One-pot synthesis of metalated pyridines from two acetylenes, a nitrile, and a titanium(II) alkoxide

Article abstract of DOI:10.1021/ja050261e

Four-component coupling process involving two acetylenes, a nitrile, and a divalent titanium alkoxide reagent, Ti(O-i-Pr)₄/2i-PrMgCl, directly yielded titanated pyridines in a highly selective manner. The reaction can be classified into four categories: (i) a combination of an internal acetylene, a terminal acetylene, sulfonylnitrile, and the titanium reagent to yield α-titanated pyridines, (ii) a combination of an internal acetylene, a (sulfonylamino)acetylene, a nitrile, and the titanium reagent to yield alternative α-titanated pyridines, (iii) a combination of an internal acetylene, a (sulfonylamino)acetylene, a nitrile, and the titanium reagent to yield titanated aminopyridines, and (iv) a combination of an acetylenic amide, a terminal acetylene, a nitrile, and the titanium reagent to yield pyridineamides with their side chain titanated. Some of these reactions enabled virtually completely regioselective coupling of two different, unsymmetrical acetylenes and a nitrile to form a single pyridine. Synthetic applications of these reactions have been illustrated in the preparation of optically active pyridines and medicinally useful compounds.

Full text of DOI:10.1021/ja050261e

Published on Web 04/29/2005
One-Pot Synthesis of Metalated Pyridines from Two
Acetylenes, a Nitrile, and a Titanium(II) Alkoxide
Ryoichi Tanaka,† Akio Yuza,† Yuko Watai,† Daisuke Suzuki,‡ Yuuki Takayama,‡
Fumie Sato,*,‡ and Hirokazu Urabe*,†,‡
Contribution from the Departments of Biological Information and Biomolecular Engineering,
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology,
4259-B-59 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
Received January 14, 2005; E-mail: hurabe@bio.titech.ac.jp; fsato@bio.titech.ac.jp
Abstract: Four-component coupling process involving two acetylenes, a nitrile, and a divalent titanium
alkoxide reagent, Ti(O-i-Pr)4/2i-PrMgCl, directly yielded titanated pyridines in a highly selective manner.
The reaction can be classified into four categories: (i) a combination of an internal acetylene, a terminal
acetylene, sulfonylnitrile, and the titanium reagent to yield R-titanated pyridines, (ii) a combination of an
internal acetylene, a (sulfonylamino)acetylene, a nitrile, and the titanium reagent to yield alternative
R-titanated pyridines, (iii) a combination of an internal acetylene, a (sulfonylamino)acetylene, a nitrile, and
the titanium reagent to yield titanated aminopyridines, and (iv) a combination of an acetylenic amide, a
terminal acetylene, a nitrile, and the titanium reagent to yield pyridineamides with their side chain titanated.
Some of these reactions enabled virtually completely regioselective coupling of two different, unsymmetrical
acetylenes and a nitrile to form a single pyridine. Synthetic applications of these reactions have been
illustrated in the preparation of optically active pyridines and medicinally useful compounds.
Introduction
Pyridines are a most fundamental heterocyclic compound, and
numerous methods for their preparation have been developed.1
Among these methods, Reppe-type reactions, that is, the cycli-
zation of two molecules of acetylenes and one molecule of nitrile
as formulated in eq 1, attract much attention,2,3 because this
protocol is conceptually straightforward, requires simple starting
materials, and provides synthetic versatility. However, one prob-
lem associated with this transformation is that of regioselectivity.
Completely organized assembly of two different unsymmetrical
acetylenes and one nitrile, giving a single pyridine, is an ideal
goal of this transformation and is essential also from the practical
point of view.3-5 In addition, in consideration of the pivotal
role of organometallic compounds in current organic synthesis,
we conceived that a direct preparation of a pyridylmetal
reagent,1c a new transformation as formulated in eq 2, would
be an attractive alternative of eq 1. In this article, we describe
(3) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Chem. Commun. 1973, 280.
Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Dalton Trans. 1978, 1278-
1282. There had been no reports on the selective cyclotrimerization of two
different, unsymmetrical acetylenes and a nitrile before we and others
reported such examples (see refs 4 and 5). For recent reports, which deal
with cyclotrimerization of the same (ref 3a-h), symmetrical (ref 3i), or
tethered (ref 3j-p) substrates, see: (a) Bianchini, C.; Meli, A.; Peruzzini,
M.; Vacca, A.; Vizza, F. Organometallics 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, 11, 1275-1288. (c) Viljoen J. S.; du Plessis,
J. A. K. J. Mol. Catal. 1993, 79, 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, 179-180. (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, 4994-4995. (j) Saa´, C.; Crotts, D. D.; Hsu, G.; Vollhardt,
K. P. C. Synlett 1994, 487-489. (k) Takai, K.; Yamada, M.; Utimoto, K.
Chem. Lett. 1995, 851-852. (l) Varela, J. A.; Castedo, L.; Saa´, C. J. Org.
Chem. 1997, 62, 4189-4192. (m) Varela, J. A.; Castedo, L.; Saa´, C. J.
Am. Chem. Soc. 1998, 120, 12147-12148. (n) Varela, J. A.; Castedo, L.;
Saa´, 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.
† Department of Biological Information.
‡ Department of Biomolecular Engineering.
(1) For reviews, see: (a) ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 2. (b)
Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001, 2491-2515. (c)
Mongin, F.; Que´guiner, G. Tetrahedron 2001, 57, 4059-4090. (d) Henry,
G. D. Tetrahedron 2004, 60, 6043-6061. (e) Katritzky, A. R., Ed. Chem.
ReV. 2004, 104, 2127-2812.
(2) For reviews, see: (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104,
2127-2198. (b) Varela, J. A.; Saa´, C. Chem. ReV. 2003, 103, 3787-3802.
(c) Bo¨nnemann, H.; Brijoux, W. In Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 1, pp 114-
135. (d) Grotjahn, D. B. In ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon
Press: Oxford, 1995; Vol. 12, pp 741-770. (e) Chelucci, G. Tetrahedron:
Asymmetry 1995, 6, 811-826. (f) Schore, N. E. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 5, pp 1129-1162. (g) Bo¨nnemann, H. Angew. Chem., Int. Ed. Engl.
1985, 24, 248-262. (h) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl.
1984, 23, 539-556.
9
7774
J. AM. CHEM. SOC. 2005, 127, 7774-7780
10.1021/ja050261e CCC: $30.25 © 2005 American Chemical Society

One-Pot Synthesis of Metalated Pyridines
A R T I C L E S
Scheme 1. Formulation of New Synthesis of Metalated Pyridines
Scheme 2. Preparation of Metalated Pyridines
new syntheses of metalated pyridines according to eq 2, where
solutions to the above two issues are presented.
The transformation of eq 2 described in this article will be
divided into four categories, types A-D, as shown in Scheme
1. These transformations always involve a combination of
acetylenes, a nitrile, and a low-valent titanium reagent under
similar reaction conditions, but the products cover a wide range
of metalated pyridines, which will be discussed in order.
Scheme 3. Proposed Reaction Course
Results and Discussion
Type-A Preparation of Pyridines from Two Acetylenes
and a Nitrile Having a Leaving Group. Two different, unsym-
metrical acetylenes 1 and 2 (as the first and second acetylenes)
were first treated with a divalent titanium alkoxide reagent, Ti-
(O-i-Pr)4/2i-PrMgCl (3),6,7 at -50 °C to generate dialkoxytitan-
acyclopentadienes 4 in a highly regioselective manner according
to the previously published protocol (Scheme 2).8 Then, p-
toluenesulfonylnitrile (5, TolSO2- ) p-MeC6H4SO2-)9 was
added as the nitrile component. After hydrolytic workup of the
reaction mixture, pyridine 7 was obtained as a single isomer,
showing that the regioselective uptake of the nitrile into the ti-
tanacyclopentadiene 4 took place. More importantly, deuteri-
olysis gave deuterated counterpart 7d with high deuterium in-
corporation at the depicted position, confirming the presence
of pyridyltitanium compounds 6 before aqueous workup (type
A in Scheme 1). The pyridylmetal species 6, in fact, enabled
subsequent transformations:10,11 on treatment of 6 with iodine,
allyl bromide, or ethylidenemalonate-furnished iodopyridine 8
or homologated aromatic compounds 9 and 10 (Scheme 2).
Thus, an advantageous feature of the formation of titanated pyri-
dines 6 over the conventional metal-catalyzed pyridine synthesis
(eq 1) was demonstrated.
The reaction course may be explained by either path a or b
in Scheme 3.12 Path a involves the [4 + 2]-type cycloaddition
of titanacycle 4 and nitrile 5. The carbon-titanium bond in the
resultant titanacycle 11 rearranges to a suitable position to
eliminate the sulfonyl group (12) to complete the aromatization
(f6). Alternatively, in path b, regioselective insertion of nitrile
5 to the titanacycle 4 followed by electrocyclization of 13
yielded 14, from which the elimination of the sulfonyl group
took place via 12 to furnish the same final product 6 as in path
a. In any event, the high regioselectivity of the cycloaddition
(in path a) or that of the insertion reaction (in path b), most
likely controlled by the amide group in 4, is the key to the
selective formation of single metalated pyridine 6.
(4) Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2002, 124,
3518-3519. Portions of type-A and type-D reactions in Scheme 1 have
been reported in this communication.
(5) Takahashi, T.; Tsai, F.-Y.; Li. Y.; Wang, H.; Kondo, Y.; Yamanaka, M.;
Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 5059-5067.
(6) Sato, F.; Urabe, H. In Titanium and Zirconium in Organic Synthesis; Marek,
I., Ed.; Wiley-VCH: Weinheim, 2002; pp 319-354. Sato, F.; Okamoto,
S. AdV. Synth. Catal. 2001, 343, 759-784. Sato, F.; Urabe, H.; Okamoto,
S. Chem. ReV. 2000, 100, 2835-2886.
(7) Eisch, J. J. J. Organomet. Chem. 2001, 617-618, 148-157. Kulinkovich,
O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789-2834.
(8) Sato, F.; Urabe, H.; Okamoto, S. Pure Appl. Chem. 1999, 71, 1511-1519.
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-
7344. Urabe, H.; Nakajima, R.; Sato, F. Org. Lett. 2000, 2, 3481-3484.
(9) p-Toluenesulfonylnitrile is commercially available.
More examples of the present synthesis of metalated pyridines
achieving the coupling of two different unsymmetrical acetyl-
(10) For synthetic application of organotitanium compounds, see: Reetz, M. T.
Organotitanium Reagents in Organic Synthesis; Springer-Verlag: Berlin,
1986. Ferreri, C.; Palumbo, G.; Caputo, R. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 1, pp 139-172. Reetz, M. T. In Organometallics in Synthesis;
Schlosser, M., Ed.; Wiley: Chichester, 1994; pp 195-282.
(11) Urabe, H.; Hamada, T.; Sato, F. J. Am. Chem. Soc. 1999, 121, 2931-
2932.
(12) However, the intermediates in this scheme so far remain unidentified.
9
J. AM. CHEM. SOC. VOL. 127, NO. 21, 2005 7775

A R T I C L E S
Tanaka et al.
enes and a nitrile are shown in eq 3 in order to reinforce its
generality. Various acetylenic amides (as the first acetylene)
and the second acetylenes afforded the desired products 19-
22 under the same reaction conditions as Scheme 2. In all cases,
the presence of the intermediate metalated pyridines was
guaranteed by deuteriolysis.
Figure 1. Benzocyclohepatapyridines.
Scheme 4. Synthesis of 30
In place of the acetylenic amides, acetylenic ester 23 afforded
the expected pyridine 24a as a single isomer as well after
hydrolysis (eq 4) yet accompanied with a small amount of
sulfonylated pyridine 24b. The latter product 24b may arise from
aerial oxidation of dihydropyridines produced by the hydrolysis
of the intermediate titanium species such as 11, 12, 14, etc. in
Scheme 3 before elimination of the sulfonyl group.13 Thus, this
observation implies that the reaction most likely proceeds via
the proposed path depicted in Scheme 3. When the reaction
was started with dialkylacetylene 25 (eq 5), the regiochemical
control of the nitrile uptake appears to be problematic, because
both R-substituents of the intermediate titanacyclopentadiene
26 are alkyl groups that are hardly discriminated. However, eq
5 highlighted a device to secure the regioselective incorporation
of the nitrile, where the neighboring benzyl ether in the side
chain apparently controls the direction of the incoming nitrile
to achieve the selective production of 27.14
allergic substance15a and is actually sold under the commercial
name Claritin (Figure 1). Its substituted derivatives having a
common structure of benzocycloheptapyridine 29 have been
synthesized and were subjected to medicinal evaluation.15
A
derivative 3015b was chosen as a representative synthetic target
to demonstrate the utility of the aforementioned coupling of
acetylenes and a nitrile (retrosynthetic analysis, Figure 1).
Acetylenic amide 31 equipped with a chlorophenyl group,
phenylacetylene (2), and nitrile 5 were submitted to the titanium-
mediated coupling reaction, which proceeded without difficulty
to give 33 after hydrolytic workup (Scheme 4). A few additional
steps consisting of (i) a functional group transformation (33f
The quick assembly of acetylenes and nitriles to yield pyridine
derivatives as shown above should be particularly useful for
the construction of polysubstituted pyridines often found in
medicinally important substances. Loratadine (28) is an anti-
(15) (a) Schumacher, D. P.; Murphy, B. L.; Clark, J. E.; Tahbaz, P.; Mann, T.
A. J. Org. Chem. 1989, 54, 2242-2244. (b) Wong, J. K.; Piwinski, J. J.;
Green, M. J.; Ganguly, A. K.; Anthes, J. C.; Billah, M. M. Bioorg. Med.
Chem. Lett. 1993, 3, 1073-1078. (c) Njoroge, F. G.; et al. J. Med. Chem.
1997, 40, 4290-4301. (d) Njoroge, F. G.; et al. J. Med. Chem. 1998, 41,
4890-4902. (e) Njoroge, F. G.; Vibulbhan, B.; Pinto, P.; Chan, T.-M.;
Osterman, R.; Remiszewski, S.; Rosario, J. D.; Doll, R.; Girijavallabhan,
V.; Ganguly, A. K. J. Org. Chem. 1998, 63, 445-451. (f) Cooper, A. B.;
Strickland, C. L.; Wang, J.; Desai, J.; Kirschmeier, P.; Patton, R.; Bishop,
W. R.; Weber, P. C.; Girijavallabhan, V. Bioorg. Med. Chem. Lett. 2002,
12, 601-605.
(13) When the reaction was quenched at a lower temperature (-50 °C),
sulfonylpyridine 24b became a major constituent (24b and 24a in 37 and
28% yields, respectively).
(14) For additional control experiments and discussion, see the Experimental
Section.
9
7776 J. AM. CHEM. SOC. VOL. 127, NO. 21, 2005

One-Pot Synthesis of Metalated Pyridines
A R T I C L E S
Scheme 5
34), (ii) Grignard addition (34 f 35), and finally (iii) Swern
oxidation afforded the intermediate 36, which was cyclized
under acidic conditions to give known benzocycloheptapyridine
3015b in good yields for each step. More substituted derivatives
29 in Figure 1 may be analogously obtained by interception of
the titanated pyridine 32 with an appropriate electrophile in place
of the simple hydrolysis exemplified in Scheme 4.
Type-B Preparation of Pyridines from Two Acetylenes,
One of Which Has a Leaving Group, and a Nitrile. The
proposed mechanism of the cyclization of type A suggested that
an acetylene having a leaving group (37, X ) leaving group)
could give a similar intermediate 39 like 11 or 12 in Scheme 3,
even when the nitrile does not have a leaving group (Scheme
5). This intermediate 39 then collapses to give a metalated
pyridine 40, which is an alternative to the products of type-A
transformation. The choice of the acetylene 37 is important,
because reasonable candidates, halo- or sulfonyl acetylenes (an
analogue of sulfonylnitrile 5), proved not to be suitable for this
purpose.16 However, during the course of our study on the
preparation and utility of (sulfonylamino)acetylenes,17,18 we
happened to find that these aminoacetylenes nicely fulfill the
above requirement for the requisite acetylene 37.
Figure 2. Preparation of pyridines after hydrolysis or deuteriolysis of the
reaction according of eq 6.
47 was selectively obtained in good yield. Alternatively, deu-
teriolysis gave 47-d, confirming the presence of titanated
pyridine 46 as an intermediate (type B, Scheme 1). The reaction
path may be drawn as 43 f 45 f 46, which was already
proposed in Scheme 5. Apparently, the elimination of the
sulfonamide group, which permits direct aromatization and thus
makes the overall reaction irreversible, is a driving force of this
reaction.
Other pyridines prepared by this method are summarized in
Figure 2. Dianisylacetylene in place of diphenylacetylene (41)
in eq 6 afforded pyridine 48. Unsymmetrical acetylenes such
as aryl(silyl)acetylenes underwent the regioselective coupling
with aminoacetylene 42 to generate single titanacyclopenta-
dienes, which reacted with nitrile 44 or R-methoxyacetonitrile
(53) again in a highly regioselective manner to give single
pyridines 49-52 in good yields. When R-methoxyacetonitrile
(53) was used as a nitrile component instead of 44, the formation
of the corresponding metalated 52 before aqueous workup was
again verified by deuteriolysis. In these reactions, R-hetero-
substituted nitriles such as 44 and 53 are an acceptable choice
for the nitrile, and they serve for the preparation of pyridines
having an R-functionalized side chain; but simple octanonitrile
or benzonitrile did not give the desired products.19 Although
the intermolecular coupling of acetylenes and nitriles shown in
eq 6 and Figure 2 was so far successful only for the first
acetylenes having at least one aryl group, an intramolecular
version is not subject to such limitation. Thus, bicyclic pyridines
56 and 57 are available by the cyclization of aminodiynes 54
and 55 (eq 7), showing increasing synthetic flexibility.
The coupling of internal acetylene 41 and (p-toluenesulfo-
nylamino)acetylene 42,18 according to a published procedure,17
generated the titanacyclopentadiene 43, which was then allowed
to react with nitrile 44 (eq 6). After aqueous workup, pyridine
Type-C Preparation of Aminopyridines from Two Acety-
lenes, One of Which Has a Leaving Group, and a Nitrile.
(16) Sulfonylacetylene and haloacetylene undergo the double addition to
titanacyclopropene and the elimination of halide, respectively. See: Suzuki,
D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123, 7925-7926.
Morlender-Vais, N.; Kaftanov, J.; Marek, I. Synthesis 2000, 917-920.
(17) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67-70.
9
J. AM. CHEM. SOC. VOL. 127, NO. 21, 2005 7777

A R T I C L E S
Tanaka et al.
Scheme 6. Preparation of Aminopyridines by Type-C Synthesis
group from p-toluenesulfonyl to bulky mesitylenesulfonyl
(MesSO2- ) (2,4,6-Me3C6H2)SO2-) group increased the ratio
(hence the yield) of the aminopyridine 62.20
Equation 8 summarizes the type-C synthesis of aminopy-
ridines utilizing [(mesitylenesulfonyl)amino]acetylene (65) as
the second acetylene. A variety of diarylacetylenes and R-meth-
oxynitriles afforded the aminopyridine derivatives 62 and 66-
71.21 The methoxy group of product 67 could be readily
demethylated with a routine reagent, BBr3, to give the corre-
sponding alcohol 72, if necessary (eq 9).
Scheme 7. Choice of Leaving Group
While we were investigating the type-B preparation of
pyridines from diphenylacetylene (41) and R-methoxyacetoni-
trile (53) (rather than chloroacetonitrile 44 in eq 6), we found
that an unknown product (62) became a major component
accompanied by the expected pyridine 60 that was a minor
component in the reaction this time (Scheme 6). Spectroscopic
analysis showed the structure of the unknown compound to be
aminopyridine 62 on the following basis that it lacks a
p-toluenesulfonyl group but has a polar amino group as well as
a pyridine ring. The manifold to the products 60 or 62 comes
from the elimination of the sulfonylamino group from the
common intermediate 58 to give 59 and finally 60 (type B) or
that of the sulfonyl group from 58 to give 61 and 62 (type C).
As aminopyridine is a useful functionalized pyridine derivative,
we focused our attention on increasing its composition (Scheme
7). Facile elimination of the sulfonyl group should require a
perpendicular relationship between the carbon-titanium and
nitrogen-sulfonyl bonds as depicted in 64 of Scheme 7. Thus,
the sterically demanding sulfonyl group may occupy the less
hindered position 64 (rather than 63), which fulfills the above
assumption on the favorable orientation of the C-Ti and
N-sulfonyl bonds. Actually, switching the amino-protecting
Type-D Preparation of Pyridinecarbaldehydes. In the
preceding sections, the titanium-mediated coupling of acetylenes
and a nitrile, one of which has a leaving group, furnished directly
metalated pyridines. At first glance, the presence of a leaving
group appears mandatory. However, we found that a certain
functional group could work as a surrogate of the leaving group,
which will be discussed in this section. Titanacyclopentadiene
73, prepared from two different, unsymmetrical acetylenes 1
and 16, was allowed to react with R-methoxyacetonitrile (53)
(20) For examples of elimination of a leaving group on nitrogen by a neighboring
carbanionic site, see: Scho¨nberg, A.; Moubacher, R. Chem. ReV. 1952,
50, 261-277. Smith, R. F.; Walker, L. E. J. Org. Chem. 1962, 27, 4372-
4375. Foley, H. G.; Dalton, D. R. J. Chem. Soc., Chem. Commun. 1973,
628-629.
(21) Diarylheterocycles are frequently seen in derivatives of drugs. Toma, L.;
Giovannoni, M. P.; Piaz, V. D.; Kwon, B.-M.; Kim, Y.-K.; Gelain, A.;
Barlocco, D. Heterocycles 2000, 53, 2709-2718. Toma, L.; Nava, D.;
Celentano, G.; Giovannoni, M. P.; Piaz, V. D.; Kwon, B.-M.; Kim, M.-K.;
Kim, Y.-K.; Barlocco, D. Heterocycles 2000, 53, 2709-2718. Boger, D.
L.; Soenen, D. R.; Boyce, C. W.; Hedrick, M. P.; Jin, Q. J. Org. Chem.
2000, 65, 2479-2483. Stoit, A. R.; Lange, J. H. M.; Hartog, A. P.; Ronken,
E.; Tipker, K.; Stuivenberg, H. H.; Dijksman, J. A. R.; Wals, H. C.; Kruse,
C. G. Chem. Pharm. Bull. 2002, 50, 1109-1113. Kudo, N.; Furuta, S.;
Taniguchi, M.; Endo, T.; Sato, K. Chem. Pharm. Bull. 1999, 47, 857-
868.
(18) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727-729.
(19) This suggests the importance of the presence of a coordinating moiety in
the nitrile. See: ref 4 and the following. Bertus, P.; Szymoniak, J. J. Org.
Chem. 2002, 67, 3965-3968. Nonetheless, as R-oxynitriles and their
derivatives are readily obtained by the cyanohydrin synthesis and its
modifications, this reaction will find reasonable application. See: North,
N., Ed. Tetrahedron (Symposium-in-Print) 2004, 60, 10385-10568.
9
7778 J. AM. CHEM. SOC. VOL. 127, NO. 21, 2005

One-Pot Synthesis of Metalated Pyridines
A R T I C L E S
Scheme 8. Reaction of Various Nitriles
(eq 10). After aqueous workup, what we obtained was not a
pyridineamide expected from the starting material 1 but was
pyridinecarbaldehyde 79, which was produced as a single isomer
(eq 10, hence, type D in Scheme 1). To clarify the mechanism
of this reaction, the above hydrolytic workup was replaced by
deuteriolysis, which revealed that the aldehyde hydrogen of 79
was substituted by deuterium. On the basis of these observations,
a plausible reaction course is shown in eq 10. The nitrile was
regioselectively incorporated into the titanacycle 73 to generate
the intermediate 76 or 77, from which the titanium portion
shifted to the amide group to result in the irreversible aroma-
tization as well as the formation of η2-carbonyl-titanium
complex 78.22 Finally, hydrolysis (or deuteriolysis) of the
η2-carbonyl-titanium complex gave the (deuterated) aldehyde
79.
molecules was achieved in one pot in the overall reactions of
Scheme 8.
Besides other products 80-83 obtained from a variety of
acetylenes and nitriles as shown in eq 10, an intriguing utility
of the metalated portion of 78 was demonstrated by its reac-
tion with a pronucleophile. When the same reaction was
started with excess R-chloroacetonitrile (44) or R-vinylaceto-
nitrile (84) (Scheme 8), the reaction proceeded beyond the
common intermediate 85 via the proton exchange reaction
with the initially added nitrile (85 f 86). In the case of 44, a
new product 87 was finally produced and was isolated as a
mixture of diastereoisomers. However, this product 87
On the other hand, R-bromoacetonitrile (90) afforded a
different pyridine 92 most likely via the titanium transfer
reaction from the intermediate 91 to 90 to regenerate the amide
group in 92 (eq 11)23 rather than the proton transfer as shown
in Scheme 8. That an appropriate choice of the substituted
acetonitriles, 44, 84, or 90, could lead to different types of
1
(22) For the generation of carbonyl group-group 4 metal complexes and their
synthetic application, see: Erker, G.; Rosenfeldt, F. J. Organomet. Chem.
1982, 224, 29-42. Davis, J. M.; Whitby, R. J. Tetrahedron Lett. 1992, 33,
5655-5658. Mori, M.; Uesaka, N.; Saitoh, F.; Shibasaki, M. J. Org. Chem.
1994, 59, 5643-5649. Barluenga, J.; Sanz, R.; Fan˜ana´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.
(23) This may come from lower R acidity of 90 as compared to that of 44 or
84. Moreover, the irreversible elimination of the most reactive bromo group
(among 90, 44, and 84) from titanated 90 should force the titanium transfer
reaction from 91 to 90.
spontaneously isomerized in CDCl3 (by H NMR monitoring)
at room temperature overnight to yield another diastereo-
meric mixture of 88 in 50% yield based on the starting
acetylenes. Similarly, when vinylacetonitrile (84) was used,
two molecules of the nitrile were eventually incorporated to
give pyridine 89 as a mixture of separable olefinic stereoiso-
mers. It should be noted that the selective coupling of four
9
J. AM. CHEM. SOC. VOL. 127, NO. 21, 2005 7779

A R T I C L E S
Tanaka et al.
Conclusion
substituted pyridines is an interesting aspect of this transforma-
tion.
Combination of two acetylenes, various nitriles, and the titan-
ium alkoxide reagent produced a variety of titanated pyridines
in four different ways. Some of these reactions executed a vir-
tually completely regioselective coupling of two different, un-
symmetrical acetylenes and a nitrile, which is a difficult task
and is quite important from the synthetic point of view. In ad-
dition, as the starting materials and reagents required in this
reaction are readily available, the present pyridine syntheses
are practically preferable. The utility of the resultant titanated
pyridines has been demonstrated through the reaction of repre-
sentative electrophiles, which enables the coupling of four com-
ponents in one pot. Further search for new versions of these re-
actions and synthetic utility of metalated pyridines is in progress.
Acknowledgment. This work was supported, in part, by a
Grant-in-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules” (to F.S.) and
Scientific Research on Priority Area “Creation of Biologically
Functional Molecules” (to H.U.) from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and also by
The Sumitomo Foundation (to H.U.). D.S. thanks the Japan
Society for the Promotion of Science for a Research Fellowship
of the Japan Society for the Promotion of Science for Young
Scientists. R.T. acknowledges a Grant of the 21st Century COE
Program, Ministry of Education, Culture, Sports, Science and
Technology, Japan.
When the pyridine synthesis is started with optically active
R-oxynitriles, optically active pyridinecarbaldehydes may be
obtained. However, as the reaction conditions are apparently
basic in the presence of titanium alkoxide, and the titanium in
the intermediate 77 (eq 10) could undergo a â-hydrogen
elimination/addition sequence to cause racemization, it is not
necessarily guaranteed that the optical purity of the nitriles is
retained throughout this reaction. Equation 12 shows the
preparation of pyridinecarbaldehydes 95-99 from optically
active lacto- or mandelonitriles 93 or 94.2e To our satisfaction,
the products always kept a high level of enantiopurity, indicating
that the type-D reaction provides a straightforward method to
prepare optically active pyridines in one pot.
Supporting Information Available: Experimental section and
complete refs 15c and 15d (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA050261E
9
7780 J. AM. CHEM. SOC. VOL. 127, NO. 21, 2005