Gold-catalyzed intramolecular [3 + 2]-cycloaddition of arenyne-yne functionalities

Article abstract of DOI:10.1021/ja0643826

We report a new efficient intramolecular [3 + 2]-cycloaddition of unactivated arenyne (or enyne)-yne functionalities, catalyzed mainly by the AuPPh₃SbF₆ complex (2 mol %) under ambient conditions. The value of this cyclization is ref

Full text of DOI:10.1021/ja0643826

Published on Web 08/16/2006
Gold-Catalyzed Intramolecular [3 + 2]-Cycloaddition of Arenyne-Yne
Functionalities
Jian-Jou Lian, Po-Chiang Chen, Yau-Ping Lin, Hao-Chun Ting, and Rai-Shung Liu*
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan, Republic of China
Received June 21, 2006; E-mail: rsliu@mx.nthu.edu.tw
Table 1. Catalytic [3 + 2]-Cycloaddition over Various Catalysts
The reactions of enynes (or arenynes) with alkynes were
thermally achieved in [4 + 2]-cycloaddition mode, and both
theoretic calculation and experimental results support the involve-
ment of a strained cyclic allene as reaction intermediate (eq 1).1
Such reactions normally require drastic temperatures (>300 °C)
for unactivated alkynes (eq 1, R * cyano, ester, aldehyde, and
ketone)1a unless a metal catalyst is employed.2 Yamamoto and
Gevorgyan reported the use of Pd(0) catalysts to implement the [4
+ 2]-dimerization of enynes at low temperatures (T < 100 °C),
and the key step is thought to involve the oxidative dimerization
of enynes to form Pd-allyl intermediates (eq 2). To the best of
our knowledge, there is no precedent for the efficient [3 +
2]-cycloaddition of enynes (or arenynes) with alkynes in both inter-
and intramolecular processes (eq 3).3 Here, we report realization
of an intramolecular [3 + 2]-cycloaddition of unactivated arenyne-
yne (or enyne-yne) functionalities with gold catalysts (eq 3), which
implement most cycloadditions at ambient conditions.
catalysta
solvent (conditions)
yield
PtCl2
toluene (100 °C, 12 h)
CH2Cl2 (23 °C, 0.5 h)
DCE (50 °C, 6 h)
toluene (100 °C, 24 h)
toluene (100 °C, 24 h)
toluene (100 °C, 24 h)
2 (51%)
2 (93%)
2 (18%), 3 (2%)
2 (3%), 3 (14%)
2 (14%), 3 (15%)
2 (6%), 3 (30%)
AuClPPh3/AgSbF6
AuClPPh3/AgOTf
AuCl
AuCl3
AgSbF6
a 5 mol % of PtCl2, AuClPPh3/AgOTf, AuCl, AuCl3, AgSbF6, and 2
mol % of AuClPPh3/AgSbF6, [diyne] ) 0.40 M. b Products were separated
from a silica column.
Table 2. Catalytic Intramolecular [3 + 2]-Cycloaddition of Diynes
Stimulated by a report by Echavarren that cationic gold species
efficiently catalyzed the [4 + 2]-cycloaddition of arenyne-ene func-
tionalities at 23 °C,4 we investigated the cyclization of diyne 1 using
AuPPh3SbF6 and related gold species. Table 1 shows the catalytic
results of several active metal complexes. PPh3AuSbF6 (2 mol %)5
is superior to PtCl2 (5 mol %, 100 °C) not only in the production
of cyclized species 2 with better yield but also under more mild
conditions (23 °C, entry 2). The structure of species 2 is confirmed
to have a [3 + 2]-cycloadduct framework.6 No catalytic activities
were observed for AuClPPh3/AgOTf, AuCl, AuCl3, and AgSbF6
(5 mol % each) at 23 °C in toluene or CH2Cl2, but these complexes
gave a mixture of species 2 and [4 + 2]-cycloadduct 3 in hot toluene
or dichloroethane (DCE) with poor efficiencies (entries 3-6).
We examined further the scope of the [3 + 2]-cycloaddition with
alternation of the functionalities and skeletal chain of diyne
substrates 4-16; the results are depicted in Table 2. Most reactions
were achieved with PPh3AuSbF6 (2 mol %) in CH2Cl2 (23 °C)
except substrates 11 and 13 (entries 8 and 10), for which we used
PtCl2 and PPh3AuOTf,7 respectively. Entries 1-7 show the compat-
ibility of this cycloaddition with diynes 4-10 bearing various
functional groups, including tosylamide, ester, ketone, phenylsul-
fonyl, methylene, and fluorenyl groups; the resulting [4.3.0]-
cycloadducts 17-23 were obtained in satisfactory yields (61-90%).
The structure of compound 18 has been confirmed by X-ray
diffraction study.8 The value of this cyclization is demonstrated by
a [Diyne] ) 0.4 M. b Product yields are given after separation from a
silica column. c L ) PPh3, catalyst loading: 2 mol % of LAuCl/AgSbF6
(CH2Cl2), 5 mol % of PtCl2 (toluene) and LAuCl/AgOTf (dioxane).
its applicability to construct a strained bicyclic [3.3.0] framework,
such as species 24 (64% yield), via PtCl2-catalyzed cyclization of
enediyne 11 in hot toluene (entry 8). This method is further
extensible to a [3 + 2]-dimerization of arenyne-enyne and enyne-
9
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J. AM. CHEM. SOC. 2006, 128, 11372-11373
10.1021/ja0643826 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1
alities, catalyzed mainly by the AuPPh3SbF6 complex (2 mol %)
under ambient conditions. The value of this cyclization is reflected
by its applicability to a wide range of diyne substrates bearing
various functional groups.13
Acknowledgment. The authors thank Prof. Wang Sue-Lein for
X-ray diffraction study, as well as the National Science Council,
Taiwan, for support of this work.
Supporting Information Available: Experimental procedures,
X-ray data of [3 + 2]-cycloadduct 18, spectral data, and NMR spectra
of key compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Scheme 2
References
(1) For selected examples, see: (a) Burell, R. C.; Daoust, K. J.; Bradley, A.
Z.; DiRico, K. J.; Johnson, P. R. J. Am. Chem. Soc. 1996, 118, 4218. (b)
Dunetz, J. R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776 and
references therein. (c) Hayes, M. E.; Shinokubo, H.; Danheiser, R. L.
Org. Lett. 2005, 7, 3917. (d) Rodriguez, D.; Fernanda, M.; Esperon, M.;
Navarro-Va´zquez, A.; Castedo, L.; Dominguez, D.; Saa´, C. J. Org. Chem.
2004, 69, 3842. (e) Gonza´lez, J. J.; Francesch, A.; Ca´rdenas, D. J.;
Echavarren, A. M. J. Org. Chem. 1998, 63, 2854.
(2) For metal-catalyzed [4 + 2]-cycloadditions of enynes with alkynes, see
selected reviews and the most recent paper: (a) Rubin, M.; Sromek, A.
W.; Gevorgyan, V. Synlett 2003, 2265. (b) Saito, S.; Yamamoto, Y. Chem.
ReV. 2000, 100, 2901. (c) Rubina, M.; Conley, M.; Gevorgyan, V. J. Am.
Chem. Soc. 2006, 128, 5828 and references therein.
(3) Danheiser reported a [4 + 2]-cycloaddition of ynones-ynes, which
undergoes thermal rearrangement to form a 3-alkenylfuran species. Wills,
M. S. B.; Danheiser, R. L. J. Am. Chem. Soc. 1998, 120, 9378.
(4) Nieto-Oberhuber, C.; Lo´pez, S.; Echavarren, A. M. J. Am. Chem. Soc.
2005, 127, 6178.
(5) For recent examples using AuPPh3SbF6 as π-alkyne activators, see ref 4
and: (a) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 18002. (b) Kennedy-Smith, J. J.; Staben, S. T.;
Toste, F. D. J. Am. Chem. Soc. 2004, 126, 4526. (c) Shi, X.; Gorin, D. J.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802. (d) Zhao, J.; Hughes, C.
O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 7436. (e) Zhao, J.; Hughes,
C. O.; Toste, F. D. J. Am. Chem. Soc. 2006, 128, 7436. (f) Yang, C.; He,
C. J. Am. Chem. Soc. 2005, 127, 6966. (g) Munoz, M. P.; Adrio, J.;
Carretero, C. J. Organometallics 2005, 24, 1293. (h) Zhang, L. J. Am.
Chem. Soc. 2005, 127, 16804.
(6) H2PtCl4 (5%) and Aliquat 336 were reported to catalyze the transformation
of species 1 into [3 + 2]-cycloadduct 2 in 26% yield. See: Badrieh, Y.;
Blum, J.; Vollhardt, K. P. C. J. Mol. Catal. 1990, 60, 323.
(7) In contrast with AuPPh3SbF6, heating AuPPh3OTf and diyne 13 in 1,4-
dioxane (100 °C, 24 h) did not form a gold mirror in this example.
(8) 1H NOE map of key compounds and X-ray data of cycloadduct 18 are
provided in Supporting Information.
(9) In this case, the use of methanol (1.0 equiv) led to formation of byproduct
via alkyne hydration, and the desired cyclized 2 was obtained in 51%
yield. Water acts an inhibitor for this catalytic reaction.
(10) In the cyclization of diyne 1, 2,6-lutidine (5 mol %) completely inhibits
this PPh3AuSbF6-based catalysis. The inhibition role of 2,6-lutidine is
thought to intercept the proton to avoid the formation of intermediate C.
(11) As suggested by one reviewer, the present data also support an alternative
reaction mechanism as depicted below.
enyne functionalities as represented by diynes 12 and 13, which
gave bicyclic [4.3.0] products 25 (73%) and 26 (51%) using
PPh3AuSbF6 (2%) and PPh3AuOTf (5%), respectively. Structural
1
elucidation of tetracyclic species 24 relies on H NOE spectra.8
We examined the cyclization regioselectivity of diynes 14-16
bearing two different phenyl groups. The two isomeric products
28A-28B and 29A-29B were separable on a silica column. The
C(2) carbons of the 3-methoxyphenyl groups of diynes 15 and 16
are thought to be inactive because of steric hindrance. For diyne
15, the observed product ratio 28A/28B ) 1 is indicative of a 2:1
site activity for its 3-methoxyphenyl C(6) carbon versus the phenyl
C(2) carbon. The preference for alkenylation at the 3-methoxy-
phenyl C(6) carbon of diyne 16 is also inferred from the product
ratio 29A/29B ) 3.6. The structures of compounds 28A-29A were
1
confirmed by H NOE effects.8
We performed deuterium-labeling experiments to elucidate the
cycloaddition mechanism. As shown in Scheme 1, diyne d10-1
bearing C6D5 produced cycloadduct 2 with 68% deuterium content
at its alkenyl carbon. This deuterium content was decreased to 43%
when methanol (1.0 equiv) was present.9 For undeuterated d0-1,
its corresponding product d0-2 contained 34% deuterium content
at its olefin carbon in the presence of CH3OD (1.0 equiv, entry 3).
No deuterium is scrambled into the alkenyl hydrogen of cycloadduct
d4-2 if diyne d4-1 was used (entry 4).
Scheme 2 shows our mechanistic speculation to rationalize the
preferable [3 + 2]-pathway of this gold-based catalysis. The
preference for formation of regioisomer 28A from diyne 15 suggests
that this cyclization is initiated by nucleophilic attack of the
3-methoxyphenyl substituent of intermediate A at its Au(I)-
containing π-alkyne moiety, to produce vinylgold(I) intermediate
B with loss of a proton. As 2,6-lutidine acts as a inhibitor,10 we
propose that the electron-rich AuL fragment of species B greatly
favors protonation at the alkyne functionality to generate vinyl-
cationic intermediate C, which is subsequently stabilized by the
adjacent phenyl group and the vinylgold fragment through a
pentadiene cationic delocalization. Such a cationic resonance leads
to either a 5-exo-dig or Nazazov cyclization of species C to give
diphenyl carbocation D, ultimately leading to formation of major
isomer 28A. This proposed pathway is also supported by the
deuterium labeling results depicted in Scheme 2.11,12
(12) A proposed mechanism to rationalize formation of a [4 + 2]-cycloadduct
by Au(I) species is provided in Supporting Information; see Scheme S-1.
(13) Shibata reported formation of skeletally rearranged cycloadducts D (85-
89%) from diynes 5 and 9 using AuPPh3SbF6 catalyst (0 °C, 5 h).
Following their reported procedures, we still obtained [3 + 2]-cycloadducts
18 and 22 in 85 and 67% yields, respectively, from diynes 5 and 9 in
addition to [4 + 2]-cycloadducts C (3-5%). The X-ray structure of
cycloadduct 18 supports our structural assignment. See: Shibata, T.;
Fujiwara, R.; Takano, D. Synlett. 2005, 2062.
In summary, we report a new efficient intramolecular [3 +
2]-cycloaddition of unactivated arenyne (or enyne)-yne function-
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