Intramolecular direct arylation and heck reactions in the formation of medium-sized rings: Selective synthesis of fused indolizine, pyrroloazepine and pyrroloazocine systems

Article abstract of DOI:10.1002/adsc.201400075

The intramolecular palladium-catalyzed reaction of N-(iodoarylalkyl) pyrroles can be applied for the selective synthesis of medium-sized rings by choosing the appropriate catalytic systems to direct the reaction to the alkene or to the pyrrole nucleus. Th

Full text of DOI:10.1002/adsc.201400075

UPDATES
DOI: 10.1002/adsc.201400075
Intramolecular Direct Arylation and Heck Reactions in the
Formation of Medium-Sized Rings: Selective Synthesis of
Fused Indolizine, Pyrroloazepine and Pyrroloazocine Systems
Estibaliz Coya,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 (UPV/EHU), Apdo. 644, 48080 Bilbao, Spain
Fax : (+34)-94-601-2748; e-mail: esther.lete@ehu.es
Received: January 20, 2014; Published online: April 9, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400075.
Abstract: The intramolecular palladium-catalyzed
reaction of N-(iodoarylalkyl)pyrroles can be applied
for the selective synthesis of medium-sized rings by
choosing the appropriate catalytic systems to direct
the reaction to the alkene or to the pyrrole nucleus.
These reactions can also be extended to the corre-
sponding heteroaryl halides. Thus, reaction condi-
tions have been established to access selectively to
(hetero)fused indolizine, pyrroloazepine and pyrro-
loazocine systems.
halides in polar, aprotic solvents and at elevated tem-
peratures.[8] When dppp is used instead of PPh3, anal-
ogous electrophilic palladium(II) species have been
reported for this catalytic system[9] although, in this
case, the presence of thallium salts is necessary, as
iodide ion scavenger.[10]
These electrophilic palladium(II) species have also
been considered as reactive intermediates in direct ar-
ylation reactions of (hetero)arenes with aryl hal-
ides,[11] which initially were reported to occur via an
SEAr mechanism.[12] However, the fact that the reac-
[13]
À
tivity has been shown to depend on C H acidity,
À
Keywords: C C coupling; direct arylation; Heck re-
not on (hetero)arene nucleophilicity, together with
experimental and theoretical investigations,[14] led to
the proposal of a concerted metalation–deprotonation
(CMD) pathway for these direct arylation reac-
action; palladium
tions.[15] In this mechanistic hypothesis, Pd
ACTHNUTRGNEN(UG OAc)2 is
Introduction
generally the transition metal precatalyst, and a car-
boxylate (or carbonate) anion plays a fundamental
[16]
À
Transition metal-catalyzed carbon-carbon bond-form- role in the C H cleavage, which occurs in the rate-
ing reactions represent important and useful synthetic determining step of this model simultaneously with
methods in organic synthesis.[1] In this context, palla- carbon-palladium bond formation. In the CMD mech-
dium-catalyzed coupling reactions[2] and, in particular, anism, the choice of an appropriate base represents
the Mizoroki–Heck reaction (M–H)[3] is of special an important element of catalyst design, so the influ-
relevance. These reactions have found wide applica- ence of the anionic base and its counter cation on the
tion in the preparation of complex organic molecules, outcome of the direct arylation should be taken into
including heterocycles,[4] even in an asymmetric fash- account.[17] Thus, CMD and nCMD (non-concerted
ion, and are also applied in the chemical and pharma- metalation–deprotonation) mechanisms have been
ceutical industries.[5]
identified in the base-assisted, Pd-catalyzed direct ar-
The catalytic cycle of the M–H reaction has been ylation of oxazoles and thiole-4-carboxylates with aryl
studied in detail,[6] and it depends on the catalytic halides. Modulation of intrinsic basicity (K+ vs. Cs+)
system and the presence of additives. Various types of and ligand electronic effects were shown to be impor-
palladium complexes have been reported to promote tant for controlling the subtle CMD/nCMD competi-
the vinylation of aryl halides, many of which follow tion.[18]
the “classical” neutral Pd(0)/Pd(II) mechanism, as it
is, for example, the case for Pd
(PPh3)4.[7] In the palladium-catalyzed intermolecular direct arylation of
case of Pd(OAc)2/nPPh3 (n>2) complexes, cationic several heterocycles, including pyrroles, have been
[ArPd
(PPh3)2]+ species are to be considered as reac- studied.[11] Moreover, the intramolecular palladium
tive intermediates in reactions performed with aryl coupling reaction onto pyrrole derivatives has also
In this context, the reactivity and regioselectivity of
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
Adv. Synth. Catal. 2014, 356, 1853 – 1865
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UPDATES
Estibaliz Coya et al.
Figure 2. Examples of relevant bioactive structures bearing
fused indolizine and pyrroloazepine framework.
Figure 1.
been used in the synthesis of several types of nitrogen
heterocycles.[19] However, since Mizoroki–Heck and would lead to a number of structurally diverse hetero-
direct arylation reactions share common reaction con- cyclic systems with biological relevance, such as pyr-
ditions, competition between the intramolecular M–H roloisoquinolines (anti-infertility and antitumor activi-
and direct arylation reactions could be established in ties),[26] benzazepines (muscle relaxant, antihyperten-
(hetero)arenes bearing alkenes.[20] Thus, we have dem- sive, and antipsychotic properties)[27] and benzazo-
onstrated[21] that the intramolecular palladium-cata- cines (antiviral agents),[28] and their heterofused ana-
lyzed reaction of 2-alkenyl-substituted N-(ortho-iodo- logues, as thienoindolizines (cardioprotectants and
benzyl)pyrroles can be switched from the alkene central nervous system agents).[29] Besides, these het-
(M–H reaction) to the pyrrole nucleus (direct aryla- erocyclic frameworks are found in several types of
tion) by choosing the appropriate catalytic system, re- natural products, such as the lamellarin class of
gardless of the nature of the substituent on the marine alkaloids,[30] Cephalotaxus alkaloids,[31] bufla-
alkene. We proposed that the nature of the palladium vine[32] or homoerythrinan alkaloids[33] (Figure 2).
intermediate species formed after the oxidative addi-
tion to the aryl halide determines the chemoselectivi-
ty of the reaction. The substitution patterns on the Results and Discussion
alkene do not affect the course of C-2 direct arylation
of pyrrole derivative. This is one of the few examples We started studying the direct arylation reaction on
of competition between intramolecular direct aryla- pyrroles 1 and 2[34] applying the conditions previously
tion and M–H reactions.[22]
optimized for the formation of five-membered rings.
Therefore, we decided to investigate further the As shown in Table 1 (Scheme 1), treatment of 1a with
scope of these types of intramolecular palladium-cata- Pd(OAc)2 (2.5 mol%) in the presence of PPh3
AHCTUNGTRENNUNG
lyzed reactions. Intramolecular Mizoroki–Heck and (10 mol%) and (n-Bu)4NOAc in DMSO for 3 h gave
À
C H activation reactions are well suited for the con- only 35% of pyrroloisoquinoline 3a (entry 1). The for-
struction of five- and six-membered rings. However, mation of the six-membered ring is slower than the
there are few precedents for the formation of formation of the five-membered ring,[35] so the reac-
medium-sized rings, which usually require high cata- tion could be completed in a good yield (83%) when
lyst loadings and high temperatures.[23–25]
the reaction time was extended to 23 h (entry 2). Al-
Our first goal was to examine the effect of ring size ternatively, an increase of the precatalyst loading to
on the competition, so we chose 2-alkenyl-substituted 5 mol% gave an excellent yield in 5 h (entry 3), that
N-(ortho-iodophenylalkyl)pyrroles as substrates, mod- could be reduced to only two, if the reaction was car-
ifying the linker between the nitrogen atom of the ried out in DMF (entry 4). Analogously, the reaction
pyrrole ring and the aromatic ring. On the other required a longer time when Pd
(OAc)2 (2.5 mol%)
À
hand, since C H activation reactions, both in inter- was used in the presence of dppp (5 mol%) and
and intramolecular versions, are mostly limited to TlOAc (entry 5) that could be reduced to 5 h using
coupling of aryl halides with (hetero)arenes, we also a 5 mol% of the precatalyst (entry 6).
decided to investigate heteroaryl halides, such as thio-
The formation of the seven-membered ring of the
phenes, as coupling partners (Figure 1). This approach pyrrolobenzazepine 4a was significantly slower (en-
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UPDATES
Intramolecular Direct Arylation and Heck Reactions
Table 1. Direct arylation of 1a,b and 2a,b. Synthesis of pyrroloisoquinolines 3 and pyrrolobenzazepines 4 (Scheme 1).
Entry
Substratae
Pd
(OAc)2 [mol%]
Ligand
Time [h]
Product
Yield [%]
[a]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
2a
2a
2a
2a
2a
2a
2a
2b
2.5
2.5
5
5
2.5
5
5
2.5
5
PPh3[a]
3
3a
3a
3a
3a
3a
3a
3b
4a
4a
4a
4a
4a
4a
4a
4b
35
83
94
99
63
85
84
45
60
84
71
20
60
70
70
PPh3[a]
PPh3[a]
PPh3
23
5
2[b]
15
5
dppp[c]
dppp[c]
[a]
PPh3[a]
2
PPh3[a]
PPh3[a]
PPh3[a]
PPh3
65
72
1[b]
48
72
96
72
2
9
10
11
12
13
14
15
5
10
2.5
5
10
5
dppp[c]
dppp[c]
dppp[c]
[a]
PPh3
[a]
10 mol%.
DMF was used as solvent.
5 mol%, TlOAc (1.2 equiv.) was also added.
[b]
[c]
Scheme 2.
5 mol% of palladium acetate (entry 10). The arylation
reaction was faster in both cases with the ester deriva-
tives, obtaining 3b and 4b in good yields with 5 mol%
of PdACTHNUTRGNE(NUG OAc)2 (entries 7 and 15).
We next moved to the optimization of the M–H re-
action conditions to obtain selectively pyrroloazepines
5 and pyrroloazocines 6. The application of the M–H
reaction to the formation of seven- and eight-mem-
Scheme 1.
tries 8 and 9, 11–14). In general, the formation of bered rings is not so general, and may lead to the for-
seven-membered rings by direct arylation requires mation of regioisomeric mixtures of products result-
a high catalyst loading or high temperatures, presuma- ing from competing endo and exo cyclizations.[36] In
bly due to the difficult formation of intermediate our previous work,[21] we had shown that the M–H re-
eight-membered palladacycles.[25] However, the pyrro- action occurred with complete regioselectivity for the
loazepinone 4a could be obtained in good yields by formation of an isoquinoline ring when PdACHTNUTRGNEUNG(PPh3)4 was
increasing the precatalyst loading to 5 or 10 mol% used. Thus, we took those reaction conditions as start-
(entries 13 and 14), at 608C in DMSO. Interestingly, ing point. As shown in Table 2 (Scheme 2), pyrrolo-
when DMF was used as solvent, at the same tempera-
ACHTUNGTRENUNaNG zepine 5a was obtained in moderate yield with
ture, the reaction was completed in just 1 h with 3 mol% of the catalyst using Et3N as base, and in the
Adv. Synth. Catal. 2014, 356, 1853 – 1865
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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UPDATES
Estibaliz Coya et al.
Table 2. Mizoroki–Heck reaction of 1a,b and 2a,b. Synthesis of pyrroloazepines 5 and pyrroloazocines 6 (Scheme 2).
Entry Substrate [Pd]
Ligand
Base
Additive
Solvent
Time [h] Product Yield [%]
[a]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
2a
2a
2a
2a
2a
2b
Pd
Pd(PPh3)4[a]
Pd(PPh3)4[a]
Pd(PPh3)4
Pd(dba)2[d]
Pd(dba)2[d]
Pd(dba)2[d]
Pd(dba)2[d]
Pd(dba)2[d]
Pd(dba)2
Pd2A
Pd(PPh3)4[a]
Pd(PPh3)4[d]
Pd(PPh3)4[g]
Pd(PPh3)4
Pd(dba)2[d]
Pd(dba)2
Pd(PPh3)4
N
–
–
–
–
Et3N[b]
G
23
16
3
3
6
8
3
29
24
5
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
6a
6a
6a
6a
6a
6b
64
77
86
[e]
NaHCO3[e]
NaHCO3
Et3N[b]
91
[d]
[g]
PPh3
P
P
Et3N[c]
31[k]
86
[g]
(o-Tol)3[h] Et3N[c]
(o-Tol)3
Et3N[c]
67
[g]
PCy3
Et3N[c]
53[l]
77
[g]
9
P
P
P
–
–
–
E
E
G
Et3N[c]
10
11
12
13
14
15
16
17
18
Cy2NMe[c]
Cy2NMe[c]
82
68
[i]
(dba)3 [d]
[e]
NaHCO3
6
56
Et3N[b]
25
96
3
3
168
50
47[m]
27[m]
80
[e]
NaHCO3
Et3N[b]
–
[d]
[h]
P
P
–
(o-Tol)3
(t-Bu)3
Et3N[c]
53[n]
32
Cy2NMe[c]
Et3N[b]
[g]
[a]
31
[a]
[b]
[c]
[d]
[e]
[f]
3 mol%.
12 equiv.
2 equiv.
5 mol%.
2.5 equiv.
1.5 equiv.
10 mol%.
20 mol%.
0.5 mol%.
1 mol%.
30% of 3a was obtained.
41% of 3a was obtained.
36% of 4a was obtained.
20% of 4a was obtained.
[g]
[h]
[i]
[j]
[k]
[l]
[m]
[n]
presence of (n-Bu)4NCl in CH3CN at reflux (entry 1).
In our case, when 1a was treated with PdACHTUNGTRENNUNG(dba)2/
No formation of other regioisomers or the arylation PCy3 using Et3N as the base in DMF at 1308C, the ar-
product 3a was detected by NMR. A change in the ylation product 3a was isolated (41%) together with
base to NaHCO3 improved the yield (entry 2), but the the desired M–H product 5a (53%) (entry 8). The use
best results were obtained when the reaction was car- of tri-tert-butylphosphane as ligand afforded chemose-
ried out in DMF at 1108C. Thus, 5a was obtained in lectively 5a in good yield (77%) (entry 9). The reac-
excellent yield in just 3 h using 3 mol% of the preca- tion was more efficient with P
talyst (entries 3 and 4). base to Cy2NMe (entry 10). Moreover, it was possible
Interestingly, the direct arylation reaction was com- to obtain selectively the pyrroloazepine 5a in 68%
petitive when Pd(dba)2 in the presence of PPh3 was yield by employing a low catalyst loading (0.5 mol%)
ACHTUNGTERN(NUGN t-Bu)3 on changing the
ACHTUNGTRENNUNG
used, obtaining a mixture of 5a and 3a (entry 5). The (entry 11), albeit with a longer reaction time. The for-
nature of the ligand has been shown to have an im- mation of the eight-membered ring of the pyrroloben-
portant effect both in the reactivity and in the regio- zazocine 6a with PdACHTNUTRGNE(UNG PPh3)4 was slower (entries 13 and
selectivity of Heck and arylation reactions.[22c,d] Thus, 14) and non-selective as in both cases the arylation
this loss of regioselectivity could be avoided using tri- product 4a was also isolated. However, pyrrolobenz-
ortho-tolylphosphane as ligand, leading to a good
ACHTUNGTRENaNUNG zocine 6a could be obtained in good yield (80%) by
yield of 5a (entries 6 and 7). On the other hand we increasing the catalyst loading to 10 mol% (entry 15)
studied also the bulky trialkylphosphanes (tri-tert-bu- at 1108C in DMF. No formation of the other regioiso-
tylphosphane and tricyclohexylphosphane). These li- mer or the arylation product 4a was detected. In this
gands are known to stabilize highly reactive coordina- case, the use of bulky phosphanes did not improve
tively unsaturated palladium species, and have been the results (entries 16 and 17). It was also possible to
used to perform room temperature Heck reactions.[37] control the chemoselectivity with the ester deriva-
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UPDATES
Intramolecular Direct Arylation and Heck Reactions
Table 3. Direct arylation of 7a,b and 8a,b. Synthesis of thienopyrrolizine 9 and thienoindolizine 10 (Scheme 3).
Entry
Substrate
Pd
(OAc)2 [mol%]
Ligand
Time [h]
Solvent
Product
Yield [%]
[a]
1
2
3
4
5
6
7
8
7a
7a
7a
7b
7b
7a
8a
8a
8a
8b
8a
5
5
10
10
10
5
5
5
10
10
5
PPh3[a]
23
23
4
DMSO
DMF
DMF
DMF
DMF
DMSO
DMSO
DMF
DMF
DMF
9
9
9
9
9
9
10
10
10
10
10
11
52
73
45
93
30
61
65
85
71
66
PPh3[a]
PPh3[a]
PPh3[a]
PPh3
4
16
27
23
6
6
6
dppp[b]
[a]
PPh3[a]
PPh3[a]
PPh3[a]
PPh3
9
10
11
dppp[b]
27
DMSO
[a]
10 mol%.
[b]
5 mol%, TlOAc (1.2 equiv.) was also added.
iodide 8a (entry 7). The change of the solvent en-
hanced the reaction rate, and an increase of the pre-
catalyst loading to 10 mol% gave an excellent yield of
thienoindolizine 10 (entries 8 and 9). In this case, the
reaction of the brominated thiophene 8b (entry 10)
gave a similar result. The use of dppp as ligand in the
presence of TlOAc did not improve these results (en-
tries 6 and 11).
We next moved to the optimization of the Mizoro-
ki–Heck reaction (Table 4, Scheme 4). Thus, we took
the best reaction conditions obtained for the N-
(ortho-iodoarylakyl)pyrroles as a starting point. As
shown in Table 4, only small amounts of 11 were ob-
tained with 3 mol% of the catalyst using Et3N as base,
Scheme 3.
tives, obtaining 5b and 6b in moderate yields (en- and in the presence of (n-Bu)4NCl in DMF at 1108C,
tries 12 and 18). recovering unreacted starting material (entry 1). An
Our next goal was to investigate the use of hetero- increase of catalyst loading did not improve the re-
aryl halides as coupling partners in these types of re- sults, neither did changes of the base and the solvent
actions. For this purpose, we selected the structures (entries 2 and 3). Only traces of the thienoindolizine
represented in Scheme 3, to study the influence of the 11 were obtained when employing a bulky ligand
size of the ring formed (n=1, 2), and the nature of (entry 5). No improvement was observed using bro-
the halogen atom.
mide 7b (entries 4 and 6). However, the pyrroloaze-
We started by studying the direct arylation reaction pine 12 could be obtained in moderate yield under
on thiophenes 7a,b and 8a,b[34] on applying the condi- the standard conditions, although in this case the com-
tions previously optimized for the formation of five- petitive arylation reaction was observed, isolating 10
membered rings.[21] As shown on Table 3, treatment of as a by-product (entry 7). The change of the solvent
7a with PdACHTUNGTRENNUNG(OAc)2 (5 mol%) in the presence of PPh3 to CH3CN changed completely the chemoselectivity
(10 mol%) and (n-Bu)4NOAc in DMSO for 23 h gave of the reaction giving the arylation product 10 in ex-
only 11% of the thienopyrrolizine 9 (entry 1), recov- cellent yield (entry 8), while not observing the forma-
ering unreacted starting material. The use of DMF re- tion of 12. The use of bulky ligands did not improve
sulted in a faster reaction, obtaining 9 in moderate the results (entries 10 and 11). Interestingly the use of
yield (entry 2). An increase of pre-catalyst loading PdACTHNUTRGEN(UNG OAc)2 in the presence of dppp using Et3N as
provided the best result for the iodinated thiophene a base and (n-Bu)4NI as additive in CH3CN provided
7a obtaining 9 in 73% isolated yield (entry 3). Under the benzazepine 12 as the major compound
these conditions, the brominated substrate 7b was less (entry 12).
reactive and required a longer time (16 vs. 4 h), ob-
taining the thienopyrrolizine 9 in excellent yield plained according to the intermediate palladium spe-
(93%) (entries 4 and 5). cies involved in the catalytic cycles. As has been men-
Analogously, the thienoindolizine 10 was obtained tioned, in the case of Pd(OAc)2/nPPh3 (n>2) com-
in good yield under similar conditions starting from plexes, and equilibrium could be established between
The change in the chemoselectivity could be ex-
AHCTUNGTRENNUNG
Adv. Synth. Catal. 2014, 356, 1853 – 1865
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UPDATES
Estibaliz Coya et al.
Table 4. Mizoroki–Heck reactions of 7a,b and 8a,b (Scheme 4).
Entry
Substrate [Pd]
Ligand
Base
Additive
(n-Bu)4NCl[c]
Solvent
Time [h]
Product
Yield [%]
[a]
1
2
3
4
5
6
7
8
7a
7a
7a
7b
7a
7b
8a
8a
8b
8a
8b
8a
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
–
–
–
–
P
P
Et3N[b]
N
DMF
DMF
8
7
11
11
–
5
14
–
Et3N[b]
A
[f]
NaHCO3[f]
NaHCO3
E
16
16
11
11
8
16
16
11
11
24
(n-Bu)4NCl[g] CH3CN
–
–
[e]
[d]
[d]
G
–
–
DMF
DMF
DMF
11
11
12
10
12
12
10
12
<5
<5
45[i]
87
17
27[j]
15
46[k]
(t-Bu)3
Cy2NMe[c]
Et3N[b]
[a]
–
–
–
P
P
A
[f]
NaHCO3[f]
N
9
NaHCO3
(n-Bu)4NCl[g] CH3CN
ACHTUNGTRENNUNG
[e]
10
11
12
(t-Bu)3[d] Cy2NMe[c]
–
–
DMF
DMF
CH3CN
Cy2NMe[c]
Et3N[f]
[d]
A
[a]
3 mol%.
12 equiv.
2 equiv.
10 mol%.
5 mol%.
2.5 equiv.
1.5 equiv.
10 equiv.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
23% of 10 was obtained.
41% of 10 was obtained.
26% of 10 was obtained.
[j]
[k]
reaction requires longer reaction times compared to
the formation of five-membered rings reported previ-
ously.[21] This can be attributed to the more difficult
formation of seven- and eight-membered palladacycle
intermediates. However, an increase on the catalyst
loading to 5 mol% and a switch of solvent to DMF
has allowed the efficient synthesis of these heterocy-
cles. Under similar reaction conditions the arylation
of the pyrrole nucleus with the thiophenyl halide is
slower. If the formation of the isoquinoline ring
system of 3a and the thienoindolizine ring system of
10 are compared, the reaction of the thiophene
moiety requires longer reaction times (6 vs. 2 h) and
higher catalyst loadings (10 mol% vs. 5 mol%) to
reach completion. This may suggest that the palladi-
Scheme 4.
trans-ArPd
tive addition, and cationic [ArPd
polar aprotic solvents. Thus, a mechanism involving
(PPh3)
R
ACHTUNGTRENuNGNU m(II) species formed after oxidative addition is less
ACHTUNGTRENNUNG
an electrophilic palladium(II) species that would react obtain the benzazepine and benzazocine skeletons of
preferentially at the more electron-rich pyrrole nu- 5a,b and 6a,b can be carried out selectively with
cleus through an SEAr pathway could be suggested.
PdACTHUNGTERNU(NG PPh3)4, presumably through a “classical” neutral
However, a concerted metalation–deprotonation mechanism, as stated above. However, the formation
(CMD) pathway, involving proton abstraction by the of the eight-membered ring is more difficult. The Miz-
acetate ion could also be proposed.[15–17] This mecha- oroki–Heck reactions with thiophenyl halides 7a,b
nism would explain the selective arylation when and 8a,b have not been so effective. In this case, the
a source of acetate ions, such as (n-Bu)4NOAc, is seven-membered ring of 12 is obtained with better
added. Thus, it has been shown that the arylation re- yield than the six-membered ring of 11, although,
action can be efficiently extended to the synthesis of again, in both cases the reactivity of the intermediate
six- and seven-membered rings, of pyrroloisoquino- palladium(II) species towards the alkene seems to be
lines 3a,b and pyrrolobenzazepines 4a,b, although the lower.
1858
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Adv. Synth. Catal. 2014, 356, 1853 – 1865

UPDATES
Intramolecular Direct Arylation and Heck Reactions
bered rings of pyrroloazepine 5a and pyrroloisoquino-
line 14[21] (Scheme 5, Table 5).
The formation of the seven-membered ring re-
quired an increase of the catalyst loading to 1 mol%
providing the pyrrolobenzazepine 5a in good yield
(entry 3). No reaction or low conversion was obtained
with lower catalyst loadings (entries 1 and 2). On the
other hand, the use of a higher catalyst loading
(5 mol%) did not improve the results (entry 4). It has
been shown that an increase of the catalyst loading
may diminish the reaction rate, as the formation of in-
active aggregates of Pd(0) black may be favoured at
higher concentrations.[38b] The formation of the six-
membered ring of pyrroloisoquinoline 14 was less ef-
Scheme 5.
Besides, in these cases, under “classical” conditions ficient, obtaining only moderate yields (entries 7 and
that would lead to a neutral mechanism, the forma- 8).
tion of the six-membered arylation product 10 is com-
petitive with the formation of azepine 12.
Analogously we studied the Mizoroki–Heck reac-
tion in the thiophene derivatives 7a and 8a
In view of these results, we decided to explore (Scheme 6). In both cases the reaction was non-selec-
other catalytic systems in order to achieve a selective tive. With iodide 7a, almost equal amounts of aryla-
Mizoroki–Heck reaction. In this context, oxime-based tion and Mizoroki–Heck products were obtained,
palladacycles are very efficient and versatile pre-cata- with low conversion. The reaction of iodide 8a was
À
lysts for a wide range of useful and well known C C faster for the formation of the six-membered ring ob-
coupling processes.[38] Thus, we decided to study the taining the arylation product 10 as the major com-
intramolecular Mizoroki–Heck reaction using pallada- pound. This is one of the few reported examples of
cycle 15 for the formation of six- and seven-mem- the use of this type of oxime palladacycle in direct ar-
ylation reactions.[39]
Table 5. Mizoroki–Heck reactions of 1a and 13 catalyzed by
palladacycle 15 (Scheme 5).
Conclusions
Entry Substrate 15 [mol%] Time [h] Product Yield [%]
The intramolecular palladium-catalyzed reaction of
[a]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
13
13
13
13
10À2
10À1
1
46
75
7
–
–
N-(arylalkyl)pyrroles can be applied for the selective
synthesis of medium-sized rings by choosing the ap-
propriate catalytic systems to direct the reaction to
5a
5a
5a
–
–
14
14
32
74
31
5
8
[a]
10À2
10À1
1
24
76
7
–
–
the alkene or to the pyrrole nucleus. Thus, Pd
and PPh3 or dppp provided selectively pyrrolo
a]isoquinolines 3a,b and pyrrolo[1,2-a]benzazepines
4a,b through arylation reactions. On the other hand,
Pd(PPh3)4 drives the reaction to the alkene through
a Mizoroki–Heck reaction, leading selectively to
ACHTUNGTRENNUNG
[a]
ACHTUNGTRENNUNG
36
46
AHCTUNGTRENNUNG
5
4
[a]
AHCTUNGTRENNUNG
Starting material was recovered.
Scheme 6.
Adv. Synth. Catal. 2014, 356, 1853 – 1865
ꢂ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1859

UPDATES
Estibaliz Coya et al.
up, followed by column chromatography (silica gel, hexane/
EtOAc=6:4) gave 3b which was crystallized from hexane/
EtOAc as a yellow solid; yield: 81 mg (84%); mp (hexane/
pyrroloACHTUNGTRENNUNG[1,2-a]benzazepines 5a,b and pyrroloHCATUNGTRNE[NUGN 1,2-
a]benzazocines 6a,b. The formation of six-, seven- and
eight-membered rings either by Mizoroki–Heck reac-
tion and direct arylation requires longer reaction
times and higher catalyst loadings than for the smaller
rings.
These reactions can also be extended to heteroaryl
halides. Although the direct arylation reaction is com-
petitive even under neutral mechanism conditions, se-
lective formation of heterofused systems, such as
EtOAc) 122–1258C. IR (neat): n=1685 cmÀ1
;
1H NMR
(300 MHz, CDCl3): d=3.02 (t, J=6.7 Hz, 2H, H-6), 3.89 (s,
OCH3), 3.91 (s, OCH3), 4.11 (t, J=6.7 Hz, 2H, H-5), 5.24 (s,
2H, CO2CH2Ph), 6.21 (d, J=15.5 Hz, 1H, =CH-CO), 6.76
(d, J=4.05 Hz, 1H, H-1), 6.72 (s, 1H, H-7), 6.76 (d, J=
4.05 Hz, 1H, H-2), 7.02 (s, 1H, H-10), 7.30–7.43 (m, 5H,
COCH2Ph), 7.68 (d, J=15.5 Hz, 1H, =CH-Ar); 13C NMR
(75.5 MHz, CDCl3): d=28.5 (C-6), 41.05 (C-5), 56.0, 56.1
(OCH3), 66.0 (CO2CH2Ph), 105.1 (C-1), 106.5 (C-10), 111.1
(C-7), 111.3 (=CH-CO), 113.0 (C-2), 121.3 (C-10a), 123.5
(C-6a), 128.1 (COCH2Ph), 128.2 (COCH2Ph), 128.5
(COCH2Ph), 128.7 (C-3), 132.1 (=CH-Ar), 134.6 (C-10b),
136.4 (COCH2Ph), 148.4 (C-8, C-9), 167.7 (CO); MS
(230 eV, CI): m/z (%)=390 (100) [MH]+, 389 (52) [M]+, 375
(16), 299 (24), 282 (12), 256 (18), 243 (17), 230 (40), 229
(33), 91 (38); HR-MS (CI): m/z=390.1690, calcd. for
C24H24NO4 [MH]+: 390.1705.
thieno
thieno
C
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG[2,3-d]azepine 12 can be achieved under the opti-
mized conditions. The intramolecular Mizoroki–Heck
reaction employing oxime-based palladacycle 15
allows the selective synthesis of pyrrolo
ACHTUNGTREN[NUNG 1,2-a]benza-
zepine and pyrrolo[1,2-b]isoquinoline skeletons using
AHCTUNGTRENNUNG
1 mol% of 15. On the contrary, the direct arylation re-
action is the major reaction when thiophenyl halides
are used.
(E)-3-(9,10-Dimethoxy-6,7-dihydro-5H-benzo[c]-
pyrroloACHTUNGTNER[NUNG 1,2-a]azepin-3-yl)-N,N-diethylacrylamide (4a)
(Table 1, entry 10)
Experimental Section
PdACTHUNTRGENNG(U OAc)2 (2.1 mg, 0.01 mmol) was added to a mixture of N-
phenylpropylpyrrole 2a (93 mg, 0.18 mmol), PPh3 (5.0 mg,
0.02 mmol) and (n-Bu)4NOAc (88 mg, 0.28 mmol) in DMF
(5 mL) and this mixture was stirred at 608C for 1 h. Stan-
dard work-up, followed by column chromatography (silica
gel, hexane/EtOAc=2:8) gave 4a as an oil; yield: 56 mg
(E)-3-(8,9-Dimethoxy-5,6-dihydropyrroloACTHNUGTRNEUNG[2,1-
a]isoquinolin-3-yl)-N,N-diethylacrylamide (3a) (Table
1, entry 4)
PdACHTUNGTRENNUNG(OAc)2 (2.2 mg, 0.01 mmol) was added to a mixture of N-
(84%): IR (neat): n=1630 cmÀ1
CDCl3): d=1.18–1.26 [m, 6H, N
2H, H-6), 2.60 (t, J=7.1 Hz, 2H, H-7), 3.47–3.51 [m, 4H, N-
AHCTNUTGERGUN(NN CH2CH3)2], 3.88 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.94
;
1H NMR (300 MHz,
phenethylpyrrole 1a (126 mg, 0.26 mmol), PPh3 (6.9 mg,
0.02 mmol) and (n-Bu)4NOAc (122 mg, 0.39 mmol) in DMF
(5 mL) and this mixture was stirred at 608C for 2 h. The re-
action mixture was then diluted with 50 mL of EtOAc,
washed with saturated NH4Cl (30 mL) and H2O (2ꢃ30 mL),
dried over Na2SO4, filtered and concentrated. Purification
by column chromatography (silica gel, hexane/EtOAc=2:8)
gave 3a as an oil; yield: 92 mg (99%). IR (neat): n=
AHCTNUGTREN(GNNU CH2CH3)2], 2.20–2.26 (m,
(t, J=6.6 Hz, 2H, H-5), 6.28 (d, J=3.9 Hz, 1H, H-1), 6.60
(d, J=14.9 Hz, 1H, =CH-CO), 6.69 (d, J=3.9 Hz, 1H, H-2),
6.76 (s, 1H, H-11), 6.92 (s, 1H, H-8), 7.61 (d, J=14.9 Hz,
1H, =CH-Ar); 13C NMR (75.5 MHz, CDCl3): d=13.3
(CH3), 15.1 (CH3), 29.9 (C-6), 32.2 (C-7), 41.2 (NCH2CH3),
41.7 (C-5), 42.3 (NCH2CH3), 56.0 (OCH3), 56.1 (OCH3),
107.6 (C-1), 109.6 (C-2), 111.5 (C-11), 112.5 (=CH-CO),
112.7 (C-8), 125.6 (C-11a), 130.3 (C-7a), 130.4 (=CH-Ar),
130.5 (C-3), 138.8 (C-11b), 147.8, 148.6 (C-9, C-10), 166.3
(CO); MS (230 eV, CI): m/z (%)=369 (88) [MH]+, 368
(100) [M]+, 354 (14), 297 (10), 296 (33), 256 (12), 243 (8);
HR-MS (CI): m/z=369.2182, calcd. for C22H29N2O3 [MH]+:
369.2178.
1635 cmÀ1
6H, N(CH2CH3)2], 3.01 (t, J=6.7 Hz, 2H, H-6), 3.42–3.47
[m, 4H, N(CH2CH3)2], 3.88 (s, 3H, OCH3), 3.90 (s, 3H,
;
1H NMR (300 MHz, CDCl3): d=1.18–1.25 [m,
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
OCH3), 4.12 (t, J=6.7 Hz, 2H, H-5), 6.47 (d, J=3.9 Hz, 1H,
H-1), 6.58 (d, J=14.9 Hz, 1H, =CH-CO), 6.70 (d, J=3.9 Hz,
1H, H-2), 6.71 (s, 1H, H-10), 7.01 (s, 1H, H-7), 7.70 (d, J=
14.9 Hz, 1H, =CH-Ar); 13C NMR (75.5 MHz, CDCl3): d=
13.3 (CH3), 15.1 (CH3), 29.3 (C-6), 40.9 (C-5), 41.1
(NCH2CH3), 42.1 (NCH2CH3), 55.9 (OCH3), 56.0 (OCH3),
104.4 (C-1), 106.3 (C-7), 110.3 (C-2), 111.1 (C-10), 112.2 (=
CH-CO), 121.7 (C-10a), 123.3 (C-6a), 129.6 (C-3), 129.7 (=
CH-Ar), 133.4 (C-10b), 148.0, 148.3 (C-8, C-9), 166.2 (CO);
MS (230 eV, CI): m/z (%)=355 (58) [MH]+, 354 (100) [M]+,
340 (10), 282 (17), 255 (6); HR-MS (CI): m/z=355.2020,
calcd. for C21H27N2O3 [MH]+: 355.2022.
(E)-Benzyl-3-(9,10-dimethoxy-6,7-dihydro-5H-
benzo[c]pyrrolo
ACHTUNGTRNE[NUNG 1,2-a]azepin-3-yl)acrylate (4b)
(Table 1, entry 15)
PdACTHUNTRGENNG(U OAc)2 (5.7 mg, 0.02 mmol) was added to a mixture of N-
phenylpropylpyrrole 2b (132 mg, 0.25 mmol), PPh3 (6.6 mg,
0.02 mmol) and (n-Bu)4NOAc (116 mg, 0.37 mmol) in
DMSO (5 mL) and this mixture was stirred at 608C for 2 h
30 min. Standard work-up, followed by column chromatog-
raphy (silica gel, hexane/EtOAc=4:6) gave 4b as yellow
solid which was crystallized from hexane/EtOAc; yield:
70 mg (70%): mp (hexane/EtOAc) 128–1308C. IR (neat):
(E)-Benzyl-3-(8,9-dimethoxy-5,6-dihydropyrrolo
a]isoquinolin-3-yl)acrylate (3b) (Table 1, entry 7)
ACHTUNGTNER[NUNG 2,1-
PdACHTUNGTRENNUNG(OAc)2 (2.1 mg, 0.01 mmol) was added to a mixture of N-
phenethylpyrrole 1b (132 mg, 0.25 mmol), PPh3 (4.7 mg,
0.02 mmol) and (n-Bu)4NOAc (84 mg, 0.26 mmol) in DMSO
and this mixture was stirred at 608C for 2 h. Standard work-
1
n=1695 cmÀ1; H NMR (300 MHz, CDCl3): d=2.27 (t, J=
1860
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Adv. Synth. Catal. 2014, 356, 1853 – 1865

UPDATES
Intramolecular Direct Arylation and Heck Reactions
6.8 Hz, 2H, H-6), 2.62 (t, J=7.1 Hz, 2H, H-7), 3.86–3.95 (m,
8H, 2ꢃOCH3, H-5), 5.24 (s, 2H, CO2CH2Ph), 6.22 (d, J=
15.6 Hz, 1H, =CH-CO), 6.32 (d, J=3.9 Hz, 1H, H-1), 6.75
(d, J=3.9 Hz, 1H, H-2), 6.78 (s, 1H, H-8), 6.93 (s, 1H, H-
(s, 3H, OCH3 isom E), 4.16–4.20 (m, 2H, H-5 isom E),
4.23–4.27 (m, 2H, H-5 isom Z), 5.08 (s, 2H, CH2Ph isom E),
5.18 (s, 2H, CH2Ph isom Z), 5.96 (s, 1H, CH=C isom Z),
6.14 (dd, J=3.6, 2.8 Hz, 1H, H-2 isom E), 6.16 (dd, J=3.6,
11), 7.30–7.44 (m, 5H, COCH2Ph), 7.67 (d, J=15.6 Hz, 1H, 2.8 Hz, 1H, H-2 isom Z), 6.39–6.42 (m, 2H, H-1 isom E,
=CH-Ar); 13C NMR (75.5 MHz, CDCl3): d=30.3 (C-7), 32.2
(C-6), 41.9 (C-5), 56.0 (2ꢃOCH3), 66.1 (CO2CH2Ph), 108.2
(C-1), 111.3 (C-11), 111.5 (=CH-CO), 112.2 (C-2), 112.6 (C-
8), 125.2 (C-7a), 128.0 (COCH2Ph), 128.1 (COCH2Ph), 128.5
(COCH2Ph), 128.9 (C-3), 130.4 (C-11a), 132.8 (=CH-Ar,
136.4 (COCH2Ph), 140.3 (C-11b), 147.7 (C-8), 148.7 (C-9),
167.7 (CO); MS (230 eV, CI): m/z (%)=404 (100) [MH]+,
403 (42) [M]+, 313 (14), 296 (11), 272 (15), 270 (14), 258
(13), 257 (12), 244 (40), 243 (27), 229 (13), 91 (25); HR-MS
(CI): m/z=404.1844, calcd. for C25H26NO4 [MH]+: 404.1862.
CH=C isom E), 6.51 (dd, J=3.6, 1.7 Hz, H-1 isom Z), 6.66–
6.70 (m, 3H, H-7 isom Z, H-3 both isom), 6.72 (s, 1H, H-10
isom E), 6.79 (s, 1H, H-7 isom E), 6.87 (s, 1H, H-10 isom
Z), 7.23–7.37 (m, 5H, HPh both isom); 13C NMR
(75.5 MHz, CDCl3): d=32.2 (C-6 both isom), 55.9 (OCH3
both isom), 56.1 (OCH3 both isom), 48.8 (C-5 isom Z), 49.8
(C-5 isom E), 65.8 (CH2Ph isom E), 66.1 (CH2Ph isom Z),
108.6 (C-2 isom E), 108.7 (C-2 isom Z), 109.4 (C-1 isom E),
110.7 (C-10 isom Z), 110.8 (C-10 isom E), 111.7 (C-7 isom
Z), 113.5 (H-1 isom Z), 115.5 (CH=C isom E), 117.5 (CH=C
isom Z), 124.3 (C-2 isom Z), 125.6 (C-3 isom E), 127.4 (C-
6a isom Z), 127.9 (CPh4 isom Z), 128.0 (CPh4 isom E),
128.1 (CPh3 isom Z), 128.2 (C-10c isom Z), 128.3 (CPh3
isom E), 128.4 (CPh2 isom Z/E), 128.5 (C11 isom E), 129.6
(C-10a isom E), 131.7 (C-6a isom E), 133.8 (C-10a isom Z),
136.1 (CPh1 isom Z/E), 147.1 (COCH3 isom E), 147.3 (C-11
isom Z), 147.8 (COCH3 isom Z), 148.7 (C-10b isom E),
149.0 (COCH3 isom Z), 149.2 (COCH3 isom E), 166.0 (CO
isom E), 166.8 (CO isom Z); MS (230 eV, CI): m/z (%)=
390 (100) [MH]+, 100), 389 (23) [M]+, 372 (12), 284 (12), 282
(41), 256 (11), 244 (10), 91 (13); HR-MS (CI): m/z=
390.1687, calcd. for C24H24NO4 [MH]+: 390.1705.
(Z)-2-(8,9-Dimethoxy-5H-benzo[d]pyrroloACTHNUTRGNEUG[N 1,2-a]-
azepin-11(6H)-ylidene)-N,N-diethylacetamide (5a)
(Table 2, entry 4)
PdACHTUNGTRENNUNG(PPh3)4 (7.9 mg, 0.006 mmol) was added to a mixture of
N-phenethylpyrrole 1a (109 mg, 0.22 mmol), (n-Bu)4NCl
(106 mg, 0.45 mmol) and Et3N (0.4 mL, 2.71 mmol) in dry
DMF (5 mL) and the mixture was stirred at 1108C under
argon 3 h. Standard work-up, followed by column chroma-
tography (silica gel, hexane/EtOAc=2:8) gave 5a as
a yellow solid which was crystallized from hexane/EtOAc;
yield: 71 mg (91%); mp (hexane/EtOAc) 168–1718C. IR
1
(neat):: n=1640 cmÀ1; H NMR (300 MHz, CDCl3): d=0.87
(Z)-2-(9,10-Dimethoxy-6,7-dihydrobenzo[d]-
(t, J=7.1 Hz, 3H, NCH2CH3), 1.12 (t, J=7.1 Hz, 3H,
NCH2CH3), 3.12–3.14 (m, 2H, H-6), 3.33 (q, J=7.1 Hz, 2H,
NCH2CH3), 3.42 (q, J=7.1 Hz, 2H, NCH2CH3), 3.87 (s, 6H,
OCH3), 4.21–4.24 (m, 2H, H-5), 5.95 (s, 1H, CH=C), 6.07–
6.08 (m, 1H, H-2), 6.38 (dd, J=3.7, 1.7 Hz, 1H, H-1), 6.61–
6.62 (m, 1H, H-3), 6.68 (s, 1H, H-10), 7.01 (s, 1H, H-7);
13C NMR (75.5 MHz, CDCl3): d=12.3 (NCH2CH3), 13.6
(NCH2CH3), 33.0 (ArCH2), 38.9 (NCH2CH3), 42.7
(NCH2CH3), 48.9 (CH2N), 56.1 (OCH3), 56.3 (OCH3), 108.4
(C-2), 111.5, 111.6, 111.7 (C-1, C-10, C-7), 122.6 (CH=),
123.3 (C-3), 127.8 (C-6a), 128.7 (CH=C), 133.3 (C-10a),
136.5 (C-11), 148.0, 148.6 (C-9, C-10), 168.6 (CO); MS
(230 eV, CI): m/z (%)=355 (100) [MH]+, 354 (70) [M]+, 310
(9), 283 (22), 282 (93), 256 (14), 255 (55), 242 (18); HR-MS
(CI): m/z=355.2027, calcd. for C21H27N2O3 [MH]+:
355.2022; anal. calcd. for C21H26N2O3: C 71.16, H 7.39, N
7.90; found: C 70.75, H 7.46, N 7.65.
pyrrolo
ACHTUNGTRENN[UNG 1,2-a]azocin-12(5H)-ylidene)-N,N-
diethylacetamide (6a) (Table 2, entry 15)
PdACHTNURTGNEUGN(PPh3)4 (25 mg, 0.02 mmol) was added to a mixture of N-
phenylpropylyrrole 2a (108 mg, 0.21 mmol), (n-Bu)4NCl
(102 mg, 0.43 mmol) and Et3N (0.36 mL, 2.61 mmol) in 5 mL
of dry DMF and the mixture was stirred at 1108C for 3 h.
Standard work-up, followed by column chromatography
(silica gel, hexane/EtOAc=1:9) gave 6a as a white solid;
yield: 64 mg (80%); mp (hexane/EtOAc) 166–1688C. IR
(neat): n=1645 cmÀ1; H NMR (300 MHz, CDCl3): d=1.03
1
(t, J=7.1 Hz, 3H, NCH2CH3), 1.20 (t, J=7.1 Hz, 3H,
NCH2CH3), 1.71–1.79 (m, 2H, H-6), 2.52 (t, J=6.2 Hz, 2H,
H-7), 3.37 (q, J=7.1 Hz, 2H, NCH2CH3), 3.48 (q, J=7.1 Hz,
2H, NCH2CH3), 3.64–3.71 (m, 2H, H-5), 3.91 (s, 2H,
OCH3), 5.80 (s, 1H, CH=C), 6.11–6.14 (m, 1H, H-2), 6.54–
6.56 (m, 1H, H-1), 6.56–6.59 (m, 2H, H-3, H-11), 7.06 (s,
1H, H-8); 13C NMR (75.5 MHz, CDCl3): d=12.2
(NCH2CH3), 13.9 (NCH2CH3), 29.9 (C-7), 32.8 (C-6), 38.8
(NCH2CH3), 42.5 (NCH2CH3), 45.4 (C5), 55.9 (OCH3), 56.1
(OCH3), 108.6 (C-2), 111.7 (C-11), 112.2 (C-8), 112.9 (C-3),
122.0 (CH=C), 124.5 (C-1), 129.9 (C-7a), 130.9 (C-12a),
131.8 (C-11a), 135.8 (C-12), 147.3, 149.6 (C-9, C-10), 169.3
(CO); MS (230 eV, CI) m/z (%)=369 (100) [MH]+, 368 (52)
[M]+, 297 (18), 296 (61), 269 (28); HR-MS (CI): m/z=
369.2178, calcd. for C22H29N2O3 [MH]+: 369.2178.
(Z)-Benzyl 2-(8,9-Dimethoxy-5H-benzo[d]-
pyrroloACHTUNGTRENNUNG[1,2-a]azepin-11(6H)-ylidene)acetate (5b)
(Table 1, entry 12)
PdACHTUNGTRENNUNG(PPh3)4 (13.7 mg, 0.01 mmol) was added to a mixture of
N-phenethylpyrrole 1b (121 mg, 0.23 mmol), (n-Bu)4NCl
(83 mg, 0.35 mmol) and NaHCO3 (49 mg, 0.58 mmol) in dry
CH3CN (5 mL) and the mixture was heated to reflux for
3 h. Standard work-up, followed by column chromatography
(silica gel, hexane/EtOAc=7:3) gave 5b (oil) as a mixture
of diastereomers Z/E 1:0.7 as established by 1H NMR;
yield: 51 mg (56%); data of the mixture are given. IR
(Z)-Benzyl 2-(9,10-dimethoxy-6,7-dihydrobenzo[d]-
pyrroloACHTUNGRTEN[NUNG 1,2-a]azocin-12(5H)-ylidene)acetate (6b)
(Table 2, entry 18)
1
(neat): n=1710 cmÀ1; H NMR (300 MHz, CDCl3): d=3.10–
3.21 (m, 2H, H-6 both isom), 3.69 (s, 3H, OCH3 isom E),
3.87 (s, 3H, OCH3 isom Z), 3.88 (s, 3H, OCH3 isom Z), 3.90
Pd
ACHTUNGTREN(UNNG PPh3)4 (9.5 mg, 0.008 mmol) was added to a mixture of
N-phenylpropylpyrrole 2b (143 mg, 0.24 mmol), (n-Bu)4NCl
Adv. Synth. Catal. 2014, 356, 1853 – 1865
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1861

UPDATES
Estibaliz Coya et al.
(127 mg, 0.54 mmol) and Et3N (0.5 mL) in dry CH3CN
(5 mL) and the mixture was heated under reflux for 50 h.
Standard work-up, followed by column chromatography
(silica gel, hexane/EtOAc=8:2) gave 6b as an oil; yield:
122.2 (C-2), 126.7 (C-3), 129.2 (C-7), 129.7 (=CH-Ar), 129.8
(C-9a), 130.0 (C-3a), 131.1 (C-9b), 166.1 (CO); MS (230 eV,
CI): m/z (%)=301 (100) [MH]+, 300 (58) [M]+, 229 (18),
228 (28), 201 (7), 188 (6); HR-MS (CI): m/z=301.1368,
calcd. for C17H21N2OS [MH]+: 301.1375.
1
34 mg (31%): IR (neat): n=1710 cmÀ1; H NMR (300 MHz,
CDCl3): d=1.81–1.88 (m, 2H, H-6), 2.72 (t, J=6.7 Hz, 2H,
H-7), 3.43–3.58 (m, 2H, H-5), 3.71 (s, 3H, OCH3), 3.92 (s,
3H, OCH3), 4.98 (s, 2H, CO2CH2Ph), 6.16 (dd, J=3.8,
2.6 Hz, 1H, H-2), 6.51 (s, 1H, CH=C), 6.63 (s, 1H, H11),
6.60–6.67 (m, 1H, H-1), 6.72 (s, 1H, H-8), 6.81 (dd, J=3.8,
1.7 Hz, 1H, H-3), 7.13–7.41 (m, 5H, COCH2Ph); 13C NMR
(75.5 MHz, CDCl3): d=29.5 (C-7), 32.8 (C-6), 46.5 (C-5),
55.7, 55.9 (2ꢃOCH3), 65.6 (CO2CH2Ph), 108.5 (C-2), 110.5
(C-11), 111.2 (C-3), 113.0 (CH=C), 113.3 (C-1), 127.5 (C-
12a), 127.9 (COCH2Ph), 128.2 (COCH2Ph), 128.3
(COCH2Ph), 129.5 (C-7a), 132.1 (C-11a), 136.3 (COCH2Ph),
147.0 (C-8), 148.1 (C-9), 149.8 (C-12), 166.3 (CO); MS
(230 eV, CI): m/z (%)=404 (100) [MH]+, 403 (23) [M]+, 298
(12), 296 (41), 270 (14), 107 (13), 93 (21). 91 (41); HR-MS
(CI): m/z=404.1845, calcd. for C25H26NO4 [MH]+: 404.1862.
(E)-N,N-Diethyl-2-{thieno
ylidene}acetamide (11) (Table 4, entry 2)
ACHTUNGERTN[NUNG 3,2-f]indolizin-9(4H)-
PdACHTNURTGNEUGN(PPh3)4 (27 mg, 0.02 mmol) was added to a mixture of 7a
(94 mg, 0.23 mmol), (n-Bu)4NCl (107 mg, 0.46 mmol) and
Et3N (0.4 mL) in dry DMF (5 mL) and the mixture was
stirred at 1108C for 7 h. Standard work-up, followed by
column chromatography (silica gel, hexane/EtOAc=6:4)
gave 11 as an oil; yield: 9.4 mg (14%). IR (ATR): n=
1645 cmÀ1 1H NMR (300 MHz, CDCl3): d=1.13 (t, J=
;
7.1 Hz, 3H, NCH2CH3), 1.25 (t, J=7.1 Hz, 3H, NCH2CH3),
3.43 (q, J=7.1 Hz, 2H, NCH2CH3), 3.56 (q, J=7.1 Hz, 1H,
NCH2CH3), 5.19 (s, 2H, H-4), 6.09 (s, 1H, =CH-CO), 6.30
(dd, J=3.9, 2.8 Hz, 1H, H-7), 6.67 (dd, J=3.9, 1.5 Hz, 1H,
H-8), 6.84 (d, J=1.5 Hz, 1H, H-6), 6.92 (d, J=5.1 Hz, 1H,
H-3), 7.24–7.27 (m, 1H, H-2); 13C NMR (75.5 MHz, CDCl3):
d=12.7 (NCH2CH3), 14.3 (NCH2CH3), 39.1 (NCH2CH3),
42.8 (NCH2CH3), 46.0 (C-4), 108.8 (C-8), 110.3 (C-7), 110.4
(=CH-CO), 121.4 (C-6), 124.7 (C-8a), 125.1 (C-9a), 125.2
(C-3), 125.3 (C-2), 132.4 (C-3a), 134.9 (C-9), 168.3 (CO);
MS (230 eV, CI): m/z (%)=287 (100) [MH]+, 286 (46) [M]+,
273 (20), 214 (9); H-RMS (CI): m/z=287.1228, calcd. for
C16H19N2OS for [MH]+: 287.1218.
(E)-N,N-Diethyl-3-(4H-thieno
ACHTUNGTNER[NUNG 2,3-a]pyrrolizin-6-yl)-
acrylamide (9) (Table 3, entry 5)
PdACHTUNGTRENNUNG(OAc)2 (6.1 mg, 0.02 mmol) was added to a mixture of 7b
(97.9 mg, 0.26 mmol), PPh3 (8.3 mg, 0.02 mmol) and (n-
Bu)4NOAc (105 mg, 0.40 mmol) in dry DMF (5 mL) and
was heated at 608C over 16 h. Standard work-up, followed
by column chromatography (silica gel, hexane/EtOAc=6:4)
afforded 9 as an oil; yield: 70 mg (93%). IR (neat): n=
1635 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=1.19–1.24 [m,
(E)-N,N-Diethyl-2-{4H-pyrroloACHTUNTRGENN[GU 1,2-a]thienoACHUTNGTRENN[GUN 2,3-d]-
azepin-10(5H)-ylidene}acetamide (12) (Table 4,
entry 12)
6H, N(CH2CH3)2], 3.45–3.50 [m, 4H, NACTHUNGTERN(NUG CH2CH3)2], 4.83 (s,
G
2H, H-4), 6.20 (d, J=3.7 Hz, 1H, H-8), 6.51 (d, J=15.0 Hz,
=CH-CO), 6.61 (d, J=3.7 Hz, 1H, H-7), 7.05 (d, J=4.9 Hz,
1H, H-3), 7.24 (d, J=4.9 Hz, 1H, H-2), 7.65 (d, J=15.0 Hz,
1H, =CH-Ar); 13C NMR (75.5 MHz, CDCl3): d=13.3
(NCH2CH3), 15.0 (NCH2CH3), 41.2 (NCH2CH3), 42.3
(NCH2CH3), 49.2 (C-4), 99.5 (C-7), 110.6 (C-8), 117.3 (=CH-
CO), 121.0 (C-3), 126.5 (C-2), 127.8 (C-6), 130.7 (=CH-Ar),
134.1 (C-3a), 137.6 (C-8a), 144.3 (C-8b), 166.2 (CO); MS
(230 eV, CI): m/z (%)=287 (100) [MH]+, 286 (52) [M]+, 214
(33), 187 (7), 174 (7); HR-MS (CI): m/z= 287.1217, calcd.
for C16H19N2OS [MH]+: 287.1218.
PdACTHUNTRGENNG(U OAc)2 (5.4 mg, 0.02 mmol) was added to a mixture of 8a
(101 mg, 0.24 mmol), dppp (5.1 mg, 0.01 mmol), (n-Bu)4NI
(884 mg, 2.3 mmol) and Et3N in dry CH3CN (5 mL) and was
heated at reflux over 24 h. Standard work-up, followed by
column chromatography (silica gel, hexane/EtOAc=6:4) af-
forded 12 as a solid; yield: 33 mg (46%), together with 10;
yield: 19 mg (26%).
Data for 12: mp (hexane/EtOAc) 114–1168C. IR (ATR):
1
n=1620 cmÀ1; H NMR (300 MHz, CDCl3): d=0.84 (t, J=
7.15 Hz, 3H, NCH2CH3), 1.08 (t, J=7.1 Hz, 3H, NCH2CH3),
3.06–3.08 (m, 2H, H-4), 3.23 (q, J=7.1 Hz, 2H, NCH2CH3),
3.37 (q, J=7.1 Hz, 2H, NCH2CH3), 4.22–4.26 (m, 2H, H-5),
6.01 (dd, J=3.6, 2.7 Hz, 1H, H-8), 6.32 (dd, J=3.6, 1.7 Hz,
1H, H-9), 6.39 (s, 1H, =CH-CO), 6.61–6.63 (m, 1H, H-7),
6.76 (d, J=5.2 Hz, 1H, H-3), 7.09 (d, J=5.2 Hz, 1H, H-2);
13C NMR (75.5 MHz, CDCl3): d=12.2 (NCH2CH3), 13.5
(NCH2CH3), 31.8 (C-4), 38.7 (NCH2CH3), 42.4 (NCH2CH3),
47.1 (C-5), 107.5 (C-8), 111.8 (C-1), 122.0 (C-7, =CH-CO),
123.4 (C-2), 129.5 (C-9a), 129.7 (C-10a), 130.7 (C-3), 135.8
(C-3a), 137.0 (C-10), 167.8 (CO); MS (230 eV, CI): m/z
(%)=301 (91) [MH]+, 300 (21) [M]+, 256 (13), 230 (14), 229
(37), 228 (100), 201 (19), 188 (29), 116 (28): HR-MS (CI):
m/z=301.1389, calcd. for C17H21N2OS [MH]+: 301.1375.
(E)-3-(4,5-Dihydrothieno
diethylacrylamide (10) (Table 3, entry 9)
ACHTUNGTNER[NUNG 3,2-g]indolizin-7-yl)-N,N-
PdACHTUNGTRENNUNG(OAc)2 (51 mg, 0.02 mmol) was added to a mixture of 8a
(94 mg, 0.22 mmol), PPh3 (5.8 mg, 0.02 mmol) and (n-
Bu)4NOAc (5.8 mg, 0.02 mmol) in dry DMF (5 mL) and was
heated at 608C over 6 h. Standard work-up, followed by
column chromatography (silica gel, hexane/EtOAc=7:3) af-
forded 10 as an oil; yield: 56 mg (85%). IR (ATR): n=
1630 cmÀ1
6H, N
4H, N
;
1H NMR (300 MHz, CDCl3): d=1.18–1.25 [m,
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
3.9 Hz, 1H, H-9), 6.60 (d, J=15.0 Hz, 1H, =CH-CO), 6.66
(d, J=3.9 Hz, 1H, H-8), 6.87 (d, J=4.9 Hz, 1H, H-3), 7.08
(d, J=4.9 Hz, 1H, H-2), 7.69 (d, J=15.0 Hz, 1H, =CH-Ar);
13C NMR (75.5 MHz, CDCl3): d=13.2 (NCH2CH3), 15.0
(NCH2CH3), 24.9 (C-4), 41.1 (NCH2CH3) 41.3 (C-5), 42.1
(NCH2CH3), 105.0 (C-8), 110.3 (C-9), 112.6 (=CH-CO),
1862
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Adv. Synth. Catal. 2014, 356, 1853 – 1865

UPDATES
Intramolecular Direct Arylation and Heck Reactions
[4] Selected reviews on the application of the Heck reac-
(Z)-2-{7,8-Dimethoxypyrrolo
10(5H)-ylidene}-N,N-diethylacetamide (14) (Table 5,
entry 8)
ACHTUNGTREN[NUNG 1,2-b]isoquinolin-
tion to the synthesis of heterocycles: a) G. Zeni, R. C.
Larock, Chem. Rev. 2006, 106, 4644–4680; b) Palladium
in Heterocyclic Chemistry, (Eds.: J. J. Li, G. W. Grib-
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in: The Mizoroki–Heck reaction, (Ed.: M. Oestreich),
Wiley, Chichester, 2009, pp 215–258; d) K. C. Majum-
dar, S. Samanta, B. Sinha, Synthesis 2012, 817–847;
e) S. G. Stewart, Cross Coupling and Heck-Type reac-
tions, in: Science of Synthesis, Vol. 3, (Ed.: M. Larhed),
Georg Thieme Verlag, Stuttgart, 2013, pp 441–520.
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2007, 10, 672–690; c) C. Torborg, M. Beller, Adv. Synth.
Catal. 2009, 351, 3027–3043; d) K. Suzuki, Y. Hori, Y.
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Pd complex 15 (9.0 mg, 0.01 mmol) was added to a mixture
of N-phenethylpyrrole 13[21] (101 mg, 0.21 mmol) and Et3N
(0.04 mL) in 5 mL of dry DMF and the mixture was stirred
at 1108C for 4 h. Standard work-up, followed by column
chromatography (silica gel, hexane/EtOAc=1:9) gave 14 as
a yellow solid which was crystallized from Et2O; yield:
33 mg (46%); the data are coincidental to those report-
ed:[21]; mp (Et2O) 113–1158C. IR (ATR): n=1610 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=1.00 (t, J=7.1 Hz, 3H,
NCH2CH3), 1.23 (t, J=7.1 Hz, 3H, NCH2CH3), 3.33 (q, J=
7.1 Hz, 2H, NCH2CH3), 3.52 (q, J=7.1 Hz, 3H, NCH2CH3),
3.89 (s, 3H, OCH3), 3.91 (s, 3H,OCH3), 5.06 (s, 2H, H-5),
6.21 (bs, 2H, =CH-CO, H-1), 6.57 (bs, 1H, H-2), 6.68 (s, 1H,
H-6), 6.77 (bs, 1H, H-3), 7.2 (s, 1H, H-9); 13C NMR
(75.5 MHz, CDCl3): d=12.5 (NCH2CH3), 14.1 (NCH2CH3),
39.0 (NCH2CH3), 42.7 (NCH2CH3), 47.4 (C-5), 55.9 (2ꢃ
OCH3), 106.8 (C-2), 108.4 (C-1), 108.7 (C-9), 109.7 (=CH-
CO), 119.6 (C-6), 120.6 (C-3), 123.9 (C-5a), 124.5 (C-10a),
125.9 (C-9a), 128.1 (C-10), 148.5 (C-8), 149.7 (C-7), 169.1
(C=O).
Acknowledgements
We wish to thank the Ministerio de Ciencia e Innovaciꢀn
(CTQ2009-07733), the Gobierno Vasco (IT-623-13) and the
Universidad del Paꢁs Vasco/Euskal Herriko Unibertsitatea
UPV/EHU (UFI11/22, GIU 09/46) for their financial sup-
port. We also thank Gobierno Vasco for a grant (to E.C.).
Technical and human support provided by Servicios Gener-
ales de Investigaciꢀn SGIker (UPV/EHU, MICINN, GV/EJ,
ERDF and ESF) is gratefully acknowledged.
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