Intramolecular palladium-catalyzed direct arylation vs. Heck reactions: Synthesis of pyrroloisoquinolines and isoindoles

Article abstract of DOI:10.1002/adsc.200900368

The competition between C-H activation and Heck reactions has been studied on 2-alkenylsubstituted o-iodobenzylpyrroles. The reaction can be switched from the alkene to the pyrrole nucleus by choosing the adequate catalytic system, regardless of the natur

Full text of DOI:10.1002/adsc.200900368

FULL PAPERS
DOI: 10.1002/adsc.200900368
Intramolecular Palladium-Catalyzed Direct Arylation vs. Heck
Reactions: Synthesis of Pyrroloisoquinolines and Isoindoles
Sergio Lage,a Unai Martꢀnez-Estꢀbalez,a Nuria Sotomayor,a and Esther Letea,*
a
Departamento de Quꢀmica Orgꢁnica II, Facultad de Ciencia y Tecnologꢀa, Universidad del Paꢀs Vasco/Euskal Herriko
Unibertsitatea, Apdo. 644, 48080 Bilbao, Spain
Fax : (+34)-49-4601-2748; e-mail: esther.lete@ehu.es
Received: May 27, 2009; Published online: October 1, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900368.
À
Abstract: The competition between C H activation taining excellent yields of pyrrolo
[1,2-b]isoquinolines
and Heck reactions has been studied on 2-alkenyl- or pyrrolo
substituted o-iodobenzylpyrroles. The reaction can
be switched from the alkene to the pyrrole nucleus
ACHTUNGTREN[NUNG 2,1-a]isoindoles.
À
by choosing the adequate catalytic system, regardless Keywords: C C coupling; direct arylation; Heck re-
of the nature of the substituent on the alkene, ob- action; palladium
À
Introduction
lar MH and C H activation reactions (or direct aryla-
tion reaction).
À
Palladium-catalyzed coupling reactions of aryl and
Direct construction of biaryl C C bonds by a Pd-
vinyl halides with alkenes have demonstrated to be catalyzed coupling of (hetero)arenes with aryl halides
extremely powerful methods for the construction of is a relatively clean and efficient method to generate
[1]
À
C C bonds. Since the important contribution made the products in the most efficient and environmental-
by Mizoroki and Heck in the early 1970s,[2] these tran- ly friendly way.[10] In this context, in 1990 Grigg[11] re-
sition metal-catalyzed transformations have found ported the first example of the palladium-catalyzed
wide application in synthesis for preparing complex direct arylation of pyrrole using a tethered aryl
organic structures,[3] even in an asymmetric fashion.[4] iodide, the utility of which was demonstrated in the
In particular, intramolecular versions of the Mizoro- synthesis of the lamellarin class of marine natural
ki–Heck (MH) reaction have provided a very useful products[12] or the pyrrolo
ACTHNUTRGNE[NUG 2,1-a]isoindolone nucleus
route to several types of heterocyclic systems.[5] In of a novel series of potent Cdk4 inhibitors.[13] The po-
connection with our work on Parham-type cycliza- tential of palladium-catalyzed functionalization of the
tions,[6] we have recently developed[7] an intramolecu- pyrrole C H function has also been shown by Trau-
À
lar carbolithiation for the synthesis of pyrroloCAHTUNGTRENNUNG
b]isoquinolines, which represents the structural core this intramolecular palladium coupling reaction onto
of the lycorine class of Amaryllidaceae alkaloids[8] and pyrrole derivatives has been used in the synthesis of
the phenanthroindolizidine alkaloids.[9] Therefore, we other nitrogen heterocycles, such as hetero-fused qui-
decided to investigate the MH reaction as an alterna- nolones[15] and azepinones.[16] In a similar way, Laut-
tive strategy for the synthesis of these compounds, ens has reported the preparation of annulated nitro-
since the same substrates, 2-alkenyl-substituted N-(o- gen heterocycles via a one-pot palladium-catalyzed al-
iodobenzyl)pyrroles, can be used in both types of in- kylation/norbornene-mediated direct arylation se-
tramolecular reactions. In addition, we were also in- quence.[17] Direct arylation of pyrroles has also been
trigued by the possibility of a direct arylation reaction carried out using other types of aryl derivatives, such
to take place on the C-2 pyrrole carbon to construct as iodine hipervalent reagents[18] or boronic acids.[19]
À
biaryl C C bonds and give the corresponding isoin-
Herein we describe our results on the competition
doles. Therefore, one of our challenges was to control between the MH and direct arylation reactions on 2-
the chemoselectivity associated with the intramolecu- alkenyl-substituted N-(o-iodobenzyl)pyrroles with dif-
ferent substitution patterns on the alkene. We have
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Intramolecular Palladium-Catalyzed Direct Arylation vs. Heck Reactions:
FULL PAPERS
demonstrated that the cyclization may be switched predicts both the relative rate and the regioselectivity
from the isoquinoline to the isoindole nucleus by of palladium-catalyzed direct arylation of electron-
choosing the adequate catalytic system.
rich heteroarenes, which have been more commonly
proposed to react via an SEAr pathway.[24]
With this in mind, we tested the first intramolecular
Pd-catalyzed coupling reaction on 2-alkenyl-substitut-
ed N-(o-iodobenzyl)pyrrole 3a (R=CO2Bn), using
Results and Discussion
À
To investigate the competition between MH and C H different catalytic systems in order to optimize the re-
activation reactions, we prepared a series of 2-alken- action conditions (Table 1).
yl-substituted N-(o-iodobenzyl)pyrroles 3a–e by
Wittig reaction of aldehyde 1[20] with the correspond- reaction from compound 3a employed the Jeffery[25]
ing phosphorus ylides 2, previously prepared (2a, R= conditions: Pd(OAc)2 (10 mol%), PPh3 (40 mol%),
CO2Bn, 2b R=CONEt2), or generated in situ starting (n-Bu)4NCl and NaHCO3 in acetonitrile at 608C.
from the corresponding phosphomiun salt (2c R=Ph, Gratifyingly, the direct arylation product, pyrrolo[2,1-
2e R=OCH3) (Scheme 1). When the reactions were a]isoindole 4a was obtained as major product. The
carried out with stabilized ylides, compounds 3a, b dihydropyrrolo[1,2-b]isoquinoline 5a, formed by intra-
Initial efforts to effect the carbon-carbon coupling
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
were isolated in good yields as single E stereoisomers. molecular MH reaction, was also isolated as minor
However, the reactions with ylides 2c, e led to a mix- product (8% yield) (Table 1, entry 1). The reaction in
ture of both E and Z isomers, which could not be DMF at 608C was equivalent to that in acetonitrile
easily separated by column chromatography, so their (entry 2), and superior to the reaction in less polar
1
ratio was calculated by H NMR spectroscopy. Finally, solvents. A series of palladium sources and ligands
3d was prepared by DIBALH reduction of 3a to the were screened in an effort to develop a cleaner reac-
corresponding alcohol and subsequent alkylation with tion. Changing the ammonium salt [(n-Bu)4NOAc in-
MeI.
stead of (n-Bu)4NCl, entry 3] increased the yield of
Our goal was to search for adequate catalytic sys- isoindole derivative 4a to a 92% in only 3 h. Similar
tems to direct the intramolecular palladium-catalyzed results were obtained using NEt3 as base or even in
reaction to the pyrrole ring or to the alkene. The cata- the absence of base (entries 4 and 5). Decreasing the
lytic cycle of the MH reaction has been studied in catalyst loading in the original PdACHTUNRTGNEUNG(OAc)2/PPh3 system
detail,[21] and it depends strongly on the catalytic also led to good yield (90%) with 100% conversion
system and the presence of additives. On the other (entry 7). Bidentate phosphines, such as dppp, could
hand, mechanistically the direct arylation of heteroar- also be used for direct arylation when using TlOAc as
enes has been proposed to occur via oxidative addi- additive (entries 8–10). The chemoselectivity could be
tion of the transition metal into the aryl halide, fol- shifted to the electron-deficient alkene with this cata-
lowed by different pathways for the key carbon- lytic system in the absence of TlOAc, and with (n-
carbon bond forming step.[10c] In this context, Bu)4NI as iodide anion source, obtaining the pyrroloi-
Fagnou[22] has recently reported that the concerted soquinoline 5a though in moderate yield. Similar
metalation-deprotonation (CMD) pathway,[23] first yields of 5a were obtained using Pd
proposed by Echavarren and Maseras,[23d] accurately under classical conditions [(n-Bu)4NCl NaHCO3 in
acetonitrile under reflux]. Thus, Pd(OAc)2
(2.5 mol%), PPh3A(10 mol%), using (n-Bu)4NOAc as
ACHTUNGTRENN(NUG PPh3)4 as catalyst
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
additive in DMSO at 608C, emerged as the catalyst
that offered the optimal balance of reaction rate and
selectivity for C-functionalization over MH reaction,
together with dppp (5 mol%) in the presence of
TlOAc (1.2 equiv.).
Thus, we extended the procedure to benzylpyrroles
3b–e that incorporate alkenes both with electron-
withdrawing and electron-donating groups. As shown
on Table 2, in all cases the reaction with Pd
ACHTUNGERTN(NUNG OAc)2/
PPh3/A(n-Bu)4NOAc was completely selective towards
CTHUNGTRENNUNG
Scheme 1. Reagents and conditions: (i) For 3a, b: Ph3P=
CHCO2Bn or Ph3P=CHCONEt2, CH2Cl2, reflux, 4 days. (ii)
For 3c: Ph3P+CH2Ph ClÀ , n-BuLi, THF, 08C to À788C,
12 h. (iii) For 3e: Ph3P+CH2OCH3 ClÀ, t-BuOK, toluene,
room temperature, 5 h. (iv) For 3d: DIBALH, toluene,
À788C, 15 min; then MeOH, room temperature, 1 h. (v)
NaH, THF, room temperature, 1.5 h; then MeI, room tem-
perature, 16 h.
the direct arylation reaction, obtaining the pyrroloi-
sondoles 4b–e in excellent yields. It is interesting to
point out the relevance of the ammonium salt. When
(n-Bu)4NCl was used instead,[26] the reaction was not
selective, furnishing variable yields of the MH reac-
tion, products 5b–d (5–20%), showing the importance
of the presence of acetate ions on the mechanism. As
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Table 1. MH reaction or direct arylation of 3a.
Entry
Pd
Pd(OAc)2[a]
Ligand
Additive
Base
Solvent
Time [h]
4a [%]
5a [%]
[a]
[b]
1
2
3
4
5
6
7
8
G
R
PPh3[b]
Bu4NCl
Bu4NCl
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NCl
–
NaHCO3
NaHCO3
NaHCO3
Et3N
–
–
CH3CN
DMF
DMF
DMF
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
CH3CN
8
8
3
3
3
3
3
6
9
3
24
16
73
70
92
94
93
97
90
86
80
85
–
8
8
–
–
–
–
–
–
–
Pd(OAc)2[a]
Pd(OAc)2[a]
Pd(OAc)2[a]
Pd(OAc)2[a]
Pd(OAc)2[c]
Pd(OAc)2[c]
Pd(OAc)2[c]
Pd(OAc)2[c]
Pd(OAc)2[c]
Pd(OAc)2[c]
Pd(PPh3)4
PPh3[b]
PPh3[b]
PPh3[b]
PPh3[b]
PPh3[b]
PPh3
R
N
R
R
N
N
R
E
–
dppp[d]
dppp[d]
dppp[d]
dppp[d]
–
TlOAc
TlOAc
TlOAc
–
9
10
11
12
Bu4NOAc
Bu4NI
Bu4NCl
R
A
40
42
NaHCO3
–
[a]
10 mol%.
40 mol%.
2.5 mol%.
5 mol%.
[b]
[c]
[d]
Table 2. Direct arylation of 3b–e. Synthesis of pyrroloisoin- reaction. This is one of the few examples of competi-
doles 4b–e.
tion between intramolecular direct arylation and MH
reactions.[27]
We then extended the procedure for the MH reac-
tion. The optimal reactions conditions were deter-
mined to be PdACTHNUTRGNEUNG(PPh3)4 (2.5 mol%), (n-Bu)4NCl, and
NaHCO3 in acetonitrile at 608C, as shown on Table 1
for 3a. Under these conditions, the reactions proceed-
ed with complete +chemo and regioselectivity on the
alkene in favor of the exo cyclization product to
afford the pyrroloisoquinolines 5b–d in good yields.
Only in the case of 3e, a minor endo product, the pyr-
rolobenzazepine 6e (21%) was obtained (Scheme 2).
To explain the change in the chemoselectivity it is
necessary to understand the intermediate palladium
species involved in the catalytic cycles, which have
been studied in detail by Jutand.[28] Thus, when
Entry Substrate Ligand Base
Product Yield [%]
[a]
1
2
3
4
5
6
7
8
3b
3b
3c
3c
3d
3d
3e
3e
PPh3
–
4b
84
96
92
96
90
60
70
86
dppp[b] TlOAc[c] 4b
[a]
PPh3
–
4c
dppp[b] TlOAc[c] 4c
[a]
PPh3
–
4d
dppp[b] TlOAc[c] 4d
[a]
PPh3
–
4e
Pd
ACHTUNGTRNEN(UNG OAc)2/nPPh3 (n>2) is used, trans complex I (X=
dppp[b] TlOAc[c] 4e
OAc) is formed, while the intermediate species for
[a]
[b]
[c]
10 mol%.
5 mol%.
1.2 equiv.
PdACHTNURTGNEUG(N PPh3)4 is II (X=I), with an iodide ligand
(Scheme 3).[28] On the other hand, it has also been
found[29] that the acetate ion is easily dissociable, and
equilibrium could be established between trans-
ArPd
(PPh3)]+ in polar aprotic solvents. Thus, a mechanism
involving an electrophilic palladium(II) species that
ACHUTGTNERNG(NU PPh3)ACHTUNGTRENN(UGN OAc) species I, and cationic [ArPd-
shown on Table 2, the use of dppp/TlOAc gave com-
parable yields.
ACHTUNGTRENNUNG
Although the direct arylation of pyrroles with aryl would react preferentially at the more electron-rich
iodides has been reported,[10–19] the reaction described pyrrole nucleus through an SEAr pathway could be
herein can be carried out in the presence of alkenes suggested. However, Fagnou[23b] has reported that, on
(both electron-rich and poor) by choosing the ade- direct arylation reactions, the reactivity depended on
À
quate catalytic system, avoiding the competing MH C H acidity, not on arene nucleophilicity. Thus, a
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Intramolecular Palladium-Catalyzed Direct Arylation vs. Heck Reactions:
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Scheme 2. MH reaction of 3b–e. Synthesis of pyrroloisoquinolines 5b–e.
Conversely, catalytic species II (X=I) would favor
a Heck-type a,b-insertion reaction.[21] In this case, the
anchimeric assistance of the iodide anion to remove a
proton in an intermediate such as III would be much
more difficult to take place, and the only catalytic re-
action would be a Heck-type via a neutral mecha-
nism, preferentially in the b-position (with the only
exception of the minor formation of 6e) of the more
electron-deficient alkene, therefore affording an inter-
mediate VI. After rotation, syn palladium hydride
elimination would give the Z configuration of the
double bond on 5a–c and 5e. The minor formation of
pyrroloisoquinolines in the presence of (n-Bu)4NCl
(Table 1, entries 1 and 2) could be attributed to the
formation of a chloride coordinated palladium spe-
cies, as reported by Jutand,[28c] that would react
through a Heck mechanism.
This alternative Heck reaction mechanism could
also explain the formation of pyrroloisoquinoline 5a
with PdACTHNURTGNENG(U OAc)2/dppp when a source of iodide is used
Scheme 3. Proposed CMD and MH mechanisms.
(Bu4NI) instead of acetate (Table 1, entry 11), through
the formation of an iodide coordinated species analo-
gous to II, that would react through a neutral path-
way.
concerted metalation-deprotonation (CMD) path-
way,[23]involving proton abstraction by the acetate ion Conclusions
could be proposed (Scheme 3). This mechanism
would explain the selective arylation even in the pres- In conclusion, we have demonstrated that the intra-
ence of an electron-rich alkene, such as 3e (Table 2, molecular palladium-catalyzed reaction of 2-alkenyl-
entries 7 and 8) and the improvement of the chemose- substituted N-(o-iodobenzyl)pyrroles can be switched
lectivity towards the direct arylation when a source of from the alkene to the pyrrole nucleus by choosing
acetate ions, such as (n-Bu)4NOAc is added (Table 1, the adequate catalytic system. In fact, the nature of
entries 1–3).
the X ligand on the palladium intermediate species
A similar CMD mechanism could be proposed (X=OAc, I) determines the chemoselectivity of the
when dppp is used instead of PPh3, as analogous pal- reaction. The reactions employ only 2.5 mol% of
ladium species have been reported for this catalytic commercially available catalyst to effect 5-exo-trig
system.[30] In this case, the presence of thallium salts is direct arylation or 6-exo-trig MH cyclizations to gen-
necessary, as iodide ion scavenger.[31]
erate pyrroloACTHNGUTERNNU[G 2,1-a]isoindoles or dihydropyrroloACHTUNGTRENNUNG[1,2-
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6.27 (d, J=3.7 Hz, 1H isomer E), 6.42 (d, J=15.3 Hz, 1H
isomer E)*, 6.44 (d, J=12.5 Hz, 1H isomer Z)*, 6.65 (d, J=
3.7 Hz, 1H isomer E), 6.77 (d, J=3.7 Hz, 1H isomer Z), 6.92
(s, 1H isomer Z), 7.01 (s, 2H isomer E and Z), 7.06 (s, 1H
isomer E), 7.67 ppm (d, J=15.3 Hz, 1H isomer E) (*desig-
nates partially overlapped signals); 13C NMR (75.5 MHz,
CDCl3, 258C): d=13.3 (CH3 isomer Z), 15.0 (CH3 isomer
E), 41.1 (CH2 isomer Z), 42.2 (CH2 isomer E), 48.9 (CH2
isomer Z), 50.4 (CH2 isomer E), 56.1 (CH3 isomers Z and
E), 99.0 (CH isomer Z), 99.3 (CH isomer E), 102.6 (CH
isomer Z), 102.7 (CH isomer E), 106.9 (CH isomer E), 107.1
(CH isomer Z), 110.4 (CH isomer E), 115.5 (CH isomer Z),
116.5 (CH isomer Z), 117.2 (CH isomer E), 122.3 (CH
isomer Z), 125.7 (C isomer E), 125.8 (C isomer Z), 126.6 (C
isomer Z), 127.4 (C isomer E), 131.0 (CH isomer E), (132.3
(C isomer Z), 132.7 (C isomer E), 139.7 (C isomer Z), 142.2
(C isomer E), 147.6 (C isomer Z), 148.0 (C isomer E), 149.4
(C isomer Z), 149.6 (C isomer E), 166.3 (C isomer E),
b]isoquinolines, respectively. The substitution patterns
on the alkene do not affect the course of C-2 direct
arylation of pyrrole derivative. The selectivity of the
reactions appears to be controlled by the catalytic
system
Experimental Section
Intramolecular Palladium-Catalyzed Direct Arylation.
Synthesis of Pyrroloisoindoles 4a–e; General
Procedure
PdACHTUNGTRENNUNG(OAc)2 (2.5 or 10.0 mol%) was added to a mixture of N-
benzylpyrrole 3a–e (1 mmol), PPh3 (10 or 40 mol%) and (n-
Bu)4NOAc (1.5 mmol) in 5 mL of dry DMSO. Next, the
mixture was stirred at 608C under argon until TLC showed
complete reaction. The reaction mixture was then diluted
with 50 mL of AcOEt, washed with saturated NH4Cl (1ꢃ
30 mL) and H2O (2ꢃ30 mL), dried over Na2SO4, filtered
and concentrated. The oil crude was purified by flash
column chromatography (silica gel, hexane/AcOEt) to give
the corresponding pyrroloisoindoles 4a–e.
168.0 ppm (C isomer Z); IR (CHCl3): u=2995, 1625 cmÀ1
;
MS (EI): m/z (%)=341 (18) [M+1]+, 340 (47) [M]+, 241
(29), 240 (55), 226 (20), 224 (15), 196 (22), 91 (70); HR-MS
(EI+): m/z=340.1787, calcd. for C20H24N2O3 (M+):
340.1787.
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(E)-Benzyl 3-(7,8-dimethoxy-5H-pyrrolo
yl)acrylate (4a): According to the general procedure, Pd-
ACHTUNGTRENNUNG(OAc)2 (2.2 mg, 0.01 mmol) was added to a mixture of N-
ACHTUNGTREN[NUNG 2,1-a]isoindol-3-
0.04 mmol) was added to a mixture of N-benzylpyrrole 3c
(200 mg, 0.45 mmol), PPh3 (47 mg, 0.18 mmol) and (n-
Bu)4NOAc (203 mg, 0.67 mmol) in DMSO and this mixture
was stirred at 608C for 6 h. After work-up, purification by
column chromatography (silica gel, hexane/AcOEt 40%)
gave 4c as an oil as an isomeric mixture Z/E in a 1/1.1 ratio;
yield: 131 mg 892%). 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=3.88 (s, 3H isomer Z), 3.93 (s, 6H), 3.96 (s, 3H
isomer E), 4.53 (s, 2H isomer Z), 4.97 (s, 2H isomer E), 6.14
(d, J=3.7 Hz, 1H isomer Z), 6.28 (d, J=3.6 Hz, 1H isomer
E)*, 6.29 (d, J=3.7 Hz, 1H isomer Z)*, 6.39 (d, J=12.1 Hz,
1H isomer Z), 6.44 (d, J=12.1 Hz, 1H isomer Z), 6.49 (d,
J=3.6 Hz, 1H isomer E), 6.72 (d, J=16.4 Hz, 1H isomer E),
6.87 (s, 1H isomer Z), 7.01 (s, 2H isomer Z and E), 7.06 (d,
1H isomer E)*, 7.07 (s, 1H isomer E)*, 7.20–7.49 ppm (m,
10H) (*designates partially overlapped signals); 13C NMR
(75.5 MHz, CDCl3, 258C): d=49.3 (CH2 isomer Z), 50.8
(CH2 isomer E), 56.1 (CH3), 56.2 (CH3), 97.9 (CH isomer
Z), 98.5 (CH isomer E), 102.2 (CH isomer Z), 102.3 (CH
isomer E), 106.8 (CH isomer Z), 106.9 (CH isomer E), 112.8
(CH isomer Z), 114.2 (CH isomer E), 118.7 (CH isomer E),
118.9 (CH isomer Z), 123.0 (CH isomer E), 125.7 (C), 125.9
(C), 126.4 (CH isomer Z), 126.7 (CH isomer E), 127.0 (CH
isomer Z), 128.3 (CH isomer Z), 128.4 (CH isomer Z), 128.6
(CH isomer E), 128.7 (CH), 132.4 (C), 138.1 (C isomer E),
138.2 (C isomer Z), 138.5 (C isomer Z), 140.5 (C isomer E),
147.2 (C isomer Z), 147.5 (C isomer E), 149.2 (C isomer Z),
benzylpyrrole 3a (201 mg, 0.40 mmol), PPh3 (10.5 mg,
0.04 mmol) and (n-Bu)4NOAc (181 mg, 0.60 mmol) in
DMSO and this mixture was stirred at 608C for 3 h. After
work-up, purification by column chromatography (silica gel,
hexane/AcOEt 40%) gave 4a which was crystallized from
Et2O as a green solid; yield: 142 mg (97%); mp 148–1508C;
1H NMR (300 MHz, CDCl3, 258C, TMS): d=3.92 (s, 3H),
3.94 (s, 3H), 4.89 (s, 2H), 5.25 (s, 2H), 5.97 (d, J=15.8 Hz,
1H), 6.31 (d, J=3.9 Hz, 1H), 6.67 (d, J=3.9 Hz, 1H), 6.97
(s, 1H), 7.08 (s, 1H), 7.33–7.45 (m, 5H), 7.66 ppm (d, J=
15.8 Hz, 1H); 13C NMR (75.5 MHz, CDCl3, 258C): d=51.2
(CH2), 56.1 (CH3), 56.2 (CH3), 66.0 (CH2), 99.9 (CH), 102.8
(CH), 106.5 (CH), 109.2 (CH), 120.8 (CH), 124.9 (C), 126.3
(C), 128.1 (CH), 128.2 (CH), 128.5 (CH), 133.3 (C), 133.6
(CH), 136.4 (C), 144.0 (C), 148.4 (C), 149.5 (C), 167.8 ppm
(C); IR (KBr): u=2930, 1701, 1615 cmÀ1; MS (EI): m/z
(%)=376 (26) [M+1]+, 375 (100) [M]+, 285 (10), 284 (50),
256 (44), 241 (44), 240 (13), 226 (18), 224 (12), 196 (19), 91
(52); anal. calcd (%) for C23H21NO4: C 73.60, H 5.60, N
3.73; found: C 73.39, H 5.55, N 3.81.
A
ACHTUNGERTN[NUNG 2,1-a]isoindol-3-yl)-
ACHTUNGTRENNUNG
of N-benzylpyrrole 3b (210 mg, 0.45 mmol), PPh3 (10.5 mg,
0.04 mmol) and (n-Bu)4NOAc (202 mg, 0.67 mmol) in
DMSO and this mixture was stirred at 608C for 1.5 h. After
work-up, purification by column chromatography (silica gel,
hexane/AcOEt 80%) gave 4b as an oil as an isomeric mix-
ture Z/E in a 1/3 ratio; yield: 129 mg (84%). 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=1.12 (t, J=7.0 Hz, 6H
isomer Z), 1.20–1.28 (m, 6H isomer E), 3.39 (c, J=7.0 Hz,
4H isomer Z), 3.49–3.52 (m, 4H isomer E), 3.89 (s, 3H
isomer Z), 3.92 (s, 6H isomers Z and E), 3.94 (s, 3H isomer
E), 4.78 (s, 2H isomer Z), 4.90 (s, 2H isomer E), 5.82 (d, J=
12.5 Hz, 1H isomer Z), 6.19 (d, J=3.7 Hz, 1H isomer Z),
149.4 ppm (C isomer E); IR (CHCl3): u=2932, 1626 cmÀ1
;
MS (EI): m/z (%)=318 (13) [M + 1]+, 317 (58) [M]+, 303
(21), 302 (100), 274 (45), 273 (63), 272 (19), 259 (17), 258
(16), 230 (27), 228 (31), 215 (17); anal. calcd. (%) for
C21H19NO2: C 79.49, H 5.99, N 4.41; found: C 79.33, H 5.86,
N 4.26.
(E)-7,8-Dimethoxy-3-(3-methoxyprop-1-enyl)-5H-pyrrolo-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
2464
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ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2460 – 2468

Intramolecular Palladium-Catalyzed Direct Arylation vs. Heck Reactions:
FULL PAPERS
0.04 mmol) and nBu4NOAc (181 mg, 0.60 mmol) in DMSO
and this mixture was stirred at 608C for 6 h. After work-up,
purification by column chromatography (silica gel, hexane/
AcOEt 40%) gave 4d as an oil; yield: 115 mg (90%).
1H NMR (300 MHz, CDCl3, 258C): d=3.39 (s, 3H), 3.92 (s,
3H), 3.95 (s, 3H), 4.11 (dd, J=6.4, 1.2 Hz, 2H), 4.89 (s,
2H), 5.89 (dt, J=16.1, 6.4 Hz, 1H), 6.22 (d, J=3.6 Hz, 1H),
6.35 (d, J=3.6 Hz, 1H), 6.57 (d, J=16.1 Hz, 1H), 6.97 (s,
1H), 7.06 ppm (s, 1H); 13C NMR (75.5 MHz, CDCl3, 258C):
d=50.7 (CH2), 56.2 (CH3), 57.7 (CH3), 73.8 (CH3), 98.0
(CH), 102.5 (CH), 107.0 (CH), 113.8 (CH), 120.2 (CH),
123.4 (CH), 126.1 (C), 127.7 (C), 132.5 (C), 140.2 (C), 147.5
(silica gel, hexane/AcOEt) to give the corresponding pyrro-
loisoquinolines.
(Z)-Benzyl 2-(7,8-dimethoxypyrrolo
ylidene)acetate (5a): According to the general procedure,
Pd(PPh3)4 (12 mg, 0.01 mmol) was added to a mixture of N-
ACHTUNGERTN[NUNG 1,2-b]isoquinolin-10-
AHCTUNGTRENNUNG
benzylpyrrole 3a (226 mg, 0.45 mmol), (n-Bu)4NCl (167 mg,
0.60 mmol) and NaHCO3 (94 mg, 1.12 mmol) in CH3CN and
this mixture was stirred at reflux for 16 h. After work-up,
purification by column chromatography (silica gel, hexane/
AcOEt 40%) gave 5a as an oil; yield: 71 mg (42%).
1H NMR (300 MHz, CDCl3, 258C): d=3.92 (s, 3H), 3.93 (s,
3H), 5.06 (s, 2H), 5.24 (s, 2H), 6.18 (s, 1H), 6.34 (t, J=
3.9 Hz, 1H), 6.72 (s, 1H), 6.90 (s, 1H), 7.21 (s, 1H), 7.33–
7.46 (m, 5H), 7.51 ppm (t, J=2.4 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3, 258C): d=47.8 (CH2), 56.0 (CH3), 56.2
(CH3), 65.9 (CH2), 107.0 (CH), 107.6 (CH), 108.3 (CH),
109.5 (CH), 115.3 (CH), 122.6 (CH), 125.5 (C), 125.6 (C),
126.1 (C), 128.1 (CH), 128.5 (CH), 128.6 (CH), 136.1 (C),
139.2 (C), 148.6 (C), 150.1 (C), 166.2 ppm (C); IR (CHCl3):
u=2932, 1731, 1602 cmÀ1; MS (EI): m/z (%)=376 (16)
[M + 1]+, 375 (59) [M]+, 300 (31), 277 (15), 256 (21), 243
(17), 242 (25), 241 (100), 240 (69), 224 (14), 210 (14), 196
(18), 167 (17), 151 (22), 149 (20), 111 (15), 108 (17), 107
(17), 97 (23), 91 (76), 85 (24), 83 (28) 79 (19), 77 (18); HR-
MS (EI+): m/z=375.0523, calcd. for C23H21NO4 (M+):
375.0515.
(C), 149.6 ppm (C); IR (CHCl3): u=2920, 2826, 1643 cmÀ1
;
MS (EI): m/z (%)=285 (29) [M]+, 254 (100), 210 (10), 91
(47); HR-MS (EI+): m/z=285.1265, calcd. for C17H19NO3
(M+): 285.1365.
A
ACHTUNGTNER[NUNG 2,1-
ACHTUNGTRENNUNG
benzylpyrrole 3e (159 mg, 0.40 mmol), PPh3 (42 mg,
0.16 mmol) and (n-Bu)4NOAc (181 mg, 0.60 mmol) in
DMSO and this mixture was stirred at 608C for 7 h. After
work-up, purification by column chromatography (silica gel,
hexane/AcOEt 40%) gave 4e as a oil as a isomeric mixture
1
Z/E in a 2/3 ratio; yield: 76 mg (70%). H NMR (300 MHz,
CDCl3, 258C, TMS): d=3.69 (s, 3H isomer E), 3.80 (s, 3H
isomer Z), 3.90 (s, 6H), 3.94 (s, 6H), 4.74 (s, 4H), 5.21 (d,
J=6.7 Hz, 1H isomer Z), 5.80 (d, J=13.0 Hz, 1H isomer E),
6.06 (d, J=6.7 Hz, 1H isomer Z), 6.16 (d, J=3.4 Hz, 1H
isomer Z)*, 6.18 (d, J=3.4 Hz, 1H isomer Z)*, 6.21 (d, J=
3.5 Hz, 1H isomer E), 6.57 (d, J=3.5 Hz, 1H isomer E), 6.92
(d, J=13.0 Hz, 1H isomer E)*, 6.92 (s, 1H isomer Z)*, 6.95
(s, 1H isomer E)*, 7.02 (s, 1H isomer Z)*, 7.03 ppm (s, 1H
isomer E)* (*designates partially overlapped signals);
13C NMR (75.5 MHz, CDCl3, 258C): d=49.0 (CH2 isomer
Z), 50.0 (CH2 isomer E), 56.1 (CH3), 56.3 (CH3), 56.6 (CH3
isomer Z), 60.5 (CH3 isomer E), 95.6 (CH isomer Z), 97.0
(CH isomer E), 97.6 (CH isomer Z), 98.0 (CH isomer E),
102.1 (CH isomer Z), 102.3 (CH isomer E), 107.0 (CH
isomer Z), 107.1 (CH isomer E), 108.9 (CH isomer Z), 112.4
(CH isomer E), 125.8 (C isomer Z), 126.4 (C isomer E),
126.8 (C isomer Z), 127.2 (C isomer E), 131.9 (C isomer Z),
132.2 (C isomer E), 137.0 (C isomer Z), 138.0 (C isomer E),
144.9 (CH isomer Z), 146.6 (CH isomer E), 146.9 (C),
149.3 ppm (C); IR (CHCl3): u=2920, 1649, 1279 cmÀ1; MS
(EI): m/z (%)=271 (20) [M]+, 256 (29), 212 (15), 123 (11),
111 (15), 109 (16), 97 (23), 95 (28), 93 (11), 85 (65), 83 (26),
83 (100), 81 (32), 79 (13), 71 (30), 70 (11); HR-MS (EI+):
m/z=271.1208, calcd. for C16H17NO3 (M+): 271.1208.
(Z)-2-(7,8-Dimethoxypyrrolo
dene)-N,N-diethylacetamide (5b): According to the general
procedure, Pd(PPh3)4 (11.5 mg, 0.01 mmol) was added to a
mixture of N-benzylpyrrole 3b (187 mg, 0.40 mmol), (n-
Bu)4NCl (167 mg, 0.60 mmol) and NaHCO3
ACHTUNGTNER[NUNG 1,2-b]isoquinolin-10-yli-
AHCTUNGTRENNUNG
(84 mg,1.00 mmol) in CH3CN and this mixture was stirred at
reflux for 16 h. After work-up, purification by column chro-
matography (silica gel, hexane/AcOEt 90%) gave 5b which
was crystallized from Et2O as a brown solid; yield: 129 mg
(94%); mp 113–1158C. 1H NMR (300 MHz, CDCl3, 258C,
TMS): d=1.00 (t, J=7.1 Hz, 3H), 1.23 (t, J=7.1 Hz, 3H),
3.33 (c, J=7.1 Hz, 2H), 3.52 (c, J=7.1 Hz, 2H), 3.89 (s,
3H), 3.91 (s, 3H), 5.06 (s, 2H), 6.21 (s, 2H), 6.57 (s, 1H),
6.68 (s, 1H), 6.77 (s, 1H), 7.20 ppm (s, 1H); 13C NMR
(75.5 MHz, CDCl3, 258C): d=12.5 (CH3), 14.1 (CH3), 39.0
(CH2), 42.7 (CH2), 47.4 (CH2), 55.9 (CH3), 106.8 (CH), 108.4
(CH), 108.7 (CH), 109.7 (CH), 111.9 (CH), 120.6 (CH),
123.9 (C), 124.5 (C), 125.9 (C), 128.1 (C), 148.5 (C), 149.4
(C), 169.1 ppm (C); IR (KBr): u=2972, 1610 cmÀ1; MS (EI):
m/z (%)=341 (7) [M+1]+, 340 (26) [M]+, 269 (15), 268
(73), 242 (20), 241 (100), 240 (15), 224 (11); HR-MS (EI+):
m/z=340.1781, calcd. for C20H24N2O3 (M+): 340.1787.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
ture of N-benzylpyrrole 3c (200 mg, 0.45 mmol), (n-Bu)4NCl
(188 mg, 0.67 mmol) and NaHCO3 (94 mg,1.12 mmol) in
CH3CN and this mixture was stirred at reflux for 48 h. After
work-up, purification by column chromatography (silica gel,
hexane/AcOEt 40%) gave 5c as an oil as an isomeric mix-
ture Z/E in a 2.5/1 ratio; yield: 108 mg (76%). 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=3.33 (s, 3H isomer E),
3.90 (s, 3H isomer E), 3.93 (s, 3H isomer Z), 3.99 (s, 3H
isomer Z), 5.07 (s, 2H isomer E), 5.10 (s, 2H isomer Z), 5.90
(t, J=1.5 Hz, 1H isomer Z), 6.07 (t, J=2.6 Hz, 1H isomer
Z), 6.29 (t, J=2.7 Hz, 1H isomer E), 6.52 (t, J=1.6 Hz, 1H
Intramolecular Heck Reactions. Synthesis of
Pyrroloisoquinolines 5a–e: General Procedure
PdACHTUNGTRENNUNG(PPh3)4 (2.5 mol%) was added to a mixture of N-benzyl-
pyrrole (1 equiv.), (n-Bu)4NCl (1.5 equiv.) and NaHCO3
(2.5 equiv.) in 5 mL of dry CH3CN. Next, the mixture was
stirred at reflux under argon until TLC showed complete re-
action. The reaction mixture was then diluted with 50 mL of
AcOEt, washed with saturated NH4Cl (1ꢃ30 mL) and H2O
(2ꢃ30 mL), dried over Na2SO4, filtered and concentrated.
The oil crude was purified by flash column chromatography
Adv. Synth. Catal. 2009, 351, 2460 – 2468
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2465

Sergio Lage et al.
FULL PAPERS
1
isomer E), 6.71 (s, 1H isomer E), 6.73 (s, 2H isomer Z), 6.80
(d, J=1.4 Hz, 1H isomer E), 6.93 (s, 1H isomer E), 6.97 (s,
1H isomer Z), 7.08 (s, 1H isomer E), 7.21 (t, J=7.3 Hz, 1H
isomer E), 7.26–7.39 (m, 9H isomer Z and E), 7.51 ppm (d,
J=7.6 Hz, 2H isomer Z); 13C NMR (75.5 MHz, CDCl3,
258C): d=47.8 (CH2 isomer Z), 48.0 (CH2 isomer E), 55.0
(CH3 isomer E), 55.8 (CH3 isomer E), 56.0 (CH3 isomer Z),
56.1 (CH3 isomer Z), 102.2 (CH isomer E), 106.6 (CH
isomer Z), 108.4 (CH isomer Z), 108.6 (CH isomer Z and
E), 109.4 (CH isomer E), 111.8 (CH isomer E), 119.4 (CH
isomer Z), 119.5 (CH isomer E), 120.4 (CH isomer Z), 121.4
(CH isomer E), 123.6 (C isomer Z), 123.9 (C isomer E),
125.6 (C isomer E), 126.4 (CH isomer Z), 126.6 (CH isomer
E), 126.7 (C isomer Z), 126.8 (C isomer Z), 127.0 (C isomer
Z), 128.3 (CH), 128.9 (CH), 129.2 (C isomer E), 132.2 (C
isomer E), 138.4 (C isomer E), 138.7 (C isomer Z), 146.8 (C
isomer E), 148.3 (C isomer E), 148.5 (C isomer Z),
148.7 ppm (C isomer Z); IR (CHCl3): u=2932, 1602,
1261 cmÀ1; MS (EI): m/z (%)=317 (100) [M]+, 316 (33), 302
(13), 285 (17), 243 (11), 242 (18), 241 (12), 230 (13), 228
(13); HRMS (EI+): m/z=317.1420, calcd. for C21H19NO2
(M+): 317.1416.
oil; yield: 56 mg (48%). H NMR (300 MHz, CDCl3, 258C,
TMS): d=3.87 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 5.06 (s,
2H), 6.32 (t, J=3.5 Hz, 1H), 6.64 (s, 1H), 6.70 (dd, J=3.6,
1.6 Hz, 1H), 6.71–6.72 (m, 2H), 6.95 ppm (s, 1H); 13C NMR
(75.5 MHz, CDCl3, 258C): d=47.6 (CH2), 55.9 (CH3), 60.8
(CH3), 104.7 (CH), 106.6 (C), 107.5 (CH), 108.9 (CH), 109.2
(CH), 118.5 (CH), 121.7 (C), 123.5 (C), 125.8 (C), 141.6
(CH), 147.8 (C), 148.3 ppm (C); IR (CHCl3): u=2932, 2838,
1637 cmÀ1; MS (EI): m/z (%)=271 (35) [M]+, 256 (100), 228
(11), 192 (71), 190 (24), 125 (13), 123 (15), 111 (24), 109
(22), 97 (42), 95 (40); HR-MS (EI+): m/z=271.1208, calcd.
for C16H17NO3 (M+): 271.1195.
Together
benzo[e]pyrroloAHCTUNGTRENNUNG
with
5e,
the
7,8,10-trimethoxy-5H-
[1,2-a]azepine (6e) was isolated as a by-
product; yield: 36 mg (21%). 1H NMR (300 MHz, CDCl3,
258C, TMS): d=3.86 (s, 3H), 3.89 (s, 3H), 3.91 (s, 3H), 4.79
(s, 2H), 6.06 (dd, J=3.4, 1.6 Hz, 1H), 6.11 (s, 1H), 6.15 (t,
J=3.2 Hz, 1H), 6.63 (t, J=2.1 Hz, 1H), 6.76 (s, 1H),
7.22 ppm (s, 1H); 13C NMR (75.5 MHz, CDCl3, 258C): d=
51.8 (CH2), 55.5 (CH3), 56.0 (CH3), 96.0 (CH), 106.6 (CH),
108.6 (CH), 109.7 (CH), 110.9 (CH), 119.4 (CH), 127.9 (C),
128.1 (C), 129.0 (C), 148.4 (C), 149.4 (C), 152.5 ppm (C); IR
(CHCl3): u=2949, 1265 cmÀ1; MS (EI): m/z (%)=271 (29)
[M]+, 256 (100), 212 (15), 192 (75), 190 (15), 125 (22), 123
(13), 111 (28), 109 (21), 97 (35), 95 (43); HR-MS (EI+):
m/z=271.1190, calcd. for C16H17NO3 (M+): 271.1195.
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
a
0.40 mmol), (n-Bu)4NCl (167 mg, 0.60 mmol) and NaHCO3
(84 mg,1.00 mmol) in CH3CN and this mixture was stirred at
reflux for 48 h. After work-up, purification by column chro-
matography (silica gel, hexane/AcOEt 40%) gave 5d as an
oil as an isomeric mixture Z/E in a 1/4 ratio; yield: 77 mg
Acknowledgements
1
Financial support from MICINN (CTQ2006-01903), Gobier-
no Vasco (GIC07/92-IT-227-07), and Universidad del Paꢀs
Vasco is gratefully acknowledged
(67%). H NMR (300 MHz, CDCl3, 258C, TMS): d=3.59 (s,
3H), 3.71 (s, 3H), 3.88 (s, 6H isomer Z), 3.89 (s, 6H isomer
E), 4.43 (d, J=8.8 Hz, 1H isomer E), 4.60 (dd, J=9.5,
6.0 Hz, 1H isomer Z), 4.86 (dd, J=12.6, 8.8 Hz, 1H isomer
E), 5.00–5.07 (m, 4H isomer E and Z), 5.12 (d, J=9.4 Hz,
1H isomer Z), 6.02 (dd, J=2.3, 1.7 Hz, 2H isomer E and
isomer Z), 6.20–6.23 (m, 3H isomer E and Z), 6.49 (d, J=
12.6 Hz, 1H isomer E), 6.70–6.73 (m, 4H isomer E and Z),
6.90 (s, 1H isomer E), 6.94 ppm (s, 1H isomer Z); 13C NMR
(75.5 MHz, CDCl3, 258C): d=33.2 (CH isomer Z), 37.5 (CH
isomer E), 47.2 (CH2 isomer E and Z), 56.0 (CH3 isomer E
and Z), 59.8 (CH isomer Z), 103.7 (CH isomer Z), 104.3
(CH isomer E), 104.9 (CH isomer E), 108.2 (CH isomer Z
and E), 108.4 (CH isomer Z), 108.9 (CH isomer E and Z),
111.0 (CH isomer E and Z), 118.0 (CH isomer Z), 118.3
(CH isomer E), 123.5 (C isomer Z), 123.7 (C isomer E),
129.0 (C isomer E), 129.1 (C isomer Z), 131.2 (C isomer Z),
131.3 (C isomer E), 147.4 (C isomer E), 147.5 (C isomer Z),
147.7 (CH isomer E), 148.2 (CH isomer Z), 148.7 ppm (CH
isomer E and Z); IR (CHCl3): u=2932, 2838 cmÀ1; MS (EI):
m/z (%)=285 (47) [M]+, 284 (29), 270 (20), 125 (14), 111
(21), 109 (15); HRMS (EI+): m/z=285.1367. calcd. for
C17H19NO3 (M+): 285.1365.
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2466
asc.wiley-vch.de
ꢂ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 2460 – 2468

Intramolecular Palladium-Catalyzed Direct Arylation vs. Heck Reactions:
FULL PAPERS
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