Carbopalladation/Suzuki Coupling Cascade for the Generation of Quaternary Centers: Access to Pyrrolo[1,2-b]isoquinolines

Article abstract of DOI:10.1021/acs.joc.9b01357

A convergent route to pyrrolo[1,2-b]isoquinolines with a quaternary center at C-10 has been developed, which implies a sequential Pd(0)-catalyzed carbopalladation followed by cross-coupling reaction with boronic acids. The adequate catalytic system and experimental conditions, with and without the use of phosphane ligands, have been selected to control the chemoselectivity of the process, allowing a 6-exo-carbopalladation to generate a quaternary center and avoiding a direct Suzuki coupling. A variety of electron-rich and electron-deficient arylboronic acids can be used providing an efficient route to substituted pyrrolo[1,2-b]isoquinolines in moderate to good yields (up to 94percent, 22 examples).

Full text of DOI:10.1021/acs.joc.9b01357

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Article
Carbopalladation/Suzuki Coupling Cascade for the Generation
of Quaternary Centers. Access to Pyrrolo[1,2-b]isoquinolines
Iratxe Barbolla, Nuria Sotomayor, and Esther Lete
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01357 • Publication Date (Web): 29 Jul 2019
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Page 1 of 44
The Journal of Organic Chemistry
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Carbopalladation/Suzuki Coupling Cascade for the
Generation of Quaternary Centers. Access to
Pyrrolo[1,2-b]isoquinolines
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Iratxe Barbolla, Nuria Sotomayor* and Esther Lete*
Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco /
Euskal Herriko Unibertsitatea UPV/EHU. Apdo. 644. 48080 Bilbao (Spain)
nuria.sotomayor@ehu.es; esther.lete@ehu.es
R3
R2
I
Pd(0)
N
N
R3-B(OH)2
R1
R1
R2
22 examples
up to 94%
6-exo carbopalladation / Suzuki coupling
wide scope
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Abstract. A convergent route to pyrrolo[1,2-b]isoquinolines with a quaternary center at C-10 has been
developed, that implies a sequential Pd(0)-catalyzed carbopalladation followed by cross-coupling
reaction with boronic acids. The adequate catalytic system and experimental conditions, with and
without the use of phosphane ligands, have been selected to control the chemoselectivity of the process,
allowing a 6-exo-carbopalladation to generate a quaternary center, and avoiding a direct Suzuki
coupling. A variety of electron rich and electron deficient arylboronic acids can be used providing an
efficient route to substituted pyrrolo[1,2-b]isoquinolines in moderate to good yields (up to 94%, 22
examples).
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Page 2 of 44
Introduction
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Cascade reactions play an important role in modern synthetic organic chemistry.1 In particular,
palladium-catalyzed carbopalladation initiated domino reactions (cascade cyclizations) are powerful
carbon-carbon bond-forming processes for the construction of functionalized carbocycles and
heterocycles with quaternary stereocenters.2 The ideal starting point is an intramolecular Heck reaction,3
i.e. the initiation is the oxidative insertion of Pd(0) in carbon-(pseudo)halide bonds, followed by the
intramolecular carbopalladation of an 1,1-disubstituted alkene, to direct the carbopalladation to the most
substituted position preventing -hydride elimination. The termination step may be another cross-
coupling reaction (Heck, Suzuki, Stille, Sonogashira, etc.).4 For example, the generated σ-
alkylpalladium (II) species may undergo an insertion with an alkene in an inter- or intramolecular way
(second Heck reaction), so carbopalladation is repeated one or several times.5 In the context of our
interest in intramolecular palladium-catalyzed reactions,6 we have achieved the enantioselective
synthesis of the tetracyclic framework of Lycorane alkaloids via a Heck-Heck cascade reaction.7
Another termination approach for these palladium-catalyzed cascade reactions is the Suzuki coupling,8
where the σ-alkylpalladium (II) intermediate reacts with boronic acids or esters to produce cross-
coupling product. Since Grigg’s seminal work (Scheme 1a, PG = SO2Ph, Bn; X = I, Y = H2, O; Z = CH,
R2 = H, R3 = Me),9 these domino Heck/Suzuki cascade reactions have been widely exploited for the
formation of five-membered rings. Thus, domino 5-exo-trig intramolecular carbopalladation-cross
coupling reactions with various organoboranes provide access to functionalized 3,3-disubstituted
azaindolines (Scheme 1a, PG = Ts; X = Br, Y = H2; Z = N; R2 = H, R3 = Me)10 and oxindoles (Scheme
1a, PG = Me; X = I, Y = O; Z = CH; R2 = Ph, Ar, R3 = Me)11 bearing quaternary stereocenters. In the
latter case, the diasterocontrol in the syn palladation step allowed the stereoespecific generation of two
vicinal stereocenters. A similar Ni-catalyzed Heck/Suzuki cascade reaction has been recently applied to
the synthesis of oxindoles (Scheme 1a, PG = Me, Bn; X = OTf, OPiv, Cl, Br, I; Y = O; Z = CH; R2 = H,
R3 = Me.12 Moreover, this cascade reaction is not limited to carbopalladation of alkenes, but can also be
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applied to alkynes, as exemplified in the synthesis of alkylidene substituted indenes,13 benzofurans14 or
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Page 3 of 44
The Journal of Organic Chemistry
cyclopenta[b]indoles,15 which are interesting kinase inhibitor precursors. The E/Z selectivity of the
alkylidene formation is also determined in the 5-exo-dig syn carbopalladation step. However, to the best
of our knowledge, the diastereoselective synthesis of 3,4,4-trisubstituted tetrahydroquinolines via a 6-
exo-trig carbopalladation/Suzuki coupling of adequately functionalized o-bromoanilines (Scheme 1b)16
is one of the few of examples of the construction of six-membered rings.17 Therefore, we decided to
explore the domino palladium-catalyzed intramolecular Heck/Suzuki coupling cascade, employing o-
iodobenzylpyrroles 1 with an alkene in the proper position and boronic acids (Scheme 1c). Herein, we
report a convergent route to pyrrolo[1,2-b]isoquinolines, which combines the cyclization by
carbopalladation followed by the cross-coupling reaction with a boronic acid, and allows the
straightforward preparation of a wide variety of derivatives bearing a quaternary stereocenter.
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a) Previous work: 5-exo-trig / Suzuki coupling
references 9b, 10, 11
reference 12 (with Ni(0))
R2
R2
R3
R3
R4
Y
Z
Pd(0)
N
Y
"R4-B"
N
R1
Z
R1
X
PG
PG
R2
R3
[Pd]
Y
N
Z
R1
PG
b) Previous work: 6-exo-trig / Suzuki coupling
(reference 16 )
Ar2
Ar1
Pd(0)
N
Ar1
Ar2-B(OH)2
N
Br Bn
Bn
c) This work
I
R3
R2
Pd(0)
N
N
R3-B(OH)2
R1
R1
R2
2
1
3
R2
[Pd]
R3-B(OH)2
Suzuki coupling
6-exo
carbopalladation
N
R1
Scheme 1. Carbopalladation - Suzuki cascade.
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Pyrrolo[1,2-b]isoquinoline is a common structural motif among many biologically active alkaloids, such
as the lycorine class of Amaryllidaceae alkaloids18 and the phenanthroindolizidine alkaloids,19 and in
many molecules exhibiting useful therapeutic properties. Some examples are displayed in Figure 1.
Lycorine and Galanthine exhibit anticancer, acetylcholinesterase (AChE) inhibitory, antiplasmodial, or
neuroprotective activities20 while Tylophorine and Hypoestestatin 1 present cytotoxic properties and
antiviral activity.21 Among the synthetic pyrrolo[1,2-b]isoquinolines, the 10-amino derivatives are also
used as AChE inhibitors for anti-amnesic action in the treatment of Alzheimer's disease, senile
dementia, or other conditions characterized by memory loss,22 while the 1,2-bis(hydroxymethyl)-5,10-
dihydropyrrolo[1,2-b]isoquinolines and their bis(alkylcarbamates) exhibit significant antitumor activity
and are able to induce DNA interstrand cross-linking.23 Therefore, the development of new
methodologies for the synthesis of pyrrolo[1,2-b]isoquinolines that allows the preparation of a wide
variety of derivatives, could be useful in future studies of structure-activity relationships for drug
development.
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Lycorane-type and phenanthroindolizine alkaloids
OR3
H
CH3O
CH3O
HO
R1
N
R1O
R2O
H
N
CH3O
R1 = H, (S)-Tylophorine
R1= CH3, Hipoestatin 1
Synthetic pyrrolo[1,2-b]isoquinolines
OR1
OR1
R2
R3
N
N
R1
R2
R1 = OH, OCONHMe
R2 = Me, Et. etc.
R1 = H, OH, alkoxy..
R2 = NHalkyl, NHalkanoyl...
R3 = H, alkyl,...
Figure 1. Selected bioactive compounds that contain fused pyrrolo[1,2-b]isoquinoline frameworks
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The Journal of Organic Chemistry
Results and Discussion
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We started our study using 2-iodobenzylpyrrole 1a as substrate, in the presence of (p-
methoxyphenyl)boronic acid (2a) (Table 1).24 The nature of the intermediate palladium(II) species
would be crucial for the rate of carbopalladation to compete successfully with the rate of an early
Suzuki cross-coupling (Scheme 1c). Therefore, the first challenge was to control the chemoselectivity
by the adequate choice of the catalytic system and/or experimental conditions. We first focused on the
use of catalytic systems in the absence of phosphane ligands. Besides the economical and environmental
reasons for the development and application of phosphane-free catalytic systems, we reasoned that these
conditions could be, in principle, suitable for the sterically more demanding generation of a quaternary
stereocenter. Previous work on related reactions (Scheme 1a,b) had shown that complete conversions
could be obtained in the absence of phosphane ligands using various palladium precatalysts.10 On the
other hand, moderate to excellent conversions have been obtained as well in the presence of phosphane
ligands.9b, 11 Interestingly, the presence of a phosphane has been shown to be required for the 6-exo
cyclization cascade,9b,16 with complete loss of reactivity in its absence.16 However, in our case, using
Pd(OAc)2 and sodium carbonate as the base in DMF, the reaction took place sluggishly, recovering
unreacted 1a (24%) after 48 hours at 120 ºC. The major product isolated was pyrroloisoquinoline 3aa,
although in a low yield (entry 1). Under these conditions, the reaction was not selective, as two by-
products, biaryl 4a and pyrroloazepine 5 were isolated from the reaction mixture. This result shows the
feasibility of the cascade reaction using a phosphane-free catalytic system, but also shows the difficulty
of performing the 6-exo carbopalladation process for the generation of a quaternary center, as both the
direct Suzuki coupling of 2a with the aryl iodide to form 4a and the 7-endo palladation/-elimination
leading to 5 compete effectively. Consequently, we focused on the optimization of reaction conditions
to favor the 6-exo carbopalladation reaction vs. the 7-endo process and the direct Suzuki coupling
(Table 1). In the presence of water, the reaction was completed in 48 h, but only to increase the amount
of isolated 4a (entry 2). The addition of nBu4NCl (1 equiv) dramatically increased the reaction rate,25
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that was completed in 2 h, but the reaction was not selective. In this case, direct Suzuki coupling was the
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major pathway (4a), with also a significant amount of the 7-endo Heck pathway (entry 3). Lowering the
temperature to 90 ºC resulted in a much slower reaction, with almost no selectivity, isolating the three
reaction products in comparable yields (entry 4). In the absence of water, using DMF as solvent, 3aa
was isolated as the major compound (entry 5) and, finally, the addition of 2 equivalents of nBu4NCl
completely suppressed the direct Suzuki pathway, isolating 3aa as the major compound (entry 6). The
presence of halide anions has been shown to increase the rates of some of the steps of the catalytic cycle
of the Heck reaction,25 while an increasing concentration of halide anions has the opposite effect on the
transmetalation step of the Suzuki reaction.26 Thus, the use of a higher concentration of this additive
may slow down the direct Suzuki coupling allowing the 6-exo carbopalladation to occur at a competitive
rate. However, the use of 3 equivalents, or the change to nBu4NI or nBu4NOAc did not improve the
isolated yield of 3aa (entries 7-9). We then modified the palladium precatalyst (entries 10-12) and the
solvent (entries 13-15), obtaining moderate isolated yields of 3aa. Interestingly, in the presence of PPh3,
the Suzuki coupling was the major pathway (28 % of 4a), despite the use of nBu4NCl, obtaining a low
yield of 3aa (25%) (entry 11). Unfortunately, the 7-endo Heck pathway could not be completely
suppressed under any of the reaction conditions tested. For these reactions, the overall isolated yield is
rather low due to the difficulties associated with the separation and purification of compounds by
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1
chromatography, but no formation of other products was detected by H-NMR of the crude reaction
mixtures.
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The Journal of Organic Chemistry
Table 1. Carbopalladation/Suzuki sequence on 1a. Optimization of reaction conditions with phosphane-
1
2
3
free catalytic systems
4
5
6
OCH3
7
8
9
N
N
OCH3
[Pd] (10 mol%)
Na2CO3 (1.3 equiv.)
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
I
+
N
10
11
12
13
14
15
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N
CH3O
additive, t
solvent, 120 ºC
B(OH)2
OCH3
1a
OCH3
2a
3aa
4a
5
entry
[Pd]
Additive
Solvent
Time
(h)
48b
48
3aaa
4aa
5a
(equiv)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(PPh3)4
-
-
DMF
34
30
22
27
47
56
52
51
10
46
25
42
34
52
56
40
4
12
33
27
7
-
23
21
26
29
19
13
7
2
DMF/H2Oc
DMF/H2Oc
3
n-Bu4NCl (1)
n-Bu4NCl (1)
n-Bu4NCl (1)
n-Bu4NCl (2)
n-Bu4NCl (3)
n-Bu4NI (1)
2
4
DMF/H2Oc,d 48e
5
DMF
DMF
DMF
DMF
1
1
1
1
1
2
9
4
2
5
1
2
6
7
-
8
-
16
14
11
15
10
21
17
25
29
9
n-Bu4NOAc (2) DMF
-
10
11
12
13
14
15
16
n-Bu4NCl (2)
n-Bu4NCl (2)
DMF
9
28
-
DMF
Pd2(dba)3·CHCl3 n-Bu4NCl (2)
DMF
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
n-Bu4NCl (2)
n-Bu4NCl (2)
n-Bu4NCl (2)
n-Bu4NCl (2)
Toluenef
THFf
-
-
Dioxanef
CH3CNf
-
-
aYield (%) of isolated pure compound. Reactions were carried out in a 0.3 mmol scale. 76%
b
conversion. cDMF:H2O 80:20. d90 ºC. e84% conversion. f Reflux
With the best reaction conditions in hand (Table 1 entry 6, Table 2 entry 1), we extended the reaction to
the use of different boronic acids 2b-m (Table 2).
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1
2
3
Table 2. Extension of phosphane-free reaction to boronic acids 2a-m.
4
5
6
7
8
9
R1
Pd(OAc)2 (10 mol%)
Na2CO3 (1.3 equiv.)
nBu4NCl (2 equiv.)
CH3O
+ R1-B(OH)2
2a-m
1a
N
3aa-3am
DMF, 120 ºC, t
CH3O
10
11
12
13
14
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Entry R1
Time
(h)
Product Yield
(%)a
OCH3
1
1
3aa
56b
F
2
3
2
1
3ab
3ac
54
60b
NO2
CF3
4
5
2
1
3ad
3ae
52
38b
CF3
CF3
47b
OCH3
OCH3
6
1
3af
7
8
9
4
1
1
3ag
3ah
3ai
46c
53
63
10
11
1
3aj
70
48
3ak
15d
S
12
13
48
2
3al
21e
37
Ph
3am
aYield (%) of isolated pure product. Reactions were carried out in a 0.3 mmol scale. b11-17% of 5 was
also isolated. c19% of 3ag was obtained when phenyl boronic acid pinacol ester was used instead of 2g.
d 76% conversion. ePotasium trifluorovinyl borate was used. 89% conversion
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The Journal of Organic Chemistry
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Moderate to good yields of pyrrolosiquinolines 3aa-3aj were obtained when electron rich, electron
deficient or even polycyclic aryl boronic acids were used. Minor amounts of the pyrroloazepine 5 were
detected by NMR that in some of the experiments was isolated and quantified (entries 1, 3, 5, 6), but no
formation of the direct Suzuki coupling was detected. A lower yield of 3ag was obtained when phenyl
boronic acid pinacol ester was used instead of 2g (19% vs 46%, entry 7). However the reaction with
thiophen-3-ylboronic acid 2k was much slower (48 h), recovering 24% of starting material and giving
only a low yield of 3ak, (entry 11). Alkenes could also be coupled with this procedure, although with a
lower yield (entries 12, 13).
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Next, we studied the extension to 2-iodobenzylpyrroles 1b-h, with different substitution patterns on the
aromatic ring and the alkene. It is interesting that when an electron-withdrawing group, such as CF3, is
incorporated in the alkene (1b, R2 = CF3), the intramolecular direct arylation of the aryl iodide with
pyrrole C-5 position becomes the major pathway leading to 6 as the major compound (Table 3). Thus,
3ba and 3bc were obtained only in low yields. This type of reactivity has been shown to be competitive
in Heck reactions with related substrates, using Pd/phosphane catalytic systems, specially when a
cationic mechanism is favored.6b,27 In this case, formation of pyrrolo[2,1-a]isoindoles was not observed
when the alkene is substituted with an alkyl group, and 3cc was obtained from 1c, (R2 = Et) with similar
yield. The reaction could also be extended to benzylpyrroles with different substitution patterns on the
aromatic ring (1d-h), obtaining the corresponding pyrroloisoquinolines with moderate to good yields
(Table 3). However, benzylpyrroles 1 bearing electron rich aromatic rings led to better yields of 3.
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Table 3. Synthesis of pyrroloisoquinolines 3.
1
2
3
4
5
6
7
8
R3
N
Pd(OAc)2 (10 mol%)
Na2CO3 (1.3 equiv.)
nBu4NCl (2 equiv,)
R2
I
N
R3-B(OH)2 (1.3 equiv.)
DMF, 120 ºC
R1
R1
R2
1b-h
3a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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NO2
OCH3
F3C
F3C
H3CO
H3CO
CH3O
CH3O
CH3O
N
N
N
CH3O
F3C
6
3ba
3bc
(26%)
6
(51%)
(27%)
6
(61%)
NO2
NO2
NO2
Et
CH3O
CH3O
O
O
N
N
N
3cc
3dc
3ec
(47%)
(54%)
(23%)
R
NO2
NO2
CH3O
N
N
N
CH3O
CH3O
F
CH3O
3hc
3fa
3fc
3gc
(32 %)
(R = OCH3, 22%)
(R = NO2, 37%)
(60%)
aYield (%) of isolated pure product. Reactions were carried out in a 0.3 mmol scale.
At this point, we have shown that is it possible to carry out the 6-exo-trig carbopalladation/Suzuki
cascade using a phosphane-free catalytic system. However, the overall yields obtained are moderate in
many cases, as the competitive 7-endo cyclization/elimination leading to 5 could not be completely
suppressed under these conditions. Although we had previously shown that the formation of quaternary
stereocenters via Heck reaction was possible on related substrates in the presence of phosphane
ligands,27 the use of Pd(PPh3)4 on the coupling of 1a with 2a led to a non-selective reaction (Table 1,
entry 11). With these precedents, we carried out a further optimization of the reaction conditions,
studying the effect of a phosphane ligand, using the reaction of 1a with boronic acid 2c (Table 4), which
had given a moderate yield of 3ac under the phosphane-free reaction conditions (60%, Table 2, entry 3).
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The Journal of Organic Chemistry
1
2
3
Table 4. Optimization of reaction conditions in the presence of phosphanes.
4
5
6
7
8
9
NO2
[Pd] (10 mol%)
L
(20 mol%)
Na2CO3 (1.3 equiv.)
nBu4NCl (2 equiv.)
CH3O
CH3O
1a
2c
+
N
DMF, 120 ºC, 1 h
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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38
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46
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52
53
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56
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58
59
60
3ac
Cy
O
O
P
P
PPh3
P(tBu)3
Me2N
Cy
O
L1
L2
L3
L4
tBu
P
PPh2
PPh2
L5
L6
tBu
entry [Pd]
L
3aca
5a
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
L1
L2
70
74
4
2
9
3
L2b,c 67
8
4
L3
L4
L5
70
65
66
6
5
4
6
9
7
L6d 53
L2e 79
12
-
8
9
Pd2(dba)3.CHCl3 L2
Pd2(dba)3.CHCl3 L2g,h 30
Pd2(dba)3.CHCl3 L2i
29
86 (94)f
-
10
11
33
18
aYield (%) of isolated pure product. Reactions were carried out in a 0.3 mmol scale. 28% of L2 was
b
used. c Reaction time: 3 h. d Reaction time: 24 h. e Reaction time: 4 h. f The reaction was performed in a
1.32 mmol scale (506 mg of 1a).g Reaction time: 48 h. h nBu4NCl was not used. Ag3PO4 was used as
i
base instead of Na2CO3.
We were pleased to find that the reaction took place efficiently using the same reaction conditions in the
presence of various phosphanes (20 mol%), such as triphenylphosphane (L1) (Table 4, entry 1),
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tri(furan-2-yl)phosphane (L2) (Table 4, entry 2) or tri-tert-butylphosphane (L3) (Table 4, entry 4).
Although, the formation of the 7-endo Heck product (5) could not be completely avoided (4-9% of 5
was isolated as by-product), the use of phosphane ligands led to the formation of 3ac with an increased
yield (70-74%). The use of a higher amount of the phosphane led to a slower reaction with a lower
isolated yield of 3ac (entry 3). The choice of the phosphane ligand has been shown to have a
determinant effect on the endo/exo selectivity in related Heck cyclizations.28 However, minor amounts
of 5 (entries 5 and 6) were also isolated when the reaction was carried out in the in the presence of
DavePhos (L4) and TrixiePhos (L5). The reaction using rac-BINAP (L6) was less efficient, and
required 24 h to obtain a moderate yield of 3ac (entry 7). The formation of the endo adduct 5 could be
completely avoided changing the palladium source. Thus, the use of bis(dibenzylidene)palladium(0)
with tri(furan-2-yl)phosphane (L2) gave 3ac in good yield, with complete selectivity (entry 8). Finally,
the reaction was more efficient when tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct
(86%, entry 9). The reaction could be carried out in a 0.5 gram scale (1.3 mmol of 1a) also in high yield
(94%, entry 9). The use of nBu4NCl is still neccesary, as a much slower (48 h) and non selective
reaction is took place when in its absence (entry 10), obtaining 5 as the major product, although no
direct Suzuki coupling product was detected under these conditions. The change of the base for a silver
salt (Ag3PO4) also resulted in a selectivity loss (entry 11).
1
2
3
4
5
6
7
8
9
10
11
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Once the reaction conditions were optimized, we tested the use of selected boronic acids 2. As shown in
Tables 4 and 5, in most of the cases (3aa, 3ac, 3ae, 3af, 3aj, 3al, 3am), the results could be significantly
improved with respect to the yield obtained with the phosphane-free catalytic system (see Table 2).
However, in some of the cases, minor ammounts of 5 were also isolated (Table 5, 11-16%). In the case
of 3ag, a lower yield (36%) was obtained, isolating also the endo-Heck cyclization product 5 (22%).
The reaction with thiophen-3-ylboronic acid 2k gave again a low yield of 3ak (15% Table 2 vs. 14%
Table 5,), although under these conditions the main reaction pathway was the direct Suzuki coupling,
obtaining 4k with a 50% yield. The coupling with alkenes was also significantly improved (Table 5, 3al
and 3am).
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The Journal of Organic Chemistry
Table 5. Synthesis of pyrroloisquinolines 3 using L2 as ligand
1
2
3
4
5
6
7
8
Pd2(dba)3.CHCl3 (10 mol%)
R3
L2
P(2-furyl)3 ( ) (20 mol%)
R2
Na2CO3 (1.3 equiv.)
nBu4NCl (2 equiv,)
I
N
N
R3-B(OH)2 ( ) (1.3 equiv.)
2
R1
R1
DMF, 120 ºC, 1 h
R2
1
3a
9
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OCH3
OCH3
OCH3
CF3
CH3O
CH3O
CH3O
CH3O
CH3O
N
N
N
CH3O
b
3aa
5
(61%)
(12%)
3ae
5
3af
(62%)
(55%)
(16%)
S
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
N
N
N
c
3aj
3ak
4k
(83%)
(14%)
(50%)
3ag
(36%)
5
(22%)
5
(11%)
Ph
N
CH3O
CH3O
CH3O
CH3O
CH3O
CH3O
N
N
d,e
3al
(38%)
3am
4k
(60%)
S
5
(24%)
NO2
NO2
OCH3
F3C
F3C
CH3O
CH3O
CH3O
CH3O
N
N
N
3ba
3bc
3dc
(52%)
(84%)
(38%)
NO2
NO2
O
O
N
N
F
3hc
(57%)
3ec
(65%)
aYield (%) of isolated pure product. Reactions were carried out in a 0.3 mmol scale. b Reaction time: 4
h. c Reaction time: 6 h.dPotasium trifluorovinyl borate was used. eReaction time: 24 h.
Significantly, the use of the phosphane ligand completely changed the chemoselectivity when 1b (R2
= CF3) was reacted with 2a and 2c. Thus, the direct arylation pathway leading to 6 (Table 3) was
completely suppressed and 10b-trifluoromethylsubstituted pyrroloisoquinolines 3ba and 3bc were
obtained in good yields (Table 5). This result probably reflects the change from a cationic (phosphane-
free) to a neutral pathway for the initial carbopalladation step. The use of 1d, 1e and 1h gave also
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improved yields of the expected pyrroloisoquinolines 3dc, 3ec and 3hc. (Table 5). In view of these
results, we explored the possibility of an enantioselective version of the reaction, in the presence of
chiral non-racemic phosphanes. In this context, we have reported an enantioselective Heck-Heck
cascade using related substrates, showing that it is possible to control the enantioselectivity of the
carbopalladation step using (R)-BINAP.7 However, it was not possible to induce stereocontrol using
(R)-BINAP or other chiral non-racemic phosphane ligands for the generation of quaternary stereocenters
through Heck reactions on related alkenylpyrroles.27 Once again, we selected the reaction of 1a with 2c
as a model for optimization of the reaction conditions. Although different ligands, solvents and reaction
conditions have been tested, only modest enantioselectivities (up to 44% ee) have been obtained so far.
Some selected results are shown on Table 6 (see the Supporting Information for additional essays). We
found that phosphoramidite L7 led to the best results in terms of enantioselectivity, using palladium
acetate in toluene, although with low conversion (Table 6, entries 1 and 2). The reaction is more
efficient in DMF, but with no stereocontrol (Table 6, entries 4-6). On the other hand, n-Bu4NCl
accelerates the reaction, but leads to an almost racemic compound (entries 4 and 5). In the absence of n-
Bu4NCl, using solid Na2CO3 in DMF the reaction is much slower (entry 6), and does not proceed at all
in toluene (see SI, Table S2). The reactivity could be recovered using an aqueous solution of base (Table
6, entries 1-3 and 7). The use of a more concentrated base (10 M) led to an improved ee, but with a
lower conversion (Table 6, entry 2). In the absence of n-Bu4NCl, the reaction was again non-selective,
isolating the direct Suzuki coupling product 4c as a by-product (see SI). The use of Pd2(dba)3·CHCl3 led
to improved yields, but with lower enantioselection (Table 6, entries 5 and 7) (see SI).
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
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17
18
19
20
21
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60
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The Journal of Organic Chemistry
Table 6. Chiral phosphane L7 mediated reaction of 1a
1
2
3
NO2
4
5
6
7
[Pd] (10 mol%)
L7
Na2CO3 (2 M)
(20 mol%)
CH3O
CH3O
*
1a
2c
+
N
toluene, 110 ºC, t
8
3ac
9
Ph
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
P
O
O
O
NMe2
L7
Ph
Ph
entry [Pd]
time
48
3aca eeb
1
2
3
4
5
6
7
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
63c
28c
61
34
44
4
48d
24e,,f
3g
64c
86
<2
6
Pd2(dba)3·CHCl3 1e,,f,g
Pd2(dba)3·CHCl3 48f,g
Pd2(dba)3·CHCl3 24
23
6
72
22
aYield (%) of isolated pure product.bDetermined by chiral stationary phase HPLC (Chiralcel ADH).
c
Due to the low ee the configuration could not be determined. 4c was isolated as by product (see SI).
dNa2CO3 (10 M aq. solution) was used. enBu4NCl (1 equiv) was used as additive. Solid Na2CO3 was
f
used. gDMF was used as solvent.
In conclusion, it has been shown that N-(2-iodobenzyl)-2-(alkenyl)-1H-pyrroles 1 undergo cyclization
through a 6-exo carbopalladation process to generate a quaternary center. The resulting -
alkylpalladium can be trapped with arylboronic acids to generate C-10 disubstituted pyrrolo[1,2-
b]isoquinolines 3. A phosphane free precatalytic system can be used in order to favor the 6-exo
carbopalladation reaction vs. the direct Suzuki coupling, although the 7-endo process is competitive in
some cases. Nevertheless, the 7-endo process can be suppressed in the presence of phosphane ligands,
such as tri(furan-2-yl)phosphane (L2). In combination with Pd2(dba)3.CHCl3, this phosphane ligand
leads in most cases to a significant increase in the yields of the pyrroloisoquinolines 3. Using both
procedures, the presence of n-Bu4NCl is crucial to allow the 6-exo carbopalladation to occur at a
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competitive rate, avoiding the direct Suzuki coupling. Electron rich and electron deficient arylboronic
acids can be used, although coupling with alkenyl or heteroaryl (thiophenyl) boronic acids provide
lower yields. The use of chiral non racemic phosphanes, such as phosphoramidite L7 gave only low
enantioselectivities. Overall, this domino process allows the synthesis of interesting pyrrolo[1,2-
b]isoquinolines, a common structural motif among biologically active alkaloids.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
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19
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21
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60
Experimental Section
General experimental methods. Melting points were determined in unsealed capillary tubes and are
uncorrected. IR spectra were obtained using an ATR. NMR spectra were recorded at 20-25 ˚C, at 300
MHz for 1H and 75.5 MHz for 13C in CDCl3 solutions. Assignments of individual 13C and 1H resonances
are supported by DEPT experiments and 2D correlation experiments (COSY, HSQCed or HMBC).
Mass spectra were recorded under electron impact (EI) at 70 eV or with an ESI+ source. Exact mass was
obtained using a TOF detector. TLC was carried out with 0.2 mm thick silica gel plates. Visualization
was accomplished by UV light. Flash column chromatography was performed on silica gel (230-400
mesh). Chiral stationary phase HPLC was performed using Chiralcel ADH column (0.46 cm  25 cm) in
isocratic elution mode (hexane/i-propanol 9/1, 1 mL/min). All solvents used in reactions were
anhydrous and purified according to standard procedures. All air- or moisture-sensitive reactions were
performed under argon; the glassware was dried (130 ˚C) and purged with argon. Palladium catalysts
were commercially available, and were used without further purification: Pd(OAc)2: 98% purity¸
Pd(TFA)2: 97% purity; Pd(PPh3)4: 99% purity; Pd2(dba)3·CHCl3: 97% purity.
Synthesis of 1-(o-iodobenzyl)-2-alkenylpyrroles 1a-h. Substrates 1a-h were prepared following the
procedure described in the Supporting Information. Thus, acylpyrroles 8a-c were alkylated with o-
iodobenzylbromides 7a-f to obtain 2-acyl-N-benzylpyrroles 9a-h. Subsequent Wittig reation afforded
1a-g in good yields.
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The Journal of Organic Chemistry
Alkylation reactions. Synthesis of 2-acyl-N-benzylpyrroles 9a-h. General procedure. 2-
1
2
Acylpyrrole 8 (1 mmol) was added over a suspension of powdered KOH (2 mmol) in DMSO (3 mL).
The mixture was stirred at rt for 2 h, the corresponding bromide 7a-f (1.2 mmol) was added, and the
reaction mixture was stirred until the reaction was completed. H2O (5 mL) was added and the resulting
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The combined organic extracts were washed
with brine (3 × 10 mL), dried (Na2SO4) and concentrated in vacuo. Flash column chromatography
afforded the corresponding 2-acylpyrroles 9a-h.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
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22
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1-[1-(2-Iodo-4,5-dimethoxybenzyl)-1H-pyrrol-2-yl]ethan-1-one (9a).27 According to general
procedure, 8a (854 mg, 7.82 mmol) was treated with benzylbromide 7a (3.34 g, 9.39 mmol) and KOH
(1.03 g, 15.65 mmol) in DMSO (20 mL). The mixture was stirred at rt for 4 h. After work up,
purification by column chromatography (silica gel, petroleum ether/EtOAc 8/2) afforded N-
benzylpyrrole 9a as a white solid (2.45 g, 81%). mp (Hexane/EtOAc): 121-124 °C; IR (ATR): 1650 cm-
1
1; H NMR (300 MHz, CDCl3): δ 2.42 (s, 3H), 3.64 (s, 3H), 3.82 (s, 3H), 5.51 (s, 2H), 6.16-6.18 (m,
13
1H), 6.25 (s, 1H), 6.85-6.86 (m, 1H), 7.00-7.02 (m, 1H), 7.22 (s, 1H) ppm; C{1H} NMR (75.5 MHz,
CDCl3): δ 27.2, 55.6, 56.1, 56.9, 86.2, 108.6, 111.1, 120.3, 121.5, 130.0, 130.3, 132.9, 148.8, 149.6,
188.4 ppm; MS (CI) m/z (rel intensity): 386 (MH+,65), 276 (71), 259 (100). HRMS (CI-TOF): calcd. for
C15H17INO3 [MH+] 386.0248; found, 386.0237.
2,2,2-Trifluoro-1-(1-(2-iodo-4,5-dimethoxybenzyl)-1H-pyrrol-2-yl)ethan-1-one (9b). According to
general procedure, 8b (1.09 g, 6.66 mmol) was treated with benzylbromide 7a (2.84 g, 7.99 mmol) and
KOH (439 mg, 6.66 mmol) in DMSO (30 mL). The mixture was stirred at rt for 2 h. After work up,
purification by column chromatography (silica gel, petroleum ether/EtOAc 8/2) afforded N-
benzylpyrrole 9b as a white solid (2.51 g, 86 %): mp (petroleum ether/EtOAc): 93-95 ºC; IR (ATR):
1
1665 cm-1; H NMR (300 MHz, CDCl3): δ 3.67 (s, 3H), 3.85 (s, 3H), 5.51 (s, 2H), 6.27 (s, 1H), 6.32
13
(dd, J = 4.3, 2.5 Hz, 1H), 7.07 (m, 1H), 7.26 (s, 1H), 7.30-7.33 (m, 1H) ppm; C{1H} NMR (75.5
MHz, CDCl3): δ 55.7, 56.2, 57.5, 86.6, 110.8, 111.1, 117.0 (q, J = 290.5 Hz), 121.8, 124.4, 124.6 (q, J =
4.0 Hz), 131.4, 134.0, 149.2, 149.8, 169.9 (q, J = 35.4 Hz) ppm; MS (ESI) m/z (rel intensity): 440
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(MH+, 31), 314 (12), 313 (100). HRMS (ESI-TOF): calcd. for C15H14F3INO3 [MH+] 439.9965; found,
439.9978.
1
2
3
4
5
6
7
8
9
1-(1-(2-Iodo-4,5-dimethoxybenzyl)-1H-pyrrol-2-yl)propan-1-one (9c). According to general
procedure, 8c (194 mg, 1.57 mmol) was treated with benzylbromide 7a (674 mg, 1.89 mmol) and KOH
(208 mg, 3.15 mmol) in DMSO (5 mL). The mixture was stirred at rt for 4 h. After work up, purification
by column chromatography (silica gel, petroleum ether/EtOAc 8/2) afforded N-benzylpyrrole 9c as a
yellow solid (475 mg, 76%): mp (petroleum ether/EtOAc): 114-116 ºC; IR (ATR): 1650 cm-1; 1H NMR
(300 MHz, CDCl3): δ 1.12 (t, J = 7.4 Hz, 3H), 2.78 (q, J = 7.4 Hz, 2H), 3.60 (s, 3H), 3.78 (s, 3H), 5.49
(s, 2H), 6.14 (dd, J = 4.1, 2.6 Hz, 1H), 6.19 (s, 1H), 6.83 (dd, J = 2.6, 1.7 Hz, 1H), 6.99 (dd, J = 4.1, 1.7
Hz, 1H), 7.19 (s, 1H) ppm; 13C{1H} NMR (75.5 MHz, CDCl3): δ 9.2, 32.4, 55.7, 56.2, 56.9, 86.1, 108.7,
110.1, 119.4, 121.6, 129.9, 130.0, 133.2, 148.8, 149.7, 191.9 ppm; MS (ESI) m/z (rel intensity): 400
(MH+, 36), 274 (13), 273 (100); HRMS (ESI-TOF): calcd. for C16H19INO3 [MH+] 400.0404; found,
400.0413.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
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44
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59
60
1-(1-(2-Iodobenzyl)-1H-pyrrol-2-yl)ethan-1-one (9d).29According to general procedure, 8a (933
mg, 8.55 mmol) was treated with benzylbromide 7b (3.05 g, 10.25 mmol) and KOH (1.13 g, 17.09
mmol) in DMSO (30 mL). The mixture was stirred at rt for 4 h. After work up, purification by column
chromatography (silica gel, petroleum ether/EtOAc 8/2) afforded N-benzylpyrrole 9d as a white solid
1
(2.32 g, 83 %): mp (Petroleum ether /EtOAc): 95-97 °C; IR (ATR): 1650 cm-1; H NMR (300 MHz,
CDCl3): δ 2.42 (s, 3H), 5.56 (s, 2H), 6.24 (dd, J = 4.1, 2.6 Hz, 1H), 6.47 (dd, J = 7.8, 1.6 Hz, 1H), 6.84-
6.85 (m, 1H), 6.90-6.96 (m, 1H), 7.06 (dd, J = 4.1, 1.7 Hz, 1H), 7.17-7.22 (m, 1H), 7.83 (dd, J = 7.8, 1.6
Hz, 1H) ppm; 13C{1H} NMR (75.5 MHz, CDCl3): δ 27.3, 57.8, 97.6, 108.9, 120.4, 127.2, 128.6, 129.0,
130.5, 130.5, 139.3, 140.8, 188.2 ppm; MS (ESI) m/z (rel intensity): 326 (MH+, 100), 199 (10). HRMS
(ESI-TOF): calcd. for C13H13INO [MH+] 326.0036; found, 326.0048.
1-(1-((6-Iodobenzo[d][1,3]dioxol-5-yl)methyl)-1H-pyrrol-2-yl)ethan-1-one (9e). According to
general procedure, 8a (2.46 g, 22.56 mmol) was treated with benzylbromide 7c (9.20 g, 27.07 mmol)
and KOH (2.98 g, 45.12 mmol) in DMSO (50 mL). The mixture was stirred at rt for 4 h. After work up,
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purification by column chromatography (silica gel, petroleum ether/EtOAc 9/1) afforded N-
benzylpyrrole 9e as a yellow solid (6.95 g, 84 %): mp (Petroleum ether/EtOAc): 123-125 °C; IR (ATR):
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1650, 1265 cm-1; H NMR (300 MHz, CDCl3): δ 2.45 (s, 3H), 5.49 (s, 2H), 5.91 (s, 2H), 6.09 (s, 1H),
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6.23 (dd, J = 4.1, 2.6 Hz, 1H), 6.87 (dd, J = 2.6, 1.7 Hz, 1H), 7.05 (dd, J = 4.1, 1.7 Hz, 1H), 7.26 (s, 1H)
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ppm; C{1H} NMR (75.5 MHz, CDCl3): δ 27.3, 57.4, 85.5, 101.7, 107.8, 108.9, 118.5, 120.4, 130.2,
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130.4, 134.2, 147.7, 148.8, 188.4 ppm; MS (ESI) m/z (rel intensity): 370 (MH+, 100), 243 (10). HRMS
(ESI-TOF): calcd. for C14H13INO3 [MH+] 369.9935; found, 369.9942.
1-(1-(6-Iodo-2,3-dimethoxybenzyl)-1H-pyrrol-2-yl)ethan-1-one (9f). According to general
procedure, 8a (741 mg, 6.79 mmol) was treated with benzylbromide 7d (2.91 g, 8.15 mmol) and KOH
(897 mg, 13.58 mmol) in DMSO (30 mL). The mixture was stirred at rt for 4 h. After work up,
purification by column chromatography (silica gel, petroleum ether/EtOAc 9/1) afforded N-
benzylpyrrole 9f as a colorless oil (1.82 g, 69 %): IR (ATR): 1650 cm-1; 1H NMR (300 MHz, CDCl3): δ
2.46 (s, 3H), 3.63 (s, 3H), 3.81 (s, 3H), 5.71 (s, 2H), 6.01 (dd, J = 4.0, 2.7 Hz, 1H), 6.45-6.47 (m, 1H),
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6.67 (d, J = 8.7 Hz, 1H), 6.95 (dd, J = 4.0, 1.6 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H) ppm; C{1H} NMR
(75.5 MHz, CDCl3): δ 27.6, 51.9, 55.9, 61.0, 90.3, 108.1, 114.7, 120.0, 128.0, 131.0, 133.0, 134.7,
149.0, 153.3, 188.6 ppm; MS (ESI) m/z (rel intensity): 386 (MH+, 100), 277 (41), 259 (14). HRMS
(ESI-TOF): calcd. for C15H17INO3 [MH+] 386.0248; found, 386.0253.
1-(1-(2-Iodo-6-methoxybenzyl)-1H-pyrrol-2-yl)ethan-1-one (9g). According to general procedure,
8a (35.6 mg, 0.33 mmol) was treated with benzylbromide 7e (140 mg, 0.39 mmol) and KOH (43 mg,
0.65 mmol) in DMSO (10 mL). The mixture was stirred at rt for 4 h. After work up, purification by
column chromatography (silica gel, petroleum ether/EtOAc 9/1) afforded N-benzylpyrrole 9g as a white
1
solid (94.3 mg, 75%): mp (petroleum ether/EtOAc): 142-144 °C; IR (ATR): 1650 cm-1; H NMR (300
MHz, CDCl3): δ 2.42 (s, 3H), 3.63 (s, 3H), 3.85 (s, 3H), 5.57 (s, 2H), 5.70 (d, J = 2.7 Hz, 1H), 6.21 (dd,
J = 4.0, 2.6 Hz, 1H), 6.32 (d, J = 2.7 Hz, 1H), 6.85 (dd, J = 2.6, 1.7 Hz, 1H), 7.03 (dd, J = 4.0, 1.7 Hz,
1H) ppm; 13C{1H} NMR (75.5 MHz, CDCl3): δ 27.2, 55.3, 56.5, 58.1, 78.6, 97.3, 104.9, 108.8, 120.3,
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130.5, 130.5, 142.9, 158.8, 161.4, 188.3 ppm; MS (ESI) m/z (rel intensity): 386 (MH+, 90), 259 (100).
HRMS (ESI-TOF): calcd. for C15H17INO3 [MH+] 386.0248; found, 386.0255.
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1-(1-(5-Fluoro-2-iodobenzyl)-1H-pyrrol-2-yl)ethan-1-one (9h). Acetylpyrrole 8a (179 mg, 1.64
mmol) was added over a suspension of powdered NaH (131 mg, 3.28 mmol) in dry DMF (10 mL) and
the mixture was stirred at 60 ºC for 30 min. Benzyl bromide 7f (620 mg, 1.97 mmol) was added and the
reaction mixture was stirred at 60 ºC for 4 h. After work up, purification by column chromatography
(silica gel, petroleum ether/EtOAc 9/1) afforded N-benzylpyrrole 9h as a white solid (556 mg, 99%):
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mp (Petroleum ether/EtOAc): 122-124 °C; IR (ATR): 1640 cm-1; H NMR (300 MHz, CDCl3): δ 2.42
(s, 3H), 5.51 (s, 2H), 6.08-6.11 (m, 1H), 6.26 (dd, J = 4.1, 2.6 Hz, 1H), 6.68-6.71 (m, 1H), 6.88 (dd, J =
2.6, 1.7 Hz, 1H), 7.07 (dd, J = 4.1, 1.7 Hz, 1H), 7.75-7.78 (m, 1H) ppm; 13C{1H} NMR (75.5 MHz,
CDCl3): δ 27.2, 57.7, 89.5 (d, J = 3.4 Hz), 109.2, 114.3 (d, J = 23.9 Hz), 116.2 (d, J = 22.1 Hz), 120.6,
130.3, 130.5, 140.3 (d, J = 7.3 Hz), 143.4 (d, J = 7.3 Hz), 163.6 (d, J = 247.4 Hz), 188.3 ppm; MS (ESI)
m/z (rel intensity): 344 (MH+, 100), 302 (24), 235 (8), 217 (10). HRMS (ESI-TOF): calcd. for
C13H12FINO [MH+] 343.9942; found, 343.9957.
Wittig Reaction. Synthesis of 2-alkenylpyrroles 1a-g. General procedure: Potassium tert-butoxide
(2 mmol) was added to a solution of methyltriphenylphosphonium bromide (2 mmol) in dry THF (10
mL) at 0 ºC. The reaction mixture was stirred at room temperature under argon for 30 min and then
cooled at 0 ºC. A solution of N-benzylpyrrole 9a-g (1 mmol) in dry THF (10 mL) was added over 5 min
and the mixture was heated under reflux for 24 h. The reaction mixture was allowed to reach room
temperature and filtered under vacuum. The filtrate was diluted with Et2O (5 mL) and sequentially
washed with NaHSO3 sat. (5 mL), Na2CO3 sat. (5 mL) and brine (5 mL). The organic extracts were
dried over anhydrous Na2SO4 and concentrated to dryness. The crude was subjected to flash
chromatography (silica gel) obtaining 1a-g.
1-(2-Iodo-4,5-dimethoxybenzyl)-2-(prop-1-en-2-yl)-1H-pyrrole (1a). According to general
procedure, 9a (1.00 g, 2.61 mmol) in dry THF (20 mL) was treated with potassium tert-butoxide (598
mg, 5.22 mmol) and methyltriphenylphosphonium bromide (1.90 g, 5.22 mmol) in dry THF (20 mL).
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After work up, purification by column chromatography (silica gel, petroleum ether/EtOAc 7/3) afforded
N-benzylpyrrole 1a as a yellow solid (856 mg, 86%): mp (petroleum ether /EtOAc): 96-98 °C; IR
(ATR): 1590 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.05 (s, 3H), 3.62 (s, 3H), 3.85 (s, 3H), 4.73 (s, 1H),
4.98-4.99 (m, 1H), 5.08 (s, 2H), 6.00 (s, 1H), 6.20-6.23 (m, 1H), 6.25-6.27 (m, 1H), 6.64-6.65 (m, 1H),
7.24 (s, 1H) ppm; 13C{1H} NMR (75.5 MHz, CDCl3): δ 24.2, 55.7, 56.2, 56.2, 84.2, 108.2, 109.2, 110.6,
112.1, 121.4, 123.9, 133.5, 134.8, 135.3, 148.8, 149.7 ppm; MS (ESI) m/z (rel intensity): 384 (MH+,
17), 276 (100), 256 (54). HRMS (CI): calcd. for C16H19INO2 [MH+] 384.0455; found, 384.0442.
1-(2-Iodo-4,5-dimethoxybenzyl)-2-(3,3,3-trifluoroprop-1-en-2-yl)-1H-pyrrole (1b). According to
general procedure, 9b (818 mg, 1.86 mmol) in dry THF (20 mL) was treated with potassium tert-
butoxide (418 mg, 3.72 mmol) and methyltriphenylphosphonium bromide (1.33 g, 3.72 mmol) in dry
THF (20 mL). After work up, purification by column chromatography (silica gel, petroleum
ether/EtOAc 8/2) afforded N-benzylpyrrole 1b as a yellow solid (490.6 mg, 60%): mp (petroleum
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ether/EtOAc): 72-74 °C; IR (ATR): 1505 cm-1; H NMR (300 MHz, CDCl3): δ 3.62 (s, 3H), 3.85 (s,
3H), 5.01 (s, 2H), 5.38 (dd, J = 3.5, 1.7 Hz, 1H), 5.95-5.97 (m, 2H), 6.26 (dd, J = 3.8, 2.8 Hz, 1H), 6.41-
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6.43 (m, 1H), 6.74 (dd, J = 2.8, 1.7 Hz, 1H), 7.23 (s, 1H) ppm; C{1H} NMR (75.5 MHz, CDCl3): δ
55.6, 55.7, 56.2, 84.3, 108.8, 110.4, 112.0, 120.9 (q, J = 5.4 Hz), 121.4, 122.8 (q, J = 273.9 Hz), 124.9,
125.2, 130.4 (q, J = 31.6 Hz), 132.7, 148.9, 150.0 ppm; MS (ESI) m/z (rel intensity): 438 (MH+, 100).
HRMS (ESI-TOF): calcd. for C16H16F3INO2 [MH+] 438.0172; found, 438.0182
2-(But-1-en-2-yl)-1-(2-iodo-4,5-dimethoxybenzyl)-1H-pyrrole (1c). According to general
procedure, 9c (195 mg, 0.49 mmol) in dry THF (5 mL) was treated with potassium tert-butoxide (110
mg, 0.98 mmol) and methyltriphenylphosphonium bromide (350 mg, 0.98 mmol) in dry THF (10 mL).
After work up, purification by column chromatography (silica gel, petroleum ether/EtOAc 9/1) afforded
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N-benzylpyrrole 1c as a colorless oil (139.0 mg, 72 %): IR (ATR): 1500 cm-1; H NMR (300 MHz,
CDCl3): δ 1.04 (t, J = 7.4 Hz, 3H), 2.35 (q, J = 7.4 Hz, 2H), 3.62 (s, 3H), 3.85 (s, 3H), 4.80-4.81 (m,
1H), 5.04-5.05 (m, 3H), 6.00 (s, 1H), 6.19-6.23 (m, 2H), 6.63-6.65 (m, 1H), 7.23 (s, 1H) ppm; 13C{1H}
NMR (75.5 MHz, CDCl3): δ 13.2, 30.4, 55.7, 55.8, 56.2, 84.3, 108.2, 108.6, 110.6, 111.5, 121.4, 123.4,
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133.7, 134.7, 141.8, 148.7, 149.8 ppm; MS (ESI) m/z (rel intensity): 398 (MH+, 100), 277 (56), 242
(10). HRMS (ESI-TOF): calcd. for C17H21INO2 [MH+] 398.0611; found, 398.0614.
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1-(2-Iodobenzyl)-2-(prop-1-en-2-yl)-1H-pyrrole (1d). According to general procedure, 9d (603 mg,
1.85 mmol) in dry THF (10 mL) was treated with potassium tert-butoxide (416 mg, 3.71 mmol) and
methyltriphenylphosphonium bromide (1.32 g, 3.71 mmol) in dry THF (20 mL). After work up,
purification by column chromatography (silica gel, petroleum ether/EtOAc 9/1) afforded N-
benzylpyrrole 1d as a colorless oil (556 mg, 93 %): IR (ATR): 1740 cm-1; 1H NMR (300 MHz, CDCl3):
δ 2.08 (s, 3H), 4.69 (s, 1H), 4.98-4.99 (m, 1H), 5.18 (s, 2H), 6.26-6.33 (m, 2H), 6.53-6.56 (m, 1H), 6.67-
6.68 (m, 1H), 6.96-7.02 (m, 1H), 7.25-7.30 (m, 1H), 7.86-7.89 (m, 1H) ppm; 13C{1H} NMR (75.5 MHz,
CDCl3): δ 24.2, 56.7, 96.5, 108.3, 109.1, 111.9, 124.0, 127.5, 128.8, 129.0, 134.7, 135.3, 139.2, 141.0
ppm. MS (ESI) m/z (rel intensity): 324 (MH+, 100). HRMS (ESI-TOF): calcd. for C14H15IN [MH+]
324.0244; found, 324.0250.
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1-((6-Iodobenzo[d][1,3]dioxol-5-yl)methyl)-2-(prop-1-en-2-yl)-1H-pyrrole (1e). According to
general procedure, 9e (661 mg, 1.79 mmol) in dry THF (20 mL) was treated with potassium tert-
butoxide (402 mg, 3.58 mmol) and methyltriphenylphosphonium bromide (1.28 g, 3.58 mmol) in dry
THF (20 mL). After work up, purification by column chromatography (silica gel, petroleum
ether/EtOAc 9/1) afforded N-benzylpyrrole 1e as a yellow solid (427 mg, 65 %): mp (Petroleum
ether/EtOAc): 114-116 °C; IR (ATR): 1620 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.06 (s, 3H), 4.69 (s,
1H), 4.97-4.98 (m, 1H), 5.06 (s, 2H), 5.93 (s, 2H), 6.05 (s, 1H), 6.22-6.27 (m, 2H), 6.62-6.63 (m, 1H),
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7.26 (s, 1H) ppm; C{1H} NMR (75.5 MHz, CDCl3): δ 24.2, 56.5, 84.0, 101.7, 108.0, 108.3, 109.2,
111.8, 118.4, 123.9, 134.5, 134.6, 135.2, 147.7, 149.0 ppm; MS (ESI) m/z (rel intensity): 368 (MH+,
100), 261 (28). HRMS (ESI-TOF): calcd. for C15H15INO2 [MH+] 368.0142; found, 368.0152.
1-(6-Iodo-2,3-dimethoxybenzyl)-2-(prop-1-en-2-yl)-1H-pyrrole (1f). According to general
procedure, 9f (599 mg, 1.56 mmol) in dry THF (20 mL) was treated with potassium tert-butoxide (351
mg, 3.11 mmol) and methyltriphenylphosphonium bromide (1.12 g, 3.11 mmol) in dry THF (20 mL).
After work up, purification by column chromatography (silica gel, petroleum ether/EtOAc 9/1) afforded
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N-benzylpyrrole 1f as a yellow solid (508.3 mg, 85 %): mp (petroleum ether/EtOAc): 54-56 °C; IR
(ATR): 1570 cm-1; 1H NMR (300 MHz, CDCl3): δ 2.24 (s, 3H), 3.57 (s, 3H), 3.87 (s, 3H), 5.16 (s, 1H),
5.29-5.30 (m, 1H), 5.35 (s, 2H), 6.07-6.10 (m, 1H), 6.19-6.21 (m, 1H), 6.37-6.39 (m, 1H), 6.72 (d, J =
8.6 Hz, 1H), 7.60 (s, J = 8.6 Hz, 1H) ppm; 13C{1H} NMR (75.5 MHz, CDCl3): δ 24.4, 51.0, 56.0, 60.7,
90.2, 107.4, 107.7, 113.3, 114.5, 121.1, 134.1, 134.7, 135.6, 136.2, 148.8, 153.4 ppm; MS (ESI) m/z (rel
intensity): 384 (MH+, 100), 277 (14), 242 (20). HRMS (ESI-TOF): calcd. for C16H19INO2 [MH+]
384.0455; found, 384.0462.
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1-(2-Iodo-3,5-dimethoxybenzyl)-2-(prop-1-en-2-yl)-1H-pyrrole (1g). According to general
procedure, 9g (283 mg, 0.73 mmol) in dry THF (10 mL) was treated with potassium tert-butoxide (165
mg, 1.47 mmol) and methyltriphenylphosphonium bromide (524 mg, 1.47 mmol) in dry THF (10 mL).
After work up, purification by column chromatography (silica gel, petroleum ether/EtOAc 95/5)
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afforded N-benzylpyrrole 1g as a colorless oil (184.9 mg, 66 %): IR (ATR): 1585 cm-1; H NMR (300
MHz, CDCl3): δ 2.07 (s, 3H), 3.64 (s, 3H), 3.89 (s, 3H), 4.69 (s, 1H), 4.96-4.97 (m, 1H), 5.17 (s, 2H),
5.75 (d, J = 2.7 Hz, 1H), 6.23-6.29 (m, 2H), 6.36 (d, J = 2.7 Hz, 1H), 6.67 (t, J = 2.3 Hz, 1H) ppm;
13C{1H} NMR (75.5 MHz, CDCl3): δ 24.2, 55.4, 56.5, 57.2, 77.1, 97.6, 104.7, 108.2, 109.0, 111.8,
124.2, 134.8, 135.2, 143.3, 158.7, 161.6 ppm; MS (ESI) m/z (rel intensity): 384 (MH+, 100), 257 (42),
242 (56). HRMS (ESI-TOF): calcd. for C16H19INO2 [MH+] 384.0455; found, 384.0465.
1-(5-Fluoro-2-iodobenzyl)-2-(prop-1-en-2-yl)-1H-pyrrole (1h). According to general procedure, 9h
(204 mg, 0.59 mmol) in dry THF (10 mL) was treated with potassium tert-butoxide (133 mg, 1.19
mmol) and methyltriphenylphosphonium bromide (424 mg, 1.19 mmol) in dry THF (10 mL). After
work up, purification by column chromatography (silica gel, petroleum ether/EtOAc 9/1) afforded N-
benzylpyrrole 1h as a colorless oil (188 mg, 93 %): IR (ATR): 1460 cm-1; 1H NMR (300 MHz, CDCl3):
δ 2.08 (s, 3H), 4.66 (s, 1H), 4.99-5.00 (m, 1H), 5.14 (s, 2H), 6.25-6.33 (m, 3H), 6.68 (dd, J = 2.7, 1.9
Hz, 1H), 6.73-6.80 (m, 1H), 7.78-7.83 (m, 1H) ppm; 13C{1H} NMR (75.5 MHz, CDCl3): δ 24.2, 56.5,
88.7 (d, J = 3.0 Hz), 108.7, 109.4, 111.9, 115.1 (d, J = 24.2 Hz), 116.4 (d, J = 22.0 Hz), 123.9, 134.6,
135.2, 140.3 (d, J = 7.7 Hz), 143.6 (d, J = 7.1 Hz), 163.8 (d, J = 248.1 Hz) ppm; MS (ESI) m/z (rel
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intensity): 342 (MH+, 85), 160 (33), 158 (100). HRMS (ESI-TOF): calcd. for C14H14FIN [MH+]
342.0149; found, 342.0161
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Domino carbopalladation-Suzuki reaction on 1. Synthesis of pyrrolo[1,2-b]isoquinolines 3.
General procedure A (Phosphane free catalytic system). Pd(OAc)2 (0.1 mmol) was added to a
mixture of N-(o-iodobenzyl)pyrrole 1 (1 mmol), boronic acid 2 (1.3 mmol), sodium carbonate (1.3
mmol) and tetrabutylammonium chloride (2 mmol) in DMF (3 ml). The mixture was stirred at 120 ºC
for the time indicated in each case. H2O (15 mL) was added and the resulting aqueous phase was
extracted with EtOAc (3 × 30 mL). The combined organic extracts were washed with brine (3 × 30 mL),
dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by column chromatography (silica
gel) of the resulting residue afforded the corresponding pyrroloisoquinoline 3.
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General procedure B (with phosphane L2). Pd2(dba)3·CHCl3 (0.1 mmol) was added to a mixture
of N-(o-iodobenzyl)pyrrole 1 (1 mmol), boronic acid 2 (1.3 mmol), sodium carbonate (1.3 mmol),
tri(furan-2-yl)phosphane (L2) (0.2 mmol) and tetrabutylammonium chloride (2 mmol) in DMF (3 ml).
The mixture was stirred at 120 ºC for 1 h. The corresponding pyrroloisoquinoline 3 was obtained after
work-up and chromatographic purification as indicated in General procedure A.
7,8-Dimethoxy-10-(4-methoxybenzyl)-10-methyl-5,10-dihydropyrrolo[1,2-b]isoquinoline (3aa).
According to General Procedure B, N-(o-iodobenzyl)pyrrole 1a (114 mg, 0.30 mmol) was treated with
Pd2(dba)3·CHCl3 (31.0 mg, 0.03 mmol), 4-methoxyphenylboronic acid (2a) (59.3 mg, 0.39 mmol),
sodium carbonate (41.3 mg, 0.39 mmol), tri(furan-2-yl)phosphane (L2) (13.9 mg, 0.06 mmol) and
tetrabutylammonium chloride (167 mg, 0.60 mmol) in DMF (1 mL) for 1 h. After work up, purification
by column chromatography (silica gel, petroleum ether/ethyl acetate 9/1) afforded 3aa as an oil (66 mg,
61 %): IR (ATR): 2970, 1510 cm-1; 1H NMR (300 MHz, CDCl3):  1.87 (s, 3H), 2.87 (d, J = 12.5 Hz,
1H), 2.99 (d, J = 12.5 Hz, 1H), 3.65-3.72 (m, 1H) 3.72 (s, 3H), 3.86 (s, 3H), 3.94 (s, 3H), 4.60 (d, J =
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15.4 Hz, 1H), 6.16-6.29 (m, 4H), 6.46-6.55 (m, 4H), 6.97 (s, 1H) ppm; C{1H} NMR (75.5 MHz,
CDCl3):  26.8, 41.1, 46.8, 53.6, 55.1, 55.9, 56.1, 102.6, 108.2, 108.2, 108.6, 112.6, 117.6, 125.1,
130.2, 131.0, 131.9, 135.0, 147.4, 148.2, 158.2 ppm; MS (ESI) m/z (rel intensity): 364 (MH+, 100), 242
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(12). HRMS (ESI-TOF): calcd. for C23H26NO3 [MH+] 364.1907; found, 364.1920. [5 (9 mg, 12 % was
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isolated as a by product. See spectroscopic data below]
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10-(4-Fluorobenzyl)-7,8-dimethoxy-10-methyl-5,10-dihydropyrrolo[1,2-b]isoquinoline
(3ab).
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According to General Procedure A, N-(o-iodobenzyl)pyrrole 1a (114 mg, 0.30 mmol) was treated with
Pd(OAc)2 (6.7 mg, 0.03 mmol), 4-fluorophenylboronic acid (2b) (55 mg, 0.39 mmol), sodium carbonate
(41.3 mg, 0.39 mmol) and tetrabutylammonium chloride (167 mg, 0.60 mmol) in DMF (1 mL) for 2 h.
After work up, purification by column chromatography (silica gel, petroleum ether/ethyl acetate 9/1)
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afforded 3ab as an oil (56.1 mg, 54 %): IR (ATR): 2965, 1510 cm-1; H NMR (300 MHz, CDCl3): 
1.85 (s, 3H), 2.88 (d, J = 12.5 Hz, 1H), 3.00 (d, J = 12.5 Hz, 1H), 3.64 (d, J = 15.4 Hz, 1H), 3.86 (s,
3H), 3.93 (s, 3H), 4.62 (d, J = 15.4 Hz, 1H), 6.14 (dd, J = 3.6, 1.7 Hz, 1H), 6.19-6.26 (m, 3H), 6.43 (s,
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1H), 6.50 (dd, J = 2.7, 1.7 Hz, 1H), 6.61-6.67 (m, 2H), 6.96 (s, 1H) ppm; C{1H} NMR (75.5 MHz,
CDCl3):  27.0, 41.0, 46.6, 53.6, 55.9, 56.1, 102.6, 108.0, 108.3, 108.4 (d, J = 7.8 Hz), 113.8 (d, J =
20.8 Hz), 117.6, 124.9, 131.3, 131.4, 133.7 (d, J = 3.2 Hz), 134.5, 147.5, 148.2, 161.7 (d, J = 244.2 Hz)
ppm; MS (ESI) m/z (rel intensity): 352 (MH+, 100), 350 (10), 243 (13). HRMS (ESI-TOF): calcd. for
C22H23FNO2 [MH+] 352.1707; found, 352.1713.
7,8-Dimethoxy-10-methyl-10-(4-nitrobenzyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline
(3ac).
According to General Procedure B, N-(o-iodobenzyl)pyrrole 1a (506 mg, 1.32 mmol) was treated with
Pd2(dba)3·CHCl3 (134 mg, 0.13 mmol), 4-nitrophenylboronic acid (2c) (284 mg, 1.7 mmol), sodium
carbonate (180 mg, 1.7 mmol), tri(furan-2-yl)phosphane (L2) (60.2 mg, 0.26 mmol) and
tetrabutylammonium chloride (723 mg, 2.60 mmol) in DMF (4 mL) for 1 h. After work up, purification
by column chromatography (silica gel, petroleum ether/ethyl acetate 9:1) afforded 3ac as an oil (470
mg, 94 %): IR (ATR): 2970, 1515 cm-1; 1H NMR (300 MHz, CDCl3):  1.90 (s, 3H), 3.05 (d, J = 12.1
Hz, 1H), 3.16 (d, J = 12.1 Hz, 1H), 3.68 (d, J = 15.7 Hz, 1H), 3.87 (s, 3H), 3.97 (s, 3H), 4.66 (d, J =
15.6 Hz, 1H), 6.18 (dd, J = 3.6, 1.7 Hz, 1H), 6.27 (dd, J = 3.6, 2.7 Hz, 1H), 6.41-6.45 (m, 3H), 6.50 (dd,
J = 2.7, 1.7 Hz, 1H), 7.02 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H) ppm; 13C{1H} NMR (75.5 MHz, CDCl3): 
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27.7, 41.0, 46.6, 54.2, 55.9, 56.2, 103.1, 108.1, 108.2, 108.7, 117.9, 122.2, 124.3, 130.6, 130.5, 133.6,
146.0, 146.6, 147.8, 148.5 ppm; MS (ESI) m/z (rel intensity): 379 (MH+, 100), 243 (23). HRMS (ESI-
TOF): calcd. for C22H23N2O4 [MH+] 379.1652; found, 379.1658.
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7,8-Dimethoxy-10-methyl-10-(4-trifluoromethylbenzyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline
(3ad). According to General Procedure A, N-(o-iodobenzyl)pyrrole 1a (115 mg, 0.30 mmol) was treated
with Pd(OAc)2 (6.7 mg, 0.03 mmol), 4-trifluoromethylphenylboronic acid (2d) (74.1 mg, 0.39 mmol),
sodium carbonate (41.3 mg, 0.39 mmol) and tetrabutylammonium chloride (167 mg, 0.60 mmol) in
DMF (1 mL) for 2 h.. After work up, purification by column chromatography (silica gel, petroleum
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ether/ethyl acetate 9/1) afforded 3ad as an oil (63.1 mg, 52 %): IR (ATR): 2935, 1515 cm-1; H NMR
(300 MHz, CDCl3):  1.87 (s, 3H), 2.97 (d, J = 12.3 Hz, 1H), 3.09 (d, J = 12.3 Hz, 1H), 3.66 (d, J =
15.5 Hz, 1H), 3.87 (s, 3H), 3.93 (s, 3H), 4.64 (d, J = 15.5 Hz, 1H), 6.16-6.17 (m, 1H), 6.26 (t, J = 3.1
13
Hz, 1H), 6.40-6.45 (m, 3H), 6.50-6.52 (m, 1H), 6.95 (s, 1H), 7.21 (d, J = 7.9 Hz, 2H) ppm; C{1H}
NMR (75.5 MHz, CDCl3):  27.2, 40.9, 46.6, 54.0, 55.9, 56.1, 102.9, 108.1, 108.4, 117.8, 123.9 (q, J =
3.8 Hz), 124.4 (q, J = 271.9 Hz), 124.7, 128.4 (q, J = 32.3 Hz), 130.2, 131.1, 134.2, 142.2, 147.7, 148.3
ppm; MS (ESI) m/z (rel intensity): 402 (MH+, 100), 243 (7). HRMS (ESI-TOF): calcd. for C23H23F3NO2
[MH+] 402.1675; found, 402.1682.
10-(3,5-bis(Trifluoromethy)lbenzyl)-7,8-dimethoxy-10-methyl-5,10-dihydropyrrolo[1,2-
b]isoquinoline (3ae). According to General Procedure B, N-(o-iodobenzyl)pyrrole 1a (114 mg, 0.30
mmol) was treated with Pd2(dba)3·CHCl3 (31 mg, 0.03 mmol), 3,5-bis(trifluoromethyl)phenylboronic
acid (2e) (101 mg, 0.39 mmol), sodium carbonate (41.3 mg, 0.39 mmol), tri(furan-2-yl)phosphane (L2)
(14 mg, 0.06 mmol) and tetrabutylammonium chloride (167 mg, 0.60 mmol) in DMF (1 mL) for 1 h.
After work up, purification by column chromatography (silicagel, petroleum ether/ethyl acetate 9/1)
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afforded 3ae as an oil (77.5 mg, 55%): IR (ATR): 2940, 1520 cm-1; H NMR (300 MHz, CDCl3): 
1.91 (s, 3H), 2.99 (d, J = 12.3 Hz, 1H), 3.12 (d, J = 12.3 Hz, 1H), 3.46 (d, J = 15.9 Hz, 1H), 3.84 (s,
3H), 3.96 (s, 3H), 4.64 (d, J = 15.9 Hz, 1H), 6.18 (dd, J = 3.6, 1.7 Hz, 1H), 6.27 (dd, J = 3.6, 2.7 Hz,
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1H), 6.40 (s, 1H), 6.46 (dd, J = 2.7, 1.7 Hz, 1H), 6.61-6.62 (m, 2H), 7.01 (s, 1H), 7.62 (s, 1H) ppm;
13C{1H} NMR (75.5 MHz, CDCl3):  26.9, 40.9, 46.2, 54.0, 56.0, 56.3, 103.1, 108.2, 108.8, 118.0,
119.9 (sept, J = 3.9 Hz), 123.2 (q, J = 272.7 Hz), 124.3, 130.0, 130.1 (q, J = 33.0 Hz), 133.0, 140.5,
148.2, 148.8 ppm; MS (ESI) m/z (rel intensity): 470 (MH+, 100), 360 (11). HRMS (ESI-TOF): calcd. for
C24H22F6NO2 [MH+] 470.1549; found, 470.1553. [5 (12.2 mg, 16%) was isolated as a by product. See
spectroscopic data below]
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10-(3,4-Dimethoxybenzyl)-7,8-dimethoxy-10-methyl-5,10-dihydropyrrolo[1,2-b]isoquinoline
(3af). According to General Procedure B, N-(o-iodobenzyl)pyrrole 1a (114 mg, 0.30 mmol) was treated
with Pd2(dba)3·CHCl3 (31.0 mg, 0.03 mmol), 3,4-dimethoxyphenylboronic acid (2f) (71 mg, 0.39
mmol), sodium carbonate (41.3 mg, 0.39 mmol), tri(furan-2-yl)phosphane (L2) (13.9 mg, 0.06 mmol)
and tetrabutylammonium chloride (167 mg, 0.60 mmol) in DMF (1 mL) for 4 h. After work up,
purification by column chromatography (silica gel, petroleum ether/ethyl acetate 9/1) afforded 3af as an
oil (72.8 mg, 62 %): IR (ATR): 2935, 1515 cm-1; 1H NMR (300 MHz, CDCl3):  1.88 (s, 3H), 2.85 (d,
J = 12.4 Hz, 1H), 2.98 (d, J = 12.4 Hz, 1H), 3.51 (s, 3H), 3.54 (d, J = 15.4 Hz, 1H), 3.80 (s, 3H), 3.86 (s,
3H), 3.96 (s, 3H), 4.57 (d, J = 15.4 Hz, 1H), 5.72 (d, J = 2.0 Hz, 1H), 5.87 (dd, J = 8.1, 2.0 Hz, 1H),
6.17 (dd, J = 3.6, 1.7 Hz, 1H), 6.27 (dd, J = 3.6, 2.7 Hz, 1H), 6.42 (s, 1H), 6.46-6.49 (m, 2H), 7.02 (s,
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1H) ppm; C{1H} NMR (75.5 MHz, CDCl3):  27.1, 41.2, 46.7, 54.2, 55.4, 55.8, 55.9, 56.2, 102.5,
108.0, 108.3, 108.5, 109.9, 112.9, 117.5, 121.9, 125.2, 130.6, 131.7, 134.8, 147.4, 147.5, 147.6, 148.2
ppm; MS (ESI) m/z (rel intensity): 394 (MH+, 86), 242 (11). HRMS (ESI-TOF): calcd. for C24H28NO4
[MH+] 394.2013; found, 394.2017.
10-Benzyl-7,8-dimethoxy-10-methyl-5,10-dihydropyrrolo[1,2-b]isoquinoline (3ag). According to
General Procedure A, N-(o-iodobenzyl)pyrrole 1a (114 mg, 0.30 mmol) was treated with Pd(OAc)2 (6.7
mg, 0.03 mmol), phenylboronic acid (2g) (47.5 mg, 0.39 mmol), sodium carbonate (41.3 mg, 0.39
mmol) and tetrabutylammonium chloride (167 mg, 0.60 mmol) in DMF (1 mL) for 4 h. After work up,
purification by column chromatography (silica gel, petroleum ether/ethyl acetate 9/1) afforded 3ag as a
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solid (45.8 mg, 46%): mp (petroleum ether/EtOAc): 98-100 °C; IR (ATR): 2970, 1515 cm-1; H NMR
(300 MHz, CDCl3):  1.86 (s, 3H), 2.90 (d, J = 12.3 Hz, 1H), 3.02 (d, J = 12.3 Hz, 1H), 3.61 (d, J =
15.3 Hz, 1H), 3.85 (s, 3H), 3.91 (s, 3H), 4.59 (d, J = 15.3 Hz, 1H), 6.15 (dd, J = 3.6, 1.7 Hz, 1H), 6.25
(dd, J = 3.6, 2.6 Hz, 1H), 6.28-6.32 (m, 2H), 6.43 (s, 1H), 6.50 (dd, J = 2.7, 1.7 Hz, 1H), 6.92-6.98 (m,
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3H), 7.06-7.11 (m, 1H) ppm; C{1H} NMR (75.5 MHz, CDCl3):  26.9, 41.0, 46.7, 54.3, 55.9, 56.1,
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102.6, 108.1, 108.2, 108.6, 117.6, 125.1, 126.1, 127.1, 130.1, 131.7, 134.9, 137.9, 147.4, 148.1 ppm;
MS (ESI) m/z (rel intensity): 334 (MH+, 100), 243 (11). HRMS (ESI-TOF): calcd. for C22H24NO2
[MH+] 334.1802; found, 334.1813.
7,8-Dimethoxy-10-methyl-10-(naphthalen-2-ylmethyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline
(3ah). According to General Procedure A, N-(o-iodobenzyl)pyrrole 1a (114 mg, 0.30 mmol) was treated
with Pd(OAc)2 (6.7 mg, 0.03 mmol), naphthalen-2-ylboronic acid (2h) (67.1 mg 0.39 mmol), sodium
carbonate (41.3 mg, 0.39 mmol) and tetrabutylammonium chloride (167 mg, 0.60 mmol) in DMF (1
mL) for 1 h. After work up, purification by column chromatography (silica gel, petroleum ether/ethyl
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acetate 9/1) afforded 3ah as an oil (61 mg, 53%): IR (ATR): 3010, 1275 cm-1; H NMR (300 MHz,
CDCl3):  1.91 (s, 3H), 3.06 (d, J = 12.4 Hz, 1H), 3.18 (d, J = 12.4 Hz, 1H), 3.47 (d, J = 15.4 Hz, 1H),
3.83 (s, 3H), 3.91 (s, 3H), 4.50 (d, J = 15.4 Hz, 1H), 6.19 (dd, J = 3.6, 1.7 Hz, 1H), 6.27-6.29 (m, 1H),
6.36 (s, 1H), 6.41 (dd, J = 8.4, 1.7 Hz, 1H), 6.45-6.47 (m, 1H), 6.75 (s, 1H), 6.98 (s, 1H), 7.35-7.43 (m,
3H), 7.49-7.52 (m, 1H), 7.70-7.73 (m, 1H) ppm; 13C{1H} NMR (75.5 MHz, CDCl3):  26.8, 41.1, 46.8,
54.4, 55.9, 56.1, 102.7, 108.2, 108.3, 108.6, 117.7, 124.9, 125.2, 125.4, 126.2, 127.3, 127.6, 128.6,
128.7, 131.8, 132.0, 132.9, 134.8, 135.5, 147.4, 148.2 ppm; MS (ESI) m/z (rel intensity): 384 (MH+,
100), 242 (23). HRMS (ESI-TOF): calcd. for C26H26NO2 [MH+] 384.1958; found, 384.1964.
7,8-Dimethoxy-10-methyl-10-(phenanthren-9-ylmethyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline
(3ai). According to General Procedure A, N-(o-iodobenzyl)pyrrole 1a (115 mg, 0.30 mmol) was treated
with Pd(OAc)2 (6.7 mg, 0.03 mmol), phenanthren-9-ylboronic acid (2i) (86.8 mg 0.39 mmol), sodium
carbonate (41.3 mg, 0.39 mmol) and tetrabutylammonium chloride (167 mg, 0.60 mmol) in DMF (1
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mL) for 1 h. After work up, purification by column chromatography (silica gel, petroleum ether/ethyl
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acetate 9/1) afforded 3ai as an oil (82.6 mg, 63%): IR (ATR): 2970, 1515 cm-1; H NMR (300 MHz,
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CDCl3):  1.97 (s, 3H), 3.48-3.56 (m, 3H), 3.74 (s, 3H), 3.81 (s, 3H), 4.43 (d, J = 15.5 Hz, 1H), 6.19-
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6.23 (m, 3H), 6.35-6.36 (m, 1H), 6.69 (s, 1H), 6.95 (s, 1H), 7.23-7.28 (m, 1H), 7.43-7.60 (m, 5H), 8.58-
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8.61 (m, 2H) ppm; C{1H} NMR (75.5 MHz, CDCl3):  26.2, 41.2, 47.1, 49.5, 56.0, 56.2, 102.8,
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108.2, 108.6, 109.1, 118.0, 122.2, 122.4, 124.5, 125.3, 125.4, 125.7, 126.1, 126.3, 128.3, 129.5, 129.6,
131.3, 131.8, 132.3, 132.4, 135.2, 147.6, 148.3 ppm; MS (ESI) m/z (rel intensity): 434 (MH+, 100), 242
(59). HRMS (ESI-TOF): calcd. for C30H28NO2 [MH+] 434.2115; found, 434.2119.
7,8-Dimethoxy-10-methyl-10-(pyren-1-ylmethyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline (3aj).
According to General Procedure B, N-(o-iodobenzyl)pyrrole 1a (115 mg, 0.30 mmol) was treated with
Pd2(dba)3·CHCl3 (31.0 mg, 0.03 mmol), pyren-1-ylboronic acid (2j) (96 mg, 0.39 mmol), sodium
carbonate (41.3 mg, 0.39 mmol), tri(furan-2-yl)phosphane (L2) (13.9 mg, 0.06 mmol) and
tetrabutylammonium chloride (167 mg, 0.60 mmol) in DMF (1 mL) for 1 h. After work up, purification
by column chromatography (silica gel, petroleum ether/ethyl acetate 9/1) afforded 3aj as an oil (114.2
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mg, 83%): IR (ATR): 2970, 1515 cm-1; H NMR (300 MHz, CDCl3):  2.06 (s, 3H), 2.85 (d, J = 15.4
Hz, 1H), 3.68 (s, 3H), 3.72-3.73 (m, 2H), 3.91 (s, 3H), 4.20 (d, J = 15.4 Hz, 1H), 6.09 (s, 1H), 6.25-6.33
(m, 3H), 6.99 (d, J = 7.9 Hz, 1H), 7.08 (s, 1H), 7.51 (d, J = 9.4 Hz, 1H), 7.71 (d, J = 9.4 Hz, 1H), 7.79
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(d, J = 7.9 Hz, 1H), 7.92-8.13 (m, 5H) ppm; C{1H} NMR (75.5 MHz, CDCl3):  26.6, 41.7, 46.8,
50.5, 56.0, 56.3, 102.9, 108.2, 108.6, 109.0, 118.1, 123.4, 123.7, 124.2, 124.5, 124.6, 124.7, 125.5,
125.7, 126.2, 126.9, 127.5, 129.5, 129.9, 130.2, 130.6, 131.3, 132.0, 132.5, 134.8, 147.7, 148.4 ppm;
MS (ESI) m/z (rel intensity): 458 (MH+, 100), 242 (56). HRMS (ESI-TOF): calcd. for C32H28NO2
[MH+] 458.2115; found, 458.2123
7,8-Dimethoxy-10-methyl-10-(thiophen-3-ylmethyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline
(3ak). According to General Procedure B, N-(o-iodobenzyl)pyrrole 1a (114 mg, 0.30 mmol) was treated
with Pd2(dba)3·CHCl3 (31.0 mg, 0.03 mmol), thiophen-3-ylboronic acid (2k) (50 mg, 0.39 mmol),
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