(N-heterocyclic carbene)gold(I)-catalyzed cycloisomerization of cyclohexadienyl alkynes to tetracyclo[3.3.0.02,8.0 4,6]octanes

Article abstract of DOI:10.1002/anie.200702028

(Chemical Equation Presented) Biscyclopropanation: Dienynes containing a cyclohexadienyl unit can be converted into tetracyclo[3.3.0.0 ^2,8.0^4,6]-octanes by treatment with an (N-heterocyclic carbene)gold catalyst. When the dienynes be

Full text of DOI:10.1002/anie.200702028

Communications
DOI: 10.1002/anie.200702028
Cycloisomerization
(N-Heterocyclic Carbene)Gold(I)-Catalyzed Cycloisomerization of
Cyclohexadienyl Alkynes to Tetracyclo[3.3.0.02,8.04,6]octanes**
Soo Min Kim, Ji Hoon Park, Soo Young Choi, and Young Keun Chung*
Transition-metal-catalyzed reactions of polyunsaturated sys-
tems have attracted much attention owing to their enormous
synthetic potential in the preparation of a wide variety of
carbo- and heterocyclic building blocks.[1] Among them, gold-
catalyzed cycloisomerization is one of the hottest branches of
research in the formation of functionalized cyclic struc-
tures.[2,3] In particular, the cycloisomerization of enynes
producing novel modes is one of the most studied areas.[4]
In research carried out in this field it must be taken into
consideration that the reaction patterns vary widely, depend-
ing upon both the nature of the substrates and the catalyst
systems. Minor changes in the substrate structures can lead to
drastically different products. Thus, in many instances, some
catalysts work only with a limited group of substrates bearing
a particular tether. However, in some cases, substantial
structural variations can be accommodated and different
functional groups are found to be compatible.[5] We recently
showed that the introduction of a cyclohexadienyl moiety to
enynes influences the reaction pathway of cycloisomeriza-
tion.[6]
Tetracyclo[3.3.0.02,8.04,6]octane derivatives have been
known for some time.[9,10] However, there have been no
reports on an intramolecular double-cyclopropanation reac-
tion leading to this tetracyclic ring system. Thus, this is the
first observation of their catalytic formation from dienynes.
Herein we communicate our preliminary results.
As shown in Equation (1), the reaction of 1a in the
presence of a catalytic amount of [Au(IPr)Cl]AgSbF6 in
dichloromethane gave a mixture of 1b and 1c in 70% and
30% yields, respectively. The structure of 1b was confirmed
by X-ray diffraction analysis (Figure 1).[11] According to the
Recently, the use of metal complexes of N-heterocyclic
carbenes (NHCs) has attracted much attention.[7] However,
the use of gold–NHC complexes in catalytic reactions is quite
rare.[8] In our latest work we turned our attention to the
synthesis of gold–NHC complexes and their use in catalytic
reactions. Thus, in the hope of finding a new type of
transformation, we tested a cycloisomerization of dienynes
containing a cyclohexadiene unit in the presence of a catalytic
amount of [Au(IPr)Cl]AgSbF6 (IPr= N,N’-bis(2,6-diisopro-
pylphenyl)imidazol-2-ylidene) [Eq. (1)]. To our great delight,
a new cycloisomerized product formed as one of the two
1
major products. According to its H and 13C NMR spectra,
Figure 1. X-ray structure of 1b.
À
product 1b contains no unsaturated C C bonds. Compound
1b is a biscyclopropanated product and a derivative of
tetracyclo[3.3.0.02,8.04,6]octane.
X-ray diffraction study, two isomers (1:1) exist in the crystal.
In structural terms, four carbon–carbon bonds are formed.
Initially, this multiple reaction appeared to be rather complex,
but it proved to be surprisingly general. Conversion of 1c into
1b in the presence or absence of the gold catalyst was not
observed.
[*] S. M. Kim, J. H. Park, S. Y. Choi, Prof. Y. K. Chung
Intelligent Textile SystemResearch Center
Department of Chemistry, College of Natural Sciences
Seoul National University
Seoul 151-747 (Korea)
Fax: (+82)2-889-0310
E-mail: ykchung@snu.ac.kr
Encouraged by these results, we screened reaction param-
eters such as the counter anion, solvent, reaction temperature,
and reaction time (Table 1). When the reaction was con-
ducted in dichloromethane (entries 1–5, Table 1), the effect of
the counter anion on the yield of 1b was negligible. However,
the nature of the solvent (entries 5–8, Table 1) had a
substantial effect on the efficiency of the reaction. The best
yield (86%) was obtained in toluene solution. The temper-
ature for the reactions in toluene (entries 8–11, Table 1) did
not have a noticeable effect on the yield of 1b. However, as
[**] This work was supported by the Korea Research Foundation grant
funded by the Korean Government (MOEHRD) (R02-2004-000-
10005–0 and KRF-2005-070-C00072) and the SRC/ERC programof
MOST/KOSEF (R11-2005-065). S.M.K., J.H.P., and S.Y.C. were
supported by Brain Korea 21 Fellowships and Seoul Science
Fellowships.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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Chemie
Table 1: Reaction of 1a under various conditions [Eq. (1)].
Entry Cat. Additive Solv. T [8C]
[mol%]
t
Yield [%]
(1b/1c)[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
5
AgSbF6
AgOTf
AgClO4
AgPF6
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
CH2Cl2
10–15 30 min 100 (70:30)
10–15 2 h 69 (60:9)
10–15 30 min 79 (72:7)
10–15 30 min 86 (71:15)
10–15 30 min 79 (73:6)
5
5
5
5
5
5
5
5
5
5
5
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN 10–15 18 h
MeOH 10–15 18 h
100 (72:28)
45 (22:23)
toluene 10–15 30 min 100 (86:14)
24 h 100 (87:13)
Figure 2. X-ray structure of 7d.
toluene À78
toluene
toluene 40
0
30 min 100 (83:17)
10 min 100 (89:11)
steric effect in the vicinity of the carbenoid moiety would be
an important factor for the cyclopropanation to proceed. To
examine the relation between 7b and 7d, 7d was further
reacted with and without the catalysts; however, no reaction
was observed.
toluene 10–15 10 min 100 (85:15)
toluene 10–15 10 min 98 (82:16)
[a] Yield of product isolated after chromatography.
As an extension of the chemistry developed here, enynes
bearing an open-chain diene, 9a and 10a, were treated with
[Au(IPr)Cl]AgBF4 under the same reaction conditions
(entries 11 and 12, Table 2). Substrate 9a was previously
used by Shibata and Tahara[12] in the rhodium-catalyzed
enantioselective intramolecular [2+2+2] cycloaddition reac-
tion. After work-up, we obtained the tetracyclic compounds
9b and 10b, with two sides missing from the cage, in 77% and
70% yields, respectively. Thus, it seems that the biscyclopro-
panation is quite a general process provided the conformation
and distances between bonds concerned are satisfied. How-
ever, in most entries except entries 2and 3 shown in Table 2,
minor amounts of the cyclopropanated products analogous to
1c accompany the biscyclopropane derivatives formed as the
major reaction products. Unfortunately, enyne substrates
bearing an internal alkyne did not give the expected cage
products.
the reaction temperature was lowered, the reaction time
increased. At 10–158C, the reaction time was shortened to
10 min with a high yield (entry 12, Table 1; 85%). Moreover,
the amount of the catalyst could be reduced to 2mol% and
still lead to a high yield (entry 13, Table 1; 82%). A brief
survey of different metal complexes such as [Au-
(IMes)Cl]AgSbF6 (IMes = N,N’-bis(2,4,6-trimethylphenyl)-
imidazol)-2-ylidene) (66%), [AuCl(PPh3)]AgBF4 (37%),
and PtCl2 (45%) indicated that [Au(IPr)BF4] is the best
catalyst of those examined for Equation (1).
We next investigated the cycloisomerization of various
dienynes containing a cyclohexadienyl moiety (Table 2).
Change of the tether group (or atom) from N-tosyl to
oxygen and malonate (entries 2and 3, Table 2) led to the
isolation of 2b and 3b in 68% and 45% yields, respectively.
Thus, variation of the tether group does not influence the
reaction pattern. The introduction of a methyl group to the
cyclohexadiene ring resulted in a mixture of two isomers (4a
and 4a’) in a ratio of 1:2. When this mixture was used as a
substrate, the same ratio of two isomeric cyclized products
(4b and 4b’) was obtained in an overall yield of 67% (entry 4,
Table 2). In the same way, treatment of 5a and 5a’ yielded the
same ratio of two products (5b and 5b’) in an overall yield of
63% (entry 5, Table 2). The introduction of a methyl group at
the position between the nitrogen atom and the cyclohex-
adiene moiety (entry 6, Table 2) did not change the reaction
pathway. Thus the expected products were obtained in 75%
yield. However, when two methyl groups were introduced to
the cyclohexadiene ring (entries 8 and 10, Table 2), new
cycloisomerized products (7d and 8d) were formed.
A
plausible reaction mechanism is outlined in
Scheme 1.[13] The first step is the formation of the metal
cyclopropyl carbene complexes I and (5-exo-dig) or III (6-
endo-dig). A further reaction of I leads to the intermediate II.
=
The interaction of II with the second C C bond can take place
1
The formation of 7d was confirmed by H and 13C NMR
spectroscopy and by X-ray diffraction analysis (Figure 2).[11]
We first conjectured that prohibitively high strain would be
generated when the two methyl groups are on the tetracy-
clo[3.3.0.02,8.04,6]octane ring. Alternatively, steric congestion
between the NHC ligand and two methyl groups might
prevent further reaction. Thus, the carbon–carbon bond-
formation sequence stopped at 7d to release the strain.
However, when [Au(IMes)Cl]AgBF4 was used as a catalyst
(entries 7 and 9, Table 2), products 7b and 8b were obtained
in 81% and 69% yields, respectively. Thus, it seems that a
Scheme 1. Plausible mechanism of the biscyclopropanation.
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Communications
Table 2: Gold-catalyzed cycloisomerization.[a]
methodology developed here to other sub-
strates, and other reactions exploiting NHC–
gold catalysts will be reported in due course.
Entry Reactant
Product
T [8C]/ Yield [%][b]
t [min]
1
2
1a
1b
10–15/ 82
10
Experimental Section
10–15/
68
General procedure (Table 2): The enyne substrate
(0.5 mmol) was added to a solution of [Au(IPr)Cl]
(6 mg, 10 mmol) and AgBF4 (2mg, 10 mmol) in toluene
(3 mL). The mixture was stirred until the starting
material was completely consumed (as checked by
TLC) at 10–608C. The mixture was purified by flash
chromatography.
20
3
4
40/20 45
Substrates 1a, 4a, 4a’, 7a, 8a, and 9a were
prepared by known methods.[6a,12] Other substrates
were newly synthesized in this study (see the Support-
ing Information).
67
60/10
(22/45)
63
60/10
5
6
Received: May 8, 2007
Published online: July 10, 2007
(12/51)
10–15/
75
Keywords: cycloisomerization · enynes · gold ·
.
10
strained ringcompounds
10–15/
81
7
8
[1] a) G. C. Lloyd-Jones, Org. Biomol. Chem. 2003,
1, 215; b) M. MØndez, V. Mamane, A. Fürstner,
Chemtracts 2003, 16, 397; c) C. Aubert, O.
Buisine, M. Malacria, Chem. Rev. 2002, 102, 813.
[2] For reviews, see: a) L. M. Zhang, J. W. Sun, S. A.
Kozmin, Adv. Synth. Catal. 2006, 348, 2 2 71; b) C.
Nieto-Oberhuber, S. López, E. JimØnez-Nfflæez,
A. M. Echavarren, Chem. Eur. J. 2006, 12, 5916;
c) C. Bruneau, Angew. Chem. 2005, 117, 2380;
Angew. Chem. Int. Ed. 2005, 44, 2328; d) I. J. S.
Fairlamb, Angew. Chem. 2004, 116, 1066; Angew.
Chem. Int. Ed. 2004, 43, 1048.
30
7a
60/10 86
60/10 69
9
10
8a
60/10 58
[3] For recent gold-catalyzed reactions, see:
a) A. S. K. Hashmi, G. J. Hutchings, Angew.
Chem. 2006, 118, 8064; Angew. Chem. Int. Ed.
2006, 45, 7896; b) G. Lemi›re, V. Gahdon, N.
Agenet, J. P. Goddard, A. de Kozak, C. Aubert,
L. Fensterbank, M. Malacria, Angew. Chem.
2006, 118, 6878; Angew. Chem. Int. Ed. 2006,
45, 7596; c) S. Wang, L. Zhang, J. Am. Chem. Soc.
2006, 128, 14274; d) S. Couty, C. Meyer, J. Cossy,
Angew. Chem. 2006, 118, 6878; Angew. Chem.
Int. Ed. 2006, 45, 6726.
11
12
60/10 77
60/30 70
[a] Reaction conditions: 0.5 mmol of substrate was reacted with 2 mol% of [Au(IPr)]BF4 in
toluene. [b] Yield of isolated product. [c] [Au(IMes)]BF4 was used.
[4] For recent papers, see: a) J. Marco-Contelles, N.
Arroyo, S. Anjum, E. Mainetti, N. Marion, K.
Cariou, G. Lemi›re, V. Mouri›s, L. Fensterbank,
according two ways. The first possibility is direct reductive
M. Malacria, Eur. J. Org. Chem. 2006, 4618; b) S. I. Lee, S. M.
Kim, S. Y. Kim, Y. K. Chung, Synlett 2006, 2256; c) Y. Miyano-
hana, N. Chatani, Org. Lett. 2006, 8, 2155.
elimination to form the second ring of b. In the other case,
reductive elimination is not favored and b-H elimination
=
forming new C C double bond followed by reductive
[5] For Pt-catalyzed reactions, see: a) A. Fürstner, F. Stelzer, H.
Szillat, J. Am. Chem. Soc. 2001, 123, 11863. For Fe0-catalyzed
reactions, see: b) A. Fürstner, R. Martin, K. Majima, J. Am.
Chem. Soc. 2005, 127, 12236. For Rh-catalyzed reactions, see:
c) H. Kim, C. Lee, J. Am. Chem. Soc. 2005, 127, 10180.
[6] a) S. M. Kim, S. I. Lee, Y. K. Chung, Org. Lett. 2006, 8, 5425;
b) S. I. Lee, S. M. Kim, M. R. Choi, S. Y. Kim, Y. K. Chung, J.
Org. Chem. 2006, 71, 9366.
[7] For recent reviews, see: a) P. L. Arnold, S. T. Liddle, Chem.
Commun. 2006, 3959; b) R. H. Crabtree, J. Organomet. Chem.
2005, 690, 5451; c) V. CØsar, S. Bellemin-Laponnaz, L. H. Gade,
Chem. Soc. Rev. 2004, 33, 619; d) C. M. Crudden, D. P. Allen,
elimination would give d. When the carbenoid moiety in II
is sufficiently close to react with the intramolecular olefin, c is
produced by another cyclopropanation involving carbene
transfer from the gold-carbenoid II.
In conclusion, we have developed a cycloisomerization
reaction catalyzed by NHC–gold complexes which produces
tetracyclo[3.3.0.02,8.04,6]octane derivatives from enynes bear-
ing a cyclohexadiene group. The starting materials are readily
prepared and the procedure is quite simple. Further studies
on the properties of these analogues, an application of the
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Chemie
Coord. Chem. Rev. 2004, 248, 2247; e) E. Peris, R. H. Crabtree,
Coord. Chem. Rev. 2004, 248, 2239.
[11] The synthetic procedures and spectroscopic data of the new
compounds are summarized in the Supporting Information.
CCDC- 645350 (1b) and CCDC-645351 (7d) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[12] T. Shibata, Y.-K. Tahara, J. Am. Chem. Soc. 2006, 128, 11766.
[13] For pioneering work on 1,6-enyne cycloisomerization involving
cyclopropyl gold carbenoids, see: C. Nieto-Oberhuber, M. P.
Muæoz, E. Buæuel, C. Nevado, D. J. Cꢀrdenas, A. M. Echavar-
ren, Angew. Chem. 2004, 116, 2456; Angew. Chem. Int. Ed. 2004,
43, 2402. The authors appreciate one of refereesꢁ suggestion (i.e.,
the involvement of intermediate II in Scheme 1) to explain the
formation of b and d.
[8] a) L. Ray, V. Katiyar, M. J. Raihan, H. Nanavati, M. M. Shaikh,
P. Ghosh, Eur. J. Inorg. Chem. 2006, 3724; b) N. Marion, P.
de FrØmont, G. Lemi›re, E. D. Stevens, L. Fensterbank, M.
Malacria, S. P. Nolan, Chem. Commun. 2006, 2 048; c) M. R.
Fructos, T. R. Belderrain, P. de Fremont, N. M. Scott, S. P. Nolan,
M. M. Diaz-Requejo, P. J. Perez, Angew. Chem. 2005, 117, 5418;
Angew. Chem. Int. Ed. 2005, 44, 5284.
[9] a) N. A. LeBel, R. Liesemer, J. Am. Chem. Soc. 1965, 87, 4301;
b) I. Erden, Chem. Lett. 1981, 263; c) P. K. Freeman, K. E.
Swenson, J. Org. Chem. 1982, 47, 2033. For a catalytic reaction,
see: d) H. C. Volger, H. Hogeveen, M. M. P. Gaasbeek, J. Am.
Chem. Soc. 1969, 91, 2137.
[10] T. A. Zeidan, S. V. Kovalenko, M. Manoharan, R. J. Clark, I.
Ghiviriga, I. V. Alabugin, J. Am. Chem. Soc. 2005, 127, 4270.
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