Tandem reactions are developed as efficient strategies in the
synthesis of complex organic molecules because they enable
multiple transformations via a cascade of reactions.6 Recently,
we reported a unique cascade reaction of pyrimidine-derived
aldehydes involving an iminium cyclization followed by a
Smiles rearrangement leading to pyrrolo[1,2-f]pteridines (Scheme
1).7 We envisioned that the pyridine analog 1 would react with
an amine to follow a similar path of tandem iminium cyclization
and Smiles rearrangement to yield novel pyrido[2,3-e]pyrrolo-
[1,2-a]pyrazines 3 as shown in Scheme 2. Herein, the details
of these studies are presented.
Synthesis of Pyrido[2,3-e]pyrrolo[1,2-a]pyrazine
Derivatives via Tandem Iminium Cyclization and
Smiles Rearrangement
Jinbao Xiang, Hongxiang Xie, Dongsheng Wen,
Qun Dang,* and Xu Bai*
The Center for Combinatorial Chemistry and Drug DiscoVery,
Jilin UniVersity, 75 Haiwai St., Changchun,
Jilin 130012, P. R. China
Aldehyde 1 was prepared as described in Scheme 3. Clau-
son-Kass reaction of 4 resulted in pyrrolopyridine8 5, which
reacted with ethyleneglycol under basic conditions to give 6.
Alcohol 6 was readily oxidized by Swern oxidation to give the
corresponding aldehyde 1 in good yield.
xbai@jlu.edu.cn; qdang@jlu.edu.cn
ReceiVed December 27, 2007
Initially, the reaction of pyridine aldehyde 1 with p-chloroa-
niline was investigated, and results are summarized in Table 1.
We first tested a TiCl4/CH3CN protocol employed in the
analogous pyrimidine system (entry 1, Table 1),7b but unfortu-
nately no desired pyrido[2,3-e]pyrrolo[1,2-a]pyrazine 3j was
obtained from the resulting complex mixture. Attempted
optimization of the reaction conditions by varying the amount
of TiCl4 did not result in any significant improvement (entries
2 and 3, Table 1). Changing the acid to TFA in CH2Cl2 led to
the desired product in 49% yield (entry 4, Table 1). The
reasonable yield of the desired product generated under the TFA
conditions indicated that further optimization by screening of
reaction conditions including the solvent, amount of catalyst,
and temperature might improve the yield. First, the solvents
(dioxane, toluene, ethanol, THF, and acetonitrile) were inves-
tigated using TFA as the catalyst (entries 5-9, Table 1). To
our delight, the desired product 3j was obtained in 76% yield
when acetonitrile was used (entry 9, Table 1). Second, the
amount of TFA was varied. When the above reaction was carried
out with 0.1 equiv of TFA at 8 °C, only iminium cyclization
intermediate 2j was produced (judging by LC-MS) after 4 h.
However, 48% of 2j and 7% of rearrangement product 3j (which
must have been generated from 2j during removal of the solvent
by a rotary evaporator) were isolated from the reaction mixture
(entry 10, Table 1). This result is consistent with the proposed
cascade reaction of iminium cyclization and Smiles rearrange-
ment similar to the one reported in the pyrimidine systems.7
Third, the reaction temperature was increased to refluxing
acetonitrile, which led to the desired 3j in 76% (entry 11, Table
1). Finally, aldehyde 1 was added dropwise to the solution of
p-chloroaniline and TFA in CH3CN to prevent potential side
reactions similar to the aldol condensation that occurred in the
pyrimidine systems under TFA conditions.7b Eventually, the
desired 3j was obtained in nearly quantitative yield under
The tandem iminium cyclization and Smiles rearrangement
of pyridinyloxyacetaldehyde 1 and a primary amine generated
a novel pyrido[2,3-e]pyrrolo[1,2-a]pyrazine scaffold. TFA
was discovered to be an efficient catalyst in the reactions
with aromatic amines, whereas TiCl4 was found to be
superior in the case of aliphatic amines. This methodology
proved to be efficient in the preparation of a library of
diversified pyrido[2,3-e]pyrrolo[1,2-a]pyrazine derivatives.
Novel fused heterocyclic systems are often considered
important scaffolds in medicinal chemistry.1 Heterocyclic
compounds possessing a pyrrolo[1,2-a]pyrazine moiety are of
biological interest. For example, pyrrolo[1,2-a]quinoxalinones
are reported to have oral antiallergic activity,2 and thieno[3,2-
e]pyrrolo[1,2-a]pyrazines3 and pyrido[2,3-e]pyrrolo[1,2-a]py-
razines4 have been shown to be selective 5-HT3 receptor
agonists. However, few synthetic methodologies to access
pyrido[2,3-e]pyrrolo[1,2-a]pyrazines are available.4,5
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10.1021/jo702754r CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/21/2008
J. Org. Chem. 2008, 73, 3281-3283
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