Facile preparation of various heteroaromatic compounds via azatitanacyclopentadiene intermediates

Article abstract of DOI:10.1021/ja0502730

Coupling of acetylene, nitrile, and a titanium reagent, Ti(O-i-Pr) ₄/2 i-PrMgCl, generated new azatitanacyclopentadienes in a highly regioselective manner. Their subsequent reaction with sulfonylacetylene afforded pyridyltitanium compounds, which, upon reaction with electrophiles, gave substituted pyridines virtually as a single isomer. When optically active nitriles were used in this reaction, chiral pyridines were obtained without loss of the enantiopurity. Alternatively, the azatitanacyclopentadiene prepared from an unsymmetrical acetylene reacted with an aldehyde or another nitrile to give furans or pyrroles having four different substituents again in a regioselective manner.

Full text of DOI:10.1021/ja0502730

Published on Web 04/27/2005
Facile Preparation of Various Heteroaromatic Compounds via
Azatitanacyclopentadiene Intermediates
†
‡
‡
‡
†
Daisuke Suzuki, Youhei Nobe, Yuko Watai, Ryoichi Tanaka, Yuuki Takayama,
,
†
,†,‡
Fumie Sato,* and Hirokazu Urabe*
Contribution from the Departments of Biomolecular Engineering and Biological Information,
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.
4
Abstract: Coupling of acetylene, nitrile, and a titanium reagent, Ti(O-i-Pr) /2 i-PrMgCl, generated new
azatitanacyclopentadienes in a highly regioselective manner. Their subsequent reaction with sulfonylacety-
lene afforded pyridyltitanium compounds, which, upon reaction with electrophiles, gave substituted pyridines
virtually as a single isomer. When optically active nitriles were used in this reaction, chiral pyridines were
obtained without loss of the enantiopurity. Alternatively, the azatitanacyclopentadiene prepared from an
unsymmetrical acetylene reacted with an aldehyde or another nitrile to give furans or pyrroles having four
different substituents again in a regioselective manner.
Introduction
acetonitrile (6) was added to complex 5 at the same temperature
to form dialkoxyazatitanacyclopentadiene 7, which was identi-
Titanacyclopentadienes 2 generated from acetylenes and a
divalent titanium alkoxide reagent, Ti(O-i-Pr)4/2 i-PrMgCl (1),
have been utilized for various transformations (eq 1). On the
other hand, their nitrogen analogue, azatitanacyclopentadienes
fied by hydrolysis or deuteriolysis to give R,â-unsaturated ketone
with high deuterium incorporation at the specified position
8
1
,2
4
in good yield.
3
possibly prepared by the same coupling reaction of acetylene
and nitrile, has not yet been explored (eq 2), because the
attempted generation of azatitanacyclopentadiene 3 from an
alkanenitrile or benzonitrile is so far unsuccessful. However,
we describe here that certain nitriles such as R-heterofunction-
alized ones exceptionally undergo the titanium-mediated cou-
pling with an acetylene to generate the desired azatitanacyclo-
pentadiene 3 in good yield.3
The azatitanacyclopentadienes 3, as exemplified by 7 in eq
3
, proved to be a useful intermediate for new synthesis of
heterocyclic compounds such as metalated pyridines 9, furans
0, and pyrroles 11 through reaction with another unsaturated
1
(
3) For other azametallacyclopentadienes of group 4 metals, see: Buchwald,
S. L.; Nielsen, R. B. Chem. ReV. 1988, 88, 1047-1058. Negishi, E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, U.K., 1991; Vol. 5, pp 1163-1184. Negishi, E.;
Takahashi, T. Acc. Chem. Res. 1994, 27, 124-130. Fagan, P. J.; Nugent,
W. A.; Calabrese, J. C. J. Am. Chem. Soc. 1994, 116, 1880-1889.
Takahashi, T.; Xi, C.; Xi, Z.; Kageyama, M.; Fischer, R.; Nakajima, K.;
Negishi, E. J. Org. Chem. 1998, 63, 6802-6806.
Thus, 5-decyne (4) was first treated with a divalent titanium
alkoxide reagent, Ti(O-i-Pr)4/2 i-PrMgCl (1) at -50 °C, to give
a known acetylene-titanium complex 5 (eq 3).1 R-Methoxy-
,2
†
Department of Biomolecular Engineering.
Department of Biological Information.
‡
(4) This suggests the importance of the presence of a coordinating moiety in
the nitrile. See ref 8 and the following: Bertus, P.; Szymoniak, J. J. Org.
Chem. 2002, 67, 3965-3968. Nonetheless, since 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.
Utimoto, K.; Wakabayashi, Y.; Shishiyama, Y.; Inoue, M.; Nozaki, H.
Tetrahedron Lett. 1981, 22, 4279-4280.
(
1) Sato, F.; Urabe, H. In Titanium and Zirconium in Organic Synthesis; Marek,
I., Ed.; Wiley-VCH: Weinheim, Germany, 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. Sato, F.; Urabe, H.;
Okamoto, S. Pure Appl. Chem. 1999, 71, 1511-1519.
(
2) Eisch, J. J. J. Organomet. Chem. 2001, 617-618, 148-157. Kulinkovich,
O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789-2834.
7474
9
J. AM. CHEM. SOC. 2005, 127, 7474-7479
10.1021/ja0502730 CCC: $30.25 © 2005 American Chemical Society

Facile Preparation of Heteroaromatic Compounds
A R T I C L E S
Scheme 1. Preparation of Heteroaromatic Compounds
Scheme 2. Preparation of Metalated Pyridine
compound, as summarized in Scheme 1. These transformations
consist of an organized assembly of unsaturated compounds
around the titanium reagent, allowing a one-pot, multicomponent
coupling process, which will be described in order.
Results and Discussion
Preparation of Pyridines. Among a wide variety of prepara-
tive methods of pyridines, cycloaddition of two acetylenes and
a nitrile has attracted much attention.6,7 Starting from titanacy-
clopentadienes 2, we have recently reported a selective pyridine
synthesis (i.e., 13) by the coupling with p-toluenesulfonylnitrile
12, TolSO2- ) p-MeC6H4SO2-) (eq 4).8,9 If a similar reaction
5
is started with azatitanacyclopentadienes 3 and these successfully
undergo the uptake of a likely reaction partner, sulfonylacetylene
10
1
4 in eq 5, metalated pyridines 15 with a different substitution
pattern will be produced.
(
(
5) For reviews, see: (a) Katritzky, A. R., Rees, C. W., Eds. ComprehensiVe
Heterocyclic Chemistry; Pergamon Press: Oxford, U.K., 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. (d) Henry,
G. D. Tetrahedron 2004, 60, 6043-6061. (e) Katritzky, A. R., Ed. Chem.
ReV. 2004, 104, 2127-2812.
(6) For reviews, see: (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104,
2
127-2198. (b) Varela, J. A.; Sa a´ , C. Chem. ReV. 2003, 103, 3787-3802.
(
c) B o¨ nnemann, H.; Brijoux, W. In Transition Metals for Organic Synthesis;
Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, Germany, 1998; Vol.
, pp 114-135. (d) Grotjahn, D. B. In ComprehensiVe Organometallic
1
Chemistry II; Hegedus, L. S., Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon Press: Oxford, U.K., 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, U.K., 1991; Vol. 5, pp 1129-1162. (g)
B o¨ 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.
7) (a) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Chem. Commun. 1973,
To azatitanacycle 7 generated from 4 and 6 as described in
eq 3 was added sulfonylacetylene 14, and the reaction was
11
continued at -30 °C (Scheme 2). Gratifyingly, the formation
of a single pyridine 18 was observed after aqueous workup.
The presence of the titanated pyridine 17 was separately
confirmed by its deuteriolysis to give 18-d with high deuterium
incorporation. A proposed mechanism of this reaction is also
depicted in Scheme 2. Sulfonylacetylene 14 was incorporated
into the azatitanacycle 7 in a regioselective manner to give
(
2
80. (b) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Dalton Trans. 1978,
278-1282. There had been no reports on the selective cyclotrimerization
1
of two different unsymmetrical acetylenes and a nitrile, before we and others
reported such examples (see refs 8 and 9). For recent reports, which deal
with the cyclotrimerization of the same (refs 7c-j), symmetrical (ref 7k),
or tethered (refs 7l-r) substrates, see: (c) Bianchini, C.; Meli, A.; Peruzzini,
M.; Vacca, A.; Vizza, F. Organometallics 1991, 10, 645-651. (d) Smith,
D. P.; Strickler, J. R.; Gray, S. D.; Bruck, W. A.; Holmes, R. S.; Wigley,
D. E. Organometallics 1992, 11, 1275-1288. (e) Viljoen J. S.; du Plessis,
J. A. K. J. Mol. Catal. 1993, 79, 75-84. (f) Diversi, P.; Ermini, L.; Ingrosso,
G.; Lucherini, A. J. Organomet. Chem. 1993, 447, 291-298. (g) Hill, J.
E.; Balaich, G.; Fanwick, P. E.; Rothwell, I. P. Organometallics 1993, 12,
1
2
intermediates 16a,b. Elimination of the sulfonyl group from
16b leads to the formation of the pyridyltitanium compound
1
7.
Other results of the present pyridine synthesis are summarized
2
2
1
3
1
911-2924. (h) Jerome, K. S.; Parsons, E. J. Organometallics 1993, 12,
991-2993. (i) Heller, B.; Oehme, G. J. Chem. Soc., Chem. Commun.
995, 179-180. (j) Fatland, A. W.; Eaton, B. E. Org. Lett. 2000, 2, 3131-
133. (k) Takahashi, T.; Tsai, F.-Y.; Kotora, M. J. Am. Chem. Soc. 2000,
22, 4994-4995. (l) Sa a´ , C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P. C.
in Table 1. Besides simple R-methoxyacetonitrile (6), a branched
homologue 20 afforded the desired pyridine 21 (entry 2) and
25 (entry 5) in good yield. Silylacetylene 22 underwent the
regioselective coupling with nitrile 6, followed by the regio-
selective uptake of sulfonylacetylene 14, to yield virtually single
titanated pyridines, which, after hydrolysis or deuteriolysis, gave
pyridine 23 or its deuterium-labeled compound 23-d (entry 3).
The synthetic utility of the pyridyltitanium species was further
Synlett 1994, 487-489. (m) Takai, K.; Yamada, M.; Utimoto, K. Chem.
Lett. 1995, 851-852. (n) Varela, J. A.; Castedo, L.; Sa a´ , C. J. Org. Chem.
1
997, 62, 4189-4192. (o) Varela, J. A.; Castedo, L.; Sa a´ , C. J. Am. Chem.
Soc. 1998, 120, 12147-12148. (p) Varela, J. A.; Castedo, L.; Sa a´ , C. Org.
Lett. 1999, 1, 2141-2143. (q) Yamamoto, Y.; Okuda, S.; Itoh, K. Chem.
Commun. 2001, 1102-1103. (r) Yamamoto, Y.; Ogawa, R.; Itoh, K. J.
Am. Chem. Soc. 2001, 123, 6189-6190.
(
8) Suzuki, D.; Tanaka, R.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2002, 124,
3
518-3519. This reaction has the following feature: (i) single pyridines
were obtained, for the first time, from two different, unsymmetrical
acetylenes and a nitrile, and (ii) titanated pyridines were produced rather
than pyridines themselves.
(10) Suzuki, D.; Urabe, H.; Sato, F. J. Am. Chem. Soc. 2001, 123, 7925-7926.
(11) This is commercially available.
(
9) See also: Takahashi, T.; Tsai, F.-Y.; Li. Y.; Wang, H.; Kondo, Y.;
Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124,
5
(12) The intermediates 16a,b correspond to the [4 + 2]-type and insertion
059-5067.
mechanisms, respectively. See: ref 10.
J. AM. CHEM. SOC.
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A R T I C L E S
Suzuki et al.
Table 1. Preparation of Pyridines
Figure 1. Preparation of optically active pyridines according to eq 6. Dotted
lines show the position of newly formed carbon-carbon and carbon-
nitrogen bonds.
that of the starting nitrile, a convenient preparative method of
highly optically active pyridines was established.
Pyridine 45, which is a potential intermediate for the synthesis
1
4
of cyclothiazomycin (Scheme 3), was efficiently prepared by
Scheme 3. Preparation of Pyridine 45, a Key Compound to
Cyclothiazomycin
demonstrated by the preparation of iodopyridine 24 (entry 4).13
It should be emphasized that this transformation achieved a
completely organized assembly of two unsymmetrical acetylenes
and a nitrile and, when including an electrophile, a four-
component coupling process was executed in one pot. R-Chlo-
roacetonitrile (26) similarly participated in the reaction to give
(halomethyl)pyridine 27 (entry 6) in good yield after hydrolytic
workup. Like 1-silyl-1-alkyne 22, silyl(phenyl)acetylene 28
afforded the desired product 29 as well.
To prepare optically active pyridines, we carried out the
6
e
reaction of Scheme 2 with chiral R-oxynitriles 30 and 31 as
the starting material (eq 6). Since the reaction conditions are
apparently basic in the presence of titanium alkoxide and the
intermediate titanium species could undergo a â-hydrogen
elimination/addition sequence to cause racemization at the
benzylic position, the ee value of the products was individually
determined. Figure 1 summarizes the products 32-39 obtained
after routine hydrolysis, deuteriolysis, or iodinolysis. In all cases,
as the enantiomeric excess of the products did not change from
(
13) For synthetic application of organotitanium compounds, see: Reetz, M. T.
the above method. Acetylene 40, chiral nitrile 30, sulfonyl-
acetylene 14, and the titanium reagent 1 gave pyridyltitanium
species 41, which upon iodinolysis afforded single iodopyridine
Organotitanium Reagents in Organic Synthesis; Springer-Verlag: Berlin,
1
986. Ferreri, C.; Palumbo, G.; Caputo, R. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, U.K.,
1
991; Vol. 1, pp 139-172. Reetz, M. T. In Organometallics in Synthesis;
42. This compound was transformed to pyridinecarboxaldehyde
Schlosser, M., Ed.; Wiley: Chichester, U.K., 1994; pp 195-282. Urabe,
H.; Hamada, T.; Sato, F. J. Am. Chem. Soc. 1999, 121, 2931-2932.
43 by the reaction with t-BuLi and dimethylformamide (DMF).
7476 J. AM. CHEM. SOC.
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Facile Preparation of Heteroaromatic Compounds
A R T I C L E S
Then, acetalization and desilylation afforded pyridinediol 44.
Selective protection of its primary alcohol with tert-butyldiphen-
ylsilyl chloride ((TBDPS)Cl) gave the desired compound 45 of
Table 2. Preparation of Fully Substituted Furans
9
9% ee. Therefore, the key pyridine 45 was prepared in five
steps, in 25% overall yield, and with high optical purity,
improving its known synthetic route.15
Preparation of Furans. Since substituted furans are not only
a constituent of biologically active compounds but also a useful
intermediate in organic synthesis,1 their preparation in short
steps is quite desirable. During the course of our study, we found
that an aldehyde 46 also reacts with the carbon-titanium bond
of the azatitanacyclopentadiene to give directly polysubstituted
furans 47 as formulated in eq 7.17
6
The experimental procedure is quite simple as illustrated in
eq 8. To azatitanacyclopentadiene 7 generated from 4 and 6
was added benzaldehyde, and the reaction mixture was gradually
warmed to room temperature to give adduct 48. The reaction
mixture was quenched with 1 N HCl, which effected the
spontaneous cyclization and aromatization of 48 most likely via
4
9 to 50, eventually giving fully substituted furan 51.
four different substituents with nearly complete regioselectivity
entries 4-6). Diphenylacetylene (57) and benzaldehyde pro-
(
vided polyaromatic compound 58 in good yield (entry 7).
Among many known preparations of polysubstituted furans, this
multicomponent coupling process should provide an extremely
concise synthetic method.
Preparation of Pyrrolecarboxaldehydes. Functionalized
pyrroles are ubiquitous constituents in natural and artificial
organic compounds and are versatile starting materials for their
1
8
synthesis as well. Among such pyrroles, pyrrolecarboxalde-
hydes are one of the most representative members. However,
concise preparation of pyrrolecarboxaldehydes themselves,
Other results are summarized in Table 2. An aliphatic
aldehyde, nonanal, in place of the benzaldehyde in entry 1
furnished furan 52 in good yield (entry 2). Notably, an
unsymmetrical acetylene such as 1-(trimethylsilyl)-1-octyne
(17) Intermolecular double addition of acetylene-group 4 metal complexes to
electrophilic carbon-heteroatom multiple bonds such as aldehydes, ketones,
and imines is quite rare and is so far limited to a reactive acetylene complex
such as that derived from enyne or an active electrophile represented by
carbon dioxide: Hamada, T.; Mizojiri, R.; Urabe, H.; Sato, F. J. Am. Chem.
Soc. 2000, 122, 7138-7139. Gao, Y.; Shirai, M.; Sato, F. Tetrahedron
Lett. 1997, 38, 6849-6852. Six, Y. Eur. J. Org. Chem. 2003, 1157-1171.
To the contrary, the selective monoaddition of acetylene-group 4 metal
complexes to these compounds is well-documented in the following reviews.
See: refs 1-3.
(18) Ferreira, V. F.; de Souza, M. C. B. V.; Cunha, A. C.; Pereira, L. O. R.;
Ferreira, M. L. G. Org. Prep. Proc. Int. 2001, 33, 411-454. Katritzky, A.
R., Rees, C. W., Eds. ComprehensiVe Heterocyclic Chemistry; Pergamon
Press: Oxford, U.K., 1984; Vol. 4. References 5b,e.
(
22), nitrile 6, and an aldehyde afforded furans 54-56 having
(
14) Okabe, A.; Ito, A.; Okamura, K.; Shin, C. Chem. Lett. 2001, 380-381.
Shin, C.; Okabe, A.; Ito, A.; Ito, A.; Yonezawa, Y. Bull. Chem. Soc. Jpn.
2
002, 75, 1583-1596. Endoh, N.; Yonezawa, Y.; Shin, C. Bull. Chem.
Soc. Jpn. 2003, 76, 643-644.
(
15) Pyridine 45 was previously prepared in 10 steps, in 8% overall yield, and
as 96% ee from 1,1-dimethoxy-2-propanone. See: ref 14.
(
16) For reviews, see: Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.;
Lo, T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955-
2
020. Katritzky, A. R., Rees, C. W., Eds. ComprehensiVe Heterocyclic
Chemistry; Pergamon Press: Oxford, U.K., 1984; Vol. 4. References 5b,e.
J. AM. CHEM. SOC.
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A R T I C L E S
Suzuki et al.
Scheme 5. Regiochemical Aspects of the Pyrrole Formation
especially that of polysubstituted ones in a regioselective
manner, is quite limited, because they are usually derived from
the parent pyrroles in a stepwise manner.18,19 In this section,
we describe a novel and straightforward synthesis of pyrrole-
carboxaldehydes 59 via azatitanacyclopentadienes as formulated
in eq 9.
When excess nitrile 6 was allowed to react with the
acetylene-titanium complex 5, the 1:1 adduct 8 (see eq 3)
became a minor component, and, instead, a new product,
pyrrolecarboxaldehyde 61, was isolated after acidic workup of
the reaction mixture (Scheme 4).20 This compound was most
Scheme 4. Preparation of Pyrrolecarboxaldehyde from Acetylene
and Nitrile
Table 3. One-Pot Preparation of Various Pyrrolecarboxaldehydes
likely produced via the double addition of the nitrile to the
acetylene complex 5,1 and the resultant diazatitanacyclohep-
tatriene 60 was hydrolyzed to diimine 62, which underwent ring
closure via the enamine intermediate to give five-membered
nitrogen cycle 63. Elimination of the ammonium group from
7,21
63 with concomitant hydration of the terminal vinyl ether moiety
gave the observed pyrrolecarboxaldehyde 61 as the final product.
The same reaction starting with an unsymmetrical acetylene
6
4 shown in Scheme 5 illustrates the viable regiochemical
control in the present transformation. Upon reaction with nitrile
(3 equiv), acetylene complex 65 afforded the regioisomeric
6
pyrrolecarboxaldehydes 67 in equal amounts. Thus, the ring
closure from 66a to 67 (through both paths a and b) could not
be controlled by the substituents (Ph and C4H9). On the other
(
19) Gschwend, H. W.; Rodriguez, H. R. In Organic Reactions; Dauben, W.
G., Ed.; Wiley: New York, 1979; Vol. 26, pp 1-360.
(
20) For other syntheses of pyrroles by the use of metalacycles of group 4 metals,
see: Buchwald, S. L.; Wannamaker, M. W.; Watson, B. T. J. Am. Chem.
Soc. 1989, 111, 776-777. Gao, Y.; Shirai, M.; Sato, F. Tetrahedron Lett.
1
996, 37, 7787-7790. Nakamoto, M.; Tilley, T. D. Organometallics 2001,
2
0, 5515-5517.
(
21) To our best knowledge, the double addition of acetylene-group 4 metal
complexes to nitriles has not been reported (see ref 3). A relevant double
addition of a titanacycle to nitriles was only reported for titanacyclobutenes,
yielding pyridines after aqueous workup: Doxsee, K. M.; Mouser, J. K.
M. Organometallics 1990, 9, 3012-3014.
a
When the first and second nitriles are the same, 3 equiv of the nitrile
was added in one portion. b Where applicable and unless otherwise stated,
the depicted product was obtained as a single regioisomer. When the ratio
is specified, the major regiosisomer is shown. c Isolated yield.
7478 J. AM. CHEM. SOC.
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Facile Preparation of Heteroaromatic Compounds
A R T I C L E S
hand, the successive coupling of 65 with two different nitriles
2
0 (1 equiv) and 6 (0.8 equiv) proceeded in a regioselective
manner, leading to the selective generation of a single pyrrole-
carboxaldehyde 68 resulting solely from the cyclization of path
a in 66b. Formation of the sterically less encumbered trisub-
stituted enamine or the higher acidity of the methylene proton
2
2
in 66b may account for the preference for path a over path b.
It should be emphasized that the latter reaction allowed the
selective preparation of pyrroles having four different substit-
uents. The ready availability of the requisite R-oxynitriles by
4
the cyanohydrin and related reactions and the one-pot procedure
as illustrated above should reinforce the synthetic advantage of
this method.
mediated assembly of acetylene, R-oxynitrile, and an additional
unsaturated compound. The reaction was highly regioselective
to afford these heteroaromatic compounds virtually as a single
isomer. In addition, as the starting materials and reagents
required in this reaction are readily available, the present
syntheses are preferable from a practical point of view. Further
investigation on the preparation of new heterocyclic compounds
is now in progress.
Additional results summarized in Table 3 show the generality
of the present synthesis of pyrrolecarboxaldehydes. R-Benzyl-
oxynitrile could be used as well in place of methoxynitriles to
give 69 (entry 2). An unsymmetrical dialkylacetylene showed
reasonably good regioselectivity, giving 72 as the major isomer
(entry 5). Aromatic acetylenes having a functional group on
the phenyl group in entries 7 and 8 afforded virtually single
products 73 and 74, as discussed in Scheme 5. Analogously,
pyrrole 75 having an additional hetereoaromatic group can be
prepared by the present method (entry 9). Macrocyclic pyrroles
Acknowledgment. This work was supported, in part, by a
Grant-in-Aid for Scientific Research on Priority Areas (A)
7
6 and 77 were conveniently obtained in good yields from the
“Exploitation of Multi-Element Cyclic Molecules” (to F.S.) and
23
corresponding cycloalkyne (entries 10 and 11). Since an
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.
2
4
R-alkoxy group in the products could be deprotected, deoxy-
genated (to 78, eq 10), or eliminated to give olefin 79 (eq 11),
the oxygen functional groups at the R and R′ positions of the
pyrroles25 will facilitate further synthetic elaboration.
Conclusion
A concise synthesis of polysubstituted pyridines, furans, and
pyrrolecarboxaldehydes has been achieved by the titanium-
(
(
(
(
22) House, H. O. Modern Synthetic Reactions, 2nd ed.; Benjamin: Menlo Park,
CA, 1972; pp 570-581.
23) Brummond, K. M.; Gesenberg, K. D.; Kent, J. L.; Kerekes, A. D.
Tetrahedron Lett. 1998, 39, 8613-8616.
Supporting Information Available: Experimental Section
(PDF). This material is available free of charge via the Internet
at http://pubs.acs.org.
24) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
2
nd ed.; Wiley: New York, 1991; pp 14-86.
25) R,R′-Dioxygenated pyrroles themselves recently attract interest in medicinal
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