Synthesis of 5-azaindoles via a cycloaddition reaction between nitriles and donor-acceptor cyclopropanes

Article abstract of DOI:10.1021/ol101078z

(Figure Presented) A new method for the synthesis of 5-azaindole derivatives is reported. A [3+2] dipolar cycloaddition between nitriles and a 3,4-cyclopropanopiperidine followed by SeO₂ oxidation affords the target compounds in moderate to excellent yields. The divergent nature and cost effectiveness of this method makes it very suitable for combinatorial applications in the pharmaceutical industry.

Full text of DOI:10.1021/ol101078z

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3168-3171
Synthesis of 5-Azaindoles via a
Cycloaddition Reaction between Nitriles
and Donor-Acceptor Cyclopropanes
Mahmoud M. Abd Rabo Moustafa and Brian L. Pagenkopf*
Department of Chemistry, The UniVersity of Western Ontario,
London, Ontario, N6A 5B7, Canada
bpagenko@uwo.ca
Received May 11, 2010
ABSTRACT
A new method for the synthesis of 5-azaindole derivatives is reported. A [3+2] dipolar cycloaddition between nitriles and a 3,4-
cyclopropanopiperidine followed by SeO2 oxidation affords the target compounds in moderate to excellent yields. The divergent nature and
cost effectiveness of this method makes it very suitable for combinatorial applications in the pharmaceutical industry.
Considerable attention has been directed to the development
of azaindole based pharmaceuticals as indole isosteres due
to their role in patent evasion, often enhanced solubility, and
perhaps superior bioavailability.1 These efforts have resulted
in the discovery of many active drug candidates (see Figure
1 for representative examples).2 Despite the promising
potential of these heterocycles, they remain largely under-
explored, in part due to the limited synthetic methods to
prepare and functionalize the azaindole nucleus.
While there are many synthetic methods available for the
preparation of substituted indoles,3 only a few have been
developed for the preparation of azaindoles. Some of the
classic methods either do not work or are inefficient.1 The
(1) For recent reviews and references cited therein see: (a) Popowyez,
F.; Me´rour, J.-Y.; Joseph, B. J. Tetrahedron 2007, 63, 8689–8707. (b) Song,
J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H.
Chem. Soc. ReV. 2007, 36, 1120–1132. (c) Popowycz, F.; Routier, S.; Joseph,
B.; Me´rour, J.-Y. Tetrahedron 2007, 63, 1031–1064.
(2) (a) Bastian, J. A.; Fisher, M. J.; Harper, R. W.; Lin, H.-S.; Mccowan,
J. R.; Sall, D. J.; Smith, G. F.; Takeuchi, K.; Wiley, M. R.; Zhang, M. Eur.
Figure 1. Examples of pharmacologically active azaindoles.
Pat. Appl. EP 997465, 2000. Chem. Abstr. 2000, 132, 293756. (b) Wei, Z.;
Dolaine, R.; Walpole, C.; Yang, H. Appl. Int. WO 2004087704, 2004. Chem.
Abstr. 2004, 141, 332183. (c) Cooper, L. C.; Chicchi, G. G.; Dinnell, K.;
Elliott, J. M.; Hollingworth, G. J.; Kurtz, M. M.; Locker, K. L.; Morrison,
D.; Shaw, D. E.; Tsao, K.-L.; Watt, A. P.; Williams, A. R.; Swain, C. J.
Bioorg. Med. Chem. Lett. 2001, 11, 1233–1036. (d) Jinnin, M.; Ihn, H.;
Tamaki, K. Mol. Pharmacol. 2006, 69, 597–607.
alternative methods generally rely on highly functionalized
pyridine substrates, which are expensive or require multistep
syntheses to prepare.4 Additionally, C2 and C3 substituted
5-azaindoles are notoriously difficult to access as they often
(3) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 7, 1045–1075.
10.1021/ol101078z  2010 American Chemical Society
Published on Web 06/15/2010

depend on multistep approaches involving highly function-
alized pyridines, or strong bases to lithiate the 5-azaindole
itself followed by electrophile trapping.5 The formal dipolar
cycloaddition reaction developed by our group6 has been
shown to be useful for the preparation of pyrroles,7 bipyr-
roles,8 indolizines,9 and indole alkaloid natural products.10
Herein, we report a two-step sequence for the synthesis of
5-azaindoles by oxidation of a tetrahydro-1H-pyrrolo[3,2-c]-
pyridine intermediate obtained through a cycloaddition
reaction between nitriles and a 3,4-cyclopropanopiperidine
(Scheme 1).11
Scheme 2. Attempted Synthesis of the Cyclopropanopiperidine
Scheme 1. Retrosynthetic Analysis
ethyl diazoacetate in the presence of Cu(TBS)2,14 the ethyl
cinnamate 5 was obtained in 60% yield and none of the
desired cyclopropane was observed. The cinnamate is likely
formed by carbene insertion at the benzylic position followed
by elimination. To avoid this undesired reaction a tosyl
protecting group was employed (Scheme 3),15 and cyclo-
This strategy allows access to a wide variety of C2
functionalized azaindoles simply by varying the starting
nitrile.
The synthesis of the cyclopropanopiperidine began with
benzyl protection of 4-piperidone 1 followed by acetalization
in acidic methanol (Scheme 2).12 Then the resulting acetal
3 was converted to enol ether 4 under standard conditions;13
however, when 4 was subjected to cyclopropanation with
Scheme 3. Access to Cyclopropanopiperidines
(4) (a) Evans, G. B.; Furneaux, R. H.; Hutchison, T. L.; Kezar, H. S.;
Morris, P. E., Jr.; Schramm, V. L.; Tyler, P. C. J. Org. Chem. 2001, 66,
5723–5730. (b) Zhu, J.; Wong, H.; Zhang, Z.; Yin, Z.; Meanwell, N. A.;
Kadow, J. F.; Wang, T. Tetrahedron Lett. 2006, 47, 5653–5656. (c) Roy,
P. J.; Dufresne, C.; Lachance, N.; Leclerc, J.-P.; Boisvert, M.; Wang, Z.;
Leblanc, Y. Synthesis 2005, 2751–2757. (d) Zhang, Z.; Yang, Z.; Meanwell,
N. A.; Kadow, J. F.; Wang, T. J. Org. Chem. 2002, 67, 2345–2347. (e)
Saab, F.; Be´ne´teau, V.; Schoentgen, F.; Me´rour, J.-Y.; Routier, S.
Tetrahedron 2010, 66, 102–110. (f) Zheng, X.; Kerr, M. A. Org. Lett. 2006,
8, 3777–3779.
propanation under the same conditions afforded the desired
cyclopropane 6 in 90% yield as an inconsequential 8:1
mixture of trans to cis diastereomers.16
With cyclopropane 6 in hand it was allowed to react with
acetonitrile under the standard annulation conditions (1.0
equiv of Me3SiOTf, -40 °C) to give the tetrahydropyrrolo-
pyridine 7a in 95% isolated yield (Scheme 4).7 This material
(5) (a) Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007, 72, 5152–
5160. (b) Roy, P.; Boisvert, M.; Leblanc, Y. Org. Synth. 2007, 84, 262–
271. (c) Lefoix, M.; Daillant, J.-P.; Routier, S.; Merour, J.-Y.; Gillaizeau,
I.; Coudert, G. Synthesis 2005, 20, 3581–3588. (d) Xu, L.; Lewis, I. R.;
Davidsen, S. K.; Summers, J. B. Tetrahedron Lett. 1998, 39, 5159–5162.
(e) Bisagni, E.; Ducrocq, C.; Civier, A. Tetrahedron 1976, 32, 1383–1390.
(f) Zhang, S.; Sun, X.; Zhang, W.-X.; Xi, Z. Chem.sEur. J. 2009, 15,
12608–12617. (g) Shaykoon, M. S. A.; Inagaki, F.; Mukai, C. Heterocycles
2010, 80, 133–139. (h) Whelligan, D. K.; Thomson, D. W.; Taylor, D.;
Hoelder, S. J. Org. Chem. 2010, 75, 11–15.
Scheme 4. Nitrile Annulation
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(7) Yu, M.; Pagenkopf, B. L. Org. Lett. 2003, 5, 5099–5101.
(8) Yu, M.; Pantos, G. D.; Sessler, J. L.; Pagenkopf, B. L. Org. Lett.
2004, 6, 1057–1059.
(9) Morra, N. A.; Morales, C. L.; Bajtos, B.; Wang, X.; Jang, H.; Wang,
J.; Yu, M.; Pagenkopf, B. L. AdV. Synth. Catal. 2006, 348, 2385–2390.
(10) (a) Morales, C. L.; Pagenkopf, B. L. Org. Lett. 2008, 10, 157–
159. (b) Bajtos, B.; Pagenkopf, B. L. Eur. J. Org. Chem. 2009, 1072–
1077.
was easily and economically prepared on gram scale, and
was selected as a model substrate for screening oxidation
conditions to provide the desired azaindole nucleus (Table
(11) (a) Reissig, H.-U. Top. Curr. Chem. 1988, 144, 73–135. (b) Reissig,
H.-U.; Zimmer, R. Chem. ReV. 2003, 103, 1151–1196. (c) Yu, M.;
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N. R.; Kim, K.; Breininger, M. L.; Gentry, P. R.; Brogan, J. T.; Jones,
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5439–5442.
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(15) Engler, T. A.; Wanner, J. J. Org. Chem. 2000, 65, 2444–2457.
(16) (a) Benzyl protecting group was first selected to allow for an easy
deprotection in the subsequent oxidation step. (b) Both diastereomers work
equally well in the subsequent cyclization.
(13) Gassman, P. G.; Burns, S. J. J. Org. Chem. 1988, 53, 5576–5578.
Org. Lett., Vol. 12, No. 14, 2010
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1). It was thought that either a two-step sequence involving
elimination or deprotection of the tosylate followed by
With reaction conditions established for both the nitrile
annulation and subsequent oxidation the reaction scope was
explored, and the results are summarized in Table 2. The
reaction works well with other aliphatic nitriles (entry b) as
well as benzylic and electron rich benzylic nitriles (entries
c and d). Unsaturated nitriles are effective (entry e) as are
those containing heteroatoms, such as 2-thiophenecarbonitrile
(entry f). The annulation reaction is conveniently run with a
large excess of nitrile as solvent, but where this is impractical,
nitromethane was employed. Sterically hindered (e.g., piva-
lonitrile and isobutyronitrile) or electron deficient nitriles
(e.g., 4-bromobenzonitrile) did not engage in the reaction.
Table 1. Deprotection and Oxidation
We have shown previously that other functional groups
can react in formal dipolar cycloadditions with DA cyclo-
propanes, including electron deficient pyridines9 and in-
doles.22 While not intended to be exhaustive, Table 3 shows
entry
conditions
yield (%)
1
2
3
4
5
6
7
MeONa/MeOH
decomposition
decomposition
decomposition
decomposition
no reaction
t-BuOK/t-BuOH
Na-naphthalenide/THF
DDQ/toluene
5% Pd/C, mesitylene
MnO2,CH2Cl2
no reaction
92% (azaindole)
Table 3. [3+2] Cycloannulation between Pyridines and Indole
with Cyclopropane 6a
SeO2, dioxane
oxidation would be acceptable, as well as a one-step process
to give the azaindole directly. Various strategies were
explored, including strong bases,17 Na-naphthalenide,18
DDQ,19 Pd/C,10 and MnO2.20 In each case, either decom-
position or no reaction was observed (Table 2, entries 1-
Table 2. Scope of Azaindole Synthesisa
a Relative stereochemistry was not determined but was assigned by
analogy only. For a relevant discussion with similar systems, see ref 22.
that the 3,4-cyclopropanopiperidine reacts analogously to
afford fused azaindoles very efficiently. The reactions with
both 4-cyanopyridine and 2-cyanopyridine gave their respec-
tive tetrahydropyridoindolizines (Table 3, entries a and b),
and both underwent oxidation with SeO2 to the pyridoin-
dolizine. The single crystal X-ray structure of 10b was solved
and the ORTEP is presented in Figure 2. The cycloaddition
a Cycloaddition reactions were run at -40 °C, using 1.0 equiv of
cyclopropane, 2.0 equiv of nitrile, and 1.0 equiv of Me3SiOTf in ni-
tromethane solvent. In the case of acetonitrile (entry a), excess nitrile was
used as solvent. Oxidation conditions: 5 equiv of SeO2 in refluxing dioxane.
(17) Harrison, D. M.; Sharma, R. B. Tetrahedron Lett. 1986, 27, 521–
524.
6). Ultimately it was found that SeO2 executed the desired
oxidation extraordinarily well and afforded the azaindole in
92% isolated yield.21
(18) Becker, M. H.; Chua, P.; Downham, R.; Douglas, C. J.; Garg, N. K.;
Hiebert, S.; Jaroch, S.; Matsuoka, R. T.; Middleton, J. A.; Ng, F. W.;
Overman, L. E. J. Am. Chem. Soc. 2007, 129, 11987–12002.
3170
Org. Lett., Vol. 12, No. 14, 2010

In summary, we have reported a novel and practical two-
step sequence for the preparation of C2 substituted 5-aza-
indoles and fused azaindoles, in 34-87% overall yield. The
synthetic sequence starts with an easily prepared and
inexpensive piperidine based DA cyclopropane, which is then
allowed to react with nitriles, pyridines, and indoles. A
subsequent SeO2 mediated oxidation cleaves the tosyl
protecting group and oxidizes the substrates to provide the
aromatic azaindoles.
Acknowledgment. We thank the National Sciences and
Engineering Research Counsil of Canada for financial
assistance. We thank Dr. Michael Jennings (The University
of Western Ontario) for determination of the X-ray structures
and Prof. Michael A. Kerr (The University of Western
Ontario) for helpful discussions. Mahmoud Moustafa thanks
the Egyptian Academy of Scientific Research and Technol-
ogy for financial support.
Figure 2. X-ray structure of 10b.
with indole provided the cycloadduct 9c in 57% yield, but
the standard SeO2 oxidation conditions were ineffective in
this case.
Supporting Information Available: General experimental
procedures and characterization of all new compounds, and
copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) Wallace, D. J.; Gibb, A. D.; Cottrell, I. F.; Kennedy, D. J.; Brands,
K. M. J.; Dolling, U. H. Synthesis 2001, 12, 1784–1789.
(20) Bagley, M. C.; Lubinu, M. C. Synthesis 2006, 8, 1283–1288.
(21) Gatta, F.; Misiti, D. J. Heterocycl. Chem. 1987, 24, 1183–1187.
(22) Bajtos, B.; Yu, M.; Zhao, H.; Pagenkopf, B. L. J. Am. Chem. Soc.
2007, 129, 9631–9634.
OL101078Z
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