the gold complex (PPh3)AuCl/
baldehyde failed to undergo hydroamination to afford silver salt combination to PPh3AuNTf2 afforded 6a-cis
4t-cis and 4u-cis. The transformation of 3v-cis in 40% yield (Table 2, entries 24). Decreasing the
°
°
bearing trimethylsilyl group into 4v-cis encumbered reaction temperature from 70 C to 25 C led to product
the steric hindrance. Compound 3w-cis having 2- formation in 55% yield (Table 2, entries 25). The
ethynylphenyl moiety did not afford cyclized product efficiency of metal-catalyzed reaction was diminished
4w-cis probably due to the formation of a gold in toluene (Table 2, entries 26). The product 6a-cis
acetylide complex which blocked further cyclization. was obtained in excellent yield in acetonitrile (Table 2,
The presence of either electron-donating (4f-cis, 4g- entries 27). Finally, the utilization of a double amount
°
cis, 4h-cis, 4k-cis, 4l-cis, 4n-cis, 4p-cis, 4r-cis and of PPh3AuNTf2 (20 mol%) at 25 C in CH3CN for 12 h
4s-cis) or withdrawing groups (4c-cis, 4d-cis and 4o- afforded the desired product 6a-cis in 87% isolated
yield (Table 2, entries 28).
With optimized conditions in hand, we next
investigated the substrate scope of aza-Claisen-type
rearrangement (Table 3). Substrates bearing either
electron withdrawing or donating group (R2) on the
phenyl ring afforded corresponding products (6e, 6f
and 6g) in excellent yields. Gratifyingly, substrates
functionalized with substituted allyl group undergo a
smooth cyclization and prenyl group transformation to
give products 6d, 6e, and 6f in good yield. The
functionalization of the allyl chain has impact on the
distereoselectivity.
Figure 2. ORTEP diagram of 4a-cis.
Adv. Synth. Catal. 2021, 363, 1–10
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
Table 1. Substrate scope for the synthesis of isoquinolino[1,2-a]isoquinolines 4.[a]
[a]
°
Reaction conditions: Step 1: 1 (1 equiv.), 2 (1 equiv.), BF3.OEt2 (1 equiv.), MS 4 Å, DCE (10 mL), 55 C, 16 h. Step 2: AuCl
(10 mol%), DCE (15 mL), 8 h.
Accordingly, the substrates 5i-cis and 5r-cis alky- ray crystallographic study[27] (Figure 3). On the other
lated with cinnamyl chloride furnished 6i-cis and 6r- hand, the reaction of 5j-cis and 5k-cis yielded 6j-cis
cis as a single diastereomer. The stereochemistry of 6i-
and 6k-cis in 2:1 distereomeric ratio with an
cis, as a representative example was confirmed by X- efficient migration of the crotyl and neryl groups. The
Adv. Synth. Catal. 2021, 363, 1–10
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
Table 2. Optimization of reaction conditions for the synthesis of 6a-cis.[a]
Entry
Catalyst
(mol%)
Additive
Solvent
Temp
Yield[b]
°
( C)
1
2
3
InCl3 (10)
AgSbF6 (10)
AgOTf (10)
–
–
–
DCE
DCE
DCE
reflux
70
–
–
–
70
4
AuCl3 (10)
–
DCE
70
–
5
AuCl (5)
–
DCE
50
–
6
7
AuCl (5)
AuCl (10)
–
–
DCE
DCE
reflux
70
–
–
8
AuCl (5)
dppBz
DCE
50
–
9
AuCl (5)
AuCl (5)
AuCl (5)
AuCl (5)
AuCl (5)
AuCl (5)
(PPh3)AuCl (10)
(PPh3)AuCl (100)
(PPh3)AuCl (10)
(PPh3)AuCl (10)
(PPh3)AuCl (10)
(PPh3)AuCl (10)
(PPh3)AuCl (10)
(PPh3)AuCl (10)
(PPh3)AuCl (10)
PPh3AuNTf2 (10)
PPh3AuNTf2 (10)
PPh3AuNTf2 (10)
PPh3AuNTf2 (10)
PPh3AuNTf2 (20)
dppBz
–
–
–
–
–
–
–
Ag2CO3
AgOCOCF3
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
DCE
reflux
reflux
70
80
reflux
50
70
70
70
70
70
reflux
90
70
reflux
70
25
25
25
25
–
–
–
–
–
–
–
37
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28b
CH2Cl2
CH3CN
toluene
THF
CHCl3
DCE
DCE
DCE
DCE
DCE
CH2Cl2
toluene
CH3CN
DMF
DCE
–
40
22
40
45
–
40
55
12
85
87
–
–
–
–
–
DCE
toluene
CH3CN
CH3CN
[a] Reaction conditions: 5a-cis (1 equiv.), catalyst (20 mol%), additive (10 mol%), MS 4 Å, solvent (15 mL), 16 h.
[b] Reaction was stirred for 12 h.
difference in outcome could be attributed to the steric
effect of the R5 group.
The presence of the bulky phenyl substituent in 6i-
cis and 6r-cis allowed a complete stereocontrol,
whereas sterically less demanding CH3- and alkyl
chain led to diastereomeric mixture (6q-cis, 6s-cis, 6t-
cis). Aza-claisen-type rearrangement of intermediate
6i-cis could form two diastereomers, 9i-cis-A and 9i-
cis-B. Molecular modeling revealed that there is a
possible steric crowding present in the intermediate 9i-
cis-B owing to the presence of a sterically demanding
Figure 3. ORTEP diagram of 6i-cis (Atomic displacement
ellipsoids are drawn at the 50% probability level).
Adv. Synth. Catal. 2021, 363, 1–10
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
Table 3. Substrate scope for the synthesis of 6-cis.[a]
[a] Reaction conditions: 5a-cis (1 equiv.), catalyst (20 mol%), MS 4 Å, solvent (15 mL), 16 h.
[b] Reaction was stirred for 12 h.
phenyl group on the allyl chain and the phenyl groups
A plausible mechanism for the gold-catalyzed syn-
of attached catalyst -AuP(PPh3). Whereas, this steric thesis of 6-cis is depicted in Scheme 2. Initially, a
hindrance from allyl substituent is less in 9i-cis-A due carbophilic cationic gold catalyst coordinates to
to the remoteness between these two bulky groups alkynyl moiety of 5-cis. Intramolecular nucleophilic
(Figure 4). We also attempted the cyclization of attack of nitrogen lone pairs of 7-cis on the activated
diastereomers 5-trans. Notably, substrates 5a, 5p, 5s CÀ C triple bond generates a cationic intermediate 8-
and 5u, under the usual reaction conditions, gave cis. Subsequent concerted aza-Claisen-type rearrange-
corresponding products 6-trans in good yields (Ta- ment affords 9-cis.25 Finally, 9-cis undergoes deaura-
ble 4).
tion step to give the observed product 6-cis.
Adv. Synth. Catal. 2021, 363, 1–10
6
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
Conclusion
In conclusion, we have demonstrated a one-pot two-
step strategy for the rapid synthesis of isoquinoline-
fused isoquinoline as a novel scaffold through a
sequential Pictet-Spengler cyclization/intramolecular
hydroamination. The process proceeds with BF3.OEt2-
mediated Pictet-Spengler reaction between α-amino
acids with 2-alkynyl benzaldehydes to afford tetrahy-
droisoquinolines as a diastereomeric mixture in 10:1
(cis:trans) ratio. The intramolecular hydroamination of
cis-tetrahydroisoquinolines in the presence of AuCl
undergoes smoothly to give isoquinoline-fused isoqui-
nolines. The scope of this protocol is further broadened
by accessing multisubstituted isoquinoline-fused iso-
quinolines. For that, cis-tetrahydroisoquinolines were
allylated first and the subsequent gold-catalyzed intra-
molecular hydroamination/aza-Claisen type rearrange-
ment cascade furnished the substituted isoquinoline-
fused isoquinolines in good yield. The diastereoselec-
tivity of the final product is controlled by the
substitutents present on the allyl moiety. Sterically
demanding phenyl group yields a single diastereomer
whereas less bulky methyl or alkyl chain give
distereomeric mixture of final products.
Figure 4. Diastereoselectivity in the reaction of 5i-cis.
Table 4. Substrate scope for the synthesis of 6-trans.[a]
Experimental Section
General Information
[a] Reaction conditions: 5a-trans (1 equiv.), catalyst (20 mol%),
1H NMR (400 MHz) and 13C NMR (101 MHz) spectra were
recorded on 400-MR automated spectrometer. Chemical shifts
are reported in parts per million (ppm) on the δ scale from an
internal standard (TMS). Analytical thin-layer chromatography
(TLC) was performed using 0.25 mm silica gel-coated Kiselgel
60 F254 plates. Flash chromatography was performed using the
indicated solvent and silica gel 60 (Merck, 230–400 mesh).
High-resolution mass spectra (HRMS) were recorded in ESI
mode using TOF mass spectrometer. IR spectra were recorded
using a Bruker spectrophotometer. All materials were purchased
from commercial sources and used without further purification.
MS 4 Å, solvent (15 mL), 16 h.
Representative experimental Procedure for the Syn-
thesis of Methyl (8S,15bR)-6-phenyl-9,12,13,15b-
tetrahydro-8H-[1,4]dioxino[2,3-g]isoquinolino
[1,2-a]isoquinoline-8-carboxylate (4a-cis)
To the stirred solution of methyl (S)-2-amino-3-(2,3-dihydro-
benzo[b][1,4]dioxin-6-yl)propanoate 1a (63 mg, 0.265 mmol)
in DCE (10 mL) was added 2-(phenylethynyl)benzaldehyde 2a
(55 mg, 0.265 mmol), 4 Å MS (70 mg) and BF3.OEt2 (38 mg,
0.265 mmol) at room temperature and the reaction was heated
°
at 55 C for 16 h. After completion, the reaction was then
allowed to cool down to room temperature, AuCl (6 mg,
0.027 mmol) was added and the reaction was stirred for 8 h.
After completion of the reaction, reaction mixture was filtered
through celite bed. The filtrate was concentrated under reduced
pressure. The crude residue was diluted with aq. NaHCO3
(20 mL) and extracted by ethyl acetate (10 mL×3). The organic
Scheme 2. A plausible mechanism for the synthesis of 6-cis.
Adv. Synth. Catal. 2021, 363, 1–10
7
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
layers were combined, dried over MgSO4 and concentrated in
vacuo. The crude product was purified by column chromatog-
raphy (ethyl acetate in hexanes) to obtain 4a-cis as yellow solid
(82 mg, 73%).
[4] a) T. Enomoto, A. L. Girard, Y. Yasui, Y. J. Takemoto,
Org. Chem. 2009, 74, 9158–9164; b) Y. M. Sun, P. Gu,
Y. N. Gao, Q. Xu, M. Shi, Chem. Commun. 2016, 52,
6942–6945.
1H NMR (400 MHz, CDCl3) δ 7.73 (d, J=8.1 Hz, 2H), 7.45–
7.37 (m, 3H), 7.25–7.14 (m, 3H), 7.01 (d, J=7.4 Hz, 1H), 6.86
(d, J=2.4 Hz, 2H), 6.67 (s, 1H), 5.12 (s, 1H), 4.36–4.26 (m,
4H), 3.82 (d, J=6.1 Hz, 1H), 3.20 (dd, J=15.9, 6.1 Hz, 1H),
3.03 (d, J=15.9 Hz, 1H), 2.65 (s, 3H); 13C NMR (101 MHz,
CDCl3) δ 171.5, 148.6, 142.9, 141.7, 135.9, 135.7, 130.1, 129.1,
128.8, 128.3, 126.9, 126.8, 126.7, 124.4, 123.7, 123.2, 117.3,
117.2, 111.7, 64.6, 57.8, 52.8, 50.6, 30.1; HRMS (EI) m/z:
[M]+ Calcd for C27H23NO4 425.1622; Found 425.1586.
[5] D. Ye, J. Wang, X. Zhang, Y. Zhou, X. Ding, E. Feng, H.
Sun, G. Liu, H. Jiang, H. Liu, Green Chem. 2009, 11,
1201–1208.
[6] a) A. S. K. Hashmi, W. Yang, F. Rominger, Adv. Synth.
Catal. 2012, 354, 1273–1279; b) H. Ito, T. Harada, H.
Ohmiya, M. Sawamura, Beilstein J. Org. Chem. 2011, 7,
951–959.
[7] a) A. S. K. Hashmi, S. Schäfer, J. W. Bats, W. Frey, F.
Rominger, Eur. J. Org. Chem. 2008, 4891–4899; b) S.
Fustero, I. Ibáñez, P. Barrio, M. A. Maestro, S. Catalán,
Org. Lett. 2013, 15, 832–835.
[8] a) T. Wang, S. Shi, D. Pflästerer, E. Rettenmeier, M.
Rudolph, F. A. Rominger, S. K. Hashmi, Chem. Eur. J.
2014, 20, 292–296; b) N. D. Rode, I. Abdalghani, A.
Arcadi, M. Aschi, M. Chiarini, F. Marinelli, J. Org.
Chem. 2018, 83, 6354–6362; c) A. Yamaguchi, S. Inuki,
Y. Tokimizu, S. Oishi, H. Ohno, J. Org. Chem. 2020, 85,
2543–2559; d) X. Tian, L. Song, K. Farshadfar, M.
Rudolph, F. Rominger, T. Oeser, A. Ariafard, A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2020, 59, 471–478.
[9] T. D. Tan, Y. B. Chen, M. Y. Yang, J. L. Wang, H. Z. Su,
F. L. Hong, J. M. Zhou, L. W. Ye, Chem. Commun. 2019,
55, 9923–9926.
Representative Procedure for the Synthesis of
Methyl (6S,13bR)-9-allyl-2,3-dimethoxy-8-phenyl-
5,13b-dihydro-6H-isoquinolino[1,2-a]isoquinoline-
6-carboxylate (6a-cis)
To the stirred solution of 5a-cis (100 mg, 0.21 mmol) in
acetonitrile (15 mL) was added 4 Å MS (70 mg) and
PPh3AuNTf2 (7.9 mg, 0.01 mmol) and the reaction mixture was
stirred at room temperature for 16 h. After the complete
consumption of starting material, the solvent was removed
under vacuum. The crude reside was purified by flash column
chromatography (10-15% ethyl acetate in hexanes) to obtain
6a-cis as red liquid (76 mg, 76%).
1H NMR (400 MHz, Acetone-d6) δ 7.65 (d, J=7.4 Hz, 2H),
7.49–7.41 (m, 4H), 7.24 (t, J=7.4 Hz, 1H), 7.17 (t, J=7.5 Hz,
1H), 6.91 (s, 1H), 6.88 (s, 2H), 5.90 (m, 1H), 5.10 (d, J=
17.2 Hz, 1H), 5.05 (s, 1H), 4.98 (d, J=10.1 Hz, 1H), 3.86 (s,
3H), 3.83 (s, 3H), 3.59 (dd, J=16.5, 6.3 Hz, 1H), 3.54–3.51
(m, 1H), 3.43 (dd, J=16.6, 4.9 Hz, 1H), 2.98 (s, 1H), 2.97 (s,
1H), 2.63 (s, 3H); 13C NMR (101 MHz, Acetone-d6) δ 170.6,
148.7, 147.4, 145.5, 138.3, 136.4, 135.7, 131.1, 130.8, 128.6,
128.1, 126.1, 126.1, 125.9, 123.8, 122.5, 121.8, 118.2, 114.8,
112.5, 112.1, 57.7, 55.4, 55.1, 52.2, 49.7, 41.3, 32.4, 29.7; MS
(ESI): m/z 468; HRMS (ESI, m/z) Calcd. C30H29NO4 [M+H]+:
468.2175; Found 468.2169 (M+H)+.
[10] a) A. S. K. Hashmi, P. Haufe, C. Schmid, A. R. Nass, W.
Frey, Chem. Eur. J. 2006, 12, 5376–5382; b) A. S. K.
Hashmi, F. Ata, E. Kurpejovic, J. Huck, M. Rudolph,
Top. Catal. 2007, 44, 245–251; c) A. S. K. Hashmi, M.
Rudolph, J. W. Bats, W. Frey, F. Rominger, T. Oeser,
Chem. Eur. J. 2008, 14, 6672–6678; d) A. S. K. Hashmi,
F. Ata, P. Haufe, F. Rominger, Tetrahedron 2009, 65,
1919–1927.
[11] J. D. Scott, R. M. Williams, Chem. Rev. 2002, 102,
1669–1730.
[12] I. P. Singh, P. Shah, Expert Opin. Ther. Pat. 2017, 27,
17–36.
[13] F. Ji, W. B. Yi, M. Sun, M. F. Lv, C. Cai, Mol. Diversity
2013, 17, 295–305.
[14] J. W. Zhang, Z. Xu, Q. Gu, X. X. Shi, X. B. Leng, S. L.
You, Tetrahedron 2012, 68, 5263–5268.
[15] J. Yin, H. Xing, J. Ye, Metabolism 2008, 57, 712–717.
[16] S. M. Allin, S. N. Gaskell, J. M. R. Towler, P. C. B. Page,
B. Saha, M. J. Mckenzie, W. P. Martin, J. Org. Chem.
2007, 72, 8972–8975.
Acknowledgements
The authors thank the Ministry of Science and Technology
(MOST) of Taiwan for financial assistance and the authorities
of the National Chiao Tung University for providing laboratory
facilities.
[17] B. Liu, Z. Wang, N. Wu, M. Li, J. You, J. Lan, Chem.
Eur. J. 2012, 18, 1599–1603.
References
[18] X. Cheng, X. Cao, S. J. Zhou, B. G. Cai, X. K. He, J.
Xuan, Adv. Synth. Catal. 2019, 361, 1230–1235.
[19] A. K. Verma, T. Kesharwani, J. Singh, V. Tandon, R. C.
Larock, Angew. Chem. Int. Ed. 2009, 48, 1138–1143;
Angew. Chem. 2009, 121, 1158–1163.
[20] M. Mishra, D. Twardy, C. Ellstrom, K. A. Wheeler, R.
Dembinski, B. Török, Green Chem. 2019, 21, 99–108.
[21] H. C. Ouyang, R. Y. Tang, P. Zhong, X. G. Zhang, J. H.
Li, J. Org. Chem. 2011, 76, 223–228.
[1] R. R. Ramsay, M. R. Popovic-Nikolic, K. Nikolic, E.
Uliassi, M. L. Bolognesi, Clin. Trans. Med. 2018, 7, 1–
14.
[2] J. Zhou, X. Jiang, S. He, H. Jiang, F. Feng, W. Liu, W.
Qu, H. Sun, J. Med. Chem. 2019, 62, 8881–8914.
[3] O. Benek, O. Soukup, M. Pasdiorova, L. Hroch, V.
Sepsova, P. Jost, M. Hrabinova, D. Jun, K. Kuca, D.
Zala, R. R. Ramsay, J. Marco-Contelles, K. Musilek,
ChemMedChem 2016, 11, 1264–1269.
Adv. Synth. Catal. 2021, 363, 1–10
8
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
[22] E. Ausekle, S. A. Ejaz, S. U. Khan, P. Ehlers, A.
Villinger, J. Lecka, J. Sévigny, J. Iqbalb, P. Langer, Org.
Biomol. Chem. 2016, 14, 11402–11414.
[23] N. S. Kumar, L. C. Rao, N. J. Babub, H. M. Meshram,
RSC Adv. 2015, 5, 95539–95544.
[24] Y. Wang, L. Zhu, M. Wang, J. Xiong, N. Chen, X. Feng,
Z. Xu, X. Jiang, Org. Lett. 2018, 20, 6506–6510.
[25] A. V. Malkov, M. M. Westwater, A. Gutnov, P. Ramírez-
López, F. Friscourt, A. Kadlčíková, J. Hodačová, Z.
Rankovic, M. Kotora, P. Kočovský, Tetrahedron 2008,
64, 11335–11348.
[26] a) A. S. K. Hashmi, L. Schwarz, J. H. Choi, T. M. Frost,
Angew. Chem. Int. Ed. Engl. 2000, 39, 2285–2288;
b) A. S. K. Hashmi, T. M. Frost, J. W. Bats, J. Am.
Chem. Soc. 2000, 122, 11553–11554.
paper. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk_request/cif .
[28] a) A. S. K. Hashmi, Angew. Chem. Int. Ed. 2010, 49,
5232–5241; Angew. Chem. 2010, 122, 5360–5369; b) T.
Lauterbach, A. M. Asiri, A. S. K. Hashmi, Adv. Organo-
met. Chem. 2014, 62, 261–297.
[29] a) M. Pernpointner, A. S. K. Hashmi, J. Chem. Theory
Comput. 2009, 5, 2717–2725; b) M. Lein, M. Rudolph,
S. K. Hashmi, P. Schwerdtfeger, Organometallics 2010,
29, 2206–2210.
[30] a) F. Gagosz, F. M. Istrate, Org. Lett. 2007, 9, 3181–
3184; b) A. S. K. Hashmi, C. Lothschütz, R. Döpp, M.
Ackermann, J. De B. Becker, M. Rudolph, C. Scholz, F.
Rominger, Adv. Synth. Catal. 2012, 354, 133–147; c) M.
Ackermann, J. Bucher, M. Rappold, K. Graf, F.
Rominger, A. S. K. Hashmi, Chem. Asian J. 2013, 8,
1786–1794; d) A. S. K. Hashmi, K. Graf, M. Acker-
mann, F. Rominger, ChemCatChem 2013, 5, 1200–1204.
[27] CCDC 2039735 (4a-cis) and CCDC 2048023 (6i-cis)
contain supplementary crystallographic data for this
Adv. Synth. Catal. 2021, 363, 1–10
9
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

FULL PAPER
One-pot Synthesis of Isoquinoline-Fused Isoquinolines via
Intramolecular Hydroamination/Aza-Claisen Type Rearrange-
ment Cascade
Adv. Synth. Catal. 2021, 363, 1–10
W.-J. Chiu, J.-Y. Chen, S.-I Liu, I. J. Barve, W.-W. Huang,
C.-M. Sun*