Intramolecular cyclization of δ-iminoacetylenes: A new entry to pyrazino[1,2-a]indoles

Article abstract of DOI:10.1021/jo0502246

The synthesis of the pyrazino[1,2-a]indole nucleus was achieved by intramolecular cyclization of several 2-carbonyl-1-propargylindoles in the presence of ammonia. The reaction conditions were optimized using microwave heating and a pool of catalysts. Cycl

Full text of DOI:10.1021/jo0502246

Intramolecular Cyclization of δ-Iminoacetylenes: A New Entry to
Pyrazino[1,2-a]indoles
Giorgio Abbiati,*,† Antonio Arcadi,‡ Alessandra Bellinazzi,† Egle Beccalli,†
Elisabetta Rossi,† and Simona Zanzola§
Istituto di Chimica Organica “Alessandro Marchesini”, Facolta` di Farmacia, Universita` degli Studi di
Milano Via Venezian 21, 20133 Milano, Italy, Dipartimento di Chimica, Ingegneria Chimica e Materiali,
Facolta` di Scienze, Universita` de L’Aquila, Via Vetoio, 67010 Coppito due, L’Aquila, Italy, and Rotta
Research Laboratorium SpA, Via Valosa di Sopra, 7, 20052 Monza (MI), Italy
giorgio.abbiati@unimi.it
Received February 4, 2005
The synthesis of the pyrazino[1,2-a]indole nucleus was achieved by intramolecular cyclization of
several 2-carbonyl-1-propargylindoles in the presence of ammonia. The reaction conditions were
optimized using microwave heating and a pool of catalysts. Cyclization of 1-alkynylindole-2-
carbaldehydes was easily accomplished under standard heating conditions, whereas microwave
heating contributed to reduced reaction times and improved overall yields. Moreover, a fine-tuning
of the microwave irradiation time made possible the selective synthesis of both pyrazino[1,2-a]-
indole isomers. TiCl4 proved the catalytic system of choice to achieve pyrazinoindoles in satisfactory
yields starting from 1-alkynyl-2-acetylindoles and 1-alkynyl-2-benzoylindole derivatives. Also in
these cases, microwave heating contributed to faster reactions and improved yields. The uncatalyzed
versus catalyzed reaction mechanism is discussed.
Introduction
recently some papers related to the chemistry and the
pharmacology of pyrazino[1,2-a]indole nucleus have ap-
peared in the literature. Whereas the synthesis of 1-ox-
opyrazino[1,2-a]indole derivatives was widely explored,6
the preparation of simple pyrazino-7 and 3,4-dihydropy-
razino[1,2-a]indoles8 has been less examined. For ex-
ample, Hegedus7a prepared the pyrazinoindole nucleus
Polycyclic indoles represent the framework of a large
number of compounds characterized by a wide range of
biological activities.1 The isolation from natural sources,
synthesis, and the study of the biological properties of
these molecules is still a research field of great interest
and continuous evolution. For instance, the explosive
growth of the carbazole chemistry is demonstrated by the
many reviews and monographs that appeared in the
literature.2 In addition, nitrogen analogues of carbazoles
commonly called carbolinessare under active investiga-
tion for their potential pharmacological activities,3 in
particular the â4 and γ5 forms. Although a-fused aza-
polycyclic indoles are less studied than the b-fused,
(4) See: Condie, G. C.; Bergman, J. Eur. J. Org. Chem. 2004, 1286-
1297.
(5) See: Zhang, H.; Larock, R. C. J. Org. Chem. 2003, 68, 5132-
5138.
(6) (a) Suzuki, H.; Shinpo, K.; Yamazaki, T.; Niwa, S.; Yokoyama,
Y.; Murakami, Y. Heterocycles 1996, 42, 83-86. (b) Barry, J. F.;
Wallace, T. W.; Walshe, N. Tetrahedron 1995, 51, 12797-12806. (c)
Boes, M.; Jenck, F.; Martin, J. R.; Moreau, J. L.; Mutel, V.; et al. Eur.
J. Med. Chem. Chim. Ther. 1997, 32, 253-262. (d) Modi, N. T.; et al.
J. Org. Chem. 1970, 35, 2228-2230. (e) Saxena, A. J. Heterocycl. Chem.
1977, 14, 595-597. (f) Voss, M. E.; Carter, P. H.; Tebben, A. J.; Scherle,
P. A.; Brown, G. D.; Thompson, L. A.; Xu, M.; Lo, Y. C.; Yang, G.; Liu,
R.-Q.; Strzemienski, P.; et al. Bioorg. Med. Chem. Lett. 2003, 13, 533-
538. (g) Tapia, R. A.; Prieto, Y.; Pautet, F.; Domard, M.; Sarciron, M.-
E.; Walchshofer, N.; Fillion, H. Eur. J. Org. Chem. 2002, 23, 4005-
4010. (h) Campiani, G.; Butini, S.; Trotta, F.; Fattorusso, C.; Catalanotti,
B.; Aiello, F.; Gemma, S.; Nacci, V.; Novellino, E.; Stark, J. A.;
Cagnotto, A.; et al. J. Med. Chem. 2003, 46, 3822-3839.
(7) (a) Hegedus, L. S.; Mulhern, T. A.; Asada, H. J. Am. Chem. Soc.
1986, 108, 6224-6228. (b) Kibalnyi, A. V.; Kikolyukin, Yu. A.; Dulenko,
V. I. Chem. Heterocycl. Compd. 1994, 30, 1041-1047. (c) Grinev, A.
N.; Shvedov, V. I.; Krichewskii, E. S.; Romanova, O. B.; Altukhova L.
B. Pharm. Chem. J. 1984, 18, 94-98.
* Corresponding author. Tel: +39-02-50314474. Fax: +39-02-
50314476.
† Universita` degli Studi di Milano.
‡ Universita` de L’Aquila.
§ Rotta Research Laboratorium.
(1) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press:
New York, 1970. (b) Sundberg, R. J. Indoles; Academic Press: London,
1996.
(2) Kno¨lker, H. J.; Reddy, K. R. Chem. Rev. 2002, 11, 4303-4428
and references cited therein.
(3) See: Khorana, N.; Smith, C.; Herrick-Davis, K.; Purohit, A.;
Teitler, M.; Grella, B.; Dukat, M.; Glennon, R. A. J. Med. Chem. 2003,
46, 3930-3937.
10.1021/jo0502246 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/16/2005
4088
J. Org. Chem. 2005, 70, 4088-4095

Intramolecular Cyclization of δ-Iminoacetylenes
TABLE 1. 1-Alkynyl Derivatives 1 Prepareda
in moderate yield starting from N-allylskatole by activa-
tion of the olefin moiety with a strong electrophilic
palladium complex as Pd(MeCN)4(BF4)2 followed by
treatment with acetonitrile. Some pyrazino[1,2-a]indoles
have been obtained by heating skatole[2,1-c]-1,4-ox-
azinium salts7b or 2-acyl-N-methylcarbonylskatoles7c with
ammonia, whereas a series of 3,4-dihydropyrazino[1,2-
a]indoles were synthesized according to Hendi8a through
POCl3-promoted cyclodehydration of 1-(2-amidoethyl)-3-
phenylindoles. Moreover, the relevance of pyrazinoindole
compounds, as potential serotoninergic and antitumoral
agents, is further demonstrated by the number of recent
patents appearing in the literature.9
For many years, we have been interested in developing
new synthetic strategies for the construction of hetero-
cycles from alkynes.10 Recently, we focused on the
synthesis of nitrogen containing rings by sequential
addition/annulation reactions of γ-ketoalkynes with ben-
zylamine or ammonia. In particular, 5-exo-dig cyclization
of 4-pentynones11 and 2-propynyl-1,3-dicarbonyl12 com-
pounds gave polysubstituted and fused pyrrole deriva-
tives. The presence of a γ-ketoalkyne moiety in an
aromatic framework is responsible for the 6-endo-dig
cyclization of 5-acetyl-4-alkynylthiazoles13 and 2-acyl-3-
alkynylindoles14 to pyrido[3,4-c]thiazoles and pyrido[3,4-
b]indoles, respectively. Furthermore, an original one-pot
synthesis of pyridines was developed through a sequen-
tial amination/6-endo-dig cyclization/aromatization of
carbonyl compounds and propargylamine.15
In a recent short communication,16 we reported our
preliminary investigations on the synthesis of pyrazino-
[1,2-a]indoles through a thermal sequential imination/
annulation of 1-alkynylindole-2-carbaldehydes 1a-d and
2-acetyl-1-alkynyl-indoles 1f,h-j in the presence of am-
monia (Table 1, 2). The main drawbacks of these reac-
tions were the long times required for the cyclization of
2-acetyl derivatives and the formation of isomeric mix-
a Reaction conditions: molar ratio indole 1a, f, k/aryl-halide/
K2CO3/CuI/Pd(PPh3)4 ) 1:1.01:5:0.04:0.02; DMF, N2, 60 °C. b Iso-
lated yields.
tures of pyrazino and dihydropyrazino indoles. Thus, the
target of this new work was to develop and optimize this
approach through the reduction of reaction times for the
2-acetyl derivatives, the extension of this methodology
to some new 2-acetyl-, 2-formyl-, and 2-benzoylindoles
(Table 1, 1e,g,k-o), and the selective preparation of both
isomeric pyrazinoindoles. We now report the full details
of the results we have obtained, as well as scope and
limitations of this synthetic strategy. It is worth noting
that, although intramolecular cyclization reactions in-
volving 2-substituted-1-alkynylpyrrole or indole deriva-
tives have been described in the synthesis of indol-
ophenanthridine and isoindoloindole derivatives,17 pyr-
rolizines,18 pyrrolophenanthridines,19 2a-azacyclopen-
tafluorenes,20 pyridopyrrolizines, and 10-aza-indenoin-
doles,21 our methodology represents the first example of
intramolecular cyclization of N-alkynyl-substituted het-
erocycles with proximate nitrogen nucleophiles.
(8) (a) Hendi, S. B.; Basanagoudar, L. D. Indian J. Chem. Sec. B
1981, 20, 285-287. (b) Matia, M. P.; Ezquerra, J.; Sanchez-Ferrando,
F.; Garcia-Navio, J. L.; Vaquero, J. J.; Alvarez-Builla, J. Tetrahedron
1991, 47, 7329-7342. (c) Terenin, V. I.; Kabanova, E. V.; Baranova,
N. A.; Bundel, Yu. G. Chem. Heterocycl. Compd. 1995, 31, 331-335.
(9) (a) Bentley, J. M.; Hebeisen, P.; Muller, M.; Richter, H.; Roever,
S.; Mattei, P.; Taylor, S. (F. Hoffmann-La Roche A.-G., Switzerland;
Vernalis Research Ltd, Great Bretain). Patent No. WO 0210169, 2002;
Chem. Abstr. 2002, 136, 167392. (b) Menta, E.; Nicotra, F.; Pescalli,
N.; Spinelli, S. (Novuspharma S. P. A., Italy). Patent No. WO 01009136,
2001; Chem. Abstr. 2001, 134, 163063. (c) McCort, G.; Hoornaert, C.;
Duclos, O.; Guilpain, E.; Cadilhac, C.; Dellac, G. (Synthelabo S. A.,
France). Patent No. WO 9842710, 1998; Chem. Abstr. 1998, 129,
275933.
(10) (a) Rossi, E.; Arcadi, A.; Abbiati, G.; Attanasi, O. A.; De
Crescentini, L. Angew. Chem. 2002, 114, 1458-1460; Angew. Chem.,
Int. Ed. 2002, 41, 1400-1402. (b) Abbiati, G.; Arcadi, A.; Marinelli,
F.; Rossi, E. Synthesis 2002, 1912-1916. (c) Abbiati, G.; Arcadi, A.;
Marinelli, F.; Rossi, E. Eur. J. Org. Chem. 2003, 1423-1427.
(11) (a) Arcadi, A.; Marinelli, F.; Pini, E.; Rossi, E. Tetrahedron Lett.
1996, 37, 3387-3390. (b) Arcadi, A.; Rossi, E. Synlett 1997, 667-668.
(c) Arcadi, A.; Rossi, E. Tetrahedron 1998, 54, 15253-15272.
(12) (a) Arcadi, A.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. Adv.
Synth. Catal. 2001, 5, 443-446. (b) Arcadi, A.; Di Giuseppe, S.;
Marinelli, F.; Rossi, E. Tetrahedron: Asymmetry 2001, 12, 2715-2720.
(13) Arcadi, A.; Attanasi, O. A.; Guidi, B.; Rossi, E.; Santeusanio,
S. Chem. Lett. 1999, 59-60. (b) Arcadi, A.; Attanasi, O. A.; Guidi, B.;
Rossi, E.; Santeusanio, S. Eur. J. Org. Chem. 1946, 11, 3117-3126.
(14) Abbiati, G.; Beccalli, E.; Marchesini, A.; Rossi, E. Synthesis
2001, 2477-2483.
(17) Xiong, Y.; Moore, H. W. J. Org. Chem. 1996, 61, 9168-9177.
(18) Montgomery, J.; Chevliakov, M. V.; Brielmann, H. L. Tetrahe-
dron 1997, 53, 16449-16462.
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(15) Abbiati, G.; Arcadi, A.; Bianchi, G.; Di Giuseppe, S.; Marinelli,
F.; Rossi E. J. Org. Chem. 2003, 68, 6959-6966.
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2003, 44, 5331-5334.
J. Org. Chem, Vol. 70, No. 10, 2005 4089

Abbiati et al.
SCHEME 1
Results and Discussion
The 1-propargyl-1H-indole-2-carbaldehyde 1a,22 the
2-acetyl-1-propargyl-1H-indole 1f, and the 2-benzoyl-1-
propargyl-1H-indole 1k were synthesized by standard
procedures,23 starting from readily accessible 1H-indole-
2-carbaldehyde,24 2-acetyl-1H-indole25 and 2-benzoyl-1H-
indole,26 respectively. The corresponding 1-alkynyl-1H-
indole-2-carbaldehydes 1b-e, 2-acyl-1-alkynyl-1H-indoles
1g-j, and 2-benzoyl-1-alkynyl-1H-indoles 1l-o (Table 1)
were synthesized from 1-propargylindoles 1a, 1f, and 1k
by palladium-catalyzed Sonogashira-(Hagihara) cou-
pling with aryl halides.27
As reported in ref 16, when 1-propargyl derivatives 1a
and 1f and 1-alkynyl derivatives 1b-d and 1h-j were
treated in a sealed tube at 100 °C with 2 M ammonia in
methanol, 1a and 1f gave the corresponding pyrazino-
[1,2-a]indoles 2a and 2f in good yields, whereas 1-alkynyl
derivatives 1b-d and 1h-j afforded a mixture of iso-
meric pyrazino[1,2-a]indoles 2b-d and 2h-j and 3,4-
dihydropyrazino[1,2-a]indoles 2′b-d and 2′h,i (Table 2,
entries 1-8). Moreover, the cyclization reactions of the
newly prepared 2-benzoyl derivatives 1k and 1n took
place very awkwardly giving rise to the corresponding
pyrazino derivatives 2k and 2′n in very poor yields (Table
2, entries 9,10). The reaction times vary from 3 to 4 h
for the carbaldehyde derivatives 1a-d (entries 1-4), to
50-200 h for the 2-acetyl derivatives 1f,h-j (entries 5-8)
and 240-387 h for 2-benzoyl derivatives 1k,n (entries
9-10).
dihydro isomers 2′ derived from 2-acetyl- and 2-formylin-
doles can be converted, in almost quantitative yields, to
the corresponding fully conjugated isomers 2 under basic
conditions (NaOMe/MeOH 15%, reflux). The same reac-
tion failed when performed on dihydro isomers derived
from 2-benzoylindoles.
In our opinion, the experimental evidence could be
related to two main features: the mutual stability of
pyrazinoindoles with respect to dihydropyrazino deriva-
tives and the divergent reaction times required by the
different substituted substrates. The formation of dihy-
dropyrazino derivatives is a kinetically governed process,
whereas pyrazinoindoles are the thermodynamically
controlled products, and as is well-known, prolonged
reaction times promote the formation of second ones.
These statements were confirmed by the theoretical
calculations performed on derivatives 2a,b,f,g,k,l and
2′a,b,f,g,k,l at the DFT28 level (Table 3).
As expected, the pyrazinoindoles derivatives 2 were
thermodynamically favored with respect to the corre-
sponding dihydro isomers 2′. It is worth noting that the
energetic differences among the isomers derived from
cyclization of 1-propargyl derivatives 1a, 1f, and 1k are
significantly higher (13.41-14.98 kcal/mol) than those
calculated for cyclization products of 1-alkynyl deriva-
tives 1b, 1g, and 1l (7.51-8.94 kcal/mol). This is related
to the stabilizing effect caused by the aryl substituents
conjugated with the exocyclic double bonds on compounds
2′b, 2′g, and 2′l. The lack of this stabilization on
hypothetical methylene derivatives 2′a, 2′f, and 2′k make
them so unfavored that they can never be isolated. In
addition, it is worth noting that the energy difference
between 2-benzoyldihydropyrazino derivatives 2′k,l and
the corresponding fully conjugated isomers 2k,l are the
lowest in the series.
All compounds were identified on the basis of analytical
and spectral data (IR, 1H NMR, 13C NMR, MS). In
particular, the stereochemistry around the exocyclic
double bond of dihydro derivatives was clearly estab-
lished for compound 2′h through 2D NOESY experiments
and extended by analogy to the entire series. Diagnostic
NOE interactions and proton chemical shifts are reported
in Figure 1.
The suggested reaction mechanism involves the forma-
tion of an imine intermediate that undergoes a stereo-
selective 6-exo-dig cyclization to 3,4-dihydropyrazinoin-
dole 2′ followed by partial isomerization to give pyrazinoin-
dole 2 (Scheme 1).
The ratio between compounds 2 and 2′ is switched
toward the formation of the fully conjugated rings in the
experiments performed with 1-propargyl derivatives 1a,
1f, and 1k (Table 2, entries 1, 5, and 9) or with 1-alkynyl-
2-acylindoles 1h-j (Table 2, entries 6-8), whereas di-
hydro derivatives were the main products when the
reactions are performed with 1-alkynylindole-2-carbal-
dehydes 1b-d (Table 2, entries 2-4) or with 1-alkynyl-
2-benzoylindole 1n (Table 2, entry 10). Moreover, the
With the aim to maximize the efficiency of this
synthetic approach in terms of reaction times (2-acetyl
and 2-benzoyl derivatives), overall yields (2-benzoyl
derivatives), and the internal ratio between dihydro and
fully conjugated compounds, we customized the method-
ology according to two different strategies: (1) the employ
of a different energy source and (2) the support of
catalysts.
(22) Jones, G. B.; Moody, C. J.; Padwa, A.; Kassir, J. M. J. Chem.
Soc., Perkin Trans. 1 1991, 7, 1721-1727.
Microwave29 heating as a nonconventional energy
source has become a very popular and valuable technol-
ogy in organic chemistry. Although the subsistence of a
“specific microwave effect” (nonthermal effect) is an
argument of active discussion in the scientific com-
(23) Broggini, G.; Bruche´, L.; Zecchi, G. J. Chem. Soc., Perkin Trans.
1 1990, 533-539.
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1975, 50, 4467-4470. (b) For a recent review on Sonogashira-
(Hagihara) coupling applications, see: Sonogashira, K. In Handbook
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4090 J. Org. Chem., Vol. 70, No. 10, 2005

Intramolecular Cyclization of δ-Iminoacetylenes
TABLE 2. Thermal Cyclization of 1-Alkynyl Derivatives 1a
a Reaction conditions: molar ratio indole 1/2 M NH3 in MeOH ) 1:20, sealed tube. b Isolated yields.
munity,30 a huge number of articles and reviews31 testi-
fies that microwave heating can speed up reactions and
improve the yields by decreasing decomposition of prod-
ucts, substrates, and reagents. These remarks prompted
(30) (a) de la Hoz, A.; D´ıaz-Ortiz, AÄ .; Moreno, A. Chem. Soc., Rev.
2005, 34, 164-178. (b) Kuhnert, N. Angew. Chem., Int. Ed. 2002, 41,
1863-1866. (c) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199-
9223.
(31) (a) Nu¨chter, M.; Ondruschka, B.; Bonrath, W.; Gum, A. Green
Chem. 2004, 6, 128-141 (b) Nu¨chter, M.; Mu¨ller, U.; Ondruschka, B.;
Lautenschla¨ger, W. Chem. Eng. Technol. 2003, 26, 1208-1216. (c)
Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717-
727. (d) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron
2001, 57, 9225-9283.
FIGURE 1. NOE interactions and proton NMR chemical
shifts for derivative 2′h.
J. Org. Chem, Vol. 70, No. 10, 2005 4091

Abbiati et al.
TABLE 3. Calculated Energies for Pyrazinoindoles
time of 40 min the fully conjugated isomer 2e was
isolated in 65% yield (entry 6). Unfortunately, under
these reaction conditions no yield improvement was
observed for the cyclization of 2-acetyl-1-propargylindole
1f in a reasonable reaction time (entry 7). This latter
result discouraged us from attempting the microwave
methodology on 2-benzoyl-1-propargylindole derivatives.
As depicted in Scheme 1, 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.32 In the literature, a great number of examples
of imine synthesis promoted by a variety of agents such
as molecular sieves,33 zinc chloride,34 titanium tetrachlo-
ride,35 alumina,36 and other Lewis acids37 are reported.
On the other hand, considering the annulation step, a
number of recent reviews suggest that catalytic hy-
droamination of multiple bonds is a powerful synthetic
method to obtain nitrogen-containing compounds.38 In
particular, a variety of protocols are available for the
intermolecular hydroamination of alkynes,39 and a num-
ber of metal complexes of group 440 and organolan-
thanides41 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.11f,42
2a,b,f,g,k,l and Dihydropyrazinoindoles 2′a,b,f,g,k,l
2
R1
R2
E DFTa (kcal/mol)
Erel DFTa (kcal/mol)
2a
2′a
2f
H
H
-359521.04
-359506.46
-384201.37
-384186.39
-504544.33
-504530.92
-504540.44
-404532.23
-529219.35
-529210.41
-649562.46
-649554.95
0
H
H
14.58
0
Me
Me
Ph
Ph
H
H
2′f
2k
2′k
2b
2′b
2g
2′g
2l
H
14.98
0
13.41
0
8.21
0
8.94
0
7.51
H
H
Ph
Ph
Ph
Ph
Ph
Ph
H
Me
Me
Ph
Ph
2′l
a B3LYP/6-311+G**//HF/6-31+G*.
TABLE 4. Microwave-Assisted Cyclization of 1-Alkynyl
Derivatives 1a-fa
Based on these accounts, we tested a variety of water
scavengers/catalytic systems. The screening was per-
formed by heating, in a silicon oil bath, a sealed tube
containing a solution of the 1-alkynyl-2-acetylindoles 1h
or 1i in 2 M ammonia in methanol and in the presence
of suitable Lewis acids, water scavengers, or metal
catalytic systems. The obtained results are summarized
in Table 5.
The reaction performed at 150 °C and in the presence
of molecular sieves failed, giving rise to the corresponding
mixture of pyrazino indoles in very low yields and a large
amount of starting material (entry 3). Activation of the
intermediate imine function and/or triple bond was then
tentatively achieved by means of palladium/phosphane
catalyst or with phosphane-free silver or copper catalysts
(entries 4-7). However, such reactions ran worse and
were slower than the corresponding uncatalyzed reac-
tions (entries 4 and 5) or did not produce significant
improvements (entries 6 and 7). Surprisingly, the gold-
(III) salt, which acts as a Lewis acid and also increases
a Reaction conditions: molar ratio indole 1/2 M NH3 in MeOH
) 1:20, sealed tube, 150 °C. b Including 15 min “ramp time” = 10
°C/min. c Isolated yields. d 34% of unreacted starting product 1f
was recovered.
us to test the cyclization of our substrates under micro-
wave heating. Thus, a solution of the appropriate alkynyl
indole in 2 M ammonia in methanol was heated in a
multimode microwave oven at 150 °C until no more
starting product was detectable by TLC analysis. The
results are summarized in Table 4.
The microwave-assisted reaction of carbaldehyde de-
rivatives 1a-e took place quicker than conventional-
heated ones (cf. Table 2, minutes vs hours), and overall
yields were incremented by 11-36% (entries 1-6). The
ratio between dihydropyrazinoindoles (2′) and pyrazi-
noindoles (2) 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 (entries 5 and 6). When 1e was
reacted for 25 min, under usual reaction conditions, the
dihydro derivative 2′e was obtained as the sole reaction
product in 95% yield (entry 5), whereas with a reaction
(32) Layer, R. W. Chem. Rev. 1963, 63, 489-510.
(33) Taguchi, K.; Westheimer, F. H. J. Org. Chem. 1971, 36, 1570-
1572.
(34) Billman, J. H.; Tai, K. M. J. Org. Chem. 1958, 23, 535-539.
(35) Weingarten, H.; Chupp, J. P.; White, W. A. J. Org. Chem. 1967,
32, 3246-3249.
(36) Texier-Boullet, F. Synthesis 1985, 679-681.
(37) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999,
40, 6709-6712.
(38) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675-703.
(39) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104-114.
(40) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 6, 935-946.
(41) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673-686.
(42) (a) Mu¨ller, T. E. Tetrahedron Lett. 1998, 39, 5961-5962. (b)
Tamaru, Y.; Kimura, M. Synlett. 1997, 749-757. (c) Fukuda, Y.;
Matsubara, S.; Utimoto, K. J. Org. Chem. 1991, 56, 5812-5816.
4092 J. Org. Chem., Vol. 70, No. 10, 2005

Intramolecular Cyclization of δ-Iminoacetylenes
TABLE 5. Screening of Water Scavengers/Catalytic Systemsa
entry
1
T (°C)
t (h)
water scavenger/catalytic system
1 (rec, %)b
1h (75)d
2 (yield, %)b
2′ (yield, %)b
1c
2c
3
1h
1i
1h
1i
1h
1i
1i
1h
1i
1h
1h
1h
100
100
150
100
100
100
100
100
100
100
100
100
200
160
48
137
158
172
112
94
2h (58)
2i (76)
2h (10)d
2i (60)
2h (44)
2i (18)
2i (40)
2h (27)
2i (77)
2h (20)d
2h (20)
2h (18)
2′h (31)
2′i (12)
2′h (15)d
2′i (14)
2′h (16)
2′i (21)
2′i (22)
2′h (28)
2′i (12)
2′h (35)d
2′h (60)
2′h (52)
molecular sieves 3 Å (1.0 g)
Pd(OAc)2 (0.05 mol), PPh3 (0.10 mol)
Pd(OAc)2 (0.05 mol), PPh3 (0.10 mol)
AgNO3 (0.10 mol)
4
5
6
1i (36)
1i (18)
1h (23)
7
CuI (0.10 mol)
8
NaAuCl4 (0.04 mol)
NaAuCl4 (0.10 mol)
AlCl3 (1 mol)
9
160
36
36
10
11
12
1h (45)d
ZnCl2 (1 mol)
TiCl4 (0.50 mol)
8.5
1h (29)
a Reaction conditions: molar ratio indole derivatives 1h or 1i/2 M NH3 in MeOH ) 1:20, water scavenger/cat., sealed tube, conventional
heating. Workup: flash column chromatography (petroleum ether/ethyl acetate ) 98:2). b Unless other stated, isolated yields. c To simplify
the evaluation, entries 1 and 2 report once more the results of uncatalyzed thermal cyclization of compounds 1h and 1i. d Yields determined
by analysis of the proton NMR spectrum of the reaction mixture.
the electrophilicity of the triple bond by coordination,
TABLE 6. TiCl4-Catalyzed Cyclization of 2-Acyl and
seems to be irrelevant for the reaction outcome (entries
8 and 9). Instead, reasonable reduction of reaction time
can be achieved working in the presence of Lewis acids
catalyst/water scavengers such AlCl3, ZnCl2, and TiCl4
(entries 10-12). Among these catalysts, titanium tetra-
chloride was selected for further investigation in order
to establish the most advantageous ratio substrate/
catalyst with respect to reaction time and conversion
yields. Derivative 1h was reacted under standard condi-
tions in the presence of 0.5, 1, 2, 3 equiv of TiCl4 and
TLC analysis, run at regular intervals, and showed that
an indole/TiCl4 ratio of 1:3 gave a faster conversion time
(disappearance of 1h in ca. 2 h).
2-Benzoyl Derivatives
The optimized methodology was then applied to 2-acyl
and 2-benzoyl derivatives using either conventional or
microwave heating. The obtained results are summarized
in Table 6.
The obtained results show that titanium tetrachloride,
under mild conventional heating conditions, accelerates
the cyclization of 2-acetylindoles (entries 1, 3, 4, 6, and
7) and allowed the cyclization of 2-benzoylindoles with
good yields and reasonable reaction times (entries 9, 11,
14, and 15). Moreover, reaction times were further
reduced by microwave heating (entries 2, 5, 8, 10, 12, 13,
and 16). On the whole, the overall yields on pyrazinoin-
doles 2/2′ appeared slightly improved with respect to
reactions performed without catalyst. Finally, titanium
tetrachloride catalyzed cyclization of internal alkynes
gave preferentially (entries 3, 4, 6, and 12) and sometimes
exclusively (entries 7, 8, 11, and 13-16) the dihydropy-
razino derivatives 2′.
To better understand this behavior, we performed a
semiquantitative kinetic study via 1H NMR. In two sealed
tubes, two identical samples (A and B) containing 154
mg of derivative 1h in 5 mL of 2 M ammonia in methanol
were prepared. Three equivalents of TiCl4 were added
to sample B, and then both samples were heated in an
oil bath at 100 °C for several hours. The ratio among
starting material 1h, dihydro derivative 2′h, and pyrazi-
no derivative 2h was detected by sampling the reaction
a Isolated yields. b Reaction conditions: molar ratio indole
derivative 1/2 M NH3 in MeOH/TiCl4 ) 1:20:3, sealed tube, 100
°C (silicon oil bath). c Reaction conditions: molar ratio indole
derivative 1/2 M NH3 in MeOH/TiCl4 ) 1:20:3, sealed tube, 130
°C (microwave oven). d Including 13 min “ramp time” = 10 °C/
min.
1
at different reaction times via H NMR and comparing
the integrals of characteristic methylene signals of 1h
(δ ) 5.72 ppm), 2′h (δ ) 4.85 ppm), and 2h (δ ) 4.08
ppm). The results are reported in Figure 2.
After an induction time of 4 h, the uncatalyzed reaction
(sample A) runs very slowly. Although the conversion of
2′h to 2h is a slow process, the sluggishness of cyclization
of 1h under thermal uncatalyzed conditions allows for
the tautomerization of 2′h to the more stable isomer 2h.
Therefore, after 210 h of reaction, when 1h was nearly
J. Org. Chem, Vol. 70, No. 10, 2005 4093

Abbiati et al.
Conclusions
In conclusion, the synthesis of the pyrazino[1,2-a]indole
nucleus, achieved by intramolecular cyclization of 2-car-
bonyl-1-alkynylindoles in the presence of ammonia, dem-
onstrates once again the efficiency of annulation reactions
involving alkynes with neighboring nucleophiles.
The cyclization reactions of 1-alkynylindole-2-carbal-
dehydes 1a-e, in the presence of ammonia, run well
under conventional heating giving rise to isomeric pyrazi-
no[1,2-a]indoles 2a-e and 3,4-dihydropyrazino[1,2-a]-
indoles 2′a-e in good yields. Nevertheless, reaction times
can be reduced and yields can be improved by the aid of
microwave heating.
Also the 1-propargyl-2-acetylindole 1f reacts easily
with ammonia to give in good yields the corresponding
pyrazino[1,2-a]indole 2f whereas for the less reactive
1-alkynyl-2-acetylindoles 1g-j and 1-alkynyl-2-benzoylin-
doles 1k-o the use of an inexpensive catalyst such TiCl4
allowed to achieve the corresponding isomeric pyrazino-
[1,2-a]indoles 2 and 3,4-dihydropyrazino[1,2-a]indoles 2′
in satisfactory yields with reasonable reaction times.
Furthermore, also in TiCl4-catalyzed reactions microwave
heating efficiently contributed to a widespread reduction
of reaction times and improvement of yields.
Finally, it has been demonstrated that TiCl4 catalysis
drastically modifies the cyclization kinetics for the 1-alky-
nyl-2-acetylindoles, allowing for the almost selective
isolation of both isomers by appropriate choice of the
reaction times.
FIGURE 2. Kinetic study of uncatalyzed (sample A) and
TiCl4-catalyzed (sample B) cyclization of 1h.
Experimental Section
General Procedure for the Synthesis of 1-Propar-
gylindoles 1f and 1k. To a well-stirred solution of the
appropriate 2-acetyl- or 2-benzoyl-1H-indole (6.0 mmol), pro-
pargyl bromide (0.93 g, 7.8 mmol, corresponding to 1.16 g, 0.87
mL of 80% w/w toluene solution), and tetrabutylammonium
bromide (0.097 g, 0.30 mmol) in toluene (18 mL), a 50% w/w
aqueous solution of sodium hydroxide (3.5 mL) was slowly
added at room temperature. The reaction was vigorously
stirred for 5 h until no more starting product was detectable
by TLC analysis. After that, the reaction mixture was diluted
with toluene (10 mL) and washed with water (2 × 20 mL).
The organic layer was dried over sodium sulfate and the
solvent removed at reduced pressure. The resulting crude was
used without further purification.
SCHEME 2
consumed, the ratio between 2h and 2′h was significantly
shifted toward the first one (Figure 2, sample A).
On the contrary, the titanium-catalyzed reaction (sample
B) runs quickly and the conversion of 1h in the dihydro
isomer 2′h is almost complete within 2 h. In this short
segment, only a small amount of 2′h can turn in to the
thermodynamic isomer 2h; thus, by stopping the reaction
at this point it is possible to isolate the kinetic isomer
2′h in nearly quantitative yield. Consequently, to observe
the formation of a significant amount of 2h a longer
heating time is required (Figure 2, sample B).
On the basis of these findings, we hypothesize that
titanium tetrachloride affects both critical steps of pyrazi-
noindole formation (Scheme 2). First, it can promote the
imine intermediate formation through the double activity
of vigorous water scavenger as well as useful Lewis acid.35
In the second instance, TiCl4 or a catalytically active
species generated in situ from TiCl4 and ammonia43 can
promote the cyclization step through the coordination
between the triple bond and imine.44 Moreover, this dual
activity of TiCl4 justifies the high catalyst/substrate ratio
required.
1-(1-Prop-2-ynyl-1H-indol-2-yl)ethanone 1f. Yield: 1.15
g, 98%. Dark yellow solid. Mp: 98-101 °C. IR: ν ) 3276, 2100,
1
4
1647, 1614 cm-1. H NMR: δ ) 2.26 (t, 1H, tC-H, J ) 2.6
Hz), 2.66 (s, 3H, CH3), 5.51 (d, 2H, CH2, 4J ) 2.6 Hz), 7.23 (m,
1H, arom), 7.36 (s, 1H, C3-H arom), 7.23 (m, 1H, arom), 7.45
3
(m, 1H, arom), 7.53 (d, 1H, arom, J ) 8.0 Hz), 7.74 (d, 1H,
arom, 3J ) 8.0 Hz) ppm. 13C NMR: δ ) 27.9, 34.3, 71.9, 78.9,
110.8, 113.5, 121.5, 123.2, 126.2, 126.6, 133.7, 139.5, 191.6
ppm. ESI-MS m/z: 198 [M+ + 1] (100), 154 (45), 130 (19), 100
(73).
Phenyl(1-prop-2-ynyl-1H-indol-2-yl)methanone 1k.
Yield: 1.55 g, 98%. Light brown solid. Mp: 120 °C. IR: ν )
1
3271, 2124, 1634, 1610 cm-1. H NMR: δ ) 2.30 (t, 1H, tC-
4
4
H, J ) 2.2 Hz), 5.50 (d, 2H, CH2, J ) 2.2 Hz), 7.09 (s, 1H,
C3-H arom), 7.22 (m, 1H, arom), 7.44-7.65 (m, 5H, arom),
7.72 (d, 1H, arom, J ) 8.0 Hz), 7.96 (m, 2H, arom) ppm. 13C
3
NMR: δ ) 34.4, 72.5, 79.1, 110.9, 116.5, 121.7, 123.5, 126.5,
126.7, 128.5, 130.0, 132.6, 134.2, 139.4, 139.9, 188.7 ppm. ESI-
MS m/z: 260 [M+ + 1] (100), 100 (32).
General Procedure for the Synthesis of 2-Carbonyl-
1-alkynylindoles 1b-e,g-j,l-o. Under a nitrogen atmo-
sphere, a solution of 1a or 1f or 1k (1.0 mmol), the appropriate
aryl halide (1.01 mmol), potassium carbonate (0.69 g, 5 mmol),
(43) For a recent example, see: Ackermann, L. Organometallics
2003, 22, 4367-4368.
(44) For an example of a complex among titanium, alkynes, and
carbonyl compounds, see: Kabalka, G. W.; Ju, Y.; Wu, Z. J. Org. Chem.
2003, 68, 7915-7917.
4094 J. Org. Chem., Vol. 70, No. 10, 2005

Intramolecular Cyclization of δ-Iminoacetylenes
CuI (7.6 mg, 0.04 mmol), and tetrakis(triphenylphosphine)-
palladium(0) (23.1 mg, 0.02 mmol) in dry DMF (2 mL) was
stirred at 60 °C until no more starting product was detectable
by TLC analysis. Then, the reaction mixture was diluted with
HCl 0.1 M solution (100 mL) and extracted with ethyl acetate
(2 × 30 mL). The organic layer, dried over sodium sulfate, was
evaporated to dryness and the crude purified by flash chro-
matography over a silica gel column.
yielding progressively 3,4-dihydropyrazino[1,2-a]indoles 2′ and/
or pyrazino[1,2-a]indole 2 (for yields and times, see Table 6).
3-[1-Phenylmeth-(Z)-ylidene]-3,4-dihydropyrazino[1,2-
a]indole 2′b. Eluent for chromatography: PE/EtOAc (98:2).
1
Dark yellow solid. Mp: 121 °C. IR: ν ) 1612, 1560 cm-1. H
NMR: δ ) 4.94 (d, 2H, CH2, 4J ) 1.5 Hz), 6.34 (s, 1H, dC-H),
6.84 (s, 1H, C10-H arom), 7.16-7.45 (m, 6H, arom), 7.72 (d,
1H, arom 3J ) 7.7 Hz), 7.91 (d, 2H, arom 3J ) 7.3 Hz), 8.36 (s,
1H, C1-H arom) ppm. 13C NMR: δ ) 44.5, 105.2, 109.5, 121.2,
123.1, 125.2, 126.0, 127.8, 128.3, 128.5, 128.9, 130.8, 136.1,
137.9, 138.0, 149.1 ppm. Anal. Calcd for C18H14N2 (258.32):
C, 83.69; H, 5.46; N, 10.84. Found: C, 83.58; H, 5.42; N, 10.80.
3-Benzylpyrazino[1,2-a]indole 2b. Eluent for chroma-
tography: PE/EtOAc (98:2). Dark yellow solid. Mp: 89 °C.
1-(3-Phenylprop-2-ynyl)-1H-indole-2-carbaldehyde 1b.
Reaction time: 1 h. Eluent for chromatography: PE/EtOAc
(95:5). Yield: 202 mg, 78%. Yellow solid. Mp: 76 °C. IR: ν )
1
1668, 1613 cm-1. H NMR: δ ) 5.71 (s, 2H, CH2), 7.22-7.41
3
(m, 7H, arom), 7.51 (m, 1H, arom), 7.65 (dd, 1H, arom, J )
4
3
4
8.6, J ) 1.1 Hz), 7.79 (dd, 1H, arom, J ) 8.1, J ) 1.1 Hz),
9.94 (s, 1H, CHO) ppm. 13C NMR: δ ) 35.0, 84.0, 84.5, 111.4,
118.9, 121.7, 122.7, 123.8, 126.9, 127.6, 128.5, 128.7, 132.1,
134.8, 140.5, 183.0 ppm. ESI-MS m/z: 260 [M+ + 1] (100), 199
(15). Anal. Calcd for C18H13NO (259.30): C, 83.37; H, 5.05; N,
5.40. Found: C, 83.31, H, 5.05; N, 5.38.
IR: ν ) 1619, 1530 cm-1
6.98 (s, 1H, C10-H arom), 7.37-7.43 (m, 7H, arom), 7.84-7.93
(m, 3H, arom), 9.03 (d, 1H, C1-H arom, 4J ) 1.5 Hz) ppm. 13
.
1H NMR: δ ) 4.14 (s, 2H, CH2),
C
NMR: δ ) 41.3, 95.2, 111.1, 114.5, 122.3, 122.5, 123.8, 126.8,
128.8, 128.9, 129.4, 129.8, 136.1, 139.4, 147.2 ppm (one signal
obscured). ESI-MS m/z: 259 [M+ + 1] (100). Anal. Calcd for
C18H14N2 (258.32): C, 83.69; H, 5.46; N, 10.84. Found: C,
83.57; H, 5.48; N, 10.79.
1-[1-(3-Phenylprop-2-ynyl)-1H-indol-2-yl]ethanone 1g.
Reaction time: 3 h. Eluent for chromatography: PE/EtOAc
(98:2). Yield: 200 mg, 73%. White solid. Mp: 112-113 °C. IR:
ν ) 1663, 1614 cm-1. 1H NMR: δ ) 2.65 (s, 3H, CH3), 5.71 (s,
2H, CH2), 7.16-7.28 (m, 4H, arom), 7.32-7.40 (m, 3H, arom),
1-Methyl-3-[1-phenylmeth-(Z)-ylidene]-3,4-dihydropy-
razino[1,2-a]indole 2′g. Eluent for chromatography: PE/
1
3
EtOAc (98:2). Yellow oil. IR: ν ) 1613, 1556 cm-1. H NMR:
7.44 (m, 1H, arom), 7.59 (d, 1H, arom, J ) 7.7 Hz), 7.72 (d,
4
3
δ ) 2.60 (s, 3H, CH3), 4.86 (d, 2H, CH2, J ) 1.1 Hz), 6.21 (s,
1H, arom, J ) 7.7 Hz) ppm. 13C NMR: δ ) 28.2, 35.2, 83.9,
1H, dC-H), 6.87 (s, 1H, C10-H arom), 7.15-7.41 (m, 6H, arom),
84.7, 111.2, 113.5, 121.5, 122.9, 123.3, 126.4, 126.6, 128.4,
128.5, 132.0, 133.9, 139.8, 191.7 ppm. ESI-MS m/z: 274 [M+
+ 1] (100), 232 (10). Anal. Calcd for C19H15NO (273.33): C,
83.49; H, 5.53; N, 5.12. Found: C, 83.41; H, 5.49; N, 5.14.
7.68 (d, 1H, arom
3J ) 8.1 Hz), 7.92 (d, 2H, arom 3J ) 7.3 Hz)
ppm. 13C NMR: δ ) 22.5, 44.3, 103.8, 109.8, 121.0, 122.9,
123.5, 125.0, 127.5, 127.8, 128.1, 128.2, 131.0, 136.0, 138.0,
156.9 ppm (one signal obscured). ESI-MS m/z: 273 [M+ + 1]
(100), 211 (10). Anal. Calcd for C19H16N2 (272.34): C, 83.79;
H, 5.92; N, 10.29. Found: C, 83.69; H, 5.96; N, 10.25.
3-Benzyl-1-methylpyrazino[1,2-a]indole 2g. Eluent for
chromatography: PE/EtOAc (98:2). Dark yellow oil. IR: ν )
1617, 1517 cm-1. 1H NMR: δ ) 2.80 (s, 3H, CH3), 4.14 (s, 2H,
CH2), 6.98 (s, 1H, C10-H arom), 7.29-7.42 (m, 7H, arom),
7.70-7.90 (m, 3H, arom) ppm. 13C NMR: δ ) 22.2, 41.1, 97.0,
111.2, 113.1, 121.6, 122.4, 123.7, 126.8, 128.6, 128.9, 129.5,
130.0, 136.4, 139.1, 154.9 ppm (one signal obscured). ESI-MS
m/z: 273 [M+ + 1] (100), 195 (20). Anal. Calcd for C19H16N2
(272.34): C, 83.79; H, 5.92; N, 10.29. Found: C, 83.74; H, 5.98;
N, 10.25.
Phenyl[1-(3-phenylprop-2-ynyl)-1H-indol-2-yl]metha-
none 1l. Reaction time: 1.5 h. Eluent for chromatography:
PE/EtOAc (95:5). Yield: 320 mg, 90%. Yellow oil. IR: ν ) 1635,
1614 cm-1. 1H NMR: δ ) 5.71 (s, 2H, CH2), 7.07 (s, 1H, C3-H
arom), 7.18-7.36 (m, 6H, arom), 7.42-7.72 (m, 6H, arom), 7.96
(dd, 2H, arom, 3J ) 6.6, 4J ) 1.5 Hz) ppm. 13C NMR: δ )
35.2, 84.2, 84.6, 111.2, 116.3, 121.5, 122.8, 123.4, 126.5, 126.6,
128.4, 128.5, 128.6, 130.0, 132.0, 132.5, 134.3, 139.5, 140.0,
188.8 ppm. ESI-MS m/z: 336 [M+ + 1] (100), 251 (38). Anal.
Calcd for C24H17NO (335.40): C, 85.94; H, 5.11; N, 4.18.
Found: C, 86.21; H, 5.18; N, 4.13.
General Methods for Cyclization Reactions of 2-Car-
bonyl-1-alkynylindoles 1. Conventional Thermal Cy-
clizations. A stirred solution of the appropriate indole 1 (0.3
mmol) in dry ammonia in methanol (NH3/MeOH 2 M solution,
3 mL) was heated at 90-150 °C in a sealed tube for 3-387 h
until no more starting product was detectable by TLC. The
solvent was then evaporated under reduced pressure. The
crude product was purified by flash chromatography over silica
gel column yielding progressively 3,4-dihydropyrazino[1,2-a]-
indoles 2′ and/or pyrazino[1,2-a]indole 2 (for yields, times, and
temperatures, see Table 2).
Microwave-Assisted Cyclizations. A stirred solution of
the appropriate indole 1 (0.3 mmol) in dry ammonia in
methanol (NH3/MeOH 2 M solution, 3 mL) was heated at 150
°C in a sealed tube for 25-300 min in a multimode microwave
oven until no more starting product was detectable by TLC.
The solvent was then evaporated under reduced pressure. The
crude product was purified by flash chromatography over silica
gel column yielding progressively 3,4-dihydropyrazino[1,2-a]-
indoles 2′ and/or pyrazino[1,2-a]indole 2 (for yields and times,
see Table 4).
TiCl4-Catalyzed Cyclizations. In a sealed tube, to a
solution of the appropriate indole 1 (0.3 mmol) in dry ammonia
in methanol (NH3/MeOH 2 M solution, 3 mL), was carefully
added TiCl4 (171 mg, 99 µL, 0.9 mmol) (caution!). The stirred
reaction mixture was warmed at 100 °C with a silicon oil bath
for 120-1020 min, or alternatively heated at 130 °C in a
multimode microwave oven for 43-313 min, until no more
starting product was detectable by TLC. The solvent was
evaporated under reduced pressure. The crude product was
purified by flash chromatography over silica gel column
1-Phenyl-3-[1-phenylmeth-(Z)-ylidene]-3,4-dihydropy-
razino[1,2-a]indole 2′l. Eluent for chromatography: PE/
EtOAc (99:1). Yellow orange solid. Mp: 65 °C. IR: ν ) 1613,
1
1527 cm-1. H NMR: δ ) 4.97 (s, 2H, CH2), 6.35 (s, 1H, dC-
H), 6.87 (s, 1H, C10-H arom), 7.16-7.44 (m, 6H, arom), 7.55
(m, 3H, arom), 7.69 (dd, 1H, arom 3J ) 8.1, 4J ) 0.7 Hz), 8.06
(m, 4H, arom) ppm. 13C NMR: δ ) 44.1, 106.6, 109.5, 121.0,
123.0, 124.8, 124.9, 127.6, 127.8, 128.1, 128.5, 128.7, 129.4,
130.6, 130.9, 136.5, 137.6, 138.0, 138.1, 157.2 ppm. ESI-MS
m/z: 335 [M+ + 1] (100). Anal. Calcd for C24H18N2 (334.41):
C, 86.20; H, 5.43; N, 8.38. Found: C, 86.28; H, 5.45; N, 8.35.
3-Benzyl-1-phenylpyrazino[1,2-a]indole 2l. Eluent for
chromatography: PE/EtOAc (99:1). Yellow orange solid. Mp:
1
145 °C. IR: ν ) 1638, 1530 cm-1. H NMR: δ ) 4.22 (s, 2H,
CH2), 6.83 (d, 1H, C10-H arom, 4J ) 0.8 Hz), 7.18 (m, 2H,
arom), 7.20-7.60 (m, 6H, arom), 7.65 (m, 1H, arom), 7.83 (m,
2H, arom), 7.92 (m, 4H, arom) ppm. (This compound was
obtained in a too low amount to perform 13C NMR and
elemental analysis.)
Acknowledgment. We are grateful to MIUR (Min-
istero dell’Istruzione, dell’ Universita` e della Ricerca)
for financial support.
Supporting Information Available: General experimen-
tal details, characterization data for compounds 1c-e,h-j,m-
o, 2a,c-f,h-k,m, and 2′c-e,h-j,m-o, computational meth-
ods, and details of NMR kinetic studies. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0502246
J. Org. Chem, Vol. 70, No. 10, 2005 4095