Cp*RuCl-catalyzed [2 + 2 + 2] cycloadditions of α,ω- diynes with electron-deficient carbon-heteroatom multiple bonds leading to heterocycles

Article abstract of DOI:10.1021/ja045694g

In the presence of a catalytic amount of Cp*RuCl(cod), 1,6-diynes were allowed to react chemoand regioselectively with electron-deficient nitriles and heterocumulenes at 60-90°C to afford heterocyclic compounds. The mechanism of the ruthenium-catalyzed regioselective formations of bicyclic pyridines and pyridones were analyzed on the basis of density functional calculations. Cyclocotrimerizations of ethyl propiolate with ethyl cyanoformate or propyl isocyanate gave rise to two of the four possible pyridine or pyridone regioisomers.

Full text of DOI:10.1021/ja045694g

Published on Web 12/14/2004
Cp*RuCl-Catalyzed [2 + 2 + 2] Cycloadditions of r,ω-Diynes
with Electron-Deficient Carbon-Heteroatom Multiple Bonds
Leading to Heterocycles
Yoshihiko Yamamoto,*,† Keisuke Kinpara,† Tomoaki Saigoku,† Hideyuki Takagishi,‡
Satoshi Okuda,‡ Hisao Nishiyama,† and Kenji Itoh‡
Contribution from the Department of Applied Chemistry and Department of Molecular Design
and Engineering, Graduate School of Engineering, Nagoya UniVersity,
Chikusa, Nagoya 464-8603, Japan
Received July 18, 2004; E-mail: yamamoto@apchem.nagoya-u.ac.jp
Abstract: In the presence of a catalytic amount of Cp*RuCl(cod), 1,6-diynes were allowed to react chemo-
and regioselectively with electron-deficient nitriles and heterocumulenes at 60-90 °C to afford heterocyclic
compounds. The mechanism of the ruthenium-catalyzed regioselective formations of bicyclic pyridines and
pyridones were analyzed on the basis of density functional calculations. Cyclocotrimerizations of ethyl
propiolate with ethyl cyanoformate or propyl isocyanate gave rise to two of the four possible pyridine or
pyridone regioisomers.
Introduction
reactions of cobaltacyclopentadienes with nitriles, carbon di-
sulfide, or methyl isothiocyanate, leading respectively to py-
The occurrence of heterocyclic compounds in nature is wide-
spread, and their applications to pharmaceuticals and functional
materials are becoming more and more important.1 The devel-
opment of new efficient strategies to synthesize heterocycles
with structural diversity is one major aim in modern synthetic
organic chemistry. Heterocyclic compounds have generally been
synthesized by means of condensation reactions under acidic
or basic conditions, which produce salt waste. The formation
of undesirable byproducts is also a problem to be avoided in
the conventional methods that need stoichiometric reagents. In
this respect, transition-metal catalysis is a powerful tool to con-
struct heterocyclic frameworks under neutral and mild condi-
tions.2 In particular, the catalyzed cyclocotrimerizations of
alkynes with carbon-heteroatom multiple bonds have received
growing attention, since they can form multiple carbon-carbon
and carbon-heteroatom bonds simultaneously without any
reagents other than a catalyst.3 In other words, the catalytic
[2 + 2 + 2] cycloaddition strategy is a highly convergent and
atom-economical approach to heterocyclic compounds.
ridines, a dithiopyrone, and a thiopyridone.4 Since then, various
stoichiometric and catalytic cyclocotrimerizations have been
developed,3 but the control of chemo- and regioselectivity has
been a crucial problem for the catalytic methods. In this context,
the cobalt-catalyzed partially intramolecular cycloadditions of
R,ω-diynes or ω-cyanoalkynes leading to bicyclic pyridines have
been developed by Vollhardt and others,5,6 providing access to
the syntheses of natural and artificial molecules.7 The catalytic
pyridone formation, which was first accomplished independently
by Yamazaki and Hoberg and their co-workers using Co or Ni
(4) Wakatsuki, Y.; Yamazaki, H. J. Chem. Soc., Chem. Commun. 1973, 280.
They reported that the reaction of a tetraphenylcobaltacyclopentadiene and
methyl isothiocyanate gave a thiopyridone in 10% yield, but its structure
was subsequently reassigned to a (2H)-thiopyran-2-imine (see Yamazaki,
H. J. Synth. Org. Chem., Jpn. 1987, 45, 244-257).
(5) (a) Naiman, A.; Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1977,
16, 708-709. (b) Brien, D. J.; Naiman, A.; Vollhardt, K. P. C. J. Chem.
Soc., Chem. Commun. 1982, 133-134.
(6) Other examples of the cycloaddition of R,ω-diynes with nitriles: (a)
Chiusoli, G. P.; Pallini, L.; Terenghi, G. Transition Met. Chem. 1983, 8,
250-252. (b) Battaglia, L. P.; Delledonne, D.; Nardelli, M.; Predieri, G.;
Chiusoli, G. P.; Costa, M.; Pelizzi, C. J. Organomet. Chem. 1989, 363,
209-222. (c) Zhou, Z.; Battaglia, L. P.; Chiusoli, G. P.; Costa, M.; Nardelli,
M.; Pelizzi, C.; Predieri, G. J. Organomet. Chem. 1991, 417, 51-63. (d)
Vitulli, G.; Bertozzi, S.; Lazzaroni, R.; Salvadori, P. J. Organomet. Chem.
1986, 307, C35-C37. (e) Vitulli, G.; Bertozzi, S.; Vignali, M.; Lazzaroni,
R.; Salvadori, P. J. Organomet. Chem. 1987, 326, C33-C36. (f) Moretto,
A. F.; Zhang, H.-C.; Maryanoff, B. E. J. Am. Chem. Soc. 2001, 123, 3157-
3158. (g) Yong, L.; Butenscho¨n, H. Chem. Commun. 2002, 2852-2853.
(h) Hoshi, T.; Katano, M.; Nozawa, E.; Suzuki, T.; Hagiwara, H.
Tetrahedron Lett. 2004, 45, 3489-3491. (i) Gutnov, A.; Heller, B.; Fischer,
C.; Drexler, H.-J.; Spannenberg, A.; Sundermann, B.; Sundermann, C.
Angew. Chem., Int. Ed. 2004, 43, 3795-3797.
(7) (a) Parnell, C. A.; Vollhardt, K. P. C. Tetrahedron 1985, 41, 5791-5796.
(b) Geiger, R. E.; Lalonde, M.; Stoller, H.; Schleich, K. HelV. Chim. Acta
1984, 67, 1274-1282. (c) Saa´, C.; Crotts, D. D.; Hsu, G.; Vollhardt, K. P.
C. Synlett 1994, 487-489. (d) Varela, J. A.; Castedo, L.; Saa´, C. J. Org.
Chem. 1997, 62, 4189-4192. (e) Varela, J. A.; Castedo, L.; Saa´, C. J. Am.
Chem. Soc. 1998, 120, 12147-12148. (f) Varela, J. A.; Castedo, L.; Saa´,
C. Org. Lett. 1999, 1, 2141-2143. (g) Varela, J. A.; Castedo, L.; Maestro,
M.; Mah´ıa, J.; Saa´, C. Chem. Eur. J. 2001, 7, 5203-5213.
The transition-metal-mediated cyclocotrimerization of alkynes
with carbon-heteroatom multiple bonds was first pioneered by
Wakatsuki and Yamazaki in their work on the stoichiometric
† Department of Applied Chemistry.
‡ Department of Molecular Design and Engineering.
(1) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell: Oxford,
2000.
(2) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127-2198.
(3) (a) Shore, N. E. [2 + 2 + 2] Cycloadditions. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon:
Oxford, 1991; Vol. 5, pp 1129-1162. (b) Grotjahn, D. B. Transition Metal
Alkyne Complexes: Transition Metal-catalyzed Cyclotrimerization. In
ComprehensiVe Organometallic Chemistry II; Abel, E. W., Stone, F. G.
A., Wilkinson, G. Hegedus, L. S., Eds.; Pergamon: Oxford, 1995; Vol.
12, pp 741-770. (c) Bo¨nnemann, H.; Brijoux, W. Cyclomerization of
Alkynes. In Transition Metals for Organic Synthesis; Beller, M., Bolm,
C., Eds.; Wiley: Weinheim, Germany, 1998; Vol. 1, pp 114-135. (d)
Varela, J. A.; Saa´, C. Chem. ReV. 2003, 103, 3787-3801.
9
10.1021/ja045694g CCC: $30.25 © 2005 American Chemical Society
J. AM. CHEM. SOC. 2005, 127, 605-613
605

A R T I C L E S
Yamamoto et al.
catalysts,8 has also been extended to partially intramolecular
versions utilizing isocyanatopentynes or R,ω-diynes by Vollhardt
and Earl.9,10
As can be seen from these predecessors, the catalytic partially
intramolecular cyclocotrimerizations have been almost confined
to cobalt catalysis. In addition, the substrate scope, the ef-
ficiency, and the selectivity (especially regioselectivity) have
remained to be greatly improved. Herein we report the
Cp*RuCl-catalyzed cycloadditions of R,ω-diynes with electron-
deficient carbon-heteroatom multiple bonds resulting in various
heterocyclic compounds with significant chemo- and regiose-
lectivity.
Results and Discussion
Scope and Limitations of Cp*RuCl-Catalyzed Cycload-
ditions of 1,6-Diynes with Electron-Deficient Nitriles and
Heterocumulenes. We have previously reported that Cp*RuCl-
(cod) (1; Cp* ) η5-C5Me5, cod ) 1,5-cyclooctadiene) catalyzed
the cycloaddition of 1,6-diynes 2 with electron-deficient nitriles
3, which are inefficient nitrile components under the previous
Co catalysis,5 to afford the desired bicyclic pyridines in moderate
to high yields (Scheme 1 and Figure 1),11a while simple nitriles
Figure 1.
Table 1. Cp*RuCl-Catalyzed Cycloaddition of 2 and 3a
run
substrates
1/mol %, t/h
product, yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2a/3a
2a/3b
2a/3c
2a/3d
2a/3e
2a/3f
2a/3g
2b/3a
2c/3a
2d/3a
2e/3a
2f/3a
2g/3a
2h/3a
2i/3a
2, 0.5
2, 0.5
5, 2
10, 1
10, 24
10, 24
5, 1
2, 0.5
2, 0.5
2, 0.5
2, 0.5
2, 0.5
2, 0.5
2, 2
4aa, 83%
4ab, 84%
4ac, 79%
4ad, 90%
Scheme 1
4ae, 31 (53)b %
4af, 44 (50)b %
4ag, 67 (80)b %
4ba, 88%
4ca, 90%
4da, 86%
4ea, 80%
4fa, 89%
4ga, 75%
4ha, 72%
4ia, 64%
2, 17
a All reactions were carried out with nitriles (1.5 equiv) at 60 °C (80 °C
for runs 4 and 5) in DCE under Ar. b With 3 equiv of nitriles.
ruthenium catalysis. The 1,6-diynes 2b-e bearing ester, ketone,
and nitrile moieties gave rise to bicyclic pyridines 4ba-4ea in
high yields (runs 8-11). The parent 1,6-heptadiyne 2f possess-
ing no quaternary center afforded the desired pyridine 4fa in
89% yield (run 12), indicative of the Thorpe-Ingold effect being
less important.12 Furthermore, pyridine-fused heterocycles 4ga,
4ha, and even sulfur-containing 4ia, could be obtained in 75,
72, and 64% yields, respectively (runs 13-15).
In contrast to the cycloaddition of R,ω-diynes with nitriles,
the relevant reaction with isocyanates has received less attention
until recently we found the ruthenium-catalyzed protocol,
because of the low efficiency of cobalt and nickel catalysts.9b
As previously reported,11b adding a DCE solution of 2 and 2
equiv of isocyanates 5 into a refluxing DCE solution containing
5-10 mol % 1 and another 2 equiv of 5 furnished the desired
bicyclic pyridones 6, suppressing the competitive dimerization
of 2 (Scheme 1, Figure 1, and Table 2). This procedure
converted a variety of aryl or alkyl isocyanates to the corre-
sponding pyridones 6aa-6af in 79-93% yields (runs 1-6).
Exceptionally, tert-butyl isocyanate gave no cycloadduct under
the same reaction conditions. This is probably because the
such as acetonitrile or benzonitrile failed to undergo cycload-
dition under the same reaction conditions. The scope of the
ruthenium-catalyzed pyridine formation is broad with respect
to the 1,6-diyne and the nitrile substrates as summarized in Table
1. Acyl, sulfonyl, and perhaloalkyl or aryl groups can be
employed as an electron-withdrawing group on the nitrile
component (runs 1-7), although the product yields were
moderate for tosylcyanide 3e, trichloroacetonitrile 3f, and
pentafluorobenzonitrile 3g because of the competitive dimer-
ization of 2a. The yields of 4ae, 4af, and 4ag were slightly
improved by employing 3 equiv of these cyanides. The wide
functional group compatibility is a significant advantage of the
(8) (a) Hong, P.; Yamazaki, H. Tetrahedron Lett. 1977, 1333-1336. (b) Hong,
P.; Yamazaki, H. Synthesis 1977, 50-52. (c) Hoberg, H.; Oster, B. W.
Synthesis 1982, 324-325. (d) Hoberg, H.; Oster, B. W. J. Organomet.
Chem. 1982, 234, C35-C38. (e) Hoberg, H.; Oster, B. W. J. Organomet.
Chem. 1983, 252, 359-364.
(9) (a) Earl, R. A.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1983, 105, 6991-
6993. (b) Earl, R. A.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 4786-
4800.
(10) Recent examples, see (a) Bonaga, L. V. R.; Zhang, H.-C.; Gauthier, D. A.;
Reddy, I.; Maryanoff, B. E. Org. Lett. 2003, 5, 4537-4540. (b) Duong, H.
A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438-11439.
(11) Preliminary results have been reported: (a) Yamamoto, Y.; Okuda, S.; Itoh,
K. Chem. Commun. 2001, 1102-1103. (b) Yamamoto, Y.; Takagishi, H.;
Itoh, K. Org. Lett. 2001, 3, 2117-2119. (c) Yamamoto, Y.; Takagishi, H.;
Itoh, K. J. Am. Chem. Soc. 2002, 124, 28-29.
(12) (a) Kaneti, J.; Kirby, A. J.; Koedjikov, A. H.; Pojarlieff, I. G. Org. Biomol.
Chem. 2004, 2, 1098-1103. (b) Jung, M. E. Synlett 1999, 843-846. (c)
Jung, M. E.; Gervay, J. J. Am. Chem. Soc. 1991, 113, 224-232. (d) Jager,
J.; Graafland, T.; Schenk, H.; Kirby, A. J.; Engberts, J. B. F. N. J. Am.
Chem. Soc. 1984, 106, 139-143. (e) Beesley, R. M.; Ingold, C. K.; Thorpe,
J. F. J. Chem. Soc. 1915, 107, 1080-1106.
9
606 J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005

Ru-Catalyzed [2
+
2
+
2] Cycloadditions of
R,
ω-Diynes
A R T I C L E S
Table 2. Cp*RuCl-Catalyzed Cycloaddition of 2 with 5,a 7,b or 9c
Scheme 2
run
substrates
1/mol %, t/h
product, yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
2a/5a
2a/5b
2a/5c
2a/5d
2a/5e
2a/5f
2b/5a
2c/5a
2d/5a
2e/5a
2f/5a
2g/5a
2h/5a
2i/5a
2a/7a
2a/7b
2a/7c
2a/7d
2b/7a
2c/7a
2d/7a
2e/7a
2a/9
5, 1
5, 1
5, 1
5, 1
5, 1
5, 1
10, 1
10, 1
10, 1
10, 1
5, 2
6aa, 87%
6ab, 79%
6ac, 87%
6ad, 93%
6ae, 89%
6af, 85%
6ba, 73%
6ca, 75%
6da, 58%
6ea, 18%
6fa, 62%
6ga, 82%
6ha, 58%
6ia, 60%
8aa, 88%
8ab, 50%
8ac, 71%
8ad, 76%
8ba, 35%
8ca, 74%
8da, 67%
8ea, 58%
10, 54%
bonyl, and phenacyl groups on the nitrogen underwent cycload-
dition with 2a to give 8aa-8ad in 50-88% yields (Table 2,
runs 15-18). This novel sulfur-heterocycle formation requires
the diyne substrates possessing a quaternary center at 4 position,
which facilitates the oxidative cyclization of the diynes via the
Thorpe-Ingold effect.12 Indeed, the diynes bearing a quaternary
center 2b-2e gave rise to the corresponding thiopyranimines
8bc-8ec in 35-74% yields (runs 19-22), while N,N-dipro-
pargyl tosylamide 2g and propargyl ether 2h failed to undergo
cycloaddition. Similar to the isothiocyanates, carbon disulfide
9 underwent the cycloaddition with 2a in the presence of 10
mol % 1 in CS2/DCE (2:3 v/v) at 90 °C for 6 h to furnish the
expected bicyclic dithiopyrone 10 in 50% yield along with the
recovered 2a (24%) (Scheme 1 and Table 2, run 23). On the
other hand, the use of commercially available diisopropyl or
dicyclohexyl carbodiimides as heterocumulenes led to the
formation of an intractable product mixture.
N-Thionylamines have been utilized as dienophiles for Diels-
Alder reactions, in which the cycloaddition occurred on the
SdN double bond to produce cyclic N-sulfinyl adducts.17 The
reaction of 2a with N-thionylaniline 11 was carried out by
adding a solution of 2a and 5 equiv of 11 into a refluxing
solution containing the 10 mol % 1 and another 5 equiv of 11.
As a result, a bicyclic pyrrole 13 was obtained albeit in 35%
yield instead of the expected cycloadduct 12 (Scheme 2).
Although 2a was completely consumed, its dimerization was
more pronounced compared to the cycloaddition of the above
heterocumulenes. The structure of 13 was unambiguously
confirmed by X-ray analysis (see Supporting Information). The
pyrrole ring of 13 might come from the N-sulfinyl ring of 12,
but the detailed mechanism of the SdO extrusion was not clear.
The N-sulfinyl aniline proved essential for the pyrrole formation.
Employing aniline or tosyl azide instead of 11 never gave the
corresponding pyrrole.
Regiochemistry of Cp*RuCl-Catalyzed Cycloaddition of
Diynes. (a) Steric Directing Effect. Whereas partially intramo-
lecular [2 + 2 + 2] cyclocotrimerizations of nitriles and
heterocumulenes have been developed, the regioselective cy-
cloadditions of unsymmetrical R,ω-diynes have attracted less
attention. Vollhardt and Naiman have reported only one example
of the Co(I)-catalyzed regioselective cycloaddition of unsym-
metrical 1,7-decadiyne.5a Quite recently, this regioselective
pyridine formation was elegantly extended to its asymmetric
versions by Gutnov and co-workers.6i To examine the regiose-
lectivity of the Cp*RuCl-catalyzed heterocycle formations,
unsymmetrical 1,6-diynes 14a-d having methyl or phenyl
terminal groups were subjected to cycloaddition with ethyl
cyanoformate 3a, propyl isocyanate 5e, or phenyl isothiocyanate
7a (Scheme 3 and Table 3). In the presence of 5 mol % 1, 14a
5, 1
5, 2
5, 24
10, 5
10, 24
10, 3
10, 24
10, 9
10, 6
10, 8
10, 8
10, 6
a To a refluxing solution of 5 mol % 1 and 5 (2 equiv) in DCE was
added dropwise a solution of 2 and 5 (2 equiv) in DCE at 90 °C under Ar.
b All reactions were carried out with 7 (1.2 equiv) at 90 °C in DCE under
Ar. c The reaction was carried out in CS2/DCE (2:3 v/v) at 90 °C under
Ar.
coordination of its CdN bond to the ruthenium center was
completely hampered by the sterically demanding tert-butyl
group. In contrast to the malonate derivative 2a, other diynes
2b-e required increased catalyst loadings of 10 mol % (runs
7-10). The cycloaddition of these diynes bearing cyclic ester
or ketone moieties gave rise to the desired pyridones 6ba-6da
in 58-75% yields, while the malononitrile derivative 2e resulted
in the low-yield formation of 6ea. This is probably because of
the competitive oligomerization of 2e via diyne-dicyanide
cycloaddition.13 The successful result with 1,6-heptadiyne 2f
(run 11) again shows that the Thorpe-Ingold effect is less
influential.12 Uneventfully, the pyridone-fused heterocyclic
compounds 6ga-6ia were obtained in 58-82% yields (runs
12-14).
Having examined the cycloaddition of the isocyanates, we
turned our attention to isothiocyanates, because organosulfur
compounds frequently behave as catalyst poisons.14 The cyclo-
cotrimerization of two alkyne molecules with a thiocarbonyl
compound is of synthetic significance, since two C-C bonds
as well as a C-S bond are simultaneously formed by a single
operation. To the best of our knowledge, there is only a few
examples of such an interesting sulfur ring assembly,4,15 whereas
thiocarbonyl compounds behave as more reactive dienophiles
for Diels-Alder cycloaddition than the parent carbonyl com-
pounds.16 Gratifyingly, we have found that in a refluxing DCE
solution containing 10 mol % 1, the cycloaddition of 2 and 1.2
equiv of isothiocyanates 7 took place on their CdS bond to
afford thiopyranimines 8 (Scheme 1 and Figure 1).11c The
isothiocyanates 7a-d bearing phenyl, cyclohexyl, ethoxycar-
(13) Yamamoto, Y.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2001, 123, 6189-
6190.
(14) Kondo, T.; Mitsudo, T. Chem. ReV. 2000, 100, 3205-3220.
(15) A noncatalyzed cocyclotrimerization involving a CdS double bond, see
Bianchini, C.; Meli, A. J. Organomet. Chem. 1982, 236, C75-C77.
(16) Weinreb, S. M.; Staib, R. R. Tetrahedron 1982, 38, 3087-3128, and
references therein.
(17) Weinreb, S. M. Acc. Chem. Res. 1988, 21, 313-318.
9
J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005 607

A R T I C L E S
Scheme 3
Yamamoto et al.
(b) Electronic Directing Effect. In striking contrast to the
previous regioselective cycloadditions utilizing the steric effect,
an alternative mode of regiocontrol by taking advantage of an
electronic influence of the internal substituent on the diyne
substrate has been remained unexplored until we have reported
the Ru-catalyzed regioselective cycloaddition of 1,6-diynes
having a carbonyl group at the 3 position.18 The terminal
substituent causes not only the regiocontrolling effect but also
the deteriorative effect on the cycloaddition efficiency (Table
3, run 1 vs run 4). On the other hand, an electron-withdrawing
carbonyl group introduced at the 3 position has a direct impact
on the regiochemistry without causing such a negative steric
influence. In this context, the Cp*RuCl-catalyzed cycloadditions
of the unsymmetrical diynes 20 possessing an internal carbonyl
group conjugated with one of the two alkyne moieties was
explored as outlined in Scheme 4 and Table 4.
Scheme 4
Table 3. Cp*RuCl-Catalyzed Regioselective Cycloaddition of 14
with 3a,a 5e,b or 7ac
run
substrates
1/mol %, t/h
products, yield, ratio
1
2
3
4
5
6
7
8
9
14a/3a
14b/3a
14c/3a
14d/3a
14a/5e
14b/5e
14c/5e
14d/5e
14a/7a
5, 2
5, 2
5, 2
20, 6
5, 3
15aa/16aa, 87%, 88:12
15ba/16ba, 86%, 89:11
15ca/16ca, 83%, 88:12
15da, 64%
17ae, 85%
17be, 80%
5, 6
5, 15
10, 20
10, 5
17ce, 88%
17de, 80%d
18aa/19aa, 82%, 90:10
a All reactions were carried out with 3a (1.5 equiv) at 60 °C in DCE
under Ar. b To a refluxing solution of 1 and 5e (2 equiv) in DCE was added
dropwise a solution of 14 and 5e (2 equiv) in DCE at 90 °C under Ar.c All
reactions were carried out with 7a (1.2 equiv) at 90 °C in DCE under Ar.
d A small amount of inseparable impurity was detected by 1H NMR
spectroscopy.
bearing a terminal methyl substituent was allowed to react with
1.5 equiv of 3a at 60 °C for 2 h to afford a regioisomer mixture
of the 2,3,4,6- and 2,3,4,5-substituted isomers 15aa and 16aa
in 87% combined yield with the ratio of 88:12 (run 1). In the
same manner, the tosylamide 14b and the ether 14c gave 15ba/
16ba and 15ca/16ca with similar yields and regioselectivity
(runs 2 and 3). On the other hand, a terminal phenyl group
significantly improved the regioselectivity at the expense of the
efficiency. In the presence of 20 mol % 1, the reaction of 14d
at 60 °C for 6 h gave 15da as a sole product in 64% yield (run
4). The reaction of 14a-c with the isocyanate 5e was carried
out using 5 mol % 1 in refluxing DCE for 3-15 h. Interestingly,
the pyridones 17ae-17ce were exclusively obtained in 80-
88% yields (runs 5-7). Although an increased catalyst loading
of 10 mol % was required, 14d also gave rise to 17de as a
single regioisomer (run 8). Similarly, the isothiocyanate 7a
underwent regioselective cycloaddition with 14a upon refluxing
in DCE containing 10 mol % 1 for 5 h to give rise to 18aa and
its regioisomer 19aa in 82% combined yield with the ratio of
90:10 (run 9). The regiochemistry of the obtained products were
determined on the basis of the 1H NMR analysis (see Supporting
Information). As shown in Figure S1, the diagnostic heterocyclic
ring protons Ha R to the heteroatoms appeared in the lower
magnetic field than Hb. The major isomer derived from 14a
and 7a was also unambiguously assigned to 18aa by X-ray
crystallographic analysis (see Supporting Information).
The reaction of amide-diyne 20a with the cyanide 3a was
carried out in the presence of 1 mol % 1 at 60 °C for 18 h to
afford a mixture of the expected pyridines in 77% combined
1
yield (Table 4, run 1). The H NMR analysis of the crude
mixture revealed that the major regioisomer 21aa, in which the
ethoxycarbonyl group and the amide carbonyl moiety are in a
para relationship, was formed preferentially with the ratio of
71:29. Similarly, the ester-diyne 20b gave rise to the pyridine-
fused lactones 21ba/22ba in 83% combined yield with the ratio
of 82:18 (run 2). As expected, the regioisomer ratio was
improved for 20b, indicative of the more electron-withdrawing
carbonyl group favoring the formation of 21 over 22. The
regioselectivity was further increased up to around 90:10 for
the ketodiynes 20c and 20d (runs 3 and 4). The cycloadditions
of 20a-d with the isocyanate 5e were also carried out as
summarized in Table 4. In the presence of 5 mol % 1, the
reaction completed for 18 h at 60 °C. The expected pyridones
23/24 were obtained in 66-77% combined yields (runs 9-12).
(18) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Nishiyama, H.; Itoh, K. Org.
Biomol. Chem. 2004, 2, 1287-1294.
9
608 J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005

Ru-Catalyzed [2
+
2
+
2] Cycloadditions of
R,
ω-Diynes
A R T I C L E S
Table 4. Cp*RuCl-Catalyzed Regioselective Cycloaddition of 20
with 3aa or 5eb
Interestingly, the electron-deficient diyne 20h was allowed to
react with 3a and 5e to give rise to the four-substituted pyridines
21ha/22ha or the fully substituted pyridones 23he/24he with
the 80:20 and 83:17 isomer ratios, respectively, whereas 20h
has a methyl substituent on both alkyne termini (Table 4, runs
8 and 16).
run
substrates
1/mol %, t/h
products, yield, ratio
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
20a/3a
20b/3a
20c/3a
20d/3a
20e/3a
20f/3a
20g/3a
20h/3a
20a/5e
20b/5e
20c/5e
20d/5e
20e/5e
20f/5e
20g/5e
20h/5e
1, 18
1, 18
1, 18
1, 18
20, 15
5, 0.5
5, 0.5
5, 6
5, 18
5, 18
5, 18
5, 18
5, 18
5, 6
21aa/22aa, 77%, 71:29
21ba/22ba, 83%, 82:18
21ca/22ca, 64%, 89:11
21da/22da, 89%, 91:9
21ea, 64%
21fa/22fa, 89%, 96:4
21ga/22ga, 84%, 98:2
21ha/22ha, 82%, 80:20
23ae/24ae, 67%, 82:18
23be/24be, 66%, 88:12
23ce/24ce, 75%, 97:3
23de/24de, 77%, 95:5
23ee, 46%
Mechanism of CpRuCl-Catalyzed Cyclocotrimerization.
For the [2 + 2 + 2] alkyne cyclotrimerizations, a general
mechanism involving metallacyclopentadiene and metallacy-
cloheptatriene intermediates has been proposed (the “common
mechanism”).19 On the basis of density functional theory (DFT)
calculations, we and others have reported the novel alkyne
cyclotrimerization mechanism, in which the intermediacy of an
unprecedented ruthenabicyclo[3.2.0]heptatriene was proposed
for the conversion of a ruthenacyclopentadiene-alkyne complex
to a seven-membered ruthenacycle complex.20,21a Soon after
these reports, the relevant iridabicyclo[3.2.0]heptatriene was
isolated and characterized by X-ray crystallography.22 Kirchner
and co-workers also disclosed that the cyclocotrimerizations of
acetylene with an isocyanate and an isothiocyanate proceed via
similar mechanisms involving the corresponding ruthenabicycle
intermediates, and they reasonably explained the regioselectivity
difference between these heterocumulenes.21 Thus, the new
mechanism appears to be general for the CpRuCl-catalyzed
cyclocotrimerizations, but the following two additional issues
must be addressed with respect to the pyridine formations. First,
the ruthenium catalysis prefers electron-deficient nitriles, and
this is in striking contrast to the cobalt catalysis. Second, the
oxidative cyclization between an alkyne and an electron-
deficient nitrile might give rise to an elusive azaruthenacycle
complex, which might be an alternative intermediate for the
pyridine formation. The first issue is closely related with the
second one, because the electron-accepting group facilitates the
oxidative cyclization by lowering the LUMO of the C-N triple
bond. With these points in mind, we carried out the DFT
calculations of the CpRuCl-mediated cyclocotrimerization of
acetylene with trifluoroacetonitrile as an electron-deficient nitrile
as well as acetonitrile.
23fe, 82%
23ge, 73%
23he/24he, 77%, 83:17
5, 6
5, 6
a All reactions were carried out with 3a (1.5 equiv) at 60 °C in DCE
under Ar. b To a refluxing solution of 1 and 5e (2 equiv) in DCE was added
dropwise a solution of 20 and 5e (2 equiv) in DCE at 60 °C (90 °C for
runs 14-16) under Ar.
The regioselectivity was higher than that observed for the
corresponding pyridine 21/22 (runs 1-4) and increased from
82:18 for the amide 20a to 97:3 for the ketone 20d.
The regiochemistry of the obtained products were determined
on the basis of the 1H NMR analyses (see Supporting Informa-
tion). As shown in Figure S2, the heterocyclic ring protons R
to the nitrogen atom (Ha) appeared in the lower magnetic field
than the â-protons (Hb). The Ha peaks of the major isomers
were observed in the lower field than those of the corresponding
minor isomers because of the deshielding effect of the adjacent
carbonyl groups on the fused rings. Similarly, Hb of the minor
isomers appeared in the lower field than those of the corre-
sponding major isomers. This analysis can essentially be applied
to all products except for the tricyclic pyridines 21da/22da. The
assigned regiochemistry was further confirmed by the X-ray
analyses of the major regioisomers 21ca, 21da, and 23ae (see
Supporting Information).
In addition to these 1,6-diynes, the 1,7-diyne 20e possessing
an aniline tether proved to participate in the Cp*RuCl-catalyzed
cycloadditions with 3a or 5e. In striking contrast to the
corresponding 1,6-diynes, 20e gave a tricyclic pyridine 21ea
as a sole product in 64% yield, although the increased catalyst
loading of 20 mol % was required (Table 4, run 5). The reaction
with 5e proceeded with the lower catalyst loading of 5 mol %
to afford the tricyclic pyridone 23ee in 46% yield (run 13).
(c) Synergistic Effect of Steric and Electronic Directing
Groups. To evaluate the cooperative effect of the steric and
the electronic directing groups, the amide and ester diynes
20f-h bearing both a terminal substituent and an internal
carbonyl group were subjected to the cycloaddition with 3a and
5e (Scheme 4). In the presence of 5 mol % 1, the reaction of
the amide diyne 20f with the cyanide 3a completed within 0.5
h at 60 °C to furnish the expected pyridines 21fa/22fa in 89%
combined yield (Table 4, run 6). The regioselectivity of 96:4
was higher than those observed for 15aa/16aa (88:12; Table 3,
run 1) and 21aa/22aa (71:29; Table 4, run 1). Similarly, 21ga/
22ga were obtained from the ester diyne 20g in good combined
yield and regioselectivity (Table 4, run 7). The cycloaddition
of 20f,g with the isocyanate 5e gave the pyridones 23fe and
23ge in good yields as sole products (Table 4, runs 14 and 15).
The oxidative cyclizations of two acetylene molecules or
acetylene with trifluoroacetonitrile on the coordinatively un-
saturated CpRuCl fragment were calculated by means of the
Becke’s three-parameter hybrid density functional method
(B3LYP)23 with appropriate basis sets (for details, see Support-
ing Information). The results were outlined in Figure 2. As
previously reported,20,21a the oxidative cyclization of two
acetylene molecules starts with the bis(acetylene) complex I to
result in the ruthenacyclopentatriene II. The activation energy
of this transformation is estimated as 14.8 kcal/mol.
The coordination modes of nitriles in mononuclear complexes
can be divided into two categories: σ-bonding through the
(19) Schore, N. E. Chem. ReV. 1988, 88, 1081-1119.
(20) Yamamoto, Y.; Arakawa, T.; Ogawa, R.; Itoh, K. J. Am. Chem. Soc. 2003,
125, 12143-12160.
(21) (a) Kirchner, K.; Calhorda, M. J.; Schmid, R.; Veiros, L. F. J. Am. Chem.
Soc. 2003, 125, 11721-11729. (b) Schmid, R.; Kirchner, K. J. Org. Chem.
2003, 68, 8339-8344. (c) Dazinger, G.; Schmid, R.; Kirchner, K. New. J.
Chem. 2004, 28, 153-155.
(22) Paneque, M.; Poveda, M. L.; Rendo´n, N.; Mereiter, K. J. Am. Chem. Soc.
2004, 126, 1610-1611.
(23) (a) Kohn, W.; Becke, A. D.; Parr, R. G. J. Phys. Chem. 1996, 100, 12974-
12980. (b) Stephen, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J.
Phys. Chem. Lett. 1994, 98, 11623-11627. (c) Becke, A. D. J. Chem. Phys.
1993, 98, 5648-5652. (d) Becke, A. D. Phys. ReV. A 1988, 38, 3098-
3100. (e) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
9
J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005 609

A R T I C L E S
Yamamoto et al.
Figure 2. Oxidative cyclizations resulting in ruthenacycles II, II′, and ii (energies in kcal/mol).
nitrogen lone pair (end-on mode) and π-bonding with the
nitrogen-carbon triple bond (side-on mode).24 Although the
former is the more common coordination mode, some η2 side-
bonded nitrile complexes have been isolated and unambiguously
characterized by X-ray crystallography.25 The η1-nitrile complex
I′(a) was estimated to be 3.8 and 11.2 kcal/mol more stable
than CpRuCl(cod) and the η2-nitrile complex I′(b), respectively.
The anticipated oxidative cyclization of I′(b) leading to the
azaruthenacycle II′ is expected to proceed with an activation
barrier of 14.0 kcal/mol. The formation of II′ from I′(b) is 10.8
kcal/mol less exothermic than that of II from I. This is because
II is thermodynamically more stable than II′ probably because
of its aromatic character. The Ru-C1 distance of 1.952 Å in II
shows a double-bond character, and the C1-C2 and C2-C3
bond lengths (1.395 and 1.404 Å, respectively) are very similar
to that of benzene (1.40 Å) (see Figure S8 in Supporting
Information). These features clearly show that II is a highly
delocalized metallole. On the other hand, II′ has an azaruth-
enacyclopentadiene structure, in which the C2-C3 bond is
distinctly longer than the C1-C2 and C3-N bonds. The Ru-
C1 bond length of 2.012 Å is close to typical Ru-C single-
bond distances (Figure S8).
Although both oxidative cyclizations giving II or II′ seem
to be possible in terms of the activation barriers, the azaruth-
enacycle route is less attractive because of the following reasons.
First, the η2-nitrile complex I′(b) is thermodynamically less
favorable than both the bis(alkyne) complex I and the η1-nitrile
complex I′(a). Second, in the real catalytic system, an R,ω-
diyne favors the oxidative cyclization leading to a bicyclic
ruthenacyclopentatrienes, since intramolecular cyclizations are
kinetically more favorable than the corresponding intermolecular
ones. Therefore, we further explored only pathways involving
the ruthenacycle II.
At the outset, the geometries of ruthenacycle complexes
possessing a nitrile ligand were optimized at the same level of
theory. Upon coordination of trifluoroacetonitrile to II, three
ruthenacyclopentadiene-CF3CN complexes III(a)-III(c) might
be formed as shown in Figure 3. The η1-nitrile complex III(a)
was 7.2 kcal/mol more stable than the η2-nitrile complex III-
(b), which is, in tern, 5.8 kcal/mol more stable than the isomeric
η2-nitrile complex III(c). In these η2 complexes, the C-N bond
is elongated by 3.7 Å from that of the free CF3CN because of
the back-donation from the ruthenium center to the LUMO of
the C-N triple bond (Figure S8). The C-C-N angles are
145.03° and 146.32° for III(b) and III(c), respectively. In
contrast, a smaller back-donation is expected for acetonitrile,
which has a higher LUMO level. Indeed, the C-N distance
(1.168 Å) and the C-C-N angle (179.23°) of the η2 acetonitrile
ligand in III′(b) is very similar to those of free CH3CN. The
(24) (a) Storhoff, B. N.; Lewis, H. C., Jr. Coord. Chem. ReV. 1977, 23, 1-29.
(b) Michelin, R. A.; Mozzon, M.; Bertani, R. Coord. Chem. ReV. 1996,
147, 299-338.
(25) (a) Wright, T. C.; Wilkinson, G.; Motevalli, M.; Hursthouse, M. B. J. Chem.
Soc., Dalton Trans. 1986, 2017-2019. (b) Anderson, S. J.; Wells, F. J.;
Wilkinson, G.; Hussain, B.; Hursthouse, M. B. Polyhedron 1988, 7, 2615-
2626. (c) Chetcuti, P. A.; Knobler, C. B.; Hawthorne, M. F. Organometallics
1986, 5, 1913-1914. (d) Chetcuti, P. A.; Knobler, C. B.; Hawthorne, M.
F. Organometallics 1988, 7, 650-660. (e) Barrera, J.; Sabat, M.; Harman,
W. D. J. Am. Chem. Soc. 1991, 113, 8178-8180. (f) Barrera, J.; Sabat,
M.; Harman, W. D. Organometallics 1993, 12, 4381-4390. (g) Kiplinger,
J. L.; Arif, A. M.; Richmond, T. G. Chem. Commun. 1996, 1691-1692.
(h) Lorente, P.; Carfagna, C.; Etienne, M.; Donnadieu, B. Organometallics
1996, 15, 1090-1092. (i) Thomas, S.; Tiekink, E. R. T.; Young, C. G.
Organometallics 1996, 15, 2428-2430. (j) Thomas, S.; Tiekink, E. R. T.;
Young, C. G. Organometallics 1998, 17, 182-189. (k) Tsai, Y.-C.;
Stephens, F. H.; Meyer, K.; Mendiratta, A.; Gheorghiu, M. D.; Cummins,
C. C. Organometallics 2003, 22, 2902-2913.
9
610 J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005

Ru-Catalyzed [2
+
2
+
2] Cycloadditions of
R,
ω-Diynes
A R T I C L E S
Figure 3. Reaction profile for for CpRuCl-catalyzed pyridine formation (energies in kcal/mol).
Scheme 5
Ru-C(nitrile) and Ru-N distances in III′(b) are much longer
than those in III(b).
The nitrile insertion starts with the isomerization of the η2-
nitrile complexes III(b) or III′(b) to the azaruthenabicyclo[3.2.0]-
heptatrienes IV or IV′. The conversion of III(b) to IV occurs
with a very small activation energy of 0.4 kcal/mol. This is
due to the least geometry change upon progression to the
transition state TSIII(b)-IV from III(b). The formation of IV is
thermodynamically favorable with an exothermicity of 12.5 kcal/
mol. In striking contrast, the conversion of III′(b) to IV′ turned
out to be endothermic (∆E ) +4.7 kcal/mol). In addition, the
geometry change from III′(b) to TSIII′(b)-IV′ is more pronounced,
resulting in larger activation barrier of 8.1 kcal/mol. Conse-
quently, the electron-withdrawing group on the nitrile ligand
makes the formal [2 + 2] cycloaddition with the ruthenacyclo-
pentatriene II both kinetically and thermodynamically favorable.
cyclization more favorable, are excellent substrates for the
present pyridine formation, in line with other CpRuCl-mediated
[2 + 2 + 2] cyclotrimerizations.
The subsequent conversion of IV to the azaruthenacyclohep-
tatriene V proceeds with an exothermicity of 17.0 kcal/mol via
the central Ru-C bond scission. The activation energy was
estimated as 9.8 kcal/mol. The final ring closure of V is expected
to be highly exothermic because of the formation of the aromatic
pyridine ring. In fact, the exothermicity was estimated as 48.2
kcal/mol, and the η1-pyridine complex VI is the final product.
The activation barrier of 6.8 kcal/mol is smaller than that for
the ring opening of IV.
Origin of Regioselectivity. On the basis of the theoretical
calculations, the reaction pathways for the regioselective cy-
cloaddition of the unsymmetrical diynes 14 were outlined in
Scheme 6. The regiochemistry of the cycloadducts might be
determined by the formal [2 + 2] cycloaddition of the
unsymmetrical ruthenacycle intermediate 25 with 3a or 5e,
leading to the intermediates 26 or 27. If 3a and 5e attack the
Ru-CR bond from the more substituted side, the diyne-derived
substituent R comes close to the bulky Cp* ligand, imposing
the severe steric repulsion on the unfavorable intermediates 26b
and 27b. On the other hand, the access of 3a and 5e to 25 from
the less substituted side leads to the major regioisomers 15 or
17, respectively, avoiding such a deteriorative steric repulsion
via the favorable intermediates 26a and 27a.
The overall mechanism of cyclocotrimerization of acetylene
with trifluoroacetonitrile outlined in Scheme 5 is quite similar
to that of the previously reported CpRuCl-mediated acetylene
cyclotrimerization.20,21a All elementary steps are exothermic, and
the rate-determining step is the oxidative cyclization of two
acetylene molecules to form the ruthenacyclopentatriene inter-
mediate II. Thus, the 1,6-diynes, which make the oxidative
9
J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005 611

A R T I C L E S
Yamamoto et al.
Figure 4. Reaction profile for for CpRuCl-catalyzed pyridine formation (energies in kcal/mol).
Scheme 6
The electronic directing effect is somewhat complicated
compared to the steric directing effect. As reported previously,18
the ruthenacyclopentatriene moieties in the model complexes,
which were optimized at the B3LYP/LACVP* level of theory,
are almost symmetrical, whereas the fused lactam, lactone, and
cyclopentanone rings exhibited unsymmetrical geometries.
Natural population analysis (NPA), however, revealed that these
complexes are unsymmetrical in terms of the NPA charges (see
Figure S9 in Supporting Information). With respect to the
ruthenacycle carbons, the natural charges are increased for the
R carbons anti to the carbonyl group. With these results, it is
quite reasonable to assume that the [2 + 2] cycloaddition of
these ruthenacycles with the electron-deficient nitriles and
isocyanates might take place at the more negatively charged R
carbons. To confirm this idea, we analyzed the formal [2 + 2]
cycloaddition of the ester diyne 20b with trifluoroacetonitrile
and methyl isocyanate by means of the DFT calculations. The
oxidative cyclization step was calculated and compared to that
of acetylene. As outlined in Figure 2, the activation energy of
6.6 kcal/mol for the transformation of the diyne complex i into
the bicyclic complex ii (28b) is about a half of that for I f II
(14.8 kcal/mol). Such a small barrier might be attributed not
only to the intramolecular effect of the diyne substrate but also
to the superior electron-accepting ability of the electron-deficient
20b.
Scheme 7
The coordination of ii to CF3CN affords the two isomeric
η2-nitrile complexes iii(a) and iii(b) (Figure 4). The nitrile ligand
occupies the coordination site cis to the more electronegative
R carbon in iii(a), while it is accommodated in the cis site of
the less negative carbon in iii(b). The former is 0.6 kcal/mol
more stable than the latter. The subsequent isomerization of
these complexes occurs with the activation energy of 0.2 kcal/
mol to produce the tricyclic intermediates iv(a) and iv(b). The
exothermicity of 13.3 and 11.9 kcal/mol were estimated for the
formation of iv(a) and iv(b), respectively. These results show
that the [2 + 2] cycloaddition proceeds preferably on the more
negative R carbon (ii f iii(a) f iv(a)).
a local minimum. The former is 0.5 kcal/mol more stable than
the latter. The activation barriers were estimated as 2.0 and 4.1
kcal/mol for TSv(a)-vi(a) and TSv(b)-vi(b), respectively. The
formation of vi(a) is 3.5 kcal/mol more exothermic than that of
vi(b). The difference in the activation energies for the [2 + 2]
cycloaddition step turned out to be much more pronounced with
the isocyanate than with CF3CN. This is in accordance with
the higher regioselectivity of the pyridone formations compared
to the corresponding pyridine formations.
Similarly, we also calculated the [2 + 2] cycloaddition of ii
with methyl isocyanate. In contrast to the previous reports,21
we could locate the η1-isocyanate complexes v(a) and v(b) as
Intermolecular Cyclocotrimerization Using Electron-
Deficient Monoalkyne. Previously, we have shown that electron-
deficient monoalkynes underwent cyclotrimerization at ambient
9
612 J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005

Ru-Catalyzed [2
+
2
+
2] Cycloadditions of
R,
ω-Diynes
A R T I C L E S
Scheme 8
In the same manner, phenyl isocyanate 5a was treated with
4 equiv of 29 to give the benzenetricarboxylic acid esters almost
exclusively. Thus, a large excess of an isocyanate was required
to suppress the facile cyclotrimerization of 29. In fact, employing
50 equiv of readily removable propyl isocyanate 5e resulted in
the formation of the desired pyridones 34 and 35 in 27 and
37% yields based on 29, respectively (Scheme 9). Again, only
two of the four possible regioisomers were formed, indicative
of an azaruthenacyclopentenone 36 being an exclusive inter-
mediate.
Conclusion
In conclusion, we successfully developed Cp*RuCl-catalyzed
cycloadditions of diynes with electron-deficient nitriles and
heterocumulenes, leading to various heterobicyclic compounds.
It was revealed that the regiochemistry of these cycloadditions
was successfully controlled by the steric and electronic influence
of the unsymmetrical diyne substrates. Density functional
calculations of model reactions showed that the CpRuCl-
catalyzed cyclocotrimerization of acetylene with CF3CN starts
with the oxidative cyclization of two acetylene molecules
producing a ruthenacyclopentatriene intermediate. The formal
[2 + 2] cycloaddition of the ruthenacycle intermediate with the
CtN triple bond gives rise to the azaruthenabicyclo[3.2.0]-
heptatriene and its transformation into the final η1-pyridine
complex takes place via the azaruthenacycloheptatriene complex.
The rate-determining step of the overall process was determined
as the initial oxidative cyclization; therefore, the intramolecular
system is suitable for the ruthenium catalysis. DFT calculations
also suggested that the [2 + 2] cycloadditions of the ruthen-
abicycle intermediate derived from the ester-tethered diyne with
CF3CN and methyl isocyanate take place at the more negatively
charged R carbon of the ruthenacycle, in accordance with the
observed regioselectivity.
Scheme 9
temperature under the ruthenium catalysis, while the reaction
of electronically neutral ones were not efficient under the similar
conditions.20 These facts indicate that the electron deficiency
facilitates the oxidative cyclization of the monalkynes leading
to ruthenacycle intermediates. Finally, we briefly examined the
intermolecular cyclocotrimerization of ethyl propiolate with
carbon-heteroatom multiple bonds.
In the presence of 1 mol % 1, ethyl cyanoformate 3a was
treated with 4 equiv of ethyl propiolate 29 at ambient temper-
ature for 2 h (Scheme 7). As a result, two unsymmetrical
pyridine isomers 30 and 31 were obtained in 26 and 54% yields
based on 3a, respectively, along with 1,2,4- and 1,3,5-benzene-
tricarboxylic acid triethyl esters. The obtained products showed
a couple of aromatic protons as doublets with coupling constants
of 1.8 and 8.1 Hz, respectively, which allowed us to assign 30
and 31 to 2,3,5- and 2,3,6-substituted isomers, respectively. This
interesting regioselectivity can be explained by assuming the
selective formation of an azaruthenacycle intermediate. In the
intermolecular reaction, the oxidative cyclization of a monoalkyne
and an electron-deficient nitrile might be feasible as shown by
the DFT calculations (Figure 2). Considering the polarization
of the propiolate ligand in 32, the cyclization might take place
as outlined in Scheme 8 to give rise to an azaruthenacyclopen-
tadiene 33 selectively. Subsequent reaction of 33 with 29
occurred with its Ru-C bond to furnish the only two pyridine
isomers 30 and 31.
Intermolecular cyclocotrimerizations of ethyl propiolate with
ethyl cyanoformate or propyl isocyanate gave rise to two of
the four possible regioisomers, indicative of azaruthenacycle
intermediates playing an important role.
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research on Priority Areas (No. 13029044,
14044038, “Exploitation of Multi-Element Cyclic Molecules”)
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
Supporting Information Available: Experimental details,
characterization data for the products, and the supplementary
crystallographic data and X-ray crystallographic files (PDF,
CIF). This material is available free of charge via the Internet
at http://pubs.acs.org.
JA045694G
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J. AM. CHEM. SOC. VOL. 127, NO. 2, 2005 613