Microwave-promoted synthesis of N-heterocycles by tandem imination/ annulation of γ- and δ-ketoalkynes in the presence of ammonia

Article abstract of DOI:10.1002/ejoc.200900014

The synthesis of 3-substituted l-methylpyrrolo[l,2-a]pyrazines and 3-substituted isoquinolines was achieved by the intramolecular cyclisation of 2-acetyl-l-propargylpyrroles and 2-alkynylbenzaldehydes, respectively, in the presence of ammonia under microwave heating. The tandem imination/annulation of 2-alkynylbenzaldehydes was easily accomplished under standard conditions, while TiCl₄ was used to achieve pyrrolo[l,2-a]pyrazines. The reaction mechanism and the regioselectivity were discussed on the basis of theoretical calculations and spectroscopic data. Wiley-VCH Verlag GmbH & Co. KGaA.

Full text of DOI:10.1002/ejoc.200900014

FULL PAPER
DOI: 10.1002/ejoc.200900014
Microwave-Promoted Synthesis of N-Heterocycles by Tandem Imination/
Annulation of γ- and δ-Ketoalkynes in the Presence of Ammonia
Maria Alfonsi,[b] Monica Dell’Acqua,[a] Diego Facoetti,[a] Antonio Arcadi,[b]
Giorgio Abbiati,*[a] and Elisabetta Rossi[a]
Keywords: Alkynes / Heterocycles / Domino reactions / Microwaves / Titanium
The synthesis of 3-substituted 1-methylpyrrolo[1,2-a]pyraz-
ines and 3-substituted isoquinolines was achieved by the in-
tramolecular cyclisation of 2-acetyl-1-propargylpyrroles and
2-alkynylbenzaldehydes, respectively, in the presence of am-
monia under microwave heating. The tandem imination/an-
nulation of 2-alkynylbenzaldehydes was easily accomplished
under standard conditions, while TiCl4 was used to achieve
pyrrolo[1,2-a]pyrazines. The reaction mechanism and the re-
gioselectivity were discussed on the basis of theoretical cal-
culations and spectroscopic data.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
TiCl4 and microwave heating were able to improve both the
yield and selectivity in the reactions of these less reactive
substrates with a widespread reduction of reaction times.[8a]
The aim of the present work is to explore the suitability
of this approach for the construction of some other remark-
able heterocyclic targets. In particular, we focused our atten-
tion on the synthesis of simple pyrrolo[1,2-a]pyrazines and
isoquinolines starting from 2-acetyl-N-propargylpyrroles
and 2-alkynylbenzaldehydes, respectively. In the literature,
there are only a few papers dealing with the reactivity of N-
propargylpyrrole-2-carbaldehydes as building blocks for the
synthesis of simple and polycyclic pyrrolizine derivatives,[9]
whereas the reactivity of 2-acetyl-N-propargylpyrroles is
nearly unknown and has been only briefly investigated by
us in a recent paper regarding a domino approach to
1-substituted pyrrolizin-2-carbaldehydes.[10] On the other
hand, a lot of work is reported in the literature regarding
the synthetic application of 2-carbonyl-phenylacetylenes. In
particular, some valuable approaches to isoquinoline[11]
and dihydroisoquinoline[12] skeletons starting directly from
2-acyl-phenylacetylenes[11a–11f,12a–12i] or their imine deriva-
tives[11g–11q,12j–12o] have been reported.
Polycyclic compounds containing a pyrrolo[1,2-a]pyr-
azine moiety are biologically interesting molecules. For ex-
ample, some chiral 5,5a,6,7,8,9-hexahydro-9-methylpyr-
ido[3Ј,2Ј:4,5]pyrrolo[1,2-a]pyrazines showed a potent and
selective 5-HT2C receptor agonist activity.[13] Moreover,
pyrrolo[1,2-a]quinoxalinones displayed an anti-allergic ac-
tivity,[14] whereas thieno[3,2-e]pyrrolo[1,2-a]pyrazines[15]
and pyrido[2,3-e]pyrrolo[1,2-a]pyrazines[16] have been
shown to be selective 5-HT3 receptor agonists. Finally, a
few bispyrrolo[1,2-a]quinoxalines exhibited an interesting
antimalarial activity.[17] On the other hand, the isoquinoline
nucleus is the core of well-known alkaloids such as papaver-
Introduction
The development of new domino[1] approaches for the
synthesis of heterocyclic compounds is a research field in
continuous evolution.[2] When a new domino reaction also
matches with the atom economy[3] concept of Trost, the ad-
vantages of the discovered synthetic strategy are notable.
For many years, we have been interested in the develop-
ment of new domino synthetic strategies for the construc-
tion of nitrogen-containing heterocycles from alkynes.[4] In
particular, we focused our attention on the synthesis of ni-
trogen-containing rings by sequential addition-annulation
reactions of γ- or δ-ketoalkynes with ammonia. For exam-
ple, the 5-exo-dig cyclisation of 4-pentynones[5] gave poly-
substituted and fused pyrrole derivatives, whereas the pres-
ence of a γ-ketoalkyne moiety in an aromatic framework
is responsible for the 6-endo-dig cyclisation of 5-acetyl-4-
alkynylthiazoles[6] and 2-acyl-3-alkynylindoles[7] to pyr-
ido[3,4-c]thiazoles and pyrido[3,4-b]indoles, respectively.
More recently, we reported an in depth investigation on the
synthesis of the pyrazino[1,2-a]indole nucleus through the
sequential imination/annulation of 2-carbonyl-N-propar-
gylindoles in the presence of ammonia in methanol.[8] The
reaction worked well with N-propargylindole-2-carbal-
dehydes, but yields and selectivities were unsatisfactory
using 2-acetyl-N-propargylindoles.[8b] Moreover, the reac-
tion totally failed with 2-benzoyl-N-propargylindoles. These
drawbacks were overcome when we found that 3 equiv. of
[a] Istituto di Chimica Organica “Alessandro Marchesini”, Facoltà
di Farmacia, Università degli Studi di Milano,
Via G. Venezian, 21, 20133 Milano, Italia
E-mail: giorgio.abbiati@unimi.it
[b] Dipartimento di Chimica, Ingegneria Chimica e Materiali, Uni-
versità degli Studi dell’Aquila,
Via Vetoio, 67010 Coppito, L’Aquila, Italia
2852
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Tandem Imination/Annulation of γ- and δ-Ketoalkynes
ine and local anaesthetics such as quinisocaine, whereas sat- Table 2. Preparation of 2-alkynylbenzaldehydes 2a–k.
urated, functionalized and polycyclic derivatives are known
to show different important pharmacological properties.[18]
Results and Discussion
First, we prepared a reasonable library of starting com-
pounds. We prepared 2-acetyl-N-propargylpyrrole 1a ac-
cording to the previously reported procedure[10] and then
functionalized it on the terminal alkyne moiety by means
of a typical Sonogashira coupling with aryl and heteroaryl
halides to give 1b–g in very good yields (Table 1).
Table 1. Preparation of 2-acetyl-N-alkynylpyrroles 1b–g.
[a] Yields refer to pure isolated product. [b] Prepared by the reac-
tion of 2-ethynylbenzaldehyde (quantitatively obtained by treat-
ment of 2k with 2 equiv. of K2CO3 in MeOH at room temp.) with
4-iodoacetophenone under the standard Sonogashira conditions.
The reaction of 2-acetyl-N-propargylpyrrole (1a) gave
smoothly the 1,3-dimethylpyrrolo[1,2-a]pyrazine 3a as the
sole reaction product in 1.5 h in good yield (Table 3, Entry
1). Internal alkynes also gave preferentially the pyrrolo[1,2-
a]pyrazine isomers 3 in good yields (Table 3, Entries 2, 4,
6, 7 and 9), but the reactions were in general more sluggish.
For example, when pyrroles 1c and 1f were reacted under
[a] Method A: mole ratio 1a/Ar-X/K2CO3/Pd(PPh3)4/CuI
1:1.01:5:0.02:0.04, DMF (2 mL), 60 °C. Method B: mole ratio 1a/
Ar-X/TEA/PdCl2(PPh3)4/CuI 1:1.01:29:0.02:0.01, 60 °C. [b]
Yields refer to pure isolated product.
=
=
Through a similar approach, we synthesized 2-alkynyl- standard conditions for 1 h and 2 h, respectively, both iso-
benzaldehydes 2a–k in moderate to excellent yields starting meric products 3 and 3Ј were isolated beside a significant
from commercially available 2-bromobenzaldehyde and se- amount of starting material (Table 3, Entries 3 and 8),
lected terminal acetylenes (Table 2).
whereas the reactions were almost complete after 6 h
Our initial studies focused on the possibility of obtaining (Table 3, Entries 4 and 9). With respect to conventional
the pyrrolo[1,2-a]pyrazine nucleus starting from the N-alk- heating, however, microwave irradiation increased both the
ynylpyrroles 1a–g. Following the procedure previously op- yield and selectivity in a reduced reaction time (Table 3, En-
timised for the imination/annulation of 2-acetyl and 2-ben- tries 4 and 5). The approach tolerated well the presence of
zoyl N-alkynylindoles,[8a] we dissolved alkynylpyrroles 1a–g electron-withdrawing groups (EWGs, Table 3, Entries 4, 6
in 2  ammonia in methanol (20 equiv. of NH3) in a sealed and 7) and electron-donating groups (EDGs, Table 3, Entry
microwave test tube. Three equiv. of TiCl4 were slowly 9) on the phenyl substituent bonded to the propargyl moi-
added to the solution (caution!), and the reaction mixture ety. A pyrimidine substituent was also allowed, but after
was heated in a multi-mode microwave oven at 130 °C. The the standard reaction time, we recovered a considerable
reactions gave the corresponding pyrrolo[1,2-a]pyrazines 3, amount of dihydro isomer 3Јg and starting material 1g
in some cases beside the isomeric dihydropyrrolo[1,2-a]pyr- (Table 3, Entry 10).
azine 3Ј. The isomeric products 3 and 3Ј were easily sepa-
As already reported for the TiCl4-promoted synthesis of
rated by flash column chromatography. The results are sum- pyrazino indoles,[8a] a plausible reaction mechanism in-
marized in Table 3.
volves a Lewis-acid-catalyzed formation of the imine inter-
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Table 3. Imination/annulation of 2-acetyl-N-alkynylpyrroles 1a–g.
We then turned our attention to evaluating the reactivity
of 2-alkynylbenzaldehydes 2. The microwave-promoted im-
ination/annulation of 2a–k in the presence of ammonia pro-
ceeded in a regiospecific 6-endo-dig mode and allowed for
the synthesis of isoquinolines 4a–k in moderate to excellent
yields (Table 4). Four examples of the thermal annulation
of o-alkynylbenzaldehydes in the presence of ammonia were
reported eight years ago by Sakamoto et al.[11d] Neverthe-
less, our investigation represents a more comprehensive
study showing that microwave heating gives comparable or
better yields in reduced reaction times than does conven-
tional heating.
Table 4. Imination/annulation of 2-alkynylbenzaldehydes 2a–k.
[a] Not including an 11 min “ramp time” (ca. 10 °C/min). [b] Yields
refer to pure isolated product. [c] Conventional heating (silicon oil
bath).
mediate, which undergoes a stereoselective 6-exo-dig cycli-
sation on the triple bond activated by TiCl4 or by a catalyti-
cally active species generated in situ from TiCl4 and
ammonia.[19] The annulation step gives the 3,4-dihydro-
pyrrolo[1,2-a]pyrazines 3Ј, which can isomerise to the
thermodynamically more stable pyrrolo[1,2-a]pyrazines 3
(Scheme 1). In confirmation of this, we converted the dihy-
dro isomers 3Ј, in almost quantitative yields, to the corre-
sponding fully conjugated isomers 3 under basic conditions
by treatment with NaOMe/MeOH (10%) at reflux.[20]
(Scheme 1).
[a] Not including an 11 min “ramp time” (ca. 10 °C/min). [b] Yields
refer to pure isolated product. [c] Besides the main product, a com-
plex mixture of unidentified by-products was obtained. [d] TiCl4
(3 equiv.). [e] Conventional heating (silicone oil bath).
Scheme 1.
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Tandem Imination/Annulation of γ- and δ-Ketoalkynes
Aldehydes 2a–j reacted smoothly and quickly to give the zwitterionic intermediates 4x*, 4a*, 5x*, and 5a*. We per-
corresponding 3-substituted isoquinolines in modest to formed the minimisations at the DFT level using the
good yields (Table 4, Entries 1–13). The presence of EWGs B3LYP functional and the 6-31+G(p) basis set.[24] We per-
on the aryl moiety gave rise to low reaction yields (Table 4, formed calculations on isolated molecules in the gas phase
Entries 3–7), even after a prolonged reaction time under and confirmed the character of the minima by the absence
conventional heating conditions (Table 4, Entry 6). We note of imaginary frequencies. Selected ∆E among isolated and
that even TiCl4 did not improve the reaction yield of these hypothetical isomers and intermediates are reported in
less reactive substrates (Table 4, Entry 4). Also, the presence Table 5.
of the bulky methoxy group in the ortho position of the aryl
moiety gave unsatisfactory results (Table 4, Entry 8), even
after a prolonged reaction time at a lower temperature
Table 5. Selected ∆E [kcal/mol] among isolated and hypothetical
isomers and their intermediates.
(Table 4, Entry 9). On the other hand, the smaller methyl
group in the ortho position of the aryl moiety, as well as an
aliphatic chain directly bonded to alkyne were well-toler-
ated, yielding the corresponding isoquinolines in good
yields (Table 4, Entries 10–12). When the triple bond was
substituted with an acetal moiety the reaction gave the cor-
responding isoquinoline 4j in 50% yield (Table 4, Entry 13).
We easily converted the acetal moiety into the formyl group
by treatment with p-toluenesulfonic acid (p-TsA, 5 mol-%)
in water/acetone (1:1) at reflux giving rise to the intriguing
isoquinoline-3-carbaldehyde 4l in 98% yield. It is worth
noting that this approach represents a valuable alternative
to the synthesis of this useful derivative.[21] On the other
hand, starting from 2-[(trimethylsilyl)ethynyl]benzaldehyde
(2k), the simple desilylated isoquinoline 4k was easily ob-
tained in moderate yield (Table 4, Entry 14).
Entry
Compounds
∆E [kcal/mol]
1
2
3
4
5x–4x
5a–4a
5x*–4x*
5a*–4a*
20.64
16.82
13.12
8.21
As expected, both the isoquinolines 4x and 4a are ther-
According to the literature,[7,11d] the suggested mecha- modynamically favoured with respect to the corresponding
nism involves the intermediacy of an imine that undergoes isoindoles 5x and 5a (Table 5, Entries 1 and 2). Moreover,
a regioselective 6-endo cyclisation followed by a solvent- the calculation confirmed that this trend is also preserved
promoted proton shift (Scheme 2). We never isolated or de- for the zwitterionic intermediates; both zwitterionic iso-
tected in the reaction crude the product derived from a 5- quinoline intermediates 4x* and 4a* are favoured with
exo-dig cyclisation mode. The regiospecificity achieved[22] is respect to the corresponding isoindole zwitterionic inter-
probably due to the zwitterionic intermediate 4* and the mediates 5x* and 5a* (Table 5, Entries 3 and 4). These
resulting isoquinoline 4, arising from a 6-endo-dig mecha- theoretical results seem to confirm that, from a thermo-
nism, being more thermodynamically stable than the hypo- dynamic point of view, the stabilization of the α-anion by
thetical intermediate 5* and consequent isoindole 5, derived the aryl substituent in 5a* is less significant than the
from a 5-exo-dig cyclisation mode (Scheme 2). We never ob- aromatic stabilization effect of conjugated bicyclic rings in
served the formation of the 5-exo cyclisation product 5, 4a*.[23]
even when the alkyne was substituted with an aromatic ring
potentially able to stabilize the α-anion of the zwitterionic hindrance of the o-methoxy group on the reaction (Table 4,
intermediate 5*.[23] Entry 8).[11k] On the other hand, against an almost quanti-
The low yield observed for 2f is probably due to the steric
We confirmed these statements by theoretical calcula- tative conversion of starting materials 2c–e (Table 4, Entries
tions performed on the model compounds 3-methylisoquin- 3–7), the low yields of isoquinolines 4c–e could be ex-
oline (4x), 3-phenylisoquinoline (4a), 1-ethylideneisoindole plained by the nature of the groups bonded to Cβ and their
(5x), 1-benzylideneisoindole (5a) and the corresponding effect on the polarization of the triple bond;[25] a rough
Scheme 2.
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G. Abbiati et al.
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qualitative analysis shows that whereas an EDG is able to also upon the presence of more or less proximate aniso-
decrease the electron density around Cβ and “activate” it tropic groups,[27] and for this reason, we did not evaluate
towards a nucleophilic attack, an EWG can increase the the chemical shift of alkynyl-benzaldehydes bearing an o-
electron density around Cβ, disfavouring the annulation substituted aryl group on Cβ. Thus, taking into account
step and allowing undesired secondary reactions (Figure 1). that both the shielding cone of the triple bond and the sub-
stituent on Cα are the same for all substrates 2, the differ-
ences in Cα and Cβ chemical shifts for 2b, 2c, 2e and 2i are
only related to the nature of the substituent bonded to Cβ.
In accordance with our hypothesis, 13C NMR spectra
showed that EDGs caused a deshielding of Cβ [Figure 2,
(A) and (B)]; therefore, in 2i and 2b, Cβ is more prone to
nucleophilic attack. As a result, the imination/annulation
reaction of aldehydes 2i and 2b gave the corresponding iso-
quinolines 4i and 4b in very good yields (89% and 71%,
respectively). On the other hand, the presence of an EWG
[Figure 2, (C) and (D)] increased the electron density on Cβ
(as indicated by the chemical shift at lower frequencies), so
the cyclisation step for these compounds is more awkward,
and the yields of 4e and 4c are lower (25% and 28%,
respectively).
Figure 1. Qualitative estimation of the influence of the Cβ substitu-
ent on triple bond polarization.
To gain additional insight into this hypothesis, we ana-
lysed the chemical shifts of the sp-hybridised carbons[26] of
aldehydes 2b, 2c, 2e and 2i as examples of substrates charac-
terized by the presence of different EDGs and EWGs on
Cβ. To ensure consistent conditions, we performed all the
NMR experiments on the same 500 MHz NMR spectrome-
ter. We obtained the unambiguous assignment of sp-hybrid-
ised carbon chemical shifts by means of two-dimensional
HMBC and HSQC experiments. The results are depicted in
Figure 2.
Conclusions
In summary, we proved once again that the microwave-
promoted domino imination/annulation of alkynes bearing
a proximate carbonyl group in the presence of ammonia is
a useful tool for the synthesis of nitrogen heterocycles as
pyrrolo[1,2-a]pyrazines and isoquinolines. Current efforts
are now directed at improving the synthesis of isoquinolines
by transforming the domino approach into a valuable
multicomponent process starting from the simple building
blocks 2-bromobenzaldehyde, an alkyne and ammonia.
Experimental Section
General: All chemicals and solvents were 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 µm/60 Å was employed for
flash column chromatography. Melting points are uncorrected. In-
frared spectra were recorded with a 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 (δH
=
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 chloro-
form as the internal reference (δC = 77.3 ppm). The APT and
DEPT sequences were used to distinguish the methine and methyl
carbon signals from those due to methylene and quaternary car-
1
bons. Data for H NMR are reported as follows: s = singlet, d =
doublet, t = triplet, q = quartet, qt = quintuplet, m = multiplet
and br. = broad. Coupling constants (J) are reported in Hertz. All
13C NMR spectra were recorded with complete proton decoupling.
Two-dimensional NMR experiments (NOESY and HMBC) were
used, where appropriate, to aid in the assignment of signals in pro-
ton and carbon spectra. The ammonia in methanol (2 ) solution
was purchased from standard chemical suppliers. Microwave-as-
sisted reactions were performed in a MILESTONE microSYNT
Figure 2. Experimental 13C NMR spectra of 2b, 2c, 2e and 2i.
It is well-known that one of the most important param-
eters determining the NMR chemical shift is the shielding
effect determined by the electron density around the nu-
cleus of interest. Moreover, the chemical shift may depend multimode labstation, using 12 mL sealed glass vessels. The in-
2856 Eur. J. Org. Chem. 2009, 2852–2862
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Tandem Imination/Annulation of γ- and δ-Ketoalkynes
ternal temperature was detected with a fiber optic sensor. “EtOAc”
means ethyl acetate and “TEA” means triethylamine.
H, arom.), 7.24–7.39 (m, 5 H, arom.) ppm. 13C NMR (CDCl3,
50.3 MHz): δ = 27.4, 39.7, 84.7, 84.9, 108.8, 120.7, 121.1, 128.9,
129.4, 130.3, 133.3, 134.9, 188.8 ppm. ESI-MS: m/z (%) = 258 (100)
[M + 1]+, 216 (13). C15H12ClNO (257.71): calcd. C 69.91, H 4.69,
N 5.43; found C 69.76, H 4.64, N 5.46.
General Procedure for the Synthesis of 2-Acetyl-1-propargylpyrrole
(1a):[10] To a well-stirred solution of 2-acetylpyrrole (2.00 g,
18.3 mmol), propargyl bromide (2.83 g, 23.8 mmol, corresponding
to 3.54 g, 2.65 mL of an 80% w/w toluene solution) and tetrabu-
tylammonium bromide (0.29 g, 0.9 mmol) in toluene (20 mL),
aqueous sodium hydroxide (50% w/v, 3.11 mL) was slowly added
at room temperature. The reaction was vigorously stirred for 3 h
until no more starting product was detectable by TLC analysis.
After that, the reaction mixture was diluted with toluene (15 mL)
and washed with water (2ϫ30 mL). The organic layer was dried
with sodium sulfate, and the solvent was removed at reduced pres-
sure. The resulting crude material was purified by flash chromatog-
raphy over a silica gel column (hexane/EtOAc/TEA, 97:2:1) to af-
ford 2.2 g of the desired product 1a (82% yield). Yellow solid; m.p.
1-{1-[3-(3-Trifluoromethylphenyl)prop-2-ynyl]-1H-pyrrol-2-yl}-
ethanone (1d): Eluent for chromatography: hexane/EtOAc (95:5).
Method A: Yield 345 mg (87%). Yellow oil. IR (neat): ν = 1646,
˜
1
1529 cm–1. H NMR (CDCl3, 200 MHz): δ = 2.45 (s, 3 H, CH3),
5.44 (s, 2 H, CH2), 6.21 (dd, J = 4.0, 2.6 Hz, 1 H, arom.), 7.00 (dd,
J = 4.0, 1.8 Hz, 1 H, arom.), 7.21–7.23 (m, 1 H, arom.), 7.40–7.44
(m, 1 H, arom.), 7.53–7.60 (m, 2 H, arom.), 7.68 (s, 1 H, arom.)
ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 27.3, 39.6, 84.1, 85.6,
1
3
108.9, 120.7, 123.6, 123.9 (q, JC,F = 272.4 Hz), 125.3 (q, JC,F
=
3
3.8 Hz), 128.8 (q, JC,F = 3.8 Hz), 129.1, 129.5, 130.3, 131.1 (q,
2JC,F = 32.8 Hz), 135.1, 188.8 ppm. ESI-MS: m/z (%) = 292 (100)
[M + 1]+, 250 (7). C16H12F3NO (291.27): calcd. C 65.98, H 4.15,
111–114 °C. IR (KBr): ν = 3258, 2121, 1407, 1239, 1086, 747 cm–1.
˜
1H NMR (CDCl3, 200 MHz): δ = 2.43 (m, 4 H, CϵC-H and CH3), N 4.81; found C 65.87, H 4.11, N 4.84.
5.20 (d, J = 2.6 Hz, 2 H, CH2), 6.18 (dd, J = 4.0, 2.9 Hz, 1 H,
1-{1-[3-(4-Nitrophenyl)prop-2-ynyl]-1H-pyrrol-2-yl}ethanone (1e):
Eluent for chromatography: hexane/EtOAc (85:15). Method B:
arom.), 6.98 (dd, J = 4.0, 1.8 Hz, 1 H, arom.), 7.18 (dd, J = 2.9,
1.8 Hz, 1 H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 27.3,
39.0, 74.1, 78.5, 108.8, 120.8, 129.4, 130.2, 188.9 ppm. APCI(+)-
MS: m/z (%) = 148 (100) [M + 1]+.
Yield 323 mg (83%). Brown solid; m.p. 93–95 °C. IR (KBr): ν =
˜
1
1635, 1593, 1520 cm–1. H NMR (CDCl3, 200 MHz): δ = 2.46 (s,
3 H, CH3), 5.48 (s, 2 H, CH2), 6.23 (dd, J = 4.0, 2.6 Hz, 1 H,
arom.), 7.02 (dd, J = 4.0, 1.8 Hz, 1 H, arom.), 7.19 (dd, J = 2.6,
1.8 Hz, 1 H, arom.), 7.57 (d, J = 9.2 Hz, 2 H, arom.), 8.17 (d, J =
9.2 Hz, 2 H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 27.4,
39.6, 83.6, 89.4, 109.1, 120.8, 123.7, 129.5, 130.3, 132.8, 147.5,
188.9 ppm (one signal obscured). ESI-MS: m/z (%) = 269 (20) [M
+ 1]+, 227 (5). C15H12N2O3 (268.27): calcd. C 67.16, H 4.51, N
10.44; found C 66.97, H 4.49, N 10.45.
General Procedure for the Synthesis of 2-Acetyl-1-alkynylpyrroles
1b–g (Method A): Under a nitrogen atmosphere, to a solution of 1a
(200 mg, 1.36 mmol) in DMF (2 mL), the appropriate aryl halide
(1.37 mmol), potassium carbonate (940 mg, 6.80 mmol), CuI
(10.4 mg, 0.054 mmol) and tetrakis(triphenylphosphane)palla-
dium(0) (31.4 mg, 0.027 mmol) were added. The reaction was
stirred at 60 °C until no more starting product was detectable by
TLC analysis. The reaction mixture was then diluted with aq. HCl
(0.1 , 60 mL) and extracted twice with EtOAc (2ϫ50 mL). The
organic layer, dried with sodium sulfate, was evaporated to dryness,
and the crude material was purified by flash chromatography over
a silica gel column (for reaction times, see Table 1).
1-{1-[3-(4-Methoxyphenyl)prop-2-ynyl]-1H-pyrrol-2-yl}ethanone
(1f): Eluent for chromatography: hexane/EtOAc (95:5). Method A:
Yield 327 mg (95%). Light-brown solid; m.p. 59–61 °C. IR (KBr):
1
ν = 1640, 1606 cm–1. H NMR (CDCl , 200 MHz): δ = 2.44 (s, 3
˜
3
H, CH3), 3.78 (s, 3 H, OCH3), 5.41 (s, 2 H, CH2), 6.19 (dd, J =
4.0, 2.6 Hz, 1 H, arom.), 6.82 (d, J = 8.8 Hz, 2 H, arom.), 6.99 (dd,
J = 4.0, 1.8 Hz, 1 H, arom.), 7.31 (t, J = 2.0 Hz, 1 H, arom.), 7.38
(d, J = 8.8 Hz, 2 H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): δ
General Procedure for the Synthesis of 2-Acetyl-1-alkynylpyrroles
1b–g (Method B): Under a nitrogen atmosphere, to a solution of
1a (214 mg, 1.45 mmol) in TEA (5.8 mL, 4.5 mg, 42.1 mmol), the
appropriate aryl halide (1.47 mmol), CuI (2.76 mg, 0.014 mmol) = 27.4, 39.9, 55.5, 82.3, 86.0, 108.6, 114.2, 114.7, 120.7, 129.4,
and trans-dichlorobis(triphenylphosphane)palladium(II) (20.4 mg,
0.029 mmol) were added. The reaction was stirred at 60 °C until no
more starting product was detectable by TLC analysis. The reaction
mixture was then filtered under reduced pressure, and the crude
material was purified by flash chromatography over a silica gel col-
umn (for reaction times, see Table 1).
130.3, 133.5, 160.1, 188.8 ppm. ESI-MS: m/z (%) = 254 (100) [M
+ 1]+, 212 (8). C16H15NO2 (253.30): calcd. C 75.87, H 5.97, N 5.53;
found C 75.81, H 5.96, N 5.53.
1-[1-(3-Pyrimidin-5-ylprop-2-ynyl)-1H-pyrrol-2-yl]ethanone
(1g):
Eluent for chromatography: hexane/EtOAc (8:2). Method A: Yield
254 mg (83%). Brown solid; m.p. 97–99 °C. IR (KBr): ν = 1650,
˜
1-[1-(3-Phenylprop-2-ynyl)-1H-pyrrol-2-yl]ethanone (1b): Eluent for
chromatography: hexane/EtOAc (95:5). Method A: Yield 298 mg
1541, 1529 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 2.46 (s, 3 H,
CH3), 5.48 (s, 2 H, CH2), 6.23 (dd, J = 4.0, 2.6 Hz, 1 H, arom.),
7.01 (dd, J = 4.0, 1.8 Hz, 1 H, arom.), 7.15 (t, J = 2.6 Hz, 1 H,
arom.), 8.75 (s, 2 H, arom.), 9.12 (s, 1 H, arom.) ppm. 13C NMR
(CDCl3, 50.3 MHz): δ = 27.4, 39.6, 78.6, 91.4, 109.2, 119.3, 120.8,
(98%). Orange solid; m.p. 52–54 °C. IR (KBr): ν = 1643, 1572
˜
cm–1. 1H NMR (CDCl3, 200 MHz): δ = 2.46 (s, 3 H, CH3), 5.44
(s, 2 H, CH2), 6.21 (dd, J = 4.0, 2.6 Hz, 1 H, arom.), 7.01 (dd, J =
4.0, 1.8 Hz, 1 H, arom.), 7.30–7.34 (m, 4 H, arom.), 7.43–7.47 (m, 129.5, 130.3, 157.3, 159.2, 188.9 ppm. ESI-MS: m/z (%) = 226 (100)
2 H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 27.4, 39.9, [M + 1]+. C13H11N3O (225.25): calcd. C 69.32, H 4.92, N 18.66;
83.7, 86.0, 108.7, 120.7, 122.6, 128.5, 128.8, 129.4, 130.3, 132.0,
188.9 ppm. ESI-MS: m/z (%) = 224 (65) [M + 1]+, 182 (7).
C15H13NO (223.27): calcd. C 80.69, H 5.87, N 6.27; found C 80.78,
H 5.84, N 6.30.
found C 69.22, H 4.88, N 18.69.
General Procedure for the Synthesis of 2-Alkynylbenzaldehydes 2a–
j: Under a nitrogen atmosphere, to a solution of 2-bromobenzalde-
hyde (2.50 mmol) in TEA (10 mL), the appropriate alkyne
(2.05 mmol) and trans-dichlorobis(triphenylphosphane)palladi-
um(II) (0.05 mmol) were added. The reaction was stirred at room
temp. for 15 min, and then CuI (0.025 mmol) was added. The reac-
tion mixture was stirred at 50 °C (see Table 2) until no more start-
ing product was detectable by TLC analysis (hexane/EtOAc, 95:5).
1-{1-[3-(4-Chlorophenyl)prop-2-ynyl]-1H-pyrrol-2-yl}ethanone (1c):
Eluent for chromatography: hexane/EtOAc (95:5). Method A:
Yield 259 mg (74%). Method B: Yield 359 mg (96%). Orange solid;
m.p. 67–68 °C. IR (KBr): ν = 1645, 1571, 1523 cm–1. 1H NMR
˜
(CDCl3, 200 MHz): δ = 2.45 (s, 3 H, CH3), 5.43 (s, 2 H, CH2), 6.21
(dd, J = 4.0, 2.9 Hz, 1 H, arom.), 7.00 (dd, J = 4.2, 1.6 Hz, 1 The solvent was then evaporated under reduced pressure, and the
Eur. J. Org. Chem. 2009, 2852–2862
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2857

G. Abbiati et al.
FULL PAPER
crude material was purified by flash chromatography over a silica
gel column (for reaction times, see Table 2).
m.p. 77–80 °C. IR (KBr): ν = 2938, 2859, 2215, 1693, 1590, 1259
˜
1
cm–1. H NMR (CDCl3, 200 MHz): δ = 3.93 (s, 3 H, CH3), 6.91–
7.01 (m, 2 H, arom.), 7.25–7.68 (m, 5 H, arom.), 7.95 (d, J =
7.7 Hz, 1 H, arom.), 10.74 (s, 1 H, CHO) ppm. 13C NMR (CDCl3,
50.3 MHz): δ = 56.1, 89.3, 93.3, 110.9, 111.9, 120.8, 127.2, 127.6,
128.6, 130.8, 133.2, 133.5, 133.9, 136.1, 160.7, 192.8 ppm. ESI-MS:
m/z (%) = 237 (100) [M + 1]+. C16H12O2 (236.27): calcd. C 81.34,
H 5.12; found C 81.22, H 5.10.
2-(Phenylethynyl)benzaldehyde (2a): Eluent for chromatography:
hexane/EtOAc (99:1). Yield 469 mg (91%). Yellow oil. 1H NMR
(CDCl3, 200 MHz): δ = 7.36–7.67 (m, 8 H, arom.), 7.95 (dd, J =
7.3, 1.0 Hz, 1 H, arom.), 10.65 (s, 1 H, CHO) ppm. These data are
in good agreement with literature values.[11k,12j]
2-(p-Tolylethynyl)benzaldehyde (2b): Eluent for chromatography:
hexane/EtOAc (99:1). Yield 429 mg (78%). Yellow solid; m.p. 36–
2-[(4-Methoxy-2-methylphenyl)ethynyl]benzaldehyde (2g): Eluent
for chromatography: hexane/EtOAc (99:1). Yield 565 mg (90%).
1
38 °C (ref.[28] 38 °C). H NMR (CDCl3, 500 MHz): δ = 2.42 (s, 3
Yellow solid; m.p. 72–74 °C. IR (KBr): ν = 2742, 2839, 2202, 1697,
˜
H, CH3), 7.22 (d, J = 8.0 Hz, 2 H, arom.), 7.46 (t, J = 7.6 Hz, 1
H, arom.), 7.49 (d, J = 8.0 Hz, 2 H, arom.), 7.60 (td, J = 7.6,
1.2 Hz, 1 H, arom.), 7.66 (d, J = 7.3 Hz, 1 H, arom.), 7.97 (dd, J
= 7.7, 0.8 Hz, 1 H, arom.), 10.68 (s, 1 H, CHO) ppm. 13C NMR
(CDCl3, 125.75 MHz): δ = 20.8, 83.6, 96.0, 118.6, 126.5 (2 C),
127.7, 128.6, 130.9, 132.5, 133.1, 135.1, 138.7, 191.1 ppm. These
data are in good agreement with literature values.[11e]
1594, 1240 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 2.51 (s, 3 H,
CH3), 3.82 (s, 3 H, CH3), 6.71–6.80 (m, 2 H, arom.), 7.37–7.65 (m,
4 H, arom.), 7.94 (m, 1 H, arom.), 10.66 (s, 1 H, CHO) ppm. 13C
NMR (CDCl3, 50.3 MHz): δ = 21.4, 55.5, 87.8, 95.9, 111.7, 114.6,
115.7, 127.4, 127.8, 128.3, 133.3, 133.8, 133.9, 135.7, 142.5, 160.4,
191.9 ppm. ESI-MS: m/z (%) = 251 (100) [M + 1]+. C17H14O2
(250.29): calcd. C 81.58, H 5.64; found C 81.50, H 5.66.
2-{[3-(Trifluoromethyl)phenyl]ethynyl}benzaldehyde (2c): Eluent for
chromatography: hexane/EtOAc (99:1). Yield 505 mg (74%). Yel-
2-(Hept-1-ynyl)benzaldehyde (2h): Eluent for chromatography: hex-
ane/EtOAc (99:1). Yield 456 mg (91%). Yellow oil. 1H NMR
(CDCl3, 200 MHz): δ = 0.93 (t, J = 6.8 Hz, 3 H, CH3), 1.25–1.71
(m, 6 H, CH2), 2.47 (t, J = 6.9 Hz, 2 H, Csp-CH2), 7.33–7.67 (m,
3 H, arom.), 7.90 (m, 1 H, arom.), 10.54 (s, 1 H, CHO) ppm. These
data are in good agreement with literature values.[29]
low solid; m.p. 45–48 °C. IR (KBr): ν = 2845, 2754, 1696, 1592,
˜
1
1126 cm–1. H NMR (CDCl3, 500 MHz): δ = 7.53 (t, J = 7.6 Hz,
1 H, arom.), 7.62–7.71 (m, 3 H, arom.), 7.77 (d, J = 7.7 Hz, 1 H,
arom.), 7.86 (s, 1 H, arom.), 8.00 (dd, J = 7.8, 0.8 Hz, 1 H, arom.),
10.66 (s, 1 H, CHO) ppm. 13C NMR (CDCl3, 125.75 MHz): δ =
1
3
2-(Oct-1-ynyl)benzaldehyde (2i): Eluent for chromatography: hex-
ane/EtOAc (99:1). Yield 488 mg (91%). Yellow oil. 1H NMR
(CDCl3, 500 MHz): δ = 0.92 (t, J = 6.9 Hz, 3 H, CH3), 1.31–1.38
(m, 4 H, CH2), 1.45–1.51 (m, 2 H, CH2), 1.65 (qt, J = 7.2 Hz, 2
H, CH2), 2.49 (t, J = 7.2 Hz, 2 H, Csp-CH2), 7.38 (ddd, J = 8.0,
6.1, 2.7 Hz, 1 H, arom.), 7.50–7.54 (m, 2 H, arom.), 7.89 (d, J =
7.7 Hz, 1 H, arom.), 10.56 (s, 1 H, CHO) ppm. 13C NMR (CDCl3,
125.75 MHz): δ = 13.3, 18.9, 21.8, 27.8, 27.9, 30.6, 75.64, 97.5,
126.2, 127.1, 127.3, 132.6, 132.9, 135.3, 191.4 ppm. These data are
in good agreement with literature values.[30]
85.7, 93.7, 122.7, 122.9 (q, JC,F = 272.6 Hz), 124.9 (q, JC,F
=
3
3.8 Hz), 125.2, 126.9, 127.8 (q, JC,F = 3.8 Hz), 128.4, 128.5, 130.5
2
(q, JC,F = 32.7 Hz), 132.7, 133.1, 134.1, 135.3, 190.5 ppm. ESI-
MS: m/z (%) = 275 (100) [M + 1]+. C16H9F3O (274.24): calcd. C
70.07, H 3.31; found C 69.92, H 3.28.
2-[(3-Fluorophenyl)ethynyl]benzaldehyde (2d): Eluent for chromatog-
raphy: hexane/EtOAc (99.5:0.5). Yield 488 mg (87%). Deep-yellow
oil. IR (neat): ν = 2840, 1697, 1608, 1593, 1579, 1489, 1264, 1207,
˜
1191, 761 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 7.12 (m, 1 H,
arom.), 7.29 (m, 1 H, arom.), 7.38 (m, 2 H, arom.), 7.50 (t, J =
7.5 Hz, 1 H, arom.), 7.62 (td, J = 7.7, 1.2 Hz, 1 H, arom.), 7.68 (d,
J = 7.4 Hz, 1 H, arom.), 7.99 (d, J = 7.7 Hz, 1 H, arom.), 10.64 (s,
1 H, CHO) ppm. 13C NMR (CDCl3, 125.75 MHz): δ = 85.1, 94.1
2-(3,3-Diethoxyprop-1-ynyl)benzaldehyde (2j): Eluent for chromatog-
raphy: hexane/TEA (98:2). Yield 515 mg (89%). Yellow oil. 1H
NMR (CDCl3, 200 MHz): δ = 1.28 (t, J = 7.0 Hz, 6 H, CH3), 3.60–
3.90 (m, 4 H, CH2), 5.54 (s, 1 H, CH), 7.42–7.63 (m, 3 H, arom.),
7.92 (m, 1 H, arom.), 10.51 (s, 1 H, CHO) ppm. These data are in
good agreement with literature values.[31]
4
2
2
(d, JC,F = 3.3 Hz), 115.7 (d, JC,F = 21.1 Hz), 117.7 (d, JC,F
=
=
3
4
23.0 Hz), 123.5 (d, JC,F = 9.3 Hz), 125.5, 126.8, 126.9 (d, JC,F
3
2.8 Hz), 128.3, 129.5 (d, JC,F = 8.7 Hz), 132.6, 133.1, 135.3, 161.7
(d, 1JC,F = 247.2 Hz), 190.7 ppm. ESI-MS: m/z (%) = 225 (100) [M
+ 1]+. C15H9FO (224.23): calcd. C 80.35, H 4.05; found C 80.29,
H 4.03.
2-[(Trimethylsilyl)ethynyl]benzaldehyde (2k): Eluent for chromatog-
raphy: hexane/EtOAc (99:1). Yield 319 mg (63%). Pale-yellow so-
lid; m.p. 44–48 °C (ref.[32] 50–52 °C). 1H NMR (CDCl3, 200 MHz):
δ = 0.27 (s, 9 H, CH3), 7.39–7.59 (m, 3 H, arom.), 7.90 (m, 1 H,
arom.), 10.55 (s, 1 H, CHO) ppm. These data are in good agree-
ment with literature values.[32]
2-[(4-Acetylphenyl)ethynyl]benzaldehyde (2e): Obtained by reaction
of 2-ethynylbenzaldehyde (150 mg, 1.15 mmol) with 4-iodoaceto-
phenone (340 mg, 1.38 mmol) under the standard Sonogashira con-
ditions. Eluent for chromatography: hexane/EtOAc (95:5). Yield
General Procedure for the Microwave-Assisted, TiCl4-Catalyzed
Cyclisation of 2-Acetyl-1-alkynylpyrroles 1a–g: In a sealed micro-
wave test tube, to a solution of the appropriate pyrrole 1
(0.326 mmol) in dry ammonia in methanol (2 , 3.26 mL,
6.52 mmol), TiCl4 (0.185 g, 0.107 mL, 0.978 mmol) was carefully
added. The stirred reaction mixture was heated at 130 °C in a
multimode microwave oven until no more starting product was de-
tectable by TLC. The reaction mixture was diluted with saturated
aq. NaHCO3 (50 mL) and extracted with EtOAc (2ϫ50 mL). The
organic layer, dried with sodium sulfate, was evaporated to dryness,
and the crude material was purified by flash chromatography over
a silica gel column yielding progressively 3,4-dihydropyrazino(1,2-
a)pyrroles 3Ј and/or pyrazino[1,2-a]pyrroles 3 (for reaction times,
see Table 3).
240 mg (84%). Pale-yellow solid; m.p. 106–108 °C. IR (KBr): ν =
˜
1683, 1591, 1402, 1364, 1262, 961, 829, 759 cm–1. 1H NMR (C6D6,
500 MHz): δ = 2.16 (s, 3 H, CH3), 6.97 (t, J = 7.6 Hz, 1 H, arom.),
7.04 (td, J = 7.5, 1.4 Hz, 1 H, arom.), 7.41 (d, J = 8.4 Hz, 2 H,
arom.), 7.42 (t, J = 7.9 Hz, 1 H, arom.), 7.76 (d, J = 8.3 Hz, 2 H,
arom.), 7.97 (dd, J = 7.8, 1.2 Hz, 1 H, arom.), 10.78 (s, 1 H, CHO)
ppm. 13C NMR (C6D6, 125.75 MHz): δ = 25.2, 87.4, 94.7, 125.0,
126.0, 127.4, 127.6, 128.2, 131.0, 132.4, 132.5, 135.8, 136.4, 189.2,
194.7 ppm. 13C NMR (CDCl3, 125.75 MHz): δ = 25.9, 87.3, 94.5,
125.3, 126.4, 126.9, 127.7, 128.5, 131.1, 132.7, 133.1, 135.3, 136.1,
190.5, 196.4 ppm. ESI-MS: m/z (%) = 271 (61) [M + Na]+, 249
(100) [M + 1]+. C17H12O2 (248.28): calcd. C 82.24, H 4.87; found
C 82.29, H 4.88.
2-[(2-Methoxyphenyl)ethynyl]benzaldehyde (2f): Eluent for chrom-
1,3-Dimethylpyrrolo[1,2-a]pyrazine (3a): Eluent for chromatog-
atography: hexane/EtOAc (98:2). Yield 349 mg (59%). Yellow solid;
raphy: hexane/EtOAc (95:5). Yield 39 mg (81%). Brown wax. IR
2858
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2852–2862

Tandem Imination/Annulation of γ- and δ-Ketoalkynes
(neat): ν = 1722, 1650, 1527, 1407 cm–1. 1H NMR (CDCl3, solid; m.p. 122–124 °C. IR (KBr): ν = 1603, 1513 cm–1. H NMR
1
˜
˜
200 MHz): δ = 2.37 (s, 3 H, CH3), 2.64 (s, 3 H, CH3), 6.70 (d, J = (CDCl3, 200 MHz): δ = 2.64 (s, 3 H, CH3), 4.08 (s, 2 H, CH2),
4.4 Hz, 1 H, arom.), 6.76 (dd, J = 4.4, 2.5 Hz, 1 H, arom.), 7.28
6.73–6.81 (m, 2 H, arom.), 7.30–7.32 (m, 1 H, arom.), 7.44–7.48 (m,
(dd, J = 2.5, 1.2 Hz, 1 H, arom.), 7.53 (s, 1 H, arom) ppm. 13C
3 H, arom.), 8.14–8.19 (m, 2 H, arom.) ppm. 13C NMR (CDCl3,
NMR (CDCl3, 50.3 MHz): δ = 20.9, 21.7, 102.7, 113.6, 113.9, 50.3 MHz): δ = 21.8, 41.0, 103.2, 114.5, 114.9, 115.4, 123.9, 127.2,
114.7, 127.1, 134.8, 152.7 ppm. ESI-MS: m/z (%) = 147 (100) [M
+ 1]+. C9H10N2 (146.19): calcd. C 73.94, H 6.89, N 19.16; found C
73.82, H 6.85, N 19.19. These data are in good agreement with
literature values.[33]
130.1, 136.6, 146.9, 147.5, 153.5 ppm. ESI-MS: m/z (%) = 268 (100)
[M + 1]+, 222 (5). C15H13N3O2 (267.28): calcd. C 67.40, H 4.90, N
15.72; found C 67.28, H 4.86, N 15.78.
3-(4-Methoxybenzyl)-1-methylpyrrolo[1,2-a]pyrazine (3f): Eluent for
3-Benzyl-1-methylpyrrolo[1,2-a]pyrazine (3b): Eluent for chrom-
chromatography: hexane/EtOAc (95:5). Yield 59 mg (72%). Yellow
oil. IR (neat): ν = 1615, 1584, 1512 cm–1 1H NMR (CDCl3,
.
atography: hexane/EtOAc (95:5). Yield 48 mg (66%). Brown oil. IR
˜
(neat): ν = 1618, 1519 cm–1. 1H NMR (CDCl , 200 MHz): δ = 2.66
˜
3
200 MHz): δ = 2.65 (s, 3 H, CH3), 3.80 (s, 3 H, OCH3), 3.97 (s, 2
H, CH2), 6.68–6.76 (m, 2 H, arom.), 6.84–6.91 (m, 2 H, arom.),
7.21–7.26 (m, 3 H, arom.), 7.29 (s, 1 H, arom.) ppm. 13C NMR
(CDCl3, 50.3 MHz): δ = 21.9, 40.7, 55.7, 102.8, 114.2, 114.4, 114.7,
115.3, 127.4, 130.7, 131.5, 139.3, 153.0, 158.7 ppm. ESI-MS: m/z
(%) = 253 (100) [M + 1]+, 145 (15). C16H16N2O (252.31): calcd. C
76.16, H 6.39, N 11.10; found C 76.06, H 6.32, N 11.12.
(s, 3 H, CH3), 4.04 (s, 2 H, CH2), 6.69–6.77 (m, 2 H, arom.), 7.23–
7.36 (m, 7 H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 21.9,
41.6, 102.8, 114.2, 114.8, 115.3, 126.8, 127.4, 128.9, 129.7, 138.9,
139.5, 153.1 ppm. ESI-MS: m/z (%) = 223 (100) [M + 1]+, 145 (9).
C15H14N2 (222.28): calcd. C 81.05, H 6.35, N 12.60; found C 80.87,
H 6.28, N 12.64.
3-(4-Chlorobenzyl)-1-methylpyrrolo[1,2-a]pyrazine (3c): Eluent for
3-[1-(4-Methoxyphenyl)-(Z)-methylidene]-1-methyl-3,4-dihydropyr-
rolo[1,2-a]pyrazine (3Јf): Eluent for chromatography: hexane/EtOAc
chromatography: hexane/EtOAc (95:5). Yield 61 mg (73%). Brown
1
oil. IR (neat): ν = 1621, 1519 cm–1. H NMR (CDCl , 200 MHz):
˜
3
(95:5). Yield 22 mg (26%). Yellow oil. IR (neat): ν = 1601, 1558,
˜
δ = 2.64 (s, 3 H, CH3), 3.98 (s, 2 H, CH2), 6.69–7.20 (m, 2 H,
arom.), 7.21–7.35 (m, 6 H, arom.) ppm. 13C NMR (CDCl3,
50.3 MHz): δ = 21.8, 40.7, 102.9, 114.2, 114.6, 115.3, 127.2, 128.9,
130.8, 132.5, 137.9, 138.0, 153.2 ppm. ESI-MS: m/z (%) = 257 (100)
[M + 1]+, 145 (9). C15H13ClN2 (256.73): calcd. C 70.18, H 5.10, N
10.91; found C 70.00, H 5.03, N 10.94.
1
1531 cm–1. H NMR (CDCl3, 200 MHz): δ = 2.44 (s, 3 H, CH3),
3.82 (s, 3 H, OCH3), 4.70 (s, 2 H, CH2), 5.97 (s, 1 H, Csp2-H), 6.20–
6.23 (m, 1 H, arom.), 6.49–6.50 (m, 1 H, arom.), 6.78–6.80 (m, 1
H, arom.), 6.87 (d, J = 8.8 Hz, 2 H, arom.), 7.84 (d, J = 8.8 Hz, 2
H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 22.3, 29.9, 47.7,
55.5, 109.6, 110.4, 113.8, 121.6, 124.1, 126.0, 131.8, 136.6, 155.9,
158.8 ppm. ESI-MS: m/z (%) = 253 (100) [M + 1]+, 238 (5), 145
(5). C16H16N2O (252.31): calcd. C 76.16, H 6.39, N 11.10; found C
75.99, H 6.31, N 11.10.
3-[1-(4-Chlorophenyl)-(Z)-methylidene]-1-methyl-3,4-dihydropyrrolo-
[1,2-a]pyrazine (3Јc): Eluent for chromatography: hexane/EtOAc
(95:5). Yield 9 mg (10%). Brown oil. 1H NMR (CDCl3, 200 MHz):
δ = 2.45 (s, 3 H, CH3), 4.70 (s, 2 H, CH2), 5.96 (s, 1 H, Csp2-H),
6.22 (dd, J = 3.7, 2.6 Hz, 1 H, arom.), 6.53 (dd, J = 4.0, 1.5 Hz, 1
H, arom.), 6.80 (t, J = 1.5 Hz, 1 H, arom.), 7.32 (d, J = 8.2 Hz, 2
H, arom.), 7.82 (d, J = 8.2 Hz, 2 H, arom.) ppm. We did not obtain
a sufficient amount of 3Јc to perform IR, 13C NMR, MS, and
elemental analysis. Standing in a CDCl3 solution, 3Јc partially
isomerised into the more stable isomer 3c.
1-Methyl-3-pyrimidin-5-ylmethylpyrrolo[1,2-a]pyrazine (3g): Eluent
for chromatography: hexane/EtOAc (8:2). Yield 26 mg (35 %).
Orange solid; m.p. 87–89 °C. IR (KBr): ν = 1622, 1564, 1519 cm–1.
˜
1H NMR (CDCl3, 200 MHz): δ = 2.63 (s, 3 H, CH3), 3.96 (s, 2 H,
CH2), 6.72–6.81 (m, 2 H, arom.), 7.31–7.33 (m, 1 H, arom.), 7.54
(s, 1 H, arom.), 8.72 (s, 2 H, arom.), 9.10 (s, 1 H, arom.) ppm. 13C
NMR (CDCl3, 50.3 MHz): δ = 21.7, 35.9, 103.5, 114.6 (2 C), 115.6,
127.1, 133.1, 135.7, 153.7, 157.3, 157.5 ppm. ESI-MS: m/z (%) =
225 (100) [M + 1]+, 145 (8). C13H12N4 (224.26): calcd. C 69.62, H
5.39, N 24.98; found C 69.64, H 5.35, N 25.10.
1-Methyl-3-(3-trifluoromethylbenzyl)pyrrolo[1,2-a]pyrazine (3d):
Eluent for chromatography: hexane/EtOAc (93:7). Yield 62 mg
1
(65%). Brown oil. IR (neat): ν = 1622, 1597, 1521 cm–1. H NMR
˜
(CDCl3, 200 MHz): δ = 2.65 (s, 3 H, CH3), 4.06 (s, 2 H, CH2),
6.71–6.79 (m, 2 H, arom.), 7.29–7.30 (m, 1 H, arom.), 7.40–7.57
(m, 5 H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 21.7,
41.0, 103.1, 114.3, 114.7, 115.4, 123.5 (q, 3JC,F = 3.8 Hz), 124.4 (q,
1-Methyl-3-[1-pyrimidin-5-yl-(Z)-methylidene]-3,4-dihydropyrrolo-
[1,2-a]pyrazine (3Јg): Eluent for chromatography: hexane/EtOAc
(8:2). Yield 29 mg (40%). Brown solid; m.p. 100–102 °C. IR (KBr):
3
1JC,F = 272 Hz), 126.1 (q, JC,F = 3.8 Hz), 127.2, 129.1, 131.0 (q,
1
ν = 1622, 1572, 1560, 1547 cm–1. H NMR (CDCl , 200 MHz): δ
˜
3
2JC,F = 32 Hz), 132.8, 137.4, 140.4, 153.3 ppm. ESI-MS: m/z (%)
= 291 (100) [M + 1]+, 145 (5). C16H13F3N2 (290.28): calcd. C 66.20,
H 4.51, N 9.65; found C 66.10, H 4.47, N 9.69.
= 2.45 (s, 3 H, CH3), 4.79 (s, 2 H, CH2), 5.89 (s, 1 H, Csp2-H), 6.25
(dd, J = 3.7, 2.6 Hz, 1 H, arom.), 6.59 (dd, J = 3.7, 1.5 Hz, 1 H,
arom.), 6.85 (dd, J = 2.2, 1.5 Hz, 1 H, arom.), 9.01 (s, 1 H, arom.),
9.21 (s, 2 H, arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 22.3,
47.2, 110.3, 111.9, 114.3, 125.2, 125.5, 130.8, 142.9, 156.2, 157.4 (2
C), 158.4 ppm. ESI-MS: m/z (%) = 225 (100) [M + 1]+, 198 (8),
145 (8). C13H12N4 (224.26): calcd. C 69.62, H 5.39, N 24.98; found
calcd; found 69.58; H, 5.37; N, 24.96.
1-Methtyl-3-[1-(3-trifluoromethylphenyl)-(Z)-methylidene]-3,4-dihy-
dropyrrolo[1,2-a]pyrazine (3Јd): Eluent for chromatography: hexane/
EtOAc (93:7). Yield 16 mg (18%). Brown oil. IR (neat): ν = 1661,
˜
1564, 1558 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 2.45 (s, 3 H,
CH3), 4.74 (d, J = 1.5 Hz, 2 H, CH2), 6.03 (s, 1 H, Csp2-H), 6.24
(dd, J = 4.0, 2.6 Hz, 1 H, arom.), 6.56 (dd, J = 4.0, 1.5 Hz, 1 H,
arom.), 6.83 (dd, J = 2.6, 1.5 Hz, 1 H, arom.), 7.42–7.45 (m, 2 H,
arom.), 8.00–8.04 (m, 1 H, arom.), 8.23 (s, 1 H, arom.) ppm. ESI-
MS: m/z (%) = 291 (100) [M + 1]+. We did not obtain a sufficient
amount of 3Јd to perform 13C NMR and elemental analysis. Stand-
ing in a CDCl3 solution, 3Јd partially isomerised into the more
stable isomer 3d.
General Procedure for the Microwave-Assisted Cyclisation of o-Alk-
ynylbenzaldehydes 2a–k: A stirred solution of the appropriate o-
alkynylbenzaldehyde 2a–k (0.5 mmol) in dry ammonia in methanol
(2 , 5 mL) was heated at 130 °C in a sealed tube for 15–60 min in
a multimode microwave oven until no more starting product was
detectable by TLC. The solvent was removed under reduced pres-
sure. The crude product was purified by flash chromatography over
silica gel yielding the isoquinolines 4 (for temperatures, times and
yields, see Table 4).
3-(4-Nitrobenzyl)-1-methylpyrrolo[1,2-a]pyrazine (3e): Eluent for
chromatography: hexane/EtOAc (8:2). Yield 82 mg (84%). Brown
Eur. J. Org. Chem. 2009, 2852–2862
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2859

G. Abbiati et al.
FULL PAPER
3-Phenylisoquinoline (4a): Eluent for chromatography: hexane/
H, arom.), 7.86 (d, J = 8.2 Hz, 1 H, arom.), 7.93 (dd, J = 7.6,
EtOAc (95:5). Yield 60 mg (58%). Brown solid; m.p. 100–102 °C 1.8 Hz, 1 H, arom.), 7.98 (d, J = 8.0 Hz, 1 H), 8.21 (s, 1 H, arom.),
(ref.[11e] 101–101.5 °C). 1H NMR (CDCl3, 200 MHz): δ = 7.38–7.79 9.35 (s, 1 H, arom.) ppm. 13C NMR (C6D6, 50.3 MHz): δ = 55.1,
(m, 4 H, arom.), 7.70 (dt, J = 6.6, 1.5 Hz, 1 H, arom.), 7.88 (d, J
= 8.4 Hz, 1 H, arom.), 8.00 (d, J = 8.4 Hz, 1 H, arom.) 8.08 (s, 1
H, arom.), 8.13 (d, J = 7.1 Hz, 2 H, arom.), 9.35 (s, 1 H, arom.)
ppm. These data are in good agreement with literature values.[11e]
111.7, 121.2, 126.6, 127.1, 127.7, 128.2, 129.4, 129.7, 129.8, 132.3,
136.4, 149.7, 152.1, 157.7 ppm (one signal obscured). ESI-MS: m/z
(%) = 236 (100) [M + 1]+, 221 (19). C16H13NO (235.28): calcd. C
81.68, H 5.57, N 5.95; found C 81.74, H 5.58, N 5.95.
3-p-Tolylisoquinoline (4b): Eluent for chromatography: hexane/
EtOAc (95:5). Yield 78 mg (71%). Brown solid; m.p. 74–76 °C
3-(4-Methoxy-2-methylphenyl)isoquinoline
chromatography: hexane/EtOAc (95:5). Yield 95 mg (76%). Red
(4g):
Eluent
for
1
(ref.[11e] 74–75 °C). H NMR (CDCl3, 200 MHz): δ = 2.43 (s, 3 H,
oil. IR (neat): ν = 1625, 1607, 1580, 1504, 1451, 1295, 1275, 1241,
˜
CH3), 7.32 (d, J = 7.9 Hz, 2 H, arom.), 7.53 (t, J = 8.0 Hz, 1 H,
arom.), 7.68 (s, J = 8.0 Hz, 1 H, arom.), 7.86 (d, J = 8.1 Hz, 1 H,
arom.), 7.96 (d, J = 8.2 Hz, 1 H, arom.), 8.05 (m, 3 H, arom.), 9.33
(s, 1 H, arom.) ppm. These data are in good agreement with litera-
ture values.[11e]
1162, 1055, 752 cm–1. 1H NMR (C6D6, 200 MHz): δ = 2.48 (s, 3
H, CH3), 3.36 (s, 3 H, CH3), 6.78 (dd, J = 8.4, 2.5 Hz, 1 H, arom.),
6.86 (d, J = 2.5 Hz, 1 H, arom.), 7.10 (ddd, J = 8.0, 6.8, 1.3 Hz, 1
H, arom.), 7.21 (ddd, J = 8.2, 6.8, 1.3 Hz, 1 H, arom.), 7.36–7.55
(m, 4 H, arom.), 9.19 (s, 1 H, arom.) ppm. 13C NMR (C6D6,
50.3 MHz): δ = 21.2, 54.7, 111.5, 116.6, 119.7, 126.6, 126.7, 127.3,
127.5, 130.0, 131.9, 133.9, 136.5, 138.2, 151.8, 154.6, 159.9 ppm.
ESI-MS: m/z (%) = 250 (100) [M + 1]+. C17H15NO (249.31): calcd.
C 81.90, H 6.06, N 5.62; found C 81.79, H 6.00, N 5.68.
3-[3-(Trifluoromethyl)phenyl]isoquinoline
(4c):
Eluent
for
chromatography: hexane/EtOAc (95:5). Yield 38 mg (28%). Light-
brown solid; m.p. 64–67 °C. IR (KBr): ν = 1625, 1325, 1178, 1109,
˜
1068 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 7.58–7.77 (m, 4 H,
arom.), 7.90 (d, J = 8.2 Hz, 1 H, arom.), 8.01 (d, J = 8.2 Hz, 1 H, 3-Pentylisoquinoline (4h): Eluent for chromatography: hexane/
arom.), 8.11 (s, 1 H, arom.), 8.32 (d, J = 7.0 Hz, 1 H, arom.),
EtOAc (95:5). Yield 87 mg (87%). Yellow oil. IR (neat): ν = 2955,
˜
8.42 (s, 1 H, arom.), 9.35 (s, 1 H, arom.) ppm. 13C NMR (CDCl3,
2928, 2857, 1630, 1591, 1456, 748 cm–1. 1H NMR (CDCl3,
200 MHz): δ = 0.90 (t, J = 7.0 Hz, 3 H, CH3), 1.26–1.42 (m, 4 H,
CH2), 1.74–1.89 (m, 2 H, CH2), 2.92 (t, J = 7.3 Hz, 2 H, CH2),
7.45 (s, 1 H, arom.) 7.50 (ddd, J = 8.1, 7.0, 1.5 Hz, 1 H, arom.),
7.62 (ddd, J = 8.1, 6.6, 1.5 Hz, 1 H, arom.), 7.74 (d, J = 8.1 Hz, 1
H, arom.), 7.90 (d, J = 8.1 Hz, 1 H, arom.), 9.19 (s, 1 H, arom.)
ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 14.2, 22.8, 29.9, 31.9,
38.3, 118.2, 126.3, 126.4, 127.3, 127.7, 130.4, 136.8, 152.5, 156.1
ppm. ESI-MS: m/z (%) = 200 (100) [M + 1]+, 143 (10). C14H17N
(199.29): calcd. C 84.37, H 8.60, N 7.03; found C 84.19, H 8.53, N
7.09.
3
1
50.3 MHz): δ = 117.1, 124.0 (q, JC,F = 3.8 Hz), 124.5 (q, JC,F
=
3
272.0 Hz), 125.3 (q, JC,F = 3.8 Hz), 127.2, 127.8, 127.9, 128.3,
2
129.5, 130.3, 131.0, 131.4 (q, JC,F = 32.4 Hz), 136.7, 140.6, 149.8,
152.9 ppm. ESI-MS: m/z (%) = 274 (100) [M + 1]+. C16H10F3N
(273.25): calcd. C 70.33, H 3.69, N 5.13; found C 70.23, H 3.61, N
5.16.
3-(3-Fluorophenyl)isoquinoline (4d): Eluent for chromatography:
hexane/EtOAc (95:5). Yield 42 mg (38%). Brown solid; m.p. 105–
109 °C. IR (KBr): ν = 1624, 1573, 1494, 1452, 1158, 875, 792, 746,
˜
698 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 7.11 (tdd, J = 8.3, 2.5,
0.8 Hz, 1 H, arom.), 7.46 (td, J = 8.0, 6.0 Hz, 1 H, arom.), 7.56– 3-Hexylisoquinoline (4i): Eluent for chromatography: hexane/
7.75 (m, 2 H, arom.), 7.83–7.92 (m, 3 H, arom.), 8.00, (d, J = EtOAc (95:5). Yield 95 mg (89%). Yellow oil. 1H NMR (CDCl3,
8.0 Hz, 1 H, arom.), 8.05 (s, 1 H, arom.), 9.33 (s, 1 H, arom.) ppm.
200 MHz): δ = 0.89 (t, J = 7.0 Hz, 3 H, CH3), 1.23–1.46 (m, 6 H,
13C NMR (CDCl3, 50.3 MHz): δ = 114.1 (d, 2JC,F = 22.8 Hz), 115.5 CH2), 1.81 (m, 2 H, CH2), 2.93 (t, J = 7.3 Hz, 2 H, CH2), 7.46 (s,
2
4
(d, JC,F = 21.4 Hz), 117, 122.7 (d, JC,F = 2.8 Hz), 127.2, 127.6,
1 H, arom.) 7.51 (ddd, J = 8.1, 6.8, 1.4 Hz, 1 H, arom.), 7.63 (ddd,
J = 8.2, 6.8, 1.4 Hz, 1 H, arom.), 7.74 (d, J = 8.2 Hz, 1 H, arom.),
7.92 (d, J = 8.1 Hz, 1 H, arom.) 9.20 (s, 1 H, arom.) ppm. These
data are in good agreement with literature values.[11d]
127.8, 128.2, 130.4 (d, 3JC,F = 8.2 Hz), 130.9, 136.7, 142.2 (d, JC,F
= 7.7 Hz), 150.1 (d, JC,F = 2.7 Hz), 152.7, 163.6 (d, JC,F
3
4
1
=
245 Hz) ppm. ESI-MS: m/z (%) = 224 (100) [M + 1]+. C15H10FN
(223.25): calcd. C 80.70, H 4.51, N 6.27; found C 80.62, H 4.48, N
6.29.
3-(Diethoxymethyl)isoquinoline (4j):[34] Eluent for chromatography:
hexane/TEA (96:4). Yield 56 mg (50%). Red oil. IR (neat): ν =
˜
3-(4-Acethylphenyl)isoquinoline (4e): Eluent for chromatography:
hexane/EtOAc (85:15). Yield 31 mg (25%). Orange solid; m.p. 150–
2975, 2928, 2879, 1694, 1629, 1590, 1441, 1386, 1370, 1345, 1170,
1129, 1107, 1060, 750 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 1.24
152 °C. IR (KBr): ν = 2956, 2924, 2853, 1670, 1599, 1353, 1263, (t, J = 7.1 Hz, 6 H, CH3), 3.67 (dq, CH2, J = 9.5, 7.1 Hz, 2 H,
˜
855, 832, 760 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 2.67 (s, 3 H, ABX3 system), 3.74 (dq, CH2, J = 9.5, 7.1 Hz, 2 H, ABX3 system),
CH3), 7.63 (ddd, J = 8.1, 6.7, 1.2 Hz, 1 H, arom.), 7.73 (ddd, J =
8.4, 7.0, 1.5 Hz, 1 H, arom.), 7.90 (d, J = 8.1 Hz, 1 H, arom.), 8.02
(d, J = 8.4 Hz, 1 H, arom.), 8.09 (d, J = 8.6 Hz, 2 H, arom.), 8.15
(s, 1 H, arom.), 8.25 (d, J = 8.6 Hz, 2 H, arom.), 9.36 (s, 1 H,
arom.) ppm. 13C NMR (CDCl3, 50.3 MHz): δ = 26.9, 117.7, 127.2,
127.3, 127.8, 127.9, 128.3, 129.1, 131.0, 136.7, 137.0, 144.1, 150.1,
152.9, 198.1 ppm. ESI-MS: m/z (%) = 248 (100) [M + 1]+.
C17H13NO (247.29): calcd. C 82.57, H 5.30, N 5.66; found C 82.69,
H 5.29, N 5.69.
5.69 (s, 1 H, CH), 7.60 (ddd, J = 8.0, 6.9, 1.6 Hz, 1 H, arom.), 7.70
(ddd, J = 8.3, 6.9, 1.6 Hz, 1 H, arom.), 7.87 (dd, J = 8.0, 0.8 Hz,
1 H, arom.), 7.95–8.00 (m, 2 H, arom.), 9.26 (s, 1 H, arom.) ppm.
13C NMR (CDCl3, 50.3 MHz): δ = 15.5, 62.2, 102.6, 117.9, 127.3,
127.6, 127.7, 128.6, 130.7, 136.4, 151.7, 152.4 ppm. ESI-MS: m/z
(%) = 232 (64) [M + 1]+, 218 (52), 186 (100), 172 (18), 158 (33).
C14H17NO2 (231.29): calcd. C 72.70, H 7.41, N 6.06; found C
72.60, H 7.36, N 6.09.
Isoquinoline-3-carbaldehyde (4l):
A
mixture of 4j (46 mg,
3-(2-Methoxyphenyl)isoquinoline (4f): Eluent for chromatography:
0.20 mmol) and p-TosA (1.9 mg, 0.01 mmol) in H2O/acetone (1:1,
1.5 mL) was heated at reflux for 70 min. After the reaction had
cooled to room temp., saturated aq. NaHCO3 (5 mL) was added,
hexane/EtOAc (95:5). Yield 38 mg (32%). Red oil. IR (neat): ν =
˜
1626, 1599, 1573, 14932, 1466, 1439, 1278, 1235, 1022, 755, 754,
741 cm–1. 1H NMR (CDCl3, 200 MHz): δ = 3.91 (s, 3 H, CH3), and the solution was extracted with diethyl ether (4ϫ5 mL). The
7.05 (dd, J = 8.3, 0.9 Hz, 1 H, arom.), 7.13 (td, J = 7.5, 1.1 Hz, 1 organic layer was washed with brine (20 mL), dried (Na2SO4), and
H, arom.), 7.39 (ddd, J = 8.2, 7.4, 1.8 Hz, 1 H, arom.), 7.57 (ddd,
J = 8.6, 6.8, 1.4 Hz, 1 H, arom.) 7.68 (ddd, J = 8.2, 6.7, 1.4 Hz, 1
the solvent was evaporated at reduced pressure yielding pure 4k
(31 mg, 98%). Brown solid; m.p. 45–47 °C (ref.[21c] 49.6–50 °C). 1H
2860
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2852–2862

Tandem Imination/Annulation of γ- and δ-Ketoalkynes
[12]
Dihydroisoquinolines synthesis: a) K. Gao, J. Wu, J. Org.
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2007, 72, 4462–4468; l) R. Yanada, S. Obika, H. Kono, Y. Tak-
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Asao, S. S. Yuda, T. Nogami, Y. Yamamoto, Angew. Chem. Int.
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NMR (CDCl3, 200 MHz): δ = 7.81 (m, 2 H, arom.), 8.06 (m, 2 H,
arom.), 8.40 (s, 1 H, arom.), 9.38 (s, 1 H, arom.), 10.27 (s, 1 H,
CHO) ppm. These data are in good agreement with literature val-
ues.[21c]
Computational Methods: The structures of 4x, 4a, 5x and 5a and
intermediates 4x*, 4a*, 5x* and 5a* were optimised at the DFT
level (B3LYP/) with GAUSSIAN03® using the default options.[35]
The hybrid functional B3LYP was chosen, as it generally performs
well on organic molecules, and the split-valence 6-31+G(p) basis
set was employed as a good compromise between speed and accu-
racy.[24] The character of the optimised geometries was confirmed
by the absence of imaginary frequencies. All calculations were car-
ried out assuming isolated molecules in the gas phase.
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Received: January 8, 2009
Published Online: April 28, 2009
1
and the coupling constants of some H NMR chemical shifts
given by Larock et al. are incorrect.
2862
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