F a cile a n d Ra cem iza tion -F r ee Con ver sion of Ch ir a l Nitr iles in to
P yr id in e Der iva tives†
,
‡
§
‡
‡
‡
Barbara Heller,* Bernd Sundermann, Christine Fischer, J ingsong You, Waiqiang Chen,
‡
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⊥
‡
Hans-J oachim Drexler, Paul Knochel, Werner Bonrath, and Andrey Gutnov
Leibniz-Institut f u¨ r Organische Katalyse an der Universit a¨ t Rostock e.V., Buchbinderstr. 5-6,
1
8055 Rostock, Germany, Gr u¨ nenthal GmbH, Center of Research, 52099 Aachen, Germany,
LMU M u¨ nchen, Institut f u¨ r Organische Chemie, Butenandtstr. 5-13, 81377 M u¨ nchen, Germany, and
Roche Vitamins Ltd., Reseach and Development, 4070 Basel, Switzerland
Received J une 23, 2003
The results described herein demonstrate how the very mild reaction conditions of the Co(I)-
catalyzed photochemical [2 + 2 + 2] cyclocotrimerization are suited to prepare chiral compounds
containing unsubstituted and polysubstituted 2-pyridyl moieties starting from chiral nitriles without
any detectable loss of enantiomerical purity. This further increases the already very broad synthetic
scope of this particular reaction.
In tr od u ction
SCHEME 1. [2 + 2 + 2] Cycloa d d ition
The notable successes in the application of phosphine-
free, nitrogen-containing ligands to the area of asym-
metric catalysis over the past decade has caused an
exponential growth of interest in preparation, resolution,
1
and utilization of pyridine-based chiral ligands. More-
over, pyridyl-substituted optically pure compounds are
of persistent importance for pharmaceutical drug re-
search. Thus, there is a general interest in a simple and
Through the construction of three new bonds in one
reaction, the transition-metal-catalyzed [2 +2 + 2] cy-
cloaddition of nitriles with a broad variety of alkynes
2
selective synthetic access to optically active compounds
containing a pyridyl moiety. Besides enzymatic synthe-
(cyclocotrimerization; Scheme 1) is an atom-economical
3
ses, which are of particular interest in the field of HIV
and extraordinarily effective method to prepare substi-
research, transition-metal-catalyzed reactions leading to
a variety of chiral compounds containing a pyridyl moiety
have been described.4
11,12
tuted pyridines.
Substituted pyridines bearing a chirality are in prin-
ciple accessible by this route when optically active nitriles
are used. The thermally initiated variant of this reaction
to 2-pyridines has been investigated in the groups of
-10
*
To whom correspondence should be addressed. Fax: (0049)-381-
4
66 93 24.
13,14
15-17
Botteghi
and Chelucci.
By employing ethyne
†
Dedicated to G u¨ nther Oehme.
‡
Leibniz-Institut f u¨ r Organische Katalyse an der Universit a¨ t Ros-
tock e.V.
(10) Fletcher, N. C. J . Chem. Soc., Perkin Trans. 1 2002, 1831.
(11) Many transition-metal complexes catalyze this cyclization. For
reviews on the cobalt-catalyzed synthesis of pyridines, see: (a) Voll-
hardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539. (b)
B o¨ nnemann, H.; Brijoux, W. Adv. Heterocycl. Chem. 1990, 48, 177.
Some new interesting examples: (c) Varela, A. J .; Castedo, L.; Maestro,
M.; Mahia, J .; Sa a´ , C. Chem. Eur. J . 2001, 7, 5203. (d) Fatland, A. W.;
Eaton, B. E. Org. Lett. 2000, 20, 3131. For some recent examples of
pyridines synthesis under catalysis with Rh, Ru, Ti, Zr/Ni, Zr/Cu, Ta,
and Fe complexes, see the following references. (e) Rh: Deversi, P.;
Ermini, L.; Ingresso, G.; Lucherini, A. J . Organomet. Chem. 1993, 447,
291. (f) Ru: Yamamoto, Y.; Ogawa, R.; Itoh, K. J . Am. Chem. Soc. 2001,
123, 6189. (g) Ti: Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J . Am.
Chem. Soc. 2002, 124, 3518. (h) Zr/Ni, Zr/Cu: Takahashi, T.; Tsai, F.;
Li., Y.; Wang, H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotara,
M. J . Am. Chem. Soc. 2002, 124, 5059. (i) Ta: Takai, K.; Yamada, M.;
Utimoto, K. Chem. Lett. 1995, 851. (j) Fe: Knoch, F.; Kremer, F.;
Schmidt, U.; Zenneck, U. Organometallics 1996, 15, 2713.
§
Gr u¨ nenthal GmbH.
LMU M u¨ nchen.
Roche Vitamins Ltd.
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1) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev.
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(
(
(
(
(
1
(
(
(12) For some results from our laboratory, see: (a) Heller, B.;
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(
8) Kwong, F. Y.; Yang, Q.; Mak, T. C. W.; Chan, A. S. C.; Chan, K.
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9) Chelucci, G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129.
(
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0.1021/jo030206t CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/25/2003
J . Org. Chem. 2003, 68, 9221-9225
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