Tandem imination/annulation of γ- And δ-ketoalkynes in the presence of ammonia/amines

Article abstract of DOI:10.1016/j.jorganchem.2010.08.011

In this account, we summarize the peculiar effects and advantages of gold, silver, and titanium dual role catalysis over the uncatalyzed tandem imination/annulation processes of γ- and δ-ketoalkynes.

Full text of DOI:10.1016/j.jorganchem.2010.08.011

Journal of Organometallic Chemistry 696 (2011) 87e98
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Tandem imination/annulation of
of ammonia/amines
g
- and
d
-ketoalkynes in the presence
,
b
b
Antonio Arcadi a , Giorgio Abbiati , Elisabetta Rossi
*
a Dipartimento di Chimica, Ingegneria Chimica e Materiali, Università degli Studi di L’Aquila, Via Vetoio, Coppito Due, I-67100 L’Aquila, Italy
b DISMAB, Sezione di Chimica Organica Alessandro Marchesini, Università degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
In this account, we summarize the peculiar effects and advantages of gold, silver, and titanium dual role
catalysis over the uncatalyzed tandem imination/annulation processes of g- and d-ketoalkynes.
Received 15 July 2010
Received in revised form
6 August 2010
Ó 2010 Elsevier B.V. All rights reserved.
Accepted 10 August 2010
Available online 18 August 2010
Keywords:
Ketoalkynes
Heterocycles
Dual role catalysts
Domino reactions
Hydroamination
Aminobenzannulation
1. Introduction
context of current status of designing intelligent synthetic strate-
gies on the way to the desired products by the knowledge of
organometallic Lewis acids properties. Moreover, the role of tran-
sition metal catalysis on accomplishing transformations that were
previously impractical due the severe conditions required will be
highlighted.
Domino reactions are proven to play a pivotal role for the
assembly of simple or polyfunctionalized organic molecules from
readily accessible organic compounds. [1] Unactivated alkynes are
not very reactive toward nucleophiles. This behavior changes
significantly as soon as the triple bond is activated by complexation
with a suitable metal catalyst. On the other hand, transition metals
can operate as bifunctional Lewis acids activating either (or both)
2. Results and discussion
carbonecarbon multiple bonds via
-complexes with heteroatoms. [2] The determination of the
relative ability for making - and -complexes with appropriate
p-binding or make the
During the last years, we focused our attention on the unca-
talyzed and catalyzed domino addition-annulation reaction of of
s
p
s
g
- and d-ketoalkynes in the presence of ammonia/amines. In
substrates is a valuable tool for the choice of catalysts for the
desired transformations, especially in the cases when bi- or poly-
functional substrates are involved. Computed enthalpies of
formation for various Lewis acid and metal salt complexes [3] with
aldehydes, imines, styrene and phenylacetylene have been repor-
ted to help to evaluate what kind of Lewis acids (and metal salts) is
more suitable to activate selectively individual functional group [4].
Here our own results associated with the selective transformations
particular, the sequential addition/elimination/cycloamination of
4-pentynones 1 in the presence of benzylamine or ammonia
produced 1,2,3,5-substituted and 2,3,5-substituted pyrroles and
fused pyrrole systems in good to high yields (Scheme 1). [5] The
reaction mechanism probably involves the formation of imine/
enamine intermediates 2/3 that undergo a regioselective 5-exo-
dig cyclization followed by isomerization to give pyrroles 5. We
previously published the synthesis of simple and polycondensed
furans starting from different substituted pentynones and
described for these compounds unusual base catalyzed reactions
[5b,6].
of g- and d-ketoalkyne derivatives with ammonia/amines by means
of transition metals catalysis are summarized and discussed in the
Surprisingly, under the same reaction conditions 2-propynyl-
1,3-dicarbonyl compounds 6 failed to give the pyrrole derivatives
* Corresponding author. Tel.: þ390862433773; fax: þ390862434203.
E-mail address: antonio.arcadi@univaq.it (A. Arcadi).
0022-328X/$ e see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2010.08.011

88
A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
R1
R2
R1
R2
R1
R2
R3_NH2
R
R
R
Method A or B
N
NH
O
R3
R3
1
2
3
R1
R
R1
R2
R2
R
N
N
R3
R3
4
5
Method A: R3 = Bn, toluene or xylene, ΔT, 2-23h, 76-97%
Method B: R3 = H, 2M in MeOH, 120 °C, 9-24 h, 50-89%
Scheme 1.
R2
O
O
O
HN
R2 NH2
Toluene
R
R1
R
R1
6
7
O
O
O
O
R1
R
R
R
R1
R2
[Au]
- [Au]
R
N
H
H
[Au]
H
R1
R1
N
R2
N
R2
N
H
H
R2
[Au]
8
Scheme 2.
allowing for the isolation of enaminones 7 (Scheme 2). Very likely,
the 5-exo-dig annulation reaction of 7 as well as of a variety of
alkynes containing nucleophiles near the alkyne moiety is depen-
dent on intriguing combination of electronic, coordinating, and
medium factors. Among them, the strength of the nucleophile
appears to play a prominent role. The presence of the electron-
withdrawing acyl group in 7 implies that the electron density of the
NHePh group is lower than it would be if there were no eM
resonance effects of the
b-substituent of the enamine. Conse-
quently, the intramolecular nucleophilic attack of the NHePh on
the carbonecarbon triple bond was hampered by the weakness of
the nucleophile.
O
H3CH2CO
Bn NH2
NaAuCl4 . 2H2O
N
EtOH, 40°C, 6.5 h
Bn
O
O
OCH2CH3
8a 71%
O
H3CH2CO
Bn NH2
6a
Na2PdCl4
EtOH, rt, 2h
O
9a 70%
Scheme 3.

A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
89
O
R1
R3
NH2
H
NaAuCl4
EtOH
+
6
R
CH3
R2
N
R3
R2
H
O
O
O
O
H3C
H3C
H3C
H3C
H3C
H3C
H3C
H3COOC
H3CS(H2C)2
H3C
Ph
H3C
CH3
CH3
CH3
CH3
N
N
N
N
HOH2C
H3CH2C
H
H
H
EtOOC
(H3C)2HC
H
(86%, e.e. = 98%)
(74%, e.e. = 99%)
(96%, e.e. = 97%)
(80%, e.e. = 98%)
Scheme 4.
further exploration of Au-catalyzed condensation reaction of
ketones with amines allowed the overcoming of the drawbacks
caused by more vigorous reagents and drastic reaction conditions
[11].
More recently the research group of Dake reported that, also,
silver salts can efficiently promote a similar path to pyrroles
(Scheme 5) [12]. Silver salts have been shown to increase the speed
of the reaction and gave better yields than gold(I) precatalyst. The
activation of common C]O and C]N electrophiles by using gold,
platinum, silver and copper complexes are beneficial for the design
of new catalysts triggering annulation processes. Recent progress in
this field has been highlighted [13].
O
R1
R2
R1
R2
R3
5% AgOTf
DCE
R4
+
NH2
N
R4
R3
Scheme 5.
Although the regioselective intramolecular cyclization of 7 to
pyrrole can be easily accomplished under the catalytic action of
various metal salts, NaAuCl4 resulted the catalyst of choice for the
conversion of the 2-propynyl-1,3-dicarbonyl compounds 6 into
pyrroles 8 because of its further specific quality of accelerating
the condensation of ketones with primary amines determining the
prevalence of the formation of the pyrrole over that of the
5-methylene-4,5-dihydrofuran scaffold 9 derived by a competitive
tandem intramolecular oxymetalation/protonolysis reaction
(Scheme 3).
These results clearly point out that the condensation reaction of
6 with primary amines must be faster than the oxymetalation
reaction to allow the chemoselective formation of the pyrrole
nucleus. Because of the simple experimental procedure, mild
conditions, easy availability of the starting materials, and ability to
incorporate a variety of functional groups, the method represents
a valuable tool for the synthesis of 1,2,3,5-tetrasubstituted pyrroles.
[7] On the basis of the assumption that stereogenic center in the
starting amine is not affected during this transformation, subse-
quent extension of the procedure to enantiomerically pure amines,
Interestingly, the regioselective outcome of the annulation
reaction (6-endo-dig cyclization vs. 5-exo-dig cyclization) seemed to
be directed by a suitable choice of the starting
derivative. Indeed, by contrast with the above results, the presence
of the -ketoalkyne moiety in an aromatic framework determines
g-ketoalkyne
g
the formation of the 6-endo-dig cyclization derivatives. The treat-
ment, under metals free conditions, of the readily available 2-
substituted-5-acetyl-4-alkynylthiazoles 10 with ammonia in MeOH
led to the formation of the pyrido[3,4-c]thiazoles 12. Probably the
formation of the products 12 occurs via the regioselective 6-endo-
dig cyclization of the imine intermediate 11 (Scheme 6) [14].
Analogously, the 6-endo-dig annulation reaction of 2-acyl-3-
alkynyl-1-benzenesulphonyl-1H-indoles and 3-alkynyl-1-benze-
nesulphonyl-1H-indole-2-carbaldehydes 13 in the presence of
ammonia gave the corresponding 9H-pyrido[3,4-b]indoles 14 in
satisfactory yields (Scheme 7) [15].
2-Alkynylbenzaldehydes 15 have also been reported by Saka-
moto et al. to undergo thermal annulation in the presence of
ammonia to give isoquinolines 16 [16]. A more comprehensive
study showed that microwaves heating gave comparable or better
yields in reduced reaction times (Scheme 8) [17]. The product
derived from a 5-exo-dig cyclization mode has never isolated or
b
-amino alcohols and a-aminoesters led to the formation of the
trisubstituted pyrroles in homochiral form (Scheme 4) [8]. The oxo-
and alkynophilicity of gold(III) derivatives [9] makes possible to
activate both C ¼ X (X ¼ O, N,.) unsaturated bonds and CeC
multiple bonds in a single transformation. [10] Interestingly,
R1
R1
R1
N
NH3 / MeOH
N
N
S
R
N
S
R
R
120 °C, 12 h
(74-96%)
O
NH
S
10
11
12
Scheme 6.

90
A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
R1
R1
R1
R2
R1
cat. M
R
R2-NH2
+
+
Nu-H
NH3 / MeOH
90 °C, 20 h
N
R
O
N
Nu
N
O
N
R2
PhO2S
Scheme 9.
PhO2S
R2
13
14
component coupling-cyclization using 2-ethynylbenzaldehydes,
paraformaldehyde, secondary amine, and t-BuNH2 in DMF leads to
direct and efficient formation of 3-(aminomethyl)isoquinolines in
good to high yields [24]. Moreover, a concise synthesis of 1,2-dihy-
droisoquinolines was established via three-component reactions of
2-alkynylbenzaldehydes, amines and various nucleophiles or pro-
nucleophiles in the absence of a catalyst [25] or in the presence of
carbophilic Lewis acid catalysts such as AgOTf [26], In(OTf)3, or
AuClPPh3/AgNTf2 [27] and Cu(I) or Pd(II) salts [28] CuSO3/
C12H25SO3Na [29] and Mg(ClO4)2/Cu(OTf)2 [30] (Scheme 9).
Scheme 7.
detected in the reaction crude, even when the alkyne was
substituted with an aromatic ring potentially able to stabilize the
-anion of the zwitterrionic intermediate 18. The regiospecificity
a
achieved is probably due to the zwitterionic intermediate 17 and
the resulting isoquinoline 16, arising from a 6-endo-dig mechanism,
being more thermodynamically stable than the hypothetical
intermediate 18 and consequent isoindole, derived from a 5-exo-
digcyclization mode.
Isoquinoline heterocycles have been also prepared in excellent
yields via copper-catalyzed cyclization of tert-butylimine deriva-
tives of 2-alkynylbenzaldehydes [18]. Dirhodium acetate and silver
triflates cooperatively catalyzed tandem cyclization/three-compo-
nent reactions of 2-alkynylarylaldimines with diazo compounds and
water or alcohols afforded 1,2-dihydroisoquinolines bearing
A two-component activation system that combines metal
catalysis (AgOTf) and the employment of catalytic amount of
organocatalyst (PPh3) has been successfully employed in the three-
component reaction of 2-alkynylbenzaldehyde, amine, and
a,b-
unsaturated ketone. This reaction proceeds smoothly in THF
under mild conditions leading to the functionalized 1,2-dihy-
droisoquinolines in moderate to good yields [31]. A highly efficient
silver triflate-catalyzed three-component reaction of 2-alky-
a
-hydroxyl-b-amino carboxylate skeleton in high yield [19]. AgOTf-
catalyzed addition of pronucleophiles to 2-alkynylarylaldimines led
functionalized 1-substituted-1,2-dihydroisoquinoline skeletons
[20]. With related substrates, bis(2,4,6-trimethylpyridine) silver(I)
hexafluorophosphate proved to be a more powerful catalyst for
challenging nucleophiles such as the substituted silyl enol ethers.
Compounds possessing the main structural features of karachine,
a berberine alkaloid have been accessed as well as the pyrroloiso-
quinoline core after dipolar additions to isoquinoline ylide inter-
mediates [21]. Silver catalysis, also, allowed the synthesis of
isoquinolines from ortho-alkynylarenecarbaldehyde oxime deriva-
tives [22]. Coinage metal salts [copper(I), gold(I), gold(III), silver] and
palladium(II) salts have been tested as catalysts for the cyclization of
ortho-alkynylarenecarbaldehyde hydrazones. However, only silver
nitrate gave good results [23]. Copper(I)-catalyzed domino four-
nylbenzaldehyde, sulfonohydrazide, and a,b-unsaturated carbonyl
compound gave H-pyrazolo[5,1-a]isoquinoline-1-carboxylates in
good yield [32]. For the possible mechanism, after condensation of
2-alkynylbenzaldehyde derivative with sulfonohydrazide, the
corresponding N’-(2-alkynylbenzylidene)hydrazide would be
obtained. In the presence of AgOTf, the triple bond would be acti-
vated and then the 6-endo-cyclization occurred to afford an iso-
quinolinium-2-yl amide intermediate. Subsequently, acrylate
would be involved in a [3þ2] cycloaddition process to generate
after release of tosyl group and aromatization H-pyrazolo[5,1-a]
isoquinoline-1-carboxylates.
More recently,
a
gold(I)-catalyzed, operationally simple
coupling-cyclization technique was developed for the synthesis of
isoquinoline-fused polycyclic compounds. The reaction makes use
of two coupling partners such as o-alkynylbenzaldehydes and
aromatic amines bearing tethered nucleophiles (Scheme 10) [33].
AuCl acts as a dual role catalyst [34] allowing rapid preparation of
biologically important polycyclic derivatives through gold-catalyzed
cascade cyclizations. According to the concept of a single-metal
complex which exhibits dual roles in a single transformation, metal
species which can act simultaneously as a Lewis acid and as a tran-
sition metal are beneficial for this process and have been reported to
be indispensable catalysts in a variety of sequential amination/
cyclization reaction [35]. Indeed, by switching to the less reactive 2-
alkynyl-acetophenones as substrates their reaction with ammonia is
not observed at all in the absence of a catalyst. By choosing as model
system the reaction of 1-{2-[(4-methylphenyl)ethynyl]phenyl}
ethanone 19a with ammonia, we tried some metal catalysts poten-
tially able to promote both the imine formation and the intermo-
lecular hydroamination step (Scheme 11) [36]. In the literature there
are many examples of the double activity exerted by metals like
H
NH3/MeOH
O
N
μW
R
R
15
16
H
N
R
H
H
R
17
N
R
R
H2N
N H
R
AuCl (5 mol %)
+
N
O
DCE, rt
Nu
Nu
18
Scheme 8.
Scheme 10.

A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
91
CH3
O
CH3
CH3
NH3/MeOH
+
N
120 °C, W, cat.
CH3
NH2
CH3
19a
20a
21a
20
21
Entry
t (min)a
15
Catalyst
Yield (%)b
Yield (%)b
-
1
2
TiCl4 (10 mol %)
-
-
.
TiCl4
2 THF
80
(10 mol %)
11 [18]c
46
3
100
Pd(OAc)2 (10 mol %)
25
120
120
4
5
Cu(OTf)2 (10 mol %)
CuI (10 mol %)
23 [8]
38
13
20
6
7
120
120
AgF (10 mol %)
Ag2O (10 mol %)
15 [17]
10 [18]
14
10
35
8
9
60
45
AgNO3 (10 mol %)
AgOTf (10 mol %)
46 [7]
37
6
54
.
120
11 [31]
10
NaAuCl4 2 H2O (10 mol %)
11
12
30
PPh3AuCl (10 mol %)
InCl3 (10 mol %)
41 [10]
34
-
120
5
[18]
a Not including 11 min "ramp time" (10 °C/min).
b Yields referred to pure isolated products.
c In brackett the yields of 19 recovered.
Scheme 11.
palladium[34c,d], copper[34c], silver[37], gold[38]andindium[39],
in the intramolecular annulation reactions involving alkynes bearing
a proximate nucleophile.
the yields and ratio between 20a and 21a are comparable to those
observed using palladium (Scheme 11, entry 5). Among the four
silver based catalysts tested (Scheme 11, entries 6e9), silver fluo-
ride and silver oxide gave scarce results even after a protracted
reaction time (Scheme 11, entries 6 end 7). On the other hand, silver
nitrate seemed to be a little more active than palladium despite the
ratio of products was slightly shifted toward the naphthalen-1-
amine 21a (Scheme 11, entry 8). The best result was obtained using
silver triflate with an overall reaction yield of 91% in a relative short
reaction time and a ratio 20a/21a equal to 1.5 (Scheme11, entry 9).
Gold(III) salt was not effective (Scheme 11, entry 10) whereas
cationic gold was active as silver nitrate (Scheme 11, entry 11).
As reported in Scheme 11, a catalytic amount of TiCl4 gave rise to
a complex mixture of unidentified products (Scheme 11, entry 1)
whereas the less acidic complex TiCl4$2THF gave very poor result
also after an extended reaction time (Scheme 11, entry 2). After
100 min of microwaves irradiation in the presence of a palladium
(II) catalyst the expected isoquinoline 20a was isolated in 46%
yields, beside a moderate amount of the isomeric naphthalen-1-
amine 21a (Scheme 11, entry 3). Cu(II) based catalyst gave poorer
results (Scheme 11, entry 4), whereas in the presence of Cu(I) salts

92
A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
NR2
CH3
N
CH3
R1
R1
MS 4A
rt or heat
H
O
R2NH
+
N
p-Tol
R2
R2
22
23
p-Tol
M
CH3
O
20a
M
Scheme 14.
NH3
p-Tol
NH2
NH2
CH2
H2O
unsatisfactory using 2-acetyl-N-propargylindoles. Moreover, the
reaction totally failed with 2-benzoyl-N-propargylindoles [43]. The
suggested reaction mechanism involves the formation of an imine
intermediate 27 that undergoes a stereoselective 6-exo-dig cycliza-
tion to 3,4-dihydropyrazinoindole 28 followed by partial isomeriza-
tion to give pyrazinoindole 29 (Scheme 16).
p-Tol
p-Tol
M
21a
Scheme 12.
With the aim to maximize the efficiency of this synthetic
approach in terms of reaction times (2-acetyl and 2-benzoyl deriv-
atives), overall yields (2-benzoyl derivatives), and the internal ratio
between dihydro derivatives 28 and fully conjugated compounds 29,
we customized the methodology according by the employment of
a microwave and the support of catalysts. Thus, a solution of the
appropriate alkynyl indole in 2 M ammonia in methanol was heated
in a multi-mode microwave oven at 150 ꢀC until no more starting
product was detectable by TLC analysis. The microwave-assisted
reaction took place quicker than conventional heated ones, and
overall yields were incremented. The ratio between dihydropyr-
azinoindoles 28 and pyrazinoindoles 29 was shifted toward the fully
conjugated system. Moreover, it is interesting to note that the
synthesis of a single pyrazino isomer is achieved through longer
reaction times, while the dehydro derivatives 28 can be isolated after
shorter times. As depicted in Scheme 17, the cyclization reactions of
1-propargyl-2-carbonylindole derivatives proceed in two key steps:
(1) the formation of an imine intermediate and (2) the addition of the
nitrogen nucleophile to the triple bond. It is well-known that ketones
(in particular if aromatic and/or sterically hindered) react with
amines and ammonia more slowly than aldehydes to form imines.
This process can be accelerated by protons and Lewis acid catalysts
and/or by water removal from the reaction mixture [44]. On the other
hand, considering the annulation step, a number of metal complexes
of group 4 and organolanthanides as well as various metal salts of
group 9, 10, and 11 have been reported to successfully catalyze the
intramolecular addition of nitrogen nucleophiles to alkynes [45].
Based on these accounts, we tested a variety of water scavengers/
catalytic systems. The obtained results show that titanium tetra-
chloride, under mild conventional heating conditions, accelerates the
cyclization of 2-acetylindoles and allowed the cyclization of 2-ben-
zoylindoles with good yields and reasonable reaction times. Reaction
times were further reduced by microwave heating. On the whole, the
overall yields on pyrazinoindoles 28/29 appeared improved with
respect to reactions performed without catalyst. Finally, titanium
tetrachloride catalyzed cyclization of internal alkynes gave prefer-
entially and sometimes exclusively the dihydropyrazino derivatives
28. On the basis of these findings, we hypothesize that titanium
tetrachloride affects both critical steps of pyrazinoindole formation.
Finally, indium trichloride seemed to be absolutely unsuited to the
purpose (Scheme 11, entry 12). The formation of the isomeric
naphthalen-1-amine 21a is the consequence of the conceivable
equilibrium imine/enamine of reaction intermediate which can
reacts with triple bond respectively as nitrogen nucleophile to give
20a as well as carbon-nucleophile to give 21a (Scheme 12).
The results clearly indicate that at the beginning of the cycli-
zation the triple bond should coordinate to a
p-Lewis acid. Silver
has been intensively used for this purpose [40]. Subsequent attack
of the nitrogen- or carbon nucleophile at the electron-deficient
triple bond could represent the rate determining step in the present
reaction. Analogously, the reaction proceeded smoothly with
aliphatic alkyne 19b (Scheme 13).
Further work is in progress to evaluate the product selectivity
control [41] in the sequential amination/annulation reaction of
2-alkynyl-acetophenones. The selective synthesis of different
products from the same starting materials by simple modification
of the reaction conditions is an attractive challenge for chemists.
The goal to successful address the amine-triggered benzannulation,
so-called aminobenzannulation has been achieved through reac-
tion of 2-(prop-2-ynyl)(oxo)benzenes 22 with various dialkyl-
amines (Scheme 14) [42]. This efficient and general synthesis of
2-dialkylaminonaphthalenes proceeds under mild reaction condi-
tions without metal promoters and catalysts.
A proposed reaction mechanism is shown in Scheme 15.
Initially, rapid isomerization of 22 in the presence of a dialkylamine
leads to the allene 24. Subsequent nucleophilic addition of dia-
lkylamine to the central carbon of the allene 24 followed by the
cycloaddition onto the iminium moiety probably forms the inter-
mediate 25. Finally the formation of the 2-dialkylaminonaph-
thalene 23 is allowed by the aromatization reaction of 25.
We have, also, been involved in depth investigation on the tandem
imination/annulation of
d-ketoalkynes. In this field, we reported the
synthesis of the pyrazino[1,2-a]indole nucleus through the sequen-
tial imination/annulation of 2-carbonyl-N-propargylindoles 26 in the
presence of ammonia in methanol. The reaction worked well with
N-propargylindole-2-carbaldehydes, but yields and selectivity were
CH3
CH3
N
NH2
Ag(OTf) (10 mol %)
O
+
NH3/MeOH, 30 min
120 °C, mW
R
R
R
20b (60%)
19a
21b (20%)
R = -(CH2)5-CH3
Scheme 13.

A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
93
some cases beside the isomeric dihydropyrrolo[1,2-a]pyrazine 32.
The isomeric products 32 and 33 were easily separated by flash
column chromatography. The dihydro isomers 32 can be converted,
in almost quantitative yields, into the corresponding fully conju-
gated isomers 33 under basic conditions by treatment with NaOMe/
MeOH (10%) at reflux. Furthermore, the cleverness of TiCl4 to
perform a variety of tasks allowed a new synthetic route to pyrrolo
R1
R1
R2NH
R2NH
O
NR2
OH
R2
R2
22
24
[1,2-a]indole-2-carbaldehydes 32 through
a divergent TiCl4/t-
NR2
H
NR2
BuNH2 mediated hydroamination/annulation reaction starting
from 2-acyl-1-propargyl-1H-indoles 260aeg containing a terminal
alkyne moiety (Scheme 19) [48].
R1
R1
- R2NH
R2 NR2
25
R2
Better results were observed in toluene by increasing the ratio
among the reagents; in particular, a ratio of substrate/TiCl4/t-
BuNH2 of 1:1.5:9 gave the best results already at room temperature.
A rise in temperature gave a dropout of overall yield, maybe as
a consequence of a thermal degradation of products. A different
titanium salt as well as the use of polar protic and aprotic solvents
gave a complex mixture of unidentified products. The reaction of
2-acetyl derivative 260a took place quickly and gave the corre-
sponding 3H-pyrrolo[1,2-a]indole-carbaldehyde 32a in moderate
yields (Scheme 19, entry 1). Better yields were obtained using
2-benzoyl-1-propargylindoles (Scheme 19, entries 2e4). The reac-
tion allows also a heteroaryl substituent on C]O (Scheme 19,
entries 5e7), but when reacting thiophen-2-yl and furan-2-yl
derivatives 260f-g, only the isomeric 9H-pyrrolo[1,2-a]-indole-car-
baldehydes 33f-g (fluorazene form) were isolated (Scheme 19,
entries 6 and 7). All 3H-pyrrolo[1,2-a]indole-carbaldehyde deriva-
tives 32 were isomerised in the more stable tautomeric fluorazene
form 33 standing in a CDCl3 solution at room temperature for 24 h.
The same result was obtained by stirring at room temperature
a solution of 32b in toluene for 40 min in the presence of a catalytic
amount of p-TSA. Similarly, the reaction of 2-acetyl-1-propargyl
23
Scheme 15.
First, it can promote the imine intermediate formation through
the double activity of vigorous water scavenger as well as useful
Lewis acid [46]. In the second instance, TiCl4 or a catalytically active
species generated in situ from TiCl4 and ammonia can promote the
cyclization step through the coordination between the triple bond
[47] and imine. Moreover, this dual activity of TiCl4 justifies the
high catalyst/substrate ratio required. Through a similar approach,
we synthesized the 3-substituted 1-methylpyrrolo[1,2-a]pyrazines
21 from 2-acetyl-N propargylpyrroles 19 (Scheme 18) [17].
Following the procedure previously optimised for the imina-
tion/annulation of 2-acetyl and 2-benzoyl N-alkynylindoles, we
dissolved alkynylpyrroles 26 in
2 M ammonia in methanol
(20 equiv. of NH3) in a sealed microwave test tube. Three equiv. of
TiCl4 were slowly added to the solution (caution!), and the reaction
mixture was heated in a multi-mode microwave oven at 130 ꢀC. The
reactions gave the corresponding pyrrolo[1,2-a]pyrazines 33, in
R1
R1
N
NH3/CH3OH
H2O
N
O
N
H
R2
R2
26
27
6-exo-dig
R1
R1
N
N
N
N
R2
R2
28
29
Scheme 16.
R1
R1
R1
N
N
N
NH3
O
N
N
- H2O
H
[Ti]
R2
R2
R2
[Ti]
28
Scheme 17.

94
A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
R1
R1
N
N
R1
N
N
N
NH3/MeOH
Me
CHO
H+
X
+
N
O
N
TiCl4 (3 equiv)
TiCl4 /t-BuNH2
Me
N
(1.5: 9)
N
R2
30
R2
R2
31
Me
CHO
34
O
H
H+
X
Toluene, rt
29
29a
Me
CHO
MeONa 10 mol %
MeOH
R1
R1
N
N
N
N
Scheme 20.
reflux, 5h
R2
30
R2
31
The first step is a TiCl4 catalyzed hydroamination of alkyne with
the formation of an enamine intermediate 35. The addition is highly
regioselective in anti-Markovnikov fashion, due to the steric
hindrance of the tert-butyl moiety of amine [49]. According to recent
Ackermann studies, the catalytically active species is probably
generated in situ by reaction between TiCl4 and t-BuNH2 [50]. The
second step is an aldol type intramolecular reaction: the nucleo-
philic addition of the b-carbon of enamine on the carbonyl group
gave the intermediate 36. The carbonyl group is activated by TiCl4 as
a Lewis acid catalyst. It is worth noting that the carbonyl group
Scheme 18.
pyrrole 29a under optimized conditions gave the corresponding
1-methyl-3H-pyrrolizin-2-carbaldehyde 34 in moderate yields as
a single product; interestingly, the treatment of 34 with p-TSA acid
did not give any of the possible tautomers (Scheme 20).
The proposed reaction mechanism involves three steps in which
TiCl4 has a multiplicity of activities (Scheme 21).
Toluene, p-TSA cat., rt
TiCl4/t-BuNH2
R1
(1.5/5.9)
N
N
N
R1
CHO
32
R1
CHO
+
Toluene, rt
O
H
'
26
33
Table 1. Synthesis of Pyrrolo[1,2-a]indole-2-carbaldehydes
yield %a
32
yield %a
33
entry
R1
26'
t (h)
0.3
a
50
87
1
2
3
-
-
methyl
phenyl
p-tolyl
m-tolyl
b
c
6
6
-
75
91
89
6
2
2
2
-
d
e
f
4
5
6
7
thiophe-3-yl
-
75
77
thiophe-2-yl
furan-2-yl
-
-
g
a Yields refer to isolated products
Scheme 19.

A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
95
R1
N
R1
R1
N
N
TiCl4
NH2
O
O
H
O
H
[Ti]
[Ti]
H
N
26
35
R1
O
work-up
N
N
N
R1
N
R1
[Ti]
H
H
H
H
H
N
O
36
37
Scheme 21.
reacts in preference with enamine in regard to its direct reaction
with t-BuNH2. This behavior is related to the well known inertia of
ketones toward bulky amines. In the third step, the imine 37 could
be formed by intramolecular elimination of HOTiCl3 and deproto-
nation or by an NeO proton shift followed by elimination of water
and TiCl4. Either way, the driving force of this step is the formation of
a new C]C double bond stabilized by the conjugation with the
heterocyclic ring. Also in this case, TiCl4 could play a central role,
avoiding the release of water in the reaction medium thus pre-
venting the hydrolysis of enamine/imine intermediates [51].
Besides, the excess of amine buffers the reaction solution scavenging
the acid chloride. Afterward, the usual workup leads to the hydro-
lysis of the imine intermediate to give the pyrrolo[1,2-a]indole-2-
carbaldehydes 32 or 33. This mechanism that involves a plethora of
different activities of TiCl4-catalyst/Lewis acid/water scavenger-well
explains the need to use an excess of this reagent. The 1H and 13C
NMR spectra of the reaction crude validate the final step of the
suggested mechanism highlighting the presence of the character-
istic signals of the tert-butylimine group of compound 37. A diver-
gent domino process involving the initial formation of an enamine
intermediate followed by a regioselective 6-exo-dig intramolecular
alkynes 2600 and 39 with secondary amines in the presence of an
appropriate Lewis acid (Scheme 22) [52]. The Lewis acid mediated
aminobenzoannulation reactions of 2-acyl-N-propargylindoles 2600
and 2-acyl-3-propargylindoles 39 give 9-amino-pyrido[1,2-a]
indoles 38 and 1-aminocarbazoles 40, respectively.
Both
d
-ketoalkynes 2600 and 39 contained a heteroaromatic
scaffold undergo two sequential inter and intramolecular nucle-
ophilic attacks at the two electrophilic sites, that is, the carbonyl
group and CeC triple bond. The reactions proceed in the presence
of the appropriate catalytic system through a proposed dual
activation sequence. 2-Acyl-N-propargylindoles 2600 give rise to
9-amino-pyrido[1,2-a]indoles 38 in good yield in the presence of
TiCl4 or GaCl3 as catalysts. Probably in this case both catalysts
operate as Lewis acids and water scavengers in the first step of the
reaction to give rise to enamine intermediate 41 (Scheme 23, path
a). Enamine 41 regioselectively attacks the activated alkyne to give
rise to carbometalation adduct 42 which after deprotonation,
protonolysis of the carbonemetal bond (42), and aromatization
affords 6-exo-dig adduct 38. The ability of TiCl4 and GaCl3 to
activate carbonyl groups and carbonecarbon triple bonds towards
nucleophiles is well documented. In particular, the catalytic
interaction of carboneoxygen double bonds and carbonecarbon
triple bonds with GaCl3 and TiCl4 has been proven by 1H and 13C
NMR spectroscopic measurements [53]. The intermediacy of
vinyltitanium [54] and vinylgallium [55] species like 42 is sup-
ported by literature references. Moreover it is worth noting that,
as reported in the reactions performed in the presence of GaCl3
and TiCl4 require 1.2 and 0.5 equiv. of catalyst, respectively. This
experimental evidence could be ascribed to the high stability of
the vinylgallium intermediate that does not undergo direct pro-
tonolysis in the reaction medium, thus regenerating the catalyst,
but only during the final acidic workup. 2-Acyl-3-propargylindoles
39 gave rise to 1-(pyrrolidin-1-yl)-9H-carbazoles 40 under InCl3
catalysis. The proposed mechanism (Scheme 23, path b) parallels
in part that proposed for gallium- and titanium-catalyzed reac-
tions with a single difference. The indium salt is a water-tolerant
Lewis acid, stable under hydrolytic conditions and does not work
as a water scavenger in the first step of the reaction [56]. Thus,
enamine 41 is formed through a reversible process involving
nucleophilic attack of the secondary amine on InCl3 complex 44
[57] followed by loss of water.
nucleophilic attack of the
b-carbon of the enamino moiety to the
CeC triple bond has been accomplished by the reaction of internal
N
N
H
N
N
O
cat
Ar
Ar
26''
38
Ar(Alk)
(Het)Ar
(Het)Ar
Ar(Alk)
N
H
O
N
N
H
N
H
cat
Moreover, the fastest formation of indium enolate 45
(Scheme 24) stabilized by the adjacent phenyl ring could be the
driving force for the intramolecular cyclization that gives rise to
39
40
Scheme 22.

96
A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
R
R
MClx = InCl3
path b
+
MClx
N
N
H
H
O
OH
MClx
44
R
O
R
R
O
- MClx-1OH
R
N
H
N
H
Cl
MClx-1
N
O
H
41
Clx-1M-Cl
MClx = TiCl4, GaCl3
path a
MClx-1
R
H
protonolysis
aromatization
R
H
41
38 or 40
H
N
N
42
43
Scheme 23.
1-hydroxy-9H-carbazoles 45. The reaction proceeds only in the
presence of a base (pyrrolidine) able to act as a proton acceptor/
proton donor. The intermediacy of vinylindium species [58] and
indium enolates [59] has been reported by several authors. More-
over, the dual role exerted by the catalyst was demonstrated by IR,
1H NMR, and 13CNMR spectroscopic measurements [60]. Actually,
s
-electrophilic catalyst [57]. Several reports dealing with related
reactions of -ketoalkynes have been, also, published. In particular,
g
a 6-endo-dig aminobenzannulation reaction of o-alkynylacetophe-
nones with pyrrolidine or diethylamine takes place in the presence
of a catalytic amount of palladium chloride, copper iodide, and
triphenylphosphane to give rise to aminonaphthalene derivatives
[61]. The reaction is strongly substrate dependent and works only
with alkynylsubstituted acetophenone and in the presence of the
above mentioned amines. Moreover, the 6-endo-dig amino-
benzannulation reaction has been reported to occur starting from
2-alkynyl-3-acetylquinolines, 2-alkynyl-3-acetylindoles, 2-alkynyl-
3-acetylpyridines, and 2-alkynyl-3-acetylbenzofuranes and pyrro-
lidine in the presence of 4 Å molecular sieves, yielding, respectively,
1-aminoacridines, 4-aminocarbazoles, 5-aminoquinolines, and 1-
aminobenzofurans [62]. For some other secondary amines, neutral
Al2O3 or PtCl2 catalysts are required [63].
InCl3 seems to act as a weak
whereas TiCl4 acts as a weak
s- and p-electrophilic Lewis acid,
-electrophilic catalyst and as a strong
p
Ar(Alk)
(Het)Ar
(Het)Ar
Ar(Alk)
O
R
Ph
H
InCl3
N
H
N
O
N
H
H
45
39
R = Ph
3. Conclusion
In this account, we report a summary of recent progress in the
H
field of tandem imination/annulation reactions of
g- and d-
Ar(Alk)
Cl3In
ketoalkynes in the presence of ammonia/amines. Main focus has
been devoted to the peculiar effects and advantages of the transi-
tion metal catalysis over the uncatalyzed processes for the
construction of functionalized aromatics and polycyclic aromatics
through the reaction of the carbon-tethered acetylenic carbonyls
with ammonia/amines. Notably, it was shown that the proper
choice of a Lewis acid which may exhibit dual roles catalysis makes
it possible to activate both CeC multiple bonds and C ¼ X unsatu-
rated bonds in a single transformation. In recent years, these
catalysts have gained much attention owing to their ability to
enhance selectivity and reactivity in tandem reactions. Those
H
(Het)Ar
Ar(Alk)
Ph
Ph
O
N
H
N
O-InCl2
H
H
H
Cl
H
N
N
+ InCl3
Scheme 24.

A. Arcadi et al. / Journal of Organometallic Chemistry 696 (2011) 87e98
97
processes are not only efficient but also they can achieve the direct
construction of complex molecules, without isolating any inter-
mediates, from readily accessible starting materials under mild
conditions and with high atom economy. A continuation of
progressive research is thus anticipated in this area.
arom, J ¼ 1.1 Hz), 7.28 (d, 2H, arom, J ¼ 8.4 Hz), 7.44e7.50 (m, 2H,
arom), 7.52 (s, 1H, arom), 7.61 (d, 2H, arom, J ¼ 8.1 Hz), 7.79e7.89
(m, 2H, arom) ppm. 13C NMR (CDCl3, 200 MHz):
d
¼ 21.4, 109.5,
117.1, 120.9, 123.1, 125.0, 126.5, 127.4, 129.1, 129.7, 134.9, 137.3, 138.7,
139.3, 142.6 ppm. ESI-MS m/z: 234 ((M þ 1)þ, (100)). Calcd for
C17H15N (233.31): C, 87.52; H, 6.48; N, 6.00. Found: C, 87.44; H, 6.43;
N, 6.08.
4. Experimental
General details. All chemicals and solvents are commercially
available and were used after distillation or treatment with drying
agents. Silica gel F254 thin-layer plates were employed for thin-
layer chromatography (TLC). Silica gel 40-63 micron/60A was
employed for flash column chromatography. Infrared spectra were
recorded on an FT-IR spectrophotometer using KBr tablets for
solids and NaCl disks for oils. Proton NMR spectra were recorded at
room temperature in CDCl3, at 200 or 500 MHz, with residual
chloroform as the internal reference (dH ¼ 7.27 ppm). 13C NMR
spectra were recorded at room temperature in CDCl3 at 50.3 or
125.75 MHz, with the central peak of chloroform as the internal
reference (dC ¼ 77.3 ppm). The APT or DEPT sequences were used
to distinguish the methine and methyl carbon signals from those
due to methylene and quaternary carbons. Data for 1H NMR are
4.4. 3-Hexyl-1-methylisoquinoline (20b)
Yellow-green oil. IR (neat):
n
¼ 2953, 2925, 2855, 1692, 1625,
1590, 1568, 1444, 1390, 747 cmꢁ1 1H NMR (CDCl3, 200 MHz):
d
¼ 0.88 (t, 3H, CH3, J ¼ 7.0), 1.35 (m, 6H, 3 CH2), 1.79 (qt, 2H, CH2,
J ¼ 7.6), 2.88 (t, 2H, CH2, J ¼ 7.6), 2.95 (s, 3H, CH3), 7.32 (s, 1H, arom),
7.50 (ddd, 1H, arom, J ¼ 8.2, 6.8, 1.5 Hz), 7.61 (ddd, 1H, arom, J ¼ 8.2,
6.8, 1.3 Hz), 7.72 (d, 1H, arom, J ¼ 7.5), 8.07 (d, 1H, arom. J ¼ 7.8 Hz)
ppm. 13C NMR (CDCl3, 200 MHz):
d
¼ 14.3, 22.6, 22.9, 29.4, 30.2,
32.0, 38.5, 116.7, 125.8, 126.1, 126.2, 127.0, 129.9, 136.9, 154.9,
158.2 ppm. ESI-MS m/z: 228 ((M þ 1)þ, (100)). Calcd for C16H21
N
(227.343): C, 84.53; H, 9.31; N, 6.16. Found: C, 84.41; H, 9.22; N, 6.19.
4.5. 3-Hexylnaphthalen-1-amine (21b)
reported as follows: s
¼
singlet, d
¼ doublet, t ¼ triplet,
q ¼ quartet, qt ¼ quintuplet, m ¼ multiplet, b ¼ broad. Coupling
constants (J) are reported as values in hertz. All 13C NMR spectra
were recorded with complete proton decoupling. Two-dimen-
sional NMR experiments (NOESY and HMBC) were used, where
appropriate, to aid in the assignment of signals in proton and
carbon spectra. The ammonia in methanol 2 M solution was
purchased from standard chemical suppliers. Microwave assisted
reactions were performed in a MILESTONE microSYNT multi-mode
labstation, using 12 mL sealed glass vessels. The internal temper-
ature was detected with an optical fibres sensor.
Yellow-orange oil. IR (neat):
n
¼ 3369, 2954, 2926, 2854, 1626,
1597, 1576, 1512, 1460, 1408, 741 cmꢁ1 1H NMR (CDCl3, 200 MHz):
d
¼ 0.90 (t, 3H, CH3, J ¼ 6.8), 1.27e1.41 (m, 6H, 3 CH2), 1.61e1.76 (m,
2H, CH2), 2.68 (t, 2H, CH2, J ¼ 7.6), 3.82 (bs, 2H, NH2), 6.66 (s, 1H,
arom.), 7.12 (s, 1H, arom.), 7.35e7.46 (m, 2H, arom.) 7.70e7.79 (m,
2H, arom.) ppm. 13C NMR (CDCl3, 200 MHz):
d
¼ 14.4, 22.9, 29.3,
31.5, 32.0, 36.5, 111.5, 118.0, 120.9, 122.6, 124.2, 126.1, 128.3, 134.9,
141.4, 142.0 ppm. ESI-MS m/z: 228 ((M þ 1)þ, (100)), 144 (40). Calcd
for C16H21N (227.343): C, 84.53; H, 9.31; N, 6.16. Found: C, 84.36; H,
9.28; N, 6.12.
4.1. General procedure for microwave-assisted/AgOTf-catalyzed
reaction of 2-alkynylacetophenones with ammonia: reaction of 1-
(2-(oct-1-ynyl)phenyl)ethanone (19b)
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20% yield).
4.2. 3-p-Tolyl-1-methylisoquinoline (20a)
IR (neat):
n
¼ 3056, 2920, 1621 cmꢁ1 1H NMR (CDCl3, 200 MHz):
d
¼ 2.43 (s, 3H, CH3), 3.04 (s, 3H, CH3), 7.30 (d, 2H, arom. J ¼ 8.1 Hz),
7.05e7.69 (m, 2H, arom.), 7.86 (t, 2H, arom. J ¼ 7.0 Hz), 8.07 (t, 2H,
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d
¼ 21.5, 22.9, 114.9, 125,9, 126.7, 126.8, 127.0, 127.8,
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d
¼ 2.43 (s, 3H, CH3), 4.22 (bs, 2H, NH2), 7.05 (d, 1H,

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