Copper-catalyzed annulation of 2-formylazoles with o-aminoiodoarenes

Article abstract of DOI:10.1021/jo9025644

(Chemical Equation Presented) In the presence of catalytic CuI and sparteine, 2-formylpyrroles can be annulated with o-aminoiodoarenes to give substituted pyrrolo[1,2-a]quinoxalines and related heterocycles. The reaction also works for annulation of 2-formylindoles, 2-formylimidazole, 2-formylbenzimidazole, and a 3-formylpyrazole.

Full text of DOI:10.1021/jo9025644

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SCHEME 1. Cheeseman’s Pyrrolo[1,2-a]quinoxaline Synthesis
and Our Cu-Catalyzed Approach
Copper-Catalyzed Annulation of 2-Formylazoles with
o-Aminoiodoarenes
Jonathan T. Reeves,* Daniel R. Fandrick, Zhulin Tan,
Jinhua J. Song, Heewon Lee, Nathan K. Yee, and
Chris H. Senanayake
Department of Chemical Development, Boehringer Ingelheim
Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box
368, Ridgefield, Connecticut 06877-0368
jonathan.reeves@boehringer-ingelheim.com
Received December 3, 2009
group.3 Kobayashi and co-workers have described the Lewis
acid catalyzed cyclization of 1-(2-isocyanophenyl)pyrroles to
give pyrrolo[1,2-a]quinoxalines in good yields, though the
isocyanide substrates require a multistep synthesis.4 Ma and
Yuan have recently described the synthesis of a structurally
related ring system, pyrrolo[1,2-a]quinoxalin-4(5H)-ones, by
CuI/L-proline catalyzed coupling of N-trifluoroacetyl-2-haloa-
nilines with methyl pyrrole-2-carboxylates, followed by in situ
hydrolysis of the N-trifluoroacetyl group and intramolecular
amide formation.5 Given the ready availability of substituted
2-formylpyrroles and 2-iodoanilines, a direct annulation pro-
cess by copper-catalyzed pyrrole N-arylation and imine for-
mation appeared to be an attractive one-step route to
pyrrolo[1,2-a]quinoxalines (Scheme 1).6 This method would
allow for the regioselective incorporation of diverse substitu-
tion on the heterocyclic core. Herein we describe our results on
the development of this methodology.
Initial screening experiments employed 2-iodoaniline 5
and 2-formylpyrrole 6. Several ligands, bases, and solvents
were examined. The use of NMP as solvent was preferred
because of its high boiling point, although DMF and DMAC
were also effective. A screen of bases (Na2CO3, K2CO3,
Cs2CO3, and K3PO4) showed K3PO4 to be most effective.
Various ligands promoted the cyclization, including trans-
1,2-(methylamino)cyclohexane, trans-1,2-diaminocyclohex-
ane, and N,N0-dimethylethylenediamine. These ligands were
competitively N-arylated, however, and thus a larger excess
of ligand and iodide proved necessary to reach full conver-
sion of 2-formylpyrrole.7 Sparteine was found to be an
In the presence of catalytic CuI and sparteine, 2-formyl-
pyrroles can be annulated with o-aminoiodoarenes to give
substituted pyrrolo[1,2-a]quinoxalines and related het-
erocycles. The reaction also works for annulation of 2-
formylindoles, 2-formylimidazole, 2-formylbenzimida-
zole, and a 3-formylpyrazole.
The pyrrolo[1,2-a]quinoxaline ring system is present in a
small but rapidly growing number of biologically active
molecules.1 The available methods for synthesis of this hetero-
cycle, however, are few. Cheeseman and Tuck reported the
first synthesis of the parent unsubstituted pyrrolo[1,2-
a]quinoxaline 4 in 1965 (Scheme 1).2 This two-step procedure
has limitations in the potential substitution patterns on the
pyrrole nucleus. Variations of this procedure have been de-
scribed in which compounds of structure type 3 are accessed by
alternative chemistry, typically SNAr of 2-fluoronitroarenes
with N-metalated pyrroles, followed by reduction of the nitro
(1) (a) Guillon, J.; Dumoulin, H.; Dallemagne, P.; Reynolds, R.; Rault, S.
Pharm. Pharmacol. Commun. 1998, 4, 33–38. (b) Guillon, J.; Dallemagne, P.;
Pfeiffer, B.; Renard, P.; Manechez, D.; Kervran, A.; Rault, S. Eur. J. Med.
Chem. 1998, 33, 293–308. (c) Guillon, J.; Boullouard, M.; Lisowski, V.;
Stiebing, S.; Lelong, V.; Dallemagne, P.; Rault, S. J. Pharm. Pharmacol.
2000, 52, 1369–1375. (d) Prunier, H.; Rault, S.; Lancelot, J. C.; Robba, M.;
Renard, P.; Delagrange, P.; Pfeiffer, B.; Caignard, D. H.; Misslin, R.;
Guardiola-Lemaitre, B.; Hamon, M. J. Med. Chem. 1997, 40, 1808–1819.
(e) Guillon, J.; Reynolds, R. C.; Leger, J.-M.; Guie, M.-A.; Massip, S.;
Dallemagne, P.; Jarry, C. J. Enzyme Inhib. Med. Chem. 2004, 19, 489–495.
(f) Guillon, J.; Forfar, I.; Mamani-Matsuda, M.; Desplat, V.; Saliege, M.;
Thiolat, D.; Massip, S.; Tabourier, A.; Leger, J.-M.; Dufaure, B.; Haumont,
G.; Jarry, C.; Mossalayi, D. Bioorg. Med. Chem. 2007, 15, 194–210.
(2) Cheeseman, G. W. H.; Tuck, B. Chem. Ind. 1965, 1382.
(4) (a) Kobayashi, K.; Matoba, T.; Irisawa, S.; Matsumoto, T.; Morikawa,
O.; Konishi, H. Chem. Lett. 1998, 551–552. (b) Kobayashi, K.; Irisawa, S.;
Matoba, T.; Matsumoto, T.; Yoneda, K.; Morikawa, O.; Konishi, H. Bull.
Chem. Soc. Jpn. 2001, 74, 1109–1114.
(5) Yuan, Q.; Ma, D. J. Org. Chem. 2008, 73, 5159–5162.
(6) For an approach to substituted 2-formylpyrroles, see: Reeves, J. T.;
Song, J. J.; Tan, Z.; Lee, H.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2007, 9,
1875–1878.
(3) Harrak, Y.; Weber, S.; Gomez, A. B.; Rosell, G. Arkivoc 2007, 4, 251–
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Chem. 2004, 69, 5578–5587.
992 J. Org. Chem. 2010, 75, 992–994
Published on Web 01/04/2010
DOI: 10.1021/jo9025644
r
2010 American Chemical Society

Reeves et al.
JOCNote
TABLE 1. Annulation of 2-Formylpyrrole with Substituted Aminoio-
doarenesa
TABLE 2. Annulation of Substituted 2-Formylpyrroles and 2-Formy-
lindoles with 2-Iodoanilinea
aReaction conditions: 10 mol % CuI, 20 mol % sparteine, 2 equiv of
K3PO4, 1.5 equiv of aminoiodoarene, 1.0 equiv of 6, 130 °C, 24 h.
bIsolated yields after chromatography on SiO2.
effective ligand for the reaction that avoided this undesired
side reaction due to the tertiary nature of both amino groups.8
Optimal reaction conditions were identified as 1 equiv of
2-formylpyrrole, 1.5 equiv of 2-iodoaniline, 2 equiv of K3PO4,
10 mol % CuI, 20 mol % sparteine, and NMP as solvent
(2 M in formylpyrrole) at 130 °C for 24 h. Using these
conditions, the parent pyrrolo[1,2-a]quinoxaline 4 was ob-
tained in 83% isolated yield after purification by column
chromatography on SiO2 (entry 1, Table 1). Notably, the
reaction proceeded in the absence of ligand, though in this
case complete conversion was not observed. In the absence of
CuI, no product was detected by HPLC analysis. The use of
2-bromoaniline resulted in a much slower reaction, as after
48 h at 130 °C only ∼70% conversion of 2-formylpyrrole was
achieved.
The scope of the reaction was first explored with respect
to structural variation of the aminoiodoarene (Table 1).
Trifluoromethyl, cyano, and fluoro groups were tolerated
(entries 2, 3, and 5). The methyl ester group of 11 was
converted to a carboxylic acid under the reaction conditions
(entry 4). This could be due to hydrolysis by the water
produced from imine formation or alternatively by an
iodide-mediated SN2-type demethylation.9
aReaction conditions: 10 mol % CuI, 20 mol % sparteine, 2 equiv of
K3PO4, 1.5 equiv of 5, 1.0 equiv of 2-formylazole, 130 °C, 24 h. bIsolated
yields after chromatography on SiO2. cReaction time of 36 h. dReaction
time of 48 h.
Aminoiodopyridine 15 and aminoiodopyrimidine 1710
worked well in the annulation and provided convenient
access to the unusual pyrido[2,3-e]pyrrolo[1,2-a]pyrazine
(16) and pyrrolo[2,1-h]pteridine (18) ring systems.
The reaction was next explored with respect to substitution
of the formylpyrrole component (Table 2). Substitution at
positions 3-5 of the pyrrole ring was well tolerated (entries
1-4) and allowed access to unique pyrrolo[1,2-a]quinoxalines.
In addition, the methodology could be extended to 2-formy-
lindoles to provide indolo[1,2-a]quinoxalines in good yields
(entries 5-7).11
(8) Mao, J.; Hua, Q.; Guo, J.; Shi, D. Catal. Commun. 2008, 10, 341–346.
(9) (a) Fisher, J. W.; Trinkle, K. L. Tetrahedron Lett. 1994, 35, 2505–2508.
(b) Magnus, P.; Gallagher, T. J. Chem. Soc., Chem. Commun. 1984, 389–390.
(10) Latli, B.; Jones, P.-J.; Krishnamurthy, D.; Senanayake, C. H.
J. Label. Compd. Radiopharm. 2008, 51, 54–58.
(11) Joseph, M. S.; Basanagoudar, L. D. Synth. Commun. 2003, 33, 851–
862.
J. Org. Chem. Vol. 75, No. 3, 2010 993

Reeves et al.
JOCNote
TABLE 3. Annulation of Formyldiazoles with 2-Iodoanilinea
amenable to structural variation of both reaction partners
and consequently serves as a useful alternative to existing
routes to pyrrolo[1,2-a]quinoxalines. Indolo[1,2-a]quinoxa-
lines can be prepared under the same reaction conditions by
starting with 2-formylindoles. In addition, the reaction can
be extended to 2-formylimidazole, 2-formylbenzimidazole,
and a 3-formylpyrazole to generate a range of unique
tricyclic heterocycles.
Experimental Section
General Procedure. Pyrrolo[1,2-a]quinoxaline (4). A flask
equipped with a magnetic stir bar and reflux condensor was
charged with 2-formylpyrrole (951 mg, 10.0 mmol, 1.0 equiv),
2-iodoaniline (3.29 g, 15.0 mmol, 1.5 equiv), K3PO4 (4.25 g, 20.0
mmol, 2.0 equiv), and CuI (190 mg, 1.00 mmol, 0.10 equiv). The
flask was evacuated and filled with nitrogen, and then NMP
(5.0 mL) was charged via syringe followed by sparteine
(0.46 mL, 2.00 mmol, 0.20 equiv). The flask was heated in a
130 °C oil bath for 24 h, at which time HPLC analysis indicated
complete consumption of 2-formylpyrrole. The reaction mix-
ture was cooled to room temperature, diluted with EtOAc, and
filtered through a pad of Celite, using EtOAc to rinse the flask
and Celite pad. The filtrate was concentrated, and the residue
was purified by column chromatography on SiO2 (hexanes/
EtOAc, 70:30 to 50:50) to give 4 (1.40 g, 83% yield) as a tan
solid: mp 131-133 °C; 1H NMR (500 MHz, CDCl3) δ 8.79
(s, 1 H), 7.94 (d, J = 7.95 Hz, 1 H), 7.89 (s, 1 H), 7.82 (d, J = 8.15
Hz, 1 H), 7.51-7.48 (m, 1 H), 7.44-7.41 (m, 1 H), 6.88-6.86
(m, 2 H); 13C NMR (100 MHz, CDCl3) δ 145.8, 135.8, 130.1,
128.0, 127.8, 126.5, 125.1, 114.2, 114.0, 113.8, 107.3; HRMS
calcd for C11H9N2 [M þ H] 169.0760. found 169.0769.
aReaction conditions: 10 mol % CuI, 20 mol % sparteine, 2 equiv of
K3PO4, 1.5 equiv of 5, 1.0 equiv of formyldiazole, 130 °C, 24 h. bIsolated
yields after chromatography on SiO2.
The further extension of the reaction to 2-formyldiazole
compounds was briefly explored (Table 3). Both 2-formylimi-
dazole and 2-formylbenzimidazole underwent the reaction to
give imidazo[1,2-a]quinoxaline (34) and benzimidazo[1,2-a]-
quinoxaline (36) in moderate yields. The reaction also worked
well for annulation of a formylpyrazole (entry 3) to provide
2-methylpyrazolo[1,5-a]quinoxaline (38) in 83% yield. These
results suggest the methodology may be applicable to an even
broader range of 1-aza-2-formylheterocycles.
Supporting Information Available: Analytical 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, a simple one-step copper-catalyzed synth-
esis of pyrrolo[1,2-a]quinoxalines from o-aminoiodoarenes
and 2-formylpyrroles has been developed. The method is
994 J. Org. Chem. Vol. 75, No. 3, 2010