Selective syntheses of metalated pyridines from two different unsymmetrical acetylenes, a nitrile, and a titanium(II) alkoxide

Article abstract of DOI:10.1021/ja017766z

Cyclotrimerization of two different, unsymmetrical acetylenes and p-toluenesulfonylnitrile with a divalent titanium alkoxide reagent, Ti(O-i-Pr)₄/2 i-PrMgCl, yielded single pyridyltitanium compounds in a highly selective manner. These metalated pyridines were confirmed by deuteriolysis to give the corresponding deuterated pyridines and underwent iodinolysis and copper-catalyzed alkylation to demonstrate their synthetic utility. Alternatively, a different type of cyclotrimerization of an alkynamide, terminal acetylenes, and α-alkoxynitriles mediated by the same titanium(II) alkoxide again proceeded in a highly selective manner to give single pyridines having a titanated side chain. Copyright

Full text of DOI:10.1021/ja017766z

Published on Web 03/16/2002
Selective Syntheses of Metalated Pyridines from Two Different Unsymmetrical
Acetylenes, a Nitrile, and a Titanium(II) Alkoxide
Daisuke Suzuki,†,§ Ryoichi Tanaka, Hirokazu Urabe, and Fumie Sato*
‡
‡
,†
Departments of Biomolecular Engineering and Biological Information, Graduate School of Bioscience and
Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama,
Kanagawa 226-8501, Japan
Received December 14, 2001
There is a wide variety of preparative methods of pyridines,1
among which the Reppe-type assembly of acetylenes and a nitrile
as formulated in eq 1 has recently attracted much attention, because
of its straightforward concept, easy availability of starting materials,
2
and synthetic flexibility. Although many reports along this line
3
have appeared, regioselective assembly of two different, unsym-
metrical acetylenes and a nitrile, leading to a single pyridine product,
still remains unsolved. Herein we report novel types of the selective
synthesis of pyridines, which, for the first time, realize this objective
and also directly produce metalated pyridines, often a more versatile
species than pyridines themselves,1 as shown in types I and II of
Scheme 1.
c
Scheme 1. Formulation of New Syntheses of Metalated Pyridines
most likely proceeds as depicted in eq 2 and should resemble the
metalative Reppe reaction reported previously.10
Although this pyridine synthesis starting from 1-(trimethylsilyl)-
1-octyne as the first acetylene was unsuccessful, that from dialkyl-
acetylene 13 proved to be viable as shown in eq 4, where the
neighboring benzyl ether in the side chain of the titanacycle 14
apparently controls the direction of the incoming nitrile to give
pyridine 15 as a single regioisomer.11
In both transformations, the experimental procedures are quite
simple and can be carried out in one pot. Dialkoxytitanacyclo-
pentadienes 4 were first gathered from two different, unsymmetrical
4
The advantageous feature of the formation of titanated pyridines
8 over the conventional metal-catalyzed pyridine synthesis (eq 1)
acetylenes 1 and 2 (as the first and second acetylenes) and a divalent
5
titanium alkoxide reagent, Ti(O-i-Pr)
4
/2 i-PrMgCl (3), at -50 °C
1
c,12
6
7
was demonstrated by the subsequent transformations.
treatment of 8c with iodine, allyl bromide, or ethylidenemalonate
the latter two were under Li CuCNCl catalysis) furnished pyridyl
iodide 16 or homologated aromatic compounds 17 and 18 (Figure
Thus,
in a highly regioselective manner (eq 2). Once sulfonylnitrile 5
was added, the regioselective uptake of the nitrile into the
titanacyclopentadiene took place. Hydrolytic workup afforded single
(
2
2
8
pyridines 9, and more importantly, deuteriolysis gave the single
1
).
Switching nitriles from sulfonyl derivative 5 to alkanenitriles
0 as shown in eq 5 led to another kind of selective pyridine
deuterated counterparts 9-d with high deuterium incorporation,
confirming the generation of pyridyltitanium compounds 8 before
aqueous workup (type I in Scheme 1). An informative observation
associated with the reaction course of this process has been obtained.
Acetylenic ester 10 afforded the expected pyridine 11 as a single
isomer (eq 3) similarly to the above reaction, accompanied by a
2
synthesis from two different, unsymmetrical acetylenes (type II in
Scheme 1). The addition of R-methoxyacetonitrile (20a) to titana-
cyclopentadiene 19a followed by aqueous workup produced, to our
8
,13
9
surprise, pyridinecarbaldehyde 23a as a single isomer (eq 5).
small amount of sulfonylated pyridine 12. The latter compound
Moreover, deuteriolysis of the same reaction mixture reveals that
its aldehyde hydrogen was substituted by deuterium. On the basis
of these observations, a plausible reaction course is also shown in
eq 5. The regioselective incorporation of the nitrile to the titanacycle
19 produced the intermediate 21, which aromatized most likely with
may arise from aerial oxidation of dihydropyridines produced by
the hydrolysis of the intermediate titanium complexes such as 6 or
7
in eq 2 before elimination of the sulfonyl group. Thus, the reaction
*
Address correspondence to this author. E-mail: fsato@bio.titech.ac.jp.
Department of Biomolecular Engineering.
Research Fellow of the Japan Society for the Promotion of Science.
Department of Biological Information.
†
2
14
§
‡
the concomitant formation of η -carbonyl-titanium complex 22.
This titanium complex was hydrolyzed (or deuterated) to give the
3518
9
J. AM. CHEM. SOC. 2002, 124, 3518-3519
10.1021/ja017766z CCC: $22.00 © 2002 American Chemical Society

C O MMU N I C A T I O N S
Supporting Information Available: Experimental procedures,
physical properties of products, and a proposed reaction course (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(
1) (a) Katritzky, A. R.; Rees, C. W., Eds. ComprehensiVe Heterocyclic
Chemistry; Pergamon Press: Oxford, 1984; Vol. 2. (b) Gilchrist, T. L. J.
Chem. Soc., Perkin Trans. 1 2001, 2491-2515. (c) Mongin, F.; Qu e´ guiner,
G. Tetrahedron 2001, 57, 4059-4090.
(
2) B o¨ nnemann, H.; Brijoux, W. In Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 1, pp
114-135. Grotjahn, D. B. In ComprehensiVe Organometallic Chemistry
Figure 1. Utility of pyridyltitanium reagent 8c. Yields are overall from
starting acetylenes.
II; Hegedus, L. S., Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon Press: Oxford, 1995; Vol. 12, pp 741-770. Chelucci, G.
Tetrahedron: Asymmetry 1995, 6, 811-826. Schore, N. E. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, pp 1129-1162. B o¨ nnemann, H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 248-262. Vollhardt, K. P. C. Angew.
Chem., Int. Ed. Engl. 1984, 23, 539-556.
(
deuterated) aldehyde 23. An intriguing utility of the metalated
portion of 22 was demonstrated by its reaction with a pro-
nucleophile. When allyl cyanide (24, 2 equiv) was used as the nitrile
(3) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Chem. Commun. 1973, 280.
Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Dalton Trans. 1978, 1278-
1
282. To our best knowledge, there has been no report on the selective
(eq 6), the reaction proceeded beyond the metalated pyridine 25
cyclotrimerization of two different, unsymmetrical acetylenes and a nitrile.
For recent reports, which deal with the cyclotrimerization of the same
via the proton transfer from nitrile 24, giving eventually pyridine
(
ref 3a-h), symmetrical (ref 3i), or tethered (ref 3j-p) substrates, see:
(
a) Bianchini, C.; Meli, A.; Peruzzini, M.; Vacca, A.; Vizza, F. Organo-
26 as a mixture of separable olefinic stereoisomers.
metallics 1991, 10, 645-651. (b) Smith, D. P.; Strickler, J. R.; Gray, S.
D.; Bruck, W. A.; Holmes, R. S.; Wigley, D. E. Organometallics 1992,
1
7
1, 1275-1288. (c) Viljoen J. S.; du Plessis, J. A. K. J. Mol. Catal. 1993,
9, 75-84. (d) Diversi, P.; Ermini, L.; Ingrosso, G.; Lucherini, A. J.
Organomet. Chem. 1993, 447, 291-298. (e) Hill, J. E.; Balaich, G.;
Fanwick, P. E.; Rothwell, I. P. Organometallics 1993, 12, 2911-2924.
(
f) Jerome, K. S.; Parsons, E. J. Organometallics 1993, 12, 2991-2993.
g) Heller, B.; Oehme, G. J. Chem. Soc., Chem. Commun. 1995, 179-
(
1
80. (h) Fatland, A. W.; Eaton, B. E. Org. Lett. 2000, 2, 3131-3133. (i)
Takahashi, T.; Tsai, F.-Y.; Kotora, M. J. Am. Chem. Soc. 2000, 122,
4
1
8
4
1
994-4995. (j) Sa a´ , C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C. Synlett
994, 487-489. (k) Takai, K.; Yamada, M.; Utimoto, K. Chem. Lett. 1995,
51-852. (l) Varela, J. A.; Castedo, L.; Sa a´ , C. J. Org. Chem. 1997, 62,
189-4192. (m) Varela, J. A.; Castedo, L.; Sa a´ , C. J. Am. Chem. Soc.
998, 120, 12147-12148. (n) Varela, J. A.; Castedo, L.; Sa a´ , C. Org.
Lett. 1999, 1, 2141-2143. (o) Yamamoto, Y.; Okuda, S.; Itoh, K. Chem.
Commun. 2001, 1102-1103. (p) Yamamoto, Y.; Ogawa, R.; Itoh, K. J.
Am. Chem. Soc. 2001, 123, 6189-6190.
(
(
4) For details, see the Supporting Information.
5) Sato, F.; Urabe, H.; Okamoto, S. Pure Appl. Chem. 1999, 71, 1511-
1519. Sato, F.; Urabe, H.; Okamoto, S. Synlett 2000, 753-775. Sato, F.;
Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835-2886. Kulinkovich,
O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789-2834. Eisch, J. J. J.
Organomet. Chem. 2001, 617-618, 148-157. Sato, F.; Okamoto, S. AdV.
Synth. Catal. 2001, 343, 759-784. Sato, F.; Urabe, H. In Titanium and
Zirconium in Organic Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim,
in press.
(
6) Urabe, H.; Sato, F. J. Am. Chem. Soc. 1999, 121, 1245-1255. Hamada,
T.; Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 1999, 121, 7342-
7
344. Urabe, H.; Nakajima, R.; Sato, F. Org. Lett. 2000, 2, 3481-3484.
(
(
7) p-Toluenesulfonylnitrile is commercially available and used as such.
8) The rationale of this regioselection of nitrile uptake so far remains unclear
and should await further study on the structure of intermediates and the
reaction mechanism.
(
9) When the reaction was quenched at a lower temperature (-50 °C),
sulfonylpyridine 12 became a major constituent (12 and 11 in 37 and
28% yields, respectively).
(
(
(
10) Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123, 7925-
7926.
11) For additional control experiments and discussion, see the Supporting
Information.
12) For synthetic application of organotitanium compounds, see: Ferreri, C.;
Palumbo, G.; Caputo, R. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, pp 139-
In conclusion, a combination of two acetylenes, various nitriles,
and the titanium alkoxide reagent produced titanated pyridines in
a novel way. Particularly, starting this reaction with alkynamide
or alkynoate allowed the perfectly regioselective three-component
coupling process. Further utility of these metalated heteroaromatic
compounds and the mechanistic rationale are under active inves-
tigation.
1
72. Reetz, M. T. In Organometallics in Synthesis; Schlosser, M., Ed.;
Wiley: Chichester, 1994; pp 195-282.
(
13) So far, a simple alkanenitrile such as octanenitrile showed sluggish
reaction, suggesting the importance of the presence of a coordinating
moiety in the nitrile. Nonetheless, as R-oxynitriles are readily obtained
by the cyanohydrin synthesis and its modifications, this reaction will find
reasonable application.
(14) For the generation of carbonyl group-group 4 metal complexes and their
synthetic application, see: Erker, G.; Rosenfeldt, F. J. Organomet. Chem.
1
982, 224, 29-42. Davis, J. M.; Whitby, R. J. Tetrahedron Lett. 1992,
3
3, 5655-5658. Mori, M.; Uesaka, N.; Saitoh, F.; Shibasaki, M. J. Org.
Acknowledgment. This work was supported, in part, by a
Grant-in-Aid for Scientific Research on Priority Areas (A) “Ex-
ploitation of Multi-Element Cyclic Molecules” from the Ministry
of Education, Culture, Sports, Science and Technology, Japan.
Chem. 1994, 59, 5643-5649. Barluenga, J.; Sanz, R.; Fa n˜ an a´ s, F. J. Chem.
Eur. J. 1997, 3, 1324-1336. Urabe, H.; Takeda, T.; Hideura, D.; Sato, F.
J. Am. Chem. Soc. 1997, 119, 11295-11305.
JA017766Z
J. AM. CHEM. SOC.
9
VOL. 124, NO. 14, 2002 3519