Gold(I)-catalyzed cycloisomerization of 3-methoxy-1,6-enynes featuring tandem cyclization and [3,3]-sigmatropic rearrangement

Article abstract of DOI:10.1002/anie.200705117

(Chemical Equation Presented) Golden reactivity: A new gold(I)-catalyzed cycloisomerization of 3-methoxy-1,6-enynes was discovered. Structurally simple 3-methoxy-1,6-enynes engage in a tandem cyclization/[3,3]-sigmatropic rearrangement to deliver a variety of 1-methoxy-1,4-cycloheptadienes (see scheme). Notably, the reaction can be performed under very mild conditions and the synthetic utility of this reaction was demonstrated by facile conversion of the product into various cyclohept-4-en-1-ones.

Full text of DOI:10.1002/anie.200705117

Angewandte
Chemie
DOI: 10.1002/anie.200705117
Tandem Reactions
Gold(I)-Catalyzed Cycloisomerization of 3-Methoxy-1,6-enynes
Featuring Tandem Cyclization and [3,3]-Sigmatropic Rearrangement**
Hyo J. Bae, Baburaj Baskar, Sang E. An, Jae Y. Cheong, Daniel T. Thangadurai, In-Chul Hwang,
and Young H. Rhee*
The transition-metal-catalyzed cycloisomerization of 1,6-
enynes is one of the most powerful strategies for the synthesis
of highly functionalized carbocyclic compounds.[1] Recent
studies on the gold- and platinum-catalyzed cycloisomeriza-
tions are particularly noteworthy because of the structural
diversity of the products provided by these reactions.[2]
Numerous carbocyclic frameworks have been assembled by
using structurally simple 1,6-enyne precursors. In many
reactions, addition of internal olefins to the metal-activated
alkynes has been proposed as the key event.[3]
Unlike the structurally simple 1,6-enynes mentioned
above, 3-alkoxy-1,6-enynes 1 offer an alternative mode of
reaction as depicted in Scheme 1. In this case, the oxygen
atom can participate as a competing nucleophile in the
addition to the metal-activated alkynes. The resulting cyclic
oxonium ion 2 has a structural platform for a [3,3]-sigmatropic
rearrangement, which generates cycloheptenyl cation 3.[4]
Elimination of the cationic metal species produces 1-alkoxy-
1,4-cycloheptadiene 4 in a catalytic manner.
On the basis of the recent reports on Lewis acid promoted
(or catalyzed) Claisen rearrangement of cyclic enol ethers,[5]
we envisioned that the involvement of the oxonium ion
intermediate 2 could facilitate the key [3,3]-sigmatropic
process. Moreover, the enol ether moiety in 4 can be
chemoselectively transformed into a variety of other func-
tional groups. Thus, we envisaged that the proposed reaction
would provide highly efficient access to cycloheptene frame-
works having diverse functional groups, which are important
building blocks in a variety of bioactive natural products.[6]
In light of the proposed catalytic cycle, a potentially
competing pathway is the metal-catalyzed carboalkoxylation
(Scheme 2; pathway B).[7] This alternative pathway would
Scheme 1. Proposed mechanism for the gold(I)-catalyzed cycloisomeri-
zation of 3-alkoxy-1,6-enynes.
Scheme 2. Sigmatropic rearrangement (pathwayA) versus carboalkox-
ylation (pathway B).
[*] H. J. Bae, B. Baskar, S. E. An, J. Y. Cheong, D. T. Thangadurai,
Prof. Dr. Y. H. Rhee
result in a mixture of cycloheptadiene 4 and cyclopentene 4’
formed from allylic cation 5, whereas the concerted nature of
the proposed sigmatropic pathway leads to the selective
formation of 4 (Scheme 2; pathway A).[8]
Department of Chemistry
POSTECH (Pohang Universityof Science and Technology)
Pohang, 790-784 (Korea)
Fax: (+82)54-279-3399
E-mail: yhrhee@postech.ac.kr
To investigate this mechanistic proposal, we initially
examined various platinum and gold complexes by using 6
as the substrate (Table 1). Preliminary investigations using a
platinum catalyst (Table 1, entry 1)[7c,d] or neutral [Au{P-
(C6H5)3}Cl] (Table 1, entry 2) failed to give the desired
bicyclic heptadiene 7a. To our delight, switching to pregen-
erated cationic gold complex 8a (5 mol%) in CH2Cl2
produced the cycloisomerized product 7a in 55% yield
within 10 minutes at room temperature, and there was no
evidence of the formation of carbocyclic five-membered rings
(Table 1, entry 3).[9] Notably, employing a more electrophilic
catalyst (8b)[10] gave 7a almost instantaneously in 92% yield
Dr. I.-C. Hwang
Department of Chemistry
Center for Superfunctional Molecules
Center for Basic Sciences
POSTECH (Pohang Universityof Science and Technology) (Korea)
[**] This work was supported bythe Korea Science and Engineering
Foundation (KOSEF), which is funded bythe Korean government
(R01-2007-000-10889-0). H.J.B. thanks the BK21 program for a
fellowship. We thank Prof. Dr. Kwang S. Kim for the supporting
crystal structure analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2008, 47, 2263 –2266
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2263

Communications
Table 1: Optimization of the reaction conditions.
the internal position (Table 2, entry 4), as well as on the
terminal positions of the vinyl group (Table 2, entries 5 and
6). Interestingly, no significant difference in the yield was
observed between the two latter examples.
Remarkably, even substrate 20, which possesses dimethyl
substituents at the terminal vinylic positions, produced ketone
21b with a quartenary carbon center in good yield after
hydration (Table 2, entry 7).[13b,14] Introducing an alkyl sub-
stituent on the homopropargylic position had little effect on
the yield of the cycloisomerization reaction (Table 2, entry 8).
Notably, substrate 24, bearing a phenyl substituent at the
allylic position, also produced cycloheptadiene 25a in near-
quantitative yield (Table 2, entry 9).
The data compiled in Table 2are consistent with the
working hypothesis involving the concerted sigmatropic
pathway (Scheme 2, pathway A) because the exclusive for-
mation of cycloheptadienes was observed in all cases, even
when the substrate containing a carbocation stabilizing
phenyl group (24) was employed.[15] To investigate the
nature of the rearrangement of the oxonium-ion intermediate
2, two olefin isomers (26 and 28) were tested. The E olefin
substrate 26 was converted into ketone 27 in 80% yield as a
single diastereomer [Eq. (2)],[16] and the structure was unam-
EntryCastatl[ymol%]
Solvent
T
t
Yield [%][a]
[b]
1
2
3
4
5
6
7
8
PtCl2/CO (5%)
[Au{P(C6H5)3}Cl]
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
808C
RT
RT
6 h
1 h
–
n.r.
55
92
8a (5%)
8b (5%)
8b (5%)
8b (1%)
8b (0.3%)
8b (1%)
10 min
2 min
2 min
2 min
10 min
6 h
RT
À158C
À158C
À158C
RT
95
>99(97[c])
95(91[c])
25[d]
[a] Yield determined by 1H NMR spectroscopywith 1,3,5-trimethoxyben-
zene as an internal standard. RT=room temperature, n.r.=no reaction.
[b] A mixture of unidentified compounds was obtained. [c] Yield of
isolated product. [d] A significant amount of 6 was recovered (ca. 60%).
(Table 1, entry 4). Lowering the temperature to À158C
increased the yield with little effect on the rate of the reaction
(Table 1, entry 5). Interestingly, reducing the catalyst loading
to 1 mol% produced 7a in almost quantitative yield (Table 1,
entry 6). Moreover, purification of this acid-labile compound
by silica gel chromatography (deactivated with triethylamine)
gave an analytically pure isolated sample of 7a in 97% yield.
Reduction of the catalyst loading to 0.3 mol% resulted in a
completed reaction within 10 minutes, albeit with a small
decrease in the yield (Table 1, entry 7).[11] Changing the
solvent to CH3CN significantly slowed the formation of 7a
(Table 1, entry 8).
Conversion of 7a into bicyclic cyclohept-4-en-1-one 7b
was investigated to demonstrate the synthetic utility of the
cycloisomerization process. After extensive optimization, we
found that using catalytic p-TsOH (10 mol%) in aqueous
THF furnished 7b in 90% yield [Eq. (1)].[12]
biguously determined by the X-ray crystallographic analysis
(Figure 1).[17] Under identical conditions, Z olefin substrate 28
produced the diastereomeric ketone 29 in a comparable yield
(81%) without evidence of the formation of 27.[16] The
complete transfer of stereochemical information observed in
these experiments confirms the concerted nature of the
rearrangement of the oxonium ion intermediate
(Scheme 2).
2
In summary, we discovered a highly efficient gold(I)-
catalyzed cycloisomerization of 3-methoxy-1,6-enynes that
features a tandem cyclization and an unprecedented [3,3]-
sigmatropic rearrangement as the key event. Notably, the
reaction can be performed under very mild conditions by
using a low catalyst loading (maximum turnover number
ca. 300). The synthetic potential of the reaction was demon-
strated by the facile conversion into the various cyclohept-4-
en-1-ones. Extrapolation of this method to the formation of
other carbocyclic rings and the application to the total
synthesis of bioactive natural products are currently under
investigation.
By using 1–5 mol% of the optimized catalyst shown in
Table 1, various 3-methoxy-1,6-enynes were converted into 1-
methoxy-1,4-cycloheptadienes in high yields (Table 2). Fur-
thermore, all of the cycloisomerized products obtained were
transformed into the corresponding cyclohept-4-en-1-ones by
using the optimized conditions [Eq. (1)].[13a] As shown in
Table 2, substrates with a cyclopentane framework (9 and 11)
reacted with comparable efficiency to give cycloheptadienes
(10a and 12a) in nearly quantitative yields (Table 2, entries 1
and 2). Gratifyingly, acyclic substrate 13 also furnished the
monocyclic product 14a in high yield (Table 2, entry 3). The
cycloisomerization was tolerant of the methyl substitution on
Experimental Section
Cycloisomerization of 6 to 7a: Methylene chloride (10 mL) was
added to a mixture of gold complex [Au{P(C6F5)3}Cl] (5.1 mg,
2264 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 2263 –2266

Angewandte
Chemie
Table 2: Scope of the gold(I)-catalyzed cycloisomerization of 3-methoxy-1,6-enynes.[a]
EntrySubstrate
Cstataly
Product
Yield
[%][b]
Ketone
Yield
[%][b]
[mol%]
1
2
9 R1 =H
1
5
10a
12a
96
95
10b
12b
90
88
11 R1 =CH3
3
4
13 R2 =H
1
1
14a
16a
90
85
14b
16b
84
85
15 R2 =CH3
5
17 R3 =CH3, R4 =H
19 R3 =H, R4 =CH3
20 R3 =CH3, R4 =CH3
1
1
2
18a
18a
21a
89
18b
18b
21b
80
6
95
–-
7[e]
74[c]
60[d]
8
9
22
24
5
2
23a
25a
94
97
23b
25b
90
74
[a] Conditions: Substrate (0.05m), catalyst 8b, À158C, dryCH Cl2. [b] Yield of isolated product for each step. [c] Yield determined by 1H NMR
2
spectroscopywith 1,3,5-trimethoxybenzene as an internal standard. [d] Yield of isolated product for the two-step conversion. [e] The reaction was
performed at room temperature.
it was stirred for 5 min. The resulting reaction mixture was passed
through a pad of celite and concentrated. The residual oil was purified
by flash chromatography on silica gel (deactivated by triethylamine
before use, eluted with pentane/ether= 95:5) to give compound 7a as
a colorless oil (117 mg, 0.65 mmol, 97% yield). Rf = 0.45 (pentane/
ether= 95:5); 1H NMR (300 MHz, CDCl3): d = 1.14–1.47 (m, 3H),
1.66–1.77 (m, 3H), 1.87–1.95 (m, 1H), 2.04–2.14 (m, 2H), 2.38–2.40
(m, 2H), 2.45–2.57 (m, 2H), 2.64–2.74 (m, 1H), 3.47 (s, 3H), 4.79 (app
t, J = 6.4 Hz, 1H), 5.45 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d =
23.6, 27.0, 28.9, 35.7, 37.5, 38.8, 39.2, 54.6, 95.7, 120.3, 143.8,
159.4 ppm; IR: n˜ = 2925, 2852, 1666, 1155 cmÀ1; HRMS calcd for
C12H18O: 178.1358. found: 178.1358.
Conversion of 7a into 7b: Water (0.1 mL) and p-toluenesulfonic
acid (2.3 mg, 0.012 mmol) was added to a solution of 7a (22 mg,
0.12mmol) in THF (1 mL) at 0 8C. The reaction mixture was stirred
Figure 1. View of the molecular structure of compound 27 with
displacement ellipsoids at 30% probability. Selected bond lengths [Š]
for 7 h at 08C and then diluted with ether (20 mL). This solution was
washed with a saturated aq NaHCO3 solution (2” 10 mL), water
(10 mL), dried over anhydrous Na2SO4, and concentrated. The
residual oil was purified by flash chromatography on silica gel
(eluted with pentane/ether= 85:15) to give the compound 7b as a
colorless oil (18 mg, 0.11 mmol, 90% yield). The spectral data are in
complete agreement with those in the literature.[13a]
Crystal structure analysis: a suitable crystal was mounted onto a
specially constructed apparatus[18] with cooling in an inert atmosphere
on a Bruker SMART CCD1000 APEX diffractometer and ana-
lyzed.[17] After semi-empirical absorption correction by equalization
and angles [8]: O–C1 1.212(3), C4–C5 1.329(4); O-C1-C2 120.0(2),
C4-C5-C10 127.0(2).
0.0067 mmol) and AgSbF6 (2.3 mg, 0.0067 mmol), and the reaction
mixture was stirred for 10 min. The resulting solution was filtered
through a pad of celite and concentrated. The residue was dried under
high vacuum for 2h and then cooled to À158C. A solution of 6
(120 mg, 0.67 mmol) in CH2Cl2 (13.4 mL, 0.05m, precooled to À158C)
was added to this residue to give a colorless solution, which was
stirred for 2min. Triethylamine (1 mL) was added to the solution and
Angew. Chem. Int. Ed. 2008, 47, 2263 –2266
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2265

Communications
of like-symmetry reflections (SADABS), structure solution and
127, 15024; c) A. Fürstner, H. Szillat, F. Stelzer, J. Am. Chem.
Soc. 2000, 122, 6785; d) A. Fürstner, F. Stelzer, H. Szillat, J. Am.
Chem. Soc. 2001, 123, 11863; e) I. Nakamura, T. Sato, Y.
Yamamoto, Angew. Chem. 2006, 118, 4585; Angew. Chem. Int.
Ed. 2006, 45, 4473.
refinement was carried out with the SHELX programs.[19,20]
Received: November 6, 2007
Revised: January 4, 2008
[8] a) Related discussions on the aza-Claisen rearrangement in
pyrrole formation: F. M. Istrate, F. Gagosz, Org. Lett. 2007, 9,
3181; b) For selected examples on other gold-catalyzed Claisen
rearrangements: B. D. Sherry, F. D. Toste, J. Am. Chem. Soc.
2004, 126, 15978; N. W. Reich, C.-G. Yang, Z. Shi, C. He, Synlett
2006, 1278; G. E. Veitch, E. Beckmann, B. J. Burke, A. Boyer,
S. L. Maslen, S. V. Ley, Angew. Chem. 2007, 119, 7773; Angew.
Chem. Int. Ed. 2007, 46, 7629; H. Menz, S. F. Kirsch, Org. Lett.
2006, 8, 4795.
Published online: February 11, 2008
Keywords: cyclization · gold · homogeneous catalysis ·
.
sigmatropic rearrangement
[1] Reviews on transition-metal-catalyzed cycloisomerization of
enynes: a) B. M. Trost, F. D. Toste, A. B. Pinkerton, Chem.
Rev. 2001, 101, 2067; b) G. C. Lloyd-Jones, Org. Biomol. Chem.
2003, 1, 215; c) C. Bruneau, Angew. Chem. 2005, 117, 2380;
Angew. Chem. Int. Ed. 2005, 44, 2328; d) S. T. Diver, A. J.
Giessert, Chem. Rev. 2004, 104, 1317.
[9] Using in situ generated cationic complexes gave lower yields of
the desired products.
[10] J.-E. Kang, H.-B. Kim, J.-W. Lee, S. Shin, Org. Lett. 2006, 8, 3537.
[11] We found that a pure sample of 7a decomposes slowly under the
reaction conditions with formation of an unidentified mixture of
compounds. Thus, the decrease in yield in this case can be
explained by the instability of the product 7a.
[2] Recent reviews on the gold- and platinum-catalyzed reactions
involving enyne cycloisomerizations: a) A. Fürstner, P. W.
Davies, Angew. Chem. 2007, 119, 3478; Angew. Chem. Int. Ed.
2007, 46, 3410; b) S. Ma, S. Yu, Z. Gu, Angew. Chem. 2006, 118,
206; Angew. Chem. Int. Ed. 2006, 45, 200; c) L. Zhang, J. Sun,
S. A. Kozmin, Adv. Synth. Catal. 2006, 348, 2271; d) A. S. K.
Hashmi, G. J. Hutchings, Angew. Chem. 2006, 118, 8064; Angew.
Chem. Int. Ed. 2006, 45, 7896; e) E. JimØnez-Nfflæez, A. M.
Echavarren, Chem. Commun. 2007, 333; f) D. J. Gorin, F. D.
Toste, Nature 2007, 446, 395.
[3] Catalytic alkyne activation with concomitant nucleophilic trap-
ping: a) P. Y. Toullec, E. Genin, L. Leseurre, J.-P. GenÞt, V.
Michelet, Angew. Chem. 2006, 118, 7587; Angew. Chem. Int. Ed.
2006, 45, 7427; b) S. F. Kirsch, J. T. Binder, B. Crone, A.
Duschek, T. T. Haug, C. LiØbert, H. Menz, Angew. Chem.
2007, 119, 2360; Angew. Chem. Int. Ed. 2007, 46, 2 310; c) G. Y.
Lin, C. Y. Yang, R.-S. Liu, J. Org. Chem. 2007, 72, 6753; d) V.
Belting, N. Krause, Org. Lett. 2006, 8, 4489; e) J. Barluenga, A.
DiØguez, A. Fernµndez, F. Rodríguez, F. J. Faæanµs, Angew.
Chem. 2006, 118, 2145; Angew. Chem. Int. Ed. 2006, 45, 2091;
[12] We also investigated the one-step preparation of 7b from 6 by
adding various amounts of water to the reaction mixture. In all
cases the yield of ketone 7b was significantly lower (max. 60%).
[13] a) Although cyclohept-4-en-1-ones can be synthesized from the
corresponding 1,6-enyne-3-ols by a one-pot cyclization/rear-
rangement, this thermal rearrangement generally requires forc-
ing conditions. References on this reaction: X. Li, R. E. Kyne,
T. V. Ovaska, J. Org. Chem. 2007, 72, 6624, and also see the
references cited therein; b) this type of substitution pattern is
known to be resistant to thermal Claisen rearrangement: E. N.
Marvell, D. Titterington, Tetrahedron Lett. 1980, 21, 2123.
[14] Although the cycloisomerized product was not obtained in pure
form, generation of the product was undoubtedly confirmed by
the analysis of 1H NMR data of the reaction mixture.
1
[15] Within the limits of detection by H NMR and GC methods.
[16] 1H NMR spectrum of the crude reaction mixture from the
cycloisomerization also clearly shows the formation of single
diastereomer.
´
f) A. S. K. Hashmi, M. C. Blanco, E. Kurpejovic, W. Frey, J. W.
Bats, Adv. Synth. Catal. 2006, 348, 709; g) C. Lim, J.-E. Kang, J.-
E. Lee, S. Shin, Org. Lett. 2007, 9, 3539; h) A. K. Buzas, F. M.
Istrate, F. Gagosz, Angew. Chem. 2007, 119, 1159; Angew. Chem.
Int. Ed. 2007, 46, 1141.
[17] Crystallographic data for compound 27: monoclinic, space group
P21/c, a = 5.264(2), b = 22.873(8), c = 8.654(3) Š, b = 97.418(7)8,
V= 1033.3(6) Š3, T= À308C, Z = 4, MoKa radiation, graphite
monochromator, scan width 0.38 in w, 20 s irradiation time per
measurement reflections, 2830 measurements, 11733 measured
reflections, 2128 independent reflections, 119 parameters,
[4] General reviews on the [3,3]-sigmatropic rearrangement of allyl
vinyl ethers (Claisen rearrangement): a) A. M. Castro, Chem.
Rev. 2004, 104, 2939; b) F. E. Ziegler, Chem. Rev. 1988, 88, 1423.
[5] Examples of Lewis acid mediated/catalyzed Claisen rearrange-
ment of cyclic enol ethers: a) C. M. G. Philippo, N. H. Vo, L. A.
Paquette, J. Am. Chem. Soc. 1991, 113, 2762; b) L. A. Paquette,
D. Friedrich, R. D. Rogers, J. Org. Chem. 1991, 56, 3841.
[6] Reviews on the synthesis of natural products containing
carbocyclic seven-membered rings: M. A. Battiste, P. M. Pel-
phrey, D. LWright, Chem. Eur. J. 2006, 12, 3438, and references
therein.
GOF = 1.058,
R1(I>2s(I)) = 0.0888,
wR2 = 0.1680.
CCDC 671143 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre at www.ccdc.
cam.ac.uk/data_request/cif.
[18] T. Kottke, D. Stalke, J. Appl. Crystallogr. 1993, 26, 615.
[19] G. Sheldrick, Program for Crystal Structure Solution, Universi-
taet Goettingen, 1986.
[20] G. Sheldrick, Program for Crystal Structure Refinement, Uni-
versitaet Goettingen, 1993.
[7] Recent examples of transition-metal-catalyzed carboalkoxyla-
tion of alkynes: a) P. Dube, F. D. Toste, J. Am. Chem. Soc. 2006,
128, 12062; b) A. Fürstner, P. W. Davies, J. Am. Chem. Soc. 2005,
2266 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 2263 –2266