Ruthenium-catalyzed aromatization of enediynes via highly regioselective nucleophilic additions on a π-alkyne functionality. A useful method for the synthesis of functionalized benzene derivatives

Article abstract of DOI:10.1021/ja043047j

TpRu(PPh₃)(CH₃CN)₂PF₆ (10 mol %) catalyst effected the nucleophilic addition of water, alcohols, aniline, acetylacetone, pyrroles, and dimethyl malonate to unfunctionalized enediynes under suitable conditions (100 °C, 12-24 h) and gave functionalized benzene products in good yields. In this novel cyclization, nucleophiles very regioselectively attack the internal C1′ alkyne carbon of enediynes to give benzene derivatives as a single regioisomer. Experiments with methoxy substituents exclude the possible involvement of naphthyl cations as reaction intermediates in the cyclization of (o-ethynylphenyl) alkynes. Deuterium-labeling experiments indicate that the catalytically active species is ruthenium-π-alkyne rather than ruthenium-vinylidene species. This hypothesis is further confirmed by the aromatization of o-(2′-iodoethynyl)phenyl alkynes with alcohols. We propose a nucleophilic addition/insertion mechanism for this nucleophilic aromatization on the basis of a series of experiments.

Full text of DOI:10.1021/ja043047j

Published on Web 02/19/2005
Ruthenium-Catalyzed Aromatization of Enediynes via Highly
Regioselective Nucleophilic Additions on a π-Alkyne
Functionality. A Useful Method for the Synthesis of
Functionalized Benzene Derivatives
Arjan Odedra, Chang-Jung Wu, Taduri Bhanu Pratap, Chun-Wei Huang,
Ying-Fen Ran, and Rai-Shung Liu*
Contribution from the Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu,
Taiwan, ROC
Received November 18, 2004; E-mail: rsliu@mx.nthu.edu.tw
Abstract: TpRu(PPh3)(CH3CN)2PF6 (10 mol %) catalyst effected the nucleophilic addition of water, alcohols,
aniline, acetylacetone, pyrroles, and dimethyl malonate to unfunctionalized enediynes under suitable
conditions (100 °C, 12-24 h) and gave functionalized benzene products in good yields. In this novel
cyclization, nucleophiles very regioselectively attack the internal C1′ alkyne carbon of enediynes to give
benzene derivatives as a single regioisomer. Experiments with methoxy substituents exclude the possible
involvement of naphthyl cations as reaction intermediates in the cyclization of (o-ethynylphenyl) alkynes.
Deuterium-labeling experiments indicate that the catalytically active species is ruthenium-π-alkyne rather
than ruthenium-vinylidene species. This hypothesis is further confirmed by the aromatization of o-(2′-
iodoethynyl)phenyl alkynes with alcohols. We propose a nucleophilic addition/insertion mechanism for this
nucleophilic aromatization on the basis of a series of experiments.
Scheme 1
Introductions
Bergman aromatization of enediynes1 has attracted consider-
able attention because of its potential applications in medicinal
and materials chemistry (Scheme 1, eq 1).2,3 The Bergman
reaction of unstrained enediynes can be implemented by an
excess (>1.0 equiv) of metal complexes under mild conditions
via metal-vinylidene intermediates4a,b (eq 2) or through a metal-
chelated effect.4c-f The metal-vinylidene process mimics the
cyclization of 5-allene-3-en-1-ynes (Saito-Myers cyclization)5
occurring at 50-100 °C (eq 3).4-6 Uemura et al. recently
reported6 rhodium-catalyzed Bergman reactions via this protocol,
(1) (a) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25. (b) Lockhart, T. P.; Comita,
P. B.; Bergman, R. G. J. Am. Chem. Soc. 1981, 103, 4082.
(2) Reviews: (a) Enediyne Antibiotics as Antitumor Agents; Borders, D. B.,
Doyle, T. W. Eds.; Marcel Dekker: New York, 1995. (b) Xi, Z.; Goldberg,
I. H. In ComprehensiVe Natural Product Chemistry; Barton, D. H. R.,
Nakanishi, K. Eds.; Pergamon: Oxford, 1999; Vol. 7, p 553.
(3) Recent reviews: (a) Basak, A.; Mandal, S.; Bag, S. S. Chem. ReV. 2003,
103, 4077. (b) Rawat, D. S.; Zaleski, J. M. Synlett. 2004, 393. (c) Bowles,
D. M.; Palmer, G. J.; Landis, C. A.; Scott, J. L.; Anthony J. E. Tetrahedron
2001, 57, 3753. (d) Grissom, J. W.; Gunawardena, G. U.; Klingberg, D.;
Huang, D. Tetrahedron 1996, 52, 6453. (e) Wang, K. K. Chem. ReV. 1996,
96, 207.
(4) For selected examples of stoichiometric metal-mediated Bergman cycliza-
tion, see: (a) Wang, Y. S.; Finn, M. G. J. Am. Chem. Soc. 1995, 117,
8045. (b) O’Connor, J. M.; Friese, S. J.; Tichenor, M. J. Am. Chem. Soc.
2002, 124, 3506. (c) Zaleski, J. M.; Rawat, D. S. J. Am. Chem. Soc. 2001,
123, 9675. (d) Warner, B. P.; Millar, S. P.; Broene, R. D.; Buchwald, S. L.
Science 1995, 269, 814. (e) Konig, B.; Hollnagel, H.; Ahrens, B.; Jones,
P. G. Angew. Chem., Int. Ed. Engl. 1995, 34, 2538. (f) Landis, C. A.; Payne,
M. M.; Eaton, D. L.; Anthony, J. E. J. Am. Chem. Soc. 2004, 126, 1338.
(5) (a) Myers, A. G.; Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989, 111,
8057. (b) Nagata, R.; Yamanaka, H.; Okazaki, E.; Saito, I. Tetrahedron
Lett. 1989, 30, 4995.
which led to dehydrogenation or C-H bond insertion of an
tethered alkane (eq 2). In all examples reported to date, the
cyclization of enediynes via metal-vinylidene intermediates has
followed the traditional diradical mechanism, and these reactions
have very limited applications in organic synthesis because they
cannot give functionalized benzenes from unstrained and
unfunctionalized enediynes.1-5
In contrast, the aromatization of enediynes via nucleophilic
addition (anionic Bergman cyclization) is more useful because
organic functionality can be introduced onto aromatic products
via suitable nucleophiles.7,8 Although anionic Bergman cycliza-
tion was first reported by Magnus in the early 1990s,7c such
reactions have never been implemented by metal catalysts. The
(6) (a) Ohe, K.; Kojima, M.-a; Yohehara, K.; Uemura, S. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1823. (b) Manabe, T.; Yanagi, S.-I.; Ohe, K.; Uemura,
S. Organometallics 1998, 17, 2942.
9
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J. AM. CHEM. SOC. 2005, 127, 3406-3412
10.1021/ja043047j CCC: $30.25 © 2005 American Chemical Society

Ruthenium-Catalyzed Aromatization of Enediynes
A R T I C L E S
Scheme 2
widespread use of this protocol has been restricted by its limited
scope: the reactions required either anionic nucleophiles, such
as sodium methoxide and thiophenoxide,7 or strained cyclic
enediynes.8 Techniques for the cyclization of unstrained ene-
diynes using mild nucleophiles and metal catalysts are currently
unavailable and thus provide a challenge in synthetic chemistry.
This report describes a novel ruthenium-catalyzed aromatization
of unstrained enediynes with mild nucleophiles. This new
pathway is mechanistically interesting because it does not follow
the traditional Saito-Myers protocol; the active intermediate
is metal-alkyne rather than metal-vinylidene species.4a,b,6
Results and Discussions
Although cyclization of unfunctionalized enediynes has been
performed with different approaches, including diradical
pathways,1b,9 eletrophilic additions,10a-c and radical cation,10d
these reactions only gave benzene1b,9 or fulvene products10 of
special types. We seek to find a new method to realize the
aromatization of functionalized enediynes with various nucleo-
philes. We selected TpRuPPh3(CH3CN)2PF6 [Tp ) tris(1-
pyrazolyl)borate]11,12 as the catalyst because it reacts with
terminal alkyne to form a cationic ruthenium-π-alkyne complex
that equilibrates with ruthenium-vinylidene species.13 Scheme
2 shows the catalytic protocols that we design to realize this
nucleophilic aromatization with high regioselectivity: (1) elec-
trocyclic cyclization of these ruthenium-π-alkyne or -vinyl-
idene intermediates to generate reactive naphthyl carbocations
A (path i) and B (path ii) that can be trapped by suitable
nucleophiles and (2) nucleophilic attack at ruthenium-π-alkyne
species to give vinylruthenium species (path iii), followed by a
6-endo-dig insertion reaction. We envisage that nucleophilic
additions preferably occur at the internal alkynyl C′(1) carbon
for species A and B and at the terminal alkynyl C′(1) carbon
Scheme 3
for species C because of its electron-deficient character. For
paths (i) or (ii), the success of this nucleophilic cyclization relies
on the hypothesis that the resonance structures are best
represented by singlet state species A and B rather than the
diradical resonance forms A′ and B′.
As shown in Scheme 3, treatment of o-ethynylphenyl alkyne
1a (1.50 M) in a solvent mixture of water and 3-pentanone (1:1
volume ratio, 100 °C, 24 h) using 10 mol % TpRuPPh3(CH3-
CN)2PF6 catalyst gave 1-naphthol 2a in 75% yield. The yield
was decreased to 51% for a 5% loading of catalyst. Similar
cyclizations were also observed for enediynes bearing prop-1-
ynyl and but-1-ynyl substituents 1b and 1c, which gave
2-substituted 1-naphthol 2b and 2c in respective yields of 71
and 65%. The reaction was inhibited by basic additives,
including Et3N (10 mol %) or DBU (10 mol %).14 Such a
nucleophilic aromatization is novel and surprising because many
electrophilic metals catalyze the hydration of terminal alkynes
to give methyl ketones very efficiently.15 The value of this
cyclization is shown by the regioselectivity of the addition of
water, which occurs only at the internal C5 alkyne carbon. The
structure of 2a was easily determined by its 1H NMR spectra.16
Ketone 3 was unlikely to be a reaction intermediate because it
failed to give 1-naphthol 2a under similar catalytic conditions.
We examined the cyclization of 1a using various ruthenium
(7) For anionic Bergman cyclization, see: (a) Wu, M.-J.; Lin, C.-F.; Lu, E.-D.
J. Org. Chem. 2002, 67, 5907. (b) Wu, M.-J.; Lee, C.-Y.; Lin, C.-F. Angew.
Chem., Int. Ed. Engl. 2002, 41, 4077. (c) Magnus, P.; Eisenbeis, S. A.;
Rose, W. C.; Zein, N.; Solmon, W. J. Am. Chem. Soc. 1993, 115, 12627.
(d) Sugiyama, H.; Yamashita, K.; Nishi, M.; Saito, I. Tetrahedron Lett.
1992, 33, 515.
(8) For the cyclization of strained enediynes with anionic nucleophiles, the
enediynes actually underwent traditional Bergman or Saito-Myers diradical
processes after attack of anionic nucleophiles. For examples, see: (a)
Nicolaou, K. C.; Dai, W. M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387
and references therein. (b) Hirama, M.; Fujiwara, K.; Shigematsu, K.;
Fukazara, Y. J. Am. Chem. Soc. 1989, 111, 4120. (c) Wender, P. A.;
Hartmata, M.; Jefferey, D.; Mukai, C.; Suffert, J. Tetrahedron Lett. 1988,
29, 909. (d) Bekele, T.; Brunette, S. R.; Lipton, M. A. J. Org. Chem. 2003,
68, 8741.
(9) For cyclization of enediynes via diradical pathways, see: ref 1b and (a)
Jones, L. H.; Hartwig, C. W.; Wentworth, P., Jr.; Simeonov, A.; Wentworth,
A. D.; Py, S.; Ashley, J. A.; Lerner, R. A.; Janda, K. D. J. Am. Chem. Soc.
2001, 123, 3607. (b) Grissom, J. W.; Gunawardena, G. U. Tetrahedron
Lett. 1995, 36, 4951. (c) Schottelius, M.; Chen, P. J. Am. Chem. Soc. 1996,
118, 4896. (d) Dai, W.-M. Curr. Med. Chem. 2003, 10, 2265.
(10) For cyclization of enediynes with electrophile additiona-c and radical cation,d
see: (a) Whitlock, H. W., Jr.; Sandvick, P. E.; Overman, L. E.; Reichardt,
P. B. J. Org. Chem. Soc. 1969, 34, 879. (b) Whitlock, H. W., Jr.; Sandvick,
P. E. J. Am. Chem. Soc. 1966, 88, 4525. (c) Schreiner, P. R.; Prall, M.;
Lutz, V. Angew. Chem., Int. Ed. 2003, 42, 5757. (d) Schmittel, M.; Kiau,
S. Liebigs Ann./Recl. 1997, 1391.
(11) For catalytic reactions that use this ruthenium catalyst, see the following
selected examples: (a) Yeh, K.-L.; Liu, B.; Lo, C.-Y.; Liu, R.-S. J. Am.
Chem. Soc. 2002, 124, 6510. (b) Datta, S.; Chang, C.-L.; Yeh, K.-L.; Liu,
R.-S. J. Am. Chem. Soc. 2003, 125, 9294. (c) Shen, H.-C.; Pal, S.; Lian,
J.-J.; Liu, R.-S. J. Am. Chem. Soc. 2003, 125, 15762. (d) Madhushaw, R.
J.; Lin, M.-Y.; Abu Sohel, S. M.; Liu, R.-S. J. Am. Chem. Soc. 2004, 126,
6895. (e) Madhushaw, R.-J.; Lo, C.-Y.; Huang, C.-W.; Su, M.-D.; Shen,
H.-C.; Pal, S.; Shaikh, I. R.; Liu, R.-S. J. Am. Chem. Soc. 2004, 126, 15560.
(12) Chan, W.-C.; Lau, C.-P.; Chan, Y.-Z.; Fang, Y.-Q.; Ng, S.-M.; Jia, G.
Organometallics 1997, 166, 34.
(14) In the presence of aliphatic amine base, cationic ruthenium complex tends
to react with terminal alkyne to give alkynyl ruthenium species. See: (a)
Bustelo, E.; Carbo, J. J.; Lledos, A.; Mereiter, K.; Puerta, M. C.; Valerga,
P. J. Am. Chem. Soc. 2003, 125, 3311. (b) Bruce, M. I.; Wallis, R. C.
Aust. J. Chem. 1979, 32, 1471. (c) Haquette, D. T.; Pirio, N.; Touchard,
L.; Toupet, P. H.; Dixneuf, J. J. Chem. Soc., Chem. Commun. 1993, 163.
(d) Yang, S.-M.; Chan, M. C.-W.; Cheung, K.-K.; Che, C.-M.; Peng, S.-
M. Organometallics 1997, 16, 2819.
(15) (a) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int.
Ed. Engl. 2002, 41, 4563. (b) Tokunaga, M.; Wakatsuki, Y. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2867. (c) Damiano, J. P.; Postel, M. J. Organomet.
Chem. 1996, 522, 303. (d) Uemura, S.; Miyoshi, H.; Okano, M. J. Chem.
Soc., Perkin Trans. 1 1980, 1098. (e) Baidossi, W.; Lahav, M.; Blum, J. J.
Org. Chem. 1997, 62, 669.
(13) (a) Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (b) Bruneau, C.; Dixneuf,
P. Acc. Chem. Res. 1999, 32, 311. (c) Puerta, M. C.; Valerga, P. Coord.
Chem. ReV. 1999, 193-195, 977.
(16) The structures of the addition products in Tables 1-4 were assigned on
the basis of two new doublets (J ) 7.8-8.0 Hz) in the aromatic regions.
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A R T I C L E S
Odedra et al.
Table 2. Aromatization via Addition of Anilines to Enediynes
Table 1. Regioselective Alkoxylation and Hydration in the
Aromatization Reactions
a 10 mol % catalyst, aniline (6.0 equiv), 100 °C, 15 h. b Yields were
reported after purification from a silica column.
Table 3. Aromatization via Carbon Nucleophiles to Enediyne 1a
a 10 mol % catalyst, 100 °C, 12 h for alcohols (6.0 equiv) and 24 h for
water. b Water and 3-pentanone (vol. 1:1) were used as a mixing solvent.
c Yields were reported after separation from a silica column.
catalysts, including CpRuL(CH3CN)2PF6 [L ) PPh3, P(t-Bu)3,
and P(n-Bu)3] and C5Me5RuPPh3(CH3CN)2PF6,17 which failed
to show any catalytic activity. One possible reason is that these
complexes may react with benzene to give stable XRu(π-
benzene)PF6 (X ) Cp, C5Me5) species.4b
We used this new method for the synthesis of substituted
aromatic compounds containing hydroxy and alkoxy function-
alities via treatment of various unfunctionalized enediynes with
water and alcohols. As shown in Table 1, entries 1-5 show
examples of the regioselective alkoxylation of o-ethynylphenyl
alkynes 1a-1c with n-butanol, i-butanol, and sec-butanol; the
corresponding 1-alkoxynaphthalenes 2d-2h were obtained in
good yields (60-81%). We further established the reliability
of this method by conducting similar alkoxylation and hydroxy-
lation reactions using the enediynes 1d-1h, which gave highly
substituted benzene derivatives 2i-2o (entries 6-12) in good
yields (70-81%), each as a single regioisomer.
We extended this method to the synthesis of diphenylamine
derivatives via nucleophilic carbon-nitrogen bond formation
(Table 2). In a typical operation, enediynes and neat aniline
(6.0 equiv) were heated with 10% ruthenium catalyst (100 °C,
15 h). For enediynes 1a, 1d, and 1f, nucleophilic cyclization
worked for anilines but not for aliphatic amines.14 Although
the same regiochemistry was observed for these enediynes, we
obtained both N-aryl (A) and ortho-C-aryl (B) products in most
cases. The amounts of the corresponding para-C-aryl products
were too low for isolation except for entry 2, where (4b-C) was
obtained in 32% yield. For enediyne 1a, the N-aryl and ortho-
C-aryl products were obtained in equal proportions (entries 1
and 2), whereas the analogues 1d and 1f preferably gave N-aryl
products (4c-A)-(4f-A) in 52-63% (entries 3-6). Notably,
such an aniline addition failed to work with enediynes 1b, 1c,
and 1e, which have an internal alkyne. Compared to enediyne
1a, species 1b and 1c bearing an internal alkyne were also less
a 10 mol % catalyst, nucleophiles (6.0 equiv), 100 °C, 15 h. b Yields
were reported after separation from a silica column.
effective in the water and alcohol addition reactions (Scheme 3
and Table 1).
The synthetic potential of this method is further enhanced
by its compatibility with carbon-centered nucleophiles, as is
evidenced by the range of examples in Table 3. These reactions
were performed by heating enediyne 1a with neat carbon-
centered nucleophiles (6.0 equiv) at 100 °C for 15 h. The method
worked well for pyrrole, which gave 2-aryl pyrrole 5a in 73%
yield. The efficiency of cyclization for silyl enol ether was low
(entry 2), and the corresponding product 5b was obtained in
28% yield. Ethyl acetoacetonate (EA) was active in cyclization,
and gave C-aryl product 5c (62%), whereas dimethyl malonate
(DMA) gave 1-naphthalene species 5d in 64% yield through
decarboxylation reaction. Heating 1a with neat Et3SiH (6.0
equiv) and catalyst (10 mol %, 100 °C, 15 h) only led to a 66%
recovery yield of starting 1a.
Table 4 summarizes the results for the generality of this
cyclization with suitable carbon-centered nucleophiles. Ene-
diynes 1b, 1e, and 1h bearing an internal alkyne were compat-
ible with this new method. EA, DMA, and pyrrole were added
very regioselectively to these enediynes and gave aromatic
products 5e-5p as a single regioisomer; except for entry 3, the
yields exceeded 60%. Notably, the reaction with methyl-
substituted ethyl acetoacetate (entry 2) gave 1-naphthalene 5f
(60% yield), which contains a tertiary acetoacetate substituent.
(17) CpRuL(CH3CN)2PF6 [L ) PPh3, P(t-Bu)3, and P(n-Bu)3] and C5Me5-
RuPPh3(CH3CN)2PF6 complexes were prepared in situ by treatment of
CpRu(CH3CN)3PF6 and C5Me5Ru(CH3CN)3PF6 with an equimolar amount
of phosphine ligand.
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Ruthenium-Catalyzed Aromatization of Enediynes
A R T I C L E S
Table 4. Regioselective Aromatizations of Enediynes with Carbon
Scheme 5
Nucleophiles
a 10 mol % catalyst, [substrate] ) 1.2 M, isobutanol 95 °C, 12 h. bYields
were isolated from a silica column.
Scheme 6
a 10 mol % catalyst, nucleophiles (6.0 equiv), 15 h. b Yields were reported
after separation from a silica column. c EA ) ethyl acetoacetate. DMA )
dimethyl malonate.
Scheme 4
a 10 mol % catalyst, [substrate] ) 0.75 M, toluene 100 °C, 15 h. bYields
were isolated from a silica column.
aromatization via the C-H bond insertion. We prepared
substrates 1m-1o and 1p-1r bearing a methoxy group at the
phenyl C(4) and C(5) carbons, respectively, to clarify the role
of the cationic nature of the reaction intermediates. As shown
in Scheme 5, (1-isobutoxy)naphthalene derivatives 7a-7c were
obtained in 58-61% yields, which were slightly lower than that
(65%) of the parent compound 2e (X ) Y ) H, Table 2),
whereas cyclopentane derivatives 8a-8c were obtained in 78-
85% yields (Scheme 6), which are much higher than that (54%)
of the unsubstituted analogue 6b (Scheme 4). This information
suggests that the key intermediates for nucleophilic aromatiza-
tion are likely to be neutral species, whereas those in intramo-
lecular C-H bond insertion may be cationic naphthyl carbene
intermediates A and B (Scheme 2).18 The notation that cationic
naphthyl carbene intermediates are involved in nucleophilic
cyclization is contradicted by the inactivity of the enediyne 1a
toward Et3SiH19 (Table 3, entry 5).
a 10 mol % catalyst, nbutanol (6.0 equiv) 100 °C, 15 h. bToluene solvent.
cYields were separated from a silica column.
Scheme 4 shows the structural effects of the substrates on
the catalytic activity. Enediyne 1i, which bears a pent-1-ynyl
group, failed to react with n-butanol, but cyclized itself to give
cyclopentyl species 6a (27%) via a C-H bond insertion. The
yield of compound 6a was increased to 35% by heating species
1i in toluene (100 °C, 15 h). Interestingly, enediynes 1j and 1k
bearing a long hex-1-ynyl and oct-1-ynyl group gave improved
yields of cyclopentyl products 6b (54%) and 6c (61%). The
enhancing effect of the longer alkynyl alkyl group of enediynes
is opposite to the results observed in preceding nucleophilic
cyclizations. Furthermore, the structures of products 6a-6c are
distinct from those using rhodium catalysts, which gave a
cyclopentyl ring fused at the naphthyl C(2) and C(3) carbons.6b
These results suggest that this C-H bond insertion does not
proceed via a diradical mechanism (Scheme 1, eq 2). The
nBuOH addition failed to work with enediyne 1l, which has
two internal alkyne substituents.
(18) These methoxy experiments suggest that the intermediates for the C-H
bond insertion likely involve the following two cationic naphthyl carbenes
A and B via electrocyclization of ruthenium-π-alkyne and ruthenium-
vinylidene species, respectively (see Scheme 2). The methoxy groups will
stabilize these carbenium species and give better yields of insertion products.
In our preliminary results, we found that the alkynyl deuterium of starting
ruthenium-π-alkyne species 1j (X ) Y ) H, R ) nBu) was transferred
equally to the C(3) and C(4) carbons of the cyclopentyl product 6b.
We are uncertain whether the mechanism of nucleophilic
aromatization of enediynes is the same as that for intramolecular
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A R T I C L E S
Scheme 7
Odedra et al.
Scheme 9
π-alkyne species rather than ruthenium-vinylidene because
there is no 1,2-hydrogen shift in the cyclization.
The direct support of ruthenium-π-alkyne intermediates in
this nucleophilic aromatization is shown in Scheme 9. Treatment
of enediynes 10a,10b with TpRuPPh3(CH3CN)2PF6 catalyst (10
mol %) in hot isobutanol gave addition products 11a and 11b
in respective yields of 56 and 59%. The absence of a 1,2-iodo
shift in this aromatization is indicative of a ruthenium-π-alkyne
species as an active intermediate. Ruthenium-vinylidene in-
termediates are expected to lead to a 1,2-shift of alkynyl iodide.22
Formation of naphthalene products 11a and 11b may arise from
the attack of iBuOH at the more electron-rich alkyne substituent
(R ) H, Me), and this regiochemistry is identical to that in the
preceding examples in considering this electronic effect. The
structures of 11a and 11b were characterized on the basis of
Scheme 8
a 10.0 equiv of D2O. b22 equiv of D2O. Unreacted 1a after catalytic
reaction.
c
1
the H NOE effect.23
The stoichiometric reaction described in Scheme 7 is very
informative and leads us to propose a plausible mechanism based
on the observation that the Ru-Cl bond of TpRuPPh3(CH3-
CN)Cl12 is inserted into the internal alkyne group of enediyne
1j to trigger aromatization. The proposed mechanism in Scheme
10 is consistent with our observations (see Schemes 6, 8, and
9), which preclude the involvement of cationic naphthyl species
A (or B) and ruthenium-vinylidene intermediates. We propose
The mechanism for nucleophilic aromatization has been
elucidated on the basis of a series of experiments. As shown in
Scheme 7, we found that TpRuPPh3(CH3CN)Cl12 (1.0 equiv)
reacted with enediyne 1j (2.5 equiv) in hot 3-pentanone (100
°C, 12 h) and gave 1-chloronaphthalene 9 in 76% yield on the
basis of ruthenium reagent. This cyclization followed the same
regiochemistry as preceding examples, and C-H bond insertion
did not occur in this case although a n-butyl group is tethered
with 1j. We did not observe a similar chloride insertion for
internal alkyne 1s. This phenomenon suggests that a diyne
functionality is required for this chloride insertion. The terminal
alkyne of species ij is thought to serve as an entering group to
facilitate the chloride insertion via intramolecular coordination.20
+
that TpRuPPh3(CH3CN)2 species, after the loss of a CH3CN
ligand, selectively binds to the more electron-rich internal alkyne
(R ) H, alkyl) of enediyne and gives ruthenium-π-alkyne
species (I). This π-alkyne selectivity is attributed to the cationic
ruthenium nature of species (I). A possible route involves the
ligand exchange of nucleophiles with CH3CN at the ruthenium
center, followed by insertion of the Ru-NuH σ-bond of species
(II) into the alkyne group to form vinylruthenium species (III).
An intramolecular 6-endo-dig cyclization of species (III) gave
naphthylruthenium intermediate (IV) and ultimately led to the
observed aromatization products via protonation.
An alternative route involves a direct nucleophilic addition
at species (I) to form vinylruthenium species (III), with
ruthenium coordinated to a remaining alkynyl group (X ) H,
I). This pathway is applicable to pyrrole nucleophiles because
they cannot undergo ligand exchange with ruthenium center
since the pyrrole nitrogen is not a good ligating atom. The
nucleophilic attack at ruthenium-di-π-alkyne species depicted
in Scheme 2 (path iii) is unlikely to occur because the expected
regiochemistry is not consistent with our observations.
Scheme 8 shows deuterium labeling experiments. Treatment
of enediyne 1b with D2O (10.0 equiv) in 3-pentanone gave
naphthalene d-2b with deuterium contents of 100 and 46%,
respectively, at the C4 and C3 carbons (entry 1). Notably, the
alkynyl proton of unreacted 1b was also deuterated (50%),
which indicated that proton exchange with D2O occurred.21 This
exchange process accounts for the lower proton content (30%)
at the C3 carbon of d-2b in the presence of D2O in 22-fold
proportions (entry 2). The alkynyl deuterium of 1b was
transferred mainly to the C3 carbon of the product d-2b (entry
3) with a 40% loss of deuterium content. This labeling
experiment indicates that the catalytic cycle is achieved by
(19) Et3SiH will add to carbene intermediate via a Si-H bond insertion. See:
(a) Alder, R. W. In Carbene Chemistry; Bertrand, G., Ed.; Marcel Dekker:
New York, 2002; p 153. (b) Bertrand G. In Carbene Chemistry; Bertrand,
G., Ed.; Marcel Dekker: New York, 2002; pp 177-203.
(20) Although our proposed mechanism suggests the feasibility of the catalytic
addition of HCl to enediyne 1j, the yield was only 15% using 10 mol %
TpRuPPh3(CH3CN)2PF6 (3-pentanone, 100 °C, 72 h) and HCl (aq, 2.0
equiv). Under this condition, unreacted enediyne 1j was only recovered in
15% with formation of a black heavy oil. This information suggests that
this catalytic reaction is slower than the decomposition of enediynes 1j by
ruthenium catalyst alone.
The insertion process (I) f (II) f (III) is proposed on the
basis of stoichiometric cyclization of enediyne 1j using
TpRuPPh3(CH3CN)Cl complex (see Scheme 7), which appar-
ently coordinates to the more electron-rich alkyne group (R )
H, Me, Et) before delivery of the chloride ligand. According to
the literature,12 the structure of intermediate (II) is proposed to
(21) The exchange between D2O and alkynyl proton can proceed via an alkynyl
ruthenium hydride species, which was responsible for the ruthenium-π-
alkyne and ruthenium-vinylidene equilibrium. See refs 12 and 16.
(22) Miura, T.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 518.
(23) The 1H NOE map of naphthalenes 11a and 11b is shown in the Supporting
Information.
9
3410 J. AM. CHEM. SOC. VOL. 127, NO. 10, 2005

Ruthenium-Catalyzed Aromatization of Enediynes
A R T I C L E S
Scheme 10
Scheme 11
Conclusions
In summary, we have reported a new nucleophilic aromati-
zation of unstrained enediynes catalyzed by TpRu(PPh3)(CH3-
CN)2PF6 catalyst. The value of this cyclization is indicated by
the regioselectivity of nucleophilic addition, which occurs only
at the more electron-rich alkyne carbon. The cyclization is
compatible with various mild nucleophiles including water,
alcohols, aniline, pyrrole, ethyl acetylacetonate, and dimethyl
malonate, which reflects nucleophilic C-X (X ) O, N, C) bond
formation. This method is very useful because it provides easy
access to functionalized aromatic compounds from readily
available unfunctionalized enediynes. We propose a nucleophilic
addition/insertion mechanism27 based on the results of a series
of experiments, which preclude the involvement of ruthenium-
vinylidene and cationic naphthyl species in the reaction mech-
anism. In the case of enediynes bearing a long alkyl substituent,
we observed the aromatization of these enediynes accompanied
by a C-H bond insertion, and the mechanism likely involves a
naphthyl cation18 according to the methoxy substituent effects.
We will expand the scope of this C-H bond insertion and
characterize its mechanism in future studies.
be a TpRuL(NuH)(π-alkyne)+ cation rather than a neutral
species, TpRuL(Nu)(π-alkyne). This insertion step also provides
a good rationale for the aniline-addition regiochemistry, which
gives ortho-C-aryl products B (Table 2), whereas the para-C-
aryl products are not seen in most cases. The preference for
ortho-C-aryl product is thought to arise from the intramolecular
cyclization of species (II), depicted in Scheme 11. The resulting
cis-insertion species cis-III′ can be transformed into the vinyl-
ruthenium π-alkyne III via isomerization of cis-vinylmetal to
its trans-vinylmetal species.24,25 The feasibility of this process
is likely to occur by rotation of the σ-carbon-carbon bond of
the resonance structure (III′).
Experiment Section
(1) General Sections. Unless otherwise noted, all reactions were
carried out under a nitrogen atmosphere in oven-dried glassware using
standard syringe, cannula, and septa apparatus. Benzene, diethyl ether,
tetrahydrofuran, and hexane were dried with sodium benzophenone and
distilled before use. TpRuPPh3(CH3CN)2PF6 (1) catalyst was prepared
by heating TpRu(PPh3)2Cl with LiPF6 in CH3CN.12 Enediyne 1a was
prepared according to the literature procedure.4b Synthesis of repre-
sentative enediynes is given in the Supporting Information.
In this catalytic reaction, enediyne 1l bearing two internal
alkynes (Scheme 4, entry 5) is not catalytically active in the
nBuOH addition. We believe that this is caused by the congested
environment of intermediate III, in which the two methyl groups
exert steric hindrance with the bulkyl TpRuPPh3 fragment. Such
a hindrance inhibits the formation of intermediate III. The
adverse effects of a long internal alkynyl on the aromatization
have been observed in our results. For example, the endiyne
(26) Enediyne 1t bearing a CO2Me group is not active in the nBuOH addition.
We envisage that this enediyne will give the intermediate III according to
our proposed mechanism. We believe that the ester group of species III
exerts steric hindrance with the TpRuPPh3 fragment to destabilize this
species in accordance with our proposal in the text. This observation
strengthens our views about the steric effects of enediynes on the catalytic
activity.
n
n
bearing a R′ ) Pr group is inactive in the BuOH addition,
whereas its analogues R′ ) H(1a), Me(1b), and Et (1c) show
catalytic activities with product yields following the trend 1a
> 1b > 1c. Similarly, aniline and pyrrole addition reactions
work only for enediynes 1a, 1d, and 1f (Table 3), but not for
those enediynes 1b, 1c, 1e, and 1h bearing an internal alkyne.26
(24) For a mechanistic study of the cis-vinylmetal and trans-vinylmetal
isomerization reaction, see: Bodner, G. S.; Smith, D. E.; Hatton, W. G.;
Heah, P. C.; Georgiou, S.; Reingold, A. L.; Geib, S. J.; Hutchinson, J. P.;
Gladysz, J. A. J. Am. Chem. Soc. 1987, 109, 7688.
(25) For the trans-insertion of alkyne into metal-hydride and -chloride bonds,
see: (a) Huggins, J. M.; Bergman, R. G. J. Am. Chem. Soc. 1981, 103,
3002. (b) Vessey, J. D.; Mawby, R. J. J. Chem. Soc., Dalton Trans. 1993,
51.
(27) As suggested by one reviewer, this nucleophilic aromatization should be
effected by other π-alkyne activators such as PtCl2 and AuCl3 according
to the propose mechanism. In the reaction of enediyne 1a and 1b with
water/3-pentanone, PtCl2 (10 mol %) gave 1-naphthnols 2a and 2b in 30
and 35% yields, respectively, whereas AuCl3 was catalytically inactive. In
the Pt case, water preferably attacks the propynyl C(1) carbon, following
the same regiochemistry as ruthenium catalyst. The mild activity of PtCl2
gives additional support for the proposed π-alkyne intermediate.
9
J. AM. CHEM. SOC. VOL. 127, NO. 10, 2005 3411

A R T I C L E S
Odedra et al.
(2) Standard Procedure for Ruthenium-Catalyzed Aromatization
of Enediynes by Water. To a 3-pentanone/water mixture (vol 1:1,
0.60 mL) of enediyne 1a (100 mg, 0.79 mmol) was added TpRuPPh3-
(CH3CN)2PF6 (60 mg, 0.079 mmol), and the mixture was heated at
100 °C for 24 h. The solution was concentrated and eluted through a
silica column (hexane/EA ) 5:1) to give 1-naphthol 2a (86 mg, 0.60
mmol, 75%) as a white solid.
(3) Standard Procedure for Ruthenium-Catalyzed Aromatization
of Enediynes by Alcohols. To an isobutanol solution (0.60 mL, 6.48
mmol) of enediyne 1a (100 mg, 0.79 mmol) was added TpRuPPh3(CH3-
CN)2PF6 (60 mg, 0.079 mmol), and the mixture was heated at 100 °C
for 12 h. The solution was concentrated and eluted through a silica
column (hexane) to give (1-isobutanoxy)naphthelene 2d (128 mg, 0.64
mmol, 81%).
(4) Standard Procedure for Ruthenium-Catalyzed Aromatization
of Enediynes by Anilines. To an aniline solution (0.50 mL, 5.48 mmol)
of enediyne 1a (100 mg, 0.79 mmol) was added TpRuPPh3(CH3-
CN)2PF6 (60 mg, 0.079 mmol), and the mixture was heated at 100 °C
for 15 h. The solution was eluted through a short silica column with
hexane to remove catalyst and excess aniline. The hexane eluent was
concentrated and eluted through a silica column to give naphthalene
4aA (73 mg, 0.33 mmol) and 4aB (61 mg, 0.28 mmol) in 42 and 35%
yields, respectively.
125.9, 125.8, 125.0, 122.1, 119.9, 104.5, 74.4, 28.4, 19.4; HRMS calcd.
for C14H16O 200.1201. Found 200.1205.
(9) Spectral Data for Naphthalen-1-yl-phenylamine (4a-A): IR
(neat, cm-1): 3411 (vs), 3022 (w), 1622 (w), 1308 (m); 1H NMR (400
MHz, CDCl3): δ 8.01 (d, 1 H, J ) 8.8 Hz), 7.85 (d, 1 H, J ) 8.8 Hz),
7.56 (d, 1 H, J ) 7.6 Hz), ∼7.51-7.44 (m, 2 H), ∼7.43-7.35 (m, 2
H), 7.25 (t, 2 H, J ) 7.6 Hz), 6.98 (d, 2 H, J ) 7.6, Hz), 6.90 (t, 1 H,
J ) 7.6 Hz), 5.86 (br, 1 H); 13C NMR (150 MHz, CDCl3): δ 144.7,
138.7, 134.7, 129.3 (×2), 128.5, 127.7, 126.1, 126.0, 125.7, 123.0,
121.8, 120.5, 117.4 (×2), 115.9; HRMS calcd. for C16H13N 219.1048.
Found 219.1040.
(10) Spectral Data for 2-Naphthalen-1-yl-phenylamine (4a-B):
1
IR (neat, cm-1): 3401 (vs), 3022 (w), 1628 (w), 1265 (m); H NMR
(600 MHz, CDCl3): δ 7.82 (d, 1 H, J ) 8.1 Hz), 7.81 (d, 1 H, J ) 8.2
Hz), 7.57 (d, 1 H, J ) 8.4 Hz), 7.47 (t, 1 H, J ) 7.7 Hz), 7.42 (t, 1 H,
J ) 7.0 Hz), 7.37 (d, 1 H, J ) 7.0 Hz), 7.34 (t, 1 H, J ) 7.2 Hz), 7.18
(td, 1 H, J ) 8.0, 1.5 Hz), 7.01 (dd, 1 H, J ) 8.0, 1.5 Hz), 6.80 (td, 1
H, J ) 6.8, 1.5 Hz), 6.75 (d, 1 H, J ) 8.0 Hz), 3.38 (br, 2 H); 13C
NMR (150 MHz, CDCl3): δ 144.3, 136.9, 133.8, 131.6, 131.1, 128.7,
128.2, 127.9, 127.5, 126.2, 126.0, 125.9, 125.8, 125.7, 118.2, 115.2;
HRMS calcd. for C16H13N 219.1048. Found 219.1040.
(11) Spectral Data for 2-Naphthalen-1-yl-3-oxo-butyric Acid
Ethyl Ester (5c): IR (neat, cm-1): 3054 (w), 2982 (w), 1709 (s), 1637
1
(5) Standard Procedure for Ruthenium-Catalyzed Aromatization
of Enediynes Carbon-Centered Nucleophile. To an ethyl acetonate
solution (0.5 mL, 3.94 mmol) of enediyne 1a (100 mg, 0.79 mmol)
was added TpRuPPh3(CH3CN)2PF6 (60 mg, 0.079 mmol), and the
mixture was heated at 100 °C for 15 h. The solution was eluted through
a short silica column with hexane to remove catalyst and excess ethyl
acetonate. The hexane eluent was concentrated and eluted through a
silica column to give naphthalene 5c (126 mg, 0.49 mmol, 62%).
(6) Standard Procedure for Ruthenium-Catalyzed Cyclization
via C-H Bond Insertion. To a toluene solution (0.60 mL) of enediyne
1i (100 mg, 0.59 mmol) was added TpRuPPh3(CH3CN)2PF6 (45 mg,
0.059 mmol), and the mixture was heated at 100 °C for 15 h. The
solution was concentrated and eluted through a short silica column with
hexane to give cyclopentane derivative 6a (35 mg, 0.21 mmol, 35%).
(7) Spectral Data for Naphthalen-1-ol (2a): IR (neat, cm-1): 3300
(br, vs), 3066 (w), 1600 (m), 1085 (m); 1H NMR (400 MHz, CDCl3):
δ ∼8.18-8.15 (m, 1 H), ∼7.82-7.79 (m, 1 H), ∼7.49-7.42 (m, 3 H),
(s), 1127 (s); H NMR (400 MHz, CDCl3): δ ∼7.88-7.85 (m, 1 H),
∼7.82-7.80 (m, 1 H), 7.72 (d, 1 H, J ) 8.4 Hz), ∼7.52-7.48 (m, 2
H), 7.44 (t, 1 H, J ) 8.4 Hz), 7.13 (d, 1 H, J ) 8.4 Hz), 4.78 (s, 1 H)
4.02 (q, 2 H, J ) 6.8 Hz), 2.63 (s, 3 H), 1.14 (t, 3 H, J ) 6.8 Hz); 13
C
NMR (150 MHz, CDCl3): δ 172.6, 167.6, 149.1, 134.9, 128.0, 126.7
(×2), 126.5, 125.8, 125.7, 121.5, 117.9, 96.3, 59.5, 18.2, 14.2; HRMS
calcd. for C16H16O3 256.1099. Found 256.1150.
(12) Spectral Data for 2,3-Dihydro-1H-cyclopenta[r]naphthalene
1
(6a): IR (neat, cm-1): 3028 (w), 2986 (w), 1717 (s), 1618 (w); H
NMR (400 MHz,CDCl3): δ 7.86 (d, 1 H, J ) 7.6 Hz), 7.81 (d, 1 H,
J ) 8.4 Hz), 7.69 (d, 1 H, J ) 8.4 Hz), 7.50 (t, 1 H, J ) 6.8 Hz), 7.43
(t, 2 H, J ) 9.2 Hz), 3.27 (t, 2 H, J ) 7.2 Hz), 3.13 (t, 2 H, J ) 7.2
Hz), 2.31-2.25 (m, 2 H); 13C NMR (150 MHz): δ 140.9, 139.4, 132.5,
130.4, 128.3, 126.6, 125.8, 124.6, 124.3, 123.3, 33.8, 31.0, 24.5; HRMS
calcd. for C13H12 168.0939. Found 168.0934.
Acknowledgment. We thank the National Science Council,
Taiwan, for supporting this work.
7.29 (t, 1 H, J ) 8.0 Hz), 6.80 (d, 1 H, J ) 8.0 Hz), 5.20 (s, 1 H); 13
C
NMR (100 MHz, CDCl3): δ 151.2, 134.7, 127.6, 126.4, 125.8, 125.3,
124.3, 121.4, 120.7, 108.7; HRMS calcd. for C10H8O 144.0575. Found
144.0585.
Supporting Information Available: Synthetic procedures for
enediynes, NMR spectra, spectral data of compounds 1a-1r,
2a-2o, 3, 4a(A)-4f(B), 5a-5p, 6a-6c, 7a-7c, 8a-8c, 9,
(8) Spectral Data for 1-Isobutoxynaphthalene (2d): IR (neat,
1
cm-1): 3056 (w), 1610 (w), 1582 (s), 1245 (s), 1130 (s); H NMR
1
10a,10b, 11a,11b, and H NMR spectra of deuterium-labeled
(400 MHz, CDCl3): δ ∼8.34-8.31 (m, 1 H), ∼7.82-7.79 (m, 1 H),
∼7.52-7.45 (m, 2 H), ∼7.43-7.35 (m, 2 H), 6.79 (d, 1 H, J ) 7.2
Hz), 3.91 (d, 2 H, J ) 6.4 Hz), ∼2.31-2.21 (m, 1 H), 1.12 (d, 6 H, J
) 9.6 Hz); 13C NMR (100 MHz, CDCl3): δ 154.9, 134.5, 127.4, 126.3,
2b. This material is available free of charge via the Internet at
http://pubs.acs.org.
JA043047J
9
3412 J. AM. CHEM. SOC. VOL. 127, NO. 10, 2005