Ruthenium(II)-Catalyzed Cycloaddition of 1,6-Diynes with Isocyanates Leading to Bicyclic Pyridones

Article abstract of DOI:10.1021/ol016082t

(matrix presented) A ruthenium(II) complex possessing a planar Cp* ligand, Cp*Ru(cod)Cl, effectively catalyzed the [2 + 2 + 2] cycloaddition of 1,6-diynes with isocyanates to afford bicyclic pyridones in 58-87% yields.

Full text of DOI:10.1021/ol016082t

ORGANIC
LETTERS
2
001
Vol. 3, No. 13
117-2119
Ruthenium(II)-Catalyzed Cycloaddition of
,6-Diynes with Isocyanates Leading to
2
1
Bicyclic Pyridones
Yoshihiko Yamamoto, Hideyuki Takagishi, and Kenji Itoh*
Department of Molecular Design and Engineering, Graduate School of Engineering,
Nagoya UniVersity, Chikusa, Nagoya 464-8603, Japan
itohk@apchem.nagoya-u.ac.jp
Received May 9, 2001
ABSTRACT
A ruthenium(II) complex possessing a planar Cp* ligand, Cp*Ru(cod)Cl, effectively catalyzed the [2 + 2 + 2] cycloaddition of 1,6-diynes with
isocyanates to afford bicyclic pyridones in 58−87% yields.
Transition-metal-catalyzed cyclocotrimerization of two mol-
ecules of an alkyne and an isocyanate is an efficient method
to construct substituted 2-pyridone rings. Such a catalytic
with â-phenethyl isocyanate were carried out in the presence
of 15 mol % CpCo(CO) by the same authors, but the
2
1
expected pyridones were obtained only in 16% and 31%
4
pyridone formation has first been accomplished indepen-
yields, respectively. Moreover, no pyridone was formed as
2
dently by Yamazaki using Co catalysts and by Hoberg using
a result of the facile cyclotrimerization of the diyne substrate
Ni catalysts.3
when the reaction was conducted with Ni(cod)
catalyst.
as the
2
4
The cobalt catalysis has further been extended to partially
intramolecular versions utilizing isocyanatopentynes or R,ω-
diynes by Vollhardt and co-workers. The cycloadditions of
isocyanatoalkynes with several silylalkynes effectively gave
With these facts in mind, we developed more efficient
Type II cycloaddition using the ruthenium catalyst. Herein,
we wish to report our preliminary results of the ruthenium-
catalyzed cycloaddition of 1,6-diynes with isocyanates.
To search for a new catalytic system, we first attempted
the cycloaddition of a malonate-derived 1,6-diyne 1a (X )
4
2,3-dihydro-5(1H)-indolizinones (Figure 1, Type I), and this
strategy was elegantly applied to the total synthesis of the
5
4
antitumor agent Camptothecin. In contrast, the related
cycloadditions of R,ω-diynes with isocyanates (Figure 1,
Type II) have been less attractive, although a wide variety
of readily accessible diynes and isocyanates can be directly
used for this type of cycloaddition. Actually, the reactions
of 1,7-octadiyne with phenyl isocyanate or 1,6-heptadiyne
2 2
C(CO Me) ) and phenyl isocyanate (2a) in the presence of
(1) (a) Grotjahn, D. B. In ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.;
Pergamon: Oxford, 1995; Vol. 12, Chapter 7.3, pp 741-770. (b) Shore,
N. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 5, Chapter 9.4, pp 1129-1162.
(
(
(
2) Hong, P.; Yamazaki, H. Tetrahedron Lett. 1977, 1333-1336.
3) Hoberg, H.; Oster, B. W. Synthesis 1982, 324-325.
4) Earl, R. A.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 4786-
4
800.
Figure 1. Partially intramolecular [2 + 2 + 2] cyclocotrimeriza-
tions of alkynes and isocyanates.
(
5) For other examples, see: (a) Flynn, S. T.; Hasso-Henderson, S. E.;
Parkins, A. W. J. Mol. Catal. 1985, 32, 101-105. (b) Diversi, P.; Ingrosso,
G.; Lucherini, A.; Malquori, S. J. Mol. Catal. 1987, 40, 267-280.
1
0.1021/ol016082t CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/01/2001

a catalytic amount of Cp*Ru(cod)Cl (Cp* ) pentamethyl-
cyclopentadienyl, cod ) 1,5-cyclooctadiene), which is the
excellent catalyst for the related cycloaddition of 1,6-diynes
2 2
[Cp*RuCl ] , also gave 3aa, albeit in slightly lower yield
(run 5). The importance of the planar Cp* ligand was clearly
elucidated by the fact that a ruthenium(II) complex without
6
with alkenes or monoalkynes. A 1,2-dichloroethane (DCE)
2 2
the Cp* ligand, Ru(cod)(AN) Cl , gave 3aa only in 35%
solution of 1a was added to the solution of 2a (2 equiv) and
yield along with an inseparable mixture of 4a and unknown
byproducts (run 6). On the other hand, a ruthenium(0)
complex having a bulky planar hexamethylbenzene ligand,
10 mol % Cp*Ru(cod)Cl in DCE at room temperature, and
the resultant solution was then refluxed for 2 h to afford the
desired bicyclic pyridone 3aa and the diyne dimer 4a in 45%
and 18% yields, respectively (Scheme 1 and Table 1, run
6 6
C Me Ru(cod), was found totally ineffective for the present
cycloaddition (run 7). Finally, the catalyst amount was
optimized using the best catalyst. A lower catalyst load of 5
mol % Cp*Ru(cod)Cl gave 3aa in similar high yield (run
8
), although 2 mol % of the catalyst was not enough for the
Scheme 1
completion of the reaction (run 9).
Having optimized the reaction conditions, other isocyan-
ates were subjected to the cycloaddition with the diyne 1a
as summarized in Table 2. In the same manner with 2a,
Table 2. Cp*Ru(cod)Cl-Catalyzed Cydoaddition of
1
,6-Heptadiynes 1a-d with Isocyanates 2a-fa
1). The competitive formation of 4a was effectively sup-
pressed by improving the procedure as follows: to a refluxed
Table 1. Ru-Catalyzed Cycloaddition of 1,6-Heptadiyne 1a
with Isocyanate 2aa
catalyst
(mol %)
2a
time 3a a yield
run
(equiv) solventb (h)
(%)c
1
2
3
4
5
6
7
8
9
Cp*Ru(cod)Cl (10)
Cp*Ru(cod)Cl (10)
Cp*Ru(cod)Cl (10)
Cp*Ru(cod)Cl (10)
[Cp*RuCl2]2 (10)
2
DCE
DCE
C6H6
AN
DCE
DCE
DCE
DCE
DCE
2
1
20
27
1
3
18
1
45
89
34
7e
74
35
0
d
d
d
d
d
d
d
d
2 + 2
2 + 2
2 + 2
2 + 2
Ru(cod)(AN)2Cl2 (10) 2 + 2
C6Me6Ru(cod) (10)
Cp*Ru(cod)Cl (5)
Cp*Ru(cod)Cl (2)
2 + 2
2 + 2
2 + 2
87
65
2
a
To a solution of a catalyst and 2a (2 equiv) was added a solution of
b
1
a, and the solution was refluxed for the time indicated. DCE ) 1,2-
c
d
dichloroethane; AN ) acetonitrile. Isolated yields. To a refluxed solution
of a catalyst and 2 equiv of 2a in DCE was added dropwise a solution of
e
1
a and another 2 equiv of 2a in DCE. The diyne 2a was recovered in
6
1% yield.
solution of the catalyst and 2 equiv of 2a in DCE was added
dropwise a solution of 1a and another 2 equiv of 2a in DCE.
7
As a result, the yield of 3aa was raised to 89% (run 2).
The yield was, however, considerably lowered in benzene
(run 3), and the reaction hardly proceeded in acetonitrile even
after 27 h (run 4).
We then examined other typical organoruthenium com-
plexes with various oxidation states and ligand fields. A
dinuclear ruthenium(III) complex having a Cp* ligand,
a
To a refluxing solution of 5 mol % Cp*Ru(cod)Cl and 2 (2 equiv) in
DCE was added dropwise a solution of 1 and 2 (2 equiv) in DCE, and the
solution was refluxed for 1 h (2 h for runs 6 and 7). b Isolated yields.
(
6) (a) Yamamoto, Y.; Ogawa, R.; Itoh, K. Chem. Commun. 2000, 549-
50. (b) Yamamoto, Y.; Kitahara, H.; Ogawa, R.; Kawaguchi, H.; Tatsumi,
K.; Itoh, K. J. Am. Chem. Soc. 2000, 122, 4310-4319.
7) An excess of the isocyanate 2a was recovered as carbanilide.
5
1
-naphthyl isocyanate (2b) and 2-furyl isocyanate (2c)
(
underwent the cycloaddition with 1a to afford the corre-
2118
Org. Lett., Vol. 3, No. 13, 2001

sponding products 3ab and 3ac in 79% and 87% yields,
respectively (runs 1 and 2). In addition to the aryl isocyan-
ates, alkyl isocyanates can be employed in the present
protocol. Isocyanates 2d and 2e, which possess a primary
or secondary alkyl group on their nitrogen atom, effectively
gave the desired N-alkyl pyridones 3ad and 3ae in high
yields. Exceptionally, tert-butyl isocyanate 2f gave no
pyridone product under the same reaction conditions. This
is probably because the coordination of its CdN bond to
the ruthenium center was completely hindered by the bulky
tert-butyl group on the nitrogen atom. In this case, the diyne
cyclotrimerization products 4a and 5a were formed in 17%
and 71% yields, respectively.
supported by the fact that isolated cobaltacyclopentadienes
and isocyanates produced the corresponding pyridones. On
9
the other hand, an alternative mechanism, which starts with
the formation of an azanickelacyclopentenone from an alkyne
and an isocyanate, was proposed in Hoberg’s nickel-
10
catalyzed cyclocotrimerizations. According to these claims,
two mechanisms including ruthenacyclopentadiene interme-
11,12
diates
5 or azaruthenacyclopentenones 6 can be assumed
for our case. In either event, common intermediates 7 is
consequently produced, and the reductive elimination of the
[Cp*RuCl] fragment from 7 gives the bicyclic pyridones 3.
The metallacyclopentadiene mechanism is, however, prefer-
able to the ruthenium-catalyzed cycloaddition using diynes
as alkyne components. Without exception, 1,6-diynes are
essential substrates for our previously reported ruthenium-
The generality of the present ruthenium catalysis was
further examined with respect to the diyne substrate. Parent
6
1,6-heptadiyne (1b) and dipropargyl ether (1c), having no
catalyzed [2 + 2 + 2] cycloadditions. This is also true of
tertiary center on the tether chain, also reacted with 2a to
afford the expected N-phenyl pyridones 3ba and 3ca in 62%
and 58% yields, respectively (runs 5 and 6), although these
diynes were anticipated to be ineffective without the kinetic
Thorpe-Ingold effect. N,N-Dipropargyl p-toluenesulfon-
amide (1d) efficiently afforded a pyrroline-fused pyridone
the present pyridone annulation. A typical monoalkyne,
1-hexyne, did not undergo [2 + 2 + 2] cyclocotrimerization
with 2a under the same reaction conditions with the diyne
cycloaddition. This is probably because the ruthenacyclo-
pentadiene formation from a 1,6-diyne is entropically more
favorable than that from two molecules of a monoalkyne.
These facts supports the ruthenacyclopentadiene mechanism
(1 + 2 f 5 f 7 f 3).
8
3da in high yield with the aid of the proximity effect caused
by the bulky p-tosyl group (run 7).
Scheme 2 shows a plausible mechanism of the Ru(II)-
catalyzed cycloaddition of 1,6-diynes 1 with isocyanates 2.
Acknowledgment. We gratefully acknowledge financial
support (09750947, 09305059, 10132222, 12450360, and
1
3875174) from the Ministry of Education, Science, Sports,
and Culture, Japan.
Scheme 2
Supporting Information Available: Typical procedure
for the cycloaddition of 1 and 2 and analytical data for the
pyridones 3. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL016082T
(
9) Hong, P.; Yamazaki, H. Synthesis 1977, 50-52.
(
10) (a) Hoberg, H.; Oster, B. W. J. Organomet. Chem. 1982, 234, C35-
C38. (b) Hoberg, H.; Oster, B. W. J. Orgnomet. Chem. 1983, 252, 359-
3
64.
(11) For catalytic reactions involving ruthenacyclopentadiene intermedi-
ates, see: (a) Lidner, E.; Jansen, R.-M.; Mayer, H. A.; Hiller, W.; Fawzi,
R. Organometallics 1989, 8, 2355-2360. (b) Yi, C. S.; Torres-Lubian, J.
R.; Liu, N.; Rheingold, A. L.; Guzei, I. A. Organometallics 1998, 17, 1257-
1
259. (c) Chatani, N.; Fukumoto, Y.; Ida, T.; Murai, S. J. Am. Chem. Soc.
Yamazaki has proposed that a cobaltacyclopentadiene is
initially formed from the oxidative cyclization of two
molecules of an alkyne, and the subsequent reaction of the
cobaltacycle intermediate with an isocyanate affords a
pyridone. Such a metallacyclopentadiene mechanism was
1993, 115, 11614-11615. Also, see ref 6.
(12) For the formation of ruthenacyclopentadiene/ruthenacyclopentatriene
complexes from alkynes, see: (a) Bruce, M. I.; Matisons, J. G. J.
Organomet. Chem. 1983, 251, 249-260. (b) Albers, M. O.; de Waal, D. J.
A.; Liles, D. C.; Robinson, D. J.; Singleton, E.; Wiege, M. B. J. Chem.
Soc., Chem. Commun. 1986, 1680-1682. (c) Campion, B. K.; Heyn, R.
H.; Tilley, T. D. Organometallics 1990, 9, 1106-1112. (d) Bruce, M. I.;
Koutsantonis, G. A. Aust. J. Chem. 1991, 44, 207-217. (e) Ernst, C.; Walter,
O.; Dinjus, E.; G o¨ rls J. Prakt. Chem. 1999, 341, 801-804. Also see refs
10a and 10b.
(8) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
1
07, 1080-1106.
Org. Lett., Vol. 3, No. 13, 2001
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