Palladium(II)/copper halide/solvent combination for selective intramolecular domino reactions of indolecarboxylic acid allylamides: An unprecedented arylation/esterification sequence

Article abstract of DOI:10.1002/adsc.201100614

Intramolecular oxidative palladium-catalyzed reactions of indolylallylamides in the presence of the couple bis(acetonitrile) palladium dichloride and copper(II) halide are described. Starting from 2-and 3-indolylallylamides and involving in both cases the C-3 position of the indole nucleus, variously substituted b-carbolinones were obtained by arylation/ halogenation, arylation/esterification or arylation/ carboalkoxylation processes. On the other hand, an unusual aminohalogenation/halogenation sequence performed on 2-indolylallylamides gave rise to pyrazino[1,2-a]indole products. The carboesterification process is the result of an unknown path that involves the DMF or DMA used as solvent. The outcome of the reactions of the 3-indolylallylamides arises from a totally selective 1,2-migration of the acyl group on the supposed spiro intermediates formed from the nucleophilic attack of the C-3 indole position.

Full text of DOI:10.1002/adsc.201100614

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DOI: 10.1002/adsc.201100614
Palladium(II)/Copper Halide/Solvent Combination for Selective
Intramolecular Domino Reactions of Indolecarboxylic Acid Allyl-
amides: An Unprecedented Arylation/Esterification Sequence
Gianluigi Broggini,a,* Vincenzina Barbera,b Egle M. Beccalli,c Elena Borsini,c
Simona Galli,a Giuseppe Lanza,b and Gaetano Zecchia
a
Dipartimento di Scienze Chimiche e Ambientali, Universitꢀ dell’Insubria, via Valleggio 11, 22100 Como, Italy
Fax : (+39)-(0)31-238-6449; phone: (+39)-(0)31-238-6444; e-mail: gianluigi.broggini@uninsubria.it
Dipartimento di Scienze del Farmaco, Universitꢀ di Catania, viale Andrea Doria 6, 95125 Catania, Italy
DISMAB, Sezione di Chimica Organica “A. Marchesini” Universitꢀ di Milano, Via Venezian 21, 20133 Milano, Italy
b
c
Received: August 2, 2011; Published online: January 12, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100614.
Abstract: Intramolecular oxidative palladium-cata- pyrazinoACHTNUTRGNE[NUG 1,2-a]indole products. The carboesterifica-
lyzed reactions of indolylallylamides in the presence tion process is the result of an unknown path that in-
of the couple bis(acetonitrile) palladium dichloride volves the DMF or DMA used as solvent. The out-
and copper(II) halide are described. Starting from 2- come of the reactions of the 3-indolylallylamides
and 3-indolylallylamides and involving in both cases arises from a totally selective 1,2-migration of the
the C-3 position of the indole nucleus, variously sub- acyl group on the supposed spiro intermediates
stituted b-carbolinones were obtained by arylation/ formed from the nucleophilic attack of the C-3
halogenation, arylation/esterification or arylation/ indole position.
carboalkoxylation processes. On the other hand, an
unusual aminohalogenation/halogenation sequence Keywords: copper; domino reactions; homogeneous
performed on 2-indolylallylamides gave rise to catalysis; palladium
Introduction
of bonds constitutes a challenge that justifies ongoing
efforts in this field.
The transformation of unsaturated hydrocarbons
The indole nucleus represents a basic motif with
through the action of transition metal catalysts contin- broad occurrence in biologically or synthetically rele-
ues to represent a very important topic in organome- vant molecules endowed with pharmacological and
tallic chemistry. In this field, oxidative Pd(II)-cata- agrochemical activities.[6] For this reason, great efforts
lyzed alkene functionalization has emerged as one of have been devoted to improve the preparation of in-
the main focuses to build carbon-carbon and carbon- dolyl compounds employing innovative synthetic
heteroatom bonds.[1] The classic pathway for this pro- methodologies.[7] Within these synthetic protocols,
cedure typically requires the activation of the ethylen- several oxidative reactions based on Pd(II) catalysis
ic bond induced by its coordination to the metal, have been used for indole functionalization, some of
which makes the bond susceptible to addition reac- which represent a convenient tool for the direct elab-
tions, and the presence of a reoxidant agent in order oration of the indole core motif.[8]
to generate the suitable catalytic species. In the con-
Following our interest towards transition metal-cat-
text of oxidative Pd(II) catalysis, domino processes alyzed reactions[9] as well as towards the synthesis of
such as carboaminations,[2] diaminations,[3] aminooxy- complex heteropolycyclic structures containing the
genations[4] and aminohalogenations,[5] enabling easy indole nucleus,[10] herein we present the results of a
access to (poly)functionalized acyclic and cyclic com- project aimed at developing domino procedures for
pounds as well as bicyclic ring systems, are particular- the regioselective cyclization of indole derivatives
ly fascinating and useful in organic synthesis. As a bearing an ethylenic moiety. More specifically, our
consequence, the set-up of selective and tailored pro- work focused on the behavior of allylamides of 2- and
cedures based on new combinations of various kinds 3-indolecarboxylic acids. This search relies on the re-
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domino reactions that rely upon a first carbon-carbon
or carbon-heteroatom bond forming reaction.[2h,3-
f,4i,5a,b,11]
In agreement with this assumption, the use of
this bimetallic couple in THF at room temperature al-
lowed the conversion of the N-allylmethylindole-2-
carboxamide 1a to the chloro derivative 3a arising
from an arylation/chlorination process (Table 1,
entry 1). On increasing the temperature, the reaction
was cleaner giving compound 3a in a shorter time and
higher yield (entry 2). The same outcome was ob-
served when the reaction was performed in MeOH or
dioxane as solvent (entries 3 and 4). Conversely, we
found that the use of DMF as solvent triggers a com-
petitive reaction pathway giving the formic ester 4a,
beside the chloro derivative 3a. This unusual domino
pathway, which is based on an oxidative Pd(II)-cata-
lyzed arylation/esterification sequence involving the
solvent, prompted us to further undertake investiga-
Figure 1. Concept of the present work.
activity of the 2-indolylallylamides (1), that undergo tions. The ratio of the carbochlorination and carboes-
carbopalladation or aminopalladation of the carbon- terification products is markedly depending on the re-
carbon double bonds (previously converted in p- action temperature, as shown by entries 5–7, and a de-
olefin complexes) exploiting the nucleophilicity of the cisive improvement to yield formate 4a was achieved
C-3 and N-1 indole positions (Figure 1).
by heating the reaction mixture at 1508C (entry 8).
The so-formed A and B intermediates could then We also tried to individualize less harsh selective con-
evolve affording variously substituted 3,4-dihydro-b- ditions for the carboesterification process by using ox-
carbolinones and pyrazino
an appropriate nucleophile combined with a catalytic chlorination process. However, the attempts to obtain
system that prevents the usual b-hydride elimination. 4a from 1a with Cu(OAc)2, CuCl2 (5 mol%)/O2, and
ACHTUNGERTN[NUNG 1,2-a]indoles by means of idant agents unable to promote the competitive
AHCTUNGTRENNUNG
O2 as oxidant agents failed, thus confirming the pivo-
tal role of CuCl2 in our procedures.
Results and Discussion
According to the optimal conditions previously re-
ported, the divergent carbochlorination and carboes-
At the outset of the investigation, we considered the terification processes were probed on 2-indolylallyla-
N-allylmethylindole-2-carboxamide (1a) and we envi- mides differently substituted at the amide group. In
sioned as suitable catalytic system PdCl2ACTHNUTRGNE(UNG MeCN)2 (2) all cases, the outcome of the reaction was consistent
(5 mol%) and CuCl2 (3 equiv.), typically effective in with our prior results on the model substrate 1a. As
Table 1. Optimization of selective reaction conditions.
Entry
Solvent
Temperature [8C]
Time [h]
Conversion [%]
Yield[a] of 3a [%]
Yield[a] of 4a [%]
1
2
3
4
5
6
7
8
THF
THF
r.t.
3
2
2
3
72
3
3
100
100
100
100
30
100
100
100
65
92
81
70
20
61
68
2
reflux
reflux
reflux
r.t.
60
100
dioxane
MeOH
DMF
DMF
DMF
DMF
7
29
33
87
150
3
[a]
Isolated yield.
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Palladium(II)/Copper Halide/Solvent Combination for Selective Intramolecular Domino Reactions
Table 2. Scope of carbohalogenation and carboesterification reactions.
Entry
1
Substrate
Conditions[a]
Products
Yield [%]
82
1b
A
3b X=Cl; R=cyclohexyl
2
3
4
5
6
1c
1d
1e
1a
1b
A
A
A
A
A
3c X=Cl; R=phenyl
3d X=Cl; R=allyl
3e X=Cl; R=cyclopentyl
5a X=Br; R=methyl
5b X=Br; R=cyclohexyl
76
77
88
78
71
7
1b
B
4b R=cyclohexyl; R’=H
84
8
9
10
11
12
13
1c
1d
1e
1a
1b
1c
B
B
B
C
C
C
4c R=phenyl; R’=H
4d R=allyl; R’=H
4e R=cyclopentyl; R’=H
6a R=methyl; R’=methyl
6b R=cyclohexyl; R’=methyl
6c R=phenyl; R’=methyl
73
75
86
65
68
62
[a]
Conditions A: 2 (5 mol%), CuX2 (3 equiv.), THF, reflux. Conditions B: 2 (5 mol%), CuCl2 (3 equiv.), DMF, 1508C. Condi-
tions C: 2 (5 mol%), CuCl2 (3 equiv.), DMA, 1508C.
shown in Table 2, the indole derivatives 1b–e under- structure. The reasonably first-formed s-alkylpalladi-
went carbochlorination giving compounds 3b–e (en- um complex is possibly stabilized by the intervention
tries 1–4) when conducting the reactions in THF as of CuCl2 that inhibits the more common palladium b-
solvent (i.e., the conditions of entry 2, Table 1). On hydride elimination through a transient palladium ox-
replacing CuCl2 with CuBr2, bromo derivatives 5a and idation[3f,13] or a heterobimetallic s-Pd/Cu complex
b were isolated as final products (entries 5 and 6). (Figure 2, L=DMF or DMA).[14] Reductive metal
Conversely, using the conditions referred to in entry 8 elimination may result in the iminium intermediate C,
of Table 1, allylamides 1b–e underwent an arylation/ susceptible to hydrolysis to the final product 4a. How-
esterification sequence with formation of compounds ever, we cannot exclude that the iminium species C
4b–e. Gratifyingly, the reaction was demonstrated to arises from a direct nucleophilic attack by the solvent
be more general. When carried out in DMA as sol- oxygen on the exocyclic carbon of the s-palladium
vent, acetate derivatives 6a–c were achieved in satis- complex. An alternative mechanism involving a
factory yields (entries 11–13). Under these conditions,
chloro derivatives 3a–e were never detected.
Concerning the mechanistic aspects of the above
reactions, the following picture may be suggested.
While the formation of the chloroarylation product,
arising from a domino process with participation of
CuCl2 in the chlorine transfer step, could be foresee-
ACHTUNGTRENNUNG
able having precedents in literature,[5,8i,j,12] the forma-
tion of compound 4a is somehow unexpected. This
new domino arylation/esterification reaction, whose
detailed mechanism should be elucidated, clearly in-
Figure 2. Iminium intermediate for the carboesterification
volves the amidic solvent in determining the final reaction.
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Table 3. Carbohalogenation and carboesterification reactions on allylamides of 3-indolecarboxylic acid.
Entry
1
Substrate
Conditions[a]
Products
Yield [%]
79
7a
A
3a R=methyl
2
3
4
5
7b
7c
7d
7e
A
A
A
A
3b R=cyclohexyl
3c R=phenyl
3d R=allyl
75
74
83
81
3e R=cyclopentyl
6
7a
B
4a R=methyl; R’’=H
81
7
8
9
10
11
7b
7c
7d
7e
7a
B
B
B
B
C
4b R=cyclohexyl; R’’=H
4c R=phenyl; R’’=H
4d R=allyl; R’’=H
4e R=cyclopentyl; R’’=H
6a R=methyl; R’’=methyl
72
69
81
70
73
[a]
Conditions A: 2 (5 mol%), CuCl2 (3 equiv.), THF, reflux. Conditions B: 2 (5 mol%), CuCl2 (3 equiv.), DMF, 1508C. Con-
ditions C: 2 (5 mol%), CuCl2 (3 equiv.), DMA, 1508C.
Pd(IV) intermediate can be ruled out because the re-
action did not occur when changing CuCl2 with
PhIACHTUNGTRENNUNG(OAc)2, which is an established oxidant for
Pd(II)/Pd(IV) reactivity.[15] On the other hand, the hy-
pothesis that chloro derivative 3a may act as the pre-
cursor of 4a by a non-metal- or metal-promoted dis-
placement of the chloride anion was excluded on the
basis of its inactivity when heated in DMF either in
Figure 3. Spiro intermediate from allylamides of 3-indolecar-
the absence or in the presence of the catalytic system. boxylic acid.
The chloroarylation and carboesterification reac-
tions were then proven also on the allylamides of the
3-indolecarboxylic acid 7a–e. The cyclizations, per- 1,2-migration of the acyl moiety to give the final
formed in the conditions of entries 2 and 8 of Table 1, products.[16] Thus, the 6-exo-trig cyclizations on the al-
proceeded satisfactorily giving, however, the com- lylamides 7a–e presumably proceed via spiro inter-
pounds 3a–e and 4a–e, already obtained starting from mediates of type D, which undergo selectively acyl
the allylamides of the 2-indolecarboxylic acid (en- migration before or after the elimination of the metal
tries 1–10, Table 3). The treatment of the amide 7a (Figure 3).
with 2 as catalyst and CuCl2 (3 equiv.) in DMA at
1508C confirmed the behaviour previously observed, totally selective migration of the acyl group from the
affording the product 6a (entry 11, Table 3). quaternary centre was confirmed submitting the ally-
The tendency of the spiro intermediates D to give a
The isolation of the rearranged products 3a–e, 4a–e lamides of the 3-indolecarboxylic acid to a palladium-
and 6a suggests that cyclizations of C-3 substituted in- catalyzed carbonylative process (Scheme 1). In fact,
doles, catalyzed by the 2/CuCl2 system, take place by treatment of allylamides 7a–e with a catalytic amount
À
an initial formation of C C bond at C-3 followed by of 2 (5 mol%) and a stoichiometric amount of CuCl2
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Palladium(II)/Copper Halide/Solvent Combination for Selective Intramolecular Domino Reactions
Table 4. Base-promoted cyclization reactions.
Entry Substrate Products
Yield[a] [%]
1
2
3
4
5
6
7
1a
1b
1c
1d
1a
1b
1c
9a X=Cl; R=methyl
9b X=Cl; R=cyclohexyl
9c X=Cl; R=phenyl
9d X=Cl; R=allyl
10a X=Br; R=methyl
10b X=Br; R=cyclohexyl 75
10c X=Br; R=phenyl 71
91
85
81
83
73
Scheme 1. Arylation/carboalkoxylation reaction of the
indole nucleus.
(3 equiv.) in methanol under CO (1 atm) for 3 h at
608C gives the methyl b-carbolin-4-ylacetates 8a–e,
arising from an arylation/carboalkoxylation reac-
tion.[17]
[a]
Isolated yield.
The b-carboline structure was unambiguously deter-
To explain the formation of the products 9 and 10,
mined by an X-ray diffraction analysis carried out on we propose a mechanism which implies two inde-
the compound 8b (Figure 4). pendent reactions, as depicted in Figure 5. In the light
After the success in the synthesis of variously func- of previous literature data,[8e,18] the halogenation of
tionalized b-carbolinones involving the C-3 position the indolyl 3-position leading to the 3-halo derivative
of the indole nucleus, having in mind an opposite re- E can be due solely to the Cu(II) salt without involve-
gioselective path at the indolyl nitrogen, we tried to ment of the palladium catalyst. On the other hand, an
develop a new protocol in a basic medium. For this aminopalladation of the p-olefin complexes F allows
purpose, allylamides 1a–d were subjected to the treat- the formation of the s-alkylpalladium complexes G,
ment with 2 (5 mol%) and a Cu(II) salt (5 equiv.) as the evolution of which implies, rather than the usual
catalytic system in the presence of K2CO3 (1 equiv.). b-hydride elimination, a chlorine transfer on the tran-
The reactions proceeded cleanly giving dihalogenated
pyrazinoACHTUNGTRENNUNG[1,2-a]indoles 9a–d and 10a–c in good yields
by an aminohalogenation/halogenation sequence
(Table 4). Acetonitrile was proved to be the best sol-
vent, while DMF and dioxane allow the formation of
the dihalogenated products in traces.
Figure 4. ORTEP representation, at 30% probability level,
of the molecular structure of compound 8b. One of the two
molecules of the asymmetric unit was arbitrarily chosen for
the picture.
Figure 5. Proposed mechanism for the aminohalogenation/
halogenation reaction.
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Gianluigi Broggini et al.
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manner. Further studies are currently addressed to
gain more insights on the mechanism of the carbo-
AHCTUNGERTGeNNUN sterification reaction.
Experimental Section
General Remarks
Scheme 2. Simple halogenation reaction of the indole nu-
cleus.
Reagents and solvents were used as received from commer-
cial sources. Flash column chromatography was performed
employing 230–400 mesh silica gel. Analytical thin layer
chromatography was performed on silica gel 60 F254. Melt-
ing points were measured with a Bꢂchi B-540 apparatus and
are uncorrected. IR spectra were recorded on a FT-IR spec-
trophotometer. Nuclear magnetic resonance spectra were
acquired on an AVANCE 400 Bruker spectrometer operat-
sient species H to produce the halomethyl-substituted
pyrazinoACHTUNGTRENNUNG[1,2-a]indoles 9 and 10.
A sequence involving two independent processes is
supported by the observed behaviour of allylamide 1a
in the presence of CuCl2 and absence of catalyst 2
(Scheme 2). In these conditions, the chlorination of
the indole nucleus was really effective leading to the
N-allyl-N-methyl amide of 3-chloro-2-indolecarboxyl-
ic acid (11), while the aminochlorination process was
not operative. In the presence of K2CO3, the forma-
tion of 11 was faster and took place in a shorter time
in comparison to that required for the complete ami-
nohalogenation/halogenation sequence occurring in
the presence of palladium (entry 1, Table 4). On the
other hand, in the absence of K2CO3, the reaction was
much slower than the arylation/chlorination process
reported in entry 2 of Table 1, so indicating that the
direct carbopalladation is really operative in the for-
mation of 3a. Such a hypothesis was also supported
by the following findings: (i) the interruption of the
arylation/chlorination of compound 1a (entry 2,
Table 1) after 30 min provided a mixture containing
only the unreacted compound 1a and the cyclized
product 3a; (ii) conversely, the analogous interruption
1
ing at 400 MHz for H NMR and 100 MHz for 13C NMR. 13C
spectra were 1H decoupled and multiplicities were deter-
mined by the APT pulse sequence. Mass spectra were deter-
mined on an HPLC-MS LCQ-Advantage Thermo Finnigan
instrument. Elemental analyses were executed on a Perkin–
Elmer CHN Analyzer Series II 2400.
Detailed procedures for the preparation of allylamides
and details on the X-ray diffraction measurement and analy-
sis are available as Supporting Information.
General Procedure for the Arylation/Halogenation
Reactions (Conditions A)
A solution of 2-indolylallylamide (1 mmol), PdCl2ACTHNUTRGNEN(UG MeCN)2
(0.05 mmol) and CuX2 (3 mmol) in THF (5 mL) was re-
fluxed for 2 h. After cooling, the solvent was evaporated
under reduced pressure, brine was added (10 mL) and the
solution was extracted with CH2Cl2 (3ꢃ20 mL). The organic
phase was dried over Na2SO4, then the solvent was evapo-
rated under reduced pressure. The products were purified
by flash chromatography.
4-(Chloromethyl)-2-methyl-2,3,4,9-tetrahydropyrido
ACHTUNGTRENNUNG[3,4-
of the aminochlorination/chlorination sequence b]indol-1-one (3a): Yield: 92%; eluent: hexane/AcOEt 1:1;
1
pale orange solid; mp 1668C (i-Pr2O). H NMR (400 MHz,
CDCl3): d=3.24 (s, 3H), 3.49–3.53 (m, 1H), 3.62 (t, J=
11.0 Hz, 1H), 3.80 (dd, J=3.8, 11.0 Hz, 1H), 3.87 (dd, J=
2.3, 12.9 Hz, 1H), 3.97 (dd, J=5.3, 12.9 Hz, 1H), 7.20 (dd,
J=7.5, 7.8 Hz, 1H), 7.35 (dd, J=7.5, 8.2 Hz, 1H), 7.52 (d,
J=8.2 Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 9.99 (s br, 1H);
13C NMR (100 MHz, CDCl3): d=34.8 (q), 35.5 (d), 44.7 (t),
52.0 (t), 113.4 (d), 117.7 (s), 120.1 (d), 121.1 (d), 125.0 (s),
125.4 (d), 127.5 (s), 138.1 (s), 161.5 (s); IR: n=3432,
(entry 1, Table 4) gave, beside 1a and the cyclized
product 9a, also 3-chloroindole derivative 11.
Conclusions
In conclusion, we have developed some efficient and
practical PdCl
tions that provide rapid and selective access to vari-
ously functionalized b-carbolinones and pyrazinoACHTNGUTRNE[NUG 1,2- C13H13ClN2O: C 62.78, H 5.27, N 11.26; found: C 62.83, H
2ACHTUNGTRENNUNG(MeCN)2/CuX2 mediated domino reac-
1667 cmÀ1
;
MS: m/z=248 (M+); anal. calcd. for
5.43, N 11.40.
a]indoles. Among these oxidative Pd(II)-catalyzed
processes, the pathway leading directly to formic or
acetic esters represents, to the best of our knowledge,
the first example of evolution of a s-alkyl-palladium
complex by means of DMF or DMA used as solvent.
4-(Chloromethyl)-2-cyclohexyl-2,3,4,9-tetrahydropyrido-
AHCTUNGTREG[NNUN 3,4-b]indol-1-one (3b): Yield: 82%; eluent: hexane/AcOEt
8:2; pale yellow solid; mp 2248C (i-Pr2O). 1H NMR
(400 MHz, CDCl3): d=0.91–2.00 (m, 10H), 3.37–3.43 (m,
2H), 3.61–3.71 (m, 2H), 3.96 (d, J=12.9 Hz, 1H), 4.66–4.72
(m, 1H), 7.18 (dd, J=7.4, 7.9 Hz. 1H), 7.32 (dd, J=7.4,
8.3 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.62 (d, J=7.9 Hz,
1H), 10.39 (br s, 1H); 13C NMR (100 MHz, CDCl3): d=25.9
(t), 26.1 (t), 30.1 (t), 30.4 (t), 31.1 (t), 35.2 (d), 43.8 (t), 43.9
While pyrazino
ACHTUNGTRENNUNG[1,2-a]indoles arise from 2-indolylallyl-
ACHTUNGTRENNUNGamides, b-carbolinone derivatives can be achieved
starting either from 2- or 3-indolylallylamides. These
latter, in fact, follow an outcome that involves the
1,2-migration of the amide group in a totally selective (t), 52.1 (d), 113.3 (d), 117.3 (s), 120.0 (d), 121.0 (d), 124.7
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Palladium(II)/Copper Halide/Solvent Combination for Selective Intramolecular Domino Reactions
(s), 125.3 (d), 128.1 (s), 138.1 (s), 160.5 (s); IR: n=3427,
1661 cmÀ1 MS: m/z=316 (M+); anal. calcd. for
C18H21ClN2O: C 68.24, H 6.68, N 8.84; found: C 68.21, H
6.51, N 8.73.
(400 MHz, CDCl3): d=1.10–2.97 (m, 10H), 3.31–3.41 (m,
;
1H), 3.47–3.51 (m, 1H), 3.58–3.63 (m, 1H), 3.71–3.79 (m,
1H), 3.91–4.08 (m, 1H), 4.61–4.75 (m, 1H), 7.20 (dd, J=7.1,
8.0 Hz, 1H), 7.35 (dd, J=1.1 ,7.1 Hz, 1H), 7.50 (d, J=
1.1 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 10.00 (s br, 1H);
13C NMR (100 MHz, CDCl3): d=26.1 (t), 31.2 (t), 32.1 (t),
33.2 (t), 35.1 (d), 45.3 (t), 51.9 (d), 113.1 (d), 117.2 (s), 120.1
(d), 121.1 (d), 124.9 (s), 125.2 (d), 127.7 (s), 137.5 (s), 158.0
(s); IR: n=3441, 1668 cmÀ1; MS: m/z=361 (M+); anal.
calcd. for C18H21BrN2O: C 59.84, H 5.86, N 7.75; found: C
59.68, H 5.99, N 7.64.
4-(Chloromethyl)-2-phenyl-2,3,4,9-tetrahydropyridoACTHNUTRGNEU[GN 3,4-
b]indol-1-one (3c): Yield: 76%; eluent: hexane/AcOEt
1
65:35; yellow solid; mp 2068C (i-Pr2O). H NMR (400 MHz,
CDCl3): d=3.59–3.62 (m. 1H), 3.80 (t, J=10.7 Hz, 1H),
3.89 (dd, J=4.0, 10.7 Hz, 1H), 4.32 (dd, J=1.8, 12.8 Hz,
1H), 4.41 (dd, J=4.5, 12.8 Hz, 1H), 7.21 (dd, J=7.5, 8.0 Hz,
1H), 7.37–7.39 (m, 3H), 7.49–7.54 (m, 4H), 7.68 (d, J=
8.0 Hz, 1H), 10.63 (br s, 1H); 13C NMR (100 MHz, CDCl3):
d=35.9 (d), 44.4 (t), 53.6 (t), 113.5 (d), 118.7 (s), 120.3 (d),
121.2 (d), 124.8 (s), 125.8 (d), 126.4 (d), 127.2 (d), 127.7 (s),
129.5 (d), 138.3 (s), 142.4 (s), 160.6 (s); IR: n=3442,
General Procedure for the Arylation/Esterification
Reactions (Conditions B)
1675 cmÀ1
;
MS: m/z=310 (M+); anal. calcd. for
A solution of 2-indolylallylamide (1 mmol), PdCl2ACTHNUTRGNEN(UG MeCN)2
C18H15ClN2O: C 69.57, H 4.86, N 9.01; found: C 69.41, H
5.09, N 9.23.
2-Allyl-4-(chloromethyl)-2,3,4,9-tetrahydropyridoACTHNUTRGNEU[GN 3,4-
(0.05 mmol) and CuCl2 (3 mmol) in DMF (5 mL) was re-
fluxed for 3 h. After cooling, brine was added (10 mL) and
the solution was extracted with Et2O (3ꢃ20 mL). The or-
ganic phase was dried over Na2SO4, then the solvent was
evaporated under reduced pressure. The products were puri-
fied by flash chromatography.
b]indol-1-one (3d): Yield: 77%; eluent: hexane/AcOEt 7:3;
pale yellow solid; mp1718C (i-Pr2O). 1H NMR (400 MHz,
CDCl3): d=3.49–3.54 (m, 1H), 3.60 (t, J=10.8 Hz, 1H),
3.79 (dd, J=3.7, 10.8 Hz, 1H), 4.18 (dd, J=6.4, 15.0 Hz,
1H), 4.48 (dd, J=6.0, 15.0 Hz, 1H), 5.35 (d, J=10.8 Hz,
1H), 5.40 (dd, J=1.1, 17.1 Hz, 1H), 5.92–6.00 (m, 1H), 7.20
(dd, J=7.3, 8.0 Hz, 1H), 7.35 (dd, J=7.3, 8.3 Hz, 1H), 7.57
(d, J=8.3 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 11.05 (br s,
1H); 13C NMR (100 MHz, CDCl3): d=35.5 (d), 44.5 (t), 49.3
(t), 113.6 (d), 117.9 (s), 119.1 (t), 120.1 (d), 121.0 (d), 124.9
(s), 125.4 (d), 127.5 (s), 133.2 (d), 138.3 (s), 161.1 (s); IR:
n=3455, 1668 cmÀ1; MS: m/z=274 (M+); anal. calcd. for
C15H15ClN2O: C 65.57, H 5.50, N 10.20; found: C 65.55, H
5.31, N 10.36.
(2-Methyl-1-oxo-2,3,4,9-tetrahydropyridoACTHUNRTGNEUNG[3,4-b]indol-4-
yl)methyl formate (4a): Yield: 87%; eluent: hexane/AcOEt
1:1; pale orange solid; mp 1298C (i-Pr2O). 1H NMR
(400 MHz, CDCl3): d=3.23 (s, 3H), 3.56–3.65 (m, 2H), 3.97
(dd, J=5.2, 10.1 Hz, 1H), 4.26 (t, J=10.1 Hz, 1H), 4.53 (dd,
J=4.7, 11.2 Hz, 1H), 7.18 (dd, J=7.3, 7.9 Hz, 1H), 7.34 (t,
J=7.3, 8.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.67 (d, J=
7.9 Hz, 1H), 8.15 (s, 1H), 9.97 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=32.4 (d), 34.8 (q), 52.0 (t), 63.7 (t),
113.5 (d), 117.2 (s), 120.3 (d), 120.9 (d), 125.3 (d), 125.4 (s),
127.7 (s), 137.9 (s), 161.2 (s), 161.8 (s); IR: n=3421, 1658,
1730 cmÀ1; MS: m/z=258 (M+); anal. calcd. for C14H14N2O3:
C 65.11, H 5.46. N 10.85; found: C 65.24, H 5.21, N 11.04.
4-(Chloromethyl)-2-cyclopentyl-2,3,4,9-tetrahydropyrido-
ACHTUNGTRENNUNG[3,4-b]indol-1-one (3e): Yield: 88%; eluent: hexane/AcOEt
8:2; white solid; mp 2098C (i-Pr2O). 1H NMR (400 MHz,
CDCl3): d=1.70–2.07 (m, 8H), 3.45–3.55 (m, 2H), 3.74–3.90
(m, 2H), 3.91 (d, J=13.3 Hz, 1H), 5.31–5.35 (m, 1H), 7.19
(dd, J=7.5, 8.0 Hz, 1H), 7.35 (dd, J=7.5, 8.3 Hz, 1H), 7.55
(d, J=8.3 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 11.08 (s br,
1H); 13C NMR (100 MHz, CDCl3): d=24.9 (t), 25.2 (t), 28.6
(t), 30.2 (t), 35.3 (d), 43.9 (t), 44.0 (t), 53.8 (d), 113.5 (d),
117.3 (s), 120.0 (d), 121.0 (d), 124.8 (s), 125.3 (d), 128.1 (s),
138.3 (s), 161.2 (s); IR: n=3439, 1671 cmÀ1; MS: m/z=302
(M+); anal. calcd. for C17H19ClN2O: C 67.43, H 6.32, N 9.25;
found: C 67.55, H 6.05, N 9.12.
(2-Cyclohexyl-1-oxo-2,3,4,9-tetrahydropyridoACTHNUTRGNE[NUG 3,4-b]indol-
4-yl)methyl formate (4b): Yield: 84%; eluent: hexane/
1
AcOEt 8:2; pale yellow solid; mp 1798C (i-Pr2O); H NMR
(400 MHz, CDCl3): d=1.17–1.92 (m, 10H), 3.52–3.56 (m,
1H), 3.69–3.79 (m, 2H), 4.11 (t, J=10.2 Hz, 1H), 4.51 (dd,
J=4.7, 11.1 Hz, 1H), 4.69–4.71 (m, 1H), 7.18 (dd, J=7.5,
7.8 Hz, 1H), 7.33 (dd, J=7.5, 8.2 Hz, 1H), 7.51 (d, J=
8.2 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 8.16 (s, 1H), 10.30 (br
s, v); 13C NMR (100 MHz, CDCl3): d=26.0 (t), 26.2 (t), 30.1
(t), 30.5 (t), 31.0 (t), 32.0 (d), 43.8 (t), 51.9 (d), 63.1 (t),
113.1 (d), 116.3 (s), 120.4 (d), 121.0 (d), 125.1 (s), 125.2 (d),
128.4 (s), 138.0 (s), 160.6 (s), 161.1 (s); IR: n=3425, 1650,
1718 cmÀ1; MS: m/z=326 (M+); anal. calcd. for C19H22N2O3:
C 69.92, H 6.79, N 8.58; found: C 69.65, H 7.04, N 8.72.
4-(Bromomethyl)-2-methyl-2,3,4,9-tetrahydropyridoACTHNUTRGNEU[GN 3,4-
b]indol-1-one (5a): Yield: 78%; eluent: hexane/AcOEt 1:1;
white solid; mp 2028C (i-Pr2O). 1H NMR (400 MHz,
CDCl3): d=3.29 (s, 3H), 3.49–3.51 (m, 1H), 3.52–3.55 (m,
1H), 3.61–3.65 (m, 1H), 3.80–3.85 (m, 1H), 3.91–3.99 (m,
1H), 7.27 (dd, J=7.8, 7.0 Hz, 1H), 7.39 (dd, J=7.0, 8.2 Hz,
1H), 7.51 (d, J=8.2 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 10.5
(s br, 1H); 13C NMR (100 MHz, CDCl3): d=32.7 (t), 34.6
(q), 35.1 (d), 52.9 (t), 113.3 (d), 119.2 (s), 119.7 (d), 121.1
(d), 124.1 (s), 125.1 (s), 125.8 (d), 126.7 (s), 161.0 (s); IR:
n=3437, 1660 cmÀ1; MS: m/z=293 (M+); anal. calcd. for
C13H13BrN2O: C 53.26, H 4.47, N 9.56; found: C 53.44, H
4.65, N 9.77.
(2-Phenyl-1-oxo-2,3,4,9-tetrahydropyridoACTHUNRTGNEUNG[3,4-b]indol-4-
yl)methyl formate (4c): Yield: 73%; eluent: hexane/AcOEt
65:35; pale yellow solid; mp 1438C (i-Pr2O). 1H NMR
(400 MHz, CDCl3): d=3.66–3.71 (m, 1H), 4.07 (dd, J=2.6,
12.7 Hz, 1H), 4.34–4.44 (m, 2H), 4.65 (dd, J=4.8, 11.2 Hz,
1H), 7.20 (dd, J=7.5, 7.8 Hz, 1H), 7.28–7.40 (m, 5H), 7.46–
7.54 (m, 2H), 7.71 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 10.93 (br
s, 1 H); 13C NMR (100 MHz, CDCl3): d=32.8 (d), 53.4 (t),
63.5 (t), 113.5 (d), 117.8 (s), 120.5, (d), 121.1 (d), 125.1 (s),
125.7 (d), 126.2 (d), 127.1 (d), 127.8 (s), 129.5 (d), 138.5 (s),
142.6 (s), 161.0 (s), 161.1 (s); IR: n=3441, 1682, 1710 cmÀ1
;
4-(Bromomethyl)-2-cyclohexyl-2,3,4,9-tetrahydropyrido-
G
MS: m/z=320 (M+); anal. calcd. for C19H16N2O3: C 71.24, H
5.03, N 8.74; found: C 71.27, H 4.85, N 8.59.
Adv. Synth. Catal. 2012, 354, 159 – 170
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
165

Gianluigi Broggini et al.
FULL PAPERS
(2-Allyl-1-oxo-2,3,4,9-tetrahydropyrido
G
(dd, J=7.4, 8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.66 (d,
J=8.0 Hz, 1H), 10.45 (s br, 1H); 13C NMR (100 MHz,
CDCl3): d=21.0 (q), 25.8 (t), 30.1 (t), 30.5 (t), 31.7 (d), 43.6
(t), 51.6 (d), 63.6 (t), 112.7 (d), 116.6 (s), 120.1 (d), 120.4 (d),
124.7 (d), 124.9 (s), 127.8 (s), 137.6 (s), 159.2 (s), 170.8 (s);
IR: n=3441, 1668, 1720 cmÀ1; MS: m/z=340 (M+); anal.
calcd. for C20H24N2O3: C 70.57, H 7.11, N 8.23; found: C
70.62, H 7.32, N 8.07.
methyl formate (4d): Yield: 75%; eluent: hexane/AcOEt
7:3; pale yellow solid; mp 1138C (i-Pr2O). 1H NMR
(400 MHz, CDCl3): d=3.57–3.61 (m, 1H), 3.66 (dd, J=2.5,
12.8 Hz, 1H), 3.91 (dd, J=5.2, 12.8 Hz, 1H), 4.16 (dd, J=
6.5, 15.0 Hz, 1H), 4.23 (t, J=10.1 Hz, 1H), 4.44 (dd, J=5.9,
15.0 Hz, 1H), 4.51 (dd, J=4.8, 11.1 Hz, 1H), 5.30–5.37 (m,
2H), 5.88–5.97 (m, 1H), 7.19 (dd, J=7.5, 7.9 Hz, 1H), 7.34
(dd, J=7.5, 8.2 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.68 (d,
J=7.9 Hz, 1H), 8.14 (s, 1H), 10.91 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=32.2 (d), 49.1 (t), 49.2 (t), 63.6 (t),
113.4 (d), 117.0 (s), 118.9 (t), 120.4 (d), 121.0 (d), 125.2 (s),
125.4 (d), 127.7 (s), 133.4 (d), 138.3 (s), 161.1 (s), 161.3 (d);
IR: n=3432, 1678, 1728 cmÀ1; MS: m/z=284 (M+); anal.
calcd. for C16H16N2O3: C 67.59, H 5.67, N 9.85; found: C
67.48, H 5.91, N 9.76.
(2-Phenyl-1-oxo-2,3,4,9-tetrahydropyridoACTHUNRTGNEUNG[3,4-b]indol-4-
yl)methyl acetate (6c): Yield: 62%; eluent: hexane/AcOEt
65:35; pale yellow solid; mp 1568C (i-Pr2O). 1H NMR
(400 MHz, CDCl3): d=2.07 (s, 3H), 3.58–3.69 (m, 1H),
4.02–4.04 (m, 1H), 4.27 (dd, J=9.1, 2.0 Hz, 1H), 4.38–4.40
(m, 1H), 4.53–4.56 (m, 1H), 7.18–7.72 (m, 9H), 9.98 (s br,
1H); 13C NMR (100 MHz, CDCl3): d=21.0 (q), 32.4 (d),
53.2 (t), 63.9 (t), 112.8 (d), 118.0 (s), 120.4 (d), 120.7 (d),
124.9 (s), 125.3 (d), 125.7 (d), 126.6 (d), 127.3 (s), 129.1 (d),
137.7 (s), 142.2 (s), 160.3 (s), 170.8 (s); IR: n=3427, 1667,
1730 cmÀ1; MS: m/z=334 (M+); anal. calcd. for C20H18N2O3:
C 71.84, H 5.43, N 8.38; found: C 71.52, H 5.56, N 8.57.
(2-Cyclopentyl-1-oxo-2,3,4,9-tetrahydropyridoACTHNUTRGNE[UNG 3,4-b]indol-
4-yl)methyl formate (4e): Yield: 86%; eluent: hexane/
AcOEt 8:2; pale yellow solid; mp 1318C (i-Pr2O). H NMR
(400 MHz, CDCl3): d=1.62–2.01 (m, 8H), 3.55–3.58 (m,
1H), 3.67 (dd, J=2.5, 12.9 Hz, 1H), 3.78 (dd, J=4.8,
12.9 Hz, 1H), 4.10 (t, J=10.3 Hz, 1H), 4.54 (dd, J=4.8,
10.3 Hz, 1H), 5.26–5.31 (m, 1H), 7.17 (dd, J=7.4, 7.8 Hz,
1H), 7.33 (t, J=7.4, 8.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H),
7.67 (d, J=7.8 Hz, 1H), 8.16 (s, 1H), 10.81 (br s, 1H);
13C NMR (100 MHz, CDCl3): d=24.8 (t), 25.0 (t), 28.5 (t),
29.9 (t), 32.1 (d), 44.0 (t), 53.8 (d), 63.1 (t), 113.3 (d), 116.4
(s), 120.4 (d), 120.9 (d), 125.1 (s), 125.2 (d), 128.3 (s), 138.2
(s), 161.1 (s), 161.3 (s); IR: n=3440, 1664, 1738 cmÀ1; MS:
m/z=312 (M+); anal. calcd. for C18H20N2O3: C 69.21, H
6.45, N 8.97; found: C 69.33, H 6.28, N 8.78.
General Procedure for the Carbonylation Reactions
A solution of 3-indolylallylamide (1 mmol), PdCl2ACTHNUTRGNEN(UG MeCN)2
(0.05 mmol) and CuCl2 (3 mmol) in MeOH (5 mL) was
stirred at 608C for 3 h under CO atmosphere. After cooling,
brine was added (10 mL) and the solution was extracted
with Et2O (3ꢃ20 mL). The organic phase was dried over
Na2SO4 then the solvent was evaporated under reduced
pressure. The products were purified by flash chromatogra-
phy.
Methyl 2-(2-methyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido-
AHCTUNGTREG[NNUN 3,4-b]indol-4-yl)acetate (8a): Yield: 91%; eluent: hexane/
General Procedure for the Arylation/Esterification
Reactions (Conditions C)
AcOEt 1:1; white solid; mp 1688C (i-Pr2O). 1H NMR
(400 MHz, CDCl3): d=2.69 (dd, J=9.4, 15.8 Hz, 1H), 2.78
(dd, J=5.0, 15.8 Hz, 1H), 3.22 (s, 3H), 3.54 (dd, J=2.7,
12.7 Hz, 1H), 3.71 (s, 3H), 3.74–3.77 (m, 1H), 4.01 (dd, J=
5.0, 12.7 Hz, 1H), 7.16 (t, J=7.6, 8.0 Hz, 1H), 7.32 (t, J=
7.6, 8.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.63 (d, J=8.0 Hz,
1H), 10.36 (s br, 1H); 13C NMR (100 MHz, CDCl3): d=29.4
(d), 34.8 (q), 37.6 (t), 52.3 (q), 54.9 (t), 113.2 (d), 120.4 (d),
120.5 (d), 120.7 (s), 124.8 (s), 125.2 (d), 127.1 (s), 138.1 (s),
A solution of 2-indolylallylamide (1 mmol), PdCl2ACTHNUTRGNEN(UG MeCN)2
(0.05 mmol) and CuCl2 (3 mmol) in DMA (5 mL) was re-
fluxed for 3 h. After cooling, brine was added (10 mL) and
the solution was extracted with Et2O (3ꢃ20 mL). The or-
ganic phase was dried over Na2SO4 then the solvent was
evaporated under reduced pressure. The products were puri-
fied by flash chromatography.
(2-Methyl-1-oxo-2,3,4,9-tetrahydropyrido
N
161.9 (d), 172.9 (s); IR: n=3425, 1733, 1678 cmÀ1
;
yl)methyl acetate (6a): Yield: 65%; eluent: hexane/AcOEt
1:1; white solid; mp 1968C (i-Pr2O). 1H NMR (400 MHz,
CDCl3): d=2.11 (s, 3H), 3.21 (s, 3H), 3.52–3.58 (m, 1H),
3.60 (dd, J=2.6, 12.7 Hz, 1H), 3.96 (dd, J=5.3, 12.7 Hz,
1H), 4.18 (dd, J=9.1, 11.1 Hz, 1H), 4.44 (dd, J=5.3,
11.1 Hz, 1H), 7.18 (dd, J=7.5, 7.8 Hz, 1H), 7.33 (dd, J=7.5,
8.2 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 7.68 (d, J=7.8 Hz,
1H), 10.62 (br s, 1H); 13C NMR (100 MHz, CDCl3): d=21.4
(d), 32.5 (q), 34.7 (q), 52.2 (t), 64.5 (t), 113.1 (d), 117.3 (s),
120.6 (d), 121.0 (d), 125.3 (s), 125.4 (d), 127.7 (s), 137.9 (s),
161.6 (s), 171.3 (s). IR: n=3444, 1675, 1733 cmÀ1; MS: m/z=
272 (M+); anal. calcd. for C15H16N2O3: C 66.16, H 5.92, N
10.29; found: C 66.31, H 5.84, N 10.26.
MS: m/z=272 (M+); anal. calcd. for C15H16N2O3: C 66.16, H
5.92, N 10.29; found: C 66.27, H 5.74, N 10.15.
Methyl
2-(2-cyclohexyl-1-oxo-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indol-4-yl)acetate (8b): Yield: 72%; eluent:
AHCTUNGTRENNUNG
hexane/AcOEt 2:3; white solid; mp 1518C (i-Pr2O).
1H NMR (400 MHz, CDCl3): d=1.18–1.92 (m, 10H), 2.63
(dd, J=9.3, 16.1 Hz, 1H), 2.70 (dd, J=5.0, 16.1 Hz, 1H),
3.66–3.80 (m, 6H), 4.72–4.77 (m, 1H), 7.15 (t, J=7.4, 7.8 Hz,
1H), 7.31 (t, J=7.4, 8.2 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H),
7.63 (d, J=7.8 Hz, 1H), 11.03 (s br, 1H); 13C NMR
(100 MHz, CDCl3): d=26.0 (t), 26.3 (t), 29.1 (d), 30.5 (t),
30.7 (d), 30.9 (t), 36.7 (t), 46.7 (t), 51.9 (q), 52.2 (d), 113.2
(d), 120.2 (s), 120.4 (d), 120.5 (d), 124.6 (s), 125.0 (d), 127.8
(s), 138.3 (s), 161.1 (s), 173.1 (s); IR: n=3225, 1742,
1665 cmÀ1; MS: m/z=340 (M+); anal. calcd. for C20H24N2O3:
C 70.56, H 7.11, N 8.23; found: C 70.27, H 7.25, N 8.14.
(2-Cyclohexyl-1-oxo-2,3,4,9-tetrahydropyridoACTHNUTRGNE[NUG 3,4-b]indol-
4-yl)methyl acetate (6b): Yield: 68%; eluent: hexane/AcOEt
8:2; white solid; mp 1518C (i-Pr2O). 1H NMR (400 MHz,
CDCl3): d=0.81–2.21 (m, 10H), 2.11 (s, 3H), 3.45–3.53 (m,
1H), 3.68–3.75 (m, 2H), 4.02–4.07 (m, 1H), 4.36–4.40 (m,
1H), 4.58–4.79 (m, 1H), 7.15 (dd, J=7.4, 8.3 Hz, 1H), 7.30
Methyl
[3,4-b]indol-4-yl)acetate (8c): Yield: 41%; eluent: hexane/
AcOEt 7:3; white solid; mp 1718C (i-Pr2O). 1H NMR
2-(2-phenyl-1-oxo-2,3,4,9-tetrahydro-1H-pyrido-
AHCTUNGTRENNUNG
166
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Adv. Synth. Catal. 2012, 354, 159 – 170

Palladium(II)/Copper Halide/Solvent Combination for Selective Intramolecular Domino Reactions
(400 MHz, CDCl3): d=2.80–2.91 (m, 2H), 3.68 (s, 3H),
3.83–3.88 (m, 1H), 3.98 (dd, J=2.5, 12.6 Hz, 1H), 4.47 (dd,
J=4.7, 12.6 Hz, 1H), 7.18 (dd, J=7.5, 8.0 Hz, 1H), 7.30–
7.38 (m, 3H), 7.46–7.52 (m, 4H), 7.67 (d, J=8.0 Hz, 1H),
10.44 (s br, 1H); 13C NMR (100 MHz, CDCl3): d=29.9 (d),
37.5 (t), 52.3 (q), 56.3 (t), 113.3 (d), 120.7 (d), 120.9 (d),
121.6 (s), 124.6 (s), 125.6 (d), 126.1 (d), 126.9 (d), 127.2 (s),
129.4 (d), 138.4 (s), 142.7 (s), 161.0 (s), 172.8 (s); IR: n=
3278, 1732, 1651 cmÀ1; MS: m/z=334 (M+); anal. calcd. for
C20H18N2O3: C 71.84, H 5.43, N 8.38; found: C 71.66, H 5.52,
N 8.55.
7.73 (d, J=8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
34.4 (q), 41.1 (t), 48.5 (t), 52.1 (d), 109.4 (d), 111.7 (s), 112.9
(s), 120.6 (d), 121.8 (d), 126.1 (s), 126.4 (d), 133.5 (s), 158.7
(s); IR: n=1672 cmÀ1; MS: m/z=282 (M+); anal. calcd. for
C13H12Cl2N2O: C 55.14, H 4.27, N 9.89; found: C 55.36, H
4.06, N 9.78.
10-Chloro-4-(chloromethyl)-2-cyclohexyl-3,4-dihydro-
pyrazinoACTHNUTRGENUG[N 1,2-a]indol-1(2H)-one (9b): Yield: 85%; eluent:
hexane/AcOEt 7:3; white solid; mp 1638C (i-Pr2O).
1H NMR (400 MHz, CDCl3): d=1.13–1.98 (m, 10H), 3.61–
3.69 (m, 2H), 3.75–3.78 (m, 1H), 3.99–4.02 (m, 1H), 4.61–
4.77 (m, 2H), 7.24–7.42 (m, 3H), 7.75 (d, J=8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=25.4 (t), 25.6 (t), 25.7 (t),
30.1 (t), 30.3 (t), 40.5 (t), 40.9 (t), 51.1 (d), 52.2 (d), 109.3
(d), 111.7 (s), 120.5 (d), 121.7 (d), 122.0 (s), 126.2 (s), 126.3
(d), 133.3 (s), 158.0 (s); IR: n=1678 cmÀ1; MS: m/z=350
(M+); anal. calcd. for C18H20Cl2N2O: C 61.55, H 5.93, N
7.97; found: C 61.45, H 5.83, N 8.12.
Methyl 2-(2-allyl-1-oxo-2,3,4,9-tetrahydro-1H-pyridoACTHNUTRGNEU[GN 3,4-
b]indol-4-yl)acetate (8d): Yield: 68%; eluent: hexane/
AcOEt 3:2; white solid; mp 938C (i-Pr2O). 1H NMR
(400 MHz, CDCl3): d=2.66 (dd, J=9.4, 16.0 Hz, 1H), 2.75
(dd, J=5.2, 16.0 Hz, 1H), 3.55 (dd, J=2.5, 12.8 Hz, 1H),
3.70 (s, 3H), 3.74–3.76 (m, 1H), 3.95 (dd, J=5.4, 12.8 Hz,
1H), 4.09 (dd, J=6.7, 15.0 Hz, 1H), 4.48 (dd, J=5.4,
15.0 Hz, 1H), 5.29 (d, J=11.2 Hz, 1H), 5.34 (dd, J=1.2,
17.2 Hz, 1H), 5.87–5.97 (m, 1H), 7.16 (dd, J=7.4, 7.8 Hz,
1H), 7.32 (dd, J=7.8, 8.2 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H),
7.63 (d, J=7.8 Hz, 1H), 10.68 (s br, 1H); 13C NMR
(100 MHz, CDCl3): d=29.3 (d), 37.5 (t), 49.2 (t), 52.0 (t),
52.2 (q), 113.3 (d), 118.8 (t), 120.5 (d), 120.7 (d), 120.8 (s),
124.7 (s), 125.2 (d), 127.1 (s), 133.5 (d), 138.3 (s), 161.4 (s),
172.9 (s); IR: n=3218, 1738, 1661 cmÀ1; MS: m/z=298
(M+); anal. calcd. for C17H18N2O3: C 68.44, H 6.08, N 9.39;
found: C 68.28, H 6.32, N 9.17.
10-Chloro-4-(chloromethyl)-2-phenyl-3,4-dihydro-
pyrazinoACTHNUTRGENUG[N 1,2-a]indol-1(2H)-one (9c): Yield: 81%; eluent:
hexane/AcOEt 65:35; white solid; mp 1978C (i-Pr2O).
1H NMR (400 MHz, CDCl3): d=3.77 (d, J=10.3 Hz, 1H),
3.90 (dd, J=10.3, 10.5 Hz, 1H), 4.31 (d, J=12.6 Hz, 1H),
4.44 (d, J=12.6 Hz, 1H), 4.76–4.82 (m, 1H), 7.27–7.46 (m,
8H), 7.78 (d, J=8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=41.1 (t), 50.1 (t), 52.5 (d), 109.5 (d), 113.0 (s), 120.7 (d),
121.7 (s), 121.9 (d), 125.7 (d), 126.2 (s), 126.8 (d), 127.1 (d),
129.3 (d), 133.7 (s), 141.1 (s), 157.8 (s); IR: n=1673 cmÀ1
;
MS: m/z=344 (M+); anal. calcd. for C18H14Cl2N2O: C 62.62,
H 4.09, N 8.11; found: C 62.43, H 4.18, N 8.23.
Methyl
2-(2-cyclopentyl-1-oxo-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indol-4-yl)acetate (8e): Yield: 87%; eluent:
ACHTUNGTRENNUNG
hexane/AcOEt 1:1; white solid; mp 1548C (i-Pr2O).
1H NMR (400 MHz, CDCl3): d=1.62–2.03 (m, 8H), 2.63
(dd, J=0.9, 16.0.1 Hz, 1H), 2.72 (dd, J=5.0, 16.0 Hz, 1H),
3.60 (dd, J=2.2, 12.8 Hz, 1H), 3.69–3.72 (m, 1H), 3.72 (m,
3H), 3.82 (dd, J=4.7, 12.8 Hz, 1H), 5.31 (m, 1H), 7.15 (dd,
J=7.5, 8.0 Hz, 1H), 7.31 (t, J=7.5, 8.3 Hz, 1H), 7.54 (d, J=
8.3 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 11.04 (s br, 1H);
13C NMR (100 MHz, CDCl3): d=24.8 (t), 25.0 (t), 28.6 (t),
29.2 (d), 29.8 (t), 36.7 (t), 46.8 (t), 52.2 (q), 53.7 (d), 113.3
(d), 120.2 (s), 120.4 (d), 120.6 (d), 124.6 (s), 125.0 (d), 127.7
(s), 138.4 (s), 161.6 (s), 173.1 (s); IR: n=3330, 1748,
1677 cmÀ1; MS: m/z=326 (M+); anal. calcd. for C19H22N2O3:
C 69.92, H 6.79, N 8.58; found: C 70.18, H 6.65, N 8.81.
2-Allyl-10-chloro-4-(chloromethyl)-3,4-dihydro-pyrazino-
AHCTUNGTREG[NNNU 1,2-a]indol-1(2H)-one (9d): Yield: 83%; eluent: hexane/
AcOEt 7:3; pale yellow oil. 1H NMR (400 MHz, CDCl3):
d=3.60–3.68 (m, 2H), 3.90–3.93 (m, 2H), 4.00–4.06 (m,
1H), 4.41–4.48 (m, 1H), 4.62–4.73 (m, 1H), 5.31–5.38 (m,
2H), 5.81–5.93 (m, 1H), 7.26 (dd, J=7.1, 7.9 Hz, 1H), 7.36
(dd, J=7.1, 8.1 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.74 (d,
J=8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=41.0 (t),
45.6 (t), 48.6 (t), 52.2 (d), 109.4 (d), 112.0 (s), 119.8 (t), 120.6
(d), 121.6 (s), 121.8 (d), 126.1 (s), 126.5 (d), 132.2 (d), 133.6
(s), 158.1 (s); IR: n=1668 cmÀ1; MS: m/z=308 (M+); anal.
calcd. for C15H14Cl2N2O: C 58.27, H 4.56, N 9.06; found: C
58.44, H 4.25, N 8.82.
10-Bromo-4-(bromomethyl)-2-methyl-3,4-dihydro-
pyrazinoACTHNUTRGNE[UNG 1,2-a]indol-1(2H)-one (10a): Yield: 73%; eluent:
General Procedure for the Aminohalogenation/
Halogenation Reactions
hexane/AcOEt 1:1; pale yellow solid; mp 1418C (i-Pr2O).
1H NMR (400 MHz, CDCl3): d=3.21 (s, 3H), 3.41–3.49 (m,
1H), 3.51–3.61 (m, 1H), 3.91–3.99 (m, 1H), 4.05–4.11 (m,
1H), 4.73–4.83 (m, 1H), 7.25 (dd, J=8.1, 8.8 Hz, 1H), 7.35
(d, J=8.8 Hz, 1H), 7.41 (dd, J=8.1, 7.9 Hz, 1H), 7.71 (d,
J=7.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=28.7 (t),
34.6 (q), 49.0 (t), 52.1 (d), 97.4 (s), 109.6 (d), 120.6 (s), 121.7
(d), 121.9 (d), 123.0 (s), 126.4 (d), 134.2 (s), 158.8 (s); IR:
A solution of 2-indolylallylamide (1 mmol), PdCl2ACTHNUTRGNEN(UG MeCN)2
(0.05 mmol), CuX2 (5 mmol) and K2CO3 (1 mmol) in MeCN
(5 mL) was refluxed for 3 h. After cooling, solvent was
evaporated under reduced pressure, brine was added
(10 mL) and the solution was extracted with CH2Cl2 (3ꢃ
20 mL). The organic phase was dried over Na2SO4 then the
solvent was evaporated under reduced pressure. The prod-
ucts were purified by flash chromatography.
10-Chloro-4-(chloromethyl)-2-methyl-3,4-dihydro-
pyrazinoACHTUNGTRENNUNG[1,2-a]indol-1(2H)-one (9a): Yield: 91%; eluent:
hexane/AcOEt 2:1; white solid; mp 1518C (i-Pr2O).
1H NMR (400 MHz, CDCl3): d=3.20 (s, 3H), 3.62–3.74 (m,
2H), 3.90 (dd, J=1.2, 13.2 Hz, 1H), 4.04 (dd, J=4.0,
13.2 Hz, 1H), 4.68–4.72 (m, 1H), 7.25 (dd, J=8.1, 8.2 Hz,
1H), 7.35 (d, J=8.3 Hz, 1H), 7.42 (dd, J=8.2, 8.3 Hz, 1H),
n=1665 cmÀ1
;
MS: m/z=372 (M+); anal. calcd. for
C13H12Br2N2O: C 41.97, H 3.25, N 7.53; found: C 41.88, H
3.44 N, 7.41.
10-Bromo-4-(bromomethyl)-2-cyclohexyl-3,4-dihydro-
pyrazinoACTHNUTRGNE[UNG 1,2-a]indol-1(2H)-one (10b): Yield: 75%; eluent:
hexane/AcOEt 8:2; light orange solid; mp 1598C (i-Pr2O).
1H NMR (400 MHz, CDCl3): d=0.72–2.12 (m, 10H), 3.43–
3.55 (m 2H), 3.72–3.81 (m, 1H), 4.05–4.09 (m, 1H), 4.65–
4.79 (m, 2H), 7.26–7.43 (m, 3H), 7.71 (d, J=8.1 Hz, 1H);
Adv. Synth. Catal. 2012, 354, 159 – 170
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
167

Gianluigi Broggini et al.
FULL PAPERS
13C NMR (100 MHz, CDCl3): d=25.6 (t), 28.2 (t), 30.1 (t),
30.5 (t), 41.4 (t), 51.2 (d), 52.1 (d), 97.4 (s), 109.3 (d), 121.7
(d), 121.9 (d), 123.3 (d), 126.3 (s), 128.0 (s), 134.0 (s), 158.0
(s); IR: n=1669 cmÀ1; MS: m/z=440 (M+); anal. calcd. for
C18H20Br2N2O: C 49.12, H 4.58, N 6.36; found: C 49.25, H
4.31, N 6.40.
Muzart, Chem. Rev. 2011, 111, 1170–1214; g) R. I.
McDonald, G. Liu, S. S. Stahl, Chem. Rev. 2011, 111,
2981–3019.
[2] For some examples of carboamination reactions afford-
ing cyclization/functionalization compounds, see:
a) C. F. Rosewall, P. A. Sibbald, D. V. Liskin, F. E. Mi-
chael, J. Am. Chem. Soc. 2009, 131, 9488–9489; b) C. E.
Houlden, C. D. Bailey, J. Gair Ford, M. R. Gagnꢄ, G. C.
Lloyd-Jones, K. I. Booker-Milburn, J. Am. Chem. Soc.
2008, 130, 10066–10067; c) C. C. Scarborough, S. S.
Stahl, Org. Lett. 2006, 8, 3251–3254. For some examples
affording bicyclic compounds, see: d) K.-T. Yip, N.-Y.
Zhu, D. Yang, Org. Lett. 2009, 11, 1911–1914; e) B.
Zhu, G.-W. Wang, Org. Lett. 2009, 11, 4334–4337; f) K.-
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Chem. Soc. 2006, 128, 3130–3131; g) P. Kubizna, I.
Spanik, J. Kozisek, P. Szolcsanyi, Tetrahedron 2010, 66,
2351–2355.
10-Bromo-4-(bromomethyl)-2-phenyl-3,4-dihydro-
pyrazinoACHTUNGTRENNUNG[1,2-a]indol-1(2H)-one (10c): Yield: 71%; eluent:
hexane/AcOEt 65:35; pale orange solid; mp 1648C (i-Pr2O).
1H NMR (400 MHz, CDCl3): d=3.55–3.62 (m, 1H), 3.69–
3.79 (m, 1H), 4.44–4.49 (m, 2H), 4.83–4.95 (m, 1H), 7.20–
7.47 (m, 8H), 7.72–7.75 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=28.5 (t), 50.5 (t), 52.5 (d), 98.1 (s), 109.5 (d),
121.8 (d), 122.1 (d), 125.8 (d), 126.8 (d), 127.3 (d), 128.0 (s),
129.3 (d), 132.7 (s), 134.3 (s), 141.1 (s), 157.9 (s); IR: n=
1658 cmÀ1
;
MS: m/z=434 (M+); anal. calcd. for
C18H14Br2N2O: C 49.80, H 3.25, N 6.45; found: C 50.01, H
3.02, N 6.62.
[3] For some examples of diamination reactions affording
cyclization/functionalization compounds, see: a) P. A.
Sibbald, F. E. Michael, Org. Lett. 2009, 11, 1147–1149;
b) G. L. J. Bar, G. C. Lloyd-Jones, K. I. Booker-Mil-
burn, J. Am. Chem. Soc. 2005, 127, 7308–7309. For
some examples affording bicyclic compounds, see: c) K.
MuÇiz, J. Streuff, P. Chꢅvez, C. H. Hçvelmann, Chem.
Asian J. 2008, 3, 1248–1255; d) K. MuÇiz, C. H. Hçvel-
mann, J. Streuff, J. Am. Chem. Soc. 2008, 130, 763–773;
e) T. Tsujihara, T. Shinohara, K. Takenaka, S. Takiza-
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2009, 74, 9274–9279; f) C. H. Hçvelmann, J. Streuff, L.
Brelot, K. MuÇiz, Chem. Commun. 2008, 2334–2336;
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Synthesis of N-Allyl-3-chloro-N-methyl-1H-indole-2-
carboxamide (11)
A solution of N-allyl-N-methyl-1H-indole-2-carboxamide 1a
(1 mmol), CuCl2 (5 mmol) and K2CO3 (1 mmol) in MeCN
(5 mL) was refluxed for 3 h. After cooling, the solvent was
evaporated under reduced pressure, brine was added
(10 mL) and the mixture was extracted with CH2Cl2 (3ꢃ
20 mL). The organic phase was dried over Na2SO4 then the
solvent was evaporated under reduced pressure. The prod-
uct was purified by flash chromatography (eluent: hexane/
AcOEt 1:1) to afford a yellow oil; yield: 70%. 1H NMR
(400 MHz, CDCl3): d=3.17 (s, 3H), 4.20–4.21 (m, 2H),
5.25–5.32 (m, 2H), 5.84–5.89 (m, 1H), 7.19 (dd, J=7.2,
8.0 Hz, 1H), 7.28 (dd, J=7.2, 8.3 Hz, 1H), 7.39 (d, J=
8.3 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 9.71 (s br, 1H);
13C NMR (100 MHz, CDCl3): d=35.4 (q), 53.1 (t), 112.1 (d),
118.3 (t), 119.0 (d), 120.9 (d), 122.1 (d), 124.8 (d), 125.3 (s),
126.5 (s), 130.8 (s), 134.9 (s), 163.6 (s); IR: n=1658 cmÀ1
;
MS: m/z=248 (M+); anal. calcd. for C13H13ClN2O: C 62.78,
H 5.27, N 11.26; found: C 62.91, H 5.01, N 11.07.
[4] For some examples of aminooxygenation reactions af-
fording cyclization/functionalization compounds, see:
a) E. J. Alexanian, C. Lee, E. J. Sorensen, J. Am. Chem.
Soc. 2005, 127, 7690–7691; b) G. Liu, S. S. Stahl, J. Am.
Chem. Soc. 2006, 128, 7179–7181; c) E. Borsini, G.
Broggini, A. Fasana, S. Galli, M. Khansaa, U. Piarulli,
M. Rigamonti, Adv. Synth. Catal. 2011, 353, 985–994.
[5] For some examples of aminohalogenation reactions af-
fording cyclization/functionalization compounds, see:
a) S. D. R. Christie, A. D. Warrington, C. J. Lunniss,
Synthesis 2009, 148–154; b) A. Lei, X. Lu, G. Liu, Tet-
rahedron Lett. 2004, 45, 1785–1788; c) F. E. Michael,
P. A. Sibbald, B. M. Cochran, Org. Lett. 2008, 10, 793–
796; d) M. R. Manzoni, T. P. Zabawa, D. Kasi, S. R.
Chemler Organometallics 2004, 23, 5618–5621; e) S. H.
Kim„ H.-X. Wei, G. Li, Tetrahedron 2001, 57, 3869–
3873; f) Y.-N. Wang, A. Kattuboina, T. Ai, D. Banerjee,
G. Li, Tetrahedron Lett. 2007, 48, 7894–7898; g) E. Bor-
sini, G. Broggini, F. Colombo, M. Khansaa, A. Fasana,
S. Galli, D. Passarella, E. Riva, S. Riva, Tetrahedron:
Asymmetry 2011, 22, 264–269.
Acknowledgements
The authors thank the Ministero dell’Universitꢀ e della Ricer-
ca for financial support (PRIN 2008KRBX3B). They are
also grateful to Prof. Paolo Crotti and Prof. Mauro Pineschi
(Universitꢀ di Pisa) for helpful discussions.
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