Domino approach for the synthesis of pyrrolo[1,2-α]pyrazine from vinyl azides

Article abstract of DOI:10.1021/ol101538x

A domino synthesis of pyrrolo[1,2-α]pyrazine from 1H-2-pyrrolecarbaldehyde and readily synthesized vinyl azides was developed. This reaction proceeded under relatively mild conditions in the presence of base. Additionally, a possible mechanism for the entire sequence is proposed.

Full text of DOI:10.1021/ol101538x

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3863-3865
Domino Approach for the Synthesis of
Pyrrolo[1,2-r]pyrazine from Vinyl Azides
Wenteng Chen, Miao Hu, Jianwei Wu, Hongbin Zou,* and Yongping Yu*
Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang UniVersity,
Hangzhou 310058, P. R. China
zouhb@zju.edu.cn; yyu@zju.edu.cn
Received July 5, 2010
ABSTRACT
A domino synthesis of pyrrolo[1,2-r]pyrazine from 1H-2-pyrrolecarbaldehyde and readily synthesized vinyl azides was developed. This reaction
proceeded under relatively mild conditions in the presence of base. Additionally, a possible mechanism for the entire sequence is proposed.
The pyrrolo[1,2-R]pyrazine is a privileged heterocyclic
scaffold. Some pyrrolo[1,2-R]pyrazine derivatives exhibit
neuroleptic and cardiovascular activity.1,2 The range of
physiological activities has led to an array of synthetic
procedures for the preparation of pyrrolo[1,2-R]pyrazine.
Over the past decades, some of the most common synthetic
methodologies reported in the literature include TiCl4-
stereoselective 6-exo-dig cyclization of 2-acetyl-N-propar-
gylpyrrole,3 POCl3-catalyzed condensation of pyrrolacetal,4
oxidation of the 3,4-dihydropyrrolo[1,2-a]pyrazine,5 and
direct derivation of the parent pyrazine.6 However, some of
the common synthetic approaches are limited by either their
low yields, harsh experimental conditions, or substrate
complexity. In light of this, a general and straightforward
methodology to rapidly prepare structurally diverse pyr-
rolo[1,2-R]pyrazine is still in demand.
Vinyl azide is a pivotal three-atom synthon for the
formation of nitrogen-containing heterocycles (azahetero-
cycles). In recent years, novel synthetic strategies exploiting
vinyl azide have emerged from the literature.7-9 Therefore,
in principle vinyl azides might serve as a source of three
atoms when 2-pyrrolecarbaldehyde is used as a nucleophilic
attacker7d to initiate a domino process for the generation of
molecular complexity.10 In this communication, we present
a general and simple nucleophilic domino reaction to provide
the pyrrolo[1,2-R]pyrazine from vinyl azids in the presence
of base.
The reaction of vinyl azide, derived from 4-bromobenz-
aldehyde, with 1H-2-pyrrolecarbaldehyde was selected as a
prototype reaction (Table 1). No reaction was observed
without any additive (Table 1, entry 1), but the transformation
occurred in the presence of a variety of bases at 25 °C to
form 3 as the major product (Table 1). Screening of bases
revealed Cs2CO3 as the most efficient base (Table 1, entries
3-7). Optimization of solvent showed that DMF (Table 1,
entry 2) was superior to other aprotic and protic solvents
(Table 1, entries 8-11). The reaction was also assessed at a
(1) (a) Rault, S.; Lancelot, J. C.; Prunier, H.; Robba, M.; Renard, P.;
Delagrange, P.; Pfeiffer, B.; Caignard, D. H.; Guardiola-Lemaitre, B.;
Hamon, M. J. Med. Chem. 1996, 39, 2068. (b) Campiani, G.; Morelli, E.;
Gemma, S.; Nacci, V.; Butini, S.; Hamon, M.; Novellino, E.; Greco, G.;
Cagnotto, A.; Goegan, M.; Cervo, L.; Valle, F. D.; Fracasso, C.; Caccia,
S.; Mennini, T. J. Med. Chem. 1999, 42, 4362
(2) Ohtani, M. WO 99/51605, 1999
.
(7) (a) Wang, Y.-F.; Toh, K. K.; Chiba, S.; Narasaka, K. Org. Lett. 2008,
10, 5019. (b) Chiba, S.; Wang, Y.-F.; Lapointe, G.; Narasaka, K. Org. Lett.
2008, 10, 313. (c) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131,
12570. (d) Subban, K.; Ekambaram, R.; Raghavachary, R. Tetrahedron Lett.
.
(3) Alfonsi, M.; Dell’Acqua, M.; Facoetti, D.; Arcadi, A.; Abbiati, G.;
Rossi, E. Eur. J. Org. Chem. 2009, 17, 2852.
(4) Herz, W.; Tocker, S. J. Am. Chem. Soc. 1955, 77, 6355.
(5) Mın´guez, J. M.; Castellote, M. I.; Vaquero, J. J.; Garcıa´- Navio,
J. L.; Alvarez-Builla, J.; Castano, O.; Andres´, J. L. J. Org. Chem. 1996,
61, 4655.
2009, 50, 2389
(8) Yang, Y. Y.; Shou, W. G.; Chen, Z. B.; Wang, Y. G. J. Org. Chem.
2008, 73, 3928–3930
(9) Chen, Z.-B.; Hong, D.; Wang, Y.-G. J. Org. Chem. 2009, 74, 903
.
.
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(6) Terenin, V. I.; Kabanova, E. V.; Feoktistova, E. S. Khim. Geterotsikli-
cheskikh Soedin. 1991, 10, 1299.
(10) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134.
10.1021/ol101538x  2010 American Chemical Society
Published on Web 08/02/2010

Table 1. Optimization of Reaction Conditionsa
Table 2. Cyclization of 1H-Pyrrole-2-carbaldehyde with Various
Vinyl Azidesa
product yield
t
conversionb
(%)
entry
R1
R2
3
(%)b
entry
base
solvent
(°C)
1
2
3
4
5
6
7
8
Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
62
61
72
68
77
74
59
61
66
72
69
71
58
60
57
92
51
n.r.
1
2
3
4
5
6
7
8
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCM
EtOH
dioxane
CH3CN
DMF
25
25
25
25
25
25
25
25
25
25
25
40
n.r.
88
31
80
63
51
28
n.r.
n.r.
n.r.
47
4-MeOC6H4
4-BrC6H4
2-BrC6H4
4-FC6H4
3-NO2C6H4
furyl
4-PhCH2OC6H4
4-MsC6H4
3,4-di-ClC6H3
3,4-(OCH2O)C6H3 CO2Et
2,3,4-tri-FC6H2
Cs2CO3
K2CO3
NaH
t-BuOK
CH3ONa
DBU
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
9
10
11
12
13c
14c
15d
16
17
18e
10
11
12
CO2Et
COPh
80
4-BrC6H4
4-BrC6H4
a Reaction conditions: vinyl azide (0.2 mmol, 1.0 equiv), 1H-pyrrole-
2-carbaldehyde (0.22 mmol, 1.1 equiv), base (0.22 mmol, 1.1 equiv), 2
mL of solvent, 24 h, rt. b Determined by high-performance liquid chroma-
tography, based on the disappearance of the starting vinyl azide. The most
successful entry is highlighted in bold.
4-Cl-PhCO
H
H
Ph
Ph
Ph
1-(morpholinyl)-CO
CHO
H
a Reactions were performed in anhydrous DMF at rt with 1.1 equiv of
1H-pyrrole-2-carbaldyhyde 2 under N2 atomsphere. b Isolated yield. c The
reaction was performed at -30 °C for 5 h. d The reaction was performed
at 50 °C for 24 h. e E:Z ) 1:1.
higher temperature (Table 1, entry 12) but with a slight
decrease in the yield. On the basis of this initial study, the
optimal reactivity was obtained in DMF at 25 °C when
Cs2CO3 was employed (88%, Table 1, entry 2).
With the optimized reaction conditions in hand, the scope
of the reaction was studied using a set of vinyl aizdes 1 and
1H-2-pyrrolecarbaldehyde 2. The vinyl azides (entries 1-12)
were readily prepared from the corresponding benzaldehydes
with ethyl 2-azidoacetate via Knoevenagel condensation,7
and other vinyl azides (entries 13-18) were prepared from
the corresponding olefins by successive reaction with bro-
mine then with sodium azide,11 respectively.
Whereas treatment of vinyl azide (Table 2, entry 17), with
a strong electron-withdrawing group, gave the product in
lower yield (51%, Table 2, entry 17), R-N-morpholinylcar-
bonyl-substituted vinyl azide greatly accelerated this process,
providing the corresponding product in higher yield (92%,
Table 2, entry 16). The problem was considered to be the
instability of the vinyl azides in the reaction conditions.
As presented in Table 2, various substituted vinyl azides
with 1H-2-pyrrolecarbaldehyde worked well to provide the
corresponding pyrrolo[1,2-a]pyrazine in moderate to good
isolated yields. The reaction could tolerate aromatic substi-
tuted vinyl azides with various steric and electronic properties
(Table 2, entries 1-11).
Scheme 1. Proposed Mechanism for the Synthesis of
Pyrrolo[1,2-R]pyrazine
Notably, vinyl azides bearing an electron-withdrawing
group at the aryl ring gave the desired products with good
efficiency (>70%) after only 8 h at 25 °C. The retarding effect
of sterics on the reaction is illustrated in entry 4 where ortho
substituents on the aryl ring gave slightly reduced yield
(68%), compared to entry 3 (72%).
Instead of R-ethoxycarbonyl-substituted vinyl azides, the
reaction of vinyl azide (Table 2, entries 13 and 14) bearing
an arylcarbonyl group at the R-position gave the desired
products with lower yields (<60%), and the reaction of
R-azidostyrene (Table 2, entry 15) was sluggish, requiring
higher temperature and longer reaction time.
(11) Gilchrist, T. L.; Mendonca, R. ARKIVOC 2000, 769.
3864
Org. Lett., Vol. 12, No. 17, 2010

ꢀ-Azidostyrene (Table 2, entry 18), however, was detrimental
to the desired transformation. Therefore, this new reaction
constitutes an efficient and simple way to carry out the
formation of pyrrolo[1,2-a]pyrazine. This synthetic trans-
formation is nontrivial and requires several steps in other
methodologies.
was realized through a novel domino process from readily
available vinyl azides and 1H-2-pyrrolecarbaldehyde. Such
a domino process includes a Michael addition and subsequent
intramolecular condensation at room temperature and more-
over it is economical in atom count as only a molecule of
nitrogen and water is lost in the entire process.
On the basis of the results presented above, we proposed
the following possible mechanism for this reaction, as shown
in Scheme 1. First, it is expected to involve Michael
addition-elimination of the pyrrole 2 to the vinyl azides 1
affording an active intermediate I, driven by the excellent
leaving-group ability of nitrogen. Subsequently, the reaction
undergoes an intramolecular condensation to give the desired
product 3.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 30772652 and No. 90813026) and
National key Tech project for Major Creation of New Drugs
(No. 2009ZX09501-010).
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of 1H and 13C NMR
spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed a new, mild strategy to
prepare functionalized pyrrolo[1,2-a]pyrazine. This reaction
OL101538X
Org. Lett., Vol. 12, No. 17, 2010
3865