Synthesis of Substituted Pyrrolo[2,1- a ]isoquinolines by Gold-Catalyzed Domino Cyclization of Alkynyl Iminoesters

Article abstract of DOI:10.1055/s-0035-1561423

A novel gold-catalyzed double cyclization leading to a biologically important pyrroloisoquinoline skeleton was established. The reaction sequence involving 6-exo-dig cyclization of alkynyl iminoester and [3+2] cycloaddition of azomethine ylide proceeded smoothly in the presence of 0.5-1.0 mol% (CyJohnPhos)AuCl/AgOTf at 65 or 80 °C. This strategy with (-)-phenylmenthol-derived iminoester enables a generation of chiral azomethine ylide in situ to construct an optically active pyrroloisoquinoline in a highly diastereoselective manner. An alkyne and alkenes with electron-withdrawing group could be utilized as dipolarophiles. Iminoesters having terminal and internal alkynes were applied as reaction substrates to afford the corresponding pyrroloisoquinolines.

Full text of DOI:10.1055/s-0035-1561423

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
A
special topic
K. Sugimoto et al.
Special Topic
Synthesis
Synthesis of Substituted Pyrrolo[2,1-a]isoquinolines by Gold-
Catalyzed Domino Cyclization of Alkynyl Iminoesters
Kenji Sugimotoa
dipolarophile
Yuya Hoshibaa
Kiyoshi Tsugeb
Yuji Matsuya*a
R2
R2
(CyJohnPhos)AuCl
(0.5 or 1.0 mol%)
AgOTf
R2
N
H
R1O2C
R1O2C
R1O2C
N
H
[3+2]
(0.5 or 1.0 mol%)
H
N
R3
DCE (0.3 M)
65 or 80 °C
a Graduate School of Medicine and Pharmaceutical Sciences,
University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
matsuya@pha.u-toyama.ac.jp
b Graduate School of Science and Engineering, University of
Toyama, 3190 Gofuku, Toyama 930-8555, Japan
H
H
pyrroloisoquinolines
azomethine ylide
R1 = Et, (–)-8-phenylmenthyl
2 = H, Ph, 4-MeOC6H4, Me
up to 98%
10 examples
R
Received: 28.01.2016
Accepted: 23.02.2016
N
N
Published online: 13.04.2016
DOI: 10.1055/s-0035-1561423; Art ID: ss-2016-c0072-st
Abstract A novel gold-catalyzed double cyclization leading to a bio-
logically important pyrroloisoquinoline skeleton was established. The
reaction sequence involving 6-exo-dig cyclization of alkynyl iminoester
and [3+2] cycloaddition of azomethine ylide proceeded smoothly in the
presence of 0.5–1.0 mol% (CyJohnPhos)AuCl/AgOTf at 65 or 80 °C. This
strategy with (–)-phenylmenthol-derived iminoester enables a genera-
tion of chiral azomethine ylide in situ to construct an optically active
pyrroloisoquinoline in a highly diastereoselective manner. An alkyne
and alkenes with electron-withdrawing group could be utilized as dipol-
arophiles. Iminoesters having terminal and internal alkynes were ap-
plied as reaction substrates to afford the corresponding pyrroloisoquin-
olines.
1,2,3,5,6,10b-Hexahydro-
pyrrolo[2,1-a]isoquinoline (1)
Pyrrolo[2,1-a]isoquinoline
O
O
N
N
HO
MeO
MeO
OMe
OH
OMe
OMe
Crispine A
OH
Key words domino reaction, cycloaddition, gold, azomethine ylides,
pyrroloisoquinolines
Lamellarin D
Figure 1 Pyrrolo[2,1-a]isoquinolines
Pyrroloisoquinolines are broadly observed in natural
products, which exhibit attractive biological activity as
pharmacological leads (Figure 1).1 For example, unsubsti-
tuted 1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline
(1) exhibits an antagonist activity against α2-adrenorecep-
tor and 5-phenyl congener is reported as a potent antide-
pressant.2,3 Furthermore, dimethoxy-substituted analogue
crispine A, which was prepared by organic synthesis4 prior
to its isolation from Carduus crispus,5 has antitumor activi-
ty. Lamellarin family from marine tunicates also have pyr-
roloisoquinoline nucleus and shows interesting biological
activity.6 Among the diverse derivatives, lamellarin D pos-
sesses several interesting properties, such as cytotoxicity,7a
inhibition of topoisomerase I,7a and targeting of mitochon-
dria.7b
methods are known since 1950s, various characteristic re-
actions have been developed until quite recent years.9 For
example, Bischler–Napieralski reaction of 1-(2-phenyleth-
yl)-2-oxopyrrolidine was applied for the construction of
pyrroloisoquinoline framework by Boekelheide and co-
workers.8a Pearson revealed that intramolecular TfOH-
mediated Schmidt reaction-reduction sequence of azido-
indene gave a mixture of pyrroloisoquinoline and pyrrolo-
quinoline in a ratio of 1:1.8q BF3·OEt2-mediated N-acylimini-
um ion cyclization was conducted with hydroxyl lactam
derived from L-malic acid and L-tartaric acid to produce an
enantiomeric pair of pyrroloisoquinolines.8m Recently, to
make a distinction with such strong Brønsted or Lewis acid
promoted reactions, much attention has focused on the
method under milder reaction conditions such as π-acid
promoted cyclization through an activation of triple bond.
Silver reagent could be utilized for this purpose and was ap-
Because of the importance of such alkaloids, synthetic
chemists have paid attention on the approaches for these
pyrroloisoquinoline skeletons for a long time.8 Though the
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
K. Sugimoto et al.
Special Topic
Synthesis
plied for a construction of the core of crispine A. The Ag-
mediated hydroamination-oxidation reaction of propargyl
tetrahydroisoquinoline afforded pyrroloisoquinolines un-
der a neutral condition at room temperature.8z AgOTf/DTB-
MP system also catalyzed a reaction cascade including iso-
quinoline formation, dipolar cycloaddition, and oxidative
aromatization to furnish pyrroloisoquinolines.8aa
R2
R2
N
R
R1O2C
R1O2C
R
dipolarophile
N
H
R
Au catalyst
H
R
8
9
substituted
pyrroloisoquinolines
In this context, we focused on our recent work in regard
to the gold-catalyzed intermolecular three-component
domino reaction via azomethine ylide formation under
mild conditions (Scheme 1).10 The reaction was triggered by
a selective activation of triple bond on 3 with gold catalyst.
Nucleophilic attack of nitrogen on iminoester 2 onto the ac-
tivated triple bond produced a vinyl gold complex 6, from
which a gold catalyst was regenerated by protodeauration
with the acidic α-proton of the ester 6 and, at this time, re-
active azomethine ylide 7 was produced in situ. Finally, a
pyrrolidine ring was immediately formed by [3+2] cycload-
dition reaction of the ylide 7 with maleimide 4.
[Au]
R
[3+2]
R
R2
H
R1O2C
R2
[Au]
R1O2C
N
H
N
H
protodeauration
H
11
10
azomethine ylide
Scheme 2 Working hypothesis
O
R2O2C
R1O2C
sole product at room temperature within two hours in 55%
yield. The reaction at 50 °C gave a slightly better result (50
min, 61% yield). After several trials at higher reaction tem-
perature, we finally obtained the best result at 65 °C (30
min, 85%). The relative stereochemistries of the cycloadduct
14 were determined after reduction of the enamine moiety
by NaBH3CN. The NOE experiments on the resultant tetra-
hydroisoquinoline suggested the relative stereochemistries
as shown in Scheme 3.
R2O2C
R1O2C
N
R4
R3
R3
Au cat.
O
3
4
N
O
N
Ar
2
N
Ar
R4
O
O
5
R2O2C
[Au]
[3+2]
N
R4
R3
O
4
O
N
Ph
R2O2C
[Au]
R3
R2O2C
H
R1O2C
O
R1O2C
Me
13 (2 equiv)
(Ph3P)AuNTf2
(10 mol%)
EtO2C
EtO2C
N
R3
H
N
protodeauration
N
N
O
7
6
Ar
Ar
H
DCE (0.1 M)
N
azomethine ylide
H
Ph
Scheme 1 Our previous work
O
12
14
Based on this result, we planned a gold-catalyzed, dou-
ble cyclization strategy for pyrroloisoquinoline synthesis as
depicted in Scheme 2. (2-Propargyl)benzylidene iminoester
8 could be transformed into substituted pyrroloisoquino-
line 9 via 6-exo-dig cyclization of 8, protodeauration-medi-
ated azomethine ylide formation, and [3+2] cycloaddition
of 11.
Using a known benzylidene iminoester 12 as a sub-
strate, we started the examination of the working hypothe-
sis with N-phenylmaleimide (13) (2 equiv) and 10 mol%
(Ph3P)AuNTf2 (Gagosz catalyst11) in 0.1 M DCE solution
(Scheme 3). Through the assumed transformation, pyrrolo-
isoquinoline 14, which would be caused by the conjugated
isomerization of the exo-olefin of 14’, was produced as a
EtO2C
NaBH3CN
10% aq HCl
MeOH
N
H
O
quant.
N
Ph
2.9%
Me
O
14' (not observed)
1.2%
H
H
EtO2C
H
H
O
N
1.8%
NOE
N
H
Ph
H
O
4.1%
15
1.2%
Scheme 3 Trial on the domino cyclization
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
K. Sugimoto et al.
Special Topic
Synthesis
Further optimization of reaction conditions was contin-
ued as shown in Table 1. Catalyst loading could be reduced
to 1 mol% and finally 0.5 mol% catalyst proved to be enough
for the reaction in higher 0.3 M solution (Table 1, entries 1–
5). In our cases, Buchwald ligands worked effectively (en-
tries 6–8) and among them, the reaction with (CyJohn-
Phos)AuNTf2 afforded the pyrroloisoquinoline 14 in 92%
yield (entry 7). Counter anion effect was also surveyed (en-
Table 1 Optimization of Reaction Conditions
(2 equiv)
O
N
Me
Ph
EtO2C
EtO2C
H
O
13
N
H
O
N
catalyst
N
solvent
–
tries 9–11). In the presence of Cl– or BF4 , the yields were
Ph
65 °C, time
O
decreased to 70 and 75%, respectively. On the other hand,
OTf– was quite effective to produce the desired 14 in almost
quantitative yield (entry 11). It is noteworthy that the prod-
uct is completely a single stereoisomer. The reaction could
not proceed in the absence of gold catalyst (entry 12). Addi-
tionally, none of the other π-philic metals containing AgOTf
could catalyze this reaction more effectively than gold(I)
complex (entries 13–18). Although the reaction in THF pro-
ceeded in comparable yield with in DCE, other solvents
were not efficient (entries 19–23).
With optimal conditions in hand, we envisaged an en-
antioselective synthesis of pyrroloisoquinolines starting
with the iminoester 16 equipped with (–)-8-phenylmenth-
yl group as a chiral auxiliary (Scheme 4). The domino reac-
tion with sterically demanding phenylmenthyl group un-
eventfully proceeded to give 17 as a sole stereoisomer. For
the determination of the configuration of the product, the
resultant dihydroisoquinoline was transformed into crys-
talline solid 18·HCl by reduction with NaBH3CN in acidic
methanol followed by exposure with HCl in Et2O. The crys-
tal structure of 18·HCl was determined by the single crystal
X-ray analysis.12 Two crystallographically independent
18·H+ cations with the same absolute configuration were
observed in a unit cell together with two chloride anions
and 0.5 EtOAc. In Scheme 4, one of the two ions is disclosed
as an ORTEP drawing, and absolute configuration of the salt
was unambiguously confirmed as an endo-cycloadduct.
Consequently, the relative stereochemistry of the pyrrolo-
isoquinoline 14 in Table 1 was also confirmed as endo-ad-
duct by the similarity of 1H NMR spectrum for 17.
14
12
t-Bu
t-Bu
Cy
P
Cy
Cy
Cy
P
P
i-Pr
i-Pr
i-Pr
JohnPhos
CyJohnPhos
Solvent (M)
XPhos
Time (h) Yield (%)
Entry Catalyst (mol%)
1
2
(Ph3P)AuNTf2 (10)
DCE (0.1)
DCE (0.1)
DCE (0.1)
DCE (0.1)
DCE (0.3)
DCE (0.3)
DCE (0.3)
DCE (0.3)
DCE (0.3)
DCE (0.3)
30 min
85
(Ph3P)AuNTf2 (5)
30 min
88
3
(Ph3P)AuNTf2 (1)
2
86
4
(Ph3P)AuNTf2 (0.5)
(Ph3P)AuNTf2 (0.5)
(JohnPhos)AuNTf2 (0.5)
(CyJohnPhos)AuNTf2 (0.5)
(XPhos)AuNTf2 (0.5)
(CyJohnPhos)AuCl (0.5)
8
62 (68)
88
5
4
6
5
82
7
5
92
8
4
87
9
6
70
10
(CyJohnPhos)AuCl (0.5)
AgBF4 (0.5)
4.5
75
11
(CyJohnPhos)AuCl (0.5)
AgOTf (0.5)
DCE (0.3)
4.5
98
–
12
13
14
15
16
17
18
19
None
DCE (0.3)
DCE (0.3)
DCE (0.3)
DCE (0.3)
DCE (0.3)
DCE (0.3)
DCE (0.3)
19
9
AgOTf (0.5)
<51
AuCl3 (0.5)
13
10
6
79
71
CuOTf·0.5benzene (0.5)
Cu(OTf)2 (0.5)
Pd(OAc)2 (0.5)
PtCl4 (0.5)
The observed diastereoselectivity could be rationalized
as shown in Scheme 5. Chiral induction with 8-phenylmen-
thyl group in cycloaddition of azomethine ylide would rely
on a stabilization of one conformer by π-stacking.13 In our
case, TS A would be stabilized more effectively than TS B by
successful overlapping of isoquinoline ring containing ylide
structure with phenyl group on chiral auxiliary. Since one
of the diastereofaces of the ylide in TS A was blocked by the
phenyl ring on the auxiliary, dipolarophile could approach
from another side and endo-selective cycloaddition pro-
ceeded to give the observed isomer in a highly diastereose-
lective manner.
80
4
<79
41
8
(CyJohnPhos)AuCl (0.5)
AgOTf (0.5)
MeCN (0.3)
toluene (0.3)
EtOAc (0.3)
THF (0.3)
4.5
78
20
21
22
23
(CyJohnPhos)AuCl (0.5)
AgOTf (0.5)
3.5
4
82
80
88
78
(CyJohnPhos)AuCl (0.5)
AgOTf (0.5)
(CyJohnPhos)AuCl (0.5)
AgOTf (0.5)
5
Next, the scope of the dipolarophile was investigated
(Table 2). Whereas olefins having an electron-donating
group, such as ethyl vinyl ether or cyclohexene, did not af-
(CyJohnPhos)AuCl (0.5)
AgOTf (0.5)
1,4-dioxane (0.3)
5.5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
K. Sugimoto et al.
Special Topic
Synthesis
Me
XcO2C
Me
Me
O
O
N
O
N
O
Me
N
H
N
Ph
stabilized by
π-stacking
Ph
O
O
17 (observed)
TS A (more favored)
Me
Me
O
Me
XcO2C
Me
O
N
O
O
N
N
H
N
Ph
Ph
O
O
17' (not observed)
TS B
Scheme 5 Rationale for the observed diastereoselectivity
The relative stereochemistry on 22 was determined by
NOE experiments (Figure 2). Relative configuration of the
methyl group indicated that the reduction occurred from
the less hindered α-face, which was the opposite side of the
bulky SO2Ph group.
Me
CO2Et
3.7%
3.7%
H
H
N
H
H
PhO2S
2.1%
1.1%
Figure 2 Selected NOEs for tetrahydropyrroloisoquinoline 22
This domino reaction was applicable for internal
alkynes (Table 3). Although higher catalyst loading (1.0
mol%) was required than that for terminal alkynes, phenyl-
and p-methoxyphenyl-substituted alkynes afforded the
corresponding isoquinolines in moderate yields (Table 3,
entries 1 and 2). An alkyl substituent could also be intro-
duced on the pyrroloisoquinolines by the domino reaction
(entry 3).
In summary, we have accomplished a novel, double cy-
clization method for biologically important pyrroloisoquin-
oline skeleton based on the Au-catalyzed azomethine ylide
formation strategy.10 This one-pot cyclization system could
furnish highly substituted pyrroloisoquinolines and can be
applied for the preparation of optically active derivatives
under auxiliary-controlled diastereoselective process.
Merged with the findings obtained in our three-component
Scheme 4 Stereoselective synthesis of pyrrolo[2,1-a]isoquinoline us-
ing chiral auxiliary
ford desired cycloadduct, an alkyne and alkenes equipped
with electron-withdrawing group could work as dipolaro-
phile to afford corresponding pyrroloisoquinoline skeletons.
However, since the oxidation of the reaction product was
observed in reaction media (or reaction analyses on TLC),
purification process on silica gel column, and storage in
opened flask, our cycloadducts were found to be prone to
the air oxidation (Table 2, entries 1–3). The cycloadduct
with phenyl vinyl sulfone was seriously unstable to isolate.
However, after reduction with NaBH3CN, the resultant tet-
rahydroisoquinoline 22 could be partially isolated (entry
4).14
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E
K. Sugimoto et al.
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Table 2 Scope of Dipolarophile
dipolarophile
(1.05–2 equiv)
(CyJohnPhos)AuCl
(0.5 mol%)
EtO2C
H
Me
EtO2C
R1
AgOTf
(0.5 mol%)
N
N
DCE
(0.3 M)
65 °C
R2
12
Entry
Dipolarophile (equiv)
Product (time, yield)
Me
Me
EtO2C
EtO2C
MeO2C
MeO2C
MeO2C
N
N
MeO2C
1
CO2Me
MeO2C
(1.05)
(6 h, 19: 24%; 20: 36%)
Me
EtO2C
MeO2C
N
MeO2C
2
MeO2C
(2.0)
MeO2C
20 (4 h, 52%)
Me
EtO2C
N
3
MeO2C
(1.1)
MeO2C
21 (2 h, 48%)
Me
EtO2C
N
4a
PhO2S
H
(1.1)
PhO2S
22 (2 h, 32%)
aPyrroloisoquinoline was isolated after further reduction with NaBH3CN. The yield shown is for two steps.
pyrrolizine formation reaction,10 this novel strategy for pyr-
roloisoquinolines is now employed for synthetic studies on
biologically active polycyclic alkaloids in our laboratory.
spectrometer. Column chromatography was carried out by employing
Cica Silica Gel 60N (spherical, neutral, 40–50 μm or 63–210 μm). Pre-
parative TLC was performed on precoated silica gel 60 F254 plates
(Merck).
All nonaqueous reactions were carried out under an argon atmo-
sphere. Reagents were purchased from commercial suppliers and
used as received. Anhyd solvents were prepared by distillation over
CaH2, or purchased from commercial suppliers. 1H and 13C NMR spec-
tra were measured on a JEOL ECX 400 or a Varian GEMINI 300 instru-
ment, using TMS (0.00 ppm for 1H), CDCl3(77.0 ppm for 13C), benzene
(7.15 ppm for 1H), benzene-d6 (128.0 ppm for 13C) as an internal refer-
ence. Mass spectra were measured on a JEOL JMS-GCmate II or a JEOL
AX 505 mass spectrometer, and the ionization method was electron
impact (EI, 70 eV). IR spectra were recorded on a JASCO FT/IR-460Plus
Iminoesters; General Procedure
A suspension of ethyl glycinate hydrochloride (2.2 equiv) in CH2Cl2
(0.3 M) was washed with NH4OH. To the separated CH2Cl2 phase was
added MgSO4 (1 g/mmol) and the corresponding aldehyde. The reac-
tion mixture was stirred for several days at r.t. until completion of the
reaction (monitored by 1H NMR spectroscopy). After completion of
the reaction, the solution was washed with sat. aq NH4Cl. The aque-
ous phase was extracted with CH2Cl2 and the combined organic
phases were dried (MgSO4), filtered, and concentrated in vacuo. The
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
K. Sugimoto et al.
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Table 3 Reactions with Internal Alkynes
(2 equiv)
O
N
Ph
O
13
(CyJohnPhos)AuCl
(1.0 mol%)
AgOTf
R
R
EtO2C
EtO2C
(1.0 mol%)
N
H
O
N
DCE
(0.3 M)
80 °C
N
H
Ph
O
Entry
Substrate
Product
Time (h)
Yield (%)
Ph
Ph
EtO2C
EtO2C
N
N
O
1
3.5
69
H
N
H
Ph
O
23
26
MeO
OMe
EtO2C
EtO2C
2
N
H
3
48
O
N
N
H
Ph
O
27
24
Me
N
Me
EtO2C
EtO2C
N
H
O
3
4
58
N
H
Ph
O
28
25
resultant crude iminoester, the purity of which was checked by 1H
NMR spectroscopy, was conducted to the gold-catalyzed reaction
without further purification because of their instability.
Gold-Catalyzed Reaction Leading to Pyrroloisoquinolines; Pyr-
roloisoquinoline 14; Typical Procedure (Table 1, entry 11)
To a stirred solution of the iminoester 12 (37.4 mg, 0.163 mmol) and
N-phenylmaleimide (56.5 mg, 0.326 mmol) in DCE (0.4 mL) was add-
ed the gold catalyst solution in DCE [0.0058 M, 0.14 mL, prepared
from (CyJohnPhos)AuCl (3.4 mg, 0.0058 mmol) and AgOTf (1.5 mg,
0.0058 mmol) in DCE (1 mL)]. After stirring the mixture for 5 h at
65 °C, the reaction was quenched with H2O. The aqueous phase was
extracted with CH2Cl2, and the combined organic phases were
washed with brine, dried (Na2SO4), filtered, and concentrated in vac-
uo. The residue was purified by flash column chromatography on sili-
ca gel (eluent: gradient, n-hexane/EtOAc = 70:30 to 65:35) to give the
pyrroloisoquinoline 14 (64.4 mg, 98%) as a yellow solid; mp 107–114
°C; Rf = 0.48 (n-hexane/EtOAc, 60:40).
Ethyl 2-[2-(Prop-2-ynyl)benzylideneamino]acetate (12)
According to the general procedure for the preparation of iminoester,
treatment of 2-(prop-2′-ynyl)benzaldehyde15 (353 mg, 2.45 mmol)
with ethyl glycinate hydrochloride (752 mg, 5.39 mmol) for 9 days
gave the crude iminoester 12 (561 mg, quant) as a yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.59 (s, 1 H), 7.83 (dd, J = 7.6, 1.4 Hz, 1
H), 7.56 (d, J = 7.3 Hz, 1 H), 7.42 (ddd, J = 7.6, 7.6, 1.4 Hz, 1 H), 7.33 (dd,
J = 7.3, 7.3 Hz, 1 H), 4.42 (d, J = 1.4 Hz, 2 H), 4.24 (q, J = 7.3 Hz, 2 H),
3.92 (d, J = 2.8 Hz, 2 H), 2.22 (t, J = 2.8 Hz, 1 H), 1.31 (t, J = 7. 3 Hz, 3 H).
IR (CHCl3): 3019, 1714, 1499, 1383, 1215, 909, 764, 669 cm–1
.
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G
K. Sugimoto et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.41–7.30 (m, 4 H), 7.24 (d, J = 7.3 Hz, 1
H), 7.17 (dt, J = 7.3, 1.4 Hz, 1 H), 7.10 (dt, J = 7.3, 1.4 Hz, 1 H), 7.05–
7.02 (m, 2 H), 6.90 (dd, J = 7.8, 0.9 Hz, 1 H), 5.26 (s, 1 H), 5.22 (d, J = 7.8
Hz, 1 H), 5.17 (s, 1 H), 4.36–4.22 (m, 2 H), 3.96 (d, J = 7.8 Hz, 1 H), 3.62
(dd, J = 7.8, 7.8 Hz, 1 H), 1.94 (s, 3 H), 1.35 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.3, 173.5, 169.6, 139.6, 132.26,
132.25, 131.8, 128.6, 128.5, 127.1, 125.9, 125.1, 124.9, 123.9, 100.6,
64.9, 63.9, 62.3, 50.9, 47.0, 19.3, 14.1.
IR (CHCl3): 3058, 2958, 2925, 1776, 1634, 1599, 1500, 1384, 1267,
1222, 1198, 1179, 828, 733, 701 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.25 (m, 7 H), 7.20–7.06 (m, 4 H),
7.00 (d, J = 7.3 Hz, 2 H), 6.86 (d, J = 7.3 Hz, 1 H), 5.21 (s, 1 H), 5.17 (d,
J = 6.9 Hz, 1 H), 4.88 (dt, J = 10.8, 4.4 Hz, 1 H), 4.67 (s, 1 H), 3.64–3.43
(m, 2 H), 2.09 (t, J = 10.1 Hz, 1 H), 1.85 (s, 3 H), 1.77–1.64 (m, 1 H),
1.34 (s, 3 H), 1.24 (s, 3 H), 1.23–1.03 (m, 3 H), 0.91–0.87 (m, 6 H).
13C NMR (100 MHz, CDCl3): δ = 175.9, 173.5, 168.4, 150.6, 139.8,
132.3, 131.9, 129.1, 128.5, 128.1, 127.9, 127.1, 125.9, 125.5, 125.4,
125.3, 125.2, 125.0, 123.8, 100.6, 64.8, 63.9, 51.0, 50.2, 47.2, 41.8,
39.8, 34.4, 31.4, 27.6, 26.7, 26.1, 21.8, 19.7.
MS (EI) m/z = 402 (M+).
HRMS (EI): m/z calcd for C24H22N2O4: 402.1580; found: 402.1612.
MS (EI): m/z = 588 (M+).
Pyrroloisoquinoline 15
HRMS (EI): m/z calcd for C38H40N2O4: 588.2988; found: 588.2993.
To a solution of 14 (65.7 mg, 0.16 mmol) in MeOH (1.9 mL) were add-
ed NaBH3CN (21.0 mg, 0.33 mmol) and 10% aq HCl (0.5 mL) at 0 °C.
After stirring for 75 min at 0 °C, the reaction was quenched with sat.
aq NaHCO3 and the aqueous phase was extracted with CH2Cl2. The
combined organic phases were washed with brine, dried over Na2SO4,
filtered, and concentrated in vacuo. The residue was purified by flash
column chromatography (n-hexane/AcOEt, 70:30) to afford 15 quan-
titatively (65.2 mg) as a pale yellow oil.
Pyrroloisoquinoline 18
To a solution of crude 17 (from 58.1 mg of 16, 0.078 mmol) in MeOH
(0.9 mL) were added NaBH3CN (19.6 mg, 0.31 mmol) and 10% aq HCl
(0.5 mL) at 0 °C. After stirring for 75 min at 0 °C, the reaction was
quenched with sat. aq NaHCO3 and the aqueous phase was extracted
with CH2Cl2. The combined organic phases were washed with brine,
dried (Na2SO4), filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography on silica gel (eluent: n-hex-
ane/EtOAc, 85:15) to give 18 (37.6 mg, 64% for 2 steps) as a white
Rf = 0.56 (n-hexane/EtOAc, 60:40).
IR (CHCl3): 3027, 3012, 2970, 1779, 1714, 1499, 1384, 1231, 1199,
1023, 851, 804, 765, 691 cm–1
.
23
amorphous solid; Rf = 0.28 (n-hexane/EtOAc, 85:15); [α]D –113 (c
1H NMR (400 MHz, CDCl3): δ = 7.43 (d, J = 7.8 Hz, 1 H), 7.39–7.29 (m, 3
H), 7.10 (d, J = 8.2 Hz, 2 H), 7.05 (d, J = 7.3 Hz, 1 H), 4.71 (d, J = 7.3 Hz,
1 H), 4.54 (s, 1 H), 4.30–4.21 (m, 2 H), 3.84 (dd, J = 7.3, 7.3 Hz, 1 H),
3.77 (d, J = 7.3 Hz, 1 H), 3.27 (m, 1 H), 2.72 (dd, J = 16.0, 3.2 Hz, 1 H),
2.61 (dd, J = 16.0, 10.8 Hz, 1 H), 1.33 (t, J = 7.1 Hz, 3 H), 1.31 (d, J = 6.0
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.9, 174.4, 170.4, 134.6, 131.8,
129.0, 128.5, 128.3, 128.0, 126.8, 126.3, 125.2, 63.1, 62.8, 61.2, 49.5,
47.7, 46.4, 39.2, 20.2, 14.4.
1.12, CHCl3).
IR (CH2Cl2): 3054, 2966, 2926, 2304, 1780, 1716, 1498, 1386, 1266,
1201, 737, 703 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.33 (m, 7 H), 7.31–7.27 (m, 1 H),
7.19–7.11 (m, 3 H), 7.06–7.02 (m, 3 H), 4.95 (dt, J = 10.7, 4.3 Hz, 1 H),
4.55 (d, J = 7.8 Hz, 1 H), 4.09 (s, 1 H), 3.53 (t, J = 7.8 Hz, 1 H), 3.32–3.27
(m, 1 H), 2.80 (d, J = 7.8 Hz, 1 H), 2.68 (dd, J = 15.6, 2.7 Hz, 1 H), 2.55
(dd, J = 15.6, 10.5 Hz, 1 H), 2.17 (dt, J =11.3, 3.2 Hz, 1 H), 1.87 (d, J =
11.9 Hz, 1 H), 1.75 (dd, J = 13.6, 3.5 Hz, 1 H), 1.67 (d, J = 12.8 Hz, 1 H),
1.37 (s, 3 H), 1.27 (d, J = 6.0 Hz, 3 H), 1.23 (s, 3 H), 1.19–0.99 (m, 3 H),
0.96–0.85 (m, 1 H), 0.88 (d, J = 6.4 Hz, 3 H).
MS (EI): m/z = 398 (M+).
HRMS (EI): m/z calcd for C24H24O4N2: 404.1736; found: 404.1744.
13C NMR (100 MHz, CDCl3): δ = 176.4, 174.3, 169.2, 151.5, 134.9,
131.9, 131.8, 128.9, 128.33, 128.31, 128.1, 126.7, 125.5, 125.2, 125.0,
62.9, 62.7, 49.8, 49.2, 47.2, 46.6, 42.3, 39.7, 39.1, 34.4, 31.4, 28.5, 26.6.
(1R,2S,5R)-5-Methyl-2-(2-phenylpropan-2-yl)cyclohexyl 2-[(E)-2-
(Prop-2-ynyl)benzylideneamino]acetate (16)
According to the general procedure for the preparation of iminoester,
treatment of 2-(prop-2′-ynyl)benzaldehyde15 (80.0 mg, 0.55 mmol)
with (–)-8-phenylmenthan-3-yl glycinate16 (239 mg, 0.83 mmol) for a
day gave the crude iminoester 16 (238 mg, quant) as an orange oil.
1H NMR (400 MHz, C6D6): δ = 8.09 (s, 1 H), 7.79 (dd, J = 7.6, 1.6 Hz, 1
H), 7.50 (d, J = 7.8 Hz, 1 H), 7.25–7.19 (m, 6 H), 7.08–6.98 (m, 4 H),
5.04 (dt, J = 10.7, 4.4 Hz, 1 H), 3.81 (d, J = 2.3 Hz, 2 H), 3.79 (t, J = 1.4
Hz, 2 H), 1.94–1.92 (m, 4 H), 1.51 (dt, J = 13.6, 1.5 Hz, 2 H), 1.34 (s, 3
H), 1.13 (s, 3 H), 0.95–0.83 (m, 4 H).
MS (EI): m/z = 590 (M+).
Pyrroloisoquinoline 19 and 20 (Table 2, entry 1)
According to the general procedure for the gold-catalyzed reaction,
treatment of the iminoester 12 (25.4 mg, 0.111 mmol) with dimethyl
acetylenedicarboxylate (17 mg, 0.117 mmol, 1.05 equiv) in the pres-
ence of the gold catalyst solution in DCE [0.0058 M, 0.096 mL, pre-
pared from (CyJohnPhos)AuCl (3.4 mg, 0.0058 mmol) and AgOTf (1.5
mg, 0.0058 mmol) in DCE (1 mL)] for 6 h gave the pyrroloisoquinoline
19 (9.9 mg, 24%) and the pyrroloisoquinoline 20 (14.7 mg, 36%) as yel-
low solids.
Pyrroloisoquinoline 17
According to the general procedure for the gold-catalyzed reaction,
treatment of the iminoester 16 (51.3 mg, 0.123 mmol) with N-
phenylmaleimide (42.6 mg, 0.246 mmol, 2 equiv) in the presence of
the gold catalyst solution in DCE [0.0058 M, 0.11 mL, prepared from
(CyJohnPhos)AuCl (3.4 mg, 0.0058 mmol) and AgOTf (1.5 mg, 0.0058
mmol) in DCE (1 mL)] for 4 h gave the pyrroloisoquinoline 17 (26.2
mg, <60%) as a mixture with a slight amount of unidentified byprod-
uct as an orange oil; Rf = 0.31 (n-hexane/EtOAc, 80:20); [α]D23 –123 (c
1.31, CHCl3).
Pyrroloisoquinoline 19
Mp 79–86 °C; Rf = 0.53 (n-hexane/EtOAc, 60:40).
IR (CHCl3): 3027, 2952, 1722, 1468, 1455, 1252, 1228, 1197, 1162,
1126, 773 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.40–8.38 (m, 1 H), 7.58–7.55 (m, 1 H),
7.52–7.47 (m, 2 H), 6.84 (s, 1 H), 4.45 (q, J = 7.2 Hz, 2 H), 4.01 (s, 3 H),
3.90 (s, 3 H), 2.61 (s, 3 H), 1.43 (t, J = 7.2 Hz, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
K. Sugimoto et al.
Special Topic
Synthesis
13C NMR (100 MHz, CDCl3): δ = 167.0, 164.1, 163.0, 132.7, 130.6,
128.6, 128.1, 127.6, 126.3, 124.0, 123.6, 121.0, 120.1, 115.8, 109.3,
62.5, 52.7, 52.3, 20.2, 13.9.
pyrroloisoquinoline as an orange oil. Then to a solution of the crude
mixture in MeOH (1.7 mL) was added NaBH3CN (37 mg, 0.59 mmol)
and 10% aq HCl (0.9 mL) at 0 °C. After stirring for 60 min at 0 °C, the
reaction was quenched with sat. aq NaHCO3 and the aqueous phase
was extracted with CH2Cl2. The combined organic phases were
washed with brine, dried (Na2SO4), filtered, and concentrated in vac-
uo. The residue was purified by flash column chromatography (elu-
ent: gradient, n-hexane/EtOAc = 80:20 to 60:40) to afford the pyrrolo-
isoquinoline 22 (19.0 mg, 32% over 2 steps) as a yellow oil; Rf = 0.30
(n-hexane/EtOAc, 70:30).
MS (EI): m/z = 369 (M+).
HRMS (EI): m/z calcd for C20H19NO6: 369.1212; found: 369.1206.
Pyrroloisoquinoline 20
Mp 50–56 °C; Rf = 0.38 (n-hexane/EtOAc, 60:40).
IR (CHCl3): 3031, 3007, 2952, 1742, 1671, 1521, 1226, 1200, 1098,
794, 732 cm–1
.
IR (CHCl3): 3032, 3004, 1743, 1448, 1382, 1306, 1225, 1203, 1148,
1087, 790, 732 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.76 (d, J = 8.0 Hz, 1 H), 7.48 (dd, J = 8.0,
8.0 Hz, 1 H), 7.34 (dd, J = 8.0, 8.0 Hz, 1 H), 7.26 (d, J = 8.0 Hz, 1 H), 6.13
(s, 1 H), 5.03 (d, J = 2.3 Hz, 1 H), 4.30–4.23 (m, 2 H), 4.21 (d, J = 2.3 Hz,
1 H), 3.75 (s, 3 H), 3.71 (s, 3 H), 2.17 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.2, 169.6, 153.6, 137.3, 136.7,
132.0, 131.1, 125.5, 125.1, 122.5, 107.6, 90.3, 63.8, 62.5, 52.7, 50.7,
50.6, 19.0, 14.1.
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 6.8 Hz, 2 H), 7.67 (t, J = 6.8
Hz, 1 H), 7.58 (dd, J = 6.8, 6.8 Hz, 2 H), 7.36 (d, J = 7.6 Hz, 1 H), 7.22
(dd, J = 7.6 Hz, 1 H), 7.15 (dd, J = 7.6 Hz, 1 H), 7.02 (d, J = 7.6 Hz, 1 H),
5.04 (s, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.78 (ddd, J = 9.2, 8.1, 3.3 Hz, 1 H),
3.53 (dd, J = 9.6, 6.6 Hz, 1 H), 3.35 (quint, J = 6.4 Hz, 1 H), 3.11 (dd, J =
16.8, 5.6 Hz, 1 H), 2.48 (ddd, J = 13.0, 9.7, 8.0 Hz, 1 H), 2.29 (d, J = 16.8
Hz, 1 H), 2.19 (ddd, J = 13.0, 9.1, 6.7 Hz, 1 H), 1.25 (t, J = 7.1 Hz, 3 H),
1.10 (d, J = 6.9 Hz, 3 H).
MS (EI): m/z = 371 (M+).
HRMS (EI): m/z calcd for C20H21NO6: 371.1369; found: 371.1375.
13C NMR (100 MHz, CDCl3): δ = 171.3, 137.6, 135.3, 133.9, 132.5,
129.7, 129.2, 129.1, 127.0, 126.9, 126.7, 69.6, 61.1, 56.5, 47.2, 30.9,
26.8, 19.0, 14.2.
Pyrroloisoquinoline 20 (Table 2, entry 2)
According to the general procedure for the gold-catalyzed reaction,
treatment of the iminoester 12 (29.4 mg, 0.128 mmol) with dimethyl
maleate (36.9 mg, 0.256 mmol, 2 equiv) in the presence of the gold
catalyst solution in DCE [0.0058 M, 0.11 mL, prepared from (CyJohn-
Phos)AuCl (3.4 mg, 0.0058 mmol) and AgOTf (1.5 mg, 0.0058 mmol)
in DCE (1 mL)] for 4 h gave the pyrroloisoquinoline 20 (24.6 mg, 52%).
MS (FAB): m/z = 400 (M + H+).
HRMS (FAB): m/z calcd for C22H26NO4S: 400.1583; found: 400.1585.
Ethyl 2-[2-(3-Phenylprop-2-ynyl)benzylideneamino]acetate (23)
According to the general procedure for the preparation of iminoester,
treatment of 2-(3-phenylprop-2-ynyl)benzaldehyde15 (71.0 mg, 0.32
mmol) with ethyl glycinate hydrochloride (98.1 mg, 0.71 mmol) for 3
days gave the crude iminoester 23 (97.0 mg, 99%) as a yellow oil.
1H NMR (400 MHz, C6D6): δ = 8.19 (s, 1 H), 7.83 (d, J = 7.3 Hz, 1 H),
7.57 (d, J = 7.8 Hz, 1 H), 7.44–7.42 (m, 2 H), 7.10–6.96 (m, 5 H), 4.12 (s,
2 H), 4.02 (s, 2 H), 3.95 (q, J = 7.0 Hz, 2 H), 0.93 (t, J = 7.0 Hz, 3 H).
Pyrroloisoquinoline 21 (Table 2, entry 3)
According to the general procedure for the gold-catalyzed reaction,
treatment of the iminoester 12 (35.1 mg, 0.153 mmol) with methyl
acrylate (15 mg, 0.168 mmol, 1.1 equiv) in the presence of the gold
catalyst solution in DCE [0.0058 M, 0.013 mL, prepared from (CyJohn-
Phos)AuCl (3.4 mg, 0.0058 mmol) and AgOTf (1.5 mg, 0.0058 mmol)
in DCE (1 mL)] for 2 h gave the pyrroloisoquinoline 21 (23.0 mg, 48%)
as an orange oil; Rf = 0.54 (n-hexane/EtOAc, 70:30).
2-{2-[3-(4-Methoxyphenyl)prop-2-ynyl]phenyl}-1,3-dioxolane
To a solution of 2-[2-(prop-2-ynyl)phenyl]-1,3-dioxolane15 (173 mg,
0.92 mmol) in anhyd DMF (1.3 mL) were added Et3N (0.51 mL, 3.68
mmol), p-iodoanisole (258 mg, 1.10 mmol), PdCl2(PPh3)2 (19 mg, 28
μmol), CuI (11 mg, 55 μmol) at r.t. After stirring for 2 min at 50 °C, the
reaction was quenched with sat. aq NH4Cl and the aqueous phase was
extracted with Et2O. The combined organic phases were washed with
brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by flash column chromatography (n-hexane/EtOAc =
90:10) to afford the title arylacetylene (181 mg, 67%) as a yellow oil;
Rf = 0.30 (n-hexane/EtOAc, 90:10).
IR (CHCl3): 3010, 2948, 1741, 1663, 1639, 1528, 1337, 1273, 1200,
1099, 1023 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.72 (d, J = 8.0 Hz, 1 H), 7.45–7.41 (m, 1
H), 7.31–7.26 (m, 1 H), 7.20 (d, J = 8.0 Hz, 1 H), 6.00 (s, 1 H), 4.85 (dd,
J = 12.8, 3.7 Hz, 1 H), 4.28–4.18 (m, 2 H), 3.71 (s, 3 H), 3.43 (dd, J =
15.6, 12.8 Hz, 1 H), 3.14 (dd, J = 15.6, 3.7 Hz, 1 H), 2.12 (s, 3 H), 1.28 (t,
J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.4, 152.8, 137.8, 136.6, 131.6,
130.8, 128.3, 125.2, 124.8, 123.0, 106.4, 91.1, 61.9, 60.5, 50.6, 34.4,
19.0, 14.1.
IR (CHCl3): 3039, 3006, 2889, 2838, 2050, 1606, 1509, 1247, 1173,
1109, 1074, 1032, 833, 802, 759 cm–1
.
MS (EI): m/z = 313 (M+).
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 7.3
Hz, 1 H), 7.39–7.34 (m, 3 H), 7.29–7.23 (m, 1 H), 6.81 (d, J = 7.8 Hz, 2
H), 6.05 (s, 1 H), 4.14–4.00 (m, 4 H), 3.98 (s, 2 H), 3.77 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.1, 135.5, 134.7, 132.9, 129.3,
129.0, 126.6, 126.2, 115.8, 113.8, 101.9, 85.5, 82.8, 65.1, 55.7, 55.2,
22.6.
HRMS (EI): m/z calcd for C18H19NO4: 313.1314; found: 313.1309.
Tetrahydropyrroloisoquinoline 22 (Table 2, entry 4)
According to the general procedure for the gold-catalyzed reaction,
treatment of the iminoester 12 (33.6 mg, 0.147 mmol) with phenyl
vinyl sulfone (27.2 mg, 0.162 mmol, 1.1 equiv) in the presence of the
gold catalyst solution in DCE [0.0058 M, 0.13 mL, prepared from (Cy-
JohnPhos)AuCl (3.4 mg, 0.0058 mmol) and AgOTf (1.5 mg, 0.0058
mmol) in DCE (1 mL)] for 2.5 h at 65 °C gave the crude intermediate
MS (EI): m/z = 294 (M+).
HRMS (EI): m/z calcd for C19H18O3: 294.1256; found: 294.1273.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

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K. Sugimoto et al.
Special Topic
Synthesis
2-[3-(4-Methoxyphenyl)prop-2-ynyl]benzaldehyde
13C NMR (100 MHz, CDCl3): δ = 176.1, 173.5, 169.5, 142.0, 136.1,
131.8, 129.1, 128.9, 128.56, 128.55, 128.5, 127.2, 126.7, 125.9, 125.4,
125.1, 124.3, 101.8, 64.1, 62.1, 50.6, 46.9, 39.1, 14.0.
To a stirred solution of the above dioxolane (179 mg, 0.61 mmol) in a
mixture of acetone and H2O (6.1 mL, 1:1 v/v) was added 10 mol% of p-
TsOH·H2O (11.5 mg, 0.061 mmol) at r.t. After stirring for 20 h, the
mixture was quenched with sat. aq NaHCO3 and extracted with Et2O.
The combined organic phases were washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. The residue was purified
by flash column chromatography on silica gel (eluent: n-hexane/
EtOAc = 90:10) to afford the title aldehyde (109 mg, 72%) as a pale yel-
low oil; Rf = 0.47 (n-hexane/EtOAc, 90:10).
MS (EI): m/z = 478 (M+).
HRMS (EI): m/z calcd for C30H26O4N2: 478.1893; found: 478.1888.
Pyrroloisoquinoline 27 (Table 3, entry 2)
According to the general procedure for the gold-catalyzed reaction,
treatment of the iminoester 24 (51.0 mg, 0.144 mmol) with N-
phenylmaleimide (50 mg, 0.288 mmol, 2 equiv) in the presence of the
gold catalyst solution in DCE [0.0058 M, 0.25 mL, prepared from (Cy-
JohnPhos)AuCl (3.4 mg, 0.0058 mmol) and AgOTf (1.5 mg, 0.0058
mmol) in DCE (1 mL)] at 80 °C for 3 h gave the pyrroloisoquinoline 27
(35.3 mg, 48%) as a yellow solid; mp 112–118 °C; Rf = 0.40 (n-hex-
ane/EtOAc, 70:30).
IR (CHCl3): 3072, 3007, 2838, 2743, 2290, 2047, 1695, 1606, 1509,
1290, 1247, 834, 738 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 10.28 (s, 1 H), 7.83 (d, J = 7.4 Hz, 1 H),
7.79 (d, J = 7.7 Hz, 1 H), 7.69–7.58 (m, 1 H), 7.46–7.41 (m, 1 H), 7.38
(d, J = 8.5 Hz, 2 H), 6.83 (d, J = 8.5 Hz, 2 H), 4.28 (s, 2 H), 3.80 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 192.5, 159.1, 138.9, 133.9, 133.2, 133.1,
132.9, 129.8, 127.1, 115.4, 113.8, 85.1, 83.7, 55.6, 23.1.
IR (CH2Cl2): 3063, 2981, 2936, 2837, 2360, 1715, 1512, 1383, 1248,
1033, 761, 731 cm–1
.
MS (EI): m/z = 250 (M+).
1H NMR (400 MHz, CDCl3): δ = 7.42–7.32 (m, 3 H), 7.26–7.23 (m, 1 H),
7.18 (dd, J = 7.6, 7.6 Hz, 1 H), 7.16–7.06 (m, 3 H), 7.05 (d, J = 7.3 Hz, 2
H), 6.92 (d, J = 8.2 Hz, 1 H), 6.77 (d, J = 8.7 Hz, 2 H), 5.25 (d, J = 7.8 Hz,
1 H), 5.23 (s, 1 H), 5.14 (s, 1 H), 4.18–4.07 (m, 2 H), 3.90 (d, J = 7.8 Hz,
1 H), 3.75 (s, 3 H), 3.63 (dd, J = 7.8, 7.8 Hz, 1 H), 3.48 (s, 2 H), 1.19 (t, J =
7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.1, 173.5, 169.6, 158.4, 142.4,
132.2, 131.8, 129.9, 129.1, 128.7, 128.5, 127.1, 125.9, 125.3, 125.1,
124.3, 113.9, 101.5, 64.3, 64.1, 62.1, 55.2, 50.6, 46.9, 38.2, 14.2, 14.0.
HRMS (EI): m/z calcd for C17H14O2: 250.0994; found: 250.0965.
Ethyl 2-{2-[3-(4-Methoxyphenyl)prop-2-ynyl]benzylideneamino}-
acetate (24)
According to the general procedure for the preparation of iminoester,
treatment of the above aldehyde (107 mg, 0.43 mmol) with ethyl gly-
cinate hydrochloride (131 mg, 0.94 mmol) for 7 days gave the crude
iminoester 24 (144 mg, quant) as a yellow oil.
1H NMR (300 MHz, C6D6): δ = 8.24 (s, 1 H), 7.87 (d, J = 7.7 Hz, 1 H),
7.59 (d, J = 7.7 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 2 H), 7.18–7.01 (m, 2 H),
6.58 (d, J = 8.8 Hz, 2 H), 4.13 (s, 2 H), 4.04 (s, 2 H), 3.95 (q, J = 7.1 Hz, 2
H), 3.16 (s, 3 H), 0.93 (t, J = 7.1 Hz, 3 H).
MS (EI): m/z = 508 (M+).
HRMS (EI): m/z calcd for C31H28O5N2: 508.1998; found: 508.1968.
Pyrroloisoquinoline 28 (Table 3, entry 3)
According to the general procedure for the gold-catalyzed reaction,
treatment of the iminoester 25 (32.2 mg, 0.132 mmol) with N-
phenylmaleimide (45.7 mg, 0.264 mmol, 2 equiv) in the presence of
the gold catalyst solution in DCE [0.0058 M, 0.23 mL, prepared from
(CyJohnPhos)AuCl (3.4 mg, 0.0058 mmol) and AgOTf (1.5 mg, 0.0058
mmol) in DCE (1 mL)] at 80 °C for 4 h gave the pyrroloisoquinoline 28
(32.0 mg, 58%) as a yellow solid; mp 90–94 °C; Rf = 0.38 (n-hex-
ane/EtOAc, 70:30).
Ethyl 2-[2-(But-2-ynyl)benzylideneamino]acetate (25)
According to the general procedure for the preparation of iminoester,
treatment of 2-(but-2-ynyl)benzaldehyde15 (78.0 mg, 0.49 mmol)
with ethyl glycinate hydrochloride (151 mg, 1.08 mmol) for 5 days
gave the crude iminoester 25 (95.0 mg, 79%) as a yellow oil.
1H NMR (300 MHz, C6D6): δ = 8.23 (s, 1 H), 7.93 (d, J = 7.7 Hz, 1 H),
7.51 (d, J = 7.4 Hz, 1 H), 7.10–7.04 (m, 1 H), 7.04–6.99 (m, 1 H), 4.12 (s,
2 H), 3.95 (q, J = 7.1 Hz, 2 H), 3.76 (d, J = 2.5 Hz, 2 H), 1.52 (t, J = 2.5 Hz,
3 H), 0.93 (t, J = 7.1 Hz, 3 H).
IR (CHCl3): 3020, 2980, 2938, 1715, 1499, 1385, 1216, 765, 749, 668
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.30 (m, 3 H), 7.23–7.09 (m, 3 H),
7.03 (d, J = 5.5 Hz, 2 H), 6.93 (d, J = 7.1 Hz, 1 H), 5.29 (s, 1 H), 5.19 (d,
J = 7.8 Hz, 1 H), 5.18 (s, 1 H), 4.36–4.21 (m, 2 H), 3.96 (d, J = 7.8 Hz, 1
H), 3.60 (dd, J = 7.8, 7.8 Hz, 1 H), 2.33–2.13 (m, 2 H), 1.34 (t, J = 7.1 Hz,
3 H), 1.17 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 176.3, 173.5, 169.7, 145.1, 132.3,
131.8, 129.1, 128.6, 128.5, 127.0, 125.2, 125.0, 124.1, 98.9, 64.7, 64.1,
62.4, 51.1, 47.0, 25.7, 14.1, 12.1.
Pyrroloisoquinoline 26 (Table 3, entry 1)
According to the general procedure for the gold-catalyzed reaction,
treatment of iminoester 23 (32.4 mg, 0.106 mmol) with N-phenylma-
leimide (36.7 mg, 0.212 mmol, 2 equiv) in the presence of the gold
catalyst solution in DCE [0.0058 M, 0.18 mL, prepared from (CyJohn-
Phos)AuCl (3.4 mg, 0.0058 mmol) and AgOTf (1.5 mg, 0.0058 mmol)
in DCE (1 mL)] at 80 °C for 3.5 h gave the pyrroloisoquinoline 26 (34.8
mg, 69%) as a yellow solid; mp 99–104 °C; Rf = 0.23 (n-hexane/EtOAc,
70:30).
MS (EI): m/z = 416 (M+).
HRMS (EI): m/z calcd for C25H24O4N2: 416.1736; found: 416.1702.
IR (CHCl3): 3028, 3012, 2359, 1714, 1632, 1601, 1498, 1384, 1227,
1198, 1176, 1029, 753 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.33 (m, 4 H), 7.29–7.11 (m, 8 H),
7.05 (d, J = 7.3 Hz, 1 H), 6.93, (d, J = 6.9 Hz, 1 H), 5.27–5.25 (m, 2 H),
5.13 (s, 1 H), 4.15–4.04 (m, 2 H), 3.90 (d, J = 7.8 Hz, 1 H), 3.63 (t, J = 7.8
Hz, 1 H), 3.55 (s, 2 H), 1.16 (t, J = 7.1 Hz, 3 H).
Acknowledgment
This work was supported in part by the KAKENHI, a Grant-in-Aid for
Young Scientist (B: 24790007) and The Uehara Memorial Foundation.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

J
K. Sugimoto et al.
Special Topic
Synthesis
Supporting Information
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J