Direct synthesis of monofunctionalized indolizine derivatives bearing alkoxymethyl substituents at C-3 and their benzofused analogues

Article abstract of DOI:10.1021/ol051860t

(Chemical Equation Presented) Treatment of (Z)-2-pyridine and quinoline silylated vinylacetylenes at reflux with several alcohols in the presence of a suitable inorganic base (KOH, K₂CO₃, CsF, or KF) serendipitously gave 3-alkoxylmet

Full text of DOI:10.1021/ol051860t

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4305-4308
Direct Synthesis of Monofunctionalized
Indolizine Derivatives Bearing
Alkoxymethyl Substituents at C-3 and
Their Benzofused Analogues
Joseph Kaloko, Jr. and Anthony Hayford*
Department of Chemistry, Thomas Harriot College of Arts and Sciences,
East Carolina UniVersity, Science and Technology Building, Suite 300,
GreenVille, North Carolina 27858-4343
hayforda@mail.ecu.edu
Received August 3, 2005
ABSTRACT
Treatment of (Z)-2-pyridine and quinoline silylated vinylacetylenes at reflux with several alcohols in the presence of a suitable inorganic base
(KOH, K2CO3, CsF, or KF) serendipitously gave 3-alkoxylmethylindolizines and the corresponding 1-alkoxymethylpyrrolo [1,2-a]quinolines and
not the anticipated desilylated vinylacetylene derivatives. A mechanistic possibility for this unexpected chemical transformation is suggested.
Indolizine derivatives (Figure 1) have been the subject of a
number of biological and theoretical studies because of their
intriguing molecular structures1 and their therapeutic
applications.2-5 Among other uses, synthetic and natural
indolizine derivatives have considerable potential as new
calcium entry blockers, chemotherapeutics, and cardiovas-
cular agents.2-4 In addition, several O-containing synthetic
(1) (a) The Structure, Reactions, Synthesis, and Uses of Heterocyclic
Compounds. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R.,
Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vols. 1-8. (b) Flitsch,
W. In ComprehensiVe Heterocyclic Chemistry; Katritzky A. R., Rees C.
W., Eds.; Pergamon Press: Oxford, 1984; Vol. 4, p 443. (c) Swinborne, J.
H.; Klinkert, G. AdV. Heterocycl. Chem. 1978, 23, 103. (d) Heterocyclic
Systems with Bridgehead Nitrogen Atom (Part 1). In The Chemistry of
Heterocyclic Compounds; Mosby, W. L., Ed.; Wiley-interscience: New
York, 1961; Vol. 1.
(2) (a) Gubin, J.; Lucchetti, J.; Mahaux, J.; Nisato, D.; Rosseels, G.;
Clinet, M.; Polster, P.; Chatelain, P. J. Med. Chem. 1992, 35, 981. (b) Gubin,
J.; Descamps, M.; Chatelain, P. P.; Nisato, D. Eur. Pat. Appl. EP 235,111,
1988. (c) Gubin, J.; Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J.;
Mahaux, J.; Rosseels, G.; Peiren, M.; Clinet, M.; Polster, P.; Chatelain, P.
J. Med. Chem. 1993, 36, 1425. (d) Gupta, S. P.; Mathur, A. N.; Nagappa,
A. N.; Kumar, D.; Kumaran, S. Eur. J. Med. Chem. 2003, 38, 867.
(3) (a) Olden, K.; Breton, P.; Grzegorzewski, K.; Yasuda, Y.; Gause, B.
L. Pharmacol. Ther. 1991, 50, 285. (b) Ahrens, P. B,; Ankel, H. J. Biol.
Chem. 1987, 262, 7575. (c) Sasak, V. W.; Ordovas, J. M.; Elbein, A. D.;
Berninger, R. W. Biochem. J. 1985, 232, 759. (d) Dennis, J. W. Cancer
Res. 1986, 46, 5131.
Figure 1. Nuclei of indolizine, benzo[e]indolizine, and useful
synthetic indolizines.
indolizines have been screened and identified as possessing
strong antioxidant effects that prevent the initiation of
(4) Gubin, J.; Descamps, M.; Chatelain, P.; Nisato, D. Eur. Pat. Appl.
EP 235,111, 1988.
10.1021/ol051860t CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/20/2005

processes that lead to DNA damage.5 In this respect,
indolizine derivatives represent prime synthetic targets and
investigational compounds useful in the development of
drugs to treat human diseases such as cancer6 and HIV
infections.7
silylated vinylacetylene derivatives 7 and 8 from com-
mercially available 2-pyridine and 2-quinoline carboxalde-
hydes by means of modified Wittig bromoolefination/
Sonogashira coupling procedures.11b The treatment of silylated
conjugated acetylenic derivatives with basic alcoholic solu-
tions or fluoride ions has been known to afford the corre-
sponding terminal acetylenes.12 However, to our surprise,
upon the attempted desilylation of (Z)-2-pyridine-silylated
vinylacetylenes 7 and 8 under standard basic methanol
conditions at room temperature, we observed that the desired
terminal vinylacetylenes were relatively unstable under the
reaction conditions and were converted to 3-methoxymeth-
ylindolizine 9a and 1-methoxymethylpyrrolo[1,2-a]quinoline
10b, respectively (Scheme 1, Tables 1 and 2). The assigned
A number of synthetic approaches to these azabicyclic
heterocycles have been reported and reviewed in the
literature.1,8 Most previous practical syntheses of the indoli-
zine ring system have employed the Scholtz or Tschitschiba-
bin cyclocondensation reactions.1,2a,9 In addition to these
existing procedures, a number of dipolar cycloaddition
reactions of pyridinium ylides with various olefinic and
acetylenic precursors appended with electron-withdrawing
groups have been developed and proven to be quite valuable
in the synthesis of certain indolizine derivatives.1,10 However,
some of the cycloaddition methods are plagued by low-
yielding reactions and regioselectivity problems when un-
symmetrical, highly functionalized, and sterically demanding
alkynes or olefins are used as substrates.1,8-10 Therefore, an
alternate method for the preparation of indolizines that allows
functional group variation on the indolizine nucleus is highly
desirable for structural and biological activity assessments.
In this paper, we wish to report an unprecedented cyclization
reaction of the silicon-capped (Z)-2-pyridine vinylacetylene
with various basic alcohol solutions to give 3-alkoxymethyl-
substituted indolizines. Likewise, 1-alkoxymethylpyrrolo[1,2-
a]quinolines (benz[e]indolizine) derivatives were successfully
obtainedfromthecyclizationof(Z)-2-quinolinevinylacetylene.11a
Our laboratory recently described the preparation of
Scheme 1. Synthesis of 3-Alkoxymethylindolizines and
1-Alkoxymethylbenz[e]indolizines
structures of the products of the reactions are strongly
supported by 1H NMR, 13C NMR, and high-resolution mass
spectrometry studies. Notably, the 1H NMR spectra obtained
for all of the indolizine and benz[e]indolizine products
(except the deuterated compound 10a) listed in Tables 1 and
2 showed a downfield singlet signal between 4.8 and 4.90
ppm consistent with indolizy-type methylene hydrogens
bearing an alkoxyl group.
Investigations aimed at the optimization of the reaction
conditions indicated that the use of KF or CsF along with
heating the reaction mixture to reflux in the desired alcohol
as solvent resulted in rapid and efficient synthesis of
indolizine products. In subsequent reactions, the alcohol was
systematically varied to include primary, secondary, tertiary,
and cyclic alcohols. In addition, functionalized alcohols such
as propargyl, allylic, and benzyl alcohols were used to furnish
a library of 3-alkoxymethylindolizines and 1-alkoxymeth-
ylbenzo[e]indolizine derivatives (Tables 1 and 2). In some
cases (Table 1, entries 1-5, and Table 2, entries 1-6), the
desired products were simply extracted from the reaction
mixture with excellent purity, thereby eliminating the need
for further chromatographic purification. It is of interest to
note that, when the desilylation reactions were performed at
0 °C (basic methanolic solution or TBAF), the desilylated
vinylacetylenes were obtained.11b However, when the reac-
(5) (a) Gundersen, L. L.; Malterud, K. E.; Negussie, A. H.; Rise, F.;
Teklu, S.; Østby, O. B. Bioorg. Med. Chem. 2003, 11, 5409. (b) Nasir, A.
I.; Gundersen, L. L.; Rise, F.; Antonsen, Ø.; Kristensen, T.; Langhelle, B.;
Bast, A.; Custers, I.; Haenen, G.; Wikstro¨m, H. Bioorg. Med. Chem. Lett.
1998, 8, 1829. (c) Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.;
Murakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.; Ueno, M.;
Chikazawa, Y.; Yamada, K.; Ono, T.; Teshirogi, I.; Ohtani, M. J. Med.
Chem. 1996, 39, 3636.
(6) (a) Humphires, M. J.; Matsumoto, K.; White, S. L.; Olden, K. Cancer
Res. 1986, 46, 5215. (b) Ostrander, G. K.; Scribner, N. K.; Rohrschneider,
L. R. Cancer Res. 1988, 48, 1091. (c) Bols, M.; Lillelund, V. H.; Jensen,
H. H.; Liang, X. Chem. ReV. 2002, 102, 515. (d) Pearson, W. H.; Guo, L.
Tetrahedron Lett. 2001, 42, 8267. (e) Asano, N.; Nash, R. J.; Molyneux,
R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000, 11, 1645.
(7) (a) Ruprecht, R. M.; Mullaney, S.; Andersen, J.; Bronson, R. J.
Acquired Immune Defic. Syndr. 1989, 2, 149. (b) Gruters, R. A.; Neefjes,
J. J.; Tersmette, M.; De Goede, R. E. Y.; Tulp, A.; Huisman, H. G.;
Miedema, F.; Ploegh, H. L. Nature 1987, 330, 74. (c) Kaspas, A.; Fleet, G.
W. J.; Dwek, R. A.; Petursson, S.; Namgoong, S. K.; Ramsden, N. G.;
Jacob, G. S.; Radamacher, T. W. Proc. Natl. Acad. Sci. U.S.A. 1989, 86.
(8) (a) Uchida, T.; Matsumoto, K. Synthesis 1976, 209. (b) Behnisch,
R.; Behnisch, P.; Eggenweiler, M.; Wallenhorst, T. Indolizine. In Houben-
Weyl; Thieme: Stuttgart, 1994; Vol. E6b/1, 2a, pp 323-450. (c) Katritzky,
A. R.; Qui, G.; Yang, B.; He, H. Y. J. Org. Chem. 1999, 64, 7618. (d)
Zhang, X. C.; Huang, W. Synthesis 1999, 51.
(9) (a) Scholtz, M. Ber. Dtsch. Chem. Ges. 1912, 45, 734. (b) Boekel-
heide, V.; Windgassen, R. J. J. Chem. Soc. 1959, 81, 1456. (c) Tschitschiba-
bin, A. E. Ber. Dtsch. Chem. Ges. 1927, 60, 1607. (d) Jones, G.; Stanyer,
J. J. Chem. Soc. 1969, 901. (d) Kostik, E. J.; Abiko, A.; Oku, A. J. Org.
Chem. 2001, 66, 2618.
(10) (a) Padwa, A.; Austin, D. J.; Precedo, L.; Zhi, L. J. Org. Chem.
1993, 58, 1144. (b) Wei, X.; Hu, Y.; Li, T.; Hu, H. J. Chem. Soc., Perkin
Trans. 1 1993, 2487. (c) Siriwardana, A. I.; Nakamura, I.; Yamamoto, Y.
J. Org. Chem 2004, 69, 3202. (d) Acheson, R. M.; Robinson, D. A. J.
Chem. Soc. 1968, 1633. (e) Fang, X.; Wu, Y. M.; Deng, J.; Wang, S. W.
Tetrahedron 2004, 60, 5487.
(11) (a) Hayford, A.; Kaloko, J., Jr. U.S. Pat. Appl. 60/640,369, 2004.
(b) Kaloko, J. M.S. Thesis, East Carolina University, Greenville, NC, 2005.
(c) Hayford, A.; Kaloko, J., Jr.; El-Kazaz, S.; Bass, G.; Harrison, C.;
Corprew, T. Org. Lett. 2005, 7, 2671.
(12) (a) Halbes, U.; Pale, P. Tetrahedron Lett. 2002, 43, 2039. (b)
Sakamoto, T.; Shiraiwa, M.; Kondo, Y.; Yamanaka, H. Synthesis 1983,
312. (c) Konakahara, T.; Takagi, Y. Synthesis 1979, 192. (d) Eaborn, C.;
Walton, D. R. M. J. Organomet. Chem. 1965, 4, 217.
4306
Org. Lett., Vol. 7, No. 19, 2005

Table 1. Array of 3-Alkoxymethylindolizines
Table 2. Array of 1-Alkoxymethylbenz[e]indolizines
The formation of the observed products could be rational-
ized by postulating an electrocyclic reaction pathway that
begins with the formation of the terminal vinylacetylene A
via protodesilylation of 7 or 8 upon treatment with fluoride
ions (Scheme 2). A 1,6 Michael-type conjugate addition of
alkoxide at the acetylenic terminus followed by electrocy-
clization involving pyridine nitrogen results in the direct
formation of 3-alkoxymethyl-substituted indolizine or benz-
[e]indolizine derivatives under mild conditions. On the basis
of the proposed mechanism, treatment of 8 with KF in
refluxing deuterated methanol (CH3OD) gave the doubly
deuterated benzo[e]indolizine 10a in 87% yield (Table 2).
tions were allowed to warm to room temperature, the
indolizine products eventually prevailed. It is also worth
noting that the treatment of the desilylated vinylacetylenes
with various alcohols also yielded the indolizine products
in the absence of base or fluoride ions.
The use of high boiling and/or expensive alcohols such
as benzyl alcohol and deuterated alcohols as solvent in the
transformation was undesirable. Thus, we have demonstrated
that such transformations proceeded smoothly using CsF and
10-20 molar equiv of the alcohol in refluxing anhydrous
toluene (Table 1, entries 6-9, and Table 2, entries 7-10).
In terms of synthetic value, the protocol unveiled in this
paper has proven to be general and very successful in the
preparation of a variety of 3-alkoxymethyl-substituted in-
dolizines and 1-alkoxymethylbenzindolizines in moderate to
high yields. These compounds not only constitute a new class
of C(3)-hydroxymethyl-protected indolizines and C(1)-benz-
[e]indolizine analogues, they are also potential building
blocks in the synthesis of biologically relevant C(3)-
substituted hydroxymethyl indolizidines and C-1 benz[e]-
indolizidines via suitable protective group removal and
traditional hydrogenation methods.
Scheme 2. Proposed Mechanism for Formation of
Monosubstituted Alkoxymethylindolizines
Acknowledgment. We thank the Camille and Henry
Dreyfus Foundation and the Eli Lilly Scholarship in Chem-
istry at ECU for financial support.
Org. Lett., Vol. 7, No. 19, 2005
4307

Supporting Information Available: Experimental pro-
cedures and spectra data for the preparation of starting
materials, 7, and 8 in addition to the 1H NMR and 13C NMR
of 3-alkoxymethylindolizines 9a-i and 1-alkoxymethylben-
zo[e]indolizines 10a-j. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL051860T
4308
Org. Lett., Vol. 7, No. 19, 2005