Platinum-catalyzed aromatization of enediynes via a C-H bond insertion of tethered alkanes

Article abstract of DOI:10.1021/ol052962m

PtCl₂ (5 mol %) is an effective catalyst for aromatization of enediynes via a C-H bond insertion of tethered alkanes. The reaction mechanism of this cyclization is proposed to involve platinum-.T-alkyne intermediates. This cyclization works not only for terminal alkynes but also for internal alkynes.

Full text of DOI:10.1021/ol052962m

ORGANIC
LETTERS
2006
Vol. 8, No. 5
883-886
Platinum-Catalyzed Aromatization of
Enediynes via a C−H Bond Insertion of
Tethered Alkanes
Bhanu Pratap Taduri, Ying-Fen Ran, Chun-Wei Huang, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan, ROC
rsliu@mx.nthu.edu.tw
Received December 7, 2005
ABSTRACT
PtCl2 (5 mol %) is an effective catalyst for aromatization of enediynes via a C−H bond insertion of tethered alkanes. The reaction mechanism
of this cyclization is proposed to involve platinum−π-alkyne intermediates. This cyclization works not only for terminal alkynes but also for
internal alkynes.
Bergman aromatization of enediynes1 has attracted consider-
able attention because of its useful applications in materials
and medicinal chemistry.2,3 Aromatization of enediynes has
been investigated with various approaches, including diradi-
cal pathways,1b,4 electrophilic additions,5a-c radical cations,5d
and nucleophilic addition. The thermal cyclization of un-
strained enediynes requires high temperatures, but it can be
implemented with metal complexes under ambient condi-
tions.6-9 In such cases, excess metal reagents are often used
to complete the reactions;6 few examples are known for
catalytic cyclization of enediynes.7-9 Uemura reported7
rhodium-catalyzed cyclizations of enediynes via a diradical
process, which actually mimics the cyclization of 5-allene-
3-en-1-ynes (Saito-Myers cyclization) as the terminal alkyne
is transformed into a rhodium vinylidene intermediate.10 The
(1) (a) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25. (b) Lockhart, T.
P.; Commita, 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. (c)
Nicolaou, K. C.; Smith, A. L. in Modern Acetylene Chemistry; Stang, P. J.,
Diederich, F., Eds.; VCH Publishers: Weinheim, 1995; Chapter 7, p 203.
(3) Recent reviews: (a) Rawat, D. S.; Zaleski, J. M. Synlett 2004, 393.
(b) Basak, A.; Mandal, S.; Bag, S. S. Chem. ReV. 2003, 103, 4077. (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 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.
(5) (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/Recueil 1997, 1391.
(6) (a) Zaleski, J. M.; Rawat, D. S. J. Am. Chem. Soc. 2001, 123, 9675.
(b) Warner, B. P.; Millar, S. P.; Broene, R. D.; Buchwald, S. L. Science
1995, 269, 814. (c) Konig, B.; Hollnagel, H.; Ahrens, B.; Jones, P. G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2538. (d) Landis, C. A.; Payne, M. M.;
Eaton, D. L.; Anthony, J. E. J. Am. Chem. Soc. 2004, 126, 1338. (e) Wang,
Y. S.; Finn, M. G. J. Am. Chem. Soc. 1995, 117, 8045. (f) O’Connor, J.
M.; Friese, S. J.; Tichenor, M. J. Am. Chem. Soc. 2002, 124, 3506.
(7) For metal-catalyzed cyclization of enediynes, see refs 7-9: (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.
(8) (a) Odedra, A.; Wu, C.-J.; Pratap, T. P.; Huang, C.-W.; Ran, Y.-F.;
Liu, R.-S., J. Am. Chem. Soc. 2005, 127, 3406. (b) O’Connor, J. M.; Friese,
S. J.; Rodgers, B. L. J. Am. Chem. Soc. 2005, 127, 16342.
(9) In further recent experiments, we found that PtCl2 (5 mol %) was
catalytically active for aromatization of enediynes via regioselective HX
addition (X ) Cl, Br, I); see: Lo, C.-Y.; Kumar, M. P.; Chang, H.-K.;
Lush, S.-F.; Liu, R.-S. J. Org. Chem. 2005, 70, 10482
10.1021/ol052962m CCC: $33.50
© 2006 American Chemical Society
Published on Web 02/03/2006

Scheme 1
improve this cyclization efficiency using PtCl2 (5 mol %),
which is known as an efficient π-activator for alkynes.9,11
Table 1 shows our results for aromatization of enediynes
scope of such a cyclization is strictly limited to enediynes
bearing one terminal alkyne (Scheme 1). In seeking to
accomplish a new catalytic aromatization of enediynes via
metal-π-alkyne intermediates, we envisage that a suitable
π-activator may coordinate with enediynes to form bis-π-
alkyne species A (Scheme 2), thus effecting a closer C(1)-
Table 1. Cyclization of Enediynes with Platinum and
Ruthenium Catalysts
Scheme 2
C(6) distance, and to facilitate the cyclization.6 Compared
to Uemura’s system, one distinct feature is the possible
generation of carbenoid species C given from the conjugation
of diradical intermediate B for which the radical character
resides at both the metal and C(6) carbon positions. One
obvious advantage of this protocol is its applicability to
cyclization for both terminal and internal alkynes. This study
reports realization of this new catalytic reaction using PtCl2,
achieving aromatization of enediynes via an alkane C-H
bond insertion (Scheme 2).
We previously reported8a catalytic aromatization of ene-
diynes via nucleophilic additions using TpRuPPh3(CH3-
CN)2PF6 (10 mol %, eq 1), and the mechanism has been
elucidated to involve a π-alkyne intermediate. In one
instance, we accidentally found that a C-H alkane insertion
occurred for enediyne 1 bearing a propyl group and gave
benzene 7 in 35% yield (eq 2).8a Uemura’s mechanism fails
to rationalize the formation of this product. We sought to
a [Substrate] ) 1.0 M toluene, 100 °C, 10 h. b 5 mol % PtCl2 and 10
mol % TpRuPPh3(CH3CN)2PF6. c Yields were given after purification on
a silica column.
1-6 using these two catalysts to compare their catalytic
efficiency and chemoselectivity; the reactions were per-
formed in hot toluene (100 °C, 10 h). As shown in entries
1-3, PtCl2 (5 mol %) is more efficient than TpRuPPh3(CH3-
CN)2PF6 (10 mol %) in the aromatization of enediynes 1-3
despite a lower loading of PtCl2. For acyclic enediynes 4-6,
(10) Catalytic reactions via metal-vinylidene intermediates; see: (a)
Bruneau, C. Top. Organomet. Chem. 2004, 11, 125. (b) Trost, B. M. Acc.
Chem. Res. 2002, 35, 695. (c) Bruneau, C.; Dixneuf, P. Acc. Chem. Res.
1999, 32, 311. (d) Puerta, M. C.; Valerga, P. Coord. Chem. ReV. 1999,
193-195, 977.
(11) Recent reviews for PtCl2-catalyzed reactions: (a) Me´ndez, M.;
Mamane, V.; Fu¨rstner, A. Chemtracts 2003, 16, 397. (b) Aubert, C.; Buisine,
O.; Malacria, M. Chem. ReV. 2002, 102, 813. (c) Echavarren, A. M.; Nevado,
C. Chem. Soc. ReV. 2004, 33, 431.
884
Org. Lett., Vol. 8, No. 5, 2006

we found that the ruthenium species produced two cyclized
benzenes 10-12(A) (54-67%) and 10-12(B) (16-20%);
this information indicates the generation of two active
intermediates in this catalytic reaction. Formation of benzenes
10-12(B) can be rationalized on the basis of a metal-
vinylidene pathway according to Uemura’s mechanism.7 The
use of PtCl2 catalyst, however, gives only cyclized benzenes
10-12(A) in good yields (71-81%), which seems to favor
a π-alkyne intermediate.
The value of this cyclization is reflected by its applicability
to enediynes bearing two internal alkynes; the results are
presented in Table 3. Entries 1-6 show the cyclization of
Table 3. PtCl2-catalyzed Cyclization of Enediynes Bearing an
Internal Alkynes
As PtCl2 shows better efficiency and chemoselectivity than
TpRuPPh3(CH3CN)2PF6 in the preceding cyclizations, we
examined the generality of PtCl2-catalyzed reactions with
various enediynes bearing a terminal alkyne as reported in
Table 2. Entries 1 and 2 demonstrate two instances of
Table 2. PtCl2-catalyzed Cyclization of Enediynes Bearing a
Terminal Alkyne
a 5 mol % PtCl2, [substrate] ) 1.0 M toluene, 100 °C, 12 h. b Yields of
products are given after purification on a silica column.
a 5 mol % PtCl2, [substrate] ) 1.0 M toluene, 100 °C, 12 h. b Yields of
products are given after purification on a silica column.
acyclic enediynes 34-39 using PtCl2 catalyst (5 mol %);
these substrates produced cyclized benzenes 46-51 follow-
ing the same protocol. Such cyclizations work also well for
1,2-bis(alkynyl)benzenes 40-42, and the corresponding
naphthalenes 52-54 were obtained in 60-69% yields. The
structures of 53 and 56 were determined by 1H-NOE spectra.
The catalytic cyclization is also efficient for cyclization of
1,2-bis(alkynyl)benzenes 43-45 bearing one or two methoxy
groups at the C(4) and C(5) carbons, giving resulting
2-iodonaphthalenes 55-57 in 76-81% yields. The fact that
these cyclizations proceed without a 1,2-halogen shift
suggests a platinum-π-alkyne reaction intermediate.12
We have performed deuterium-labeling experiments to
study the nature of cyclization using PtCl2 catalyst. We found
that the alkynyl deuterium of species 2 located at the same
carbon with a loss of 25% deuterium content. In the presence
of D2O (1.0 equiv), the C(4)-deuterium content is up to 58%.
This information indicates that PtCl2-catalyzed cyclization
formation of a tertiary carbon through aromatization of
enediynes 13 and 14, which gave corresponding benzenes
24-25 in 46-73% yields. The 4-methoxyphenyl group of
species 14 greatly enhanced this cyclization efficiency. A
similar phenomenon was observed for compounds 15 and
16 bearing 4-methoxy- and 4,5-dimethoxyphenyl groups,
respectively (entries 3 and 4), which produced benzenes 26
and 27 in respective yields of 70% and 86%, better than
that (45%) of its unsubstituted enediyne 1 (Table 1, entry
1). This aromatization maintains the same catalytic efficiency
on electron-rich benzenes 17 and 18 bearing methoxy groups
at the C(4) and C(5) phenyl carbons (entries 5 and 6) relative
to its parent benzene derivative 3 (Table 1, entry 3). In
contrast, cyclization of benzene 19 bearing a fluoro sub-
stituent is less efficient, giving benzene product 30 in 55%
yield (entry 7). Notably, this C-H bond insertion failed to
work with enediyne 20 bearing a CH2 fragment adjacent to
a methoxy group (entry 8); in this case, a complicated
reaction mixture was obtained. Nevertheless, the methoxyl
groups of enediynes 21-23 show a surprisingly activating
effect, giving cyclized products 31-33 in 81-85% yields.
(12) Alkynyl iodide undergoes 1,2-shift with metal species to form
2-iodovinylidene intermediates in several catalytic reactions, see: (a) Miura,
T.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 518. (b) Lin, M.-Y.;
Maddirala, S. J.; Liu, R.-S. Org. Lett. 2005, 7, 1745. (c) Mamane, V.;
Hannen, P.; Fu¨rstner, A. Chem. Eur. J. 2004, 10, 4556.
Org. Lett., Vol. 8, No. 5, 2006
885

This cyclization is unlikely to arise from the pure diradical
species B, because its subsequent intermediate F is prone to
loss of a hydrogen radical, ultimately giving benzene with a
pendant 2- or 3-butene. The participation of carbene inter-
mediates C is also supported by the enhancing effect of
4-methoxyphenyl substituent, which can stabilize singlet state
carbenoid C′ through resonance (Scheme 5). In this mech-
Scheme 3
Scheme 5
of enediyne 2 is consistent with platinum π-alkyne mecha-
nism because of the absence of 1,2-hydrogen shift for the
alkynyl deuterium.
Scheme 4 shows a proposed mechanism for the C-H
alkane insertion of enediynes using PtCl2 catalyst. We
Scheme 4
anism, we do not exclude the role of triplet state platinum-
carbene species C′′.
In summary, we have demonstrated that PtCl2 (5 mol %)
efficiently catalyzed aromatization of enediynes bearing both
terminal and internal alkynes; the reaction mechanism has
been proposed to involve platinum-π-alkyne intermediates.
The product analysis and deuterium-labeling experiment are
consistent with a platinum-stabilized benzene carbenoid being
responsible for the alkane C-H bond insertion in the course
of aromatization. This work offers a new example for
generation of carbenoid reaction intermediates via metal-
catalyzed activation of alkynes.13
Acknowledgment. We thank the National Science Coun-
cil, Taiwan, for support of this work.
Supporting Information Available: Mechanistic discus-
sion,14 experimental procedures for the synthesis of ene-
diynes, PtCl2-catalyzed cyclization, NMR spectra, and spec-
tral data for compounds 1-57. This material is available free
of charge via the Internet at http://pubs.acs.org.
envisage that PtCl2 activates the cyclization of enediynes via
PtCl2-π-alkyne species A and forms diradical species B or
its resonance form C. The observed alkane insertion indicates
the role of carbenoid intermediate C, which forms cyclo-
pentyl species D. This species subsequently loses a proton
to generate species E and ultimately gives the desired
benzene product. In such a mechanism, the C(4)-deuterium
content of species 2 will be enriched in the presence of
external D2O, consistent with our observation in Scheme 3.
OL052962M
(13) For selected examples, see: (a) Nevado, C.; Echavarren, A. M.
Synthesis 2005, 167 (a review article). (b) Fu¨rstner, A.; Davies, P. W.; Gress,
T. J. Am. Chem. Soc. 2005, 127, 8244. (c) Bhanu Prasad, B. A.; Yoshimoto,
F. K.; Sarpong, R. J. Am. Chem. Soc. 2005, 127, 12468. (d) Miki, K.;
Nishino, F.; Ohe, K.; Uemura, A. J. Am. Chem. Soc. 2002, 124, 5260.
(14) One reviewer suggests that this catalytic reaction likely occurs with
initial coordination of PtCl2 to a single alkyne group; see the Supporting
Information for details of this proposed mechanism.
886
Org. Lett., Vol. 8, No. 5, 2006