TiCl4/t-BuNH2-promoted hydroamination/annulation of δ-keto-acetylenes: Synthesis of novel pyrrolo[1,2-a]indol-2-carbaldehydes

Article abstract of DOI:10.1021/ol061872u

(Chemical Equation Presented) An original TiCl₄/t-BuNH ₂-mediated hydroamination/annulation domino reaction of δ-keto-acetylenes is described. The synthesis of pyrrolo[1,2-a]indole-2- carbaldehydes, starting from 2-carbonyl-1-proparg

Full text of DOI:10.1021/ol061872u

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4839-4842
TiCl4/t-BuNH2-Promoted Hydroamination/
Annulation of -Keto-acetylenes:
Synthesis of Novel
δ
Pyrrolo[1,2-a]indol-2-carbaldehydes
Giorgio Abbiati,* Alessandro Casoni, Valentina Canevari, Donatella Nava, and
Elisabetta Rossi
Istituto di Chimica Organica “Alessandro Marchesini”, Facolta` di Farmacia,
UniVersita` degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
giorgio.abbiati@unimi.it
Received July 28, 2006
ABSTRACT
An original TiCl4/t-BuNH2-mediated hydroamination/annulation domino reaction of
δ-keto-acetylenes is described. The synthesis of pyrrolo-
[1,2-a]indole-2-carbaldehydes, starting from 2-carbonyl-1-propargyl-1H-indoles runs under mild reaction conditions. A conceivable mechanism
is also discussed. TiCl4 has proved to be an effective multiactivity reagent: catalyst/Lewis acid/water scavenger. Some unpublished 2-carbonyl-
1-propargyl-1H-indoles are prepared by means of Suzuki- and Negishi-type reactions.
The study of the synthesis and activity of polycyclic indoles
is a research field in continuous growth. The importance of
these derivatives is related to the widespread occurrence of
an indole subunit in a plethora of natural and synthetic
compounds characterized by a variety of biological and
pharmacological activities.1
From a synthetic point of view, the opportunity to prepare
complex polycyclic molecules by means of a small number
of steps is an exciting goal for every modern organic chemist.
Moreover, the demand to decrease the consumption of
reagents, solvents, and energy together with the requirement
to reduce reaction times and waste production prompt every
researcher sensible to economical and environmental issues
to explore the pathway of domino reactions.2
indoles, some new pyrazino[1,2-a]indoles4 were prepared by
sequential imination/annulation reactions. Starting from the
same building blocks, we recently reported a simple and
efficient entry to the [1,4]oxazino[4,3-a]indole nucleus
through a tandem nucleophilic addition/annulation reaction.5
In connection with our ongoing interest in the synthesis
of a-fused polycyclic indoles through domino reactions of
δ-carbonyl-alkynes, we present here a mild TiCl4/t-BuNH2-
mediated synthesis of pyrrolo[1,2-a]indole-2-carbaldehydes,
starting from 2-acyl-1-propargyl-1H-indoles. A similar sys-
(3) (a) Abbiati, G.; Beccalli, E.; Marchesini, A.; Rossi, E. Synthesis 2001,
2477. (b) Rossi, E.; Abbiati, G. Targets Heterocycl. Chem. 2003, 7, 86. (c)
Abbiati, G.; Beccalli, E. M.; Broggini, G.; Zoni, C. J. Org. Chem. 2003,
68, 7625. (d) Abbiati, G.; Canevari, V.; Rossi E.; Ruggeri, A. Synth.
Commun. 2005, 35, 1845. (e) Abbiati, G.; Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Paladino, G. Synlett 2006, 73. (f) Rossi, E.; Abbiati, G.;
Canevari, V.; Celentano, G.; Magri, E. Synthesis 2006, 299. (g) Abbiati,
G.; Arcadi, A.; Beccalli, E.; Bianchi, G.; Marinelli, F.; Rossi, E. Tetrahedron
2006, 62, 3033.
For many years, we have been interested in the synthesis
of polycyclic indole derivatives.3 In particular, N-alkynyl
indoles containing a proximate carbonyl group proved to be
versatile building blocks for domino transformations. For
example, in a few studies devoted to the synthesis of a-fused
(4) (a) Abbiati, G.; Arcadi, A.; Beccalli, E.; Rossi, E. Tetrahedron Lett.
2003, 44, 5331. (b) Abbiati, G.; Arcadi, A.; Bellinazzi, A.; Beccalli, E.;
Rossi, E.; Zanzola, S. J. Org. Chem. 2005, 70, 4088.
(1) Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998, 15, 327.
(2) Tietze, L. F. Chem. ReV. 1996, 96, 115.
(5) Abbiati, G.; Canevari, V.; Caimi, S.; Rossi, E. Tetrahedron Lett. 2005,
46, 7117.
10.1021/ol061872u CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/19/2006

tem including TiCl4 and t-BuNH2 has been recently used
for a transformation which involves an intermolecular
hydroamination and a Lewis acid catalyzed reaction.6
The interest of the pyrrolo[1,2-a]indole skeleton is con-
nected to its structural relationship with mitomycins,7 an
important class of antibiotics characterized by noteworthy
antitumoral activity. Several approaches for the synthesis and
functionalization of this system have been explored.8 Re-
cently, some interesting syntheses were reported, starting
from simple N-allyl-indole-2-carbaldehydes via inter-/intra-
molecular 1,3-dipolar-9 or hetero Diels-Alder-type10 cyclo-
additions and via Ru-catalyzed RCM reactions.11 Moreover,
intramolecular Pauson-Khand reaction of N-allyl-2-ethy-
nilindole promoted by molecular sieves gave the correspond-
ing condensed pyrrolo[1,2-a]indole.12 Finally, pyrrolo[1,2-
a]indole-2,3-dicarboxylate was easily obtained by a one-pot
reaction among indol-2-carbaldehyde, triphenylphosphine,
and acetylene dicarboxylate.13
Scheme 1. Synthesis of Starting Materials
Otherwise, our approach is characterized by some out-
standing features: (1) the use of easily accessible building
blocks, (2) the cheapness of reagents involved, and (3) the
capability to obtain in a single step several pyrrolo[1,2-a]-
indole scaffolds differently substituted on C-1 and bearing
an aldehydic function on C-2 susceptible to further trans-
formations.
Starting materials were prepared using both traditional and
catalytic strategies. The 2-acetylindole14 1a and the 2-ben-
zoylindole15 1b were prepared in good yields by standard
methods. 2-Acylindoles 1c-g were prepared starting from
the indole-2-carboxylic acid chloride, easily obtained in
almost quantitative yield by reaction of the corresponding
acid with oxalyl chloride. Thus, 2-aroylindoles 1c,d and
2-heteroaroylindole 1e were synthesized in good yield
through a Suzuki-type coupling reaction in anhydrous toluene
at 50-60 °C using a ratio of acid chloride/boronic acid/
K2CO3/Pd(OAc)2/P(o-tolyl)3 equal to 1:1.2:3:0.05:0.07
(Scheme 1). Unfortunately, this strategy failed in the
synthesis of derivatives 1f and 1g; this is probably due to
the low nucleophilicity of C-2 with respect to C-3 in the
furan- and thiophen-boronic acids.16 Otherwise, compounds
1f and 1g were prepared in moderate to good yield via a
Negishi-type coupling; the suitable furane- and thiophene-
2-zinc-halide17 were prepared in situ and reacted with indole-
2-carboxylic acid chloride in anhydrous THF at 50 °C in
the presence of 0.04 equiv of Pd(PPh3)4 (Scheme 1).
Afterward, 2-carbonyl-indoles 1a-g were converted into the
corresponding N-propargyl derivatives 2a-g in good to
excellent yield by means of PTC nucleophilic substitution
in toluene/50% aqueous NaOH and tetrabutylammonium
bromide (TBAB) as the catalyst18 (Scheme 1).
Before reacting the whole series of N-propargyl-2-carbo-
nylindoles 2a-g, we investigated the optimal reaction
conditions to obtain pyrrolo[1,2-a]indole-2-carbaldehydes 3,
taking 2b as the model compound and modifying consecu-
tively the solvent, the metal salt, the temperature, the energy
source, and the ratio among reaction partners (Table 1). Two
considerations prompted us to engage this screening: (1) the
initial reaction conditions, besides a moderate yield of 3H-
pyrrolo[1,2-a]indole-2-carbaldehydes 3b, gave a significant
amount of unreacted starting product 2b (entry 1) and (2)
the study of the optimal reaction conditions could help us to
understand the reaction mechanism involved in this original
domino cyclization.
Any modification of the combination TiCl4/t-BuNH2/
toluene gave worse results. A different titanium salt as well
as the use of polar protic and aprotic solvents gave a complex
mixture of unidentified products (entries 2-4). Although a
huge number of articles and reviews19 testify that micro-
waves20 can speed up reactions and improve the yields, our
reaction did not seem to be positively influenced by the use
of this nonconventional energy source (entries 5-7); in
(6) Ackermann, L.; Born, R. Tetrahedron Lett. 2004, 45, 9541.
(7) Hata, T.; Sano, Y.; Sugawara, A.; Matsune, A.; Kanamori, K.; Shima,
T.; Hoshi, T. J. Antiobiot., Ser. A 1956, 9, 141 (mitomycins A and B).
Wakaki, S.; Marumo, H.; Tomioka, K.; Shimizu, G.; Kato, E.; Kamada,
H.; Kudo, S.; Fujimoto, Y. Antiobiot. Chemother. 1958, 8, 288 (mitomycin
C).
(8) Takahashi, K.; Kametani, T. Heterocycles 1979, 13, 411.
(9) (a) Prajapati, D.; Gadhwal, S. Tetrahedron 2004, 60, 4909. (b)
Beccalli, E. M.; Broggini, G.; La Rosa, C.; Passarella, D.; Pilati, T.;
Terraneo, A.; Zecchi, G. J. Org. Chem. 2000, 65, 8924.
(10) Borah, H. N.; Deb, M. L.; Boruah, R. C.; Bhuyan, P. J. Tetrahedron
Lett. 2005, 46, 3391.
(11) Gonza´lez-Pe´rez, P.; Pe´rez-Serrano, L.; Casarrubios, L.; Dom´ınguez,
G.; Pe´rez-Castells, J. Tetrahedron Lett. 2002, 43, 4765.
(12) Pe´rez-Serrano, L.; Dom´ınguez, G.; Pe´rez-Castells, J. J. Org. Chem.
2004, 69, 5413.
(13) Yavari, I.; Adib, M.; Sayahi, M. H. J. Chem. Soc., Perkin Trans. 1
2002, 1517.
(14) Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Org. Chem. 1997, 62, 3597.
(15) Sundberg, R. J.; Russel, H. F.; Ligon, W. V., Jr.; Lin, L.-S J. Org.
Chem. 1972, 37, 719.
(16) Rossi, E.; Abbiati, G.; Canevari, V.; Celentano, G.; Magri, E.
Synthesis 2006, 299.
(17) Johnson, A. T.; Klein, E. S.; Wang, L.; Pino, M. E.; Chandraratna,
R. A. S. J. Med. Chem. 1996, 39, 5027.
(18) Broggini, G.; Bruche´, L.; Zecchi, G. J. Chem. Soc., Perkin Trans.
1 1990, 533.
(19) (a) Nu¨chter, M.; Ondruschka, B.; Bonrath, W.; Gum, A. Green
Chem. 2004, 6, 128. (b) Nu¨chter, M.; Mu¨ller, U.; Ondruschka, B.;
Lautenschla¨ger, W. Chem. Eng. Technol. 2003, 26, 1208. (c) Larhed, M.;
Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (d) Lidstro¨m, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
(20) AA.VV. MicrowaVes In Organic Synthesis; Loupy, A., Ed.; Wiley
VCH Verlag GmbH & Co. KGaA: Weinheim, 2002.
4840
Org. Lett., Vol. 8, No. 21, 2006

The reaction allows also a heteroaryl substituent on CdO
(entries 5-7), but when reacting thiophen-2-yl and furan-
2-yl derivatives 2f-g, only the isomeric 9H-pyrrolo[1,2-a]-
indole-carbaldehydes 4f-g (fluorazene form) were isolated
(entries 6 and 7).
Table 1. Reaction Conditions Screening
Furthermore, we found that all 3H-pyrrolo[1,2-a]indole-
carbaldehyde derivatives 3 isomerize in the more stable
tautomeric fluorazene form 4 standing in a CDCl3 solution
at room temperature for 24 h. The same result was obtained
by stirring at room temperature a solution of 3b in toluene
for 40 min in the presence of a catalytic amount of p-TSA
(Table 2).
yield %a
ratio
3b
entry solvent
Ti salt
2b/Ti/base T (°C) t (h) (2b rec.)
1
2
3
4
5
toluene TiCl4
toluene Ti(O-i-Pr)4
ethanol TiCl4
DMF
toluene TiCl4
toluene TiCl4
toluene TiCl4
1:0.5:3
1:0.5:3
1:0.5:3
1:0.5:3
1:0.5:3
80
100
80
12
48
48
15
63 (28)
Finally, with the aim to explore the scope and limitation
of this synthetic approach, we did a preliminary test on a
different substrate. The reaction of 2-acetyl-1-propargyl
pyrrole 5 under optimized conditions gave the corresponding
1-methyl-3H-pyrrolizin-2-carbaldehyde 6 in moderate yields
as a single product; interestingly, the treatment of 6 with
p-TSA acid did not give any of the possible tautomers
(Scheme 2).
TiCl4
80
110
µwb
140
µwb
180
µwb
80
0.5 35 (48)
0.5 46 (29)
0.5 21 (38)
6
7
1:0.5:3
1:0.5:3
8
9
10
toluene TiCl4
toluene TiCl4
toluene TiCl4
1:0.5:6
1:1:6
1:1.5:9
7
20
6
45 (40)
63
87
25
25
a Yields refer to isolated products. b µw ) microwave.
Scheme 2. Synthesis of 1-Methyl-3H-pyrrolizin-2-carbaldehyde
particular, an excessive rise in temperature gave a dropout
of overall yield, maybe as a consequence of a thermal
degradation of products (entry 7). Better results were obtained
by increasing the ratio among the reagents (entries 8-10);
in particular, a ratio of substrate/TiCl4/t-BuNH2 of 1:1.5:9
gave the best results already at room temperature (entry 10).
The optimized method was then extended to all derivatives
2. The results are reported in Table 2.
All compounds were identified on the basis of analytical
and spectral data. Proposed structures are in agreement with
experimental evidence of similar compounds reported in the
literature.21 In particular, the structures of tautomers were
clearly established for the couple 3b/4b and 6 via 2D NMR
experiments (NOESY, HETCOR, HMBC) and extended by
analogy to the entire series. Diagnostic NOE interactions and
3J(C,H) coupling constants are reported in Figure 1.
Table 2. Synthesis of Pyrrolo[1,2-a]indole-2-carbaldehydes
yield %a
yield %a
The proposed reaction mechanism involves three steps in
which TiCl4 has a multiplicity of activities (Scheme 3). The
first step is a TiCl4-catalyzed hydroamination of alkyne22 with
the formation of an enamine intermediate (I). The addition
is highly regioselective in anti-Markovnikow fashion, due
to the steric hindrance of the tert-butyl moiety of amine.23
According to recent Ackermann studies, the catalytically
active species is probably generated in situ by reaction
entry
2
R
t (h)
3
4
1
2
3
4
5
6
7
a
b
c
d
e
f
methyl
phenyl
p-tolyl
m-tolyl
thiophen-3-yl
thiophen-2-yl
furan-2-yl
0.3
6
6
6
2
50
87
75
91
89
-
-
-
-
-
-
2
2
75
77
g
-
a Yields refer to isolated products.
(21) (a) Caddick, S.; Aboutayab, K.; Jenkins, K.; West, R. I. J. Chem.
Soc., Perkin Trans. 1 1996, 675. (b) Xiong, Y.; Moore, H. W. J. Org. Chem.
1996, 61, 9168. (c) Carde, R. N.; Hayes, P. C.; Jones, G.; Cliff, C. J. J.
Chem. Soc., Perkin Trans. 1 1981, 1132. (d) Mazzola, V. J.; Bernady, K.
F.; Franck, R. W. J. Org. Chem. 1967, 32, 486.
(22) Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104.
(23) Tillack, A.; Garcia Castro, I.; Hartung, C. G.; Beller, M. Angew.
Chem., Int. Ed. 2002, 41, 2541; Angew. Chem. 2002, 114, 2646.
The reaction of 2-acetyl derivative 2a took place quickly
and gave the corresponding 3H-pyrrolo[1,2-a]indole-carbal-
dehyde 3a in moderate yields (entry 1). Better yields were
obtained using 2-benzoyl-1-propargylindoles (entries 2-4).
Org. Lett., Vol. 8, No. 21, 2006
4841

Scheme 3. Suggested Reaction Mechanism
Figure 1. Compounds 3b, 4b, and 6: diagnostic NOE interactions
(red arrows) and 3J(C,H) coupling constants (blue arrows), besides
significant proton (and carbon) chemical shifts.
between TiCl4 and t-BuNH2.24 The second step is an aldol-
type intramolecular reaction: the nucleophilic addition of
the â-carbon of enamine (I) on the carbonyl group gave the
intermediate (II). An analogous mechanism was reported by
Okada and co-workers for the intramolecular addition of the
enamine electron-rich carbon on a CdO activated by the
presence of a trifluoromethyl group.25 Differently, in our
reactions, the carbonyl group is activated by TiCl4 as a Lewis
acid catalyst.26 It is worth noting that the carbonyl group
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.27 In the third
step, the imine 7 could be formed by intramolecular
elimination of HOTiCl3 and deprotonation or by a N-O
proton shift followed by elimination of water and TiCl4.
Either way, the driving force of this step is the formation of
a new CdC 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 preventing the hydrolysis of enamine/imine
intermediates.28 Besides, the excess of amine buffers the
reaction solution scavenging the acid chloride. Afterward,
the usual workup leads to the hydrolysis of the imine
intermediate to give the pyrrolo[1,2-a]indole-2-carbaldehydes
3 or 4.
This mechanism that involves a plethora of different
activities of TiCl4scatalyst/Lewis acid/water scavengerswell
explains the need to use an excess of this reagent. Moreover,
the 1H and 13C NMR spectra of the reaction crude validates
the final step of the suggested mechanism highlighting the
presence of the characteristic signals of the tert-butyl-imine
group of compound 7 (Scheme 3).
In conclusion, this preliminary report demonstrates once
again the usefulness of domino addition/annulation reactions
involving δ-carbonyl-acetylenes in the synthesis of hetero-
cycles. In particular, this synthetic route to pyrrolo[1,2-a]-
indole-2-carbaldehydes represents an original example of a
TiCl4/t-BuNH2-mediated hydroamination/annulation reaction
in which the TiCl4 performs a variety of tasks. Current efforts
are now directed to widening this methodology to other
δ-carbonyl-acetylenic substrates and to theoretically clarify-
ing the tautomeric distribution of products.
Acknowledgment. We are grateful to MIUR (Ministero
dell’Istruzione, dell’ Universita` e della Ricerca) for the
financial support.
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and H and 13C spectra for
(24) Ackermann, L. Organometallics 2003, 22, 4367.
(25) Okada, E.; Tone, H.; Tsukushi, N.; Otsuki, Y.; Takeuchi, H.; Hojo,
M Heterocycles 1997, 45, 339.
(26) Kabalka, G. W.; Ju, Y.; Wu, Z. J. Org. Chem. 2003, 68, 7915.
(27) Weingarten, H.; Chupp, J. P.; White, W. A. J. Org. Chem. 1967,
32, 3246.
compounds 1c-g, 2c-g, 3a-g, 4a-g, and 5-7. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(28) Layer, R. W. Chem. ReV. 1963, 63, 489.
OL061872U
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Org. Lett., Vol. 8, No. 21, 2006